Isoxazoline as fatty acid amide hydrolase inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

 

Cross-reference to related applications

This application claims priority based on provisional patent applications U.S., having serial numbers 61/179280, 61/179283 and 61/179285, filed may 18, 2009, the complete contents of each of which is incorporated into the present application by reference.

Background of the invention

Ameritrash fatty acids (FAAH), also known as leamingtonspa and anandamayakosa, is a complete membrane protein responsible for the hydrolysis of some important endogenous neyromoduliruyuschim amides of fatty acids (FAA), including anadamide, oleoylethanolamide and palmitoylethanolamide, and is closely associated with their regulation. Because the FAA interact with cannabinoid and vanilloid receptors, they are often called "endocannabinoids" or "undownloadable". First, the interest in this area was focused on the development of FAAH inhibitors to enhance the actions of the FAA and the relief of pain. In further studies it was found that inhibitors of FAAH, through interaction with specific FAA extracellular and intracellular receptors, can be used to treat many different conditions that include but are not limited to, inflammation, metabolic disorders (e.g., associated with obesity status and related the data with depletion condition, such as cachexia and anorexia), disorders of the Central nervous system (e.g., disorders associated with neurotoxicity and/or neurotrauma, stroke, multiple sclerosis, spinal injuries, musculoskeletal disorders, such as disorders associated with basal nuclei of the brain, amyotrophic lateral sclerosis, Alzheimer's disease, epilepsy, mental disorders such as anxiety, depression, impaired learning skills and schizophrenia, sleep disorders such as insomnia, nausea and/or vomiting and drug addiction), cardiac disorders (e.g., hypertension, circulatory shock, reperfusion myocardial damage and atherosclerosis) and glaucoma (Pacher et al, "The Endocannabinoid System as Emerging Target of Pharmacotherapy" Pharmacological Reviews (2006) 58:389-462; Pillarisetti et al, "Pain and Beyond: Fatty Acid Amides and Fatty Acid Amide Hydrolase Inhibitors in Cardiovascular and Metabolic Diseases Drug Discovery Today(2009) 597:1-14).

Brief description of the invention

The present invention provides isoxazoline compounds, which are inhibitors of FAAH, of the formula (I):

or their pharmaceutically acceptable forms, where:

(i) each of Ra, Rband Rcindependently selected from-H, C1-10the alkyl or C1-10perhalogenated, Rdrepresents a group-L-Z, and Z is selected from C6-14aryl;

(ii) each of Ra, Rband Rcnot avisio selected from-H, C1-10the alkyl or C1-10perhalogenated, Rdrepresents a group-L-Z, and Z is selected from 3-14-membered heterocyclyl or a 5-14-membered heteroaryl;

(iii) Raand Rdcombined with the formation of C3-10carbocyclic or 3-14 membered condensed heterocyclic ring, and Rband Rcindependently selected from-H, C1-10the alkyl or C1-10perhalogenated; or

(iv) Rcand Rdcombined with the formation of C3-10carbocyclic or 3-14-membered heterocyclic Spiro-condensed ring, and Raand Rbindependently selected from-H, C1-10the alkyl or C1-10perhalogenated;

L is a covalent bond or a divalent C1-6hydrocarbon group, where one, two or three methylene link in L optionally and independently replaced by one or more oxygen atoms, sulfur or nitrogen;

G is selected from-CN, -NO2, -S(=O)Re, -SO2Re, -SO2NRfRe, -PO2Re, -PO2ORe, -PO2NRfRe, -(C=O)Re, -(C=O)ORe, -(C=O)NRfRe, -Br, -I, -F, -Cl, -ORe, -ONRfRe, -ONRf(C=O)Re, -ONRfSO2Re, -ONRfPO2Re, -ONRfPO2ORe, -SRe, -OSO2Re, -NRfSO2Re, -OPO2Re, -OPO2O e, -NRfPO2Re, -NRfPO2ORe, -OPO2NRfRe, -O(C=O)Re, -O(C=O)ORe, -NRfRe, -NRf(C=O)Re, -NRf(C=O)ORe, -O(C=O)NRfRe, -NRf(C=NRf)NRfRe, -O(C=NRf)NRfRe, -NRf(C=NRfORe, -[N(Rf)2Re]+X-where X-represents a counterion; and

each Reindependently selected from C1-10of alkyl, C2-10alkenyl, C2-10the quinil, C3-10carbocycle, C6-14aryl, 3-14 membered heterocyclyl or a 5-14-membered heteroaryl; each Rfassociated with the nitrogen atom, independently selected from-H, C1-10the alkyl or amino-protective group; or Reand Rfcombined with education 3-14-membered heterocyclic ring or an 5-14 membered heteroaryl ring.

The present invention also provides pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable form and pharmaceutically acceptable excipient.

The present invention also provides methods of treating FAAH-mediated condition in a subject, comprising introducing a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable form to a subject in need of it.

A detailed description will complement the selected variants of the embodiment of the present invention are presented below in sections a Detailed description of the invention” “Illustrative examples”. Other features, objectives and advantages of the present invention will be apparent from the present description and in the claims.

Definition

Definitions of specific functional groups and chemical terms are presented in more detail below. Chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., on the inside cover, and specific functional groups, mainly defined as described in this Handbook. In addition, General principles of organic chemistry, as well as specific functional groups and reactivity are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

Some compounds of the present invention can include one or more asymmetric centers and therefore may exist in different isomeric forms, for example, in the form of enantiomers and/or diastereomers. The compounds presented in this application can be in the form of an individual enantiomer, diastereoisomer or a geometric isomer, or may be in the form of a mixture of stereoisomers including a racemic see the si and mixtures enriched with one or more stereoisomers. In some embodiments embodiment, the compounds of the present invention are enantioface connection. In some other embodiments, the embodiments are provided of a mixture of stereoisomers.

In addition, some compounds described in this application may contain one or more double bonds that can exist either in the form of CIS or TRANS or E or Z isomer, unless otherwise noted. The invention also encompasses compounds in the form of individual isomers, essentially free of other isomers, and alternatively, as mixtures of various isomers, e.g., racemic mixtures of E/Z isomers or mixtures enriched in one E/Z isomer.

The terms "enantiomerically enriched," "enantiomerically pure" and "narozeniny" as they are used interchangeably in this application, refers to compositions in which the mass percent of one enantiomer is greater than the number of one enantiomer in the control racemic mixture of the composition (e.g., greater than 1:1 by weight). For example, enantiomerically enriched product (S)-enantiomer means the preparation of compounds containing more than 50% of the mass (S)-enantiomer relative to the (R)-enantiomer, more preferably at least 75% of the mass, and even more preferably, is about the least 80% of the mass. In some embodiments embodiment, the enrichment can be much more than 80% of the mass, providing essentially enantiomerically enriched", "essentially enantiomerically pure" or "essentially narozeniny medicine, and relates to the compositions which contain at least 85% of the mass of one enantiomer relative to the other enantiomer, more preferably at least 90% of the mass, and even more preferably at least 95% of the mass. In preferred embodiments embodiment, the enantiomerically enriched composition has a higher activity, with regard to therapeutic utility per unit mass compared with such a composition in the form of racemic mixtures. The enantiomers can be distinguished from mixtures by methods known to experts in this field, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred enantiomers can be obtained by asymmetric synthesis. See, for example, Jacques, et al., " Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

When you specify a range of values, it is assumed that it covers each value and under the range within the specified range. For example, "C1-6alkyl" encompasses, C1C2C3C4C5C6C1-6C1-5C1-4C1-3C1-2C2-6C2-5C2-4C2-3C3-6C3-5C3-4C4-6C4-5and C5-6alkyl.

As the term is used in this application "simple connection" or "covalent bond" refers to a single bond connecting the two groups.

As the term is used in this application, either alone or as part of another group, "halo" and "halogen" refer to fluorine (fluorine, -F), chlorine (chlorine-Cl), bromine (bromo, -Br), or iodine (iodine, -I).

As the term is used in this application, either alone or as part of another group, "alkyl" refers to monoracial linear or branched saturated hydrocarbon group containing from 1 to 10 carbon atoms ("C1-10alkyl"). In some embodiments embodiment the alkyl group contains from 1 to 9 carbon atoms ("C1-9alkyl"). In some embodiments embodiment the alkyl group contains from 1 to 8 carbon atoms ("C1-8alkyl"). In some embodiments embodiments, the alkyl group contains from 1 to 7 carbon atoms ("C1-7alkyl"). In some embodiments embodiment the alkyl group contains from 1 to 6 carbon atoms ("C1-6alkyl"). In some embodiments embodiments, the alkyl group contains from 1 to 5 atom is in carbon ("C 1-5alkyl"). In some embodiments embodiment the alkyl group contains from 1 to 4 carbon atoms ("C1-4alkyl"). In some embodiments embodiments, the alkyl group contains from 1 to 3 carbon atoms ("C1-3alkyl"). In some embodiments embodiment the alkyl group contains from 1 to 2 carbon atoms ("C1-2alkyl"). In some embodiments embodiment the alkyl group contains 1 atom of carbon ("C1alkyl"). In some embodiments embodiment the alkyl group contains from 2 to 6 carbon atoms ("C2-6alkyl"). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanol (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanol (C5), tertiary amyl (C5and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. If not stated otherwise, in each case an alkyl group is independently unsubstituted (an"unsubstituted alkyl") or substituted (a"substituted alkyl") and contains 1, 2, 3, 4, or 5 substituents as described in this application. In some embodiments embodiments, the alkyl group is nezameshchenny C1-10alkyl (for example, -CH3). In some Islands Ianto embodiment, the alkyl group is a substituted C1-10alkyl.

"Perhalogenated" as defined in this application, refers to an alkyl group containing from 1 to 10 carbon atoms, where all hydrogen atoms, each independently substituted with halogen, for example, selected from fluorine, bromine, chlorine or iodine ("C1-10perhalogenated"). In some embodiments embodiment the alkyl group contains from 1 to 8 carbon atoms ("C1-8perhalogenated"). In some embodiments embodiment the alkyl group contains from 1 to 6 carbon atoms ("C1-6perhalogenated"). In some embodiments embodiment the alkyl group contains from 1 to 4 carbon atoms ("C1-4perhalogenated"). In some embodiments embodiment the alkyl group contains from 1 to 3 carbon atoms ("C1-3perhalogenated"). In some embodiments embodiment the alkyl group contains from 1 to 2 carbon atoms ("C1-2perhalogenated"). In some embodiments embodiment, each of the hydrogen atoms replaced by fluorine. In some embodiments embodiment, each of the hydrogen atoms replaced by chlorine. Examples perhalogenated groups include-CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl and the like.

As the term is used in this application, either alone or as part of another group, "alkenyl" relation is seeking to monoracial linear or branched hydrocarbon group, containing from 2 to 10 carbon atoms and one or more carbon-carbon double bonds ("C2-10alkenyl"). In some embodiments embodiment Alchemilla group contains from 2 to 9 carbon atoms ("C2-9alkenyl"). In some embodiments embodiment Alchemilla group contains from 2 to 8 carbon atoms ("C2-8alkenyl"). In some embodiments embodiment Alchemilla group contains from 2 to 7 carbon atoms ("C2-7alkenyl"). In some embodiments embodiment Alchemilla group contains from 2 to 6 carbon atoms ("C2-6alkenyl"). In some embodiments embodiment Alchemilla group contains from 2 to 5 carbon atoms ("C2-5alkenyl"). In some embodiments embodiment Alchemilla group contains from 2 to 4 carbon atoms ("C2-4alkenyl"). In some embodiments embodiment Alchemilla group contains from 2 to 3 carbon atoms ("C2-3alkenyl"). In some embodiments embodiment Alchemilla group contains 2 carbon atoms ("C2alkenyl"). One or more carbon-carbon double bond can be internal (such as 2-butenyl) or limit (such as in 1-butenyl). Examples of C2-4alkenyl groups include ethynyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4) and the like. Examples of C2-6alkenyl the x groups include the above C 2-4alkeneamine group, and pentenyl (C5), pentadienyl (C5), hexanal (C6) and the like. Additional examples of alkenyl include heptenyl (C7), octenol (C8), octatriene (C8) and the like. If not stated otherwise, in each case Alchemilla group is independently unsubstituted (an"unsubstituted of alkenyl") or substituted (a"substituted alkenyl") 1, 2, 3, 4, or 5 substituents as described in this application. In some embodiments embodiment Alchemilla group is an unsubstituted C2-10alkenyl. In some embodiments embodiment Alchemilla group is a substituted C2-10alkenyl.

As the term is used in this application, either alone or as part of another group, "quinil" refers to monoracial linear or branched hydrocarbon group containing from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds ("C2-10quinil"). In some embodiments embodiment Alchemilla group contains from 2 to 9 carbon atoms ("C2-9quinil"). In some embodiments embodiment Alchemilla group contains from 2 to 8 carbon atoms ("C2-8quinil"). In some embodiments embodiment Alchemilla group contains from 2 to 7 carbon atoms ("C2-7quinil"). In some embodiments embodiment Alchemilla group with which contains from 2 to 6 carbon atoms ("C 2-6quinil"). In some embodiments embodiment Alchemilla group contains from 2 to 5 carbon atoms ("C2-5quinil"). In some embodiments embodiment Alchemilla group contains from 2 to 4 carbon atoms ("C2-4quinil"). In some embodiments embodiment Alchemilla group contains from 2 to 3 carbon atoms ("C2-3quinil"). In some embodiments embodiment Alchemilla group contains 2 carbon atoms ("C2quinil"). One or more carbon-carbon triple links can be internal (such as 2-butinyl) or limit (such as in 1-butinyl). Examples of C2-4etkinlik groups include, without limitation, ethinyl (C2), 1-PROPYNYL (C3), 2-PROPYNYL (C3), 1-butenyl (C4), 2-butenyl (C4) and the like. Examples of C2-6alkenyl groups include the above C2-4alkyline group, and pentenyl (C5), hexanal (C6) and the like. Additional examples of quinil include heptenyl (C7), octenol (C8) and the like. If not stated otherwise, in each case Alchemilla group is independently unsubstituted (an"unsubstituted quinil") or substituted (a"substituted quinil") 1, 2, 3, 4, or 5 substituents as described in this application. In some embodiments embodiment Alchemilla group is an unsubstituted C2-10 quinil. In some embodiments embodiment Alchemilla group is a substituted C2-10quinil.

"Divalent C1-6hydrocarbon group" is a divalent C1-6alkyl group, a divalent C1-6alkenylphenol group or a divalent C1-6alkylamino group, where one, two or three methylene link (-CH2-) hydrocarbon chain optionally and independently replaced by one or more oxygen atoms, sulfur or nitrogen. In some embodiments embodiment, the divalent C1-6the hydrocarbon group is a divalent C1-6alkyl group. In some embodiments embodiment, the divalent C1-6the hydrocarbon group is an unsubstituted divalent C1-6hydrocarbon group (for example, unsubstituted divalent C1-6alkyl group).

As the term is used in this application, either alone or as part of another group, "alkoxy" refers to an alkyl group, as defined in this application, substituted by oxygen atom, where the attachment point is an oxygen atom. In some embodiments embodiment the alkyl group contains from 1 to 10 carbon atoms ("C1-10alkoxy"). In some embodiments embodiment the alkyl group contains from 1 to 8 carbon atoms is ("C 1-8alkoxy"). In some embodiments embodiment the alkyl group contains from 1 to 6 carbon atoms ("C1-16alkoxy"). In some embodiments embodiment the alkyl group contains from 1 to 4 carbon atoms ("C1-4alkoxy"). Examples of C1-4alkoxygroup include methoxy (C1), ethoxy (C2), propoxy (C3), isopropoxy (C3), butoxy (C4), tert-butoxy (C5) and the like. Examples of C1-6alkoxygroup include the above C1-4alkoxygroup, and pentyloxy (C5), isopentane (C5), neopentane (C5), hexyloxy (C6) and the like. Additional examples of alkoxygroup include heptyloxy (C7), octyloxy (C8) and the like. If not stated otherwise, in each case the alkyl group in alkoxygroup is independently unsubstituted (an"unsubstituted alkoxy") or substituted (a"substituted alkoxy"), and may be substituted by 1, 2, 3, 4, or 5 substituents as described in this application. In some embodiments, embodiments of alkoxygroup represents an unsubstituted C2-10alkoxy (e.g.,- OCH3). In some embodiments, embodiments of alkoxygroup represents a substituted C2-10alkoxy (for example, perhalogenated defined in this application).

"Perhalogenated" refers to alkoxygroup, where all hydrogen atoms Ala the school group, each independently replaced by a halogen atoms selected from fluorine, chlorine, bromine and iodine. In some embodiments embodiment the alkyl group contains from 1 to 10 carbon atoms ("C1-10perhalogenated"). In some embodiments embodiment the alkyl group contains from 1 to 8 carbon atoms ("C1-8perhalogenated"). In some embodiments embodiment the alkyl group contains from 1 to 6 carbon atoms ("C1-6perhalogenated"). In some embodiments embodiment the alkyl group contains from 1 to 4 carbon atoms ("C1-4perhalogenated"). In some embodiments embodiment the alkyl group contains from 1 to 3 carbon atoms ("C1-3perhalogenated"). In some embodiments embodiment the alkyl group contains from 1 to 2 carbon atoms ("C1-2perhalogenated"). In some embodiments, each embodiment of the present hydrogen atoms replaced by fluorine. In some embodiments, each embodiment of the present hydrogen atoms replaced by chlorine. Examples of perhalogenated include, but are not limited to, -OCF3, -OCF2CF3, -OCF2CF2CF3, -OCCl3, -OCFCl2, -OCF2Cl and the like.

As the term is used in this application, either alone or as part of another group, "carbocyclic" refers to the radical non-aromatic cyclic hydrocarbon is Oh group, containing from 3 to 10 carbon atoms in the ring ("C3-10carbocyclic") and zero heteroatoms in non-aromatic ring system. In some embodiments embodiment carbocyclic group contains from 3 to 8 carbon atoms in the ring ("C3-8carbocyclic"). In some embodiments embodiment carbocyclic group contains from 3 to 6 carbon atoms in the ring ("C3-6carbocyclic"). In some embodiments embodiment carbocyclic group contains from 3 to 6 carbon atoms in the ring ("C3-6carbocyclic"). In some embodiments of the incarnation, carbocyclic group contains from 5 to 10 carbon atoms in the ring ("C5-10carbocyclic"). Examples of C3-6carbocyclic groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6) and the like. Examples of C3-8carbocyclic groups include the above C3-6carbocyclic group, and cycloheptyl (C7), cycloheptadiene (C7), cycloheptatriene (C7), cyclooctyl (C8), bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octenyl and the like. Examples of C3-10carbocyclic groups include the above C3-8carbocyclic group, and octahydro-1H-indenyl, decahydronaphthalene, JV is ro[4.5]decenyl and the like. As illustrated by the above examples, in some embodiments embodiment, the carbocyclic group is a monocyclic or ("monocyclic carbocyclic") or polycyclic (e.g., containing condensed related bridge connection or Spiro ring system, such as the bicyclic system ("bicyclic carbocyclic") or tricyclic system ("tricyclics carbocyclic")) and may be saturated or may contain one or more carbon-carbon double or triple bonds. "Carbocyclic" also includes ring systems, where the carbocyclic ring, as defined above, is condensed with one or more aryl or heteroaryl groups, where the attachment point is on the carbocyclic ring. If not stated otherwise, in each case, the carbocyclic group is independently unsubstituted (an"unsubstituted carbocyclic") or substituted (a"substituted carbocycle") 1, 2, 3, 4, or 5 substituents as described in this application. In some embodiments the embodiment of the carbocyclic group is an unsubstituted C3-10carbocyclic. In some embodiments embodiment, the carbocyclic group is a substituted C3-10carbocyclic.

In some embodiments of the incarnation, "carbocyclic" represents monocyclics saturated carbocyclic group, containing from 3 to 10 carbon atoms in the ring ("C3-10cycloalkyl"). In some embodiments embodiment cycloalkyl group contains from 3 to 8 carbon atoms in the ring ("C3-8cycloalkyl"). In some embodiments embodiment cycloalkyl group contains from 3 to 6 carbon atoms in the ring ("C3-6cycloalkyl"). In some embodiments embodiment cycloalkyl group contains from 5 to 6 carbon atoms in the ring ("C5-6cycloalkyl"). In some embodiments embodiment cycloalkyl group contains from 5 to 10 carbon atoms in the ring ("C5-10cycloalkyl"). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the above C5-6cycloalkyl group, and cyclopropyl (C3and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the above C3-6cycloalkyl group, and cycloheptyl (C7and cyclooctyl (C8). If not stated otherwise, in each case cycloalkyl group is independently unsubstituted (an"unsubstituted cycloalkyl") or substituted (a"substituted cycloalkyl") 1, 2, 3, 4, or 5 substituents as described in this application. In some embodiments embodiment cycloalkyl group is an unsubstituted C3-10cycloalkyl. In some variants of the Ah embodiments cycloalkyl group is a substituted C 3-10cycloalkyl.

As the term is used in this application, either alone or as part of another group, "heterocyclyl" refers to the radical 3-14-membered non-aromatic ring system containing carbon atoms in the ring and from 1 to 4 heteroatoms in the ring, where each heteroatom independently selected from nitrogen, oxygen and sulfur ("3-14-membered heterocyclyl"). In heterocyclic groups which contain one or more nitrogen atoms, the attachment point may represent a carbon atom or nitrogen as valence allows. Heterocyclic group may be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., condensed, associated bridge connection or Spiro ring system, such as the bicyclic system ("bicyclic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl")) and may be saturated or may contain one or more carbon-carbon double or triple bonds. Heterocyclic polycyclic ring system may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems, where the heterocyclic ring, as defined above, is condensed with one or more carbocyclic groups, where the attachment point of nahoditsya on carbocyclic or heterocyclic ring, or ring system, where the heterocyclic ring, as defined above, is condensed with one or more aryl or heteroaryl groups, where the attachment point is on the heterocyclic ring. In some embodiments embodiments the heterocyclic group is a 5-to 10-membered non-aromatic ring system containing carbon atoms in the ring and 1-4 heteroatoms in the ring, where each heteroatom independently selected from nitrogen, oxygen and sulfur ("5-10-membered heterocyclyl"). In some embodiments the embodiment of the heterocyclic group represents a 5-8-membered non-aromatic ring system containing carbon atoms in the ring and 1-4 heteroatoms in the ring, where each heteroatom independently selected from nitrogen, oxygen and sulfur ("5-8-membered heterocyclyl"). In some embodiments embodiments the heterocyclic group is a 5-6-membered non-aromatic ring system containing carbon atoms in the ring and 1-4 heteroatoms in the ring, where each heteroatom independently selected from nitrogen, oxygen and sulfur ("5-6-membered heterocyclyl"). In some embodiments of the incarnation, 5-6-membered heterocyclyl contains 1-3 heteroatoms in the ring selected from nitrogen, oxygen and sulfur. In some embodiments embodiment 5-6-membered heterocyclyl contains 1-2 heteroatoms in the ring selected from azo is a, oxygen and sulfur. In some embodiments embodiment 5-6-membered heterocyclyl contains 1 heteroatom in the ring selected from nitrogen, oxygen and sulfur. Examples of 3-membered heterocyclic groups containing 1 heteroatom include, without limitation, aziridinyl, oxiranyl, toranil. Examples of 4-membered heterocyclic groups containing 1 heteroatom include, without limitation, azetidine, oxetane and titanyl. Examples of 5-membered heterocyclic groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofurane, tetrahydrothiophene, dihydrothiophene, pyrrolidinyl, dihydropyrrole and pyrrolyl-2,5-dione. Examples of 5-membered heterocyclic groups containing 2 heteroatoms include, without limitation, DIOXOLANYL, oxathiolanes and dithiolane. Examples of 5-membered heterocyclic groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl and thiadiazolyl. Examples of 6-membered heterocyclic groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridines and tiani. Examples of 6-membered heterocyclic groups containing 2 heteroatoms include, without limitation, piperazinil, morpholinyl, dithienyl, dioxanes. Examples of 6-membered heterocyclic groups containing 2 heteroatoms include, without limitation, triazinyl. Examples 7-h is i.i.d. heterocyclic groups, containing 1 heteroatom include, without limitation, azepane, oxetanyl and tiapamil. Examples 8-membered heterocyclic groups containing 1 heteroatom include, without limitation, atacanli, oxetanyl and ciocanel. Examples of bicyclic heterocyclic groups include, without limitation, indolinyl, isoindolyl, dihydrobenzofuranyl, dihydrobenzofuranyl, tetrahydrobenzene, tetrahydrofuranyl, tetrahydroindole, tetrahydroquinoline, tetrahydroisoquinoline, decahydroquinoline, decahydroquinoline, octahedrally, octahydronaphthalene, decahydronaphthalene, decahydro-1,8-naphthyridines, octahedral[3,2-b]pyrrole, indolinyl, phthalimide, naphthalimide, bromanil, bromanil, 1H-benzo[e][l,4]diazepine, 1,4,5,7-tetrahydropyrido[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridines and the like. If not stated otherwise, in each case heterocyclyl is independently unsubstituted (an"unsubstituted heterocyclyl") or substituted (a"substituted heterocyclyl") 1, 2, 3, 4, or 5 substituents as described in this application. In some embodiments the embodiment of the courtesans is a cyclic group is an unsubstituted 3-14 membered heterocyclyl. In some embodiments embodiments the heterocyclic group is a substituted 3-14 membered heterocyclyl.

As the term is used in this application, either alone or as part of another group, "aryl" refers to a radical monocyclic or polycyclic (e.g. bicyclic or tricyclic) aromatic ring system (e.g., containing 6, 10 or 14 total for these rings π electrons in the cyclic arrangement) containing 6-14 carbon atoms in the ring and zero heteroatoms provided in the aromatic ring system ("C6-14aryl"). In some embodiments the embodiment of the aryl group contains 6 carbon atoms in the ring ("C6aryl", for example, phenyl). In some embodiments the embodiment of the aryl group contains 10 carbon atoms in the ring ("C10aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments the embodiment of the aryl group contains 14 carbon atoms in the ring ("C14aryl; for example, intracel). "Aryl" also includes ring systems, where the aryl ring as defined above, is condensed with one or more carbocyclic or heterocyclic groups, where the radical or point of connection is located on the aryl ring. If not stated otherwise, in each case the aryl group is independently unsubstituted (an"illegal is ewenny aryl) or substituted (a"substituted aryl") 1, 2, 3, 4, or 5 substituents as described in this application. In some embodiments the embodiment of the aryl group is an unsubstituted C6-14aryl. In some embodiments the embodiment of the aryl group is a substituted C6-14aryl.

"Aralkyl is a subgroup of "alkyl" refers to alkyl group, as defined in this application, a substituted aryl group, as defined in this application, where the attachment point is on the alkyl group.

As the term is used in this application, either alone or as part of another group, "heteroaryl" refers to the radical 5-14-membered monocyclic or polycyclic (e.g. bicyclic or tricyclic) aromatic ring system (e.g., containing 6, 10 or 14 total for these rings π electrons in the cyclic arrangement) containing carbon atoms in the ring and 1-4 heteroatoms in the ring which are present in the aromatic ring system, where each heteroatom independently selected from nitrogen, oxygen and sulfur ("5-14-membered heteroaryl"). In the heteroaryl groups contain one or more nitrogen atoms, the attachment point may represent a carbon atom or nitrogen as valence allows. Polycyclic heteroaryl ring system may contain one or more heteroatom is in one or both rings. "Heteroaryl" also includes ring systems, where the heteroaryl ring, as defined above, is condensed with one or more aryl groups, where the attachment point is either aryl or heteroaryl ring, or where the heteroaryl ring, as defined above, is condensed with one or more carbocyclic or heterocyclic groups, where the attachment point is on the heteroaryl ring. As regards polycyclic heteroaryl groups, where the one ring does not contain heteroatom (for example, indolyl, chinoline, carbazolyl and the like), the attachment point may be located anywhere on the ring, i.e., either on the ring containing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In some embodiments embodiment the heteroaryl group is a 5-10 membered aromatic ring system containing carbon atoms in the ring and 1-4 heteroatoms in the ring which are present in the aromatic ring system, where each heteroatom independently selected from nitrogen, oxygen and sulfur ("5-10-membered heteroaryl"). In some embodiments embodiment the heteroaryl group is a 5-8-membered aromatic ring system containing carbon atoms in the ring and 1-4 heteroatoms in the ring, Pris is concerned in the aromatic ring system, where each heteroatom independently selected from nitrogen, oxygen and sulfur ("5-8-membered heteroaryl"). In some embodiments embodiment the heteroaryl group is a 5-6-membered aromatic ring system containing carbon atoms in the ring and 1-4 heteroatoms in the ring which are present in the aromatic ring system, where each heteroatom independently selected from nitrogen, oxygen and sulfur ("5-6-membered heteroaryl"). In some embodiments of the incarnation, 5-6-membered heteroaryl contains 1-3 heteroatoms in the ring selected from nitrogen, oxygen and sulfur. In some embodiments embodiment 5-6-membered heteroaryl contains 1-2 heteroatoms in the ring selected from nitrogen, oxygen and sulfur. In some embodiments embodiment 5-6-membered heteroaryl contains 1 heteroatom in the ring selected from nitrogen, oxygen and sulfur. Examples of 5-membered heteroaryl containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Examples of 5-membered heteroaryl containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazole. Examples of 5-membered heteroaryl containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, thiadiazolyl. Examples of 5-membered heteroaryl containing 4 heteroatoms include, without limitation, tetrazolyl. Examples of 6-membered heteroaryl containing 1 heteroatom, include, without limitation, pyridinyl. Examples of 6-membered heteroaryl containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl and pyrazinyl. Examples of 6-membered heteroaryl containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazini, respectively. Examples 7-membered heteroaryl containing 1 heteroatom include, without limitation, azepine, oxepin and tiepins. Examples 5,6-bicyclic heteroaryl include, without limitation, indolyl, isoindolyl, indazoles, benzotriazolyl, benzothiophene, isobenzofuranyl, benzofuranyl, benzothiophenes, benzimidazoles, benzoxazoles, benzisoxazole, benzoxadiazole, benzothiazolyl, benzisothiazole, benzothiazolyl, indolizinyl and purines. Examples of 6,6-bicyclic heteroaryl include, without limitation, naphthyridine, pteridine, chinoline, ethenolysis, cinnoline, honokalani, phthalazine and hintline. Examples of tricyclic heteroaryl include, without limitation, phenanthridines, dibenzofurans, carbazoles, acridines, phenothiazinyl, phenoxazines and phenazines. If not stated otherwise, in each case, the heteroaryl group is independently unsubstituted (an"unsubstituted heteroaryl") or substituted (a"substituted heteroaryl") 1, 2, 3, 4, or 5 substituents as described in this application. In some embodiments, embodiments of Goethe is Marilena group is an unsubstituted 5 to 14-membered heteroaryl. In some embodiments embodiment the heteroaryl group is a substituted 5 to 14-membered heteroaryl.

"Heteroalkyl is a subgroup of "alkyl" refers to alkyl group, as defined in this application, a substituted heteroaryl group, as defined in this application, where the attachment point is on the alkyl group.

As the term is used in this application, the term "partially unsaturated" refers to a ring group that includes at least one double or triple bond. The term "partially unsaturated" covers a ring that contains multiple sites of unsaturation, but it does not allow for the inclusion of aromatic groups (e.g., aryl or heteroaryl groups), as defined in this application.

Alkyl, alkeline, alkyline, carbocyclic, heterocyclic, aryl and heteroaryl groups defined in this application, is optionally substituted (for example, "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" Alchemilla, "substituted" or "unsubstituted" Alchemilla, "substituted" or "unsubstituted" carbocyclic, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl or substituted" or "unsubstituted" heteroaryl group). Typically, the Ermin "substituted", regardless of whether before him the word "optional" or not, means that at least one hydrogen atom present in the group (e.g., carbon atom or nitrogen, etc.,), replaced a possible substitute, for example, the Deputy that the substitution results in a stable connection, for example, a connection that is not subject to spontaneous transformation such as by rearrangement, cyclization, elimination, or other reactions. Unless otherwise indicated, a "substituted" group contains a substituent at one or more substitutable positions of this group, and when more than one position in any particular structure is substituted, the substituents are the same or different from each other in each position.

Examples of the substituents on the carbon atom include, but are not limited to, halogen (i.e. fluorine (-F), bromo (-Br), chloro (-Cl) and iodine (I)), -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X-, -N(ORccRbb, -SH, -SRaa, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)2, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbbRaa , -C(=NRbbORaa, -OC(=NRbbRaa, -OC(=NRbbORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(S)SRaa, -P(=O)2Raa, -OP(=O)2Raa, -P(=O)(Raa)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)2N(Rbb)2, -OP(=O)2N(Rbb)2, -P(=O)(NRbb)2, -OP(=O)(NRbb)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(NRbb)2, -P(RCC)2, -P(RCC)3, -OP(RCC)2, -OP(RCC)3, -B(ORCC)2, -BRaa(ORcc), C1-10alkyl, C1-10perhalogenated, C2-10alkenyl, C2-10quinil, C3-14carbocyclic, 3-14-membered heterocyclyl, C6-14aryl and 5-14-membered heteroaryl, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rdd; or two hydrogen atoms attached to the same carbon atom, is replaced by a group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)OR aa, =NNRbbS(=O)2Raa, =NRbb, =NORCC;

in each case, Raaindependently selected from C1-10of alkyl, C1-10perhalogenated, C2-10alkenyl, C2-10the quinil, C3-10carbocycle, 3-14-membered heterocyclyl, C6-14aryl and 5-14-membered heteroaryl, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rdd;

in each case, Rbbindependently selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRccORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)2Raa, -P(=O)(Raa)2, -P(=O)2N(RCC)2, -P(=O)(NRCC)2C1-10of alkyl, C1-10perhalogenated, C2-10alkenyl, C2-10the quinil, C3-10carbocycle, 3-14-membered heterocyclyl, C6-14aryl and 5-14-membered heteroaryl, or two Rccgroups associated with the N atom combined with education 3-14-membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independent samewe is 0, 1, 2, 3, 4, or 5 groups Rdd;

in each case, Rccindependently selected from hydrogen, C1-10of alkyl, C1-10perhalogenated, C2-10alkenyl, C2-10the quinil, C3-10carbocycle, 3-14-membered heterocyclyl, C6-14aryl and 5-14-membered heteroaryl, or two Rccgroups associated with the N atom combined with education 3-14-membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rdd;

in each case, Rddindependently selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3+X-, -N(OReeRff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRffORee, -OC(=NRffRee, -OC(=NRffORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree )3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)2Ree, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2C1-6of alkyl, C1-6perhalogenated, C2-6alkenyl, C2-6the quinil, C3-10carbocycle, 3-10-membered heterocyclyl, C6-10aryl, 5-10-membered heteroaryl, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4 or 5 groups Rggor two Rddadjacent substituent can be merged to form =O or =S;

in each case, Reeindependently selected from C1-6of alkyl, C1-6perhalogenated, C2-6alkenyl, C2-6the quinil, C3-10carbocycle, C6-10aryl, 3-10-membered heterocyclyl and 3-10-membered heteroaryl, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rgg;

in each case, Rffindependently selected from hydrogen, C1-6of alkyl, C1-6perhalogenated, C2-6alkenyl, C2-6the quinil, C3-10carbocycle, 3-10-membered heterocyclyl, C6-10aryl and 5-10-membered heteroaryl, or two Rffgroups associated with the N atom combined with education 3-14-membered heterocyclic or a 5 to 14-membered heteroaryl the nogo ring, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rgg; and

in each case, Rggindependently represents a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6alkyl, -ON(C1-6alkyl)2, -N(C1-6alkyl)2, -N(C1-6alkyl)3X, -NH(C1-6alkyl)2X, NH2(C1-6alkyl)X, -NH3X, -N(OC1-6alkyl)(C1-6alkyl), -N(OH)(C1-6alkyl), -NH(OH), -SH, -SC1-6alkyl, -SS(C1-6alkyl), -C(=O)(C1-6alkyl), -CO2H, -CO2(C1-6alkyl), -OC(=O)(C1-6alkyl), -OCO2(C1-6alkyl), -C(=O)NH2, -C(=O)N(C1-6alkyl)2, -OC(=O)NH(C1-6alkyl), -NHC(=O)(C1-6alkyl), -N(C1-6alkyl)C(=O)(C1-6alkyl), -NHCO2(C1-6alkyl), -NHC(O)N(C1-6alkyl)2, NHC(=O)N(C1-6alkyl)2, -NHC(=O)NH2, -C(=NH)O(C1-6alkyl), -OC(=NH)(C1-6alkyl), OC(=NH)OC1-6alkyl, C(=NH)OC1-6alkyl, C(=NH)N(C1-6alkyl)2C(=NH)NH(C1-6alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6alkyl)2, -OC(NH)NH(C1-6alkyl), -OC(NH)NH2, -NHC(NH)N(C1-6alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-6alkyl), -SO2N(C1-6alkyl)2, -SO2NH(C1-6alkyl), -SO2NH2, -SO2C1-6alkyl, -SO2OC1-6alkyl, -OSO2C1-6alkyl, -SOC1-6alkyl, -Si(C1-6 3, -OSi(C1-6alkyl)3, -C(=S)N(C1-6alkyl)2, -C(=S)NH(C1-6alkyl), C(=S)NH2, -C(=O)S(C1-6alkyl), -C(=S)SC1-6alkyl, -SC(=S)SC1-6alkyl, -P(=O)2(C1-6alkyl), -P(=O)(C1-6alkyl)2, -OP(=O)(C1-6alkyl)2, -OP(=O)(OC1-6alkyl)2C1-6alkyl, C1-6perhalogenated, C2-6alkenyl,C2-6quinil, C3-10carbocyclic, C6-10aryl, 3-10-membered heterocyclyl, 5-10-membered heteroaryl; or two adjacent substituent Rggcan be merged to form =O or =S; where X-is a counterion.

As the term is used in this application, "counterion" is a negatively charged group, in Association with the positively charged Quaternary amine to maintain electronic neutrality. Examples of counterions include halide ions (e.g., F-, Cl-, Br-I-), NO3-, ClO4-, OH-H2PO4-, HSO4-, sulfate ions (for example, methanesulfonate, triftorbyenzola, p-toluensulfonate, bansilalpet, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, Ethan-1-sulfonic acid-2-sulfonate and the like) and carboxylate ions (for example, acetate, ethanoate, propanoate, benzoate, glycera is, lactate, tartrate, glycolate, and the like).

The nitrogen atoms can be substituted or not substituted as valence allows, atoms and include primary, secondary, tertiary and Quaternary nitrogen. Examples of the substituents on the nitrogen atoms include, but are not limited to, hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa-C(=NR'(bb)Raa, -C(=NRccORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)2Raa, -P(=O)(Raa)2, -P(=O)2N(RCC)2, -P(=O)(NRCC)2C1-10alkyl, C1-10perhalogenated, C2-10alkenyl, C2-10quinil, C3-10carbocyclic, 3-14-membered heterocyclyl, C6-14aryl and 5-14-membered heteroaryl, or two Rccgroups associated with the N atom combined with education 3-14-membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rddand where Raa, Rbb, Rccand Rddhave the meanings given above.

In some embodiments, the incarnation, the Deputy, is present on the nitrogen atom, represents the Wallpaper amino-protective group. Amino-protective groups include, but are not limited to, -OH, -ORaa, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRccRaa, -C(=NRccORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCCC1-10alkyl (for example, kalkilya group), C2-10alkenyl, C2-10quinil, C3-10carbocyclic, 3-14-membered heterocyclyl, C6-14aryl and 5-14 membered heteroaryl group, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aralkyl, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rddand where Raa, Rbb, Rccand Rddhave the meanings given above. Amino-protective groups are well known from the prior Techniki and include groups described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,3rdedition, John Wiley & Sons, 1999, is incorporated into the present application by reference.

For example, amino-protective group such as an amide group (for example, -C(=O)Raa) include, but are not limited to, formamide, ndimethylacetamide, chloracetamide, trichloroacetamide, triptorelin, phenylacetamide, 3-phenylpropanamide, picoline, 3-pyridinecarboxamide derived N-benzoylferrocene, benzamide, p-phenylbenzo the ID, o-nitrophenylacetate, o-nitrophenoxyacetic, acetoacetamide, (N'-databasemaximumpoolsize)ndimethylacetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylethanone)propanamide, 4-chlorobutane, 3-methyl-3-nitrobutane, o-nitrocinnamic derived N-acetylation, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Amino-protective group, such as a urethane group (for example, -C(=O)ORaa) include, but are not limited to, methylcarbamate, ethylcarbamate, 9-fluorenylmethoxycarbonyl (Fmoc), 9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydromyrcenol)]methylcarbamate (DBD-Tmoc), 4-methoxybenzylamine (Phenoc), 2,2,2-trichlorethylene (Troc), 2-trimethylsilyltriflate (Teoc), 2-generationbased (hZ), 1-(1-substituted)-1-methylethylketone (Adpoc), 1,1-dimethyl-2-halogenation, 1,1-dimethyl-2,2-dibromocarbene (DB-tert-BOC), 1,1-dimethyl-2,2,2-trichlorethylene (TCBOC), 1-methyl-1-(4-biphenylyl)ethylcarbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylethylketone (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethylcarbamate (Pyoc), 2-(N,N-dicyclohexylcarbodimide)ethylcarbamate, tert-BUTYLCARBAMATE (BOC), 1-adamantylamine (Adoc), vinylcarbene (Voc), allylcarbamate (Alloc), 1-isopropylcarbamate (Ipaoc), cannabiscannabis (Coc), 4-nitrocinnamyl (Noc), 8-Hino is ylcarbamate, N-hydroxypiperidine, alkalitolerant, benzylcarbamoyl (Cbz), p-methoxybenzylamine (Moz), p-nitroaniline, p-bromobenzyloxycarbonyl, p-chloraniline, 2,4-dichloraniline, 4-methylsulfonylbenzoyl (Msz), 9-antiimmigrant, diphenylmethylsilane, 2-methylthiocarbamate, 2-methylsulfonylmethane, 2-(p-toluensulfonyl)ethylcarbamate, [2-(1,3-dithienyl)]methylcarbamate (Dmoc), 4-methylthiocarbamate (Mtpc), 2,4-dimethylthiocarbamate (Bmpc), 2-phosphonothiolate (Peoc), 2-triphenylphosphorane (Ppoc), 1,1-dimethyl-2-cyanoacrylate, m-chloro-p-aryloxyalkanoic, p-(dihydroxyaryl)benzylcarbamoyl, 5-benzisoxazole, 2-(trifluoromethyl)-6-bromonicotinate (Tcroc), m-nitrophenylarsonic, 3,5-dimethoxyaniline, o-nitrobenzylamine, 3,4-dimethoxy-6-nitrobenzylamine, phenyl(o-nitrophenyl)methylcarbamate, tert-amylcinnamic, S-benzelstierna, p-cyanobenzylidene, cyclobutanecarbonyl, cyclohexylcarbamate, cyclopentanecarbonyl, cyclopropylmethanol, p-decyloxybenzoate, 2.2-dimethoxyaniline, o-(N,N-dimethylcarbamate)benzylcarbamoyl, 1,1-dimethyl-3-(N,N-dimethylcarbamate)propellernet, 1,1-dimethylphenylcarbamate, di(2-pyridyl)methylcarbamate, 2-furylmethanol, 2-idetical, isobarically, isobutylketone, sonication carbamate, p-(p'-methoxyphenylazo)benzylcarbamoyl, 1-methylcyclobutene, 1-methylcyclohexylamine, 1-methyl-1-cyclopropanecarbonyl, 1-methyl-1-(3,5-acid)ethylcarbamate, 1-methyl-1-(p-phenylazophenyl)ethylcarbamate, 1-methyl-1-generationbased, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenylcarbamate, p-(phenylazo)benzylcarbamoyl, 2,4,6-tri-tert-butylaniline, 4-(trimethylammonium)benzylcarbamoyl and 2,4,6-trimethylaniline.

Amino-protective group, such as sulfonamidnuyu group (for example, -S(=O)2Raa) include, but are not limited to, p-toluensulfonate (Ts), benzosulfimide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzaldehyde (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylbenzenesulfonamide (SES), 9-anthracenesulfonic, 4-(4',8'-dimethoxytrityl)benzosulfimide (DNMBS), benzylmalonate, triftormetilfullerenov and pencilsharpener.

Other amino-protective groups include, but are not limited to, phenothiazinyl-(10)-carbonyl derivative, N'-p-toluensulfonyl derivative, N'-phenylaminopyrimidine derivative,N-benzylpenicillin derivative, N-acetylmethionate derivative, 4,5-diphenyl-3-oxazoline-2-it, N-phthalimide, N-datasourcename (Dts), N-2,3-diphenylamine, N-2,5-dimethylpyrrole, product fitting N-1,1,4,4-tetramethyldisilazane (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-it, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-it, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropionyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, Quaternary ammonium salt, N-benzylamino, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberyl, N-triphenylmethyl (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorene (PhF)N-2,7-dichloro-9-fluorenylmethyl, N-ferrocenylmethyl (Fcm), N-2-picolylamine N'-oxide, N-1,1-dimethyltrimethylene, N-benzylideneamino, N-p-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl)mesityl]matilainen, N-(N',N'-dimethylaminomethylene)Amin, NN'-isopropylidenebis, N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylaldehyde, N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-baranovo derived derived N-diphenylphenol acid, N-[phenyl(pentacarbonyliron or tungsten)carbonyl]Amin, N-copper chelate compound, N-zinc chelate compound, N-nitroamine, N-nitrosoamine, Amin N-hydroxy is, diphenylphosphine (Dpp), dimethylthiophosphate (Mpt), diphenylthiophene (Ppt), dialkylphosphinate, dibenzyltoluene, diphenylphosphinite, benzosulfimide, o-nitrobenzenesulfonamide (Νps), 2,4-dinitrobenzenesulfonic, pentafluorobenzenesulfonyl, 2-nitro - 4-methoxybenzenesulfonamide, triphenylmethylchloride and 3-nitropyridinium (Νpys).

As the term is used in this application, "delete group" is commonly understood in the industry term which refers to a molecular fragment that is removed with a pair of electrons in heterolytic splitting of communication, where such molecular fragment is an anion or a neutral molecule. See, for example, Smith, March's Advanced Organic Chemistry 6th ed. (501-502).

These and other examples of the substituents are described in more detail in the sections entitled “Detailed description of the invention”, “Illustrative examples” and in the claims. Not provided no limitations of the present invention a list of the substituents described above as an example.

As the term is used in this application, “its pharmaceutically acceptable form” includes pharmaceutically acceptable salt, hydrate, solvate, prodrugs, tautomers, isomers, and/or polymorphs of the compounds of the present invention, defined below in this section.

As this t is pmin is used in this application, the term "pharmaceutically acceptable salt" refers to those salts which, according to the weighted medical assessment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and meet the reasonable value of benefit/risk. Pharmaceutically acceptable salts are well known from the prior tehniki. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts formed from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid additive salts include salts of an amino group formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, Perlina acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, bansilalpet, benzoate, bis is lift, Borat, butyrate, comfort, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, formate, fumarate, glucoheptonate, glycerol, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-econsultant, lactobionate, lactate, laurate, lauryl, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluensulfonate, undecanoate, valerate and the like. Salts formed from appropriate bases include alkali metal salts, alkaline earth metals, ammonium and N+(C1-4alkyl)4. Representative salts of alkaline or alkaline-earth metals include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include, if it is appropriate, salts of non-toxic ammonium, Quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

In some embodiments embodiment pharmaceutically acceptable form of the compound is an isomer. As used in this application, those who min "isomer" includes any and all geometric isomers and stereoisomers. For example, "isomer" includes CIS - and TRANS-isomers, E - and Z - isomers, R - and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures and other mixtures, which are covered by the present invention.

In some embodiments embodiment pharmaceutically acceptable form of connection is tautomer. As used in this application, the term "tautomer" includes two or more vzaimoprevrascheny compounds derived from at least one formal migration of a hydrogen atom and at least one change of valency (for example, simple changes due to the double bond, triple bond to a simple link, or Vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. Tautomerizations (i.e., reaction, providing the tautomeric pair) can be catalysed by acid or base. Examples of tautomerization include tautomerizations keto→enol; amide→imide; lactam→lactim; enamine→Imin; and the enamine→(another) enamine.

In some embodiments embodiment pharmaceutically acceptable form of the compound is a hydrate or MES. As used in this application, the term "hydrate" refers to the connection in non-covalent Association with one or more water molecules. Similarly, the MES shall apply to the connection, in non-covalent Association with one or more molecules of an organic solvent.

In some embodiments embodiment pharmaceutically acceptable form of the compound is a prodrug. As used in this application, the term "prodrug" refers to a derivative of the original connection for which you want to convert in the body to release the parent compound. In some cases, the prodrug has improved physical properties and/or properties of delivery in comparison with the reference compound. Prodrugs are typically designed to strengthen pharmaceutical and/or pharmacokinetic properties associated with the reference compound. The advantage of prodrugs may be due to its physical properties, such as higher solubility for parenteral administration at physiological pH compared to the reference compound, or it enhances the absorption from the digestive tract, or it can increase the stability of drugs during long-term storage.

In some embodiments embodiment pharmaceutically acceptable form of connection is polymorph. As used in this application, the term "polymorph" refers to a compound having more than one crystal structure is, for example, as a result of differences in molecular packing and/or molecular conformation of compounds in the solid state.

ID sequence

SEQ. ID. NO.: Homo sapiens FAAH amino acid sequence:

Detailed description of the invention

I. Connections

The present invention provides isoxazoline compounds, which are inhibitors of FAAH, having the formula (I):

or pharmaceutically acceptable forms of such compounds, where:

(i) each of Ra, Rband Rcindependently selected from-H, C1-10the alkyl and C1-10perhalogenated, Rdrepresents a group-L-Z, and Z is selected from C6-14aryl;

(ii) each of Ra, Rband Rcindependently selected from-H, C1-10the alkyl and C1-10perhalogenated, Rdrepresents a group-L-Z, and Z is selected from 3-14-membered heterocyclyl and 5-14-membered heteroaryl;

(iii) Raand Rdcombined with the formation of C3-10carbocyclic or 3-14 membered condensed heterocyclic ring, and Rband Rcindependently selected from-H, C1-10the alkyl and C1-10perhalogenated; or

(iv) Rcand Rdcombined with the formation of C3-10carbocyclic and the and 3-14-membered heterocyclic Spiro-condensed ring, and Raand Rbindependently selected from-H, C1-10the alkyl and C1-10perhalogenated;

L is a covalent bond or a divalent C1-6hydrocarbon group, where one, two or three methylene link in L optionally and independently replaced by one or more oxygen atoms, sulfur or nitrogen;

G is selected from-CN, -NO2, -S(=O)Re, -SO2Re, -SO2NRfRe, -PO2Re, -PO2ORe, -PO2NRfRe, -(C=O)Re, -(C=O)ORe, -(C=O)NRfRe, -Br, -I, -F, -Cl, -ORe, -ONRfRe, -ONRf(C=O)Re, -ONRfSO2Re, -ONRfPO2Re, -ONRfPO2ORe, -SRe, -OSO2Re, -NRfSO2Re, -OPO2Re, -OPO2ORe, -NRfPO2Re, -NRfPO2ORe, -OPO2NRfRe, -O(C=O)Re, -O(C=O)ORe, -NRfRe, -NRf(C=O)Re, -NRf(C=O)ORe, -O(C=O)NRfRe, -NRf(C=NRf)NRfRe, -O(C=NRf)NRfRe, -NRf(C=NRfORe, -[N(Rf)2Re]+X-where X-represents a counterion; and

each Reselected from C1-10of alkyl, C2-10alkenyl, C2-10the quinil, C3-10carbocycle, C6-14aryl, 3-14 membered heterocyclyl and 5-14-the member is on heteroaryl; each Rfassociated with the nitrogen atom, independently selected from-H, C1-10the alkyl or amino-protective group; or R6and Rfcombined with education 3-14-membered heterocyclic ring or an 5-14 membered heteroaryl ring.

Group G

As defined above, G is selected from-CN, -NO2, -S(=O)Re, -SO2Re, -SO2NRfRe, -PO2Re, -PO2ORe, -PO2NRfRe, -(C=O)Re, -(C=O)ORe, -(C=O)NRfRe, -Br, -I, -F, -Cl, -ORe, -ONRfRe, -ONRf(C=O)Re, -ONRfSO2Re, -ONRfPO2Re, -ONRfPO2ORe, -SRe, -OSO2Re, -NRfSO2Re, -OPO2Re, -OPO2ORe, -NRfPO2Re, -NRfPO2ORe, -OPO2NRfRe, -O(C=O)Re, -O(C=O)ORe, -NRfRe, -NRf(C=O)Re, -NRf(C=O)ORe, -O(C=O)NRfRe, -NRf(C=NRf)NRfRe, -O(C=NRf)NRfRe, -NRf(C=NRfORe, -[N(Rf)2Re]+X-where X-represents a counterion;

and where Reselected from C1-10of alkyl, C2-10alkenyl, C2-10the quinil, C3-10carbocycle, C6-14aryl, 3-14 membered heterocyclyl and 5-14-membered heteroaryl; each Rfassociated with the atom is m nitrogen, independently selected from-H, C1-10the alkyl or amino-protective group; or Reand Rfcombined with education 3-14-membered heterocyclic ring or an 5-14 membered heteroaryl ring.

In some embodiments, embodiments, G can not be a removable group, for example, G is selected from-F, -CN, -NO2, -S(=O)Re, -SO2Re, -SO2NRfRe, -PO2Re, -PO2ORe, -PO2NRfRe, -(C=O)Re, -(C=O)OReand -(C=O)NRfRe.

In some embodiments, embodiments, G is selected from-CN and-NO2. In some embodiments of the incarnation, G represents-CN. In some embodiments, embodiments, G is a-NO2.

In some embodiments, embodiments, G is selected from-S(=O)Re, -SO2Reand-SO2NRfRe. In some embodiments, embodiments, G is a-S(=O)Re. In some embodiments of the incarnation, G represents-SO2Re. In some embodiments of the incarnation, G represents-SO2NRfRe.

In some embodiments, embodiments, G is selected from-PO2Re, -PO2OReand-PO2NRfRe. In some embodiments, embodiments, G is a-PO2Re. In some embodiments, embodiments, G is a-PO2ORe. In some embodiments, embodiments,G is a-PO 2NRfRe.

In some embodiments, embodiment G is selected from -(C=O)Re, -(C=O)OReand -(C=O)NRfRe. In some embodiments of embodiment G is a -(C=O)Re. In some embodiments of embodiment G is a -(C=O)ORe. In some embodiments of embodiment G is a -(C=O)NRfRe.

However, in some embodiments of embodiment G is a removable group, for example, G is selected from-Cl, -Br, -I, -ORe, -ONRfRe, -ONRf(C=O)Re, -ONRfSO2Re, -ONRfPO2Re, -ONRfPO2ORe, -SRe, -OSO2Re, -NRfSO2Re, -OPO2Re, -OPO2ORe, -NRfPO2Re, -NRfPO2ORe, -OPO2NRfRe, -O(C=O)Re, -O(C=O)ORe, -NRfRe, -NRf(C=O)Re, -NRf(C=O)ORe, -O(C=O)NRfRe, -NRf(C=NRf)NRfRe, -O(C=NRf)NRfRe, -NRf(C=NRfOReand -[N(Rf)2Re]+X-where X-is a counterion.

In some embodiments of embodiment G is a halogen; i.e., selected from-F, -Cl, -Br, and-I. In some embodiments of embodiment G is a-F. In some embodiments, embodiment G is a-Br. In some embodiments, embodiment G presented yet a-I. In some embodiments of embodiment G is a-Cl. However, in some embodiments, embodiment G is other than halogen. For example, in some embodiments, embodiment G is non-Br. In some embodiments, embodiment G is non-I. In some embodiments, embodiment G is non-F. In some embodiments, embodiment G is a non-Cl.

In some embodiments, embodiment G is selected from-ORe, -ONRfRe, -ONRf(C=O)Re, -ONRfSO2Re, -ONRfPO2Re, -ONRfPO2ORe, -OSO2Re, -OPO2Re, -OPO2ORe, -OPO2NRfRe, -O(C=O)Re, -O(C=O)ORe, -O(C=O)NRfReand-O(C=NRf)NRfRe. In some embodiments, embodiment G is selected from-ORe, -O(C=O)Re, -O(C=O)ORe, -O(C=O)NRfReand-O(C=NRf)NRfRe. In some embodiments, embodiment G is selected from ONRfRe, -ONRf(C=O)Re, -ONRfSO2Re, -ONRfPO2Re, -ONRfPO2ORe, -OPO2NRfRe, -O(C=O)NRfReand-O(C=NRf)NRfRe. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-ONRfRe. In some embodiments, embodiment G is Soboh the-ONR f(C=O)Re. In some embodiments of embodiment G is a-ONRfSO2Re. In some embodiments of embodiment G is a-ONRfPO2Re. In some embodiments of embodiment G is a-ONRfPO2ORe. In some embodiments of embodiment G is a-OSO2Re. In some embodiments of embodiment G is a-OPO2Re. In some embodiments of embodiment G is a-OPO2ORe. In some embodiments of embodiment G is a-OPO2NRfRe. In some embodiments of embodiment G is a-O(C=O)Re. In some embodiments of embodiment G is a-O(C=O)ORe. In some embodiments of embodiment G is a-O(C=O)NRfRe. In some embodiments of embodiment G is a-O(C=NRf)NRfRe.

In some embodiments, embodiment G is selected from-OReand-SRe. In some embodiments, embodiment G is selected from-ORe. In some embodiments of embodiment G is a-SRe.

In some embodiments, embodiment G is selected from-NRfSO2Re, -NRfPO2Re, -NRfPO2ORe, -NRfRe, -NRf(C=O)Re, -NRf(C=O)ORe, -NRf(C=NRf)NRfRe, -NRf(C=NRf)OR eand -[N(Rf)2Re]+X-where X-is a counterion. In some embodiments, embodiment G is selected from-NRfSO2Re, -NRfPO2Re, -NRfPO2ORe, -NRfRe, -NRf(C=O)Reand-NRf(C=O)ORe. In some embodiments, embodiment G is selected from-NRfSO2Re, -NRfRe, -NRf(C=O)Reand-NRf(C=O)ORe. In some embodiments of embodiment G is a-NRfSO2Re. In some embodiments of embodiment G is a-NRfPO2Re. In some embodiments of embodiment G is a-NRfPO2ORe. In some embodiments of embodiment G is a-NRfRe. In some embodiments of embodiment G is a-NRf(C=O)Re. In some embodiments of embodiment G is a-NRf(C=O)ORe. In some embodiments of embodiment G is a-NRf(C=NRf)NRfRe. In some embodiments of embodiment G is a-NRf(C=NRfORe. In some embodiments of embodiment G is a -[N(Rf)2Re]+X-where X-is a counterion.

Additional variants of embodiment G, included in the description of the groups Reand Rfand more is tion is illustrated in the Tables and Examples below and in this section of the application.

ReGroup G

In General, as defined above, in some embodiments of the incarnation, where G is selected from-S(=O)Re, -SO2Re, -SO2NRfRe, -PO2Re, -PO2ORe, -PO2NRfRe, -(C=O)Re, -(C=O)ORe, -(C=O)NRfRe, -ORe, -ONRfRe, -ONRf(C=O)Re, -ONRfSO2Re, -ONRfPO2Re, -ONRfPO2ORe, -SRe, -OSO2Re, -NRfSO2Re, -OPO2Re, -OPO2ORe, -NRfPO2Re, -NRfPO2ORe, -OPO2NRfRe, -O(C=O)Re, -O(C=O)ORe, -NRfRe, -NRf(C=O)Re, -NRf(C=O)ORe, -O(C=O)NRfRe, -NRf(C=NRf)NRfRe, -O(C=NRf)NRfRe, -NRf(C=NRfOReand -[N(Rf)2Re]+X-where X-is a counterion, Reselected from C1-10of alkyl, C2-10alkenyl, C2-10the quinil, C3-10carbocycle, C6-14aryl, 3-14 membered heterocyclyl and 5-14-membered heteroaryl.

In some embodiments embodiment Reselected from C1-10of alkyl, C2-10alkenyl, C2-10the quinil, C3-10carbocycle, C6-14aryl, 3-14 membered heterocyclyl and 5-14-membered heteroaryl, where alkyl, Alchemilla, Alchemilla, carbocyclic, aryl, heterocyclic and heteroaryl groups is substituted by 0, 1, 2, 3, 4, or 5 groups Rhdescribed below and in this section of the application.

In some embodiments embodiment Rerepresents a C1-10alkyl. In some embodiments embodiment Rerepresents a C1-6alkyl. In some embodiments embodiment Rerepresents a C1-6alkyl, substituted 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Rerepresents a C1-5alkyl, substituted 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Rerepresents a C1-4alkyl, substituted 0, 1, 2, 3 or 4 groups Rh. In some embodiments embodiment Rerepresents a C1-3alkyl, substituted 0, 1, 2, or 3 groups Rh. In some embodiments embodiment Rerepresents a C1-2alkyl, substituted 0, 1 or 2 groups Rh. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl, wherein such groups are substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

In some embodiments embodiment Rerepresents a C1-6perhalogenated. In some embodiments, voploscheni the R erepresents a C1-5perhalogenated. In some embodiments embodiment Rerepresents a C1-4perhalogenated. In some embodiments embodiment Rerepresents a C1-3perhalogenated. In some embodiments embodiment Rerepresents a C1-2perhalogenated. Examples perhalogenated groups Reinclude, but are not limited to, -CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2and-CF2Cl.

In some embodiments embodiment Rerepresents a C2-10alkenyl. In some embodiments embodiment Rerepresents a C2-6alkenyl. In some embodiments embodiment Rerepresents a C2-6alkenyl, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Rerepresents a C2-5alkenyl, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Rerepresents a C2-3alkenyl, substituted by 0, 1, 2, or 3 groups Rh. Examples alkenyl groups include, but are not limited to, ethynyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl and hexenyl, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

In some embodiments embodiment Rerepresents a C 2-10quinil. In some embodiments embodiment Rerepresents a C2-6quinil. In some embodiments embodiment Rerepresents a C2-6 quinil, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Rerepresents a C2-5quinil, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Rerepresents a C2-4quinil, substituted by 0, 1, 2, 3 or 4 groups Rh. In some embodiments embodiment Rerepresents a C2-3quinil, substituted by 0, 1, 2, or 3 groups Rh. Examples etkinlik groups Reinclude, but are not limited to, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, pentenyl and hexenyl, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

However, in some embodiments of the incarnation, where G represents-ORe, Remay not be a C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, aralkyl). In some embodiments of the incarnation, where G represents-ORe, Remay not be a C2-6alkenyl (e.g., allyl).

In some embodiments of the incarnation, where G represents-SRe, Remay not be a C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, aralkyl).

In some variants of the Ah of the incarnation, where G represents-NReRfand Rfrepresents-H or C1-3alkyl (e.g. methyl, ethyl, aralkyl), Remay not be a C1-6alkyl.

In some embodiments embodiment Rerepresents a C6-14aryl. In some embodiments embodiment Rerepresents a C6-10aryl. In some embodiments embodiment Rerepresents a C6-10aryl, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Rerepresents a C6aryl (e.g. phenyl), substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Rerepresents a C10aryl (e.g. naphthyl), substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

In some embodiments embodiment Rerepresents phenyl. In some embodiments embodiment Rerepresents phenyl, substituted with 0, 1, 2, 3 or 4 groups Rh. In some embodiments embodiment Rerepresents phenyl, substituted with 0, 1, 2, or 3 groups Rh. In some embodiments embodiment Rerepresents phenyl, substituted by 0, 1 or 2 groups Rh. In some embodiments embodiment Rerepresents phenyl, substituted by 0 or 1 group, Rh. In some embodiments embodiment Reis Soboh is disubstituted phenyl (i.e., substituted 2 groups Rh). In some embodiments embodiment Rerepresents a monosubstituted phenyl (i.e., substituted by 1 group, Rh). In some embodiments embodiment Rerepresents unsubstituted phenyl (i.e., substituted 0 groups Rh).

In some embodiments embodiment Rerepresents phenyl substituted in at least one ortho Rhgroup. In some embodiments embodiment Rerepresents phenyl, substituted by at least one meta Rhgroup. In some embodiments embodiment Rerepresents phenyl, substituted, at least one pair of Rhgroup.

In some embodiments embodiment Rerepresents a phenyl group of the formula:

where x is 0, 1, 2, 3, 4 or 5, and Rhshall have the meaning given below and in this section of the application. In some embodiments embodiment x is 0, 1, 2, 3 or 4. In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1. In some embodiments, the realization of x has the value 3. In some embodiments embodiment Rerepresents a disubstituted phenyl group (i.e., where x has a value of 2). In some Islands Ianto embodiment R eis a monosubstituted phenyl group (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents an unsubstituted phenyl group (i.e., where x has a value of 0).

For example, in some embodiments embodiment Rerepresents a substituted or unsubstituted phenyl group, any of the following formulas:

where Rhshall have the meaning given below and in this section of the application.

In some embodiments embodiment Rerepresents naphthyl. In some embodiments embodiment Rerepresents naftalina group any of the following formulas:

where x is 0, 1, 2, 3, 4 or 5, and Rhshall have the meaning given below and in this section of the application. In some embodiments embodiment x is 0, 1, 2, 3 or 4. In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1. In some embodiments embodiment Rerepresents trisamino naftalina group (i.e., where x has a value of 3). In some embodiments embodiment Rerepresents a disubstituted naftalina group (i.e., where x has a value of 2). In some embodiments embodiment R erepresents a monosubstituted naftalina group (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents unsubstituted naftalina group (i.e., where x has a value of 0).

For example, in some embodiments embodiment Rerepresents a substituted or unsubstituted 1-naftalina group any of the following formulas:

where Rhshall have the meaning given below and in this section of the application.

In some embodiments embodiment Rerepresents a substituted or unsubstituted 2-naftalina group any of the following formulas:

where Rhshall have the meaning given below and in this section of the application.

However, in some embodiments of the incarnation, where G represents-ORein this case, Remay not be a C10aryl (for example, 1-naphthyl, 2-naphthyl).

In some embodiments embodiment Rerepresents a 5 to 14-membered heteroaryl. In some embodiments embodiment Reis a 5-10-membered heteroaryl, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Reis a 5-8-membered heteroaryl, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Reis a 5--membered heteroaryl, substituted by 0, 1, 2, 3 or 4 groups Rh. In some embodiments embodiment Reis a 9-10-membered heteroaryl, substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

Examples of heteroaryl groups of Reinclude, but are not limited to, pyrrolyl, furanyl and thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyridazinyl (for example, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl, tetrazines, azepine, oxepin, tiepins, indolyl, isoindolyl, indazoles, benzotriazolyl, benzothiophenes, isobenzofuranyl, benzofuranyl, benzothiophenes, benzimidazoles, benzoxazoles, benzisoxazole, benzoxadiazole, benzothiazolyl, benzisothiazole, benzothiazolyl, indolizinyl, purinol, naphthyridine, pteridine, chinoline, ethenolysis, cinnoline, honokalani, phthalazine, hintline, phenanthridines, dibenzofurans, carbazoles, acridines, phenothiazinyl, phenoxazines and phenazines, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

In some embodiments embodiment Rerepresents a 5-membered heteroaryl. In some embodiments embodiment Rerepresents a 5-membered heteros is aryl, substituted by 0, 1, 2, or 3 groups Rh. In some embodiments embodiment Rerepresents a 5-membered heteroaryl selected from pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl, where such groups are substituted by 0, 1, 2, or 3 groups Rh.

For example, in some embodiments embodiment Rerepresents a 5-membered heteroaryl formula:

where Ya, Yb, Ycand Ydindependently selected from CH, CRh, O, S, N or NRkprovided that at least one of the Ya, Yb, Ycand Ydrepresents O, S, N or NRkand where Rhand Rkhave the meaning given below and in this section of the application.

In some embodiments, the embodiments presented above formula (1-d), Yarepresents O, S, N or NRkand Yb, Ycand Ydindependently selected from CH, CRh, NRkor N. In some embodiments, the embodiments presented above formula (1-d), Yarepresents O, S, N or NRkand Yb, Ycand Ydindependently selected from CH or CRh. In some embodiments, the embodiments presented above formula (1-d), Yarepresents O, S or NRk, Ycis Soboh is N, and Yband Ydindependently selected from CH or CRh.

In some embodiments, the embodiments presented above formula (1-d), Ybrepresents O, S or NRkand Ya, Ycand Ydindependently selected from CH, CRhor N. In some embodiments, the embodiments presented above formula (1-d), Ybrepresents O, S or NRkand Ya, Ycand Ydindependently selected from CH or CRh. In some embodiments, the embodiments presented above formula (1-d), Ybrepresents O, S or NRk, Ydrepresents N and Yaand Ycindependently selected from CH or CRh.

In some embodiments embodiment Rerepresents a substituted or unsubstituted 5-membered heteroaryl any of the following formulas:

where x is 0, 1 or 2, and Rhand Rkhave the meaning given below and in this section of the application. In some embodiments embodiment Rerepresents an unsubstituted 5-membered heteroaryl (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted 5-membered heteroaryl (for example, where x has a value of 1 or 2). In some embodiments embodiment Rerepresents a monosubstituted 5-membered heteroaryl (i.e., where x has a value of 1). In some the x variants of embodiment R erepresents a disubstituted 5-membered heteroaryl (i.e., where x has a value of 2). In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

However, in some embodiments of the incarnation, where G represents-ORe, Remay not be thiazolyl, for example, of the formula:

where x is 0, 1 or 2, and Rhand Rkhave the meaning given below and in this section of the application.

In some embodiments embodiment Rerepresents a 6-membered heteroaryl. In some embodiments embodiment Rerepresents a 6-membered heteroaryl, substituted by 0, 1, 2, 3 or 4 groups Rh. In some embodiments embodiment Rerepresents a 6-membered heteroaryl selected from the group comprising pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyridazinyl (for example, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl and tetrazini, where such groups are substituted by 0, 1, 2, 3 or 4 groups Rh.

For example, in some embodiments embodiment Rerepresents a 6-membered heteroaryl group of the formula:

where Wa, Wb, Wc, Wdand Weindependently SEL is Ana from CH, CRhor N, provided that at least one of Wa, Wb, Wc, Wdand Werepresents N, and where Rhshall have the meaning given below and in this section of the application.

In some embodiments embodiment Rerepresents pyridinyl group. In some embodiments embodiment Rerepresents pyridinyl group, substituted by 0, 1, 2, 3 or 4 groups Rh. For example, in some embodiments embodiment Rerepresents pyridinyl group of the formula:

where x is 0, 1, 2, 3 or 4, and Rhshall have the meaning given below and in this section of the application. In some embodiments embodiment Rerepresents unsubstituted pyridinyl (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted pyridinyl (e.g., where x has a value of 1, 2, 3 or 4). In some embodiments embodiment Reis a monosubstituted pyridinyl (i.e., where x has a value of 1). In some embodiments embodiment Reis a disubstituted pyridinyl (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine pyridinyl (i.e., where x has a value of 3). In some embodiments embodiment x is 0, 1, 2 or 3. In some of the s variants embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Reis a 2-pyridinyl group, for example, formula (i-e), where Warepresents N, and Wb, Wc, Wdand Weindependently represent CH or CRh. In some embodiments embodiment Reis a 3-pyridinyl group, for example, formula (i-e), where Wbrepresents N, and Wa, Wc, Wdand Weindependently represent CH or CRh. In some embodiments embodiment Reis a 4-pyridinyl group, for example, formula (i-e), where Wcrepresents N, and Wa, Wb, Wdand Weindependently represent CH or CRh.

In some embodiments embodiment Rerepresents a substituted or unsubstituted 2-pyridinyl group any of the following formulas:

where Rhshall have the meaning given below and in this section of the application.

In some embodiments embodiment Rerepresents a substituted or unsubstituted 3-pyridinyl group any of the following formulas:

where Rhshall have the meaning given below and in this section of the application.

In some embodiments embodiment Re represents a substituted or unsubstituted 4-pyridinyl group any of the following formulas:

where Rhshall have the meaning given below and in this section of the application.

In some embodiments embodiment Rerepresents pyridazinyl group. In some embodiments embodiment Rerepresents pyridazinyl group, substituted by 0, 1, 2, or 3 groups Rh. For example, in some embodiments embodiment Rerepresents pyridazinyl group of the formula:

where x is 0, 1, 2 or 3, and Rhshall have the meaning given below and in this section of the application. In some embodiments embodiment Rerepresents an unsubstituted pyridazinyl (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted pyridazinyl (for example, where x is 1, 2 or 3). In some embodiments embodiment Rerepresents a monosubstituted pyridinyl (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted pyridinyl (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine pyridazinyl (i.e., where x has a value of 3). In some embodiments, the realization of x has a value is the 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Reis a 3-pyridazinyl group, for example, formula (i-e), where Waand Wbrepresent N, and Wc, Wdand Weindependently represent CH or CRh. In some embodiments embodiment Reis a 4-pyridazinyl group, for example, formula (i-e), where Wband Wcrepresent N, and Wa, Wdand Weindependently represent CH or CRh.

In some embodiments embodiment Rerepresents a substituted or unsubstituted 3-pyridazinyl group any of the following formulas:

where Rhshall have the meaning given below and in this section of the application.

In some embodiments embodiment Rerepresents a substituted or unsubstituted 4-pyridazinyl group any of the following formulas:

where Rhshall have the meaning given below and in this section of the application.

In some embodiments embodiment Rerepresents pyrimidinyl group. In some embodiments embodiment Rerepresents pyrimidinyl group, substituted by 0, 1, 2 or 3, g is uppada R h. For example, in some embodiments embodiment Rerepresents pyrimidinyl group of the formula:

where x is 0, 1, 2 or 3, and Rhshall have the meaning given below and in this section of the application. In some embodiments embodiment Rerepresents an unsubstituted pyrimidinyl (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted pyrimidinyl (for example, where x is 1, 2 or 3). In some embodiments embodiment Rerepresents a monosubstituted pyrimidinyl (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted pyridinyl (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine pyrimidinyl (i.e., where x has a value of 3). In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Reis a 2-pyrimidinyl group, for example, formula (i-e), where Waand Werepresent N, and Wb, Wcand Wdindependently represent CH or CRh. In some embodiments embodiment Reis own the th 4-pyrimidinyl group, for example, formula (i-e), where Waand Wcrepresent N, and Wb, Wdand Weindependently represent CH or CRh. In some embodiments embodiment Rerepresents a 5-pyrimidinyl group, for example, formula (i-e), where Wband Wdrepresent N, and Wa, Wcand Weindependently represent CH or CRh.

In some embodiments embodiment Rerepresents a substituted or unsubstituted 2-pyrimidinyl group any of the following formulas:

where Rhshall have the meaning given below and in this section of the application.

In some embodiments embodiment Rerepresents a substituted or unsubstituted 4-pyrimidinyl group any of the following formulas:

where Rhshall have the meaning given below and in this section of the application.

In some embodiments embodiment Rerepresents a substituted or unsubstituted 5-pyrimidinyl group any of the following formulas:

where Rhshall have the meaning given below and in this section of the application.

In some embodiments embodiment Rerepresents personilnya group. In some embodiments embodiment Reis a feast is similou group, substituted by 0, 1, 2, or 3 groups Rh. For example, in some embodiments embodiment Rerepresents personilnya group of the formula:

where x is 0, 1, 2 or 3, and Rhshall have the meaning given below and in this section of the application. In some embodiments embodiment Rerepresents an unsubstituted pyrazinyl (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted pyrazinyl (for example, where x is 1, 2 or 3). In some embodiments embodiment Rerepresents a monosubstituted pyrazinyl (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted pyrazinyl (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine pyrazinyl (i.e., where x has a value of 3). In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Rerepresents a substituted or unsubstituted personilnya group any of the following formulas:

where Rhshall have the meaning given below and in this section of the application.

In nektarinukiniai embodiment R erepresents triazinyl group. In some embodiments embodiment Rerepresents triazinyl group, substituted by 0, 1 or 2 groups Rh. For example, in some embodiments embodiment Rerepresents triazinyl group of the formula:

where x is 0, 1 or 2, and Rhshall have the meaning given below and in this section of the application. In some embodiments embodiment Rerepresents an unsubstituted pyrazinyl (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted pyrazinyl (for example, where x has a value of 1 or 2). In some embodiments embodiment Rerepresents a monosubstituted pyrazinyl (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted pyrazinyl (i.e., where x has a value of 2). In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Rerepresents a substituted or unsubstituted triazinyl group any of the following formulas:

where Rhshall have the meaning given below and in this section of the application.

In some embodiments embodiment Reis own the th thetrainline group. In some embodiments embodiment Rerepresents thetrainline group, substituted by 0 or 1 groups, Rh. In some embodiments embodiment Rerepresents thetrainline group of the formula:

where x is 0 or 1, and Rhshall have the meaning given below and in this section of the application. In some embodiments embodiment Rerepresents an unsubstituted pyrazinyl (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted pyrazinyl (for example, where x has a value of 1). In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Rerepresents a substituted or unsubstituted thetrainline group any of the following formulas:

where Rhshall have the meaning given below and in this section of the application.

In some embodiments embodiment Reis a 9-membered heteroaryl (for example, 5,6-bicyclic heteroaryl). In some embodiments embodiment Rerepresents a 5,6-bicyclic heteroaryl, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Rerepresents a 5,6-bicyclic heteroaryl selected from indolyl, isoindolyl, indazole, benzotriazol the sludge, benzothiophene, isobenzofuranyl, benzofuranyl, benzothiophene, benzimidazole, benzoxazole, benzisoxazole, benzoxadiazole, benzothiazolyl, benzisothiazole, benzothiadiazole, indolizinyl and purine, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

For example, in some embodiments embodiment Rerepresents a 5,6-bicyclic heteroaryl formula:

where Ye, Yf, Yg, Yi, Yj, Ykand Ymindependently represents C, CH, CRh, O, S, N or NRkand Ynrepresents C or N, provided that at least one of the Ye, Yf, Ygselected from O, S, N or NRkwhere Rhand Rkdefined below in this section of the application.

In some embodiments embodiment Rerepresents a 5,6-bicyclic heteroaryl group of the formula (i-f), where Yeselected from O, S or NRk, Ynis a C, and Yf, Yg, Yi, Yj, Ykand Ymindependently represents C, CH or CRh. For example, in some embodiments embodiment Rerepresents a 5,6-bicyclic heteroaryl group of the formula:

where x is 0, 1, 2, 3, 4 or 5, and Rhand Rkhave the meanings given below in this the m section of the application. In some embodiments embodiment Rerepresents unsubstituted 5,6-bicyclic heteroaryl (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted 5,6-bicyclic heteroaryl (for example, where x has a value of 1, 2, 3, 4 or 5). In some embodiments embodiment Rerepresents a monosubstituted 5,6-bicyclic heteroaryl (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted 5,6-bicyclic heteroaryl (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine 5,6-bicyclic heteroaryl (i.e., where x has a value of 3). In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Rerepresents a 5,6-bicyclic heteroaryl, where Yeselected from O, S or NRk; Ygrepresents N; Ynis a C; Yfrepresents C, CH or CRhor N, and Yi, Yj, Ykand Ymindependently represents C, CH or CRh. For example, in some embodiments embodiment Rerepresents a 5,6-bicyclic heteroaryl group of the formula:

where x is 0, 1, 2, 3, 4 or 5, and Rhand Rkhave the meanings given below in this section of the application. In some embodiments embodiment Rerepresents unsubstituted 5,6-bicyclic heteroaryl (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted 5,6-bicyclic heteroaryl (for example, where x has a value of 1, 2, 3, 4 or 5). In some embodiments embodiment Rerepresents a monosubstituted 5,6-bicyclic heteroaryl (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted 5,6-bicyclic heteroaryl (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine 5,6-bicyclic heteroaryl (i.e., where x has a value of 3). In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Rerepresents a 5,6-bicyclic heteroaryl, where Yerepresents NRk, S, or O; Ymrepresents N; Ynrepresents C; and Yf, Yg, Yi, Yjand Ykindependently represents C, CH or CRh. For example, in some embodiments waples is of R erepresents a 5,6-bicyclic heteroaryl group of the formula:

where x is 0, 1, 2, 3, 4 or 5, and Rhand Rkhave the meanings given below in this section of the application. In some embodiments embodiment Rerepresents unsubstituted 5,6-bicyclic heteroaryl (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted 5,6-bicyclic heteroaryl (for example, where x has a value of 1, 2, 3, 4 or 5). In some embodiments embodiment Rerepresents a monosubstituted 5,6-bicyclic heteroaryl (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted 5,6-bicyclic heteroaryl (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine 5,6-bicyclic heteroaryl (i.e., where x has a value of 3). In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Rerepresents a 5,6-bicyclic heteroaryl, where Ygrepresents O, S or NRk; Ymrepresents N; Ynrepresents C; and Ye, Yf, YiY jand Ykindependently represents C, CH or CRh. For example, in some embodiments embodiment Rerepresents a 5,6-bicyclic heteroaryl group of the formula:

where x is 0, 1, 2, 3, 4 or 5, and Rhand Rkhave the meanings given below in this section of the application. In some embodiments embodiment Rerepresents unsubstituted 5,6-bicyclic heteroaryl (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted 5,6-bicyclic heteroaryl (for example, where x has a value of 1, 2, 3, 4 or 5). In some embodiments embodiment Rerepresents a monosubstituted 5,6-bicyclic heteroaryl (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted 5,6-bicyclic heteroaryl (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine 5,6-bicyclic heteroaryl (i.e., where x has a value of 3). In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Rerepresents a 5,6-bicyclic heteroaryl, where Yeselected from N; Yn/sup> represents N; and Yf, Yi, Yj, Ykand Ymindependently represents C, CH or CRh. For example, in some embodiments embodiment Rerepresents a 5,6-bicyclic heteroaryl group of the formula:

where x is 0, 1, 2, 3, 4 or 5, and Rhand Rkhave the meanings given below in this section of the application. In some embodiments embodiment Rerepresents unsubstituted 5,6-bicyclic heteroaryl (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted 5,6-bicyclic heteroaryl (for example, where x has a value of 1, 2, 3, 4 or 5). In some embodiments embodiment Rerepresents a monosubstituted 5,6-bicyclic heteroaryl (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted 5,6-bicyclic heteroaryl (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine 5,6-bicyclic heteroaryl (i.e., where x has a value of 3). In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Reis a 10-h the military heteroaryl (for example, 6,6-bicyclic heteroaryl). In some embodiments embodiment Reis a 6,6-bicyclic heteroaryl, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Reis a 6,6-bicyclic heteroaryl selected from naphthyridine, pteridine, chinoline, izochinolina, cinnoline, khinoksalinona, phthalazine and hintline, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

For example, in some embodiments embodiment Reis a 6,6-bicyclic heteroaryl formula (i-g)

where Wf, Wg, Wh, Wi, Wj, Wk, Wmand Wnindependently selected from C, CH, CRhor N, provided that at least one of Wf, Wg, Wh, Wi, Wj, Wk, Wmand Wnrepresents N, and where Rhshall have the meaning given below and in this section of the application.

In some embodiments embodiment Rerepresents hyalinella group; for example, formula (i-g), where Wirepresents N, and Wg, Wh, Wf, Wj, Wk, Wmand Wnindependently represents C, CH or CRh. For example, in some embodiments embodiment Rerepresents hyalinella group of the formula:

where x is 0, 1, 2, 3, 4 or 5, and Rhshall have the meaning given below and in this section of the application. In some embodiments embodiment Rerepresents an unsubstituted chinoline (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted chinoline (for example, where x has a value of 1, 2, 3, 4 or 5). In some embodiments embodiment Rerepresents a monosubstituted chinoline (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted chinoline (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine chinoline (i.e., where x has a value of 3). In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Rerepresents athinodorou group; for example, formula (i-g), where Whrepresents N, and Wf, Wg, Wi, Wj, Wk, Wmand Wnindependently represents C, CH or CRh. For example, in some embodiments embodiment Rerepresents athinodorou group of the formula:

where x is 0, 1, 2, 3, 4 or 5, and hshall have the meaning given below and in this section of the application. In some embodiments embodiment Rerepresents an unsubstituted ethenolysis (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted ethenolysis (for example, where x has a value of 1, 2, 3, 4 or 5). In some embodiments embodiment Rerepresents a monosubstituted ethenolysis (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted ethenolysis (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine ethenolysis (i.e., where x has a value of 3). In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Rerepresents khinoksalinona group; for example, formula (i-g), where Wfand Wirepresent N, and Wg, Wh, Wj, Wk, Wmand Wnindependently represents C, CH or CRh. For example, in some embodiments embodiment Rerepresents khinoksalinona group of the formula:

where x is 0, 1, 2, 3, 4 or 5, and Rhhas the value of the specified below and in this section of the application. In some embodiments embodiment Rerepresents an unsubstituted honokalani (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted honokalani (for example, where x has a value of 1, 2, 3, 4 or 5). In some embodiments embodiment Rerepresents a monosubstituted honokalani (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted honokalani (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine honokalani (i.e., where x has a value of 3). In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Reis a 3-14 membered heterocyclyl. In some embodiments embodiment Reis a 3-14 membered heterocyclyl, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Reis a 5-10-membered heterocyclyl, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Reis a 5-8-membered heterocyclyl, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Reisone 5-6-membered heterocyclyl, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Reis a 9-10-membered heterocyclyl, substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

Examples of heterocyclic groups, Reinclude, but are not limited to, aziridinyl, oxiranyl, tiereny, azetidine, oxetane, titanyl, tetrahydrofuranyl, dihydrofurane, tetrahydrothiophene, dihydrothiophene, pyrrolidinyl, dihydropyrrole, pyrrolyl-2,5-dione, DIOXOLANYL, oxathiolane, dithiolane, triazolyl, oxadiazolyl, thiadiazolyl, piperidinyl, tetrahydropyranyl, dihydropyridines, tiani, piperazinil, morpholinyl, dithienyl, dioxane, triazinyl, azepane, oxetanyl, tepanil, atacanli, oxetanyl, ciocanel, indolinyl, isoindolyl, dihydrobenzofuranyl, dihydrobenzofuranyl, tetrahydrobenzene, tetrahydrofuranyl, tetrahydroindole, tetrahydroquinoline, tetrahydroisoquinoline, decahydroquinoline, decahydroquinoline, octahedrally, octahydronaphthalene, decahydronaphthalene, decahydro-1,8-naphthyridines, octahedral[3,2-b]pyrrole, indolinyl, phthalimide, naphthalimide, bromanil, bromanil, 1H-benzo[e][l,4]diazepine, 1,4,5,7-tetrahydro-pyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro the[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-Tetra-hydropure[3,2-c]pyridinyl and 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridines, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

In some embodiments embodiment Rerepresents a 6-membered heterocyclyl, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Rerepresents a 6-membered heterocyclyl selected from piperidinyl, tetrahydropyranyl, dihydropyridine, taanila, piperazinil, morpholinyl, dithienyl, dioxane and triazinyl, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

For example, in some embodiments embodiment Rerepresents a 6-membered heterocyclyl formula:

where W0, Wp, Wq, Wrand Wsindependently selected from CH2, CHRhC(Rh)2, NRk, O or S, and W1represents N, CH, CRhprovided that at least one of W0, Wp, Wq, Wrand Wsselected from N, NRk, O or S, where Rhand Rkhave the meanings given below in this section of the application.

In some embodiments embodiment Rerepresents piperidinyloxy group. In some embodiments embodiment Rerepresents piperidinyloxy is the Rupp, substituted by 0, 1, 2, 3, 4, or 5 groups Rhfor example, the formula:

where x is 0, 1, 2, 3, 4 or 5, and Rnand Rkdefined below in this section of the application. In some embodiments embodiment Rerepresents an unsubstituted piperidinyl (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted piperidinyl (for example, where x has a value of 1, 2, 3, 4 or 5). In some embodiments embodiment Rerepresents a monosubstituted piperidinyl (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted piperidinyl (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine piperidinyl (i.e., where x has a value of 3). In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Reis a 1-piperidinyloxy group, for example, formula (i-h), where Wtrepresents N, and W0, Wp, Wq, Wrand Wsindependently selected from CH2, CHRhC(Rh)2. In some embodiments embodiment Reis a 2-piperidinyloxy group, for example, formula (i-h), where W0represents NRk; Wp, Wq, Wrand Wsindependently represent CHRhC(Rh)2or CH2; Wtrepresents CH or CRh. In some embodiments embodiment Reis a 3-piperidinyloxy group, for example, formula (i-h), where Wprepresents NRk; W0, Wq, Wrand Wsindependently represent CHRhC(Rh)2or CH2; Wtrepresents CH or CRh. In some embodiments embodiment Reis a 4-piperidinyloxy group, for example, formula (i-h), where Wqrepresents NRk; W0, Wp, Wrand Wsindependently represent CHRhC(Rh)2or CH2; Wtrepresents CH or CRh.

In some embodiments embodiment Rerepresents piperazinilnom group. In some embodiments embodiment Rerepresents piperazinilnom group, substituted by 0, 1, 2, 3 or 4 groups Rhfor example, the formula:

where x is 0, 1, 2, 3, 4 or 5, and Rhand Rkdefined below in this section of the application. In some embodiments embodiment Rerepresents unsubstituted piperazinil (i.e., where x is meant the e 0). In some embodiments embodiment Rerepresents a substituted piperazinil (for example, where x has a value of 1, 2, 3, 4 or 5). In some embodiments embodiment Rerepresents a monosubstituted piperazinil (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted piperazinil (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine piperazinil (i.e., where x has a value of 3). In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Reis a 1-piperazinilnom group, for example, formula (i-h), where Wtrepresents N, Wqrepresents NRkand W0, Wp, Wrand Wsindependently selected from CH2, CHRhC(Rh)2. In some embodiments embodiment Reis a 2-piperazinilnom group, for example, formula (i-h), where W0and Wrindependently represent NRkand Wp, Wq, Wrand Wsindependently represent CHRhC(Rh)2or CH2; Wtrepresents CH or CRh.

In some embodiments embodiment R erepresents morpholinyl group. In some embodiments embodiment Rerepresents morpholinyl group, substituted by 0, 1, 2, 3 or 4 groups Rhfor example, the formula:

where x is 0, 1, 2, 3, 4 or 5, and Rhand Rkdefined below in this section of the application. In some embodiments embodiment Rerepresents an unsubstituted morpholinyl (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted morpholinyl (for example, where x has a value of 1, 2, 3, 4 or 5). In some embodiments embodiment Rerepresents a monosubstituted morpholinyl (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted morpholines (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine morpholinyl (i.e., where x has a value of 3). In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Rerepresents morpholinyl group of the formula (i-h), where Wtrepresents N, Wqrepresents O, and W0, Wp, Wrand Wsindependently in the gap of CH 2, CHRhC(Rh)2.

In some embodiments embodiment Rerepresents dioxolo group. In some embodiments embodiment Rerepresents dioxolo group, substituted by 0, 1, 2, 3 or 4 groups Rhfor example, the formula:

where x is 0, 1, 2, 3, 4 or 5, and Rhand Rkdefined below in this section of the application. In some embodiments embodiment Rerepresents unsubstituted dioxane (i.e., where x has a value of 0). In some embodiments embodiment Rerepresents a substituted dioxane (for example, where x has a value of 1, 2, 3, 4 or 5). In some embodiments embodiment Rerepresents a monosubstituted dioxane (i.e., where x has a value of 1). In some embodiments embodiment Rerepresents a disubstituted dioxane (i.e., where x has a value of 2). In some embodiments embodiment Rerepresents tizamidine dioxane (i.e., where x has a value of 3). In some embodiments embodiment x is 0, 1, 2 or 3. In some embodiments embodiment x is 0, 1 or 2. In some embodiments embodiment x is 0 or 1.

In some embodiments embodiment Rerepresents dioxolo group, for example, formula (i-h), where W0and Wrimagine the battle O and Wp, Wq, Wrand Wsindependently represent CHRhC(Rh)2or CH2; Wtrepresents CH or CRh.

Other 6-membered heterocyclic group, Recovered by formula (i-h), include monosaccharide sugar, for example, pyranoside selected from ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idosi, galactose and talose.

In some embodiments embodiment Rerepresents a C3-10carbocyclic. In some embodiments embodiment Rerepresents a C3-10carbocyclic, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Rerepresents a C5-8carbocyclic, substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Rerepresents a C5-6carbocyclic, substituted by 0, 1, 2, 3 or 4 groups Rh. In some embodiments embodiment Rerepresents a C9-10carbocyclic, substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

Examples of C3-10carbocyclic groups, Reinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl and cycloheptadiene, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

Rf from Gr is PI G

In General, as defined above, in some embodiments of the incarnation, where G is selected from-SO2NRfRe, -PO2NRfRe, -(C=O)NRfRe, -ONRfRe, -ONRf(C=O)Re, -ONRfSO2Re, -ONRfPO2Re, -ONRfPO2ORe, -NRfSO2Re, -NRfPO2Re, -NRfPO2ORe, -OPO2NRfRe, -NRfRe, -NRf(C=O)Re, -NRf(C=O)ORe, -O(C=O)NRfRe, -NRf(C=NRf)NRfRe, -O(C=NRf)NRfRe, -NRf(C=NRfOReand -[N(Rf)2Re]+X-where X-is a counterion, each Rfassociated with the nitrogen atom, independently selected from-H or C1-10the alkyl or amino-protective group, or Reand Rfcombined with education 3-14-membered heterocyclic ring or an 5-14 membered heteroaryl ring.

In some embodiments embodiment Rfrepresents H or C1-10alkyl group.

In some embodiments embodiment Rfrepresents H.

In some embodiments embodiment Rfrepresents a C1-10alkyl group. In some embodiments embodiment Rfrepresents a C1-10alkyl, substituted 0, 1, 2, 3, 4, or 5 groups Rh. Examples alkyl what's groups, R finclude, but are not limited to, methyl, ethyl, propyl, allyl and benzyl. In some embodiments embodiment Rfrepresents an unsubstituted methyl, i.e.,- CH3. In some embodiments embodiment Rfrepresents unsubstituted ethyl, i.e.,- CH2CH3.

In some embodiments embodiment Rfrepresents an amino-protective group. For example, in some embodiments embodiment Rfselected from-OH, -ORi, -N(Rk)2, -C(O)Ri, -C(=O)N(Rk)2, -CO2Ri, -SO2Ri, -C(=NRkRi, -C(=NRkORj, -C(=NRk)N(Rk)2, -SO2N(Rk)2, -SO2Ri, -SO2ORi, -SORi, -C(=S)N(Rk)2, -CC=O)SRi, -C(=S)SRiC1-10the alkyl (for example, aralkyl), C2-10alkenyl, C2-10the quinil, C3-10carbocycle, 3-14-membered heterocyclic, C6-14aryl and 5-14 membered heteroaryl group, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aralkyl, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rmwhere Ri, Rk, Rmdefined below in this section of the application.

However, in some embodiments of embodiment G is a-NReRfand Rfrepresents-H or C1-3alkyl, Reunable to provide the identification of a C 1-6alkyl or thiazolyl.

In addition, in some embodiments of the incarnation, where G represents-OC(=O)NRfRe, Reand Rfcan't both be a-CH3.

Alternatively, in some embodiments embodiment Reand Rfcombined with education 3-14-membered heterocyclic ring or an 5-14 membered heteroaryl ring; for example, when G represents-SO2NRfRe, -PO2NRfRe, -(C=O)NRfRe, -ONRfRe, -OPO2NRfRe, -NRfRe, -O(C=O)NRfRe, -NRf(C=NRf)NRfRe, -O(C=NRf)NRfReand -[N(Rf)2Re]+X-where X-is a counterion. In some embodiments of the incarnation, where Reand Rfcombined with education 3-14-membered heterocyclic ring or an 5-14 membered heteroaryl ring, a heterocyclic ring or heteroaryl ring is substituted by 0, 1, 2, 3, 4, or 5 groups Rhas defined below in this section of the application.

In some embodiments embodiment Reand Rfcombined with education 3-14-membered heterocyclic ring. In some embodiments embodiment Reand Rfcombined with education 3-14-membered heterocyclic ring substituted by 0, 1, 2, 3, 4, or 5 groups Rh . In some embodiments of the incarnation and Rfmerged to form a 5-10 membered heterocyclic ring substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Reand Rfcombined with education 5-8 - membered heterocyclic ring substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Reand Rfmerged to form a 5-6-membered heterocyclic ring substituted by 0, 1, 2, or 3 groups Rh. In some embodiments embodiment Reand Rfcombined with education 9-10 - membered heterocyclic ring substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

In some embodiments embodiment Reand Rfcombined with the formation of a heterocyclic group selected from aziridinyl, azetidine, pyrrolidine, dihydropyrrole, pyrrolyl-2,5-dione, triazoline, oxadiazoline, thiadiazoline, piperidinyl, dihydropyridine, taanila, piperazinil, morpholinyl, triazinyl, azepane, oxetanyl, tapanila, asokamala, indolinyl, isoindolyl, tetrahydrobenzo-tanila, tetrahydroindole, tetrahydroquinoline, tetrahydroisoquinoline, decahydroquinoline, decahydroquinoline, indolinyl and phthalimide, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

For example, in some embodiments, is oblasenia R eand Rfcombined with the formation of 5-membered heterocyclic ring selected from the group:

where x is 0, 1, 2 or 3, where Rhand Rkdefined below in this section of the application.

In some embodiments embodiment Reand Rfcombined with the formation of 6-membered heterocyclic ring selected from the group:

where x is 0, 1, 2 or 3, where Rhand Rkdefined below in this section of the application.

However, in some embodiments of the incarnation, where G represents-NReRf, Reand Rfare not combined with education pyrrolidinyl, piperidinyl or sepanloo rings.

In some embodiments embodiment Reand Rfcombined with education 5-14-membered heteroaryl ring. In some embodiments embodiment Reand Rfcombined with education 5-14-membered heteroaryl ring is substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Reand Rfmerged to form a 5-10 membered heteroaryl ring is substituted by 0, 1, 2, 3, 4, or 5 groups Rh. In some embodiments embodiment Reand Rfcombined with education 5-8-membered heteroaryl ring is substituted by 0, 1, 2, 3 or 4 groups R h. In some embodiments embodiment Reand Rfmerged to form a 5-6-membered heteroaryl ring is substituted by 0, 1, 2, 3 or 4 groups Rh. In some embodiments embodiment Reand Rfcombined with education 9-10-membered heteroaryl ring is substituted by 0, 1, 2, 3, 4, or 5 groups Rh.

In some embodiments embodiment Reand Rfcombined with the formation of 5-membered heteroaryl ring selected from:

where x is 0, 1 or 2, and Rhand Rkdefined below in this section of the application.

However, in some embodiments of the incarnation, where G represents-NRfRe, Reand Rfare not United with the formation of 1,2,4-triazoline rings, for example, of the formula:

where x is 0 or 1, and Rhshall have the meaning given below and in this section of the application.

In some embodiments embodiment Reand Rfcombined with the formation of 9-membered heteroaryl (“5,6-bicyclic heteroaryl”) ring, selected from:

where x is 0, 1, 2 or 3, and Rhand Rkdefined below in this section of the application.

Deputy Group G

Variants of the embodiment Rh

As the term COI the box is used above and in the present raslila applications in each case, Rhindependently selected from halogen (fluorine (-F), bromo (-Br), chloro (-Cl) and iodine (I)), -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORi, -ON(Rk)2, -N(Rk)2, -N(Rk)3+X-, -N(ORjRk, -SH, -SRi, -SSRj, -C(=O)Ri, -CO2H, -CHO, -CO2Ri, -OC(=O)Ri, -OCO2Ri, -C(=O)N(Rk)2, -OC(=O)N(Rk)2, -NRkC(=O)Ri, -NRkCO2Ri, -NRkC(=O)N(Rk)2, -C(=NRkRi, -C(=NRkORi, -OC(=NRkRi, -OC(=NRkORi, -C(=NRk)N(Rk)2, -OC(=NRk)N(Rk)2, -NRkC(=NRk)N(Rk)2, -C(=O)NRkSO2Ri, -NRkSO2Ri, -SO2N(Rk)2, -SO2Ri, -SO2ORi, -OSO2Ri, -S(=O)Ri, -OS(=O)Ri, -Si(Ri)3, -OSi(Ri)3-C(=S)N(Rk)2, -C(=O)SRi, -C(=S)SRi, -SC(S)SRi, -P(=O)2Ri, -OP(=O)2Ri, -P(=O)(Ri)2, -OP(=O)(Ri)2, -OP(=O)(OR)2, -P(=O)2N(Rk)2, -OP(=O)2N(Rk)2, -P(=O)(NRk)2, -OP(=O)(NRk)2, -NRkP(=O)(ORj)2, -NRkP(=O)(NRk)2, -P(Rj)2, -P(Rj)3, -OP(Rj)2, -OP(Rj)3, -B(ORj)2, -BRi(ORj), C1-10of alkyl, C 1-10perhalogenated, C2-10alkenyl, C2-10the quinil, C3-14carbocycle, 3-14-membered heterocyclyl, C6-14aryl and 5-14-membered heteroaryl, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rm;

in each case, Riindependently selected from C1-10of alkyl, C1-10perhalogenated, C2-10alkenyl, C2-10the quinil, C3-10carbocycle, 3-14-membered heterocyclyl, C6-14aryl and 5-14-membered heteroaryl, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rm;

in each case, Rkindependently selected from hydrogen, -OH, -ORi, -N(Rj)2, -CN, -C(O)Ri, -C(=O)N(Rj)2, -CO2Ri, -SO2Ri, -C(=NRjORi, -C(=NRj)N(Rj)2, -SO2N(Rj)2, -SO2Rj, -SO2ORj, -SORi, -C(=S)N(Rj)2, -C(=O)SRj, -C(=S)SRj, -P(=O)2Ri, -P(=O)(Ri)2, -P(=O)2N(Rj)2, -P(=O)(NRj)2C1-10of alkyl, C1-10perhalogenated, C2-10alkenyl, C2-10the quinil, C3-10carbocycle, 3-14-membered heterocyclyl, C6-14aryl and 5-14-membered heteroaryl, or two Rj groups associated with N and the Ohm, combined with education 3-14-membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rm;

in each case, Rjindependently selected from hydrogen, C1-10of alkyl, C1-10perhalogenated, C2-10alkenyl, C2-10the quinil, C3-10carbocycle, 3-14-membered heterocyclyl, C6-14aryl and 5-14-membered heteroaryl, or two Rj groups associated with the N atom combined with education 3-14-membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rm;

in each case, Rmindependently selected from fluorine (F), bromine (-Br), chlorine (-Cl) and iodine (I), -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORo, -ON(Rn)2, -N(Rn)2, -N(Rn)3+X-, -N(ORo)Rn, -SH, -SR0, -SSR0, -C(O)R0, -CO2H, -CO2R0, -OC(O)R0, -OCO2R0, -C(=O)N(Rn)2, -OC(=O)N(Rn)2, -NRnC(=O)R0, -NRnCO2R0, -NRnC(=O)N(Rn)2, -C(=NRnOR0, -OC(=NRnR0, -OC(=NRnOR0, -C(=NRn)N(Rn)2, -OC(=NRn)N(Rn)2, -NRnC(=NRn)N(R n)2, -NRnSO2R0, -SO2N(Rn)2, -SO2R0, -SO2OR0, -OSO2R0, -S(=O)R0, -Si(R0)3, -OSi(R0)3, -C(=S)N(Rn)2, -C(+O)SR0, -C(=S)SR0, -SC(=S)SR0, -P(=O)2R0, -P(=O)(R0)2, -OP(=O)(R0)2, -OP(=O)(OR0)2C1-6of alkyl, C1-6perhalogenated, C2-6alkenyl, C2-6the quinil, C3-10carbocycle, 3-14-membered heterocyclyl, C6-14aryl, 5-14-membered heteroaryl, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 Rp groups, or two Rmadjacent substituent can be merged to form =O or =S;

in each case, R0independently selected from C1-6of alkyl, C1-6perhalogenated, C2-6alkenyl, C2-6the quinil, C3-10carbocycle, C6-10aryl, 3-10-membered heterocyclyl and 3-10-membered heteroaryl, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rp;

in each case, Rnindependently selected from hydrogen, C1-6of alkyl, C1-6perhalogenated, C2-6alkenyl, C2-6the quinil, C3-10carbocycle, 3-10-membered heterocyclyl, C6-10aryl and 5-10-membered heteroaryl is, or two Rngroups associated with the N atom combined with education 3-14-membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rp; and

in each case, Rpindependently represents a fluorine (-F), bromo (-Br), chloro (-Cl) and iodine (I), -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6alkyl, -ON(C1-6alkyl)2, -N(C1-6alkyl)2, -N(C1-6alkyl)3X, -NH(C1-6alkyl)2X, -NH2(C1-6alkyl)X, -NH3X, -N(OC1-6alkyl)(C1-6alkyl), -N(OH)(C1-6alkyl), -NH(OH), -SH, -SC1-6alkyl, -SS(C1-6alkyl), -C(=O)(C1-6alkyl), -CO2H, -CO2(C1-6alkyl), -OC(=O)(C1-6alkyl), -OCO2(C1-6alkyl), -C(=O)NH2, -C(=O)N(C1-6alkyl)2, -OC(=O)NH(C1-6alkyl), -NHC(=O)(C1-6alkyl), -N(C1-6alkyl)C(=O)(C1-6alkyl), -NHCO2(C1-6alkyl), -NHC(=O)N(C1-6alkyl)2, -NHC(=O)NH(C1-6alkyl), -NHC(=O)NH2-C(=NH)O(C1-6alkyl), -OC(=NH)(C1-6alkyl), -OC(=NH)OC1-6alkyl, -C(=NH)N(C1-6alkyl)2-C(=NH)NH(C1-6alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6alkyl)2, -OC(NH)NH(C1-6alkyl), -OC(NH)NH2, -NHC(NH)N(C1-6alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-6alkyl), -SO2N(C1-6alkyl)2, -SO2NH(C 1-6alkyl), -SO2NH2-SO2C1-6alkyl, -SO2OC1-6alkyl, -OSO2C1-6alkyl, -SOC1-6alkyl, -Si(C1-6alkyl)3, -Osi(C1-6alkyl)3-C(=S)N(C1-6alkyl)2C(=S)NH(C1-6alkyl), C(=S)NH2, -C(=O)S(C1-6alkyl), -C(=S)SC1-6alkyl, -SC(=S)SC1-6alkyl, -P(=O)2(C1-6alkyl), -P(=O)(C1-6alkyl)2, -OP(=O)(C1-6alkyl)2, -OP(=O)(OC1-6alkyl)2C1-6alkyl, C1-6perhalogenated, C2-6 of alkenyl, C2-6 quinil, C3-10carbocyclic, C6-14aryl, 3-14 membered heterocyclyl, 5-14-membered heteroaryl; or two adjacent substituent Rp can be merged to form =O or =S;

where X-is a counterion.

In some embodiments embodiment Rhselected from fluorine (F), bromine (-Br), chlorine (-Cl) and iodine (I), -CN, -NO2, -OH, -ORi, -SRi, -SO2H, -SO3H, -N(Rk)2, -N(Rk)3+X-, -C(O)Ri, -CO2H, -CHO, -CO2Ri, -OC(O)Ri, -OCO2Ri, -C(=O)N(Rk)2, -OC(=O)N(Rk)2, -NRkC(=O)Ri, -NRkCO2Ri, -NRkC(=O)N(Rk)2, -C(=NRkRi, -C(=NRkORi, -OC(=NRkRi, -OC(=NRkORi, -C(=NRk)N(Rk)2, -OC(=NRk)N(Rk)2, -NRkC(=NRk)N(Rk)2, -C(ONR kSO2Ri, -NRkSO2Ri, -SO2N(Rk)2, -SO2Ri, -SO2ORi, -OSO2Ri, -S(=O)Ri, -OS(=O)Ri, -C(=S)N(Rk)2, -C(=O)SRi, -C(=S)SRi, -SC(S)SRi, -P(=O)2Ri, -OP(=O)2Ri, -P(=O)(Ri)2, -OP(=O)(Ri)2, -OP(=O)(ORj)2, - P(=O)2N(Rk)2, -OP(=O)2N(Rk)2, -P(=O)(NRk)2, -OP(=O)(NRk)2, -NRkP(=O)(ORj)2, - NRkP(=O)(NRk)2, -B(ORj)2, -BR(ORj), C1-10of alkyl, -C1-10perhalogenated, C3-14carbocycle, 3-14-membered heterocyclyl, C6-14aryl and 5-14-membered heteroaryl, where each alkyl, carbocycle, heterocyclyl, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rm; and where X-is a counterion.

In some embodiments embodiment Rhselected from fluorine (F), bromine (-Br), chlorine (-Cl) and iodine (I), -CN, -NO2, -OH, -ORi, -SRi, -N(Rk)2, -N(Rk)3+X-, -C(=O)Ri, -CO2Ri, -CO2H, -OC(=O)Ri, -OCO2Ri, -C(=O)N(Rk)2, -OC(=O)N(Rk)2, -NRkC(=O)Ri, -NRkCO2Ri, - NRkC(=O)N(Rk)2, -C(=O)NRkSO2Ri, -NRkSO2Ri, -SO2N(Rk)2, -SO2Ri1-10of alkyl, C6aryl and 5-6 membered heteroaryl, where each alkyl, aryl and heteroaryl independently substituted by 0, 1, 2, 3 or 4 groups Rm; and where X-is a counterion.

In some embodiments embodiment Rhrepresents-ORifor example, selected from-OCH3, -OCF3, -OCH2CH3, -OCH2CF3, -OiPr and-OnBu.

In some embodiments embodiment Rhrepresents-SRifor example, selected from SCH3.

In some embodiments embodiment Rhrepresents-N(Rk)2or-N(Rk)3+X-for example, selected from-NH2and - NH3+X-.

In some embodiments embodiment Rhrepresents-C(=O)Rifor example, selected from-C(=O)CH3.

In some embodiments embodiment Rhrepresents-CO2ifor example, selected from-CO2CH3

In some embodiments embodiment Rhrepresents-C(=O)N(Rk)2for example, selected from-C(=O)NHOH - C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHCH2CH3, -C(=O)NHCH2CF3, -C(=O)NH(CH2)1-6NH3+X-, -C(=O)NHCH2C(=O)OCH3, -C(=O)NHCH2C(=O)OH and - C(=O)NHCH2CH2OH.

In some embodiments embodiment Rhrepresents-OC(=O)Rifor example, select the from-OC(=O)CH 3.

In some embodiments embodiment Rhrepresents-OCO2Rifor example, selected from-OCO2CH3.

In some embodiments embodiment Rhrepresents-OC(=O)N(Rk)2for example, selected from-OC(=O)NH2.

In some embodiments embodiment Rhrepresents-NRkC(=O)Rifor example, selected from-NHC(=O)CH3.

In some embodiments embodiment Rhrepresents-NRkCO2Rifor example, selected from-NHC(=O)OCH3and - NHC(=O)OtBu.

In some embodiments embodiment Rhrepresents-NRkC(=O)N(Rk)2for example, selected from-NHC(=O)NH2.

In some embodiments embodiment Rhrepresents-C(=O)NRkSO2Rifor example, selected from - C(=O)NHSO2CH3, -C(=O)NHSO2CH2CH3, -C(=O)NHSO2C5H9and-C(=O)NHSO2iBu.

In some embodiments embodiment Rhrepresents-NRkSO2Rifor example, selected from NHSO2CH3.

In some embodiments embodiment Rhrepresents-SO2N(Rk)2for example, selected from-SO2NH2, - SO2N(CH3)2.

In some embodiments embodiment Rhrepresents-SO2Rifor example, selected from-SO2CH3, -SO2CH2CH3,- SO 2C5H9and-SO2iBu.

In some embodiments embodiment Rhrepresents a C1-10alkyl, for example, selected from-CH3, -CH2CH3, -iPr, -nBu, -CF3, -CH2CH2CO2Me, -CH2CH2CO2H and-CH2CH2CO2NH2.

In some embodiments embodiment Rhselected from-C(=O)Ri, -CO2H and-SO2Ri. In some embodiments embodiment Rhrepresents-C(=O)Ri. In some embodiments embodiment Rhrepresents-SO2Ri. In some embodiments embodiment Rhrepresents-CO2H or-SO2CH3. In some embodiments embodiment Rhrepresents-CO2H. In some embodiments embodiment Rhrepresents-SO2CH3.

In some embodiments, embodiments in each case, Rhindependently selected from fluorine (F), bromine (-Br), chlorine (-Cl), iodine (I)- NH2, -NH3+X-, -CN, -NO2, -SO2CH3, - SO2CH2CH3, -SO2C5H9, -SO2iBu, -SO2NH2, -SO2N(CH3)2, -C(=O)NHSO2CH3, -C(=O)NHSO2CH2CH3, -C(=O)NHSO2C5H9, -C(=O)NHSO2iBu, -C(=O)CH3, -CO2H, - CO2CH3, -OC(=O)CH3, -OCO2CH3, -C(=O)NHOH,-C(=O)NH2, -C(=O)NHCH3, (=O)N(CH 3)2, -C(=O)NHCH2CH3, -C(=O)NHCH2CF3-C(=O)NH(CH2)1-6NH3+X-, -OC(O)NH2, -NHC(=O)CH3, -NHC(=O)OCH3, -NHC(=O)OtBu, -NHC(=O)NH2, -NHSO2CH3, -CH3, -CH2CH3, -iPr, -nBu, -CF3, -OH, -OCH3, -SCH3, -OCF3, -OCH2CH3, -OCH2CF3, -OiPr, -OnBu, -CH2CH2CO2Me, -CH2CH2CO2H, -CH2CH2CO2NH2C(=O)NHCH2C(=O)OCH3, -C(=O)NHCH2C(=O)OH, -C(=O)NHCH2CH2OH, C6aryl, substituted by 0, 1 or 2 groups Rmand 5-6-membered heteroaryl, substituted by 0, 1 or 2 groups Rm; and where X-is a counterion.

In some embodiments embodiment Rhrepresents a C6aryl (e.g. phenyl), substituted by 0, 1 or 2 groups Rm. In some embodiments embodiment Rhrepresents a C6aryl (e.g. phenyl), substituted by 1 group, Rmand Rmrepresents-CO2H, -CO2CH3, -CO2CH2CH3and-C(=O)NH2.

In some embodiments embodiment Rhis a 5-6-membered heteroaryl, substituted by 0, 1 or 2 groups Rm. In some embodiments embodiment Rhrepresents a 5-membered heteroaryl, substituted by 0, 1 or 2 groups Rm. Examples of 5-membered heteroaryl groups of Rhinclude who, but not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl, where such groups substituted by 0 or 1 group, Rm. In some embodiments embodiment Rhrepresents a 5-membered heteroaryl group selected from pyrazolyl and oxadiazolyl, where such groups substituted by 0 or 1 group, Rm.

Variants of the embodiment Ri

In some embodiments, embodiments in each case, Riindependently selected from C1-10of alkyl, C1-10perhalogenated, C2-10alkenyl, C2-10the quinil, C3-10carbocycle, 3-14-membered heterocyclyl, C6-14aryl and 5-14-membered heteroaryl, where each alkyl, carbocycle, heterocyclyl, aryl and heteroaryl is unsubstituted.

In some embodiments embodiment Rirepresents unsubstituted C1-10alkyl. In some embodiments embodiment Rirepresents a C1-10perhalogenated. In some embodiments embodiment Rirepresents unsubstituted C2-10alkenyl. In some embodiments embodiment Rirepresents unsubstituted C2-10quinil. In some embodiments embodiment Rirepresents unsubstituted C3-10carbocyclic. In some embodiments of the embodiment is ia R irepresents unsubstituted 3-14 membered heterocyclyl. In some embodiments embodiment Rirepresents unsubstituted C6-14aryl. In some embodiments embodiment Rirepresents unsubstituted 5 to 14-membered heteroaryl.

Variants of the embodiment Rm

In some embodiments, embodiments in each case, Rmindependently selected from fluorine (F), bromine (-Br), chlorine (-Cl) and iodine (I), -CN, -NO2, -SO2H, -SO3H, -OH, -ORo, -ON(Rn)2, -N(Rn)2, -N(Rn)3+X-, -N(ORo)Rn, -SH, -SRo, -SSRo, -C(=O)Ro, -CO2H, -CO2Ro, -OC(=O)Ro, -OCO2Ro, -C(=O)N(Rn)2, -OC(=O)N(Rn)2, -NRnC(=O)Ro, -NR11CO2Ro, -NRnC(=O)N(Rn)2, -C(=NRn)ORo, -OC(=NRnRo, -OC(=NRn)ORo, -C(=NRn)N(Rn)2, -OC(=NRn)N(Rn)2, -NRnC(=NRn)N(Rn)2, -NRnSO2R°, -SO2N(Rn)2, -SO2Ro, -SO2ORo, -OSO2Ro, -S(=O)Ro, -C(=S)N(Rn)2, -C(=O)SRo, -C(=S)SRo, -SC(=S)SRo, -P(=O)2Ro, -P(=O)(Ro)2, -OP(=O)(Ro)2, -OP(=O)(ORo)2C1-6of alkyl, C1-6perhalogenated, C3-10carbocycle, 3-14-membered heterocyclyl, C6-14aryl, 5-14 membered heteros is aryl, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rp.

In some embodiments, embodiments in each case, Rmindependently selected from fluorine (F), bromine (-Br), chlorine (-Cl) and iodine (I), -CN, -NO2, -SO2H, -SO3H, -OH, -ORo, -ON(Rn)2, -N(Rn)2, -N(Rn)3+X-, -N(ORo)Rn, -SH, -SRo, -SSRo, -C(=O)Ro, -CO2H, -CO2Ro, -OC(=O)Ro, -OCO2Ro, -C(=O)N(Rn)2, -OC(=O)N(Rn)2, -NRnC(=O)Ro, -NRnCO2Ro, -NRnC(=O)N(Rn)2, -C(=NRn)ORo, -OC(=NRnRo, -OC(=NRn)ORo, -C(=NRn)N(Rn)2, -OC(=NRn)N(Rn)2, -NRnC(=NRn)N(Rn)2, -NRnSO2Ro, -SO2N(Rn)2, -SO2Ro, -SO2ORo, -OSO2Ro, -S(=O)Ro, -C(=S)N(Rn)2, -C(=O)SRo, -C(=S)SRo, -SC(=S)SRo, -P(=O)2Ro, -P(=O)(Ro)2, -OP(=O)(Ro)2, -OP(=O)(ORo)2C1-6of alkyl, C1-6perhalogenated, C3-10carbocycle, 3-14-membered heterocyclyl, C6-14aryl, 5-14-membered heteroaryl.

In some embodiments embodiment Rmselected from fluorine (F), bromine (-Br), chlorine (-Cl) and iodine (I)- NH2, -NH3+X-, -CN, -NO2, -SO2H 3, -SO2CH2CH3, -SO2C5H9, -SO2iBu, -SO2NH2, -SO2N(CH3)2,-C(=O)NHSO2CH3, -C(=O)NHSO2CH2CH3,-C(=O)NHSO2C5H9,-C(=O)NHSO2iBu, -C(=O)CH3, -CO2H, -CO2CH3, -OC(=O)CH3, -OCO2CH3, -C(=O)NHOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHCH2CH3, -C(=O)NHCH2CF3-, -C(=O)NH(CH2)1-6NH3+X-, -OC(O)NH2, -NHC(=O)CH3, -NHC(=O)OCH3, -NHC(=O)OtBu, -NHC(=O)NH2, -NHSO2CH3, -CH3, -CH2CH3, -iPr, -nBu, -CF3, -OH, -OCH3, -OCF3, -OCH2CH3, -OCH2CF3, -OiPr, -OnBu, -CH2CH2CO2Me, -CH2CH2CO2H, -CH2CH2CO2NH2, -C(=O)NHCH2C(=O)OCH3, -C(=O)NHCH2C(=O)OH and-C(=O)NHCH2CH2OH.

Variants of the embodiment Rk

As used above and in this section of the application, in each case, Rkindependently selected from-H, -OH, -ORi, -N(Rk)2, -C(=O)Ri, -C(=O)N(Rk)2, -CO2Ri, -SO2Ri, -C(=NRkRi, -C(=NRkORi, -C(=NRk)N(Rk)2, -SO2N(Rk)2, -SO2Ri, -SO2ORi, -SORi, -C(=S)N(Rk)2, -C(=O)SRi, -C(=S)SRiC1-10alkyl (for example, aralkyl the Noi), C2-10alkenylphenol, C2-10alkenylphenol, C3-10carbocyclic, 3-14-membered heterocyclic, C6-14aryl and 5-14 membered heteroaryl group, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aralkyl, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rmwhere Ri, Rk, Rmhave the meaning given above and in this section of the application.

In some embodiments, embodiments in each case, Rkindependently selected from-H, -C(=O)Ri, -C(=O)ORi, -SO2Rior C1-6the alkyl. In some embodiments, embodiments in each case, Rkindependently selected from-H or C1-6the alkyl. In some embodiments, embodiments in each case, Rkindependently selected from-H and-CH3. In some embodiments, embodiments in each case, Rkindependently selected from a-H. In some embodiments, embodiments in each case, Rkindependently selected from-CH3.

Group RaRband Rc

In General, as defined above, when Rdrepresents a group-L-Z, each of Ra, Rband Rcindependently selected from-H, C1-10the alkyl and C1-10perhalogenated.

In some embodiments, embodiments each of Ra, Rband Rcindependently selected from-H, C1-6the alkyl and C1-6perhalogenated. is some embodiments, embodiments each of R a, Rband Rcindependently selected from-H, C1-3the alkyl and C1-3perhalogenated. In some embodiments, embodiments each of Ra, Rband Rcindependently selected from-H, -CH3, -CH2CH3and-CF3. In some embodiments, embodiments each of Ra, Rband Rcindependently selected from-H, -CH3and-CF3.

In some embodiments embodiment Raand Rbare H, and Rcselected from C1-3the alkyl and C1-3perhalogenated. In some embodiments embodiment Raand Rbare H, and Rcselected from-CH3and-CF3. In some embodiments, embodiments, Raand Rbare H, and Rcrepresents-CH3. In some embodiments embodiment Raand Rbare H, and Rcrepresents-CF3.

In some embodiments embodiment Rband Rcare H, and Raselected from C1-3the alkyl and C1-3perhalogenated. In some embodiments embodiment Rband Rcare H, and Raselected from-CH3and-CF3. In some embodiments, embodiments, Rband Rcare H, and Rarepresents-CH3. In some embodiments embodiment Rband Rcare H, and Rapresent is employed, a-CF 3.

In some embodiments, embodiments each of Ra, Rband Rcindependently selected from H, - CH3and-CF3. In some embodiments, embodiments each of Ra, Rband Rcindependently selected from H or-CH3. In some embodiments, embodiments each of Ra, Rband Rcrepresents H.

The group Rd

In General, as defined above, in some embodiments embodiment Rdrepresents a group-L-Z, where L is a covalent bond or a divalent C1-6hydrocarbon group, where one, two or three methylene link in L optionally and independently replaced by one or more oxygen atoms, sulfur or nitrogen, and

Z is selected from C6-10aryl, 3-14 membered heterocyclyl or a 5-14-membered heteroaryl.

Group L from Rd

In General, as defined above, L is a covalent bond or a divalent C1-6hydrocarbon group, where one, two or three methylene link in L optionally and independently replaced by one or more oxygen atoms, sulfur or nitrogen.

In some embodiments of embodiment L represents a covalent bond.

In some embodiments of embodiment L represents a divalent C1-6hydrocarbon group, where one, two or three methylene link in L it is interesting and independently replaced by one or more oxygen atoms (-O-), sulfur (-S-) or nitrogen (for example, -NR1-).

In some embodiments of embodiment L represents a divalent C1-6hydrocarbon group, where one, two or three methylene link in L optionally and independently replaced by one or more oxygen atoms (-O-).

In some embodiments of embodiment L represents a divalent C1-6hydrocarbon group, where one, two or three methylene chain in L is not necessarily and independently replaced with one or more sulfur atoms (-S-).

In some embodiments of embodiment L represents a divalent C1-6hydrocarbon group, where one, two or three methylene link in L optionally and independently replaced by one or more nitrogen atoms (-NR1-). However, in some embodiments, embodiment, when L is a divalent C1-6hydrocarbon group containing one, two or three nitrogen atom, then L is an unsubstituted divalent C1-6hydrocarbon group, and L cannot represent a group-CH2NR1- where R1represents H, C1-6alkyl or amino-protective group.

In some embodiments of embodiment L represents a divalent C1-6hydrocarbon group, where one methylene link in L optionally and independently replaced by an oxygen atom, a sulfur sludge is nitrogen. In some embodiments of embodiment L represents a divalent C1-6hydrocarbon group, where one methylene link in L optionally and independently replaced by an oxygen atom. In some embodiments of embodiment L represents a divalent C1-6hydrocarbon group, where one methylene link in L optionally and independently replaced by a sulfur atom. In some embodiments of embodiment L represents a divalent C1-6hydrocarbon group, where one methylene link in L optionally and independently replaced by nitrogen atom.

In some embodiments of embodiment L, divalent C1-6the hydrocarbon group is an unsubstituted divalent C1-6hydrocarbon group. In some embodiments of embodiment L, divalent C1-6the hydrocarbon group contains one atom of oxygen, sulfur or nitrogen. In some embodiments, embodiments of divalent C1-6the hydrocarbon group is an unsubstituted divalent C1-6hydrocarbon group (for example, unsubstituted divalent C1-6alkyl group).

For example, in some embodiments of embodiment L represents an unsubstituted divalent C1-6alkyl group where one methylene link in L is replaced by oxygen atom, sulfur or nitrogen. In some embodiments, voploscheni the L is an unsubstituted divalent C 1-6alkyl group where one methylene link in L replaced by an oxygen atom. In some embodiments of embodiment L represents an unsubstituted divalent C1-6alkyl, where one methylene link in L is replaced by a sulfur atom. In some embodiments of embodiment L represents an unsubstituted divalent C1-6alkyl group where one methylene link in L is replaced by a nitrogen atom. However, in some embodiments, embodiment, when L is an unsubstituted divalent C1-6alkyl group, then L cannot represent a group-CH2NR1- where R1represents H, C1-6alkyl or amino-protective group.

In some embodiments of embodiment L represents a divalent C1hydrocarbon group, where one methylene link in L is replaced by oxygen atom, sulfur or nitrogen, for example, L is selected from oxygen (-O-), sulfur (-S-) or nitrogen (for example, -NR1-). In some embodiments of embodiment L represents oxygen (-O-). In some embodiments, embodiment, L represents sulfur (-S-). In some embodiments of embodiment L represents a nitrogen (for example, -NR1-).

In some embodiments of embodiment L is selected from the group comprising -(C(R10)2)m-, - (C(R11)2)m-O-(C(R12)2)n- -(C(R11)2)m-S-(CR 12)2)n- or -(C(R11)2)m-NR1-(C(R12)2)n-, where m and n independently have a value of 0, 1, 2, 3, 4, 5 or 6, and in each case, R10, R11and R12independently selected from H, halogen, or C1-6the alkyl. In some embodiments, embodiments each of R10, R11and R12is a-H.

In some embodiments of embodiment L represents -(C(R10)2)m-. In some embodiments of embodiment L is selected from-CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and - CH2CH2CH2CH2CH2CH2-.

In some embodiments of embodiment L represents -(C(R11)2)m-O-(C(R12)2)n-. In some embodiments of embodiment L is selected from-O-, -CH2O-, -OCH2-, -OCH2CH2-, -OCH2CH2- -OCH2CH2CH2-, - CH2CH2CH2O-, -CH2OCH2CH2- and-CH2CH2OCH2-.

In some embodiments of embodiment L represents -(C(R11)2)m-S-(C(R12)2)n-. In some embodiments of embodiment L is selected from-S-, -CH2S-, -SCH2-, -SCH2CH2-, -CH2CH2S-, -SCH2CH2CH2-, - CH2CH2CH2S-, -CH2SCH 2CH2- and-CH2CH2SCH2-.

In some embodiments of embodiment L represents -(C(R11)2)m-NR1-(C(R12)2)n-. In some embodiments, embodiments, L is selected from-NR1-, -CH2NR1-, -NR1CH2-, -NR1CH2CH2-, -CH2CH2NR1-, -NR1CH2CH2CH2-, -CH2CH2CH2NR1-, -CH2NR1CH2CH2- and-CH2CH2NR1CH2- where R1selected from H, C1-6the alkyl or amino-protective group.

In some embodiments embodiment R1selected from H or C1-6the alkyl. In some embodiments embodiment R1represents hydrogen. In some embodiments embodiment R1represents-CH3.

Variants of the embodiment, where the group Z of Rdrepresents aryl

In General, as defined above, in some embodiments embodiment Z represents C6-14aryl.

In some embodiments embodiment Z represents C6-14aryl. In some embodiments embodiment Z represents C6-14aryl. In some embodiments embodiment Z represents C6-14aryl, substituted by 0, 1, 2, 3, 4, or 5 groups R15. In some embodiments embodiment Z represents C6aryl (e.g. phenyl), substituted 0,1, 2, 3, 4, or 5 groups R15. In some embodiments embodiment Z represents C10aryl (e.g. naphthyl), substituted by 0, 1, 2, 3, 4, or 5 groups R15.

In some embodiments embodiment Z represents phenyl. In some embodiments embodiment Z represents phenyl, substituted with 0, 1, 2, 3 or 4 groups R15. In some embodiments embodiment Z represents phenyl, substituted with 0, 1, 2, or 3 groups R15. In some embodiments embodiment Z represents phenyl, substituted by 0, 1 or 2 groups R15. In some embodiments embodiment Z represents phenyl, substituted by 0 or 1 group, R15. In some embodiments, embodiments Z is a disubstituted phenyl (i.e., substituted 2 groups R15). In some embodiments, embodiments Z is a monosubstituted phenyl (i.e., substituted by 1 group, R15). In some embodiments embodiment Z represents unsubstituted phenyl (i.e., substituted 0 groups R15).

In some embodiments embodiment Z represents a phenyl substituted in at least one ortho group, R15. In some embodiments embodiment Z represents phenyl, substituted by at least one meta group, R15. In some embodiments embodiment Z represents phenyl, substituted, at least one pair of group R .

In some embodiments, embodiments Z is a monosubstituted phenyl, substituted one ortho group, R15. In some embodiments, embodiments Z is a monosubstituted phenyl, substituted one meta group, R15. In some embodiments, embodiments Z is a monosubstituted phenyl, substituted with one pair of group R15.

In some embodiments, embodiments Z is a disubstituted phenyl, substituted ortho group, R15and meta group, R15. In some embodiments, embodiments Z is a disubstituted phenyl, substituted ortho group, R15and a couple of group R15. In some embodiments, embodiments Z is a disubstituted phenyl, substituted meta group, R15and a couple of group R15. In some embodiments, embodiments Z is a disubstituted phenyl, substituted two meta-groups, R15.

In some embodiments embodiment Z represents a phenyl group of the formula:

where z is 0, 1, 2, 3, 4 or 5, and R15shall have the meaning given below and in this section of the application. In some embodiments embodiment z has the value 0, 1, 2, 3 or 4. In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments, is oblasenia z has the value 0 or 1. In some embodiments embodiment z has the value 3. In some embodiments, embodiments Z is a disubstituted phenyl group (i.e., where z has a value of 2). In some embodiments, embodiments Z is a monosubstituted phenyl group (i.e., where z has a value of 1). In some embodiments embodiment Z represents an unsubstituted phenyl group (i.e., where z has the value 0).

For example, in some embodiments embodiment Z represents a substituted or unsubstituted phenyl group, any of the following formulas:

where R15shall have the meaning given below and in this section of the application.

In some embodiments embodiment Z represents naphthyl. In some embodiments embodiment Z represents naftalina group any of the following formulas:

where z is 0, 1, 2, 3, 4 or 5, and R15shall have the meaning given below and in this section of the application. In some embodiments embodiment z has the value 0, 1, 2, 3 or 4. In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1. In some embodiments embodiment Z represents trisamino naftalina group (i.e., where z has a value of 3).In some embodiments, embodiments Z is a disubstituted naftalina group (i.e., where z has the value 2). In some embodiments, embodiments Z is a monosubstituted naftalina group (i.e., where z has a value of 1). In some embodiments embodiment Z represents unsubstituted naftalina group (i.e., where z has the value 0).

For example, in some embodiments embodiment Z represents a substituted or unsubstituted 1-naftalina group any of the following formulas:

where R15shall have the meaning given below and in this section of the application.

In some embodiments embodiment Z represents a substituted or unsubstituted 2-naftalina group any of the following formulas:

where R15shall have the meaning given below and in this section of the application.

Variants of the embodiment, where the Group Z of Rdrepresents heterocyclyl or heteroaryl

In General, as defined above, in some embodiments, embodiments Z is selected from 3-14-membered heterocyclyl and 5-14-membered heteroaryl.

In some embodiments embodiment Z represents a 5 to 14-membered heteroaryl. In some embodiments embodiment Z represents a 5-10 membered heteroaryl, substituted by 0, 1, 2, 3, 4, or 5 groups R15. In some embodiments embodiment Z represents a 5-8-membered, heteroa the sludge, substituted by 0, 1, 2, 3, 4, or 5 groups R15. In some embodiments, embodiments Z is a 5-6-membered heteroaryl, substituted by 0, 1, 2, 3 or 4 groups R15. In some embodiments, embodiments Z is a 9-10-membered heteroaryl, substituted by 0, 1, 2, 3, 4, or 5 groups R15.

Examples of heteroaryl groups Z include, but are not limited to, pyrrolyl, furanyl and thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyridazinyl (for example, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl, tetrazines, azepine, oxepin, tiepins, indolyl, isoindolyl, indazoles, benzotriazolyl, benzothiophene, isobenzofuranyl, benzofuranyl, benzothiophenes, benzimidazoles, benzoxazoles, benzisoxazole, benzoxadiazole, benzothiazolyl, benzisothiazole, benzothiazolyl, indolizinyl, purinol, naphthyridine, pteridine, chinoline, ethenolysis, cinnoline, honokalani, phthalazine, hintline, phenanthridines, dibenzofurans, carbazoles, acridines, phenothiazinyl, phenoxazines and phenazines, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups R15.

In some embodiments embodiment Z represents-membered heteroaryl, substituted by 0, 1, 2, or 3 groups R15. In some embodiments embodiment Z represents a 5-membered heteroaryl selected from pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl, where such groups are substituted by 0, 1, 2, or 3 groups R15.

For example, in some embodiments embodiment Z represents a 5-membered heteroaryl formula:

where Y1, Y2, Y3and Y4independently selected from CH, CR15, O, S, N or NR18provided that at least one of the Y1, Y2, Y3and Y4selected from O, S, N or NR18and where R15and R18have the meanings given below in this section of the application.

In some embodiments, the embodiments presented above formula (ii-d), Y1represents O, S or NR18and Y2, Y3and Y4independently selected from CH, CR15or N. In some embodiments, the embodiments presented above formula (ii-d), Y1represents O, S or NR18and Y2, Y3and Y4independently selected from CH or CR15. In some embodiments, the embodiments presented above formula (ii-d), Y1represents O, S or NR18, Y3represents N and Y2and Y4not avisio selected from CH or CR 15. In some embodiments, the embodiments presented above formula (ii-d), Y1represents S, Y3represents N and Y2and Y4represent CH or CR15. In some embodiments, the embodiments presented above formula (ii-d), Y1represents S, Y3represents N, Y2represents CR15and Y4represents CH. In some embodiments, the embodiments presented above formula (ii-d), Y1represents S and Y2, Y3and Y4represent CH or CR15.

In some embodiments, the embodiments presented above formula (ii-d), Y2represents O, S or NR18and Y1, Y3and Y4independently selected from CH, CR15or N. In some embodiments, the embodiments presented above formula (ii-d), Y2represents O, S or NR18and Y1, Y3and Y4independently selected from CH or CR15. In some embodiments, the embodiments presented above formula (ii-d), Y2represents O, S or NR18, Y4represents N and Y1and Y3independently selected from CH or CR15.

In some embodiments embodiment Z represents a 5-membered heteroaryl any of the following formulas:

where R15and R18defined below and nastojashem the section of the application and z is 0, 1 or 2,

where z is 0, 1 or 2, and R15and R18defined below in this section of the application. In some embodiments embodiment Z represents an unsubstituted 5-membered heteroaryl (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted 5-membered heteroaryl (for example, where z has a value of 1 or 2). In some embodiments, embodiments Z is a monosubstituted 5-membered heteroaryl (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted 5-membered heteroaryl (i.e., where z has a value of 2). In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents a 6-membered heteroaryl, substituted by 0, 1, 2, 3 or 4 groups Rh. In some embodiments embodiment Z represents a 6-membered heteroaryl selected from the group comprising pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyridazinyl (for example, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl and tetrazini, where such groups are substituted by 0, 1, 2, 3 or 4 groups R15.

For example, in some embodiments embodiment Rerepresents a 6-membered heteroaryl the th group of the formula:

where W1, W2, W3, W4and W5independently selected from CH, CR15or N, provided that at least one of W1, W2, W3, W4and W5represents N, and where R15shall have the meaning given below and in this section of the application.

In some embodiments embodiment Z represents pyridinyl group. In some embodiments embodiment Z represents pyridinyl group, substituted by 0, 1, 2, 3 or 4 groups R15. For example, in some embodiments embodiment Z represents pyridinyl group of the formula:

where z is 0, 1, 2, 3 or 4, and R15shall have the meaning given below and in this section of the application. In some embodiments embodiment Z represents unsubstituted pyridinyl (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted pyridinyl (e.g., where z has a value of 1, 2, 3 or 4). In some embodiments, embodiments Z is a monosubstituted pyridinyl (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted pyridinyl (i.e., where z has a value of 2). In some embodiments embodiment Z represents tizamidine pyridinyl (i.e., where z has a value of 3). In some vari is ntah embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents a 2-pyridinyl group, for example, formula (ii-e), where W1represents N, and W2, W3, W4and W5independently represent CH or CR15. In some embodiments embodiment Z represents a 3-pyridinyl group, for example, formula (ii-e), where W2represents N, and W1, W3, W4and W5independently represent CH or CR15. In some embodiments embodiment Z represents a 4-pyridinyl group, for example, formula (ii-e), where W3represents N, and W1, W2, W4and W5independently represent CH or CR15.

In some embodiments embodiment Rerepresents a substituted or unsubstituted 2-pyridinyl group any of the following formulas:

where R15shall have the meaning given below and in this section of the application.

In some embodiments embodiment Z represents a substituted or unsubstituted 3-pyridinyl group any of the following formulas:

where R15shall have the meaning given below and in the us oasam section of the application.

In some embodiments embodiment Z represents a substituted or unsubstituted 4-pyridinyl group of the formula:

where R15shall have the meaning given below and in this section of the application.

In some embodiments embodiment Z represents pyridazinyl group. In some embodiments embodiment Z represents pyridazinyl group, substituted by 0, 1, 2, or 3 groups R15. For example, in some embodiments embodiment Z represents pyridazinyl group of the formula:

where z is 0, 1, 2 or 3, and R15shall have the meaning given below and in this section of the application. In some embodiments embodiment Z represents an unsubstituted pyridazinyl (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted pyridazinyl (for example, where z is 1, 2 or 3). In some embodiments, embodiments Z is a monosubstituted pyridinyl (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted pyridinyl (i.e., where z has a value of 2). In some embodiments embodiment Z represents tizamidine pyridazinyl (i.e., where z has a value of 3). In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments, the GP is osenia z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents a 3-pyridazinyl group, for example, formula (ii-e), where W1and W2represent N, and W3, W4and W5independently represent CH or CR15. In some embodiments embodiment Z represents a 4-pyridazinyl group, for example, formula (ii-e), where W2and W3represent N, and W1, W4and W5independently represent CH or CRh.

In some embodiments embodiment Z represents a substituted or unsubstituted 3-pyridazinyl group any of the following formulas:

where R15shall have the meaning given below and in this section of the application.

In some embodiments embodiment Z represents a substituted or unsubstituted 4-pyridazinyl group any of the following formulas:

where R15shall have the meaning given below and in this section of the application.

In some embodiments embodiment Z represents pyrimidinyl group. In some embodiments embodiment Z represents pyrimidinyl group, substituted by 0, 1, 2, or 3 groups R15. For example, in some embodiments embodiment Z represents pyrimidinyl GRU is PU formula:

where z is 0, 1, 2 or 3, and R15shall have the meaning given below and in this section of the application. In some embodiments embodiment Z represents an unsubstituted pyrimidinyl (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted pyrimidinyl (for example, where z is 1, 2 or 3). In some embodiments, embodiments Z is a monosubstituted pyrimidinyl (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted pyridinyl (i.e., where z has a value of 2). In some embodiments embodiment Z represents tizamidine pyrimidinyl (i.e., where z has a value of 3). In some embodiments, embodiments, z is 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents a 2-pyrimidinyl group, for example, formula (ii-e), where W1and W5represent N, and W2, W3and W4independently represent CH or CR15. In some embodiments embodiment Z represents a 4-pyrimidinyl group, for example, formula (ii-e), where W1and W3represent N, and W2, W4and W5independently represent CH or CR 15. In some embodiments embodiment Z represents a 5-pyrimidinyl group, for example, formula (ii-e), where W2and W4represent N, and W1, W3and W5independently represent CH or CR15.

In some embodiments embodiment Z represents a 2-pyrimidinyl group any of the following formulas:

where R15shall have the meaning given below and in this section of the application.

In some embodiments embodiment Reis a 4-pyrimidinyl group any of the following formulas:

where R15shall have the meaning given below and in this section of the application.

In some embodiments embodiment Z represents a 5-pyrimidinyl group any of the following formulas:

where R15shall have the meaning given below and in this section of the application.

In some embodiments embodiment Z represents personilnya group. In some embodiments embodiment Z represents personilnya group, substituted by 0, 1, 2, or 3 groups R15. For example, in some embodiments embodiment Z represents personilnya group of the formula:

where z is 0, 1, 2 or 3, and R15has is definitely the below and in this section of the application. In some embodiments embodiment Z represents an unsubstituted pyrazinyl (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted pyrazinyl (for example, where z is 1, 2 or 3). In some embodiments, embodiments Z is a monosubstituted pyrazinyl (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted pyrazinyl (i.e., where z has a value of 2). In some embodiments embodiment Z represents tizamidine pyrazinyl (i.e., where z has a value of 3). In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents personilnya group any of the following formulas:

where R15shall have the meaning given below and in this section of the application.

In some embodiments embodiment Z represents triazinyl group. In some embodiments embodiment Z represents triazinyl group, substituted by 0, 1 or 2 groups R15. For example, in some embodiments embodiment Z represents triazinyl group of the formula:

where z is 0, 1 or 2, and R15has, specified below and in this section of the application. In some embodiments embodiment Z represents an unsubstituted pyrazinyl (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted pyrazinyl (for example, where z has a value of 1 or 2). In some embodiments, embodiments Z is a monosubstituted pyrazinyl (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted pyrazinyl (i.e., where z has a value of 2). In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents a substituted or unsubstituted triazinyl group any of the following formulas:

where R15shall have the meaning given below and in this section of the application.

In some embodiments embodiment Z represents thetrainline group. In some embodiments embodiment Z represents thetrainline group, substituted by 0 or 1 groups, R15. For example, in some embodiments embodiment Z represents thetrainline group of the formula:

where z is 0 or 1, and R15shall have the meaning given below and in this section of the application. In some embodiments Z represents an unsubstituted pyrazinyl (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted pyrazinyl (for example, where z has a value of 1). In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents thetrainline group any of the following formulas:

where R15shall have the meaning given below and in this section of the application.

In some embodiments, embodiments Z is a 9-membered heteroaryl (for example, 5,6-bicyclic heteroaryl). In some embodiments embodiment Z represents a 5,6-bicyclic heteroaryl, substituted by 0, 1, 2, 3, 4, or 5 groups R15. In some embodiments embodiment Z represents a 5,6-bicyclic heteroaryl selected from indolyl, isoindolyl, indazole, benzotriazole, benzothiophene, isobenzofuranyl, benzofuranyl, benzothiophene, benzimidazole, benzoxazole, benzisoxazole, benzoxadiazole, benzothiazolyl, benzisothiazole, benzothiadiazole, indolizinyl and purine, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups R15.

For example, in some embodiments embodiment Z represents a 5,6-bicyclic heteroaryl formula:

where Y5, Y6, Y7, Y9, Y10, Y11and Y12independent PR is astavliaut a C CH, CR15, O, S, N or NR18and Y13represents C or N, provided that at least one of the Y5, Y6, Y7selected from O, S, N or NR18and where R15and R18defined in this application.

In some embodiments embodiment Z represents a 5,6-bicyclic heteroaryl group of the formula (ii-f), where Y5selected from O, S or NR18, Y13is a C, and Y6, Y7, Y9, Y10, Y11and Y12independently represents C, CH or CR15. For example, in some embodiments embodiment Z represents a 5,6-bicyclic heteroaryl group of the formula:

where z is 0, 1, 2, 3, 4 or 5, and R15and R18have the meanings given below in this section of the application. In some embodiments embodiment Z represents unsubstituted 5,6-bicyclic heteroaryl (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted 5,6-bicyclic heteroaryl (for example, where z has a value of 1, 2, 3, 4 or 5). In some embodiments, embodiments Z is a monosubstituted 5,6-bicyclic heteroaryl (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted 5,6-bicyclic heteroaryl (i.e., where z has a value of 2). In some variants of the embodiment Z represents tizamidine 5,6-bicyclic heteroaryl (i.e., where z has a value of 3). In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents a 5,6-bicyclic heteroaryl, where Y5selected from O, S or NR18; Y7represents N; Y13is a C; Y6represents C, CH or CR15or N, and Y9, Y10, Y11and Y12independently represents C, CH or CR15. For example, in some embodiments embodiment Z represents a 5,6-bicyclic heteroaryl group of the formula:

,

where z is 0, 1, 2, 3, 4 or 5, and R15and R18have the meanings given below in this section of the application. In some embodiments embodiment Z represents unsubstituted 5,6-bicyclic heteroaryl (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted 5,6-bicyclic heteroaryl (for example, where z has a value of 1, 2, 3, 4 or 5). In some embodiments, embodiments Z is a monosubstituted 5,6-bicyclic heteroaryl (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted 5,6-bicyclic heteroaryl (i.e., where z has a value of 2). what some embodiments embodiment Z represents tizamidine 5,6-bicyclic heteroaryl (i.e., where z has a value of 3). In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents a 5,6-bicyclic heteroaryl, where Y5represents NRk, S, or O; Y12represents N; Y13represents C; and Y6, Y7, Y9, Y10and Y11independently represents C, CH or CR15. For example, in some embodiments embodiment Z represents a 5,6-bicyclic heteroaryl group of the formula:

where z is 0, 1, 2, 3, 4 or 5, and R15and R18have the meanings given below in this section of the application. In some embodiments embodiment Z represents unsubstituted 5,6-bicyclic heteroaryl (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted 5,6-bicyclic heteroaryl (for example, where z has a value of 1, 2, 3, 4 or 5). In some embodiments, embodiments Z is a monosubstituted 5,6-bicyclic heteroaryl (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted 5,6-bicyclic heteroaryl (i.e., where z has a value of 2). In some embodiments of the incarnation Z pre who is tizamidine 5,6-bicyclic heteroaryl (i.e., where z has a value of 3). In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents a 5,6-bicyclic heteroaryl, where Y7represents O, S or NRk; Y12represents N; Y13represents C; and Y5, Y6, Y9, Y10and Y11independently represents C, CH or CR15. For example, in some embodiments embodiment Z represents a 5,6-bicyclic heteroaryl group of the formula:

where z is 0, 1, 2, 3, 4 or 5, and R15and R18have the meanings given below in this section of the application. In some embodiments embodiment Z represents unsubstituted 5,6-bicyclic heteroaryl (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted 5,6-bicyclic heteroaryl (for example, where z has a value of 1, 2, 3, 4 or 5). In some embodiments, embodiments Z is a monosubstituted 5,6-bicyclic heteroaryl (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted 5,6-bicyclic heteroaryl (i.e., where z has a value of 2). In some embodiments of the incarnation Z pre who is tizamidine 5,6-bicyclic heteroaryl (i.e., where z has a value of 3). In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents a 5,6-bicyclic heteroaryl, where Y5selected from O, S or NR18; Y13represents N; and Y6, Y7, Y8, Y9and Y10independently represents C, CH or CR15. For example, in some embodiments embodiment Z represents a 5,6-bicyclic heteroaryl group of the formula:

where z is 0, 1, 2, 3, 4 or 5, and R15and R18have the meanings given below in this section of the application. In some embodiments embodiment Z represents unsubstituted 5,6-bicyclic heteroaryl (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted 5,6-bicyclic heteroaryl (for example, where z has a value of 1, 2, 3, 4 or 5). In some embodiments, embodiments Z is a monosubstituted 5,6-bicyclic heteroaryl (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted 5,6-bicyclic heteroaryl (i.e., where z has a value of 2). In some embodiments embodiment Z represents tizamidine 5,6-bicikli the definition of heteroaryl (i.e., where z has a value of 3). In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents a 10-membered heteroaryl (for example, 6,6-bicyclic heteroaryl). In some embodiments, embodiments Z is a 6,6-bicyclic heteroaryl, substituted by 0, 1, 2, 3, 4, or 5 groups R15. In some embodiments, embodiments Z is a 6,6-bicyclic heteroaryl selected from naphthyridines, pteridinyl, chinoline, ethenolysis, cinnoline, honokalani, phthalazine and hintline, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups R15.

For example, in some embodiments, embodiments Z is a 6,6-bicyclic heteroaryl formula:

where W6, W7, W8, W9, W10, W11, W12and W13independently selected from C, CH, CR15or N, provided that at least one of W6, W7, W8, W9, W10, W11, W12and W13represents N, and where R15shall have the meaning given below and in this section of the application.

In some embodiments embodiment Z represents hyalinella group; for example, formula (ii-g), where W9presented EET a N and W6, W7, W8, W10, W11, W12and W13independently represents C, CH or CR15. For example, in some embodiments embodiment Z represents hyalinella group of the formula:

where z is 0, 1, 2, 3, 4 or 5, and R15shall have the meaning given below and in this section of the application. In some embodiments embodiment Z represents an unsubstituted chinoline (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted chinoline (for example, where z has a value of 1, 2, 3, 4 or 5). In some embodiments, embodiments Z is a monosubstituted chinoline (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted chinoline (i.e., where z has a value of 2). In some embodiments embodiment Z represents tizamidine chinoline (i.e., where z has a value of 3). In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents athinodorou group; for example, formula (ii-g), where W8represents N, and W6, W7, W9, W10, W11, W12and W13independently represent what a C CH or CR15. For example, in some embodiments embodiment Z represents athinodorou group of the formula:

where z is 0, 1, 2, 3, 4 or 5, and R15shall have the meaning given below and in this section of the application. In some embodiments embodiment Z represents an unsubstituted ethenolysis (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted ethenolysis (for example, where z has a value of 1, 2, 3, 4 or 5). In some embodiments, embodiments Z is a monosubstituted ethenolysis (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted ethenolysis (i.e., where z has a value of 2). In some embodiments embodiment Z represents tizamidine ethenolysis (i.e., where z has a value of 3). In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents khinoksalinona group; for example, formula (ii-g), where W6and W9represent N, and W7, W8, W10, W11, W12and W13independently represents C, CH or CR15. For example, in some embodiments embodiment Z represents the t khinoksalinona group of the formula:

where z is 0, 1, 2, 3, 4 or 5, and R15shall have the meaning given below and in this section of the application.

In some embodiments embodiment Z represents an unsubstituted honokalani (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted honokalani (for example, where z has a value of 1, 2, 3, 4 or 5). In some embodiments, embodiments Z is a monosubstituted honokalani (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted honokalani (i.e., where z has a value of 2). In some embodiments embodiment Z represents tizamidine honokalani (i.e., where z has a value of 3). In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments, embodiments Z is a 3-14 membered heterocyclyl. In some embodiments, embodiments Z is a 3-14 membered heterocyclyl, substituted by 0, 1, 2, 3, 4, or 5 groups R15. In some embodiments embodiment Z represents a 5-10 membered heterocyclyl, substituted by 0, 1, 2, 3, 4, or 5 groups R15. In some embodiments embodiment Z represents a 5-8-membered heterocyclyl, substituted by 0, 1, 2, 3, or 5 groups R 15. In some embodiments, embodiments Z is a 5-6-membered heterocyclyl, substituted by 0, 1, 2, 3, 4, or 5 groups R15. In some embodiments, embodiments Z is a 9-10-membered heterocyclyl, substituted by 0, 1, 2, 3, 4, or 5 groups R15.

Examples of heterocyclic groups Z include, but are not limited to, aziridinyl, oxiranyl, tiereny, azetidine, oxetane, titanyl, tetrahydrofuranyl, dihydrofurane, tetrahydrothiophene, dihydrothiophene, pyrrolidinyl, dihydropyrrole, pyrrolyl-2,5-dione, DIOXOLANYL, oxathiolane, dithiolane, triazolyl, oxadiazolyl, thiadiazolyl, piperidinyl, tetrahydropyranyl, dihydropyridines, tiani, piperazinil, morpholinyl, dithienyl, dioxane, triazinyl, azepane, oxetanyl, tepanil, atacanli, oxetanyl, ciocanel, indolinyl, isoindolyl, dihydrobenzofuranyl, dihydrobenzofuranyl, tetrahydrobenzene, tetrahydrofuranyl, tetrahydroindole, tetrahydroquinoline, tetrahydroisoquinolines, decahydroquinoline, decahydroquinoline, octahedrally, octahydronaphthalene, decahydronaphthalene, decahydro-1,8-naphthyridines, octahedral[3,2-b]pyrrole, indolinyl, phthalimide, naphthalimide, bromanil, bromanil, 1H-benzo[e][1,4]diazepine, 1,4,5,7-tetrahydro-pyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-Digi the ro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-Tetra-hydropure[3,2-c]pyridinyl and 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridines, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups R15.

In some embodiments embodiment Z represents a 6-membered heterocyclyl. In some embodiments embodiment Z represents a 6-membered heterocyclyl, substituted by 0, 1, 2, 3, 4, or 5 groups R15. In some embodiments embodiment Z represents a 6-membered heterocyclyl selected from piperidinyl, tetrahydropyranyl, dihydropyridines, tiani, piperazinil, morpholinyl, dithienyl, dioxane and triazinyl, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups R15.

For example, in some embodiments embodiment Z represents a 6-membered heterocyclyl formula:

where W14, W15, W16, W17, W18independently represent CH2, CHR15C(R15)2, NR18, O or S, and W19represents N, CH or CR15provided that at least one of W14, W15, W16, W17, W18and W19represents N, NR18, O or S, where R15and R18have the meanings given below in this section of the application.

In some var is the preferable embodiment Z represents piperidinyloxy group. In some embodiments embodiment Z represents piperidinyloxy group, substituted by 0, 1, 2, 3, 4, or 5 groups R15for example, the formula:

where z is 0, 1, 2, 3, 4 or 5, and R15and R18defined below in this section of the application. In some embodiments embodiment Z represents an unsubstituted piperidinyl (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted piperidinyl (for example, where z has a value of 1, 2, 3, 4 or 5). In some embodiments, embodiments Z is a monosubstituted piperidinyl (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted piperidinyl (i.e., where z has a value of 2). In some embodiments embodiment Z represents tizamidine piperidinyl (i.e., where z has a value of 3). In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents a 1-piperidinyloxy group, for example, formula (ii-h), where W19represents N, and W14, W15, W16, W17and W18independently selected from CH2, CHR15C(R15)2. In some embodiments of the incarnation Z submitted is a 2-piperidinyloxy group, for example, formula (ii-h), where W14represents NR18; W15, W16, W17and W18independently represent CHR15C(R15)2or CH2; W19represents CH or CR15. In some embodiments embodiment Z represents a 3-piperidinyloxy group, for example, formula (ii-h), where W15represents NR18; W14, W16, W17and W18independently represent CHR15C(R15)2or CH2; W19represents CH or CR15. In some embodiments embodiment Z represents a 4-piperidinyloxy group, for example, formula (ii-h), where W16represents NR18; W14, W15, W17and W18independently represent CHR15C(R15)2or CH2; W19represents CH or CR15.

In some embodiments embodiment Z represents piperazinilnom group. In some embodiments embodiment Z represents piperazinilnom group, substituted by 0, 1, 2, 3 or 4 groups R15for example, the formula:

where x is 0, 1, 2, 3, 4 or 5, and R15and R18defined below in this section of the application. In some embodiments embodiment Z represents unsubstituted piperazinil (i.e., where z has the value 0). Not what which variants of embodiment Z represents a substituted piperazinil (for example, where z has a value of 1, 2, 3, 4 or 5). In some embodiments, embodiments Z is a monosubstituted piperazinil (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted piperazinil (i.e., where z has a value of 2). In some embodiments embodiment Z represents tizamidine piperazinil (i.e., where z has a value of 3). In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents piperazinilnom group, for example, formula (ii-h), where W19represents N, W16represents NR18and W14, W15, W16, W17and W18independently represent CHR15C(R15)2or CH2. In some embodiments embodiment Z represents piperazinilnom group, where W19represents CH or CR15, W14and W17independently represent NR18and W15, W16and W18independently represent CHR15C(R15)2or CH2.

In some embodiments embodiment Z represents morpholinyl group, substituted by 0, 1, 2, 3 or 4 groups R15for example, the formula:

where z is 0, 1, 2, 3, 4 or 5, and R15and R18defined below in this section of the application. In some embodiments embodiment Z represents an unsubstituted morpholinyl (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted morpholinyl (for example, where z has a value of 1, 2, 3, 4 or 5). In some embodiments, embodiments Z is a monosubstituted morpholinyl (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted morpholines (i.e., where z has a value of 2). In some embodiments embodiment Z represents tizamidine morpholinyl (i.e., where z has a value of 3). In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents morpholinyl group; for example, formula (ii-h), where W19represents N, W16represents O, and W14, W15, W16and W17independently selected from CH2, CHR15C(R15)2. In some embodiments embodiment Z represents morpholinyl group, where W19represents CH or CR15, W14and W17independently selected from O, NR18and W15, W16and W18 independently represent CHR15C(R15)2or CH2.

In some embodiments embodiment Z represents dioxolo group. In some embodiments embodiment Z represents dioxolo group, substituted by 0, 1, 2, 3 or 4 groups R15for example, the formula:

where z is 0, 1, 2, 3, 4 or 5, and R15shall have the meaning given below and in this section of the application. In some embodiments embodiment Z represents unsubstituted dioxane (i.e., where z has the value 0). In some embodiments embodiment Z represents a substituted dioxane (for example, where z has a value of 1, 2, 3, 4 or 5). In some embodiments, embodiments Z is a monosubstituted dioxane (i.e., where z has a value of 1). In some embodiments, embodiments Z is a disubstituted dioxane (i.e., where z has a value of 2). In some embodiments embodiment Z represents tizamidine dioxane (i.e., where z has a value of 3). In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 0 or 1.

In some embodiments embodiment Z represents dioxolo group, for example, formula (ii-h), where W14and W17represent O, and W , W16and W18independently represent CHR15C(R15)2or CH2; W19represents CH or CR15. In some embodiments embodiment Z represents dioxolo group, where W19represents CH or CR15, W14and W16independently selected from O, W15, W17and W18independently represent CHR15C(R15)2or CH2. Insome embodiments of embodiment Z represents dioxolo group, where W19represents CH or CR15, W15and W17independently selected from O, W14, W16and W18independently represent CHR15C(R15)2or CH2.

In some embodiments embodiment Z represents C3-10carbocyclic. In some embodiments embodiment Z represents C3-10carbocyclic, substituted by 0, 1, 2, 3, 4, or 5 groups R15. In some embodiments embodiment Z represents C5-8carbocyclic, substituted by 0, 1, 2, 3, 4, or 5 groups R15. In some embodiments embodiment Z represents C5-6carbocyclic, substituted by 0, 1, 2, 3, 4, or 5 groups R15. In some embodiments embodiment Z represents C9-10carbocyclic, substituted by 0, 1, 2, 3, 4, or 5 groups R15.

Variants of the embodiment, where Ra R dconsolidated (condensed)

In General, as defined above, in some embodiments embodiment Raand Rdcombined with the formation of C3-10carbocyclic or 3-14 membered condensed heterocyclic ring, and Rband Rcindependently selected from-H, C1-10the alkyl and C1-10perhalogenated.

In some embodiments, embodiments each of Rband Rcindependently selected from-H, C1-6the alkyl and C1-6perhalogenated. In some embodiments, embodiments each of Rband Rcindependently selected from-H, C1-3the alkyl and C1-3perhalogenated. In some embodiments, embodiments each of Rband Rcindependently selected from-H, C1the alkyl and C1perhalogenated. In some embodiments, embodiments each of Rband Rcindependently selected from-H, -CH3and-CF3. In some embodiments, embodiments each of Rband Rcindependently selected from-H and-CH3. In some embodiments, embodiments each of Rband Rcindependently selected from-H and-CF3. In some embodiments embodiment Rband Rcboth represent-H.

In some embodiments embodiment Raand Rdcombined with the formation of C5-7carbocyclic or 5-7 membered heterocyclic condensed rings. In some the older versions embodiment R aand Rdcombined with the formation of C5-7carbocyclic or 5-7 membered heterocyclic condensed ring of the formula:

where W20, W21, W22and W23independently represent CH2, CHR15C(R15)2or NR18, R15and R18have the meaning given below and in this section of the application, s is 0, 1 or 2, and the dashed line indicates the merging of the rings.

In some embodiments embodiment Raand Rdcombined with the formation of C5-7carbocyclic condensed ring. For example, in some embodiments of the embodiments of formula (ii-j), W20, W21, W22and W23independently represent CH2, CHR15or C(R15)2. Examples of C5-7carbocyclic groups for education which Raand Rdcan be combined include, but are not limited to, cyclopentyl, cyclohexyl and cycloheptyl, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups R15.

In some embodiments embodiment Raand Rdmerged to form a 5-7 membered heterocyclic condensed rings. For example, in some embodiments of the embodiments of formula (ii-j), W20represents NR18and W21, W22and W23independently represent with the battle of CH 2, CHR15or C(R15)2. In some embodiments of the embodiments of formula (ii-j), W21represents NR18and W20, W22and W23independently represent CH2, CHR15or C(R15)2. In some embodiments of the embodiments of formula (ii-j), W22represents NR18and W20, W21and W23independently represent CH2, CHR15or C(R15)2. Examples 5-7-membered heterocyclic groups, for education which Raand Rdcan be combined include, but are not limited to, pyrrolidinyl, pyrazolidine, imidazolidine, piperidine, piperazinil and azepane, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups R15.

In some embodiments of the incarnation, where s is 0, Raand Rdcombined with the formation of C5carbocyclic or 5-membered condensed heterocyclic ring of the formula:

where W20, W21and W22independently represent CH2, CHR15C(R15)2or NR18, R15and R18have the meaning given below and in this section of the application, and the dashed line indicates the merging of the rings.

In some embodiments of the embodiments of formula (ii-k), Raand Rdcombined with the formation of C5Carbo is ilichevskogo condensed rings (i.e., cyclopentyl), for example, where W20, W21and W22independently represent CH2, CHR15C(R15)2.

In some embodiments of the embodiments of formula (ii-k), Raand Rdcombined with the formation of 5-membered heterocyclic condensed rings (e.g., pyrrolidinyl), for example, where W21represents NR18and W20, W22and W23independently represent CH2, CHR15or C(R15)2. In some embodiments of the embodiments of formula (ii-k), Raand Rdcombined with the formation of 5-membered heterocyclic condensed rings (e.g., pyrrolidinyl), for example, where W20represents NR18and W21, W22and W23independently represent CH2, CHR15or C(R15)2.

In some embodiments of the incarnation, where s is 1, Raand Rdcombined with the formation of C6carbocyclic or 6-membered condensed heterocyclic ring of the formula:

where W20, W21, W22and W23independently represent CH2, CHR15C(R15)2or NR18, R15and R18have the meaning given below and in this section of the application, and the dashed line indicates the merging of the rings.

In some the older versions embodiment of formula (ii-m), Raand Rdcombined with the formation of C6carbocyclic condensed rings (e.g., cyclohexyl), for example, where W20, W21, W22and W23independently represent CH2, CHR15C(R15)2.

In some embodiments of the embodiments of formula (ii-m), Raand Rdcombined with the formation of 6-membered heterocyclic condensed rings (e.g., piperidinyl), for example, where W21represents NR18and W20, W22and W23independently represent CH2, CHR15or C(R15)2. In some embodiments of the embodiments of formula (ii-m), Raand Rdcombined with the formation of 6-membered heterocyclic condensed rings (e.g., piperidinyl), for example, where W20represents NR18and W21, W22and W23independently represent CH2, CHR15or C(R15)2.

In some embodiments of the incarnation, where s is set to 2, Raand Rdcombined with the formation of C7carbocyclic or 7-membered heterocyclic ring of the formula:

where W20, W21, W22and W23independently represent CH2, CHR15C(R15)2or NR18, R15and R18have value, particularly the e below and in this section of the application and the dashed line indicates the merging of the rings.

In some embodiments of the embodiments of formula (ii-n), Raand Rdcombined with the formation of C7carbocyclic rings (i.e., cycloheptyl), for example, where W20, W21, W22and W23independently represent CH2, CHR15C(R15)2.

In some embodiments of the embodiments of formula (ii-n), Raand Rdcombined with the formation of 7-membered heterocyclic ring (for example, azepane), for example, where W21represents NR18and W20, W22and W23independently represent CH2, CHR15or C(R15)2. In some embodiments of the embodiments of formula (ii-n), Raand Rdcombined with the formation of 7-membered heterocyclic ring (for example, azepane), for example, where W22represents NR18and W20, W21and W23independently represent CH2, CHR15or C(R15)2.

Variants of the embodiment, where Rcand RdUnited (Spiro-condensed)

In General, as defined above, in some embodiments embodiment Rcand Rdcombined with the formation of C3-10carbocyclic or 3-14-membered heterocyclic Spiro-condensed ring, and Raand Rbindependently selected from-H, C1-1 the alkyl and C1-10perhalogenated.

In some embodiments, embodiments each of Raand Rbindependently selected from-H, C1-6the alkyl and C1-6perhalogenated. In some embodiments, embodiments each of Raand Rbindependently selected from-H, C1-3the alkyl and C1-3perhalogenated. In some embodiments, embodiments each of Raand Rbindependently selected from-H, C1the alkyl and C1perhalogenated. In some embodiments, embodiments each of Raand Rbindependently selected from-H, -CH3and-CF3. In some embodiments, embodiments each of Raand Rbindependently selected from-H and-CH3. In some embodiments, embodiments each of Raand Rbindependently selected from-H and-CF3. In some embodiments embodiment Raand Rbboth represent-H.

In some embodiments embodiment Rcand Rdcombined with the formation of C5-7carbocyclic, 5-7-membered heterocyclic, 5,6-bicyclic carbocyclic, 6,6-bicyclic carbocyclic, 5,6-bicyclic heterocyclic or 6,6-bicyclic heterocyclic Spiro-condensed ring.

For example, in some embodiments embodiment Rcand Rdcombined with the formation of C5-7carbocyclic, 5-7-membered heterocyclic 5,6-bicyclic carbocyclic or 5,6-bicyclic heterocyclic Spiro-condensed ring of the formula:

where W24, W25, W26, W27, W28and W29independently represent CH2, CHR15C(R15)2or NR18not necessarily, where W25and W26substituted condensed-C6aryl ring or the condensed 6-membered heteroaryl ring; t and v independently are 0 or 1; and R15and R18have the meaning given below and in this section of the application. In some embodiments, the realization of t is set to 0, and v has a value of 0. In some embodiments, the realization of t is set to 0, and v has a value of 1. In some embodiments of embodiment t is 1 and v is 0. In some embodiments of embodiment t is 1 and v is set to 1.

In some embodiments embodiment Rcand Rdcombined with the formation of C5-7carbocyclic Spiro-condensed ring. For example, in some embodiments of the embodiments of formula (iii-a), W24, W25, W26, W27, W28and W29independently represent CH2, CHR15or C(R15)2. Examples of C5-7carbocyclic groups for education which Rcand Rdcan be combined include, but are not limited to, cyclopentyl, cyclohexyl and cycloheptyl, where such groups are substituted by 0, 1, 2, 3, 4 or 5 R 15.

In some embodiments embodiment Rcand Rdmerged to form a 5-7 membered heterocyclic Spiro-condensed ring. For example, in some embodiments of the embodiments of formula (iii-a), W25represents NR18and W26, W27, W28and W29independently represent CH2, CHR15C(R15)2. In some embodiments of the embodiments of formula (iii-a), W26represents NR18and W24, W25, W27, W28and W29independently represent CH2, CHR15C(R15)2. In some embodiments of the embodiments of formula (iii-a), W27represents NR18and W24, W25, W26, W28and W29independently represent CH2, CHR15C(R15)2. Examples 5-7-membered heterocyclic groups, for education which Rcand Rdcan be combined include, but are not limited to, pyrrolidinyl, pyrazolidine, imidazolidine, piperidine, piperazinil and azepane, where such groups are substituted by 0, 1, 2, 3, 4, or 5 groups R15.

In some embodiments of the incarnation, where t is 0 and v is 0, Rcand Rdcombined with the formation of C5carbocyclic or 5-membered heterocyclic Spiro-condensed ring of the formula:

where W25, W26, W27and W28independently represent CH2, CHR15C(R15)2or NR18and R15and R18have the meaning given below and in this section of the application.

In some embodiments embodiment Rcand Rdcombined with the formation of C5carbocyclic Spiro-condensed ring (for example, cyclopentyl); for example, formula (iii-b), where W25represents NR18and W26, W27and W28independently represent CH2, CHR15or C(R15)2.

In some embodiments embodiment Rcand Rdcombined with the formation of 5-membered heterocyclic Spiro-condensed ring; for example, formula (iii-b), where W26represents NR18and W25, W27and W28independently represent CH2, CHR15or C(R15)2.

In some embodiments of the incarnation, where t is 0 and v is 1, Rcand Rdcombined with the formation of C6carbocyclic or 6-membered heterocyclic Spiro-condensed ring of the formula:

where W25, W26, W27, W28and W29independently represent CH2, CHR15C(R15)2or NR18and R15and R18kayttajana, specified below and in this section of the application.

In some embodiments embodiment Rcand Rdcombined with the formation of C6carbocyclic Spiro-condensed rings (e.g., cyclohexyl); for example, formula (iii-c), where W25, W26, W27, W28and W29independently represent CH2, CHR15or C(R15)2.

In some embodiments embodiment Rcand Rdcombined with the formation of 5-membered heterocyclic Spiro-condensed ring; for example, formula (iii-c), where W26represents NR18and W25, W27, W28and W29independently represent CH2, CHR15or C(R15)2. In some embodiments embodiment Rcand Rdcombined with the formation of 5-membered heterocyclic Spiro-condensed ring of the formula (iii-c), where W27represents NR18and W25, W26, W28and W29independently represent CH2, CHR15or C(R15)2.

In some embodiments of the incarnation, where t is 1 and v is 1, Rcand Rdcombined with the formation of C7carbocyclic or 7-membered heterocyclic Spiro-condensed ring of the formula:

where W24, W25, W26, 27, W28and W29independently represent CH2, CHR15C(R15)2or NR18and R15and R18have the meaning given below and in this section of the application.

In some embodiments embodiment Rcand Rdcombined with the formation of C7carbocyclic Spiro-condensed ring (for example, cycloheptyl); for example, formula (iii-d), where W24, W25, W26, W27, W28and W29independently represent CH2, CHR15or C(R15)2.

In some embodiments embodiment Rcand Rdcombined with the formation of 7-membered heterocyclic Spiro-condensed ring; for example, formula (iii-d), where W25represents NR18and W24, W26, W27, W28and W29independently represent CH2, CHR15or C(R15)2. In some embodiments embodiment Rcand Rdcombined with the formation of 7-membered heterocyclic Spiro-condensed ring, where W26represents NR18and W24, W25, W27, W28and W29independently represent CH2, CHR15or C(R15)2. In some embodiments embodiment Rcand Rdcombined with the formation of 7-membered heterocyclic Spiro-kondensirovannoi what about the ring, where W27represents NR18and W24, W25, W26, W28and W29independently represent CH2, CHR15or C(R15)2.

In some embodiments embodiment Rcand Rdcombined with the formation of 5,6-bicyclic carbocyclic Spiro-condensed ring or a 5,6-bicyclic heterocyclic Spiro-condensed ring. For example, in some embodiments of the embodiments of formula (iii-a), t and v both have the value 0, W25and W26substituted condensed-C6aryl ring or the condensed 6-membered heteroaryl ring, and W27represents CH2, CHR15C(R15)2and NR18and W28represents CH2, CHR15or C(R15)2. In some embodiments of the embodiments of formula (iii-a), Rcand Rdcombined with the formation of 5,6-bicyclic carbocyclic Spiro-condensed ring, for example, where t and v both have the value 0, W25and W26substituted condensed-C6aryl ring or the condensed 6-membered heteroaryl ring, and W27and W28independently represent CH2, CHR15or C(R15)2. In some embodiments of the incarnation W25and W26substituted condensed-C6aryl ring.

Example is, in some embodiments of the incarnation, where t and v both have a value of 0, and W25and W26substituted condensed-C6aryl ring, Rcand Rdcombined with the formation of 5,6-bicyclic carbocyclic Spiro-condensed ring of the formula:

where W27and W28independently represent CH2, CHR15and C(R15)2z is 0, 1, 2, 3 or 4; and R15shall have the meaning given below and in this section of the application. In some embodiments of the incarnation W27and W28both represent CH2. In some embodiments embodiment z has the value 0, 1, 2, 3 or 4. In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 2. In some embodiments embodiment z has the value 1. In some embodiments embodiment z has the value 0.

In some embodiments embodiment Rcand Rdcombined with the formation of 6,6-bicyclic carbocyclic Spiro-condensed ring or 6,6-bicyclic heterocyclic Spiro-condensed ring. For example, in some embodiments of the embodiments of formula (iii-a), t is 0 and v is 1, W25and W26substituted condensed-C6aryl to what lcom or the condensed 6-membered heteroaryl ring, and W27and W28independently represent CH2, CHR15C(R15)2and NR18and W29represents CH2, CHR15C(R15)2. In some embodiments of the embodiments of formula (iii-a), Rcand Rdcombined with the formation of 6,6-bicyclic carbocyclic Spiro-condensed ring, for example, where t is 0 and v is 1, W25and W26substituted condensed-C6aryl ring or the condensed 6-membered heteroaryl ring, and W27, W28and W29independently represent CH2, CHR15or C(R15)2. In some embodiments of the incarnation W25and W26substituted condensed-C6aryl ring.

For example, in some embodiments of the incarnation, where t is 0 and v is 1 and W25and W26substituted condensed-C6aryl ring, Rcand Rdcombined with the formation of 6,6-bicyclic carbocyclic Spiro-condensed ring of the formula:

where W27, W28and W29independently represent CH2, CHR15and C(R15)2z is 0, 1, 2, 3 or 4, and R15shall have the meaning given below and in this section of the application. In some embodiments of the incarnation W27, 28and W29each CH2. In some embodiments embodiment z has the value 0, 1, 2, 3 or 4. In some embodiments embodiment z has the value 0, 1, 2 or 3. In some embodiments embodiment z has the value 0, 1 or 2. In some embodiments embodiment z has the value 2. In some embodiments embodiment z has the value 1. In some embodiments embodiment z has the value 0.

In another aspect, Rcand Rdcombined with the formation of the associated bridge connection carbocyclic or associated bridge connection heterocyclic Spiro-condensed ring of the formula:

where W30, W31, W32, W33and W36independently represent CH2, CHR15C(R15)2or NR18; W34and W35independently represent CH or CR15and R15and R18have the meaning given below and in this section of the application.

In some embodiments of the embodiments of formula (iii-f), W30, W31, W32, W33independently represent CH2, CHR15or C(R15)2; W36represents NR18; W34and W35independently represent CH or CR15. In some embodiments of the embodiments of formula (iii-f), W30, W31, W32, W33and W36independently represent H 2, CHR15or C(R15)2; W34and W35independently represent CH or CR15. In some embodiments of the embodiments of formula (iii-f), W34and W35represent CH.

R75Group

As the term is used in this application, in each case, R15independently selected from halogen (i.e. fluorine (-F), bromo (-Br), chlorine (-Cl) and iodine (I)), -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR16, -ON(R18)2, -N(R18)2, -N(R18)3+X-, -N(OR17R18, -SH, -SR16, -SSR17, -C(=O)R16, -CO2H, -CHO, -CO2R16, -OC(=O)R16, -OCO2R16, -C(=O)N(R18)2, -OC(=O)N(R18)2, -NR18C(=O)R16, -NR18CO2R16, -NR18C(=O)N(R18)2, -C(=NR18R16, -C(=NR18OR16, -OC(=NR18R16, -OC(=NR18OR16, -C(=NR18)N(R18)2, -OC(=NR18)N(R18)2, NR18C(=NR18)N(R18)2, -C(=O)NR18SO2R16, -NR18SO2R16, -SO2N(R18)2, -SO2R16, -SO2OR16, -OSO2R16, -S(=O)R16, -OS(=O)R16, -Si(R16)3, -Osi(R16)3-C(=S)N(R18)2, -C(=O)SR16, -C(=S)SR16, -SC(S)SR16, -P(=O)2R16, -OP(=O)2R16, -P(=O)(R16)2, -OP(=O)(R )2, -OP(=O)(OR17)2, -P(=O)2N(R18)2, -OP(=O)2N(R18)2, -P(=O)(NR18)2, -OP(=O)(NR18)2, -NR18P(=O)(OR17)2, -NR18P(=O)(NR18)2, -P(R17)2, -P(R17)3, -OP(R17)2, -OP(R17)3, -B(OR17)2, -BR16(OR17), C1-10of alkyl, C1-10perhalogenated, C2-10alkenyl, C2-10the quinil, C3-14carbocycle, 3-14-membered heterocyclyl, C6-14aryl and 5-14-membered heteroaryl, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups R19; or two adjacent R15group substituted by a group-O(C(R2)2)1-2O-, where each R2independently represents H, C1-6alkyl or halogen;

in each case, R16independently selected from C1-10of alkyl, C1-10perhalogenated, C2-10alkenyl, C2-10the quinil, C3-10carbocycle, 3-14-membered heterocyclyl, C6-14aryl and 5-14-membered heteroaryl, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups R19;

in each case, R18independently selected from hydrogen, -OH, -OR16, -N(R17)2, -CN, -C(=O)R16, -C(=O)N(R17)2, -CO2R16 , -SO2R16, -C(=NR17OR16, -C(=NR17)N(R17)2, -SO2N(R17)2, -SO2R17, -SO2OR17, -SOR16, -C(=S)N(R17)2, -C(=O)SR17, -C(=S)SR17, -P(=O)2R16, -P(=O)(R16)2, -P(=O)2N(R17)2, -P(=O)(NR17)2C1-10of alkyl, C1-10perhalogenated, C2-10alkenyl, C2-10the quinil, C3-10carbocycle, 3-14-membered heterocyclyl, C6-14aryl and 5-14-membered heteroaryl, or two R17groups associated with the N atom combined with education 3-14-membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups R19;

in each case, R17independently selected from hydrogen, C1-10of alkyl, C1-10perhalogenated, C2-10alkenyl, C2-10the quinil, C3-10carbocycle, 3-14-membered heterocyclyl, C6-14aryl and 5-14-membered heteroaryl, or two R17groups associated with the N atom combined with education 3-14-membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups R19;

in each case, R19independently researched the Simo selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR20, -ON(R21)2, -N(R21)2, -N(R21)3+X-, -N(OR20R21, -SH, -SR20, -SSR20, -C(=O)R20, -CO2H, -CO2R20, -OC(=O)R20, -OCO2R20, -C(=O)N(R21)2, -OC(=O)N(R21)2, -NR21C(=O)R20, -NR21CO2R20, -NR21C(=O)N(R21)2, -C(=NR21OR20, -OC(=NR21R20, -OC(=NR21OR20, -C(=NR21)N(R21)2, -OC(=NR21)N(R21)2, -NR21C(=NR21)N(R21)2, -NR21SO2R20, -SO2N(R21)2, -SO2R20, -SO2OR20, -OSO2R20, -S(=O)R20, -Si(R20)3, -Osi(R20)3, -C(=S)N(R21)2, -C(=O)SR20, -C(=S)SR20, -SC(=S)SR20, -P(=O)2R20, -P(=O)(R20)2, -OP(=O)(R20)2, -OP(=O)(OR20)2C1-6of alkyl, C1-6perhalogenated, C2-6alkenyl, C2-6the quinil, C3-10carbocycle, 3-10-membered heterocyclyl, C6-10aryl, 5-10-membered heteroaryl, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups R22or two adjacent substituent R19can be merged to form =O or =S;

in each case, R20the independent is selected from C 1-6of alkyl, C1-6perhalogenated, C2-6alkenyl, C2-6the quinil, C3-10carbocycle, C6-10aryl, 3-10-membered heterocyclyl and 3-10-membered heteroaryl, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups R22;

in each case, R21independently selected from hydrogen, C1-6of alkyl, C1-6perhalogenated, C2-6alkenyl, C2-6the quinil, C3-10carbocycle, 3-10-membered heterocyclyl, C6-10aryl and 5-10-membered heteroaryl, or two R21groups associated with the N atom combined with education 3-14-membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups R22; and

in each case, R22independently represents a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6alkyl, -ON(C1-6alkyl)2, -N(C1-6alkyl)2, -N(C1-6alkyl)3X, -NH(C1-6alkyl)2X, -NH2(C1-6alkyl)2X, -NH3X, -N(OC1-6alkyl)(C1-6alkyl), -N(OH)(C1-6alkyl), -NH(OH), -SH, -SC1-6alkyl, -SS(C1-6alkyl), -C(=O)(C1-6alkyl), -CO2H, -CO2(C1-6alkyl), -OC(=O)(C1-6alkyl), -OCO2(C1-6lcil), -C(=O)NH2, -C(=O)N(C1-6alkyl)2, -OC(=O)NH(C1-6alkyl), -NHC(=O)(C1-6alkyl), -N(C1-6alkyl)C(=O)(C1-6alkyl), -NHCO2(C1-6alkyl), -NHC(=O)N(C1-6alkyl)2, -NHC(=O)NH(C1-6alkyl), -NHC(=O)NH2, -C(=NH)O(C1-6alkyl), -OC(=NH)(C1-6alkyl), -OC(=NH)OC1-6alkyl, C(=NH)N(C1-6alkyl)2, -C(=NH)NH(C1-6alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6alkyl)2, -OC(NH)NH(C1-6alkyl), -OC(NH)NH2, -NHC(NH)N(C1-6alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-6alkyl), -SO2N(C1-6alkyl)2, -SO2NH(C1-6alkyl), -SO2NH2, -SO2C1-6alkyl, -SO2OC1-6alkyl, -OSO2C1-6alkyl, -SOC1-6alkyl, -Si(C1-6alkyl)3, -OSi(C1-6alkyl)3, -C(=S)N(C1-6alkyl)2, -C(=S)NH(C1-6alkyl), C(=S)NH2, -C(=O)S(C1-6alkyl), -C(=S)S(C1-6alkyl), -SC(=S)S(C1-6alkyl), -P(=O)2(C1-6alkyl), -P(=O)(C1-6alkyl)2, -OP(=O)(C1-6alkyl)2, -OP(O)(OC1-6alkyl)2C1-6alkyl, C1-6perhalogenated, C2-6alkenyl, C2-6quinil, C3-10carbocyclic, C6-10aryl, 3-10-membered heterocyclyl, 5-10-membered heteroaryl; or two adjacent substituent can be merged to form =O or =S;

where X-is a counterion.

In some embodiments, embodiments in each case, R15ezavisimo selected from fluorine (F), bromine (-Br), chlorine (-Cl) and iodine (I), -OR16, -C(=O)N(R18)2, -SO2N(R18)2C1-10of alkyl, C1-10perhalogenated, C2-10alkenyl, C2-10the quinil, C6-14aryl and 5-14-membered heteroaryl, where each alkyl, alkenyl, quinil, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups R19.

In some embodiments embodiment R15independently selected from fluorine (F), bromine (-Br), chlorine (-Cl) and iodine (-1), -OR16and C1-10perhalogenated. In some embodiments embodiment R15independently selected from fluorine (F), bromine (-Br), chlorine (-Cl) and iodine (I), and-OR16. In some embodiments embodiment R15independently selected from fluorine (F), bromine (-Br), chlorine (-Cl) and iodine (I), and C1-10perhalogenated.

In some embodiments embodiment R15selected from-OR16and C1-10perhalogenated.

In some embodiments embodiment R15represents-OR16. In some embodiments embodiment R16selected from C1-10of alkyl, C1-10perhalogenated, C2-10alkenyl, C2-10the quinil, C6-10aryl and 5-6 membered heteroaryl, where each alkyl, alkenyl, quinil, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups R19.

In some embodiments embodiment R15represents-OR16and R16selected from C1-10the alkyl. In some the x variants of embodiment R 15represents-OR16and R16selected from C1-6the alkyl. In some embodiments embodiment R15represents - OR16and R16selected from C1-4the alkyl. In some embodiments embodiment R15represents-OR16and R16selected from C1-2the alkyl. In some embodiments embodiment R15represents-OR16and R16represents-CH3, -Et, -iPr, -nBu, -n-pentyl. In some embodiments embodiment R15represents-OR16and R16represents-CH3.

In some embodiments embodiment R15represents-OR16and R16selected from C1-10perhalogenated. In some embodiments embodiment R15represents-OR16and R16selected from C1-6perhalogenated. In some embodiments embodiment R15represents-OR16and R16selected from C1-4perhalogenated. In some embodiments, embodiments, R15represents-OR16and R16selected from C1-2perhalogenated. In some embodiments embodiment R15represents-OR16and R16represents-CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2or-CF2Cl. In some embodiments embodiment R15represents-OR6 and R16represents-CF3.

In some embodiments embodiment R15represents-OR16and R16selected from C2-10alkenyl. In some embodiments embodiment R15represents-OR16and R16selected from C2-6alkenyl. In some embodiments embodiment R15represents-OR16and R16selected from C2-4alkenyl. In some embodiments embodiment R15represents-OR16and R16selected from-CH2CHCH2(i.e., allyl).

In some embodiments embodiment R15represents-OR16and R16selected from C2-10the quinil. In some embodiments embodiment R15represents-OR16and R16selected from C2-6the quinil. In some embodiments embodiment R15represents-OR16and R16selected from C2-4the quinil. In some embodiments embodiment R15represents-OR16and R16selected from-CH2CCH (i.e. propargyl).

In some embodiments embodiment R15represents-OR16and R16selected from C6aryl (e.g. phenyl), substituted by 0, 1, 2, 3 or 4 groups R19. In some embodiments embodiment R15represents-OR16and R16represents phenyl, substituted by 0, 1 or 2 groups R19. what some embodiments embodiment R 15represents-OR16and R16represents phenyl, substituted by 1 group, R19. In some embodiments embodiment R15represents-OR16and R16represents phenyl, substituted 0 groups R19(i.e.,- C6H5).

In some embodiments embodiment R15represents-OR16and R16selected from 5-6-membered heteroaryl, substituted by 0, 1, 2, 3 or 4 groups R19. In some embodiments embodiment R15represents-OR16and R16selected from 6-membered heteroaryl, substituted by 0, 1, 2, 3 or 4 groups R19. In some embodiments embodiment R15represents-OR16and R16selected from pyridinyl (for example, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), substituted by 0, 1, 2, 3 or 4 groups R19. In some embodiments embodiment R15represents-OR16and R16selected from pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), substituted by 0, 1, 2, or 3 groups R19.

In some embodiments embodiment R15represents-C(=O)N(R18)2.

In some embodiments embodiment R15represents-SO2N(R18)2.

In some embodiments embodiment R15represents a C1-10perhalogenated. In some embodiments of the embodiment is ia R 15represents a C1-6perhalogenated. In some embodiments embodiment R15represents a C1-4perhalogenated. In some embodiments embodiment R15represents a C1-2perhalogenated. In some embodiments embodiment R15chosen from-CF3, -CF2CF3, -CF2CF2CF3, - CCl3, -CFCl2and-CF2Cl. In some embodiments embodiment R15chosen from-CF3.

In some embodiments embodiment R15represents a C1-10alkyl, substituted 0, 1, 2, 3, 4, or 5 groups R19. In some embodiments embodiment R15represents a C1-6alkyl, substituted 0, 1, 2, 3, 4, or 5 groups R19. R15represents a C1-4alkyl, substituted 0, 1, 2, 3, 4, or 5 groups R19. In some embodiments embodiment R15the alkyl group is unsubstituted (0 groups, R19). In some embodiments embodiment R15represents-CH3, -Et, -iPr, -nBu, -n-pentyl.

In some embodiments embodiment R15represents a C2-10alkenyl, substituted by 0, 1, 2, 3, 4, or 5 groups R19. In some embodiments embodiment R15represents a C2-6alkenyl, substituted by 0, 1, 2, 3 or 4 groups R19. In some embodiments embodiment R15represents a C2-4alkenyl, Zam is on 0, 1, 2, or 3 groups R19. In some embodiments embodiment R15Alchemilla group is unsubstituted (0 groups, R19). In some embodiments embodiment R15represents-CH2CHCH2(i.e., allyl).

In some embodiments embodiment R15represents a C2-10quinil, substituted by 0, 1, 2, 3, 4, or 5 groups R19. In some embodiments embodiment R15represents a C2-6quinil, substituted by 0, 1, 2, or 3 groups R19. In some embodiments embodiment R15represents a C2-4quinil, substituted by 0, 1 or 2 groups R19. In some embodiments embodiment R15Alchemilla group is unsubstituted (0 groups, R19). In some embodiments embodiment R15represents-CH2CCH (i.e. propargyl).

In some embodiments embodiment R15represents a C6-14aryl. In some embodiments embodiment R15selected from C6aryl (e.g. phenyl), substituted by 0, 1, 2, 3 or 4 groups R19. In some embodiments embodiment R15represents unsubstituted phenyl. In some embodiments embodiment R15represents a monosubstituted phenyl (i.e., substituted by 1 group, R19).

In some embodiments embodiment R15represents a 5 to 14-membered heteroaryl, substituted by 0, 1, 2, 3 4, or 5 groups R 19. In some embodiments embodiment R15is a 5-6-membered heteroaryl, substituted by 0, 1, 2, 3 or 4 groups R19. In some embodiments embodiment R15represents a 6-membered heteroaryl, substituted by 0, 1, 2, 3 or 4 groups R19. In some embodiments embodiment R15represents pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl) substituted with 0, 1, 2, 3 or 4 groups R19. In some embodiments embodiment R15is pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), substituted by 0, 1, 2, or 3 groups R19. In some embodiments embodiment R15heteroaryl group is unsubstituted (0 groups, R19).

Group R18

In some embodiments, embodiments in each case, R18independently selected from-H, -OH, -OR16, -N(R17)2, -C(=O)R16, -C(=O)N(R17)2, -CO2R16, -SO2R16, -C(=NR17R16, -C(=NR17OR16, -C(=NR17)N(R17)2, -SO2N(R17)2, -SO2R16, -SO2OR16, -SOR16, -C(=S)N(R17)2, -C(=O)SR16, -C(=S)SR16C1-10alkyl (for example, aranceles), C2-10alkenylphenol, C2-10alkenylphenol, C3-10carbocyclic, 3-14-membered heterocyclic, C6-14aryl and 5-14 membered, heteroa the ilen groups, where each alkyl, alkenyl, quinil, carbocyclic, heterocyclic, aralkyl, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups R19where R16, R17, R19have the meaning given above and in this section of the application.

In some embodiments, embodiments in each case, R17independently selected from-H, -C(=O)R16, -C(=O)OR16, -SO2R16or C1-6the alkyl. In some embodiments, embodiments in each case, R17independently selected from-H or C1-6the alkyl. In some embodiments, embodiments in each case, R17independently selected from-H and-CH3. In some embodiments, embodiments in each case, R17independently selected from a-H. In some embodiments, embodiments in each case, R17independently selected from-CH3.

Additional options embodiments of compounds of formula (I)

In General, as defined above, the present invention provides compounds of formula (I):

or pharmaceutically acceptable forms of such compounds, where G, Ra, Rb, Rcand Rdhave the meaning given in this application.

In one aspect, where each Ra, Rb, Rcrepresents H, and Rdrepresents a group Z, the present invention provides compounds of formula (II):

or pharmaceutically acceptable forms of such compounds, where G and Z have the meaning given in this application. In some embodiments of embodiment L represents a covalent bond. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I).

For example, in some embodiments of the incarnation, where L is a covalent bond, each Ra, Rb, Rcrepresents H, and G represents a group-ORe, the present invention provides compounds of formula (II-a):

or pharmaceutically acceptable forms of such compounds, where Reand Z have the meaning given in this application.

In some embodiments of the incarnation, where Z is a phenyl ring, the present invention provides compounds of formula (II-b):

or pharmaceutically acceptable forms of such compounds, where G, L, Ra, Rb, Rc, R15and z have the meaning given in this application. For example, in some embodiments embodiment z has the value 1, and R15is in the position ortho. In some embodiments embodiment z has the value 1, and R15on titsa in the meta position. In some embodiments embodiment z has the value 1, and R15is in position pair. In some embodiments embodiment z has the value 2, and R15is in position meta, and para. In some embodiments of embodiment L represents a covalent bond. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I). In some embodiments embodiment R15selected from-OR16and C1-10perhalogenated.

For example, in some embodiments embodiment z has the value 1, and R15is in position pair, providing compounds of the formula (II-c):

or pharmaceutically acceptable forms of such compounds, where G, L, Ra, Rb, Rc, R15and z have the meaning given in this application. In some embodiments of embodiment L represents a covalent bond. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I). In some embodiments embodiment R15selected from-OR16and C1-10perhalogenated.

For example, in some VA is Ianto embodiment z has the value 2, and one of R15is meta and one R15in the para position, providing compounds of the formula (II-c):

or pharmaceutically acceptable forms of such compounds, where G, L, Ra, Rb, Rc, R15and z have the meaning given in this application. In some embodiments of embodiment L represents a covalent bond. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I). In some embodiments embodiment R15selected from-OR16and C1-10perhalogenated.

For example, in some embodiments of the incarnation, where Z is a phenyl ring and G is a group-ORe, the present invention provides compounds of formula (II-d):

or pharmaceutically acceptable forms of such compounds, where L, Ra, Rb, Rc, R15, Reand z have the meaning given in this application. For example, in some embodiments embodiment z has the value 1, and R15is in the position ortho. In some embodiments embodiment z has the value 1, and R15is in the meta position. In some embodiments embodiment z has the value 1, and R5 is in position pair. In some embodiments of embodiment L represents a covalent bond. In some embodiments embodiment R15selected from-OR16and C1-10perhalogenated.

In some embodiments of the incarnation, where Z is a phenyl ring, G is a group-OReand Reis a phenyl ring, the present invention provides compounds of formula (II-e):

or pharmaceutically acceptable forms of such compounds, where L, Ra, Rb, Rc, R15, Rh, x and z have the meaning given in this application. For example, in some embodiments embodiment z has the value 1, and R15is in the position ortho. In some embodiments embodiment z has the value 1, and R15is in the meta position. In some embodiments embodiment z has the value 1, and R15is in position pair. In some embodiments of embodiment L represents a covalent bond. In some embodiments embodiment R15selected from-OR16and C1-10perhalogenated.

In some embodiments of the incarnation, where Z is a phenyl ring, G is a group-OReand Rerepresents a 5-membered heteroaryl ring, the present invention provides compounds of formula(II-f):

or pharmaceutically acceptable forms of such compounds, where Ya, Yb, Yc, Yd, L, Ra, Rb, Rc, R15and z have the meaning given in this application. For example, in some embodiments embodiment z has the value 1, and R15is in the position ortho. In some embodiments embodiment z has the value 1, and R15is in the meta position. In some embodiments embodiment z has the value 1, and R15is in position pair. In some embodiments of embodiment L represents a covalent bond. In some embodiments embodiment R15selected from-OR16and C1-10perhalogenated.

In some embodiments of the incarnation, where Z is a phenyl ring, G is a group-OReand Rerepresents a 6-membered heteroaryl ring, the present invention provides compounds of formula (II-g):

or pharmaceutically acceptable forms of such compounds, where Wa, Wb, Wc, Wd, We, L, Ra, Rb, Rc, R15and z have the meaning given in this application. For example, in some embodiments embodiment z has the value 1, and R15is in the position ortho. In some embodiments embodiment z has the value 1, and R15 is in the meta position. In some embodiments embodiment z has the value 1, and R15is in position pair. In some embodiments embodiment R15selected from-OR16and C1-10perhalogenated. In some embodiments of embodiment L represents a covalent bond. In some embodiments of the incarnation Wbrepresents N, and Wa, Wc, Wdand Weselected from CH or CRh. In some embodiments of the incarnation Wbrepresents N, Wcrepresents CRhand every Wa, Wc, Wdand Werepresents CH. In some embodiments of the incarnation Wband Wdrepresent N, and Wa, Wc, Wdand Weselected from CH or CRh.

In some embodiments of the incarnation, where Z is a phenyl ring, G is a group-OReand Reis a 9-membered heteroaryl ring, the present invention provides compounds of formula (II-h):

or pharmaceutically acceptable forms of such compounds, where Ye, Yf, Yg, Yi, Yj, Yk, Ym, Yn, L, Ra, Rb, Rc, R15and z have the meaning given in this application. For example, in some embodiments embodiment z has the value 1, and R15náchod is raised in the position ortho. In some embodiments embodiment z has the value 1, and R15is in the meta position. In some embodiments embodiment z has the value 1, and R15is in position pair. In some embodiments embodiment R15selected from-OR16and C1-10perhalogenated. In some embodiments of embodiment L represents a covalent bond.

In some embodiments of the incarnation, where Z is a phenyl ring, G is a group-OReand Reis a 10-membered heteroaryl ring, the present invention provides compounds of formula (II-i):

or pharmaceutically acceptable forms of such compounds, where Wf, Wg, Wh, Wi, Wj, Wk, Wm, Wn, L, Ra, Rb, Rc, R15and z have the meaning given in this application. For example, in some embodiments embodiment z has the value 1, and R15is in the position ortho. In some embodiments embodiment z has the value 1, and R15is in the meta position. In some embodiments embodiment z has the value 1, and R15is in position pair. In some embodiments embodiment R15selected from-OR16and C1-10perhalogenated. In some embodiments of embodiment L represents a covalent bond.

In some embodiments of the incarnation, where Z represents a phenyl ring and G is a group-NReRf, the present invention provides compounds of formula (II-j):

or pharmaceutically acceptable forms of such compounds, where L, Ra, Rb, Rc, Re, Rf, R15and z have the meaning given in this application. For example, in some embodiments embodiment z has the value 1, and R15is in the position ortho. In some embodiments embodiment z has the value 1, and R15is in the meta position. In some embodiments embodiment z has the value 1, and R15is in position pair. In some embodiments embodiment R15selected from-OR16and C1-10perhalogenated. In some embodiments of embodiment L represents a covalent bond. In some embodiments embodiment Reand Rfcombined with education, 3-10-membered heterocyclic ring. In some embodiments embodiment Reand Rfcombined with education 5-14-membered heteroaryl ring.

In some embodiments of the embodiments of formula (II), where Z represents a 5-membered heteroaryl ring, the present invention provides compounds of formula (III-a):

or pharmaceutically acceptable forms of such compounds, where Y 1, Y2, Y3, Y4, G, L, Ra, Rband Rchave the meaning given in this application. In some embodiments of embodiment L represents a covalent bond. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I). In some embodiments of the incarnation Y1represents S, Y2represents CR15, Y3represents N and Y4represents CH or CR15where R15shall have the meaning given above and in this section of the application. In some embodiments of the incarnation Y4represents CH. In some embodiments embodiment Deputy, is present on the Y2represents a C6aryl (e.g. phenyl).

In some embodiments of the incarnation, where Z is a 6-membered heteroaryl ring, the present invention provides compounds of formula (III-b):

or pharmaceutically acceptable forms of such compounds, where W1, W2, W3, W4, G, L, Ra, Rband Rchave the meaning given in this application. In some embodiments of embodiment L represents a covalent bond. In some vari is ntah embodiment G is a-OR e. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I). In some embodiments, embodiment 6-membered heteroaryl ring is a pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl or pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl).

In some embodiments of the incarnation, where Z is a 9-membered heteroaryl ring, the present invention provides compounds of formula (III-c):

or pharmaceutically acceptable forms of such compounds, where Y5, Y6, Y7, Y9, Y10, Y11, Y12, Y13, G, L, Ra, Rband Rchave the meaning given in this application. In some embodiments of embodiment L represents a covalent bond. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I).

In some embodiments of the incarnation, where Z is a 10-membered heteroaryl ring, the present invention provides compounds of formula (III-e):

or pharmaceutically acceptable form such a connection is in, where W6, W7, W8, W9, W10, W11, W12, W13, G, L, Ra, Rband Rchave the meaning given in this application. In some embodiments of embodiment L represents a covalent bond. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I).

In some embodiments of the incarnation, where Z is a 6-membered heterocyclyl, the present invention provides compounds of formula (III-f):

or pharmaceutically acceptable forms of such compounds, where W14, W15, W16, W17, W18, W19, G, L, Ra, Rband Rchave the meaning given in this application. In some embodiments of embodiment L represents a covalent bond. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I).

In another aspect, where Raand Rdcombined with the formation of C3-10carbocycle or 3-14 membered heterocyclyl, the present invention provides compounds of formula (IV):

or pharmaceutically acceptable forms of such compounds, where s is 0, 1 or 2, and W20, W21, W22, W23, G, Rc, Rd, R15and R18have the meaning given above and in this section of the application. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I).

In some embodiments of the incarnation, where s is 0, the present invention provides compounds of formula (IV-a):

or pharmaceutically acceptable forms of such compounds, where G, Rb, Rc, W20, W21and W22have the meaning given above and in this section of the application. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I).

In some embodiments of the incarnation, where s is 0, W21represents NR18and W20, W22and W23independently represent CH2, CHR15or C(R15)2, the present invention provides compounds of formula (IV-b):

or pharmaceutically acceptable forms of such compounds, where G, Rb, Rc, R18and R15have the meaning given above and in this section of the application. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I).

In some embodiments of the incarnation, where s has a value of 1, the present invention provides compounds of formula (IV-c):

or pharmaceutically acceptable forms of such compounds, where G, Rb, Rc, W20, W21, W22and W23have the meaning given above and in this section of the application. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I).

In some embodiments of the incarnation, where s has a value of 1, W21represents NR18and W20, W22and W23independently represent CH2, CHR15or C(R15)2, the present invention provides compounds of formula (IV-d):

or pharmaceutically acceptable forms of such compounds, where G, Rb/sup> , Rc, R18and R15have the meaning given above and in this section of the application. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I).

In some embodiments of the incarnation, where s has a value of 1, W22represents NR18and W20, W21and W23independently represent CH2, CHR15or C(R15)2, the present invention provides compounds of formula (IV-e):

or pharmaceutically acceptable forms of such compounds, where G, Rb, Rc, R18and R15have the meaning given above and in this section of the application. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I).

In some embodiments of the incarnation, where s has a value of 2, the present invention provides compounds of formula (IV-f):

or pharmaceutically acceptable forms of such compounds, where G, Rb, Rc, W20, W21, W22and W23have the meaning given above and in the us oasam section of the application. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I).

In some embodiments of the incarnation, where s has a value of 2, W22represents NR18and W20, W21and W23independently represent CH2, CHR15or C(R15)2, the present invention provides compounds of formula (IV-g):

or pharmaceutically acceptable forms of such compounds, where G, Rb, Rc, R18and R15have the meaning given above and in this section of the application. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I).

In another aspect, where Rcand Rdcombined with the formation of C3-10carbocyclic or 3-14-membered heterocyclic ring, the present invention provides compounds of formula (V):

or pharmaceutically acceptable forms of such compounds, where W24, W26, W27, W28and W30independently represent CH2, CHR15C(R15) 2or NR18not necessarily, where W25and W26substituted condensed-C6aryl ring or the condensed 6-membered heteroaryl ring; t and v independently are 0 or 1; where G, Ra, Rb, R15and R18have the meaning given above and in this section of the application. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I). In some embodiments, the realization of t is set to 0, and v has a value of 0. In some embodiments, the realization of t is set to 0, and v has a value of 1. In some embodiments of embodiment t is 1 and v is 0. In some embodiments of embodiment t is 1 and v is set to 1.

In some embodiments of the incarnation, where t is 0 and v is 0, the present invention provides compounds of formula (V-a):

or pharmaceutically acceptable forms of such compounds, where G, Ra, Rb, W25, W26, W27and W28have the meaning given above and in this section of the application. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some the older variants of embodiment G is not halogen (e.g., -Br, -Cl, -I). In some embodiments of the incarnation W27represents NR18and W25, W26and W28independently represent CH2, CHR15or C(R15)2. In some embodiments of the incarnation W25, W26, W27and W28independently represent CH2, CHR15or C(R15)2.

In some embodiments of the incarnation, where t is 0, v is 0, W27represents NR18and W25, W26and W28independently represent CH2, CHR15or C(R15)2, the present invention provides compounds of formula (V-b):

or pharmaceutically acceptable forms of such compounds, where G, Ra, Rb, R15and R18have the meaning given above and in this section of the application. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I).

In some embodiments of the incarnation, where t has the value 0, and v has a value of 1, the present invention provides compounds of formula (V-c):

or pharmaceutically acceptable forms of such compounds, where G, Ra, Rb, W25, W2627, W28and W29have the meaning given above and in this section of the application. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I). In some embodiments of the incarnation W26represents NR18and W25, W27, W28and W29independently represent CH2, CHR15or C(R15)2. In some embodiments of the incarnation W27represents NR18and W25, W26, W28and W29independently represent CH2, CHR15or C(R15)2. In some embodiments of the incarnation W25, W26, W27, W28and W29independently represent CH2, CHR15or C(R15)2.

In some embodiments of the incarnation, where t is 0, v is 1, W27represents NR18and W25, W26, W28and W29independently represent CH2, CHR15or C(R15)2, the present invention provides compounds of formula (V-d):

or pharmaceutically acceptable forms of such compounds, where G, Ra, Rb, R15and R18have the meaning given above ive this section of the application. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I).

In some embodiments of the incarnation, where t has a value of 1, and v has a value of 1, the present invention provides compounds of formula (V-e):

or pharmaceutically acceptable forms of such compounds, where G, Ra, Rb, W24, W25, W26, W27, W28and W29have the meaning given above and in this section of the application. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I). In some embodiments of the incarnation W25represents NR18and W24, W26, W27, W28and W29independently represent CH2, CHR15or C(R15)2. In some embodiments of the incarnation W26represents NR18and W24, W25, W27, W28and W29independently represent CH2, CHR15or C(R15)2. In some embodiments of the incarnation W27represents NR18and W24, W25, W26, 28and W29independently represent CH2, CHR15or C(R15)2. In some embodiments of the incarnation W24, W25, W26, W27, W28and W29independently represent CH2, CHR15or C(R15)2.

In some embodiments of the incarnation, where t is set to 1, v is 1, W27represents NR18and W24, W25, W26, W28and W29independently represent CH2, CHR15or C(R15)2, the present invention provides compounds of formula (V-f):

or pharmaceutically acceptable forms of such compounds, where G, Ra, Rb, R15and R18have the meaning given above and in this section of the application. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I).

In some embodiments of the incarnation, where t is 0, v is 0, W27and W28independently represent CH2, CHR15and C(R15)2and W25and W26substituted condensed-C6aryl ring, Rcand Rdcombined with the formation of 5,6-bicyclic carbocyclic sleep is about-condensed ring of the formula (V-g):

or its pharmaceutically acceptable forms, where G, Ra, Rband R15have the meaning given above and in this section of the application. In some embodiments embodiment Raand Rbare-H. In some embodiments embodiment z has the value 1. In some embodiments of embodiment G is a-ORe. In some embodiments of embodiment G is a-Br. However, in some embodiments, embodiment G is not halogen (e.g.,- Br, -Cl, -I). In some embodiments embodiment R15selected from-OR16and C1-10perhalogenated.

Examples of compounds according to the present invention

Examples of compounds of formula (I) and (II) and subtypes related to this type of compounds are presented in tables 1a-1m below, and more details are disclosed in the Examples 1-253 presented in this application. Compounds were tested as inhibitors of human FAAH using the method described in Example 351.

In some embodiments embodiment the compound is any of compounds represented in Table 1a, or pharmaceutically acceptable forms of such compounds:

Table 1a

In some embodiments embodiment the compound is any of compounds represented in Table 1b, or a pharmaceutically acceptable forms of such compounds:

Table 1b

In some embodiments embodiment the compound is any of compounds represented in Table 1c, or pharmaceutically acceptable forms of such compounds:

Table 1c

In some embodiments embodiment the compound is any of compounds represented in Table 1d, or pharmaceutically acceptable forms of such compounds:

Table 1d

In some embodiments embodiment the compound is any of compounds represented in Table 1e, or pharmaceutically acceptable forms of such compounds:

Table 1e

In some embodiments embodiment the compound is any of compounds, n is redstavleny in Table 1f, or pharmaceutically acceptable forms of such compounds:

Table 1f

In some embodiments embodiment the compound is any of compounds represented in Table 1, or pharmaceutically acceptable forms of such compounds:

Table 1g

In some embodiments embodiment the compound is any of compounds represented in Table 1h, or pharmaceutically acceptable forms of such compounds:

Table 1h

In some embodiments embodiment the compound is any of compounds represented in Table 1i, or pharmaceutically acceptable forms of such compounds:

Table is CA 1i

In some embodiments embodiment the compound is any of compounds represented in Table 1j, or pharmaceutically acceptable forms of such compounds:

Table 1j

In some embodiments embodiment the compound is any of compounds represented in Table 1k, or pharmaceutically acceptable forms of such compounds:

Table 1k

In some embodiments embodiment the compound is any of compounds represented in Table 1l, or pharmaceutically acceptable forms of such compounds:

Table l

In some embodiments embodiment the compound is any of compounds represented in Table 1, or pharmaceutically acceptable forms of such compounds:

Table 1m

Additional examples of compounds of formula (I), (II), (III) and subtypes related to this type of compounds are presented below in Tables 2a-2e, and disclosed in more detail in the Examples 254-284 presented in this application. Compounds were tested as inhibitors of human FAAH using the method described in Example 351.

In some embodiments embodiment the compound is any of compounds represented in Table 2a, or a pharmaceutically acceptable forms of such compounds:

Table 2a

In some embodiments embodiment the compound is any of compounds represented in Table 2b, or a pharmaceutically acceptable forms of such compounds:

Table 2b

In some embodiments embodiment the compound is any of compounds represented in Table 2c, or pharmaceutically acceptable forms of such compounds:

Table 2c

In some embodiments embodiment the compound is any of compounds represented in Table 2d, or pharmaceutically acceptable forms of such compounds:

Table 2d

In some embodiments embodiment the compound is any of compounds represented in Table 2e, or pharmaceutically acceptable forms of such compounds:

Table 2e

Additional examples of compounds of formula (I), (IV) and (V) and subtypes related to this type of compounds are presented below in Tables 3a-3d and disclosed in more detail in the Examples 285-350 presented in this application. Compounds were tested as inhibitors of human FAAH using the method described in Example 351.

In some embodiments embodiment the compound is any of compounds represented in Table 3a, or pharmaceutically acceptable forms of such compounds:

Table 3a

In some embodiments embodiment the compound is any of compounds represented in Table 3b, or pharmaceutically acceptable forms of such compounds:

Table 3b

In some embodiments embodiment the compound is any of compounds represented in Table 3c, or pharmaceutically acceptable forms of such compounds:

Table 3c

In some embodiments embodiment the compound is any of compounds represented in Table 3d, or pharmaceutically acceptable forms of such compounds:

Table 3d

However, in some embodiments of the embodiments of formula (I) and (II) or subtypes related to this type of compounds, any of the following compounds are specifically excluded:

In some embodiments of the embodiments of formula (I) (II) and (III) or subtypes related to this type of compounds, where R18has the meaning given in this application specifically excluded:

In some embodiments of the embodiments of formula (I), (IV) and (V) or subtypes related to this type of compounds, any of the following compounds, where R18has the meaning given in this application and R15represents-OCH3, -CN, -CO2H, -CO2CH3, -CO2CH2CH3concrete is a Braz excluded:

II. The pharmaceutical composition

In some embodiments, embodiments of the present invention provides a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable form and pharmaceutically acceptable excipient.

Pharmaceutically acceptable excipients include any and all solvents, diluents, or other liquid carriers, dispersing or suspendresume substances, surface-active agents, isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like, which are suitable for a particular desired dosage forms. General principles of formulation and/or pharmaceutical compositions can be found, for example, in Remington''s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21stEdition (Lippincott Williams & Wilkins, 2005).

The pharmaceutical compositions described in this application can be obtained by any method known in the field of pharmacology. Typically, such methods include receiving a stage of bringing the active ingredient into Association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or the packing of the product into a desired single - or mnogochasovuyu unit.

The pharmaceutical composition can be obtained in a Packed form and/or sold without packaging, in the form of individual doses and/or multiple unit doses. Used in this application, the term “unit dose” means a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is usually equal to the dose of the active ingredient that you want to enter the subject, and/or convenient part of such a dosage such as, for example, 1/2 or 1/3 of this dose.

The relative amount of the active ingredient, a pharmaceutically acceptable carrier and/or any additional ingredients in a pharmaceutical composition of the present invention vary depending upon the identity, size and/or condition of the subject, which is treated, and also depend on the route of administration of the composition. As an example, the composition may include from 0.1% to 100% (mass/mass) of the active ingredient.

Pharmaceutically acceptable excipients that are used to receive presents pharmaceutical compositions, include inert diluents, dispersing and/or granulated substances, surfactants and/or emulsifiers, disintegrant, binders, preservatives, buffering agents, lubricants and/or oils. The former is pienty, such as cocoa butter and waxes for suppositories, dyes, coating agents, sweeteners, fragrances and flavorings may also be present in the composition.

Examples of diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, Inositol, sodium chloride, dry starch, corn starch, powdered sugar, etc., and combinations thereof.

Examples granulating and/or dispersing substances include potato starch, corn starch, tapioca starch, matrikamantra, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood processing products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, crosslinked poly(vinyl-pyrrolidone) (crosspovidone, sodium carboximetilkrahmal (sodium starch glycolate), carboxymethylcellulose, crosslinked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pre gelatinizing starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminosilicate (Veegum), sodium lauryl sulfate, Quaternary ammonium compounds, and so the., and their combinations.

Examples of surfactants and/or emulsifiers include natural emulsifiers (for example, Arabian gum, agar, alginic acid, sodium alginate, tragakant, Chondrus, cholesterol, xanthan gum, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [silicate] and Veegum [aluminosilicate of magnesium]), derivatives of long chain amino acids, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, alerby alcohol, treatymonitoring, the glycol distearate, glycerylmonostearate and the propylene glycol monostearate, polyvinyl alcohol)carbomer (for example, carboxypolymethylene, polyacrylic acid, a polymer of acrylic acid and carboxyvinyl polymer), carrageen, cellulose derivatives (for example, sodium carboxymethyl cellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hypromellose, methylcellulose), esters of fatty acids sorbitan (for example, polyoxyethylenesorbitan [Tween 20], polyoxyethylenesorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], servicemanagement [Span 40], servicemonitor [Span 60], corbettreport [Span 65], glycerylmonostearate, servicemanual [Span 80]), esters of polyoxyethylene (for example, Poliak italinvertebrato [Myrj 45], polyoxyethylene-gidrirovannoe castor oil, polyethoxysiloxane castor oil, Polyoxymethylene and Solutol), esters of fatty acids sucrose esters of fatty acids of polyethylene glycol (e.g., Cremophor), polyoxyethylene ethers (for example, polyoxyethyleneglycol ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine, sodium oleate, potassium oleate, etiloleat, oleic acid, tillaart, sodium lauryl sulfate, Pluronic F68, Poloxamer 188, cerimoniale, cetylpyridinium, benzylaniline, docusinate sodium, etc. and/or combinations thereof.

Examples of the binder include starch (e.g. corn starch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactic, mannitol, etc.,), natural and synthetic resins (for example, Arabian gum, sodium alginate, extract of Cartagena, panwar gum, gum, ghatti, vegetable glue from the husk isapol, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, microcrystalline cellulose, cellulose acetate, poly(vinyl pyrrolidone), magnesium aluminosilicate (Veegum) and erbogachan larch), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylate is, waxes, water, alcohol, etc. and/or combinations thereof.

Examples of preservatives include antioxidants, hepatoblastoma substances, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives and other preservatives.

Examples of antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butyl-hydroxyanisole, butyl-hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite and sodium sulfite.

Examples chelat forming substances include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, disodium edetate, trinacria edetate, calcium disodium edetate, dicalcium edetate, Dikili edetate and the like), citric acid and its salts and hydrates (e.g., monohydrate citric acid), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Examples of antimicrobial preservatives include benzylaniline, benzenehexachloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, kidmuseinu, phenol, Phenoxyethanol, phenethyl alcohol,nitrate of finalstate, propylene glycol and thimerosal.

Examples of antifungal preservatives include butyl paraben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate and sorbic acid.

Examples of alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorbutanol, hydroxybenzoate and phenethyl alcohol.

Examples of acid preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, along with dehydroacetic acid, ascorbic acid, sorbic acid and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, datarock mesilate, cetrimide, butyl-hydroxyanisole (BHA), butyl-hydroxytoluene (BHT), Ethylenediamine, sodium lauryl sulfate (SLS), laurelthirst sodium (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, nealon, Kathon and Euxyl. In some embodiments embodiment the preservative is an antioxidant. In other variants of the embodiment, the preservative is a chelate forming agent.

Examples of buffering agents include citrate buffer solution, acetate buffer solution, phosphate buffer solutions, ammonium chloride, carb is NAT calcium, calcium chloride, calcium citrate, glubionate calcium, gluceptate calcium, calcium gluconate, D-gluconic acid, glycerol calcium, calcium lactate, propanoic acid, levulinic calcium, pentane acid, hydroalcoholic calcium, phosphoric acid, tricalcium phosphate, hydroxyphosphate calcium, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, hydroalcoholic potassium, dihydroorotase phosphate, califofnia mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, hydroalcoholic sodium, mononitrite, acrivastine mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, ringer's solution, ethyl alcohol, etc., and combinations thereof.

Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, silicon dioxide, talc, malt, glycerinated, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, lauryl sulfate, magnesium lauryl sulfate, etc., and combinations thereof.

Examples of oils include almond oil, apricot stone oil, avocado oil, babassu, bergamot, black currant seed, borage pharmacy, juniper oil, canola, caraway, Carnauba, castor, cinnamon, cocoa butter, coconut about the yekha, cod liver, coffee, corn, cotton seed, EMU, eucalyptus, evening primrose, fish oil, oil from flax seeds, geraniaceae, pumpkin, grape seed, hazelnut, hyssop pharmacy, isopropylmyristate, jojoba oil, moluccana, of Lavandin, lavender, lemon, butter cubby, Australian nut, mallow, mango seeds, seeds pennica meadow, mink oil, oil of nutmeg, olive, orange, fish oil orange trachyte, palm, palm stone, stone fruit, peach, peanut, poppy seed, pumpkin seed, rapeseed, from rice bran, rosemary, safflower, sandalwood, sasquana, savory, sea buckthorn, sesame, oil from the seeds of the Shea(oil on wood), silicone savioe, sunflower, tea, king, Tsubaki, before planting, walnut and wheat germ. Examples of oils include, but are not limited to, butilstearat, triglyceride Caprylic acid, capric triglyceride acid, cyclomethicone, diethylbenzene, Dimethicone 360, isopropylmyristate, mineral oil, octyldodecanol, alerby alcohol, silicone oil, and combinations thereof.

Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, idgie dosage forms may include inert diluents, usually used in this field, such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (for example, oil of cotton seed, peanut oil, corn oil, the oil from the leaves of plants, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of fatty acids sorbitan, and mixtures of these substances. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifiers and suspendresume agents, sweeteners, fragrances and flavors. In some embodiments, embodiments for parenteral administration, the conjugates of the present invention is mixed with solubilizers agents such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.

Injectable preparations, for example, sterile aqueous or oily suspension for injection can be formulated according to methods known from the prior art, using suitable dispersing or wetting agents and suspendida substances. Sterile is a preparation for injection can be a sterile solution, the suspension or emulsion for injection in a non-toxic parenterally acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol. Acceptable carriers or solvents that can be used include water, ringer's solution U. S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are usually used as a solvent or medium for suspension. For these purposes you can use any light non-volatile oils, including synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid, is used to produce drugs for injection.

Compositions for injection can be sterilized, for example, by filtration through a bacterial filter or by incorporating stabiliziruyushchikh substances in the form of sterile solid compositions which can be dissolved or dispersing in sterile water or other sterile environment for injection before use.

For prolongation of drug action, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be done by using a liquid suspension of crystalline or amorphous material with poor water-solubility. The rate of absorption of the drug then depends on the speed of e is about dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of parenterally injected drugs obtained by dissolution or suspension of the drug in an oil medium.

Compositions for rectal or vaginal introduction typically represent suppositories, which can be obtained by mixing the conjugates of the present invention with suitable non-irritating with excipients or carriers such as cocoa butter, polyethylene glycol or wax for suppositories, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms the active ingredient is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and/or a) fillers or creating the amount of additives such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidon the Inon, sucrose and Arabian gum, (c) humectants, such as glycerol, d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) slow dissolving substances such as paraffin, f) absorption accelerators such as Quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerylmonostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures of these substances. In the case of capsules, tablets and pills, the dosage form can include a buffering agent.

Solid compositions of a similar type can be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight polyethylene glycols and the like. Solid dosage forms such as tablets, coated tablets, capsules, pills and granules can be obtained with coatings and shells, such as intersolubility coatings and other coatings well known in the field of pharmaceutical formulation. They optionally may include substances that make the composition C is Otradnoe, and may have such a composition that the release of the active ingredient(ingredient) occurred only, or preferentially, in a certain part of the intestinal tract, it is not necessarily slow. Examples of compositions for coatings and shells, which can be used include polymeric substances and waxes. Solid compositions of a similar type can be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight polyethylene glycols and the like.

The active ingredients can be in micro-encapsulated form with one or more excipients mentioned above. Solid forms such as tablets, coated tablets, capsules, pills and granules can be obtained with coatings and shells, such as enterosorbents coating that controls the release coatings and other coatings well known in the field of pharmaceutical formulation. In such solid forms of active ingredient may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such forms may include, as it usually occurs, additional substances, in addition to inert diluents, for example, lubricant for tableting and other support on which the additives for tabletting, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may include a buffering agent. They optionally may include substances that make the composition opaque, and may have such a composition that the release of the active ingredient(ingredient) occurred only, or preferentially, in a certain part of the intestinal tract, it is not necessarily slow. Examples of compositions for coatings and shells, which can be used include polymeric substances and waxes.

Dosage forms for local and/or percutaneous introduction of the compounds of the present invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalations and/or patches. Typically, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and/or any necessary preservatives and/or buffers that will be required. In addition, the present invention provides for the use of transdermal patches, which often have the added advantage of providing controlled delivery of the active ingredient into the body. These forms can be obtained, for example, by dissolving and/or dispersing the active ingredient in a suitable medium. Alternative or additionally, the speed can be controlled either by software controlling the speed of the membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.

Suitable devices for use in intradermal delivery of the pharmaceutical compositions described in this application include devices with short needles, such as described in U.S. patents№№ 4886499; 5190521; 5328483; 5527288; 4270537; 5015235; 5141496 and 5417662. Intradermal compositions can be entered using the devices, which limit the effective length of penetration of the needle into the skin, such as described in PCT publication WO 99/34850 and their functional equivalents. Inkjet devices for injection, which delivers liquid vaccine into the skin without needle through the device for injection and/or through a needle that pierces the top layer of the skin and forms a jet that reaches the dermis layer, are suitable. Inkjet devices for injection is described, for example, in U.S. patents№№ 5480381; 5599302; 5334144; 5993412; 5649912; 5569189; 5704911; 5383851; 5893397; 5466220; 5339163; 5312335; 5503627; 5064413; 5520639; 4596556; 4790824; 4941880; 4940460; and PCT publication WO 97/37705 and WO 97/13537. Ballistic device delivery of the powder/particles, which use compressed gas to accelerate penetration of the vaccine in powder form through the outer layers of skin into the dermis, are appropriate. Alternative or additionally, traditional syringes can be used in classic Mantoux test method for intradermal injection.

Compositions suitable for topical administration, include, but are not limited to those who, liquid and/or semi-liquid preparations such as liniments, lotions, emulsions oil-in-water and/or water-in-oil, such as creams, ointments and/or pasta and/or solutions and/or suspensions. Compositions for topical administration, for example, can include about 1% to about 10% (mass/mass) of the active ingredient, although the concentration of the active ingredient may be as high as permitted by the limits of solubility of the active ingredient in the solvent. Compositions for topical administration, in addition, may include one or more additional ingredients described in this application.

The pharmaceutical composition of the present invention can be produced, packaged and/or delivered for sale in a form suitable for pulmonary insertion through the mouth. Such composition may include dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions convenient in the form of dry powders for administration using a device comprising a reservoir dry powder, which can be directed flow of propellant to disperse the powder, and/or using kumarapalayam container with solvent/powder for dispersion, such as a device comprising the active ingredient, RAS is voennyi and/or suspended in the low-boiling propellant in a tightly closed container. Such powders comprise particles, where at least 98% of the mass. particles have a diameter of more than 0.5 nanometers and at least 95% of the particles have a diameter less than 7 nanometers. Alternatively, at least 95% of the mass. particles have a diameter greater than 1 nanometer, and at least 90% of the particles have a diameter less than 6 nanometers. The dry powder composition may include a solid diluent in the form of a fine powder, such as sugar and convenient way to provide in a single dosage form.

Low-boiling propellants typically include a liquid propellant having a boiling point below 650F(18,30(C) at atmospheric pressure. Typically, the propellant may vary from 50 to 99.9% (mass/mass) of the composition, and the active ingredient may be from 0.1 to 20% (mass/mass) of the composition. The propellant, in addition, may include additional ingredients, such as liquid nonionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as the particles comprising the active ingredient).

The pharmaceutical compositions of the present invention formulated for pulmonary delivery, can provide the active ingredient in the form of drops of a solution and/or suspension. Such compositions can be obtained by the UE is cowani and/or delivered for sale as water and/or dilute alcohol solutions and/or suspensions, optionally sterile, comprising the active ingredient and conveniently be administered using any spray and/or spray device. Such compositions can also include one or more additional ingredients including, but not limited to, an odorant, such as saccharin sodium, volatile oils, buffering agent, a surfactant and/or a preservative, such as methylhydroxybenzoate. Drops, obespechenie way of introduction, may have an average diameter ranging from about 0.1 to about 200 nanometers.

The compositions described in this application as useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition of the present invention. Another composition suitable for intranasal, is a coarse powder comprising the active ingredient and having an average particle size of from about 0.2 to 500 μm. Such a composition is administered by rapid inhalation through the nasal passage from a container containing the powder held in the immediate vicinity of the nostrils.

Compositions suitable for nasal administration, for example, may include from about 0.1% (mass/mass) and up to 100% (mass/mass) of the active ingredient, and may include one or more additional ingredients, op the toboggan in this application. The pharmaceutical composition of the present invention can be produced, packaged and/or delivered for sale in a form suitable for buccal administration. Such compositions, for example, can be in the form of tablets and/or pellets produced using traditional methods, and can contain, for example, from 0.1 to 20% (mass/mass) of the active ingredient, the remainder is orally dissolvable and/or degradable composition and, optionally, one or more additional ingredients described in this application. Alternatively, compositions suitable for buccal injection may include powder and/or applied in the form of an aerosol and/or sprayed solution and/or suspension comprising the active ingredient. Such powder applied in aerosol form and/or sprayable compositions, in their dispersion, can have an average size of the particles and/or droplets in the range from about 0.1 to about 200 nanometers and, in addition, may include one or more additional ingredients described in this application.

The pharmaceutical composition of the present invention can be produced, packaged and/or delivered for sale in a form suitable for ophthalmic administration. Such compositions, for example, can be in the form of eye drops including, for example, 0,1/1,0% (mass/mass) RAS is a thief and/or suspension of the active ingredient in aqueous or oily liquid medium. Such drops can also include buffering agents, salts and/or one or more other optional ingredients described in this application. Others enter the eye through the composition that are useful include compositions containing the active ingredient in microcrystalline form or in a liposomal form of the drug. Ear drops and/or eye drops are provided as covered by the scope of the present invention.

Although the descriptions of pharmaceutical compositions provided in the present application is primarily directed to pharmaceutical compositions which are suitable for administration to humans, experts should be understood that such compositions generally are suitable for administration to animals of any kind. Modification of pharmaceutical compositions suitable for administration to a person to make such compositions suitable for administration to various animals is well known, and veterinary pharmacologist with average skills can develop and/or implement such modification using conventional experimentation. General considerations on the formulation and/or pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21ststed., Lippincott Williams & Wilkins, 2005.

Also covered hereby izobreteny the m pharmaceutical packaging and/or sets. Provided by the invention for pharmaceutical packaging and/or kits can include provided by the invention composition and the container (e.g., vial, ampoule, bottle, syringe, and/or dosing container or other suitable container). In some embodiments, embodiments provide kits, optionally, may further include a second container comprising a suitable aqueous media for dilution or suspension provide a composition for its preparation for administration to a subject. In some embodiments, embodiments provide content container with a composition and a container of solvent combined with the receipt of at least one unit dosage form.

In some embodiments, embodiments provide a composition of the present invention may be useful in connection with devices controlled by the subject of the introduction of opioid analgesia (PCA), when a subject can enter, for example, the opioid analgesia as necessary to cope with the pain.

Optionally, a separate container may include one or more compartments for keeping them provide a composition and/or a suitable aqueous media for suspension or dilution. In some embodiments, embodiment a separate container may be suitable for modification of t is thus, so that the container can undergo physical modification that allows you to combine separate and/or components of the individual offices. For example, a package of foil or plastic may include two or more branches, separated perforirovannoi wall that can be destroyed, so you can combine the contents of two separate branches immediately after the signal to destroy the wall. Pharmaceutical packaging or set, thus, may include containers with multiple compartments, including provide a composition and a suitable solvent and/or a suitable aqueous medium for suspension.

Optionally, such kits according to the present invention is additionally provided with instructions for use. Such instructions typically include, for example, instructions for dosage and administration. In other variants of the embodiment, the instructions may also include additional details, refer to the special instructions for the specific container and/or delivery systems. And in addition, the instructions may include specific instructions for use with and/or in combination with an additional therapy. In one non-limiting example, the compositions of the present invention can be used in conjunction with the introduction of opioid analgesia, which, it is interesting, may include the use of devices controlled by the subject of the introduction of opioid analgesia (PCA). Thus, instructions for use provided compositions can include instructions for use with PCA devices for injection.

III. Methods of application and treatment

The present invention provides methods of treating FAAH-mediated condition comprising the administration to a subject in need, a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable forms.

The present invention also provides methods of inhibiting FAAH in a subject, comprising introducing to a subject in need, a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable forms.

The present invention also provides a method of inhibiting activation of FAAHin vitroorex vivocomprising contacting FAAH protein with the compound of the formula (I) in a quantity sufficient to reduce the activation FAAH path.

The present invention also provides the use of compounds of formula (I) for treating FAAH-mediated condition in the subject.

The present invention also provides the use of compounds of formula (I) to obtain medicines. In some embodiments, voploscheni the drug is useful for treating FAAH-mediated condition.

"Subject", the introduction to which is provided includes, but is not limited to this man (i.e. a man or woman of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young, middle-aged or older) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercial interest mammals, such as cattle, pigs, horses, sheep, goats, cats and/or dogs; and/or birds, including commercial interest in birds, such as chickens, ducks, geese and/or turkeys.

As used in this application and unless otherwise indicated, the terms "treat," "treating" and "treatment" means the action that occurs when a subject suffering from said disease, disorder or condition, which reduces the severity of such disease, disorder or condition, or retards or slows the progression of such disease, disorder or condition.

As used in this application, unless otherwise indicated, the terms "prevent", "prevention" and "prevention" means an action that occurs before the subject begins to suffer from the specified disease, disorder or condition that inhibits or cigaettes such disease, disorder or condition.

As used in this application and unless otherwise indicated, the terms "to observe and treat further and further observation and treatment" includes preventing relapse specified disease, disorder or condition in the subject, which has already suffered from this disease, disorder or condition, and/or extension of the period of time during which the subject who suffered from this disease, disorder or condition is in remission. The terms cover a modulation threshold, development and/or duration of the disease, disorder or condition or change how the subject responds to this disease, disorder or condition.

As the term is used in this application and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide therapeutic benefit in the treatment or further management of the disease, disorder or condition, or to delay or minimize one or more symptoms associated with a disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in treating ileannasim the conduct of such disease, disorder or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or eliminates the symptoms or causes of a disease or condition, or enhances therapeutic efficacy of another therapeutic agent.

As the term is used in this application and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent the disease, disorder or condition or one or more symptoms associated with a disease, disorder or condition, or prevent its recurrence. Prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with another agent that provides a prophylactic benefit in the prevention of disease, disorder or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

As the term is used in this application "inhibition", "inhibit", "inhibiting" and "inhibitor" and the like refer to the ability of the compound to reduce, slow down to stop or prevent the ü activity of a biological process (e.g., FAAH activity in the cell compared with the carrier.

The term "FAAH-mediated condition", as used in this application, refers to a disease, disorder or condition that can be treated by inhibition of FAAH activity. "Disease", "disorder" or "condition" represents the terms that are used interchangeably in this application. FAAH-mediated condition include, but are not limited to, painful conditions, inflammatory conditions, immune disorders, disorders of the Central nervous system, metabolic disorders, cardiac disorders, and glaucoma.

In some embodiments the embodiment of the FAAH-mediated condition is a painful condition. As used in this application, "a painful condition" includes, but is not limited to, neuropathic pain (for example, peripheral neuropathic pain, Central pain, differentional pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain, as postoperative pain, such as pain resulting from plastic surgery of hip, knee, or so on), preoperative pain, irritation nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transitors the Yu acute pain), non-inflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain arising from itching, painful bladder syndrome, pain associated with premenstrual dysphoric disorder and/or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with preterm birth, the pain associated with withdrawal symptoms from drug addiction, pain in joints, arthritic pain (e.g. pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or arthritis Reiter), lumbar-sacral pain, musculoskeletal pain, headache, migraine, muscle pain, lumbar pain, neck pain, toothache, dental/maxillofacial pain, visceral pain and the like.

One or more painful conditions provided in this application may include mixtures of different types of pain, above and in this section of the application (for example, nociceptive pain, inflammatory pain, neuropathic pain, etc). In some embodiments, the embodiment of a certain type of pain can dominate. In other embodiments, the embodiment causes pain when standing includes two or more types of pain, without any dominiruyushchego. An experienced Clinician will be able to determine the dose to obtain a therapeutically effective amount for a specific subject on the basis of the painful condition.

In some embodiments embodiment painful condition is a neuropathic pain. The term "neuropathic pain" refers to pain in the nerve damage. Neuropathic pain is different from nociceptive pain, which is pain caused by acute tissue damage involving small cutaneous nerves or small nerves in the muscle or connective tissue. Neuropathic pain is typically a long-term or chronic and often develops within a few days or months after the initial acute tissue damage. Neuropathic pain may include persistent spontaneous pain and allodynia, which is a painful response to a stimulus that is not normally painful. Neuropathic pain can also be characterized by hyperalgesia, which is amplified response to a painful stimulus, which is usually trivial, such as a pin prick. State neuropathic pain can develop after nerve damage, and the resulting pain can last for months or years, even after the zlecenia initial damage. Nerve damage may occur in the peripheral nerves, posterior roots, spinal cord or in some areas of the brain. The state of neuropathic pain include, but are not limited to, diabetic neuropathy (e.g., peripheral diabetic neuropathy; sciatica; non-specific lumbar pain; pain in multiple sclerosis; their carpal canal syndrome, fibromyalgia; HIV-associated neuropathy; neuralgia (e.g., post-herpetic neuralgia, trigeminal neuralgia), pain caused by physical injury (e.g., amputation; surgery, invasive medical procedures, toxins, burns, infections), pain caused by cancer or chemotherapy (e.g., chemotherapy-induced pain, such as that induced by chemotherapy peripheral neuropathy)and the pain caused by inflammatory condition (e.g., chronic inflammatory condition). Neuropathic pain may result from disorders of the peripheral nerves, such as neuroma; nerve compression; compression of the nerve, stretching of the nerve or incomplete nerve crossing; mononeuropathy or PN. Neuropathic pain can also be caused by disorders such as compression sadakosasada ganglion; inflammation of the spinal cord, injury, tumors or hemisection pinnage brain; tumors of the brain stem, thalamus or cortex; or injury of the brain stem, thalamus or cortex.

Symptoms of neuropathic pain are heterogeneous, and they are often called spontaneous firing and acute pain, or are long burning pain. In addition, there is pain associated with normally nebriini sensations, such as tingling type "pin and needle pricks" (paresthesia and dysesthesia), increased sensitivity to prikazane (hyperesthesia), pain after safe stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, low-temperature, mechanical hyperalgesia), long-lasting pain sensation after removal of the stimulus (hyperpathia) or absence or deficiency of selective sensory pathways (hypoalgesia).

In some embodiments embodiment painful condition is a non-inflammatory pain. Types of non-inflammatory pain include, without limitation, peripheral neuropathic pain (such as pain caused by a lesion or dysfunction of the peripheral nervous system), Central pain (for example, pain caused by a lesion or dysfunction of the Central nervous system), differentional pain (n is an example, the pain caused by the loss of sensory input into the Central nervous system), chronic nociceptive pain (e.g., some types of cancer pain), harmful stimulus of nociceptive receptors (for example, pain that is felt in response to tissue damage or impending tissue damage), phantom pain (e.g. pain, felt in the parts of the body, which no longer exists, for example, in the limb, which amputated), pain, perceived psychiatric subjects (for example, pain when there is no physical cause) and wandering pain (e.g. pain with continuously variable localization in the body).

In some embodiments embodiment painful condition is an inflammatory pain. In some embodiments the embodiment of the painful condition (for example, inflammatory pain) associated with the inflammatory condition and/or immune disorder.

In some embodiments the embodiment of the FAAH-mediated condition is an inflammatory condition. The term "inflammatory condition" refers to such diseases, disorders or conditions which are characterized by signs of pain (pain due to the formation of harmful substances and the stimulation of nerves), heat (heat as a result of vasodilation), redness of the skin (redness as a result of vasodilation and blood flow), swelling (tumor in the result of the excessive inflow or restricted outflow of fluid), and/or loss of function loss of function, which may be partial or complete, temporary or permanent. Inflammation takes many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatoses, hyperplastic, hypertrophic interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferative, pseudomembrane, purulent, sclerosing, ceroplastes, serous, simple, specific, substrate, pyogenic, toxic, traumatic, and/or ulcerative inflammation.

Examples of inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, autoimmune hemolytic anemia, asthma, Takayasu (for example, polyarteritis, temporal arteritis diagnostics, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and arthritis Reiter), Ankylosaurus spondylitis, amylases, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, khron the ical prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, ceratomyxosis, diverticulitis, diabetes (e.g., diabetes mellitus type I, diabetes mellitus type 2), skin disease (e.g. psoriasis, eczema, burns, dermatitis, pruritus (itching)), endometriosis syndrome Guillena-Barre, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraleve headaches, headaches and nervous tension), bowel obstruction (for example, postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purple, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from such as peptic ulcers, regional enteritis, diverticulitis, gastrointestinal hemorrhage, eosinophilic gastrointestinal disorder (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis, gastritis, diarrhea, gastroesophageal reflux (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (for example, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, colitis mixed type, syndrome Bechet, colitis indeterminate t is a) and the syndrome of inflamed bowel (IBS)), lupus, multiple sclerosis, focal scleroderma, malignant gravis, myocardial ischemia, nephrotic syndrome, common bladderwort, pernicious anemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neurospine associated with disorders of the brain (e.g., Parkinson's disease, Huntington disease and Alzheimer's disease), prostatitis, chronic inflammation associated with cranial radiation lesions, inflammatory pelvic disease, reperfusion lesion, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, sciaridae, sarcoidosis, spondyloarthropathy, Sjogren syndrome, thyroiditis, graft rejection, tendonitis, injury or damage (e.g. caused by frostbite, chemical irritants, toxins, scarring, burns, physical traumas), vasculitis, vitiligo, and granulomatous's granulomatosis. In some embodiments, embodiments of the inflammatory disorder is selected from arthritis (e.g. rheumatoid arthritis), inflammatory bowel disease, syndrome popularnego bowel, asthma, psoriasis, endometriosis, interstitial cystitis and prostatitis. In some embodiments, embodiments of the inflammatory condition is an acute inflammatory condition (e.g., the inflammation caused in the under). In some embodiments, embodiments of the inflammatory condition is a chronic inflammatory condition (such as condition caused by asthma, arthritis and inflammatory bowel disease). The connection can also be useful for treatment of inflammation associated with trauma and non-inflammatory myalgia. The connection can also be useful for treatment of inflammation associated with cancer.

In some embodiments the embodiment of the FAAH-mediated condition is an immune disorder. Immune disorders, such as auto-immune disorders include, but are not limited to, arthritis (including rheumatoid arthritis, spondyloarthropathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren syndrome, Ankylosaurus spondylitis, undifferentiated spondylitis, a disease Bechet, autoimmune hemolytic anemia, multiple sclerosis, amyotrophic lateral sclerosis, amylases, acute shoulder pain, psoriatic and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin disease (e.g. psoriasis, eczema, burns, dermatitis, pruritus (itch), enuresis, eosinophilic disease, gastrointestinal disorder (e.g., selected from such as peptic ulcers, regional entery is, diverticulitis, gastrointestinal hemorrhage, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis, gastritis, diarrhea, gastroesophageal reflux (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (for example, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, colitis mixed type, syndrome Bechet, colitis unspecified type) and the syndrome of inflamed bowel (IBS) and disorder, the severity of which can be facilitated by using gastroprokinetic means (for example, ileus, postoperative ileus and ileus during sepsis; gastroesophageal reflux (GORD, or its synonym GERD); eosinophilic esophagitis, gastroparesis, such as diabetic gastroparesis; intolerance to certain foods and food allergies and other functional bowel disorders such as non-ulcer dyspepsia (NUD) and non-cardiac pain in the chest (NCCP, including rib chondrite)).

In some embodiments, embodiments of inflammatory disorders and/or immune disorder is a gastrointestinal disorder. In some embodiments, embodiments of the gastro-intestinal disorder in which elected from gastrointestinal disorders (e.g., selected from such as peptic ulcers, regional enteritis, diverticulitis, gastrointestinal hemorrhage, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis, gastritis, diarrhea, gastroesophageal reflux (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (for example, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, colitis mixed type, syndrome Bechet, colitis unspecified type) and the syndrome popularnego bowel (IBS)). In some embodiments, embodiments of the gastrointestinal disorder is an inflammatory bowel disease (IBD).

In some embodiments, embodiments of inflammation and/or immune disorder is a skin disease. In some embodiments the embodiment of the skin disease is a pruritus (itching), psoriasis, eczema, burns or dermatitis. In some embodiments the embodiment of the skin disease is a psoriasis. In some embodiments the embodiment of the skin disease is an itch.

In some embodiments the embodiment of the FAAH-mediated condition is a disorder of the Central nervous system (CNS) ("CNS disorder"). Examples of CNS Rosstroy what to include, but not limited to, neurotoxicity and/or neurotrauma, stroke, multiple sclerosis, spinal injuries, epilepsy, mental disorder, a condition associated with sleep disorders, movement disorder, nausea and/or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease and drug addiction.

In some embodiments embodiment, the CNS disorder is a neurotoxicity and/or neurotrauma, for example, as a result of acute neuronal injury (e.g. traumatic brain damage (TBI), stroke, epilepsy) or chronic neurodegenerative disorder (e.g., multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease). In some embodiments, embodiments of the compound of the present invention provides a neuroprotective effect against, for example, acute neuronal injury or chronic neurodegenerative disorders.

In some embodiments embodiment, the CNS disorder is a hit (e.g., ischemic stroke).

In some embodiments embodiment, the CNS disorder is a multiple sclerosis.

In some embodiments embodiment, the CNS disorder is a lesion of the spinal cord.

In some embodiments of the incarnation destroy the creation of the Central nervous system is a epilepsy.

In some embodiments embodiment, the CNS disorder is a mental disorder such as depression, anxiety or related to the alarm condition, learning disability or schizophrenia.

In some embodiments embodiment, the CNS disorder is a depression. "Depression", as the term is used in this application includes, but is not limited to, depressive disorders or conditions such as, for example, a deep depression (e.g., unipolar depression), estimatesa disorders (e.g. chronic depression in mild), bipolar disorder (e.g., manic-depressive disorder), seasonal affective disorder and/or depression associated with drug addiction (e.g., withdrawal). Depression can be a clinical or subclinical depression. Depression may be associated with or premenstrual syndrome and/or premenstrual dysphoric disorder.

In some embodiments embodiment, the CNS disorder is an anxiety. "Anxiety," as this term is used in this application includes, but is not limited to, anxiety and related to anxiety States, such as, for example, clinical anxiety, panic disorder, agoraphobia, generalized anxiety, JV is Titicaca phobias, social phobia, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder, disorder associated with adaptation with symptoms of panic, anxiety associated with depression, anxiety, due to a General medical condition, and induced by certain substances anxiety, anxiety associated with drug addiction (e.g., withdrawal, addiction, recovery), and anxiety associated with nausea and/or vomiting. This treatment can also cause or contribute to sleepiness in a subject (e.g., a subject suffering from anxiety).

In some embodiments embodiment, the CNS disorder is a disorder of the ability to learn (e.g., attention deficit disorder(ADD)).

In some embodiments embodiment, the CNS disorder is a schizophrenic.

In some embodiments embodiment, the CNS disorder is a condition associated with sleep disorders. "Conditions associated with sleep disorders" include, but are not limited to, insomnia, narcolepsy, apnea during sleep, tired leg syndrome (RLS), the syndrome delayed sleep phase (DSPS), musculoskeletal disorder with periodicheskimi movements of the limbs (have plmd), syndrome of abrupt decrease the frequency and depth of breathing, behavioral Rosstroy is in rapid eye movement (RBD), sleep disturbances in shift work (SWSD) and sleep problems (e.g., parasomnias, such as nightmares, night terrors, talking in sleep, the noise in my head, snoring and coupled to the jaw and/or teeth grinding (bruxism).

In some embodiments embodiment, the CNS disorder is a movement disorder, for example, disorders associated with basal nuclei of the brain, such as Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, the syndrome of Gilles de La Tourette's, late dyskinesia and dystonia.

In some embodiments embodiment, the CNS disorder is a disease of Alzheimer's.

In some embodiments embodiment, the CNS disorder is an amyotrophic lateral sclerosis (ALS).

In some embodiments embodiment, the CNS disorder is a nausea and/or vomiting.

In some embodiments embodiment, the CNS disorder is a drug addiction (for example, addiction to opiates, nicotine, cocaine, stimulants, or alcohol).

In other embodiments, the embodiment of the FAAH-mediated condition is a cardiac disorder, for example, selected from hypertension, circulatory shock, reperfusion of myocardium lesions and atherosclerosis.

In some embodiments the embodiment of the FAAH-mediated with the standing is a metabolic disorder (e.g., associated with the depletion of the state associated with obesity status or complications).

In some embodiments embodiments, the metabolic disorder is associated with a depletion state. "Associated with the depletion of the state", as the term is used in this application includes but is not limited to, anorexia and cachexia of different nature (for example, weight loss associated with cancer, weight loss associated with other common medical conditions, weight loss associated with failure in business and the like).

In some embodiments embodiments, the metabolic disorder is linked with obesity condition or its complications. "Associated with obesity status", as the term is used in this application includes, but is not limited to, obesity, unwanted weight gain (e.g., medication-induced weight gain as a result of Smoking cessation) and disorders associated with obesity (for example, uncontrolled overeating, bulimia, an irresistible craving for food or lack of appetite control, each of which optionally can lead to unwanted weight gain or obesity). "Obesity" and "suffering from obesity", " as these terms are used in this application belong to the class I obesity, class II obesity, class III coolant is rhenium and previous obesity status (for example, being "overweight"), as defined by the world Health Organization.

The reduction of fat accumulation, as expected, can provide a variety of primary and/or secondary beneficial effects in a subject (for example, a subject who has been diagnosed with a complication associated with obesity, such as, for example, increased sensitivity to insulin (for example, a subject who has been diagnosed with diabetes mellitus type II); reduction of high blood pressure; reduction of elevated cholesterol levels; and/or reduced (or reduced risk or progression) of ischemic heart disease, arterial disease, angina, myocardial infarction, stroke, migraine headaches, congestive heart failure, deep venous thrombosis, pulmonary embolism, gallstones, gastroesophageal reflux, obstructive apnea during sleep is associated with obesity-hypoventilation syndrome, asthma, gout, low mobility, back pain, erectile dysfunction, urinary incontinence, liver disease (e.g., fatty liver disease, cirrhosis, alcoholic cirrhosis, mediated by endotoxin liver injury) or chronic renal failure. Thus, the method according to the present invention is useful for obese subjects, diabeticscialis and suffering from alcoholism entities.

In some embodiments, embodiments of the treatment associated with obesity condition or its complications include reduction of body weight in the subject. In some embodiments, embodiments of the treatment associated with obesity condition or its complications includes the control of appetite in the subject.

In other embodiments, the embodiment of the FAAH-mediated condition is a glaucoma.

IV. Introduction

Presents compounds can be administered using any amount and any route of administration effective for treatment. The exact amount needed for different subjects will be different, depending on the species, age and General condition of the subject, the severity of infection, the specific composition, method of its introduction, the nature of its activity, etc.

The compounds presented in this application, typically formulated in a unit dosage form for ease of administration and uniform dosing. However, it should be clear that the total daily quantity of compositions of the present invention is determined by the physician based on the weighted medical evaluation. The specific therapeutically effective dose for any particular subject or organism depends on various factors, including disease, disorder or condition to be treated, and the severity of the disorder; the activity of the concrete is th used active ingredient; the specific composition; the age, body weight, General health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient; the duration of the treatment; drugs used in combination or concurrently with the specific active ingredient; and like factors well known in medicine.

Compounds and compositions presented in this application, you can enter any means, including oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricularly, percutaneous, intradermal, rectal, intravaginal, intraperitoneally, local (in the form of powders, ointments, creams, and/or drops), through the mucous membrane, nasal, buccal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray and/or aerosol. Specific envisage pathways include systemic intravenous injection, regional introduction through blood and/or lymph, and/or direct injection into the affected area. As a rule, the most suitable route of administration depends on various factors, including the nature of the funds (e.g. the, its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., capable or not the subject to tolerate oral administration), etc.

The exact amount of compound necessary to achieve a therapeutically effective amount, for different subjects will vary, depending, for example, on the type, age and General condition of the subject, the severity of side effects or disorders, type-specific compounds(compounds), as a way of introduction, etc., the Desired dose can be administered three times a day, twice a day, once a day, every other day, every three days, every week, every two weeks, every three weeks or every four weeks. In some embodiments, embodiments of the desired dose can be administered using separate introductions (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or more injections).

In some embodiments, embodiments a therapeutically effective amount of the compound for introducing one or more times per day for an adult weighing 70 kg can incorporate some of 0.0001 mg to about 3,000 mg, from about 0,0001 mg to about 2000 mg, from about of 0.0001 mg to about 1000 mg, from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 1 mg to about 100 mg, OK is around 10 mg to about 1000 mg, or from about 100 mg to about 1000 mg of the compounds of the present invention on a standard unit dosage forms. It should be clear that the dose ranges described in this application provide guidance for the introduction of the provided pharmaceutical compositions adults. Necessary for the introduction of a number, for example, a child or young person identifies the medical practitioner or specialist in this field, and it may be lower or the same, which is administered to adults.

Also it should be clear that the compound or composition, described in this application, you can type in combination with one or more additional therapeutically active agents. The compound or composition can be administered simultaneously with introduction, before or after administration of one or more additional therapeutically active agents. Typically, each tool should be introduced at a dose and/or in accordance with the timetable for the introduction, specific to this tool. Also it should be clear that the additional therapeutically active agent used in this combination, you can enter together in a single composition or entered separately in different compositions. In a specific combination, intended for use, you should consider the compatibility of the compounds of the present invention with an additional therapeutically active agent and/or the desired therapeutic effect, which must be obtained. As a rule, additional the additional therapeutically active substances, used in combination, as expected, should be used at a level that does not exceed the level when they are used separately. In some embodiments, embodiments of the levels used in combination, is less than the levels used separately.

The compounds or compositions can be introduced in combination with tools that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body. Also it should be clear that your therapy can achieve desired effect for the same disorder (for example, the connection can be introduced in combination with anti-inflammatory, anti-anxiety and/or anti-depressant and so forth), and/or can achieve other effects (e.g., control of adverse effects).

Examples of active agents include, but are not limited to, anti-cancer remedies, antibiotics, antivirals, anesthetics, anticoagulants, inhibitors of the enzyme, steroid remedies, steroids or anti-inflammatory drugs, antigistaminny tools, immunosuppressants, anti-cancer agents, antigens, vaccines, antibodies, anti-inflammatory remedies, sedatives, opioids, sedatives, analgesics, antipyretics, hormones, prostaglandin, gestagenna assets, glaucoma, ocular tools, anti-cholinergic tools, antidepressants, anti-psychotic remedies, sleeping pills, tranquilizers, anticonvulsants/ANTIEPILEPTICS means (for example, Neurontin, Lyrics, valproate (for example, Depacon) and other neurostabilizers funds), muscle relaxants, anti-spazmolitiki means, means to support muscle contraction, channel blockers, mitotic tools, anti-secretory tools, antithrombotic agents, anticoagulants, anticholinergic agents, β-adrenergic blockers, diuretics, cardiovascular active funds, vasoactive means, vasodilators, antihypertensive agents, angiogenic tools, modulators of interactions cell-extracellular matrix (e.g., cell growth inhibitors and anti-adhesion molecules) or inhibitors/intercalatory DNA, RNA, protein-protein interaction, interactions protein-receptor, etc., Active tools include small organic molecules, such as pharmaceutical compounds (for example, joints, approved by the Administration for Control of Food and Drugs, as provided in the Code of Federal regulations” (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleotide sequence that is proteide, the mukoproteidov, lipoprotein, synthetic polypeptide or protein, small molecules associated with proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antimuslim the oligonucleotides, lipids, hormones, vitamins and cells.

In some embodiments of the incarnation additional therapeutically active agent is an analgesic agent. Examples of analgesics include, but are not limited to, analgesics, such as non-narcotic analgesics [e.g., salicylates, such as aspirin, ibuprofen (MOTRIN®, ADVIL®), Ketoprofen (ORUDIS®), naproxen (NAPROSYN®), acetaminophen, indomethacin] or narcotic analgesics [e.g., opioid analgesics, such as tramadol, fentanyl, Sufentanil, morphine, hydromorphone, codeine, oxycodone and buprenorphine]; non-steroidal anti-inflammatory drugs (NSAIDs) [e.g., aspirin, acetaminophen, COX-2 inhibitors]; steroids or Antirheumatic agents; drugs for migraine, such as beta-adrenergic blockers, ergot derivatives; tricyclic antidepressants (eg, amitriptyline, desipramine, imipramine); medicines for epilepsy (such as clonaxepam, volpaia acid, phenobarbital, phenytoin, teagan, gabapentin, carbamazepine, taper the Mat, valproate sodium); α2agonists, selective inhibitors of reuptake of serotonin (SSRIs), selective inhibitors of the uptake of norepinephrine; benzodiazepines; meksiletin (MEXITIL); flecainide (TAMBOCOR); antagonists of the NMDA receptor [e.g., ketamine, detromethorphan, methadone]; and funds for local administration [e.g., capsaicin (Zostrix), EMLA cream, lidocaine, prilocaine].

In other embodiments, embodiments additional therapeutically active agent is an anti-inflammatory agent. Examples of anti-inflammatory drugs include, but are not limited to, aspirin; ibuprofen; Ketoprofen; naproxen; etodolac (LODINE®); COX-2 inhibitors such as celecoxib (CELEBREX®), rofecoksib (VIOXX®), valdecoxib (BEXTRA@)parecoxib, etoricoxib (MK663), deracoxib, 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine, 4-(2-oxo-3-phenyl-2,3-dihydrooxazolo-4-yl)benzosulfimide, darbufelone, flosulide, 4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-forbindelsesfaneblad), meloxicam, nimesulide, 1-methylsulphonyl-4-(1,1-dimethyl-4-(4-forfinal)cyclopent-2,4-Dien-3-yl)benzene, 4-(1,5-Dihydro-6-fluoro-7-methoxy-3-(trifluoromethyl)-(2)-benzothiophene(4,3-c)pyrazole-1-yl)benzosulfimide, 4,4-dimethyl-2-phenyl-3-(4-methylsulphonyl)phenyl)cyclo-butene, 4-amino-N-(4-(2-fluoro-5-trifluoromethyl-thiazol-2-yl)-benzosulfimide, 1-(7-tert-bout the l-2,3-dihydro-3,3-dimethyl-5-benzo-furanyl)-4-cyclopropylmethyl-1-it or their physiologically acceptable salts, ester or solvate; sulindac (CLINORIL®); diclofenac (VOLTAREN®); piroxicam (FELDENE®); diflunisal (DOLOBID®), nabumetone (RELAFEN®), oxaprozin (DAYPRO®), indomethacin (INDOCIN®); or steroids such as PEDIAPED®oral solution prednisolone sodium phosphate SOLU-MEDROL®methylprednisolone sodium succinate for injection, syrup prednisolone brand PRELONE®.

Additional examples of anti-inflammatory drugs include naproxen, which is commercially available under the trade name EC-NAPROSYN®in the form of a slow release tablets, NAPROSYN®, ANAPROX®and ANAPROX®DS tablets and NAPROSYN®suspension from Roche Labs, tablets celecoxib under the brand name CELEBREX®, rofecoksib under the brand name VIOXX®, betamethasone under the brand CELESTONE®capsules penitsillamin under the trademark CUPR®, titrated tablet penitsillamin under the trademark DEPEN®, methylprednisolone acetate in the form of a suspension for injection brand DEPO-MEDROL pills Leflunomide ARAVA™, sulfasalazin brand AZULFIDIINE EN-tabs®in the form of tablets slow release, piroxicam brand FELDENE®in capsule form, CATAFLAM®diclofenac potassium tablets, VOLTAREN®diclofenac sodium in tablet form slow wisweb the Denia VOLTAREN®XR diclofenac sodium in tablet form prolonged release or products ENBREL®etanercept.

V. methods for determining the biological activity

The methods for determining the activity of the compounds presented in this application for various therapeutic applications, known from the prior art. These methods include, but are not limited to, high-performance screening analysis to identify compounds that bind to and/or modulate the activity of selected FAAH, andin vitroandinvivomodels of treatment.

Assays useful for screening compounds presented in this application can be used to determine the binding of the inhibitor with FAAH or discharge of the reaction product (for example, fatty acid amide or ethanolamine), formed by hydrolysis of the substrate, such as oleoylethanolamide or anandamide. The substrate can be marked to facilitate the detection of secreted products of the reaction. U.S. patent No. 5559410 reveals how high-throughput screening of proteins, and U.S. Patent No. 5576220 and 5541061 reveal how high-throughput screening to determine the binding of a ligand/antibody.

Methods of screening for inhibitors of FAAH to determine the antinociceptive effect known from the prior art. For example, the compounds can is to be tested on mice in the test with hot plate and formalin test in mice, and nociceptive response to thermal or chemical tissue damage measured (for example, see U.S. Patent No. 6326156, description of methods of screening to determine the antinociceptive activity; see also Cravatt et al Proc. Natl. Acad. Sci. U. S. A.(2001) 98:9371-9376).

Two generally accepted in pharmacology animal models of anxiety are a method of cascading the zero maze and the method of isolation-induced ultrasonic emission. Zero maze consists of a cascade of circular platform with two open and two closed sectors and are based on the conflict between the instinct of the animal to study his environment and his fear of open spaces (see, for example, Bickerdike, M. J. et al., Eur. J. Pharmacol, (994) 271, 403-411; Shepherd, J. K. et al., Psychopharmacology, (1994) 116, 56-64). Clinically used anxiolytic drugs such as benzodiazepines, increase the time spent in open offices, and the number of entries in the open division.

The second test for determining compounds with effect against anxiety, is a model of emission of the ultrasonic voice signal, which is intended to measure the amount of stress-induced voice signals emitted by the young rats, which is extracted from their nests (see, for example, Insel, T. R. et al., Pharmacol. Biochem. Behav., 24, 1263-1267 (1986); Miczek, K. A. et al, Psychopharmacology, 121, 38-56 (1995); Winslow, J. T. et al., Biol. Psychiatry, 15, 745-757 (1991).

The effect of the compounds presented in this application in the treatment of depression can be defined in the model induced by constant light stress anhedonia in rats. This model is based on the observation that a constant mild stress causes a gradual decrease in sensitivity to rewards, for example, absorption of sucrose, and that this decrease dose-dependently prevent and backward development of this process by prolonged treatment with antidepressants. See, for example, Willner, Paul, Psychopharmacology, 1997, 134, 319- 329.

Another test for determining the activity of compounds as antidepressant represents the forced swimming test (Nature 266, 730-732, 1977). In this test, animals injected vehicle for 30 or 60 minutes before you put them in a container with water and record the time during which they remain stationary. The decrease in immobility time of mice is indicative of antidepressant activity.

A similar test for determining the activity of compounds as an antidepressant is a method of hanging the mouse by the tail (Psychopharmacology, 85, 367-370, 1985). In this test, animals injected vehicle for 30 or 60 minutes before they hung up by the tail, and record the time during which they OS which are stated fixed. The decrease in immobility time of mice is indicative of antidepressant activity.

Animal models are available for the evaluation of anticonvulsant activity of the test compounds (see, for example, U.S. Patent No. 6309406 and 6326156).

Inhibition of FAAH, reportedly induces sleep in test animals (see, for example, U.S. Patent No. 6096784). Methods study inducing sleep compounds known from the prior art (see, for example, U.S. Patent No. 6096784 and 6271015). Connection, you can enter the test animal (e.g. rat or mouse) or the person and the subsequent sleep (e.g. sleep, sleep duration) can be monitored (e.g., eyes closed, a state of immobility). Cm. also WO 98/24396.

Methods of screening for inhibitors of FAAH, which induce catalepsy, also well known from the prior art (see, for example, Quistand et al., Toxicology and Applied Pharmacology 173: 48-55 (2001); Cravatt et al. Proc. Natl. Acad. Sci. U. S. A. 98:9371-9376 (2001)).

Evaluation methods appetences behavior known from the prior art (see, for example, U.S. Patent No. 6344474). One way of assessing the effect on appetence behavior includes the introduction of the FAAH inhibitor rat and the effect on the absorption of sucrose solution (see, for example, W. C. Lynch et al., Physiol. Behav., 1993, 54, 877-880).

Two generally accepted in pharmacology in animal models of neuropathic pain represents a model is Yerevani spinal nerve of the rat (a model of Chang and model of chemotherapy-induced neuropathic pain. After the establishment of neuropathy in these models, as an indicator of the mechanical allodynia, measured thresholds reaction otdergivanija feet by stimulation using fibers von Frey (see, for example, Kim SH and Chung JM, Pain (1992) 50, 355-63; Nozaki-Taguchi N, et al, Pain (2001) 93, 69-76). Clinically used drugs from neuropathic pain, such as Gabapentin (Neurontin), the threshold increases reaction otdergivanija legs, caused by stimulation of fibers von Frey.

Two generally accepted in pharmacology animal models of inflammatory and mechanical pain represent a model of compression joints of rats treated with adjuvant or substances that cause degeneration of the joints. Treatment of clinically used anti-inflammatory drugs such as naproxen, increases the threshold for behavioral response to compression of the joints (see, for example, Wilson AW, et al., Eur. J. Pain (2006) 10, 537-49; Ivanavicius SA, et al., Pain(2007) 128, 272-282).

Recognized in pharmacology animal model of cancer pain represents a murine model, where implantation in the heel bone cells fibrosarcoma causes hyperalgesia limbs. Treatment of clinically used analgesics, such as morphine, increases the threshold for behavioral response to mechanical algesia (see, for example, Khasabova, et al., J. Neurscience(2008) 28, 11141-52).

Illustrative examples

Next, from Britanie in the General form described and will be more easily understood with reference to the examples shown below, which are included merely for purposes of illustration of certain aspects and variations of the embodiment of the present invention and are not intended to limit the invention.

General methods of synthesis

Method 1

General conditions for the preparation of 3-bromo-isoxazolines: Alkene (1.2 EQ.) and potassium bicarbonate (2.5 EQ.) suspended in ethyl acetate (0,40 M per alkene). Was added N,N-dibrompropamidine (1.0 EQ.) and the reaction mixture was left to stir at 23°C for 14 to 28 hours. Immediately after completion of the reaction, as determined by thin layer chromatography, the reaction mixture was distributed between water and tert-butylmethylamine ether and the organic layer was washed with water and saturated saline solution, dried over sodium sulfate and concentrated in vacuum. A concentrated reaction mixture was purified flash chromatography on silica gel (ethyl acetate/hexane) to give the desired 3-bromo-isoxazoline.

Method 2

General conditions for the preparation of 3-bromo-isoxazolines: in the flask was loaded Glyoxylic acid monohydrate (1.0 EQ.) and hydroxylamine hydrochloride (1.1 EQ.). The mixture was dissolved in water (2.0 M in the calculation of the Glyoxylic acid monohydrate and stirred at 23°C for 24 hours. The mixture was diluted with water and was extracted with et is lacerata. The organic layer was dried over sodium sulfate and concentrated to give the desired crude oxime which was used directly in the subsequent cycloaddition reaction. The resulting oxime (1.1 EQ.) with the first phase suspended in a 3:1 mixture dimethoxyethane:water (V/V) (0.15 M per oxime) and cooled to 0°C. was Added N-bromosuccinimide(NBS) (2.0 EQ.) and the reaction mixture was left to stir at 23°C for 20 minutes. The resulting mixture was then added to a solution of alkene (1.0 EQ.) and potassium bicarbonate (2.5 EQ.) in dimethoxyethane (1,50 M per alkene) and the reaction mixture was left to stir for 20 hours at 23°C. Immediately after completion of the reaction, as determined by thin layer chromatography, the reaction mixture was distributed between water and tert-butylmethylamine ether and the organic layer was washed with saturated saline solution, dried over sodium sulfate and concentrated in vacuum. A concentrated reaction mixture was purified flash chromatography on silica gel (ethyl acetate/hexane) to give the desired 3-bromo-isoxazoline.

Method 3

General conditions for obtaining 3-aryloxy-isoxazolines or 3-heteroaromatic-isoxazolines: in a microwave reaction vessel were loaded obtained 3-bromo-isoxazole (1.0 EQ.) and alcohol (e.g. the measures phenol or hydroxypyridine) (3.0 EQ.) and was dissolved in N-methylpyrrolidine (0,50 M per isoxazolin). Added powdered sodium hydroxide (2.0 EQ.) and the mixture was tightly closed and heated in a microwave reaction vessel at 150°C for 30 minutes. The reaction mixture is then distributed between water and tert-butylmethylamine ether and the organic layer was washed with saturated saline solution, dried over sodium sulfate and concentrated in vacuum. A concentrated reaction mixture was purified flash chromatography on silica gel (ethyl acetate/hexane) to give the desired isoxazoline.

Method 4

General conditions for obtaining 3-aryloxy-isoxazolines or 3-heteroaromatic-isoxazolines: in the flask was loaded obtained 3-bromo-isoxazole (1.0 EQ.) and alcohol (such as phenol or hydroxypyridine) (2.0 EQ.) and was dissolved in N,N-dimethylformamide (0,4 M per isoxazolin). Was added sodium hydride (2.0 EQ.) and the reaction mixture was left to stir for 10 minutes until the cessation of gas evolution. The reaction mixture then was heated to 150°C for 1-5 hours. After completion of the reaction, as determined by thin layer chromatography, the reaction mixture is then distributed between water and ethyl acetate and the organic layer washed with 1 N. NaOH solution and saturated the saline solution and then dried over sodium sulfate and concentrated in vacuum. A concentrated reaction mixture was purified flash chromatography on silica gel (ethyl acetate/hexane) to give the desired isoxazoline.

Method 5

General conditions for obtaining 3-aryloxy-isoxazolines: in the flask was loaded obtained 3-bromo-isoxazole (1.0 EQ.) and alcohol (such as phenol or hydroxypyridine) (2.0 EQ.) and was dissolved in N,N-dimethylformamide or N-methylpyrrolidinone (0.15 M per isoxazol). Added cesium carbonate (1.2 to 3 EQ.) and the reaction mixture was heated to 120°C in an oil bath for 1 hour. The reaction mixture is then distributed between water and tert-butylmethylamine ether and the organic layer was washed with saturated saline solution, dried over sodium sulfate and concentrated in vacuum. A concentrated reaction mixture was purified flash chromatography on silica gel (methanol/methylene chloride) to give the desired isoxazoline.

Method 6

General conditions for obtaining alkenes: in a nitrogen atmosphere, of 0.25 M methyltriphenylphosphonium (1.1 equiv.) dissolved in tetrahydrofuran, cooled to 0°C, then the mixture was treated by adding dropwise hexamethyldisilazane sodium (NaHMDS) in tetrahydrofuran (1,0 M, 1.2 EQ.). After stirring for 30 minutes at 0°C was added to the obtained aldehyde or ketone and the reaction with whom thou gave to slowly warm to 23°C during the night. The mixture was marked with a saturated solution of ammonium chloride and concentrated to remove tetrahydrofuran. The mixture then was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate and concentrated in vacuum. A concentrated reaction mixture was purified flash chromatography on silica gel (ethyl acetate/hexane) to give the desired alkene.

Method 7

General conditions for obtaining alkenes: in an atmosphere of nitrogen, 0.15 M methyltriphenylphosphonium (1.5 equiv.) dissolved in tetrahydrofuran, cooled to -78°C, then the mixture was treated dropwise with a solution of n-utility in hexane (2.5 M, 1.5 EQ.). After stirring for 1 hour at -78°C was added to the obtained aldehyde or ketone and the reaction mixture gave to slowly warm to 23°C during the night. The mixture was marked with a saturated solution of ammonium chloride and concentrated to remove tetrahydrofuran. The mixture then was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate and concentrated in vacuum. A concentrated reaction mixture was purified flash chromatography on silica gel (ethyl acetate/hexane) to give the desired alkene.

Method 8

General conditions for obtaining alkenes: in a nitrogen atmosphere, 0,12 M methyltriphenylphosphonium (2.5 EQ.) was dissolved in tetrahydrofuran, then added tert-piperonyl potassium (4.0 EQ.) six portions. After stirring for 1 hour at 23°C was added to the obtained aldehyde or ketone and the reaction mixture was heated to 55°C for 2 hours. The mixture was marked with a saturated solution of ammonium chloride and concentrated to remove tetrahydrofuran. The mixture was then acidified to pH 5-6 with 1 n HCl solution and was extracted with methylene chloride. The organic layer was washed with saturated saline and then dried over sodium sulfate and concentrated in vacuum. A concentrated reaction mixture was purified flash chromatography on silica gel (ethyl acetate/hexane) to give the desired alkene.

Method 9

General conditions for obtaining sterols: dried flask in an argon atmosphere downloaded arilbred (1.0 EQ.), vinyltrifluoroborate potassium (1.2 equiv.) product fitting 1,1"-bis(diphenylphosphino)-ferrocenedicarboxylic(II) and methylene chloride (0.02 EQ.) and triethylamine (1.0 EQ.) and the mixture is suspended in isopropanol (0.25 M per Allbreed) and was heated at 80°C for 2-24 hours. The mixture then was diluted with water and was extracted with diethyl ether. The organic layer was washed nassen the m salt solution and then dried over magnesium sulfate and concentrated in vacuum. A concentrated reaction mixture was purified flash chromatography on silica gel (ethyl acetate/hexane) to give the desired styrene.

Method 10

General conditions for obtaining sterols: in a dried flask under nitrogen atmosphere was loaded arilbred (1.0 EQ.), tributyltinhydride (1.1 EQ.) and was dissolved in toluene (0,3 M per bromide). The resulting mixture was again purged with nitrogen for 10 minutes, then added tetrakis(triphenylphosphine)palladium (0.1 EQ.) and the reaction mixture was subjected to boiling under reflux for 1.5 hours. After completion of the reaction, as determined by TLC, the mixture was allowed to cool and was loaded directly on a column of silica gel, where it was purified flash chromatography on silica gel (ethyl acetate/hexane) to give the desired styrene.

Method 11

General conditions for hydrolysis of pyridyl - and pyrimidinedione acids to their corresponding phenols: in the flask was loaded obtained Bronevoy acid or its ester (1.0 EQ.) and was dissolved in tetrahydrofuran (1,1 M, 10 volumes). Perborate sodium (1.0 EQ.) was dissolved in water (1,1 M per Bronevoy acid, 10 volumes) and treated with ultrasound for 10 minutes. Suspension perborate then added to the THF solution using tetrahydrofuran (6 volumes) for washing the remaining solid perborate in the reaction mixture. The reaction mixture was left for stirring at room temperature (the reaction is slightly exothermic), then was added ammonium chloride in three portions (10 EQ.) and the reaction mixture was again cooled to room temperature. After 40 minutes the reaction mixture was concentrated under vacuum until complete removal of the tetrahydrofuran. The obtained solid substance was collected by vacuum filtration, washed with excess water and dried in a vacuum oven at 40°C for 3 days to give the desired phenol with yields of 80%.

Method chiral HPLC

Enantiomeric or diastereomeric mixture of compounds can be separated using known methods, including chiral high performance liquid chromatography (HPLC) and chiral supercritical fluid chromatography (SFC). Examples of chiral columns that can be used for the separation of such mixtures of compounds of the present invention, include, but are not limited to, column ChiralPak® AD-H, ChiralPak® OD-H, ChiralPak® AY, RegisPack™ S,S Whelkθ®-1 and LUX™ Cellulose2. One or more such columns used for the separation of enantiomeric mixtures of compounds of the present invention to obtain essentially enantiomerically pure compounds.

SYNTHESIS of ILLUSTRATIVE COMPOUNDS of FORMULA I

Synthesis of illustrative compounds before is submitted below. Compounds were tested as inhibitors of human FAAH using the method described in Example 351. Activity designated as "A" refers to compounds having a value of Kiless than or equal to 100 nm, "B" refers to compounds having a value of Kiin the range from 100 nm to 1 μm, and "C" refers to compounds having a value of Kigreater than or equal to 1 micron.

Example 1

3-bromo-4,5-dihydroisoxazole I-1a and I-1b were obtained in stage 1, based on styrene, using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=225,0 m/z. Activity: B

Example 2

3-bromo-4,5-dihydroisoxazole I-2a and I-2b was obtained in stage 1, from 4-torterolo, using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. Activity: B

Example 3

3-bromo-4,5-dihydroisoxazole I-3a and I-3b received in stage 1, from 4-chloresterol, using Method 2. These compounds can be divided using chiral the Oh HPLC, known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=259,0 m/z. Activity: A

Example 4

3-bromo-4,5-dihydroisoxazole I-4a I-4b were obtained in stage 1, based on 3-chloresterol, using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=258,9 m/z. Activity: B

Example 5

3-bromo-4,5-dihydroisoxazole I-5a I-5b was obtained in stage 1, based on 2-chloresterol, using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=258,9 m/z. Activity: B

Example 6

3-bromo-4,5-dihydroisoxazole I-6a and e-6b was obtained in stage 1, from 4-methoxystyrene, using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=255,0 m/z. Activity: A

Example 7

3-bromo-4,5-dihydroisoxazole I-7a I-7b was obtained in 1 with adieu, based on 3-methoxystyrene, using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=255,0. Activity: B

Example 8

3-bromo-4,5-dihydroisoxazole I-8a I-8b was obtained in stage 1, based on 2-methoxystyrene, using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=255,0 m/z. Activity: C

Example 9

3-bromo-4,5-dihydroisoxazole I-9a I-9b was obtained in stage 1, from 4-vinylbiphenyl, using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=301,6 m/z. Activity: A

Example 10

3-bromo-4,5-dihydroisoxazole I-10 and I-10b was obtained in stage 1, from 4-phenoxystyrene, using Method 2. These compounds were separated using chiral HPLC known in the art. For example, see the way chiral who ASH, disclosed in this application. [M-H]-=317,0 m/z. Activity: A

Example 11

3-bromo-4,5-dihydroisoxazole I-11a and 11b were obtained in stage 2, since the formation of the alkene of 3-phenoxybenzaldehyde using Method 8 followed by cyclopentadiene using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=317,0 m/z. Activity: A

Example 12

3-bromo-4,5-dihydroisoxazole I-12a and 12b were obtained in stage 2, since the formation of the alkene from 4-(pyridine-3-yloxy)benzaldehyde using Method 8 followed by cyclopentadiene using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=318,0 m/z. Activity: A

Example 13

3-bromo-4,5-dihydroisoxazole I-13a and 13b were obtained in stage 2, since the formation of the alkene from 4-(pyrimidine-2-yloxy)-benzaldehyde using Method 8 followed by cyclopentadiene using Method 2. These compounds can be separated using methods of Herald the th HPLC, known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=319,0 m/z. Activity: A

Example 14

3-bromo-4,5-dihydroisoxazole I-14a and 14b received in stage 2, since the formation of the alkene from 4-triphtalocyaninine using Method 8 followed by cyclopentadiene using Method 1. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=309,6 m/z. Activity: A

Example 15

3-bromo-4,5-dihydroisoxazole I-15a and 15b were obtained in stage 2, since the formation of the alkene from 4-isopropoxybenzonitrile using Method 8 followed by cyclopentadiene using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=238,0 m/z. Activity: A

Example 16

3-bromo-4,5-dihydroisoxazole I-16 and I-16b were obtained in stage 2, since the formation of the alkene from piperonal using Method 7 followed by cyclopentadiene using Method 2. These compounds m is should be split using chiral HPLC, known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=269,0 m/z. Activity: A

Example 17

3-chloro-4,5-dihydroisoxazole I-17a and 17b were obtained using a procedure analogous to the procedure of Example 10, except that he used the N-chlorosuccinimide instead of N-bromosuccinimide. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=273,1 m/z. Activity: A

Example 18

(I-18)

3-bromo-4,5-dihydroisoxazole I-18a and 18b were obtained in stage 2, since the formation of the alkene of 3-(4-bromophenoxy)-6-methylpyridazine using Method 9 with following cyclopentadiene using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=333,0 m/z. Activity: B

Example 19

3-bromo-4,5-dihydroisoxazole I-19a and 19b received in stage 2, since the formation of the alkene from 2-(4-bromophenyl)-5-phenyl-1,3,4-oxadiazole using Method 9 with following cyclopentadiene using SP is soba 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=369,0 m/z. Activity: A

Example 20

3-bromo-4,5-dihydroisoxazole I-20 and I-20b received in stage 2, since the formation of the alkene from 4-butoxybenzaldehyde using Method 8 followed by cyclopentadiene using Method 1. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=297,0 m/z. Activity:

Example 21

3-bromo-4,5-dihydroisoxazole I-21a and 21b was obtained in 2 stages, starting with the reaction of a combination of between 4-vinylbenzoic acid and benzyl alcohol, as follows: 4-vinylbenzoic acid (1.0 EQ.) was dissolved in N,N-dimethylformamide (0,20 M per acid). Added benzyl alcohol (2.0 EQ.) with the subsequent addition of EDC (of 1.05 equiv.) and catalytic amount of DMAP (of 0.05 EQ.). The reaction mixture was left to stir at 23°C for 14 hours after which the reaction mixture was distributed between water and tert-butylmethylamine ether and the organic layer was washed with 0.5 M citric acid solution (2×) and saturated what astora sodium bicarbonate (1×), was dried over magnesium sulfate and concentrated in vacuum. A concentrated reaction mixture was purified using flash chromatography on silica gel (ethyl acetate/hexane) to give the desired ether complex. This compound is then converted to the desired 3-bromo-4,5-dihydroisoxazole using Method 1. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=359,8 m/z. Activity: A

Example 22

3-bromo-4,5-dihydroisoxazole I-22a and 22b was obtained using a procedure analogous to the procedure of Example 21, except that used benzylamine instead of benzyl alcohol. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=358,9 m/z. Activity: B

Example 23

3 phenoxy-4,5-dihydroisoxazole I-23a and 23b received in stage 1, based on the compound I-10 and phenol, using Method 3. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=31,1 m/z. Activity: C

Example 24

3 phenoxy-4,5-dihydroisoxazole I-24a and 24b received in stage 1, based on the compound I-10 and 4-terfenol, using Method 4. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=350,3 m/z. Activity: C

Example 25

3 phenoxy-4,5-dihydroisoxazole I-25a and 25b received in stage 1, based on the compound I-10 and 3-terfenol, using Method 4. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=349,3 m/z. Activity: B

Example 26

3 phenoxy-4,5-dihydroisoxazole I-26a and 26b received in stage 1, based on the compound I-10 and 3-triptoreline, using Method 4. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=400,3 m/z. Activity: C

Example 27

3 phenoxy-4,5-dihydroisoxazole I-27a and 27b received in stage 1, based on the compound I-10 and 4-cyanophora, the application of Method 3. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=356,1 m/z. Activity: A

Example 28

3 phenoxy-4,5-dihydroisoxazole I-28a and 28b received in stage 1, based on the compound I-10 and 2-cyanophora, using Method 4. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=357,3 m/z. Activity: C

Example 29

3 phenoxy-4,5-dihydroisoxazole I-29a and 29b received in stage 1, based on the compound I-10 and 4-NITROPHENOL, using Method 4. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=376,8 m/z. Activity: B

Example 30

3 phenoxy-4,5-dihydroisoxazole I-30a and 30b received in stage 1, based on the compound I-10 and 4-methylsulfinylphenyl, using Method 4. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, unveiled the this application. [M-H]-=409,0 m/z. Activity: A

Example 31

3 phenoxy-4,5-dihydroisoxazole I-31a and 31b received in stage 1, based on the compound I-10 and 4-methyl-3-terfenol, using Method 4. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=364,4 m/z. Activity: C

Example 32

In a microwave reaction vessel were loaded racemic compound I-10 (1.0 EQ.) and aniline (4.0 EQ.). The mixture was tightly closed and heated in a microwave reactor at 150°C for 2 hours. The reaction mixture is then distributed between water and tert-butylmethylamine ether and the organic layer was washed with saturated saline solution, dried over sodium sulfate and concentrated in vacuum. A concentrated reaction mixture was purified using flash chromatography on silica gel (ethyl acetate/hexane) to give the desired 3-amino-4,5-dihydroisoxazole I-32a and 32b. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=330,1 m/z. Activity: C.

Example 33

1-(4,5-dihydroisoxazole-3-yl)PI is one-2(1H)-he I-33a and 33b received in stage 1, proceeding from racemic compound 1-10 and 2-hydroxypyridine, using Method 3. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=332,1 m/z. Activity: C

Example 34

(I-34)

In a microwave reaction vessel were loaded racemic compound I-10 (1.0 EQ.) and sodium salt of 1,2,4-triazole (2.0 EQ.). The reagents were dissolved in N-methylpyrrolidine (0,18 M per connection I-10). The mixture was tightly closed and heated in a microwave reactor at 100°C for 30 minutes. Added an excess amount of water, and precipitation of a brown solid, which was isolated using vacuum filtration and dried to give the desired 3-(1H-1,2,4-triazole-1-yl)-4,5-dihydroisoxazole I-34a and 34b. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=306,1 m/z. Activity: C.

Example 35

Pyrazole (3.0 EQ.) dissolved (0,60 M per pyrazole) was added NaH (60% dispersion in mineral oil, 3.0 EQ.) and the reaction mixture was left stirring in an atmosphere of nitrogen within 5 minutes. After this was added racemic compound I-10. The reaction mixture was then heated to 90°C for 14 hours, then the mixture was cooled and extinguished methanol (0,30 M in the calculation of the pyrazole). The crude mixture was filtered through cotton wool and directly subjected to purification by the method of prepreparation reverse-phase chromatography to give the desired 3-(1H-pyrazole-1-yl)-4,5-dihydroisoxazole I-35a and 35b. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+Η]+=306,4 m/z. Activity: C.

Example 36

3-(pyridine-4-yloxy)-4,5-dihydroisoxazole I-36a and 36b received in stage 1, based on the compound I-10 and 4-hydroxypyridine, using Method 3. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=332,1 m/z. Activity: C

Example 37

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-37a and 37b received in stage 1, from racemic compound 1-10 and 3-hydroxypyridine, using Method 3 or Method 5. These compounds can be divided using chiral HPLC known in the art. For example, the m the way chiral HPLC, disclosed in this application. [M-H]-=332,1 m/z. Activity: A

Example 38

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-38a and 38b received in stage 1, based on the racemic compounds 1-6 and 3-hydroxypyridine, using Method 3. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=270,1 m/z. Activity: B

Example 39

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-39a and 39b received in stage 1, from racemic compound 1-10 and methyl 5-hydroxynicotinate, using Method 3 or Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=392,2 m/z. Activity: A

Example 40

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-40a and 40b received in stage 1, from racemic compound 1-10 and 5-hydroxy-2-methylpyridine, using Method 4. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, revealed in this bid, medium, small is. [M+H]+=346,1 m/z. Activity: A

Example 41

3-(pyrimidine-5-yloxy)-4,5-dihydroisoxazole I-41a and 41b received in stage 1, from racemic compound 1-10 and 5-hydroxypyrimidine, using Method 3. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=333,1 m/z. Activity:

Example 42

3-(quinoline-3-yloxy)-4,5-dihydroisoxazole I-42a and 42b received in stage 1, from racemic compound 1-10 and 3-hydroxyquinoline solution using Method 3. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=382,1 m/z. Activity: A

Example 43

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-43a and 43b received in stage 1, from racemic compound 1-10 and 5-fluoro-3-hydroxypyridine, using Method 3. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=350,1 m/z. Activity: A

Example 44

3-(1-methyl-1H-pyrrolo[2,3-b]pyridine-5-yloxy)-4,5-dihydroisoxazole I-44a and 44b received in stage 1, from racemic compound 1-10 and 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-ol using Method 3. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=385,1 m/z. Activity: B

Example 45

The vessel was loaded racemic compound I-10 (1.0 EQ.) and was dissolved in methanol (0,05 M per isoxazol). Was added potassium carbonate (5.0 equiv.) and the reaction mixture was tightly closed and heated to 50°C for 24 hours. The reaction mixture is then distributed between water and ethyl acetate and the organic layer was washed with saturated saline solution, dried over sodium sulfate and concentrated in vacuum. A concentrated reaction mixture was purified using flash chromatography on silica gel (ethyl acetate/hexane) to give the desired 3-methoxy-4,5-dihydroisoxazole I-45a and 45b. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=269,1 m/z. Activity: C.

Example 46

3-(pyridine-3-yloxy)-4,5-dihydro shall isoxazol I-46a and 46b received in stage 1, proceeding from racemic compound 1-14 and methyl 5-hydroxynicotinate, using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=384,0 m/z. Activity: B

Example 47

Racemic compound I-39 was dissolved in ammonia in methanol (7,0 M in methanol, of 0.02 M per isoxazol). The reaction mixture was tightly sealed and left to stir at 23°C for 24 hours after which the solvent and excess ammonia were removed under a stream of nitrogen to obtain a light brown solid, which was ground into powder with hexane to give the desired amide I-47a and 47b in the form of a white solid. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=374,0 m/z. Activity: B

Example 48

3-bromo-4,5-dihydroisoxazole I-48a and 48b received in stage 1, based on 3-phenyl-1-propene, using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, RAS is ryty in this application. [M-H]-=239,0 m/z. Activity: C

Example 49

3-bromo-4,5-dihydroisoxazole I-49a and 49b received in stage 1, from 4-phenyl-1-butene, using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=253,0 m/z. Activity:

Example 50

Phenol (1.0 EQ.) was dissolved in ethanol (0.5 M per phenol) was added sodium hydroxide (1.0 EQ.) with the subsequent addition of 4-bromo-1-butene. The mixture was heated to boiling point under reflux for 1 hour, then a large part of the solvent was removed under vacuum. The reaction mixture is then distributed between water and tert-butylmethylamine ether and the organic layer was washed with saturated saline solution, dried over sodium sulfate and concentrated in vacuo to obtain the crude alkene which was directly converted to the desired 3-bromo-4,5-dihydroisoxazole I-50a and 50b in stage 1 using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=269,0 m/z. Activity: B

Example 51

Phenol (1.2 EQ.) was dissolved in N,N-dimethylformamide (0,4 M per phenol) was added cesium carbonate (1.3 EQ.) with the subsequent addition of 5-bromo-1-pentene (1.0 EQ.) and tetrabutylammonium iodide (0.10 equiv.). The mixture was heated to 50°C for 16 hours. The reaction mixture is then distributed between water and tert-butylmethylamine ether and the organic layer was washed with diluted sodium hydroxide solution, water, saturated salt solution, dried over sodium sulfate and concentrated in vacuum. The crude alkene directly converted to the desired 3-bromo-4,5-dihydroisoxazole I-51a and 51b in stage 1, using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=283,0 m/z. Activity:

Example 52

2-Phenylethanol (1.0 EQ.) was dissolved in N,N-dimethylformamide (0.8 M per alcohol) was added powdered sodium hydroxide (2.0 EQ.) with the subsequent addition of allylbromide (1.0 EQ.) and tetrabutylammonium iodide (0.10 equiv.). The mixture was stirred at room temperature for 48 hours. The reaction mixture is then distributed between water and tert-butylmethylamine ether and the organic layer was washed with diluted solution of Na2S2O3 and saturated saline solution, dried over sodium sulfate and concentrated in vacuum. A concentrated reaction mixture was purified using flash chromatography on silica gel (ethyl acetate/hexane) to give the desired alkene, which was directly converted to the desired 3-bromo-4,5-dihydroisoxazole I-52a and 52b in stage 1 using Method 1. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=285,6 m/z. Activity: B

Example 53

Racemic compound I-46 was dissolved in ammonia in methanol (7,0 M in methanol, of 0.02 M per isoxazol). The reaction mixture was tightly sealed and left to stir at 23°C for 72 hours, after which the solvent and excess ammonia were removed under a stream of nitrogen to obtain a light brown solid, which was ground into powder with hexane, to give the desired amide I-53a and 53b in the form of a white solid. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=366,0 m/z. Activity: B

Example 54

Racemic compound I-46 was dissolved in ammonia methylamine (2.0 M in tetrahydrofuran, of 0.02 M per isoxazol). The reaction mixture was tightly sealed and left to stir at 23°C for 72 hours, after which the solvent and excess ammonia were removed under a stream of nitrogen to obtain a light brown solid, which was ground into powder with hexane, to give the desired amide I-54a and 54b in the form of a white solid. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=380,0 m/z. Activity: A

Example 55

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-55a and 55b received in stage 1, based on the racemic compound I-46 and methyl 5-hydroxynicotinate, using Method 5 and was isolated as a side product of the reaction in process flash chromatography on silica gel. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=367,0 m/z. Activity: C

Example 56

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-56a and 56b received in stage 1, based on racemizes the th compound I-10 and 5-hydroxy-2-triptoreline, using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=is 401.5 m/z. Activity: A

Example 57

3-(1H-pyrrolo[3,2-b]pyridine-6-yloxy)-4,5-dihydroisoxazole I-57a and 57b received in stage 1, based on the racemic compound I-10 and 1H-pyrrolo[3,2-b]pyridine-6-ol using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=370,0 m/z. Activity: A

Example 58

3 phenoxy-4,5-dihydroisoxazole I-58a and 58b received in stage 1, based on the racemic compound I-10 and 3-cyanophora, using Method 4. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=356,8 m/z. Activity: B

Example 59

3 phenoxy-4,5-dihydroisoxazole I-59a and 59b received in stage 1, based on the racemic compound I-10 and 2-terfenol, using Method 4. These compounds can be divided using hir is through HPLC, known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=350,3 m/z. Activity: B

Example 60

3 phenoxy-4,5-dihydroisoxazole I-60a and 60b received in stage 1, based on the racemic compound I-10 and 4-fluoro-3-(trifluoromethyl)phenol, using Method 4. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. Activity: C

Example 61

3 phenoxy-4,5-dihydroisoxazole I-61a and 61b received in stage 1, based on the racemic compound I-10 and methyl 3-hydroxybenzoate, using Method 4. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=390,5 m/z. Activity: A

Example 62

3 phenoxy-4,5-dihydroisoxazole I-62a and 62b received in stage 1, based on the racemic compound I-10 and methyl 4-hydroxybenzoate, using Method 4. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [MH] +=389,7 m/z. Activity: A

Example 63

3 phenoxy-4,5-dihydroisoxazole I-63a and 63b received in stage 1, based on the racemic compound I-10 and 3-(methylsulphonyl)phenol, using Method 4. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=409,0 m/z. Activity: C

Example 64

3 phenoxy-4,5-dihydroisoxazole I-64a and 64b received in stage 1, based on the racemic compound I-10 and 3-hydroxybenzenesulfonate, using Method 4. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=409,0 m/z. Activity: C

Example 65

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-65a and 65b received in stage 1, based on the racemic compound I-10 and 5-methoxypyridine-3-ol using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=363,2 m/z. Activity: A

Example 66

3-(PI is kidin-5-yloxy)-4,5-dihydroisoxazole I-66a and 66b received in stage 1, proceeding from racemic compound I-10 and 5-hydroxypyrimidine, using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=364,6 m/z. Activity: A

Example 67

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-67a and 67b received in stage 1, based on the racemic compound I-10 and methyl 5-hydroxyproline, using Method 3. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=392,1 m/z. Activity: A

Example 68

3-(1H-pyrrolo[2,3-6]pyridine-5-yloxy)-4,5-dihydroisoxazole I-68a and 68b received in stage 1, based on the racemic compound I-10 and 1H-pyrrolo[2,3-b]pyridine-5-ol using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=370,0 m/z. Activity: A

Example 69

6-(4,5-dihydroisoxazole-3-yloxy)furo[3,2-b]pyridine I-69a and 69b received in stage 2, based on the racemic compound I-10 and f the ro[3,2-b]pyridine-6-ol, using Method 5, after furo[3,2-b]pyridine-6-ol was obtained from 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine using Method 11. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=374,2 m/z. Activity: A

Example 70

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-70a and 70b received in stage 1, based on the racemic compound I-14 and 3-hydroxypyridine, using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=324,1 m/z. Activity: A

Example 71

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-71a and 71b received in stage 1, based on the racemic compound I-14 and 5-bromo-3-hydroxypyridine, using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=402,5 m/z. Activity: A

Example 72

Racemic compound I-71 (1.0 EQ.), phenylboronic acid (1,1 ek is.), potassium acetate (1.0 EQ.), the cesium carbonate (3.0 EQ.) and the product of the merger of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) and dichloromethane (14 mol.%) suspended in 1 ml DMSO and blew through Ar. The resulting mixture was tightly closed and heated up to 80°C for 1 hour. The crude mixture was transferred into a separating funnel with excess water and was extracted with methyl tert-butyl ether (2×). The organic layers were combined, dried over Na2SO4and was purified using flash chromatography on silica gel (gradient 2-10% MeOH) to give the desired 3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-72a and 72b in the form of a white solid. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=402,3 m/z. Activity: B

Example 73

Racemic compound I-71 (1.0 EQ.), 3-carbamoilirovaniem acid (1.1 equiv.) potassium acetate (1.0 EQ.), the cesium carbonate (3.0 EQ.) and the product of the merger of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) and dichloromethane (14 mol.%) suspended in 1 ml DMSO and blew through Ar. The resulting mixture was tightly closed and heated up to 80°C for 1 hour. The crude mixture was transferred into a separating funnel with excess quantity is STV water and was extracted with methyl tert-butyl ether (2×). The organic layers were combined, dried over Na2SO4and was purified using flash chromatography on silica gel (gradient 2-10% MeOH) to give the desired 3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-73a and 73b in the form of a white solid. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=442,0 m/z. Activity: A

Example 74

3-bromo-4,5-dihydroisoxazole I-74a and 74b received in stage 1, from methyl 4-vinylbenzoate, using Method 1. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=283,6 m/z. Activity: A

Example 75

3-bromo-4,5-dihydroisoxazole I-75a and 75b received in stage 2, since the formation of the alkene from 4'(triptoreline)of acetophenone using Method 6, followed by cyclopentadiene using Method 1. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=323,0 m/z. Activity: A

Example 76

3-bromo-4,5-dihydroisoxazole I-76a and 76b received in stage 2, since the formation of the alkene from 4'-phenoxyacetophenone using Method 6, followed by cyclopentadiene using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=331,0 m/z. Activity: A

Example 77

3-bromo-4,5-dihydroisoxazole I-77a and 77b received in stage 1, on the basis of TRANS-anethole, using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=269,0 m/z. Activity: C

Example 78

3-bromo-4,5-dihydroisoxazole I-78a and 78b received in stage 2, since the formation of the alkene from 4-phenoxybenzaldehyde using Method 6 (except that used ethyltriphenylphosphonium instead of methyltriphenylphosphonium) with subsequent cyclopentadiene using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-/sup> =331,0 m/z. Activity: A

Example 79

3-bromo-4,5-dihydroisoxazole I-82a and 82b received in stage 3, from 4-phenoxybenzaldehyde, as follows: 4-phenoxybenzaldehyde (1.0 EQ.) was dissolved in tetrahydrofuran (0,20 M per tetrahydrofuran) and cooled to 0°C. was Added ethylmagnesium of (1.0 M in THF, 1.2 EQ.) dropwise, then the reaction mixture was left to stir at 23°C for 2 hours. The mixture was marked with a saturated solution of ammonium chloride and concentrated to remove tetrahydrofuran. The mixture then was diluted with water and was extracted with tert-butylmethylamine ether. The organic layer was washed with water and saturated saline and then dried over sodium sulfate and concentrated in vacuum. A concentrated reaction mixture was purified using flash chromatography on silica gel (ethyl acetate/hexane) to give the desired alcohol I-80.

The purified alcohol I-80 was then dissolved in pyridine (0,80 M per alcohol). Was added phosphorus oxychloride (1.1 EQ.) and the mixture was heated to boiling point under reflux for 2 hours. After the reaction mixture was cooled to 0°C and was suppressed by the addition of excess water. The mixture then was diluted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over sulfate is the atrium and concentrated in vacuum. A concentrated reaction mixture was purified using flash chromatography on silica gel (ethyl acetate/hexane) to give the desired alkene I-81.

Alkene I-81 then converted to the desired 3-bromo-4,5-dihydroisoxazole I-82a and 82b, using Method 2. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=331,0 m/z. Activity: B.

Example 80

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-83a and 83b received in stage 1, based on the racemic compound I-14 and methyl 3-(5-hydroxypyridine-2-yl)benzoate using the Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=460,1 m/z. Activity: B

Example 81

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-84a and 84b received in stage 1, based on the racemic compound I-14 and ethyl 3-(5-hydroxypyridine-2-yl)benzoate using the Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, revealed in this the overall application. [M+H]+=474,1 m/z. Activity: B

Example 82

Racemic compound I-83 (1.0 EQ.) was dissolved in a mixture of 1:1 tetrahydrofuran/water (0,06 M) was added lithium hydroxide (8.0 EQ.). The reaction mixture was left for stirring at room temperature for 1 hour, after which the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH<2 1 N. HCl solution to obtain the desired acid I-85a and 85b in the form of a white solid, which was isolated using vacuum filtration. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=443,0 m/z. Activity: B

Example 83

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-86a and 86b received in stage 1, based on the racemic compound I-14 and 6-vinylpyridin-3-ol using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=402,2 m/z. Activity: B

Example 84

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-87a and 87b received in stage 1, based on the racemic compound I-12 and 3-hydrox is pyridine, using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=333,5 m/z. Activity: A

Example 85

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-88a and 88b received in stage 1, based on the racemic compound I-75 and 3-hydroxypyridine, using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=340,2 m/z. Activity: B

Example 86

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-89 and I-89b received in stage 1, based on the racemic compound I-76 and 3-hydroxypyridine, using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=348,4 m/z. Activity: A

Example 87

3 phenoxy-4,5-dihydroisoxazole I-90a I-90b received in stage 1, based on the racemic compound I-10 and 4-hydroxybenzenesulfonate, using Method 4. These compounds can be divided using osobov chiral HPLC, known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=410,8 m/z. Activity: A

Example 88

TRANS-3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-91a and 91b received in stage 1, based on the racemic compound I-78 or 1-82 and 3-hydroxypyridine, using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=346,2 m/z. Activity: C

Example 89

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-92a and 92b received in stage 2, based on the racemic compound I-10 and tert-butyl methyl ether (5-hydroxy-pyridine-2-yl)-carbamino acid using Method 5 after the formation of the tert-butyl ester (5-hydroxy-pyridine-2-yl)-carbamino acid from tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-ylcarbamate using Method 11. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=447,9 m/z. Activity: C

Example 90

Racemic 3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-92 RA is tarali in triperoxonane acid (0,20 M per isoxazol) and stirred at room temperature for 1 hour. The solvent was then removed under vacuum and the crude residue was subjected to azeotropic distillation with toluene (2×) to obtain the I-93a and 93b as TFA salt (white solid). These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=347,1 m/z. Activity: A

Example 91

Racemic 3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-93 was dissolved in methylene chloride (0,03 M per isoxazol), then was added triethylamine (4.0 EQ.) and acetic anhydride (3.0 EQ.). The reaction mixture was left to stir for 16 hours, then was diluted with ethyl acetate and washed with saturated solution of NaHCO3(2×) and saturated brine (1×). The organic layer was then dried over sodium sulfate and concentrated under vacuum to obtain the acetate I-94a and 94b in the form of a white solid. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=388,1 m/z. Activity: A

Example 92

3-bromo-4,5-dihydroisoxazole I-95a and 95b received in stage 2, since the formation of the alkene of 1-(4-phenoxyphenyl)propan is she using Method 8, subsequent cyclopentadiene using Method 1. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=347,7 m/z. Activity: A

Example 93

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-96a and 96b received in stage 1, based on the racemic compound I-14 and methyl ester 5-hydroxypyridones acid, in accordance with the following procedure: 3-bromo-5-(4-(triptoreline)phenyl)-4,5-dihydroisoxazole (1.0 EQ.), methyl ester 5-hydroxypyridones acid (1.2 EQ.) and cesium carbonate (1.50 equiv.) suspended in N,N-dimethylformamide (0,32 M per dihydroisoxazole). The mixture was then degirolami with argon, then heated to 130°C for 4 hours, then watched only the desired product and the corresponding acid using LC/MS. The reaction mixture was allowed to cool to room temperature and extinguished, pouring the mixture into a solution of ammonium chloride in water (30 wt. -%, 0,08 M per dihydroisoxazole). The aqueous phase was extracted with ethyl acetate (2×), dried over sodium sulfate, filtered and concentrated to obtain the product as a brown solid, which was precrystallization of absolute ethanol, with the floor is the group of racemic 3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-96, which was isolated by filtration as a white solid (25% yield). These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=383,8 m/z. Activity: A

Example 94

Racemic 3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-96 (1.0 EQ.) was dissolved in a mixture of 1:1 tetrahydrofuran/water (0,06 M) was added lithium hydroxide (8.0 EQ.). The reaction mixture was left for stirring at room temperature for 1 hour, after which the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH<2 1 N. HCl solution to obtain the desired acid enantiomers I-97a and 97b in the form of a white solid, which was isolated using vacuum filtration. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=369,3 m/z. Activity: A

Example 95

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-98a and 98b received in stage 1, based on the racemic compound I-10 and methyl ester 3-(5-hydroxypyridine-2-yl)propanoic acid using Method 5. These compounds can be divided with what ispolzovaniem ways chiral HPLC, known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=418,1 m/z. Activity: A

Example 96

Racemic 3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-98 (1.0 EQ.) was dissolved in a mixture of 1:1 tetrahydrofuran/water (0,06 M) was added lithium hydroxide (8.0 EQ.). The reaction mixture was left for stirring at room temperature for 1 hour, after which the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH<2 1 N. HCl solution to obtain the desired acid I-99a and 99b in the form of a white solid, which was isolated using vacuum filtration. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=402,8 m/z. Activity: A

Example 97

Racemic compound I-98 was dissolved in a solution of ammonia in methanol (7,0 M in methanol, of 0.02 M per isoxazol). The reaction mixture was tightly sealed and left to stir at 23°C for 72 hours, after which the solvent and excess ammonia were removed under a stream of nitrogen to obtain a light brown solid, which was ground into powder with hexane, obtaining W is being amide I-100a and 100b in the form of a white solid. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=404,5 m/z. Activity:

Example 98

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-101a and 101b received in stage 1, based on the racemic compound I-9 and 3-hydroxypyridine, using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=316,8 m/z. Activity: A

Example 99

3-bromo-4,5-dihydroisoxazole I-102a and 102b received in stage 2, since the formation of the alkene of 1-(biphenyl-4-yl)ethanone using Method 8 followed by cyclopentadiene using Method 1. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=315,7 m/z. Activity: A

Example 100

3-(pyrimidine-5-yloxy)-4,5-dihydroisoxazole I-103a and 103b received in stage 1, based on the racemic compound I-9 and 5-hydroxypyrimidine, using Method 5. These compounds can partition the te using chiral HPLC, known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=318,7 m/z. Activity: A

Example 101

3-(pyrimidine-5-yloxy)-4,5-dihydroisoxazole I-104a and 104b received in stage 1, based on the racemic compound I-102 and 5-hydroxypyrimidine, using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=332,6 m/z. Activity: A

Example 102

Racemic 3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-97 (1.0 EQ.) was dissolved in methylene chloride (0,03 M per isoxazol). Added thionyl chloride (2.0 EQ.) and the reaction mixture was stirred for 1 hour at room temperature, then the mixture was concentrated under vacuum to obtain a beige solid, which was subjected to azeotropic distillation with toluene (2×). The obtained solid was again dissolved in tetrahydrofuran (0,03 M per isoxazol), then add methyl ester of glycine (1.5 EQ.) with the subsequent addition of triethylamine (3.0 EQ.). The reaction mixture was stirred for 1 hour at room temperature, then the mixture was transferred into a separating funnel with excess quantities of the m of water and ethyl acetate. The organic layer was then washed with saturated solution of NaHCO3and saturated saline solution, dried over magnesium sulfate and concentrated under vacuum to obtain the crude substance, which was purified using flash chromatography on silica gel (ethyl acetate/hexane), to obtain the amide I-105a and 105b in the form of a white solid. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=437,5 m/z. Activity: A

Example 103

Racemic 3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-105 (1.0 EQ.) was dissolved in a mixture of 1:1 tetrahydrofuran/water (0,06 M) was added lithium hydroxide (8.0 EQ.). The reaction mixture was left for stirring at room temperature for 1 hour, after which the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH<2 1 N. HCl solution to obtain the desired acid I-106a and 106b in the form of a white solid, which was isolated using vacuum filtration. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]-=423,7 m/z. Activity: A

Example 104

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-107a and 107b was obtained using a procedure analogous to the procedure of Example 102, except that used methylamine instead of the methyl ester of glycine. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=382,5 m/z. Activity: A

Example 105

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-108a and 108b were obtained using a procedure analogous to the procedure of Example 102, except that used dimethylamine instead of the methyl ester of glycine. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=396,6 m/z. Activity: B

Example 106

3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-109a and 109b was obtained using a procedure analogous to the procedure of Example 102, except that used ethanolamine instead of the methyl ester of glycine. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M-H]- =409,9 m/z. Activity: A

Example 107

Racemic 3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-67 (1.0 EQ.) was dissolved in a mixture of 1:1 tetrahydrofuran/water (0,06 M) was added lithium hydroxide (8.0 EQ.). The reaction mixture was left for stirring at room temperature for 1 hour, after which the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH<2 1 N. HCl solution to obtain the desired acid I-110a and 110b in the form of a white solid, which was isolated using vacuum filtration. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=376,5 m/z. Activity: A

Example 108

Racemic 3-(pyridine-3-yloxy)-4,5-dihydroisoxazole I-67 was dissolved in a solution of dimethylamine in methanol (2.0 M in tetrahydrofuran, of 0.02 M per isoxazol). The reaction mixture was tightly sealed and left to stir at 23°C for 72 hours, after which the solvent and excess dimethylamine was removed under a stream of nitrogen to obtain a light brown solid, which was ground into powder with hexane, to give the desired amide I-111a and 111b in the form of a white solid. These with the organisations can be divided using chiral HPLC, known in the art. For example, see the way chiral HPLC, disclosed in this application. [M+H]+=405,1 m/z. Activity: A

Example 109

3-(pyrimidine-5-yloxy)-4,5-dihydroisoxazole I-112a and 112b received in stage 1, based on the racemic compound I-14 and 5-hydroxypyrimidine, using Method 5. These compounds can be divided using chiral HPLC known in the art. For example, see the way chiral HPLC, disclosed in this application. Activity: A

Example 110

1. The compound of formula (I):

or its pharmaceutically acceptable form, where:
each of Ra, Rband Rcindependently represents-H, C1-10alkyl or C1-10perhalogenated, Rdrepresents a group-L-Z, and Z represents a C6-14aryl which may be substituted (R15)z, where z is 0, 1, 2, 3, 4, or 5, or unsubstituted, and R15represents fluorine, bromine, chlorine and iodine, forfinal, C1-10perhalogenated, SO2N(R18)2, -OR16-C(=O)N(R18)2C1-10alkyl, C6-14aryl, R16independently represents a C6-14aryl, C1-10alkyl, C1-10perhalogenated,2-10quinil, 5-14-membered heteroaryl containing 1-4 heteroatoms in Kohl is e, present in the aromatic ring system, where each heteroatom is independently selected sludge nitrogen, oxygen and sulfur;
or two adjacent R15group substituted by a group-O(C(R2)2)1-2O-, where each R2independently represents a halogen;
R18independently represents hydrogen, C1-10alkyl, -CH2Ph;
L is a covalent bond;
G represents-ORe;
Rerepresents a C6-14aryl or a 5-14-membered heteroaryl containing 1-4 heteroatoms in the ring which are present in the aromatic ring system, where each heteroatom is independently selected sludge nitrogen, oxygen and sulfur, and which may be substituted (Rh)xwhere x is znachenie 0, 1, 2, 3 or 4, and each Rhindependently represents a fluorine, bromine, chlorine, iodine, -CN, -NO2, -ORi, -N(Rk)2, -SRi, -CO2H, -CO2Ri, -OC(=O)Ri, -C(=O)N(Rk)2, -NRkC(=O)Ri, -NRkCO2Ri, -C(=O)NRkSO2Ri, -SO2N(Rk)2, SO2RiC1-10alkyl, C1-10perhalogenated, C6-14aryl or a 5-14-membered heteroaryl containing 1-4 heteroatoms in the ring which are present in the aromatic ring system, where each heteroatom independently selected from nitrogen, oxygen and sulfur, where each alkyl, aryl, and GE is Eroare independently substituted by 0, 1, 2, 3, 4, or 5 groups Rm;
in each case, Riindependently represents a C1-10alkyl, C3-10carbocyclic;
in each case, Rkindependently represents hydrogen, HE, C1-10alkyl, which is independently substituted by 0, 1, 2, 3, 4, or 5 groups Rm;
in each case, Rmindependently represents a fluorine, bromine, chlorine, iodine, -OH, -CO2H, -CO2Ro-C(=O)N(Rn)2C1-6alkyl, C1-6perhalogenated or two adjacent Rmthe Deputy can be merged to form =O;
in each case, Roindependently represents a C1-6alkyl;
in each case, Rnindependently represents hydrogen.

2. Connection on p. 1, where Raand Rbrepresent-N and Rcrepresents-CH3or-CF3.

3. Connection on p. 1, where each of Ra, Rband Rcrepresents-N.

4. Connection on p. 1, where z has a value of 1.

5. Connection on p. 4, where the compound is a compound of the formula:

or its pharmaceutically acceptable form.

6. Connection on p. 5, where the compound is a compound of the formula:

or its pharmaceutically acceptable form,
where R16independently represents a C1-10alkyl, C1-10 perhalogenated,2-10quinil or a 5-14-membered heteroaryl containing 1-4 heteroatoms in the ring which are present in the aromatic ring system, where each heteroatom independently selected from nitrogen, oxygen and sulfur;
or two adjacent R15group substituted by a group-O(C(R2)2)1-2O-, where each R2independently represents a halogen.

7. Connection on p. 6, where the compound is a compound of the formula:

or its pharmaceutically acceptable form.

8. Connection on p. 1, where Rerepresents a 5 to 14-membered heteroaryl.

9. Connection on p. 8, where Rerepresents pyridinyl group of the formula:

x is 0, 1, 2, 3 or 4, and
each Rhindependently represents a fluorine, bromine, chlorine, iodine, -CN, -NO2, -ORi, -N(Rk)2, -SRi, -CO2H, -CO2Ri, -OC(=O)Ri-C(=O)N(Rk)2, -NRkC(=O)Ri, -NRkCO2Ri-C(=O)NRkSO2Ri, -SO2N(Rk)2, -SO2R1C1-10alkyl, C1-10perhalogenated,6-14aryl or a 5-14-membered heteroaryl containing 1-4 heteroatoms in the ring which are present in the aromatic ring system, where each heteroatom independently selected from nitrogen, oxygen and sulfur, where each is th alkyl, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4, or 5 groups Rm;
in each case, Riindependently represents a C1-10alkyl, C3-10carbocyclic;
in each case, Rkindependently represents hydrogen, HE, C1-10alkyl, which is independently substituted by 0, 1, 2, 3, 4, or 5 groups Rm;
in each case, Rmindependently represents a fluorine, bromine, chlorine, iodine, -OH, -CO2H, -CO2Ro-C(=O)N(Rn)2C1-6alkyl, C1-6perhalogenated or two adjacent Rmthe Deputy can be merged to form =O;
in each case, Roindependently represents a C1-6alkyl;
in each case, Rnindependently represents hydrogen.

10. Connection on p. 9, where Rhrepresents fluorine, bromine, chlorine, iodine, -CN, -NO2, -ORi, -N(Rk)2, SRi, -CO2H, -CO2Ri, -OC(=O)Ri, -C(=O)N(Rk)2,-NRkC(=O)Ri, -NRkCO2Ri, -C(=O)NRkSO2Ri, -SO2N(Rk)2, -SO2RiC1-10alkyl, C6aryl or 5-6-membered heteroaryl containing 1-4 heteroatoms in the ring which are present in the aromatic ring system, where each heteroatom independently selected from nitrogen, oxygen and sulfur, where each alkyl, aryl and heteroaryl independently substituted by 0, 1, 2, 3 or 4 is the group R m.

11. Connection on p. 10, where Rhrepresents-C(=O)Ri, -CO2H, -SO2Rior 5-membered heteroaryl, independently substituted by 0 or 1 group, Rm.

12. Connection on p. 11, where the 5-membered heteroaryl is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl.

13. Connection on p. 9, where pyridinoline group is a 3-pyridinyl group of the formula:

14. Connection on p. 8, where G represents-OReformula:


















15. Connection on p. 14, where G is a:

16. Connection PP.1-15, where the connection is essentially enantiomerically pure.

17. Connection on p. 1, where the compound is:

ConnectionGRaRc
I-23-H-H
I-24-H-H
I-25-H-H
I-26-H-H
I-27-H-H
I-28-H-H
I-29-H-H
I-30-H-H
I-31-H-H
I-36-H-H
I-37-H-H
I-39-H-H
I-40-H-H
I-41-H-H
I-42-H-H

I-43-H-H
I-44-H-H
I-47-H-H
I-56-H-H
I-57-H-H
I-58-H-H
I-59-H-H
I-60-H-H
I-61-H -H
I-62-H-H
I-63-H-H
I-64-H-H
I-65-H-H
I-66-H-H

I-67-H-H
I-68-H-H
I-69-H-H
I-90 -H-H
I-92-H-H
I-93-H-H
I-94-H-H
I-98-H-H
I-99-H-H
I-100-H-H
I-110-H-H
I-111-H-H
I-146 -H-H
I-147-H-H
I-155-H-H

I-159-H-H
I-160-H-H
I-197-H-H
I-257-H-H
I-91 (trance)-CH3-H
I-89-H-CH3/td>
I-131-H-CF3
ConnectionRaRc
I-46-H-H
I-53-H-H
I-54-H-H
I-55-H-H
I-70-H-H

I-71-H-H
I-72 -H-H
I-73-H-H
I-83-H-H
I-84-H-H
I-85-H-H
I-86-H-H
I-96-H-H
I-97-H-H
I-105-H-H
I-106 -H-H
I-107-H-H
I-108-H-H

I-109-N-N
I-112-N-N
I-118-N-N
I-128-N-N
I-132-N-N
I-133-N -N
I-134-N-N
I-135-N-N
I-136-N-N
I-151-N-N
I-152-N-N
I-157-N-N
I-161-N-N
I-162-N-N
I-163-N -N

I-165-H-H
I-173-H-H
I-174-H-H
I-175-H-H
I-176-H-H
I-177-H-H
I-178-H-H
I-182-H-H
I-183 -H-H
I-184-H-H
I-186-H-H
I-187-H-H
I-188-H-H

I-189-H-H
I-190-H-H
I-191-H-H
I-192-HI-193-H-H
I-194-H-H
I-195-H-H
I-199-H-H
I-200-H-H
I-201-H-H
I-218-H-H
I-220-H-H

I-221 -H-H
I-223-H-H
I-224-H-H
I-225-H-H
I-226-H-H
I-230-H-H
I-236-H-H
I-258-H-H
I-88-H-CH3
I-113 -H-CH3

I-114-H-CH3
I-115-H-CH3
I-116-H-CH3
I-117-H-CH3
I-129-H-CH3
I-154-H-CH3
I-156-H-CH3
I-158 -H-CH3
I-164-H-CH3
I-167-H-CH3
I-172-H-CH3
I-185-H-CH3
I-196-H-CH3

-CH3
I-198-N-CH3
I-222-N-CH3
I-227-N
I-228-N-CH3
I-229-N-CH3
I-231-N-CH3
I-232-N-CH3
I-233-N-CH3
I-234-N-CH3

I-235-H-CH3
I-240-HCH 3
I-241-H-CH3
I-242-H-CH3
I-261-H-CH3
ConnectionGRaRc
I-168-H-H
I-169-H-H
I-170-H-H
I-216-H-H
I-217-H-H
I-219-H-H

td align="center"> -H
I-238-H-H
I-259-H-H
ConnectionGRaRcR15=halogen
I-121-H-H-F
I-122-H-H -F
I-123-H-H-F
I-125-H-H-Cl
ConnectionGRaRcR16=unsubstituted alkyl, quinil
I-143-H-H
I-144-H-H
I-145-H
I-140-H-H
I-141-H-H

-H
I-137-H-Hn-butyl
I-138-H-Hn-butyl
I-139-H-Hn-butyl
I-38-H-CH3
ConnectionGRaRcR15=alkyl, aryl
I-180-H-Hn-butyl
I-181-H-Hn-butyl
I-104-H-CH3-C6H5
I-101-H-H-C6H5
I-103 -H-H-C6H5
ConnectionGR15=halogen
I-153-Cl
I-149-Br

I-150-Br
I-237-Br
ConnectionGRaRc
I-87 -H-H
ConnectionGRaRc
I-166-H-H
ConnectionGRaRcR2=H, halogen
I-127-H-H-F, -F
ConnectionGRa RcR18
I-214-H-HH, -CH2Ph

I-215-N-NH, -CH2Ph
I-212-N-N-CH3, -CH3
ConnectionGR3R0R18
I-213-N-N-CH3, -CH3

or its pharmaceutically acceptable form.

18. Connection on p. 1, where the compound is:















































































img src="https://img.russianpatents.com/1192/11922293-s.jpg" height="23" width="117" />































































































or its pharmaceutically acceptable form.

19. Connection on p. 1, where the compound is:



or its pharmaceutically acceptable salt.

20. Connection on p. 19 where the compound is an (R)-enantiomer.

21. Connection on p. 1, where the connection is a

or its pharmaceutically acceptable salt.

22. Connection on p. 1, where the connection is a

or its pharmaceutically acceptable salt.

23. Connection on p. 1, where the connection is a

or its pharmaceutically acceptable salt.

24. Connection on p. 1, where the connection is a

or its pharmaceutically acceptable salt.

25. The pharmaceutical composition inhibiting niggeroes fatty acids (FAAH), which includes an effective amount of the compounds according to paragraphs.1-24 or its pharmaceutically acceptable Faure is s, and pharmaceutically acceptable excipient.

26. The pharmaceutical composition according to p. 25, where the connection is a

or its pharmaceutically acceptable salt.

27. A method of treating FAAH-mediated condition comprising the administration to a subject in need, a therapeutically effective amount of a compound according to PP 1-24 or its pharmaceutically acceptable forms, where FAAH-mediated condition is selected from pain-causing conditions, inflammatory conditions, immune disorders, disorders of the Central nervous system, metabolic disorders, cardiac disorders, and glaucoma.

28. The method according to p. 27, where painful condition selected from neuropathic pain, Central pain, differentional pain, chronic pain, postoperative pain, preoperative pain, nociceptive pain, acute pain, non-inflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, pain associated with medical procedures, pain arising from itching, painful bladder syndrome, pain associated with premenstrual dysphoric disorder, pain associated with premenstrual syndrome, pain associated with chronic fatigue syndrome, pain, associated with premature birth, pain associated with withdrawal symptoms from the drug dependence is value, joint pain, arthritis pain, lumbar-krestsovoy pain, musculoskeletal pain, headache, migraine, muscle pain, lumbar pain, neck pain, toothache, dental/maxillofacial pain and visceral pain.

29. The method according to p. 27, where the inflammatory condition or immune disorder is a gastrointestinal disorder or skin disease.

30. The method according to p. 27, where the FAAH-mediated condition is a disorder of the Central nervous system selected from neurotoxicity and/or multiple trauma, stroke, multiple sclerosis, lesions of the spinal cord, epilepsy, mental disorders, conditions associated with sleep disorders, movement disorders, nausea and/or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease and drug addiction.

31. The method according to p. 27, where the FAAH-mediated condition is a metabolic disorder selected from the associated with the depletion condition, or associated with obesity status, or their complications.

32. The method according to p. 27, where the FAAH-mediated condition is a cardiac disorder is selected from hypertension, circulatory shock, reperfusion of myocardium lesions and atherosclerosis.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula I where A is such as given in the invention formula, R is selected from the group consisting of H and C1-6 alkyl, n and p each is independently selected from 0, 1 and 2, on condition that n + p = 2; Y represents -O- or -S-; R1, R2, R3, R4 in each position are independently selected from H and C1-6 alkyl; R5 is selected from the group consisting of -C(O)-CH2-indol-3-yl, -C(O)-(CH2)2-indol-3-yl, -C(O)-(CH2)3-indol-3-yl, trans -C(O)-(CH=CH)-indol-3-yl, -SO2-4-fluorophenyl, -C(O)-CH(n-propyl)2, -C(O)-(4-hydroxy-3,5-di-tert-butylphenyl), -C(O)-CH(NH2)-CH2-indol-3-yl and -C(O)-CH2CH3; and R6 represents H. Invention also relates to pharmaceutical composition for modulation of muscarinic receptor M1, containing formula I compounds, and methods of treating disease or state, curable by modulator of muscarinic receptor M1.

EFFECT: formula I compounds as modulators of muscarinic receptor M1.

33 cl, 1 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel cyclic carbodiimide compound of formula (i): (where X is any of divalent groups of formulae (i-1)-(i-3), or a tetravalent group of formula (i-4), when X is divalent, q equals 0, and when X is tetravalent, q equals 1, and each of Ar1-Ar4 independently denotes an aromatic group and can be substituted with an alkyl group containing 1-6 carbon atoms, or a phenyl group (i-1), where n is an integer from 1 to 6, (i-2), where each of m and n is independently an integer from 0 to 3, (i-3), where each of R1 and R2 is an alkyl group containing 1-6 carbon atoms, or a phenyl group , (i-4), which is useful as a polymer chain terminating agent, specifically an acid group capturing agent. Methods of obtaining a compound of formula (i) are also described.

EFFECT: improved properties of the compound.

10 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to spiro derivatives of parthenin of formula , where R/R' is selected from a group consisting of phenyl or a substituted phenyl such as 4-ClC6H4, 2-NO2C6H4; 2,4-(MeO)2C6H3, 4-MeC6H4, and formula , where R is 4-MeOC6H4, 2-NO2C6H4, 3-NO2C6H4, 3-MeC6H4, 3-MeCO2C6H4. The invention also relates to methods of producing said spiro derivatives and a pharmaceutical composition based on said derivatives.

EFFECT: compounds of formula 1b and 1d have anticancer activity.

14 cl, 6 dwg, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to spirocyclic nitriles of formula (1a): wherein the radicals A, B, C, X, Y, R24, R25, R26 and R27 are presented in cl.1 of the patent claim, inhibiting thiol proteases, particularly cathepsins, a method for preparing and using them as a drug for treating the diseases directly or indirectly mediated by cathepsins.

EFFECT: preparing the agent for treating the diseases directly or indirectly mediated by cathepsins.

12 cl, 2 tbl, 105 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to aryl- and heteroarylsubstituted diasaspiropyridine derivatives of formula (I) to its pharmaceutically acceptable acid- or base-additive salt wherein A represents a radical of formula (II) wherein each k, l, m, n independently represents an integer equal to 0, 1, 2, 3 or 4, provided (k+1) and (m+n) are equal to 2, 3, 4 or 5; wherein one of -CH2-fragments can be substituted by atom O; and wherein one of -CH2-fragments can be substituted by an oxo group; X represents CH or N; R3 is specified in a group consisting of hydrogen, C1-5alkyl and C3-6cycloalkyl; each R4, R5 is independently specified in a group including hydrogen, halogen, oxo, C1-3alkyl and C1-3alkyloxy; p represents an integer equal to zero, 1, 2 or 3; q represents an integer equal to zero, 1, 2 or 3; each Y1, Y3, is independently specified in a group including a single bond and O; Y2 represents saturated or unsaturated C1-6hydrocarbon radical with a straight chain; B is specified in a group including phenyl optionally substituted by the number of the substitutes R6 each of which is independently specified in halogen; and wherein r represents an integer equal to zero, 1 or 2; alkyl represents a saturated hydrocarbon radical with a straight and branched chain containing said number of carbon atoms; wherein said radical can be optionally substituted by one or more carbon atoms or more radicals specified in a group including halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio and formyl; and halogen represents fluorine, chlorine, bromine or iodine. Also, the invention refers to a pharmaceutical composition based on the compounds of formula I as an active ingredient for preparing a drug for preventing and/or treating mental disorders, including but not limited to anxiety, eating behavior disorder, affective disorders, such as bipolar disorders and depression, psychosis, such as schizophrenia, and sleeping disorders; obesity, diabetes; sexual disorders and neurological disorders; to a method for preparing a pharmaceutical composition, and to using the compounds of formula I for preparing the drug.

EFFECT: there are prepared and described new compounds possessing melanin-concentrating hormone (MCH), particularly MCH-1 antagonist activity.

19 cl, 4 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to novel derivatives of quinolone or one pharmaceutically acceptable salts thereof, solvates thereof or solvates of salts thereof, having general formula I , in which R1 denotes fluorine, R3 denotes halogen, a hydroxy group or a C1-C4-alkoxy group, R4 denotes C1-C6-alkyl or C3-C8-cycloalkyl, where the alkyl can contain 1-3 substitutes, and the substitutes are independently selected from a group comprising halogen or trifluoromethyl, and where the cycloalkyl can contain 1-3 halogen atoms as substitutes, or R3 and R4 together with atoms to which they are bonded form a ring with a group of formula , in which * indicates a site for bonding with a carbon atom, and # indicates a site for bonding with a nitrogen atom, R7 and R8 independently denote halogen, trifluoromethyl, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, C1-C3-alkyl or C1-C3-alkoxy group, and R9 denotes hydrogen, halogen or C1-C3-alkyl, or R8 denotes a trifluoromethoxy group, and R7 and R9 denote hydrogen, R10 denotes a group of formula or , in which * indicates a site for bonding with a carbon atom, R2 is bonded in position 3 or 4 and denotes a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkyl, C1-C4-alkoxycarbonyl, C3-C6-cycloalkylcarbonyl or optionally hydroxy-substituted C1-C6-alkylaminocarbonyl, where the alkyl is substituted with one substitute and the substitute is selected from a group comprising a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkoxycarbonyl and 2-oxopyrrolidin-1-yl, R5 and R6 are independently bonded in positions 3, 4 or 5 and independently denote hydrogen, hydroxy group, methyl or ethyl, and Y denotes a methylene group or an oxygen atom. The invention also relates to methods of producing a compound of formula I, a medicinal agent based on the compound of formula I, use of the compound of formula I and a method of fighting viral infections.

EFFECT: novel substituted quinolone derivatives which are useful in treating viral diseases are obtained.

11 cl, 1 tbl, 69 ex

FIELD: medicine.

SUBSTANCE: invention refers to indole-3-yl-carbonyl-spiro-piperidine derivatives which have an effect of Vla-receptor antagonists and are presented by Formula I: where a tail spiropiperidine group A and residual R1, R2 and R3 are such as specified in the patent claim.

EFFECT: higher efficiency of applying the compounds in drugs effective in dysmenorrhea, hypertension, chronic heart failure, inadequate vasopressin secretion, hepatic cirrhosis, nephrotic syndrome, obsessive-compulsive disorder, anxious and depressive disorders.

22 cl, 42 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula , where R1 represents hydroxyadamantyl, methoxycarbonyladamantyl, carboxyadamantyl, aminocarbonyladamantyl or aminocarbonylbicyclo[2.2.2]octanyl and where A represents CR5R6; or phenyl, chlorobenzyl, benzyl, chlorophenylethyl, phenylethyl, difluorobenzyl, dichlorophenyl, trifluoromethylphenyl or difluorophenylethyl and where A represents CR5R6; R2 and R3 together with nitrogen atom N* and carbon atom C*, which they are bount to, form group or ; R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyl, arylalkoxygroup, arylalkoxyalkyl, hydroxyalkyl, aryl, heteroarylalkyl, heteroaryloxyalkyl, substituted aryl, substituted heteroarylalkyl or substituted heteroaryloxyalkyl, where substituted aryl, substituted heteroarylalkyl and substituted heteroaryloxyalkyl are substituted with 1-3 substituents, independently selected from alkyl, cycloalkyl, cyanogroup, halogen, halogenalkyl, hydroxygroup and alkoxygroup; R5 represents hydrogen; R6represents hydrogen; as well as to their pharmaceutically acceptable salts and esters, which can be used as 11b-HSD1 inhibitors.

EFFECT: obtaining compounds which can be used as 11b-HSD1 inhibitors.

9 cl, 1 tbl, 103 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene citrate salt. The invention also refers to pharmaceutical compositions containing the above citrate, and methods for using citrate in treating several conditions.

EFFECT: what is prepared is the new 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene salt and the pharmaceutical compositions on the basis thereof which can find application in medicine for treating a proliferative disorder.

17 cl, 30 dwg, 5 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein R1 represents an alkoxy group or halogen; each U and V independently represents CH or N; "----" means a bond or is absent; W represents CH or N, or if "----" is absent, then W represents CH2 or NH, provided not all U, V and W represent N; A represents a bond or CH2; R2 represents H, or provided A means CH2, then it also can represent OH; each m and n are independently equal to 0 or 1; D represents CH2 or a bond; G represents a phenyl group that is single or double substituted in meta- and/or para-position(s) by substitutes specified in alkyl, C1-3alkoxy group and halogen, or G represents one of the groups G1 and G2: wherein each Z1, Z2 and Z3 represents CH; and X represents N or CH and Q represents O or S; it should be noted that provided each m and n are equal to 0, then A represents CH2; or a pharmaceutically acceptable salt of such compound. Besides, the invention refers to a pharmaceutical composition for treating a bacterial infection containing an active ingredient presented by a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert additive.

EFFECT: preparing the oxazolidine compounds applicable for preparing a drug for treating and preventing the bacterial infections.

14 cl, 8 dwg, 2 tbl, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of general formula [I]: or their pharmacologically acceptable salts, wherein R1 is C1-6 alkyl; R2 is C1-6 alkoxy; m and n mean 1; W means N; the ring A represents fragments of formula , or that can be substituted; X1 is a single bond, C1-6 alkylene group or -C(O)NR3-, wherein R3 is hydrogen, C1-6 alkyl or phenyl; and the ring B represents fragments of formula [5]-[11]: that can be substituted, and a pharmaceutical composition containing them.

EFFECT: new compounds possess activity inhibiting the amyloid beta production, and are effective as a therapeutic agent for treating an Aβ-caused disease, such as Alzheimer disease or Down syndrome.

10 cl, 48 tbl, 399 ex

FIELD: chemistry.

SUBSTANCE: invention relates to antibacterial compounds of formula (I), where R1 represents alkoxygroup; U, V and W each represents CH or one of U, V and W represents N, and each other represents CH; A represents CH2 or O; G represents CH=CH-E, where E represents phenyl group, mono- or di-substituted with halogen, or G represents group of one of the formulas given below , , where Z represents CH or N, Q represents O or S and K represents O or S; or salt of such compound. In addition, invention also relates to pharmaceutical composition based on formula (I) compound for prevention or treatment of bacterial infection, as well as to application of claimed compounds for obtaining medication for prevention or treatment of bacterial infection.

EFFECT: novel compounds, which can be applied in treatment of bacterial infection, are obtained and described.

23 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of nucleoside derivatives - 1,2,5-oxadiazoles of general structural formula I where R1 and R2 are selected from phenylsulphonyl, substituted with one or more halogen atoms, nitro groups, carboxy groups, alkyl halides, CH3, OCH3, OCF3; X is selected from N or N→O; or R1 and R2 form a group, where R', R", R'" and R'''' are independently selected from hydrogen; halogens; nitro groups, hydroxy group, carboxy group, CH3; CH2Br; OCH3; phenylsulphonyl; phenylthio group; or the following groups: R' and R" can also be merged into one of the following common rings for inhibiting human immunodeficiency virus (HIV) replication. The invention also relates to a pharmaceutical composition based on compounds of formula I and a method of inhibiting HIV-1 subtypes A and B integrase, including forms which are resistant to raltegravir.

EFFECT: detecting novel activity in compounds of formula I, which can be used in medicine as HIV replication inhibitors.

3 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2,4-diamino-1,3,5-triazine derivative of general formula I, having protein kinase inhibitor properties, use thereof and a pharmaceutical composition based thereon. In general formula I Y is CH2, CHR', O, S, S(O) or S(O)2; X1, X2, X3 are independently selected from a CH groups or N; R1 is a C1-8 aliphatic group, C3-8 cycloalkyl, C6-10 aryl, ethylene-dioxyphenyl, methylene dioxyphenyl, pyridyl, each of which is optimally substituted with one or more identical or different groups R"; R' is hydrogen, OH, halogen, such as F, Cl, Br, I, or carboxyl or carboxamide, optimally N-substituted with (C1-6)alkyl, or cyano or halo(C1-8)alkyl, (C1-8)alkoxy, piperidinyl, optimally substituted with methyl; R" is R' or RD; R21, R22, R23, R24 are independently selected from groups F, Cl, Br, I, CN, (C1-16)alkyl; furthermore, R21 and R22 and/or R23 and R24 can be combined and represent one oxo (=O) group or together with a carbon atom can form a spirocycle containing 3 to 7 carbon atoms; furthermore, R21 and R24 together with two carbon atoms can form an aliphatic or aromatic ring containing 4 to 8 atoms, optionally substituted with one or more groups R'; RD is an oxo group =O or =S.

EFFECT: invention can be used to treat autoimmune or cancerous diseases, rheumatoid arthritis and non-Hodgkin lymphoma.

13 cl, 12 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a number of bicyclic nitroimidazole-replaced phenyloxazolydinones of the following structural formula (I):

,

containing nitroimidazole circle, or to its pharmaceutically acceptable salt; where R1 represents hydrogen, (C1-C6)alkyl or aryl; n is equal to 0, 1 or 2; X1 and X2 independently represent H, CF3, CI, OCF3 or F; G represents -OH, triazole or -NHCOR2; R2 represents (C1-C6)alkyl, cycloalkyl or aryl; and L represents a bond or a linker group chosen from any combination 2-3 of the following groups: 1) (C1-C6)alkylene, 2) (C3-C8)cycloalkylene, 3) arylene, arylene-replaced CN, ore arylene-replaced F, 4) group chosen from the group consisting of

,

where R10 represents H, CF3, hydroxyl, amino, alkyl, alkylamino, alkoxy or aryl, and R13 represents H, hydroxyl, amino, alkyl, alkyl amino, alkoxy or aryl, or R13 in combination with nitroimidazole circle can form spiral-shaped structure, 5) -C(=O)-, 6) -O-, 7) -S(O)n-, in which n is equal to 0.1 or 2, 8) -N(R3)-, 9) -C(R4)=C(R5)-, R3 represents hydrogen, (C1-C6) alkyl or aryl, and R4 and R5 represent hydrogen, (C1-C6) alkyl or aryl, or R4 and R5 can be combined together so that they can form a bond. Besides, the invention refers to pharmaceutical composition for treatment of bacterial infection based on compounds of formula I, as well as to a bacterial infection treatment method.

EFFECT: invention describes new compounds that have antibacterial activity against a line of wild type and stable lines of pathogenic microorganisms, and as a result, are suitable for prevention, control and treatment of a number of human and mammal bacterial infections caused by these pathogenic microorganisms such as bacillus Kochii.

15 cl, 93 ex, 1 tbl, 22 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound - 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula: .

EFFECT: novel compound, possessing antioxidant activity, is obtained.

2 cl, 6 tbl, 7 ex

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