Azaindoles useful as janus kinase inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to novel azaindole derivatives, having JAK-2 and JAK-3 kinase inhibiting activity, or pharmaceutically acceptable salts thereof. In formula (I): R3 denotes H; X1 denotes N or CR4; R2 denotes H, COOH, COOR' or CONHR'; R4 denotes H, F, R, OH, OR', COR', COOH, COOR', CONH2 or CN; or R2 and R4, taken together, form a benzene ring optionally substituted with 1-2 R10; R' denotes C1-3-alkyl or C1-3-alkenyl, each optionally substituted 1-2 R5; each R5 is independently selected from CN, unsubstituted C1-2alkyl, or two groups R5 together with a carbon atom with which they are bonded form a cyclopropyl ring; each R10 is independently selected from halogen, OCH3 or OH; R1 denotes or , R is H or denotes C1-2alkyl, optionally substituted with 1-3 R11; R6 denotes C1-4alkyl, optionally substituted with 1-5 R12; values of radicals R7 -R9, ring A, R11 -R14. The invention also relates to a pharmaceutical composition containing said compounds and a method of treating or reducing severity of a pathological condition such as allergy, asthma, amyotrophic lateral sclerosis, multiocular sclerosis, graft rejection, rheumatoid arthritis, solid malignant tumour, haematologic malignant disease, leukaemia, lymphoma and myeloproliferative disorders.

EFFECT: high efficiency of using the compounds.

41 cl, 6 ex, 6 tbl

 

The technical field to which the invention relates.

The present invention relates to compounds useful as inhibitors of Janus kinases (JAK). The invention also relates to pharmaceutically acceptable compositions containing the compounds according to the invention, and to methods of using the compositions in the treatment of various disorders.

The level of technology

The Janus kinase (JAK) are a family of tyrosine kinases, consisting of JAKl, JAK2, JAK3 and TYK2. JAK play an important role in the signaling of cytokines. The substrates of JAK family kinases down circuit signaling cascade include transferring the signal and activates transcription (STAT) proteins. JAK/STAT signaling is involved indirectly in many not conform to standard immune responses such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as solid and hematological tumors, such as leukemia and lymphoma. JAK2 is involved in myeloproliferative disorders, which include true polycythemia, essential trombozitemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome and systemic mA is Tacitus.

Accordingly, there is an urgent need to develop compounds that are useful as inhibitors of protein kinases. In particular, it is desirable to develop compounds that are useful as inhibitors of JAK family kinases.

The invention

It was found that the compounds according to the invention and their pharmaceutically acceptable compositions are useful as inhibitors of protein kinases, particularly the JAK family of kinases. These compounds have the General formula I:

or their pharmaceutical acceptable salt, where X1, R1, R2and R3are as defined in this specification.

Such compounds and their pharmaceutically acceptable salts are useful for treating or reducing the severity of various disorders, including proliferative disorders, cardiac disorders, neurodegenerative disorders, autoimmune disorders, conditions associated with organ transplantation, inflammation, or an immunologically mediated disorder in a patient.

The compounds and compositions provided by this invention are also useful for studies of the JAK-kinases in biological and pathological processes, research pathways of intracellular signal transduction mediated by such kinases, and compare Inoi evaluation of new kinase inhibitors.

Detailed description of the invention

Definitions and General terminology

Unless otherwise specified, in this specification used the following definitions. For the purposes of the present invention, the chemical elements are specified in accordance with the Periodic table of the elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. 1994. In addition, General principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March''s Advanced Organic Chemistry", 5th Ed., Smith, M.B. and March, J., eds. John Wiley & Sons, New York: 2001, the contents of which are incorporated in this description by reference.

As described herein, the compounds according to the invention can be optionally substituted by one or more substituents, such as are illustrated in General terms above, or for example a particular classes, subclasses and species features of the invention. It should be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or not substituted". In General, the term "substituted" preceded or not by the term "optional" refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise specified, optionally substituted group may have a substituent at each substitutable position of the group. When this structure can be substituted for more than one position more che is one Deputy, selected from a specified group, the Deputy may be the same or different in each position.

As described herein, when the term "optionally substituted" precedes the list, this term refers to all further substituted groups in this list. If radical or structure replacement groups are not defined or is defined as "optionally substituted", the radical or structure replacement group is unsubstituted. For example, if X is halogen; optionally substituted C1-3the alkyl or phenyl; X may be any optionally substituted alkyl or optionally substituted phenyl. Similarly, if the term "optionally substituted" is followed by the list, the term refers to all the substituted groups in the preceding list, unless otherwise noted. For example, if X is halogen, With1-3the alkyl or phenyl, where X is optionally substituted Jx, how1-3alkyl and phenyl may be optionally substituted Jx. As will be obvious to the person skilled in the art, groups such as H, halogen, NO2, CN, NH2, OH or OCF3should not be included because they are not substitutable groups.

The combination of the substituents presented in this invention, are preferred in the case where the result in the formation of a stable or chemically possible connections. The term "stable", as used herein, refers to compounds that are essentially unchanged when subjected to the conditions laid down for their production, detection, and, preferably, separation, purification, and use for one or more disclosed in this specification purposes. In some embodiments of the invention a stable compound or chemically possible connection is a connection that essentially does not change when stored at 40°C or less in the absence of moisture or chemically active compounds at least a week.

The term "aliphatic" or "aliphatic group", as used herein, means a straight (i.e. unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or which contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments the invention, the aliphatic groups contain 1-10 aliphatic carbon atoms. In the case of other embodiments of the invention aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments the invention, the aliphatic groups contain 1-6 aliphatics is their carbon atoms, and in still other embodiments the invention, the aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkeline or alkyline group. Other examples of aliphatic groups include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, and sec-butyl.

The term "cycloaliphatic" (or "carbocycle", or "cycloalkyl") refers to a hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, is attached at one point to the rest of the molecule, and where any individual ring in the specified bicyclic system is a 3-7-membered. Unless otherwise indicated, the term "cycloaliphatic" refers to a monocyclic3-C8the hydrocarbon or bicyclic8-C12the hydrocarbon. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkyl. Other examples of aliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cycloheptenyl.

The term "heterocycle", "heterocyclyl" or "heterocyclic"as used in this innovation is the description refers to monocyclic, bicyclic or tricyclic ring system, where one or more ring members are an independently selected heteroatom and which is completely saturated or which contains one or more units of unsaturation, but which is not aromatic, is attached at one point to the rest of the molecule. In some embodiments of the invention "heterocycle", "heterocyclyl" or "heterocyclic" group have three to fourteen members in the ring, where one or more atoms in the ring are heteroatoms independently selected from oxygen, sulfur, nitrogen or phosphorus and each ring in the system contains 3 to 7 atoms in the ring.

Examples of heterocyclic rings include, but are not limited to, the following monocycle: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydrofuranyl, 2-morpholino, 3 morpholino, 4-morpholino, 2-thiomorpholine, 3 thiomorpholine, 4-thiomorpholine, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl A 5-pyrazolyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidine, 3-thiazolidine, 4-thiazolidine, 1-imidazolidinyl, 2-imidazolidinyl, 4 and ideoligical, 5-imidazolidinyl; and the following Bicycle: 3-1H-benzimidazole-2-it, 3-(1-alkyl)benzimidazole-2-it, indolinyl, tetrahydropyranyl, tetrahydroisoquinoline, benzothiophen, benzodithiol and 1,3-dihydroimidazole-2-it.

The term "heteroatom" means one or more atoms of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus or silicon, and stereoselectivity of the form of any nitrogenous base or substituted nitrogen heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl).

The term "unsaturated"as used herein, means that the fragment has one or more units of unsaturation.

The term "aryl", as used in this description to one or as part of a larger moiety, such as, for example, "aralkyl", "aryloxy" or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems with a total 6-14 members in the ring, where at least one ring in the system is aromatic, where each ring in the system contains 3-7 members in the ring and the ring is attached at one point to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aryl ring". Examples of aryl rings may include FeNi is, naphthyl and anthracene.

The term "heteroaryl"used in this description to one or as part of a larger moiety, such as, for example, "heteroalkyl" or "heteroaromatics", refers to monocyclic, bicyclic and tricyclic ring systems with the total number of 5-14 members in the ring, where at least one ring in the system is aromatic, where at least one ring in the system contains one or more heteroatoms, where each ring in the system contains 3-7 members in the ring and the ring is attached at one point to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

Further examples of heteroaryl rings include the following monocycle: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (for example, 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (for example, 5-tetrazolyl), triazolyl (for example, 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (for example, 2-pyrazolyl), isothiazole, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triaz is poured, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, and the following Bicycle: benzimidazolyl, benzofuran, benzothiophene, indolyl (e.g., 2-indolyl), purinol, chinoline (for example, 2-chinoline, 3-chinoline, 4-chinoline) and ethenolysis (for example, 1-ethenolysis, 3-ethenolysis or 4-ethenolysis).

In the case of some embodiments of the invention aryl (including aralkyl, Alcoxy, aryloxyalkyl and similar groups) or heteroaryl (including heteroalkyl, heteroaromatics and similar groups) group may contain one or more substituents. Suitable substituents at the unsaturated carbon atoms of aryl or heteroaryl group are selected from those listed in the definitions of R2and R4below. Other suitable substituents include halogen;

-R°; -OR°; -SR°; 1,2-methylenedioxy; 1,2-Ethylenedioxy; phenyl (Ph), optionally substituted by R°; -O(Ph), optionally substituted by R°; -(CH2)1-2(Ph), optionally substituted by R°; -CH=CH(Ph), optionally substituted by R°; -NO2; -CN; -N(R°)2; -NR°C(O)R°; -NR°C(S)R°; -NR°C(O)N(R°)2; -NR°C(S)N(R°)2; -NR°CO2R°; -NR°NR°C(O)R°; -NR°NR°C(O)N(R°)2; -NR°NR°CO2R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -CO2R°; -C(O)R°; -C(S)R°; -C(O)N(R°)2; -C(S)N(R°)2; -OC(O)N(R°)2; -OC(O)R°; -C(O)N(OR°)R°; -C(NOR°)R°; -S(O)2R°; -S(O)3R°; -SO2N(R°)2; -S(O)R°; -NR°SO2N(R°) ; -NR°SO2R°; -N(OR°)R°; -C(=NH)-N(R°)2or -(CH2)0-2NHC(O)R°, where each independent R° is selected from hydrogen, optionally substituted aliphatic group1-6, unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or-CH2(Ph), or, if there are two independent R° one substituent or different substituents together with the atom(s)to which each R°group is attached, forms a 5-8-membered heterocyclic, aryl or heteroaryl ring or a 3-8-membered cycloalkyl ring, where the aforementioned heteroaryl or heterocyclic ring has 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Optional substituents aliphatic group of R° are selected from NH2, NH(aliphatic group, a C1-4), N(aliphatic group, a C1-4)2, halogen, aliphatic group, a C1-4, OH, O(aliphatic group C1-4), NO2CN, CO2H, CO2(aliphatic group C1-4), O(halo-aliphatic group C1-4or halogen aliphatic group C1-4where each of the above aliphatic groups of R° is unsubstituted.

In some embodiments of the invention aliphatic or heteroaromatics group or non-aromatic heterocyclic ring may contain one or more the deputies. Suitable substituents at the saturated carbon atom aliphatic or heteroaromatics group or non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon aryl or heteroaryl group and additionally include the following: =O, =S, =NNHR*, =NN(R*)2, =NNHC(O)R*, =NNHCO2(alkyl), =NNHSO2(alkyl), or =NR*, where each R* is independently selected from hydrogen or optionally substituted aliphatic group C1-4. Optional substituents aliphatic group of R* are selected from NH2, NH(aliphatic group, a C1-4), N(aliphatic group, a C1-4)2, halogen, aliphatic group, a C1-4, OH, O(aliphatic group C1-4), NO2CN, CO2H, CO2(aliphatic group C1-4), O(halo-aliphatic group C1-4or halogen aliphatic group C1-4where each of the above aliphatic groups of R* is unsubstituted.

In some embodiments the invention, the optional substituents at nitrogen non-aromatic heterocyclic ring include-R+, -N(R+)2, -C(O)R+,

-CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2, -C(=S)N(R+)2, -C(=NH)-N(R+)2or-NR+SO2R+where R+is in what oredom, optionally substituted aliphatic group1-6, optionally substituted phenyl, optionally substituted-O(Ph), optionally substituted-CH2(Ph), optionally substituted-CH=CH(Ph), optionally substituted -(CH2)1-2(Ph) or unsubstituted 5-6 membered heteroaryl or heterocyclic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, if there are two independent R+one substituent or different substituents together with the atom(s)to which each R+group is attached, forms a 5-8-membered heterocyclic, aryl or heteroaryl ring or a 3-8-membered cycloalkyl ring, where the aforementioned heteroaryl or heterocyclic ring has 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Optional substituents of aliphatic groups of R+choose from the NH2, NH(aliphatic group, a C1-4), N(aliphatic group, a C1-4)2, halogen, aliphatic group, a C1-4, OH, O(aliphatic group C1-4), NO2CN, CO2H, CO2(aliphatic group C1-4), O(halo-aliphatic group C1-4or halogen aliphatic group C1-4where each of the above aliphatic C1-4-groups of R+is unsubstituted.

As described above, in the which embodiments of the invention in the presence of two independent R° (or R +or any other group, as described in this description) may together with the atom(s)to which each group is attached to form a 5-8-membered heterocyclic, aryl or heteroaryl ring or a 3-8-membered cycloalkyl ring. Examples of rings that are formed when two independent R° (or R+or any other group, as described in this description), together with the atom(s)to which each group is attached, include, but are not limited to, the following: a) the presence of two independent R° (or R+or any other group, as described in this description)that are linked to the same atom, together with that atom to form a ring, for example, N(R°)2where both groups of R° together with the nitrogen atom form a piperidine-1-ilen, piperazine-1-ilen, or morpholine-4-ilen group; and (b) the presence of two independent R° (or R+or any other group, as described in this description)that are associated with different atoms and together with both of those atoms to form a ring, for example, when the phenyl group is substituted by two OR°,these two present two Rabouttogether with the oxygen atoms to which they are attached, form a condensed 6-membered oxygen-containing ring:.You should pay attention that can obrazovawe the change a number of other rings, when two independent R° (or R+or any other group, as described herein) are taken together with the atom(s)to which each group is attached, and the above specific examples are not intended to limit.

In some embodiments of the invention the alkyl or aliphatic chain may optionally be interrupted by another atom or group. This means that the methylene fragment alkyl or aliphatic chain optionally substituted specified by another atom or group. Examples of such atoms or groups may include, but are not limited to, -NR-, -O-, -S-, -CO2-, -OC(O)-, -C(O)CO-,

-C(O)-, -C(O)NR-, -C(=N-CN), -NRCO-, -NRC(O)O-, -SO2NR-, -NRS2-, -NRC(O)NR-,

-OC(O)NR-, -NRSO2NR-, -SO - or-SO2-, where R is defined above. Unless specified, optional replacement lead to the formation of chemically stable compounds. An optional interrupt can occur both within the chain and at the end of the chain; namely, as in the connection point and/or at the end of the chain. Two optional replacement can also be placed next to each other inside the chain, provided that this will lead to a chemically stable compound. Unless otherwise stated, if the replacement or interrupt occurs at the end of the chain, replacing the atom associated with the H on the end of the chain. For example, if CH2CH2CH3optional Prieur the by-O-, the resulting connection can be-OCH2CH3, -CH2OCH3or-CH2CH2OH.

As described herein, the link shown from a Deputy to the center of one of the rings in the polycyclic system (as shown below), is the substitution of a substituent at any substitutable position in any polycyclic ring system. For example, figa represents a possible substitution in any of the positions shown in fig.b.

This also applies to polycyclic systems, condensed with optional cyclic systems (which can be represented by broken lines) for Example, figs X is optional as Deputy for ring a and ring Century.

figs

If, however, each of the two rings in the polycyclic system is different substituents represented from the center of each ring, then, unless otherwise specified, each Deputy represents the replacement of only the ring to which it is attached. For example, on fig.d Y is an optional Deputy only rings a and X is an optional Deputy ring only B:

fig.d

Unless otherwise stated, are presented in this description of the structure is represented as on the expectation by all isomeric (e.g., enantiomeric, diastereomeric and geometric (or conformational)) forms; for example, R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of these compounds are also included in the scope of the invention.

Unless otherwise stated, all tautomeric forms of the compounds according to the invention is included in the scope of the invention. Additionally, unless otherwise noted, is also thought to that presented in this description of the structure considered to include compounds that differ only in the presence of one or more isotopic atoms. For example, compounds of these structures, except for the substitution of hydrogen by deuterium or tritium, or the replacement of carbon13With or14With the carbon included in the scope of this invention. Such compounds are useful, for example, as analytical tools or samples of biological research.

The description of the compounds according to the invention

The present invention relates to a compound of the formula I:

or its pharmaceutically acceptable salt,

where R3represents H, Cl or F;

X1represents N or CR4;

R2represents H, F, R', OH, OR', COR', COOH, COOR', CONH2, CONHR', CON(R')2or CN;

R4represents H, F, R', OH, OR', COR', COOH, COOR', CONH2, CONHR', CON(R')2or CN;

or R2or R4together form a 5-7-membered aryl or heteroaryl ring, optionally substituted by 1-4 R10;

R' represents an aliphatic group C1-3, optionally substituted by 1-4 R5; each R5independently selected from halogen, CF3, OCH3, OH, SH, NO2, NH2, SCH3, NCH3, CN or unsubstituted aliphatic group, a C1-2or two groups R5together with the carbon to which they are attached, form cyclopropyl ring or C=O;

each R10independently selected from halogen, OCH3, OH, NO2, NH2, SH, SCH3, NCH3, CN or unsubstituted aliphatic group1-2;

R1represents a

R" represents H or is an aliphatic group C1-2, optionally substituted by 1-3 R11; each R11independently selected from halogen, OCH3, OH, SH, NO2, NH2, SCH3, NCH3, CN, CON(R15)2or unsubstituted aliphatic group, a C1-2or two groups R11together with the carbon to which they are attached, form cyclopropyl ring or C=O;

R6is own the th aliphatic group C 1-4, optionally substituted by 1-5 R12; each R12independently selected from halogen, OCH3, OH, NO2, NH2, SH, SCH3, NCH3, CN or unsubstituted aliphatic group, a C1-2or two groups R12together with the carbon to which they are attached, form cyclopropyl ring;

ring A represents a 4-to 8-membered saturated nitrogen-containing ring containing up to two additional heteroatoms, selected from N, O or S, and optionally substituted by 1-4 R13;

each R13independently selected from halogen, R', NH2That other', N(R')2, SH, SR', OH, OR', NO2CN, CF3, COOR', COOH, COR', OC(O)H, OC(O)R', CONH2, CONHR', CON(R')2, NHC(O)R', or NR'r C(O)R'; or any two groups of R13at the same or different substituents, together with the atom(s)to which they are attached, form a 3-7-membered saturated, unsaturated or partially saturated carbocyclic or heterocyclic ring, optionally substituted by 1-3 R5;

R8represents an aliphatic group C1-4, optionally substituted by 1-5 R12;

R9represents an aliphatic group C1-2; or

R8and R9taken together, form a 3-7-membered carbocyclic or heterocyclic saturated ring, optionally substituted by 1-5 R12;

R14is the battle H or unsubstituted C 1-2-alkyl;

R15represents H or unsubstituted C1-2-alkyl; and

R7represents an aliphatic or cycloaliphatic group C2-3, optionally substituted up to 6 F.

In one embodiment of the invention the compound according to the invention has one of the formulasI-AorI-B:

In one embodiment of the invention R3represents H or Cl. In an additional embodiment of the invention R3represents Cl. In an additional embodiment of the invention R3represents N.

In one embodiment of the invention R2represents H, F, R', OH or or'. In an additional embodiment of the invention R2represents H or F.

In one embodiment of the invention the compound has the formula I-A and R represents H, F, R', OH or or'. In another embodiment of the invention R4represents H or F. In an additional embodiment of the invention R4represents F and R2represents H. In another embodiment of the invention R2represents F and R4represents H. In another embodiment, R2and R4both represent H. In an additional embodiment, the OS is supervising R 3represents Cl. In an alternative embodiment, R3represents H.

In another embodiment of the invention the compound has the formula I-A and R2and R4taken together form a 6-membered aryl ring. In an additional embodiment, R3represents Cl. In an alternative embodiment of the invention R3represents H.

In another embodiment, R7represents CH2CH3CH2CF3CH2CHF2CH2CH2F, CH2CH2CH3CH2CH2CF3CH2CH2CH2F or CH2CH2CHF2. In another embodiment, R7represents CH2CH3CH2CF3CH2CH2CH3or CH2CH2CF3. In still an additional embodiment of the invention R7represents CH2CF3.

In another embodiment, R" is H or CH3. In an additional embodiment, R" represents H.

In an additional embodiment, R14represents H. In yet another embodiment, R15if present, represents H. In another embodiment, R15is missing.

In another embodiment, domestic the invention relates to a compound of the formula II:

where X1Arepresents N, CH or CF and R1Arepresents a

.

In an additional embodiment, R7represents CH2CH3CH2CF3CH2CH2CH3or CH2CH2CF3. In another additional embodiment, R7represents CH2CF3.

In another embodiment, the invention relates to a compound of the formulaIII:

,

where X1Arepresents N, CH or CF and RIArepresents a

.

In an additional embodiment, R7represents CH2CH3CH2CF3CH2CH2CH3or CH2CH2CF3. In another additional embodiment, R7represents CH2CF3.

In another embodiment, any formulaI,IIorIIIR6choose from

.

In an additional embodiment, R6choose from

.

In another additional embodiment, R6choose from

.

In other variant embodiments of any of formulasI,IIorIIIring a represents a

,

and R13represents N or R13.

In an additional embodiment of the invention, ring a is a

.

In an additional embodiment of the invention, ring a is a.

In one embodiment of the invention each R13chosen independently from halogen, R', NH2That other', N(R')2, SH, SR', OH, OR', NO2CN, CF3, COOR', COOH, COR', OC(O)R' or NHC(O)R'; or any two groups of R13at the same or different substituents, together with the atom(s)to which each group R13attached, form a 3-7-membered saturated, unsaturated or partially saturated carbocyclic or heterocyclic ring, optionally substituted by 1-3 R5.

In one embodiment of this invention R13no. In another embodiment, ring A is substituted with one R13. In an additional embodiment, one of R13choose and is OH, CH3, F, OR', or other'. In another additional embodiment, R' represents a C1-2alkyl or C2-3alkenyl. In another embodiment of the invention R13represents OH.

In another embodiment, any of formulae I, II or III, R8and R9taken together, form a ring selected from the

,

where one or more carbon atoms in the specified ring is optionally and independently replaced with a N, O or S.

In other variant embodiments of any of formulasI,IIorIII, R8and R9are

In an additional embodiment, R8and R9are

.

In another additional embodiment, R8and R9are

.

In another embodiment, R8and R9are

.

In another embodiment, the invention relates to a compound of formula I, IA, IB, II, or III, where the specified connection inhibi is the duty to regulate JAK-kinase with a lower K i(and it is stronger)than these compounds inhibit one or more kinases selected from Aurora-1 (AUR-B), Aurora-2 (AUR-A), Src, CDK2, Flt-3, or e-Kit. In another embodiment, the invention relates to a compound of formula I, IA, IB, II, or III, where the specified connection inhibits JAK3 with a lower Kithan the compound inhibits one or more kinases selected from JAK2, Aurora-1, Aurora-2, Src, CDK2, Flt-3, or e-Kit.

In another embodiment, the invention relates to a compound of any of formulas I, IA, IB, II, or III, where the specified connection inhibits JAK3 with Kiless than 0.1 microns. In an additional embodiment, the invention relates to a compound of any of formulas I, IA, IB, II, or III, where the specified connection inhibits JAK3 with Kiless than 0.01 μm. In another embodiment, the invention relates to a compound of any of formulas I, IA, IB, II, or III, where the specified connection inhibits JAK3 with Kiless than 0.01 μm and inhibits Aurora-2 with Kithat is at least 5 times higher than the Kifor JAK3. In an additional embodiment, the invention relates to a compound of any of formulas I, IA, IB, II, or III, where the specified connection inhibits JAK3 with Kiless than 0.01 μm and inhibits Aurora-2 with Kithat is at least 10 times higher than the Kifor JAK3.

In another embodiment, the invention relates to a compound of formula I, IA, IB, II or III where the specified connection inhibits JAK3 in research on cells with IC 50less than 5 microns. In an additional embodiment, the specified connection inhibits JAK3 in research on cells with IC50less than 1 micron.

In another embodiment of the invention the specified connection inhibits JAK3 in research on cells with IC50that is at least 5 times less than the value at which the specified compound inhibits one or more kinases selected from JAK2, Aurora-1, Aurora-2, Src, CDK2, Flt-3 or c-Kit, in a study on the cells. In another embodiment, the invention relates to a compound of formula I, IA, IB, II, or III, where the specified connection inhibits JAK3 in research on cells with IC50less than 5 microns, where IC50in the case of JAK2 at least five times larger than the IC50in the case of JAK3. In an additional embodiment, the specified connection inhibits JAK3 in research on cells with IC50less than 1 μm, where IC50in the case of JAK2 at least five times larger than the IC50in the case of JAK3. In an additional embodiment, the specified connection inhibits JAK3 in research on cells with IC50less than 5 microns, where IC50in the case of JAK2 at least 10 times larger than the IC50in the case of JAK3. In an additional embodiment, the specified connection inhibits JAK3 in research on cells with IC50less than 1 μm, where IC50in the case of JAK2 at Merav 10 times more than IC50in the case of JAK3. In another additional embodiment, the invention relates to a compound of formula I, IA, IB, II, or III, where the specified connection inhibits JAK3 in research on cells with IC50less than 1 μm, where IC50in the case of JAK2 at least five times larger than the IC50in the case of JAK3, and where the specified connection inhibits JAK3 with Kiless than 0.01 μm and inhibits Aurora-2 with a value of Kithat is 5 times higher than the value of Kiin the case of JAK3. In another additional embodiment, the specified connection inhibits JAK3 in research on cells with IC50less than 1 μm, where IC50in the case of JAK2 at least 10 times larger than the IC50in the case of JAK3, and where the specified connection inhibits JAK3 with Kiless than 0.01 μm and inhibits Aurora-2 with a value of Kithat is at least 10 times higher than the value of Kiin the case of JAK3.

In another embodiment, the invention relates to a compound of table 1, table 2 or table 3:

Table 1

Table 2

Table 3

The use of the drug and the introduction of pharmaceutically acceptable compositions

In another embodiment, the invention relates to pharmaceutical compositions containing a compound of formula I, IA, IB, II or III.

In an additional embodiment, the composition further comprises a therapeutic agent selected from a chemotherapeutic or anti-proliferative tools, anti-inflammatory agents, immunomodulatory or immunosuppressive funds derived neurotrophic factor, a treatment for cardiovascular diseases, agents for treating destructive bone disorders, medium, the VA for treatment of liver disease, antiviral agents; agents used to treat diseases of the blood, means for treatment of diabetes or means for treating immunodeficiencies.

In accordance with another embodiment the invention relates to compositions containing a compound according to this invention or its pharmaceutically acceptable derivative and a pharmaceutically acceptable carrier, adjuvant (excipient or filler. The number of compounds in the compositions of the present invention is such that is effective to significant inhibition of protein kinases, particularly the JAK family kinase, in a biological sample or in a patient. Preferably the composition according to this invention is prepared for administration to a patient in need of such compositions. More preferably the composition according to this invention are prepared for oral administration to a patient.

The term "patient"as used herein, means an animal, preferably a mammal and most preferably a human.

Accordingly, in another aspect, the present invention relates to pharmaceutically acceptable compositions, where the compositions include any of the described compounds and optionally contain a pharmaceutically acceptable carrier, adjuvant or excipient. In some variants of the embodiment of the invention these compositions optionally additionally contain one or more additional therapeutic agents.

It should also be noted that some of the compounds of the present invention can exist in free form for treatment, or, if necessary, in the form of its pharmaceutically acceptable derivative. In accordance with the present invention pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which upon introduction to the needy in this the patient is able to provide, directly or indirectly, link, such as described herein, or a metabolite or residue. Used in this description, the term "his inhibitore active metabolite or residue" means that a metabolite or residue is also an inhibitor of JAK family kinases.

Used in this description, the term "pharmaceutically acceptable salt" refers to all of the salts which are, within the framework of a thorough medical examination, acceptable for use in contact with the tissues of humans and lower animals without nonspecific toxicity, irritation or allergic response and the like.

Pharmaceutically acceptable salts are well known in this field. For example, pharmaceutically acceptable salts are described in detail in S.M. Berge et al, J. Pharmaceutical Scinces, 1977, 66, 1-19, included in this description by reference. Pharmaceutically acceptable salts of the compounds according to this invention includes all salts derived from acceptable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid additive salts are salts of amino groups derived from inorganic acids such as hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, Perlina acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other used in the area of methods, such as ion exchange. Other pharmaceutically acceptable salts include salts such as: adipat, alginate, ascorbate, aspartate, bansilalpet, benzoate, bisulfate, borate, butyrate, comparat (comparatively), camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, format, fumarate, glucoheptonate, glycerol, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonic, lactobionate, lactate, laurate, lauryl, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, PA the oat, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluensulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal, ammonium and N+(C1-4alkyl)4. This invention also envisions the quaternization of any basic nitrogen-containing group are disclosed compounds. By such quaternization can be obtained soluble in water or oil or dispersible products. Representative salts of alkaline or alkaline earth metals include sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, Quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

As described above, the pharmaceutically acceptable compositions of the present invention optionally include a pharmaceutically acceptable carrier, adjuvant or excipient, which, as used herein, includes any and all solvents, diluents, or other liquid fillers, means for dispersing or is openservicea, surface-active agents, isotonic agents, thickening agents and emulsifying agents, preservatives, solid binders, lubricants and the like, which are suitable for the desired specific dosage forms. In Remington''s Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in the preparation of pharmaceutically acceptable compositions, and known methods for their preparation. Except insofar as any conventional media environment is not combined with the compounds according to the invention, as for example when producing any undesirable biological effect or other damaging interaction with any other connection(s), pharmaceutically acceptable compositions, believe that their use is included in the scope of this invention.

Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion-exchange substances, alumina, aluminum stearate, lecithin, serum proteins, such as serum human albumin, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, a mixture of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as Protamine sulfate, sodium chloride, zinc salts, colloidal is remni, the magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, block copolymers, polyethylene-polyoxypropylene, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragakant; malt; gelatin; talc; inert excipients, such as cocoa butter and waxes for suppositories; oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as etiloleat and tillaart; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt solution; ringer's solution, ethyl alcohol and phosphate buffer solutions, as well as other non-toxic combined lubricants, such as nutriceuticals and magnesium stearate, and colouring agents, separating agents, agents for coatings, sweeteners, taste and flavouring agents, preservatives and antioxidants can also be represented in the composition, in accordance with the opinion of the compiler of the composition.

Used in this description, the term "measurably inhibit" means the measure concentration is the second change in the activity of kinases, in particular, the activity of the JAK kinase, between the sample containing the compound according to this invention and JAK-kinase and an equivalent sample containing JAK-kinase in the absence of the specified connection.

Compositions according to the present invention can be administered orally, parenterally, by using the spray for inhalation, topical, rectal, nasal, buccal, vaginally or via an implanted reservoir. Used in this description, the term "parenteral" includes methods subcutaneous, intravenous, intramuscular, intra-articular, nutricionales, intrasternal, intrathecal, intraocular, intrahepatic, inside the affected tissue, intracranial injection or infusion. Preferably the compounds are introduced orally administered intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention can be aqueous or oil suspension. These suspensions can be prepared in accordance with methods known in this field, using suitable dispersing or wetting agents and suspendresume agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic acceptable for injecting diluent or solvent, as for example, a solution in 1,3-butanediol. Among acceptable the fillers and solvents, which can be used is water, ringer's solution and isotonic sodium chloride solution. In addition, commonly used as a solvent or medium for suspension of sterile non-volatile oil.

This purpose can be used for aseptic non-volatile oils, including synthetic mono - and diglycerides. When getting drugs for injection can be useful fatty acids such as oleic acid and its glyceride derivatives, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylene forms. Data oil solutions or suspensions may also contain long-chain alcohol diluent or dispersing agent, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the compositions of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as twins, spiny and other emulsifying agents or amplifiers bioavailability, which is usually used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used with the aim of obtaining compositions.

Pharmaceutically acceptable composition is according to this invention can be administered orally in any acceptable for oral administration of the dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, commonly used carriers include lactose and corn starch. Also usually added lubricating agents such as magnesium stearate. For oral administration in the form of a capsule useful diluents include lactose and dried corn starch. When for oral use are required aqueous suspensions of the active ingredient is combined with emulsifying and suspensorium agents. If necessary, can be added known sweetening, flavoring or coloring agents.

Alternatively, the pharmaceutically acceptable compositions of this invention can be introduced in the form of suppositories for rectal administration. They can be obtained by mixing the agent with a suitable non-irritating by excipients, which is solid at room temperature, but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such substances include cocoa butter, beeswax and polyethylene glycols.

Pharmaceutically acceptable compositions of this invention can also be administered topically, in particular, when the target of treatment includes areas or organs readily accessible when the local application is AI, including diseases of the eye, skin, or the lower intestine. Suitable formulations for topical application to easily get to each of these areas or organs.

Topical application for the lower intestine may be effective in the case of compositions for rectal suppository (see above) or in the case of a suitable drug for enemas. Can also be used topically-transdermal patches.

For local use can be made of pharmaceutically acceptable compositions in the form of a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical application of the compounds according to this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions may be formulated as a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carrier materials include, but are not limited to, mineral oil, sorbitan the monostearate, Polysorbate 60, wax with etilovyj ester groups, tatarinowii alcohol, 2-octyldodecanol, benilov the th alcohol and water.

Pharmaceutically acceptable compositions for ophthalmic use may be made, for example, in the form of micronized suspensions in isotonic, pH adjusted sterile saline, or other aqueous solution or, preferably, as solutions in isotonic, pH adjusted sterile saline, or other aqueous solution, in the presence or in the absence of a preservative, such as benzalkonium chloride. Alternatively, the pharmaceutically acceptable compositions for ophthalmic applications can be written in the form of ointment, such as vaseline. Pharmaceutically acceptable compositions of this invention can also be entered using a nasal aerosol or inhalation. Such compositions have, in accordance with methods well known in the field of production of medicines, and can be obtained as solutions in saline, using benzyl alcohol or other suitable preservatives, substances that promote the absorption (promoters suction)to increase bioavailability, fluorocarbons, and/or other traditional solubilizing or dispersing agents.

Most preferably pharmaceutically acceptable compositions of this invention are orally what about the injection.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage form may contain inert diluents commonly used in this field, such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropylene alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters with fatty acids sorbitan and mixtures thereof. Besides inert diluents, compositions for oral administration can also include adjuvants such as wetting agents, emulsifying and suspendresume agents, sweetening, gives taste and flavouring agents.

Injectable preparations, for example, sterile injectable aqueous or oil suspensions can be prepared in accordance with the prior art using suitable dispersing or wetting agents or suspendida agents. Sterile injectable drugs also may be a sterile injectable preparation, the suspension or emulsion in a nontoxic, suitable for injecting diluent or solvent, for example, such as a solution in 1,3-butanediol. Among the acceptable fillers and solvents that can be used is water, ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment traditionally used sterile non-volatile oil. For this purpose, can be used any easy non-volatile oil, including mono - and diglycerides. In addition, fatty acids such as oleic acid, are used for obtaining an injectable drug.

Formulations for injection may be sterilized, for example, by filtration through inhibiting bacteria filter, or when the introduction of the sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile environment for injection before use.

In order to prolong the effect of the compounds of the present invention, it is often desirable to slow the absorption of the compound from the area of subcutaneous or intramuscular injection. This can be achieved using a liquid suspension of crystalline or amorphous material with poor water solubility. Speed sasian the I connection then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of parenteral introduced forms compounds by dissolution or suspension of the compound in oily environments. Injectable forms of delayed absorption is obtained by forming microencapsulated matrices of the compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the compounds and polymers and the nature of the particular polymer used, the rate of release of connections can be controlled. Examples of other biodegradable biopolymers include a complex of poly(orthoevra) and poly(anhydrides). Injectable compositions delayed suction also obtained by incorporating the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal injection preferably represent suppositories, which can be obtained by mixing the compounds of this invention with suitable non-irritating with excipients or carriers such as cocoa butter, polyethylene glycol, or wax suppositories, which are solid at room temperature, but liquid at body temperature and therefore melt in the rectum or vaginal the cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage form of the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and/or a) fillers or diluents, such as starches, lactose, sucrose, glucose, lures and silicic acid, b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and the Arabian gum, (C) water-retaining agents, such as glycerol, d) dezinfeciruyuhimi agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) slow dissolving agents such as paraffin, f) accelerating the absorption of substances 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 sulphate, and mixtures thereof. In the case of capsules, tablets and pills dosage form may also comprise buffering agents.

Tonicompetition of this type may also be employed 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, pills, capsules, pills and granules can be obtained with coatings and shells, such as intersolubility coatings and other coatings well known in the preparation of pharmaceutical compositions. They may not necessarily contain radiopaque agents and can be in the form of a composition that they release the active(s) component(s) only, or preferentially in certain parts of the intestine, optional, slow way. Examples of nested compositions, which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed 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 components can also be in microencapsulated form with one or more excipients listed above. Solid dosage forms such as tablets, pills, capsules, pills and granules can be obtained with coatings and shells, such as intersolubility coating that controls the release coatings and other coatings well zvezdnye in the preparation of pharmaceutical compositions. In such solid dosage forms the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as is the normal practice, additional substances in addition to the inert diluents, for example, lubricant for tableting and other additional substances for tableting, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may not necessarily contain radiopaque agents and may also be a composition that they release the active(s) component(s) only, or preferentially in certain parts of the intestine, optional, slow way. Examples of nested compositions, which can be used include polymeric substances and waxes.

Dosage forms for local or transdermal injection of the compounds according to this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, means for inhalation and patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffer substances, which may be necessary. Of etimologically formulations ear drops and eye drops are also considered as included in the scope of this invention. In addition, the present invention involves the use of transdermal patches, which have the added advantage of providing controlled delivery of compounds into the body. Such dosage forms can be obtained by dissolving or distribution of compounds in a suitable medium. Can also be used for enhancing absorption of a substance for increasing the flow of substances through the skin. Speed can be controlled either by software controlling the rate of release of the membrane or by dispersing the compound in a polymer matrix or gel.

The compounds of this invention are preferably prepared in unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form"as used herein, refers to physically discrete units of the funds intended for the patient, which is subjected to treatment. It should be understood, however, that the total daily dose of the compounds and compositions of the present invention will be selected by the attending physician within the medical conclusion. The specific effective dose for any particular patient or organism will be the head of the network from a number of factors, including being treated with the disorder and the severity of the disorder; activity of the specific applicable compounds; specific applicable compound; the age, body weight, General health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific applicable connection, duration of the treatment; drugs used in combination or mixed with specific applicable connection, and like factors well known in medicine.

A number of compounds of the present invention, which may be combined with substances native to obtaining the composition in a single dosage form will vary depending on the subject to the treatment of the body, the specific type of introduction. Preferably the composition should be such that the patient receiving these compositions could be injected dose of the inhibitor in the range of 0.01-100 mg/kg body weight/day.

Depending on specific conditions or diseases, which is subjected to treatment or to prevent, in the compositions of this invention can also contain additional therapeutic agents that are normally administered to treat or prevent this condition. As used herein, additional therapeutic when estva, which is usually administered to treat or prevent a specific disease or condition referred to as "suitable for the disease or condition being treated".

For example, chemotherapeutic agents or other anti-proliferative tools can be combined with the compounds according to this invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, Gleevec™, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, Taxol, interferons and platinum derivatives.

Other examples of tools that inhibitors of this invention can be combined include, but without limitation, for the treatment of Alzheimer's disease such as Aricept®and Excelon®; for the treatment of Parkinson's disease such as L-DOPA/carbidopa, entacapone, ropinirol, pramipexol, bromkriptin, pergolid, trihexyphenidyl and amantadine; means for treatment of multiple sclerosis (MS)such as beta interferon (e.g., Avonex®and Rebif®), Copaxone®and mitoxantrone; means for asthma, such as albuterol and Singulair®; means for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, blockers factor n is Crozat tumors (TNF), antagonists of the receptor for IL-I RA, azathioprine, cyclophosphamide and sulfasalazin; immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazin; neurotropic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, blockers of ion channels, riluzole, and anti-Parkinson's disease; a means for treating cardiovascular disease such as beta-blockers, inhibitors of angiotensin-converting enzyme (ACE), diuretics, nitrates, calcium blockers channel and statins; means for the treatment of liver disease such as corticosteroids, cholestyramine, interferons and antiviral agents; means for treatment of blood disorders such as corticosteroids, protivoanemicheskoe agents and growth factors; and means for treating immunodeficiencies, such as gamma globulin.

The amount of additional therapeutic agent present in the compositions according to this invention, is not more than the quantity that is usually introduced in the composition containing therapeutic agent as the only active substance. Preferably the amount of additional therapeutic agent disclosed in which omposite will be in the range from approximately 50% to 100% of the quantities usually present in the composition containing this substance as the only therapeutically active funds.

The use of compounds and compositions

In one embodiment, the invention relates to a method of inhibiting the activity of a JAK kinase in a patient, comprising the introduction of a specified patient compounds or compositions according to the invention.

In another embodiment, the invention relates to a method of treating or reducing the severity of JAK-mediated condition or disease in a patient. Used in this description, the term "JAK-mediated condition" means any disease or other adverse condition in which it is known that the JAK family of kinases, in particular JAK2 or JAK3, play a role. In an additional embodiment, the invention relates to a method for the treatment of JAK3-mediated diseases. Such conditions include, but without limitation, immune responses, such as allergies or allergic reactions (type I), asthma, autoimmune diseases such as transplant rejection, graft versus host, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, neurodegenerative disorders, such as familial amyotrophic lateral sclerosis (FALS), as well as solid and hematological tumors, such as l is ikeji and lymphoma.

In another embodiment, the invention relates to a method of treating or reducing the severity of the pathological condition selected from a proliferative disorder, cardiac disorders, neurodegenerative disorders, autoimmune disorders, conditions associated with organ transplantation, inflammatory disorders, immune disorders, or immunologically mediated disorder, comprising the introduction of a specified patient compounds or compositions according to the invention.

In an additional embodiment, the method includes the additional step of introducing a specified patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative tools, anti-inflammatories, immune-modulating and suppressing immunity means neurotrophic factor, a treatment for cardiovascular disease, a treatment for diabetes or means for treating immunodeficiency disorders, where the specified additional therapeutic agent corresponds to the disease being treated, and the specified additional therapeutic agent is introduced together with the above composition in the form of a single dosage form or separately from the specified composition as part of a multiple is karstenii form.

In one embodiment, the disease or disorder is an Allergy or allergic reaction type I, asthma, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, amyotrophic lateral sclerosis (als, the disease Lou Gehrig's disease (als), multiple sclerosis (MS), schizophrenia, hypertrophy of cardiomyocytes, reperfusion/ischemia, stroke, baldness, transplant rejection, graft versus host, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, solid and hematological tumors, such as leukemia and lymphoma. In an additional embodiment, the disease or disorder is an asthma. In another embodiment, the disease or disorder is a rejection of the graft. In another embodiment, the disease or disorder is a rheumatoid arthritis.

In another embodiment, the compound or composition of this invention can be used for the treatment of myeloproliferative disorders. In another embodiment, myeloproliferative infringement is true polycythemia, primary trombozitemia or chronic idiotically myelofibrosis. In another embodiment, assests is of myeloproliferative violation is a myeloid metaplasia with myelofibrosis, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome, systemic mastocytosis, atypical CML or juvenile myelomonocytic leukemia.

In another embodiment, the invention relates to the use of compounds of formula I, IA, IB, II, or III for the treatment of JAK-mediated diseases. In an additional embodiment, the invention relates to the use of the compounds for the treatment of any disease discussed above. In another embodiment, the invention relates to the use of compounds of formula I, IA, IB, II, or III for the production of a medicinal product for the treatment of JAK-mediated diseases. In an additional embodiment, the invention relates to the use of the compounds for the manufacture of a medicinal product for the treatment of any disease described above.

In another embodiment, the invention relates to a method of inhibiting the activity of a JAK kinase in a biological sample, comprising contacting the specified biological sample with a compound or composition according to the invention.

Used in this description, the term "biological sample" means a sample ofex vivoand includes, but without limitation, cell cultures or extracts is; samples of tissue or body or their extracts; biopsy material obtained from a mammal or extracts and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts.

Inhibition of kinase activity, in particular activity of the JAK kinase, in a biological sample is useful for a number of tasks that are well-known specialist in the field of technology. Examples of such tasks include, but are not limited to, blood transfusion, organ transplantation, storing a biological sample, and biological tests.

In some embodiments, implementation of the present invention an "effective amount" of a compound or pharmaceutically acceptable composition is an amount that is effective for treating or reducing the severity of one or more of the above disorders. Compounds and compositions in accordance with the method of the present invention may be applied using any amount and any route of administration effective for treating or reducing the severity of the disorder or disease. The specific quantity required will vary from subject to subject, depending on the species, age and General condition of the subject, the severity of infection, specific tools, type of administration and the like.

Alternatively, the implementation of which of the methods according to this invention include the additional step of introducing a separately specified patient an additional therapeutic agent. When these therapies are introduced separately, they can be administered to the patient prior to, simultaneously with or after administration of the compositions according to this invention.

The compounds of this invention or pharmaceutical compositions may also be useful for coating implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices that are exposed to the risk of clotting or platelet activation. Such undesirable effects can be prevented or reduced by pre-coating device pharmaceutically acceptable composition comprising the compound according to this invention.

Suitable coatings and the General getting coated implantable devices are described in U.S. patents 6099562, 5886026 and 5304121. Coatings are typically biocompatible polymeric materials, such as polymer hydrogel, polymethylsiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. The coating can be optionally additionally coated with a suitable top coating ferrosilicon, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart the characteristics of a controlled release composition. The implantable device coated with a compound according to this invention, are another embodiment of the present invention. The connection can also be applied in the form of a coating on an implantable medical device, such as spheres or jointly composed in a mixture with a polymer or other molecules to get "drug depot", thus enabling the drug to be released over a longer period of time than in the case of the introduction of an aqueous solution of the drug.

Methods synthesis and characterization of compounds

Compounds according to this invention can be obtained, in General, by methods known to experts in the field for similar compounds, or techniques described in the examples below. See, for example, the examples described in WO 2005/095400, which is fully incorporated into this description by reference.

All references given in the examples included in this description by reference. Used in this specification, all acronyms, symbols, and symbols are consistent with those used in the contemporary scientific literature. See, for example, Janet S. Dodd, ed., The ACS Style Guie: A Manual for Authors and Editors, 2nd Ed., Washington, D.C.: American Chemical Society, 1997, which is fully incorporated into this description by reference.

Examples

Example 1: obtaining the compounds according to the invention

The General scheme of synthesis

Stage 1

To a stirred solution of the BOC-protected valine (1, R1represents IU; 3.8 g, 0.02 mol), EDC (4,63 g 0,024 mol), HOBt (4.0 g, was 0.026 mol), DEEA (10.5 ml, 0.06 mol) in 100 ml of DCM (dichloromethane) was added triptorelin HCl (2,92 g of 0.022 mol). The reaction mixture was stirred for 16 hours. Concentrated to dryness and re-dissolved in EtOAc (ethyl acetate), washed successively 0,5h. HCl, saturated aqueous NaHCO3and a saturated solution of salt. The organic layer was dried (Na2SO4) and concentrated in vacuum to obtain 5.4 g (98%) of compound 2 as a white solid.

Stage 2

Remove protection from connection 2 (5.32 g, 0,0197 mol) using a mixture of 1:1 DCM/TFA (triperoxonane acid) at room temperature for 45 minutes. Concentration to dryness gave the intermediate amine which was used directly in the next stage. A mixture of 5-fluoro-2,4-dichloropyrimidine (3; R represents F; 3.28 g, 0,0197 mol), the crude TFA salt of amine (5,25 g, 0,0197 mol) and DIEA (10,27 ml, 0,059 mol) was stirred in isopropanol at room temperature is over 16 hours. The reaction mixture was concentrated in vacuo and re-dissolved in EtOAc, washed successively 0,5h. HCl, saturated aqueous NaHCO3and a saturated solution of salt. The organic layer was dried (Na2SO4) and concentrated in vacuo to obtain the crude oil, which was subjected to chromatography (50% EtOAc/50% hexane) to give the desired compound 4.

Stage 3

A mixture of compound 5 (30 mg, of 0.075 mmol, obtained in accordance with WO 2005/095400), compound 4 (23 mg, of 0.075 mmol), Pd(Ph3P)4(9 mg, 0,0078 mmol) and 2M sodium carbonate (115 μl, 0.23 mmol) in 1 ml DME was subjected to microwave irradiation at 150°C for 10 minutes. The reaction mixture was filtered through a small layer of silica gel with a mixture of 30% EtOAc-70% hexane as eluent to give, after concentration to dryness, the crude intermediate, which was directly used in the next stage.

The crude intermediate compound was dissolved in 1 ml of dry methanol was added 200 μl of a 25% sodium methylate in methanol. The reaction mixture was stirred at 60°C for 1 hour and extinguished 6N. HCl (154 μl). The mixture was dried in a stream of nitrogen and purified HPLC with reversed phase (10-60 MeCN/water w/in 0.5% TFA) to give the desired substances of formula 6A.

The compounds of formula 6b and 6C can be obtained in a similar way, using appropriate and the initial reagents. For example, the compound of formula 6b can usually be obtained by substituting tert-butyl 2-(2,2,2-triptoreline)pyrrolidin-1-carboxylate for connection 1, while the compound of formula 6 can be obtained by substituting tert-butyl 2-(2,2,2-triptoreline)propane-2-ylcarbamate to connect 1.

Example 2: the results of the analysis

In tables 4, 5 and 6 below presents illustrative data1H NMR and data analysis liquid chromatography-mass spectrometry, presents as mass plus a proton (M+N), as determined by the method of electrocapillary, and retention time (RT) for some compounds of the present invention, where the numbering of the compounds in tables 4, 5 and 6 corresponds to the compounds described in tables 1, 2 and 3, respectively (empty cells indicate that the analysis did not).

52 DMSO-d6: 12,35 (users, 1H); to 8.7 (s, 1H); 8.3 and is 8.25 (m, 3H); or 8.2 (m, 1H); with 4.65 (d, 1H); 4.0 a (m, 1H); and 3.8 (m, 1H); 3,5-3,3 (m, 2H); 2,4-2,2 (m, 3H); 2.0 (m, 3H)
Table 4
Connect no.M+HRtNMR
1442,902,20DMSO-d6: 12,4 (users, 1H); to 8.7 (DD, 1H); 8,65 (s, 1H); of 8.25 (m, 2H); or 8.2 (m, 1H); and 4.8 (d, 1H); about 4.0 to 3.8 (m, 4H); 2,3 (m, 1H); 2.05 is to 1.9 (m, 3H)
2 442,902,20DMSO-d6: 12,4 (users, 1H); to 8.7 (DD, 1H); 8,65 (s, 1H); of 8.25 (m, 2H); or 8.2 (m, 1H); and 4.8 (d, 1H); about 4.0 to 3.8 (m, 4H); 2,3 (m, 1H); 2.05 is to 1.9 (m, 3H)
3430,902,50(CD3OD) of 1.7 (s, 6H), and 3.8 (m, 2H), 8,15 (s, 1H), and 8.2 (d, 1H), 8,25 (m, 1H), 8,5 (t, 1H), cent to 8.85 (d, 1H)
4463,001,90(CD3OD) of 1.9 (s, 6H), and 3.8 (m, 2H), of 7.75 (t, 1H), 7,9 (d, 1H), with 8.05 (t, 1H), 8,35 (d, 1H), 8,55 (d+t, 2H), and 8.7 (s, 1H), cent to 8.85 (d, 1H)
5399,001,70DMSO-d6: of 8.92 (m, 1H); at 8.60 (m, 2H); 8,32 (s, 1H); 8,18 (m, 1H); of 6.65 (m, 1H); 6,72 (m, 1H); 4.80 to (m, 1H); 4,00 (m, 2H); of 1.42 (d, 3H)
6417,002,40DMSO-d6: to 8.70 (DD, 1H); 8,65 (s, 1H); 8,28 (m, 2H); to 8.20 (m, 1H); of 7.90 (m, 1H); to 4.62 (m, 1H); 3,88 (m, 2H); of 1.41 (d, 3H)
7449,002,10DMSO-d6: 8,86 (m, 1H); 8,76(m, 1H); 8,55 (m, 1H); to 8.40 (m, 1H); of 7.96 (m, 1H); a 7.85 (m, 1H); of 7.70 (m, 1H); 5,00 (m, 1H); 3,98 (m, 2H); was 1.58 (d, 3H)
8459,301,70DMSO-d6: 12,3 (users, 1H); to 8.7 (s, 1H); 8,6 (t, 1H); to 8.3 (m, 2H); or 8.2 (m, 1H); 4.75 in (m, 1H); 4,4 (m, 1H); 4,053,7 (m, 5H); 1,9 (m, 1H)
9457,302,20DMSO-d6: 12,3 (users, 1H); 8,8 (m, 1H); to 8.7 (s, 1H); to 8.3 (m, 2H); or 8.2 (m, 1H); 4,3 (m, 1H); 4,05 to 3.8 (m, 4H); to 2.25 (m, 1H); 2,1 (m, 1H); 1,7 (m, 1H); to 1.15 (m, 3H)
10459,301,80DMSO-d6: 12,35 (users, 1H); 8,8 (m, 1H); 8,65 (s, 1H); of 8.25 (m, 2H); 8,15 (m, 1H); 4,6 (m, 1H); 4,3 (m, 1H); of 4.05 (m, 1H); from 3.9 to 3.8 (m, 3H); 1,95 (m, 2H)
11455,302,10DMSO-d6: 12,35 (users, 1H); 8,95 (m, 1H); to 8.7 (s, 1H); to 8.3 (m, 2H); or 8.2 (m, 1H)and 4.9 (m, 1H); 4.1 and a 3.9 (m, 4H); 1,8-1,6 (m, 2H); 0.75 in (m, 1H); 0,4 (m, 1H)
12459,301,70DMSO-d6: 12,3 (users, 1H); to 8.7 (s, 1H); 8,6 (t, 1H); of 8.25 (m, 2H); 8,15 (m, 1H); 4.75 in (m, 1H); 4,4 (m, 1H); 4,05-the 3.65 (m, 5H); 1,9 (m, 1H)
13459,301,70DMSO-d6: 12,3 (users, 1H); 8,8 (m, 1H); to 8.7 (s, 1H); to 8.3 (m, 2H); or 8.2 (m, 1H); and 4.8 (m, 1H); of 4.45 (m, 1H); 4,05-the 3.65 (m, 4H); to 2.25 (m, 1H);1,9 (m, 1H)
14425,001,70DMSO-d6: 12,9 (users, 1H); 8,9 (m, 1H); to 8.6 (m, 2H); and 8.4 (s, 1H); 8,35 (m, 1H); 6,7 (m, 1H)and 4.9 (m, 1H); 4.1 and a 3.9 (m, 2H); and 3.8 (m, 1H); the 3.65 (m, 1H); 2,4 (m, 1H); 2,15-of 1.95 (m, 3H)
15461,302,10
16425,001,70DMSO-d6: 12,9 (users, 1H); cent to 8.85 (m, 1H); to 8.6 (m, 2H); 8,35 (s, 1H); to 8.3 (m, 1H); 6,7 (m, 1H)and 4.9 (m, 1H); 4.1 and a 3.9 (m, 2H); 3.75 to (m, 1H); 3,6 (m, 1H); 2,4 (m, 1H); 2,15-of 1.95 (m, 3H)
17461,302,20
18427,201,90DMSO d6: 13,0 ppm (users, 1H), and 9.0 (t, 1H), and 8.7 (s, 1H), and 8.6 (s, 1H), and 8.4 (s, 1H), and 8.2 (d, 1H), 6,8 (users, 1H), and 4.8 (t, 1H), 4,1 (m, 1H), and 3.8 (m, 2H), 2,3 (m, 1H), of 1.05 (d, 3H), and 1.0 (d, 3H)
19441,202,00DMSO d6: 13,0 ppm (users, 1H), and 9.0 (t, 1H), 8,7 (s, 2H), and 8.4 (s, 1H)and 8.1 (d, 1H), and 6.6 (d, 1H), and 4.8 (t, 1H), 3,8-4,2 (m, 4H), 1,7 (users, 2H), and 1.0 (d, 3H), and 0.9 (d, 3H)
20445,202,90DMSO d6: to 12.4 ppm (users, 1H), 8,8 (t, 1H), and 8.7 (s, 1H), and 8.3 (s, 1H), and 8.2 (d, 2H), and 7.6 (d, 1H), and 4.5 (t, 1H), 3,9-4,1 (m, 2H), 2,2 (m, 1H), and 1.0 (d, 3H), and 0.9 (d, 3H)
21459,203,00DMSO d6: to 12.4 ppm (users, 1H), 8,8 (t, 1H) 8,7 (s, 1H), and 8.3 (m, 3H), and 7.8 (d, 1H), 4,7 (t, 1H), 3,9 (m, 2H), and 1.9 (m, 1H),.8 (m, 1H), 1,6 (m, 1H), and 1.0 (d, 3H), and 0.9 (d, 3H)
22473,203,40DMSO d6: to 8.7 ppm (t, 1H), and 8.6 (s, 1H), and 8.4 (s, 1H), 8,35 (s, 1H), and 8.3 (s, 1H), 7,9 (d, 1H), 4,7 (t, 1H), 4,0 (m, 2H), 3,9 (s, 3H), and 1.9 (m, 1H), 1.8 m (m, 1H), 1,7 (m, 1H), and 1.0 (d, 3H), 3,9 (d, 3H)
23431,102,50DMSO d6: 12,4 (users, 1H), 8,8 (t, 1H), and 8.7 (s, 1H), 8.3 (the C, H), of 8.25 (DD, 2H), 7,7 (users, 1H), 4,5 (kV, 1H), 3,8-4,0 (m, 2H), and 1.9 (q, 2H), 1,0 (t, 3H)
24413,101,80DMSO d6: 12,9 ppm (users, 1H), 9,0 (t, 2H), 8,65 (s, 1H), and 8.6 (s, 1H), and 8.4 (s, 1H)and 8.1 (d, 1H), 6,7 (users, 1H), 4,7 (m, 1H), 3,8-4,2 (m, 2H), and 1.9 (m, 2H), 1,0 (t, 3H)
25439,202,001H NMR (CD3OD, 500 MHz): 1,53-2,05 (m, 6H), 2,45 of $ 2.53 (m, 1H), 3.46 in-3,59 (m, 1H), 3,83-4,32 (m, 3H), 7,06 (with, of user., 1H), 8,18 (d, 1H), scored 8.38 (d, 1H), 8,42 (s, 1H), 8,83 (with, of user., 1H)
26457,103,201H NMR (CD3OD, 500 MHz): 1,57-2,03 (m, 6H), 2,37 is 2.44 (m, 1H), 3,50 is 3.57 (m, 1H), 3,90-4.09 to (m, 2H), 4,49-of 4.57 (m, 1H), 5,38 (with, of user., 1H), compared to 8.26 (s, 1H), 8,28 (d, 1H), 8,31 (d, 1H), at 8.60 (d, 1H)
27429,30 2,30(CD3OD) 1,3 (m, 2H), 1.8 m (m, 2H), 3,9 (m, 2H), 8,25 (m, 3H), 8,6 (t, 1H), and 8.8 (d, 1H)
28439,201,90DMSO d6: 13,0 ppm (users, 1H), and 9.0 (s, 1H), and 8.7 (s, 1H), and 8.6 (s, 1H), and 8.4 (s, 1H), and 8.2 (d, 1H), 6,7 (s, 1H), 4,9 (d, 1H), 3,9-4,1 (m, 3H), 1,9 (kV, 1H), 1,6 (kV, 1H), 0,9 (users, 1H), 0,5 (m, 2H), 0,2 (m, 2H)
29457,102,80DMSO d6: to 12.4 ppm (users, 1H), 8,8 (t, 1H), and 8.7 (s, 1H), and 8.3 (s, 1H), 8,25 (m, 2H), 7,8 (users, 1H), 4,7 (kV, 1H), 3,8-4,0 (m, 3H), and 1.9 (m, 1H), 1,6 (m, 1H), and 0.9 (m, 1H), and 0.4 (m, 2H), 0,2 (m, 2H)
30459,101,90DMSO d6: 12,9 ppm (users, 1H), and 9.0 (s, 1H), and 8.7 (s, 1H), and 8.6 (s, 1H), and 8.4 (s, 1H), and 8.2 (d, 1H), 6,7 (s, 1H), 4,9 (s, 1H), 3,9-4,1 (m, 2H), 2.5 and 2.7 (m, 2H), 2,1 (m, 3H), 2,0 (s, 3H)
31477,102,70DMSO d6: to 12.4 ppm (users, 1H), 8,8 (t, 1H), and 8.7 (s, 1H), 8,3 (s, 2H), of 8.25 (s, 1H), and 7.9 (s, 1H), 4,8 (kV, 1H), 3,8-4,0 (m, 2H), 2.5 and 2.7 (m, 2H), 2,2 (m, 2H), 2,1 (s, 3H)
32458,101,90(d4-methanol) 8,71 (s, 1H), 8,24 (d, 1H), to 8.20 (s, 1H), 8,15 (s, 1H), 5,11 (users, 1H), 4,32 (d, 1H), 4,01-3,55 (m, 4H), 3,17 (DD, 1H), 3,11-2,95 (m, 2H)
3340,10 1,40(d4-methanol) 8,72 (d, 1H), 8,28 (d, 1H), they were 8.22 (s, 1H), 8,21 (d, 1H), 6,65 (d, 1H), 5.25-inch (users, 1H), 4,12-a 3.87 (m, 3 H),.57 (d, 1H), 3,44 (DD, 1H), 3,14-2,82 (m, 3 H)
34457,003,00DMSO-d6: 12,4 (s, 1H); 8,65 (s, 1H); 8,35 is 8.25 (m, 3H); 8,1 (s, 1H); 3.95 to to 3.8 (m, 2H); 3,7 (m, 2H); is 2.05 (m, 4H); of 1.65 (s, 3H)
35483,102,80
36469,102,50DMSO d6 12,5 (users, 1H); 9,0 (m, 1H); to 8.7 (m, 3H); to 8.3 (m, H); 4,8 (users, 1H); 4,0-3,5 (m, 4); 2,3 (m, 1H); 2.0 (m, 3H)
37411,102,101H NMR (CD3OD, 500 MHz): 2,42-2,52 (m, 1H), 2,80-of 2.93 (m, 1H), 3,89-to 4.14 (m, 2H), 4,27-4,37 (m, 2H), 5,09-5,16 (m, 1H), 7,34 (d, 1H), 8,18 (d, 1H), 8.30 to (s, 1H), and 8.50 (s, 1H), 8,66 (s, 1H)
38459,102,901H NMR (CD3OD, 500 MHz): 3.46 in at 3.69 (m, 2H), 3,88-Android 4.04 (m, 3H), 4,13-to 4.52 (m, 3H), of 4.83-of 4.90 (m, 1H), 6,47 (d, 1H), 7,44 (d, 1H), 8,00 (d, 1H), 8,14 (d, 1H), 8,27-8,35 (m, 2H), 8,68 (s, 1H)
39458,101,80(d4-methanol) to € 8.74 (d, 1H), 8,42 (d, 1H), of 8.25 (s, 1H), 8,23 (who, 1H), 5,62 (users, 1H), to 4.62 (d, 1H), 4.04 the-3,95 (m, 3H), 3,66 (DDD, 1H), 3.46 in (DD, 1H), 3,41-to 3.34 (m, 2H)
40440,101,40(d4-methanol) 8,72 (d, 1H), 8,28 (d, 1H), they were 8.22 (s, 1H), 8,21 (d, 1H), 6,65 (d, 1H), 5,26 (users, 1H), 4,10-2,84 (m, 8H)
41525,102,70(d4-methanol) 8,72 and 8,70 (2D, 1H), 8,31 and 8,27 (2D, 1H), 8,21 (d, 1H), 8,18 and 8,14 (2s, 1H), 7,35, 7,24 (2D, 1H), are 5.36 (users, 1H), 4,51-to 3.52 (m, 10H)
42508,101,80(d4-methanol) 8,73 and 8,70 (2D, 1H), at 8.36 and 8,33 (2D, 1H), of 8.25 (s, 1H), they were 8.22 (d, 1H), 6.73 x, 6,61 (2D, 1H), 5,50, 5,22 (2 users, 1H), 4,51-3,51 (m, 10H)
43427,101,90DMSO d6: 13,0 ppm (users, 1H), and 9.0 (s, 1H), and 8.6 (d, 2H), and 8.4 (s, 1H), and 8.2 (d, 1H), 6,7 (s, 1H), 4,8 (s, 1H), 3,8-4,2 (m, 3H), and 1.9 (m, 2H), 1,4-1,5 (m, 2H), and 0.9 (t, 3H)
44445,102,70DMSO d6: to 12.4 ppm (s, 1H), 8,8 (t, 1H), and 8.7 (s, 1H), 8,3 (m, 3H), 7,8 (users, 1H), 4,6 (kV, 1H), 3,8-4,0 (m, 2H), 1.8 m (m, 2H), 1.3 to 1.5 (m, 2H), and 0.9 (t, 3H)
45425,102,20DMSO-d6: 12,45 (s, 1H); 8,65 (s, 1H); and-8.5 (m, 1H); to 8.3 (m, 2H); or 8.2 (m, 1H); at 5.9 (t, 1H); and 4.8 (d,1H); to 4.0 (m, 1H); of 3.85 (m, 1H); 3,6-3,4 (m, 2H); to 2.25 (m, 1H); 2.0 (m, 3H)
46443,102,50DMSO was 1.9 (m, 2H), 2,3 (q, 2H), 2,75 (userc, 2H), and 3.8 (m, 2H), 8 (d, 1H), 8,15 (blocking. ushort, users, 2H), of 8.25 (s, 1H), 8.3 (l, 1H), and 8.7 (s, 1H), 12,3 (users, 1H)
47407,101,60DMSO-d6: 13,0 (users, 1H); to 8.7 and 8.6 (m, 3H); and 8.4 (m, 1H); to 8.3 (m, 1H); 6.75 in (d, 0,7H); and 6.3 (d, 0,3H); at 5.9 (t, 1H)and 4.9 (d, 0,7H); 4,65 (0,3H); 4,05-3,6 (m, 2H); 2,35 (m, 1H); is 2.05 (m, 3H)
48413,101,70(CD3OD) of 1.75 (s, 6H), 3,85 (m, 2H), 6.75 in (d, 1H), with 8.05 (d, 1H), 8.3 (l, 1H), and 8.5 (d, 1H), 8,65 (ushort, 1H), and 8.8 (s, 1H)
49389,102,00DMSO-d6: 12,4 (users, 1H); 8,65 (s, 1H); to 8.3 (m, 2H); of 8.25 (m, 1H); with 8.05 (m, 1H); 4.7 in (d, 1H); 3,95 (m, 1H); and 3.8 (m, 1H); 3,5 (m, 1H); 3,1 (m, 1H); to 2.25 (m, 1H); 2.0 (m, 3H); 3,95 (m, 3H)
50457,102,701H NMR (500 MHz, methanol-d4) 8,76 (d, J=2.3 Hz, 1H), 8,48 (t, J=6.2 Hz, 1H), 8,31-8,29 (m, 3H), 3,82 (m, 2H), 3,31 (kv.n, methanol-d4), 2,55 of $ 2.53 (m, 2H), 2,27-of 2.24 (m, 2H), of 1.88 (m, 4H)
51471,10of 3.07
371,201,50DMSO-d6: 13,0 (s, 1H); 8,75 and 8.6 (m, 2H); and 8.4 (m, 1H); to 8.3 (m, 1H); or 8.2 (m, 1H); 6.75 in (d, 0,7H) 6,35 (d, 0,3H); 4,85 (d, 0,7H); 4,55 (d, 0,3H); 3,8-3,6 (m, 2H); and 3.2 to 3.0 (m, 2H); 2,35 (m, 1H); was 2.05 (m, 3H); 1,05 (DD, 0,7H); of 0.95 (DD, 2,3H)
53439,201,80DMSO-d6: 12,85 (users, 1H); to 8.7 (s, 1H); and 8.5 (s, 1H); 8.4 to 8,35 (m, 2H); 8.3 (l, 1H); 6,7 (m, 1H); 3.95 to to 3.7 (m, 4H); to 2.15 (m, 4H); and 1.7 (s, 3H)
54456,802,95DMSO-d6: 12,25 (users, 1H); to 8.7 (s, 1H); to 8.3 (m, 3H); 8,0 (m, 1H); to 4.1 to 3.7 (m, 4H); 2.05 is (m, 4H); 1,6 (s, 3H)
55439,201,80DMSO-d6: 12,85 (users, 1H); to 8.7 (s, 1H); and 8.5 (s, 1H); 8.4 to 8,35 (m, 2H); 8.3 (l, 1H); 6,7 (m, 1H); 3.95 to to 3.7 (m, 4H); to 2.15 (m, 4H); and 1.7 (s, 3H)
56469,102,00DMSO-d6: of 9.30 (m, 1H); to 8.70 (s, 1H); 8,35 (m, 1H); 8,28 (m, 2H); 4.75 in (m, 1H); 3.40 in (m, 2H); to 2.25 (m, 2H); 2,00 (m, 4H)
57497,102,70DMSO-d6: 8,80 (m, 2H); 8,55 (s, 1H); 8,28 (m, 2H); 4.80 to (m, 1H); 4,24 (m, 2H); of 3.80 (m, 4H); of 2.20 (m, 1H); 1,90 (m, 23H); 1,20 (t, 2H)
58441,10 2,001H NMR (500 MHz, DMSO-d6) 12,9 (users, 1H), 9,00 (s, 1H), 8,66 (s, 1H), 8,63 (s, 1H), to 8.41 (d, J=2.0 Hz, 1H), 8,16 (d, J=6.2 Hz, 1H), 6,80 (s, 1H), 4,81 (s, 1H), 4,11-4,06 (m, 1H), a 3.87 (m, 2H), 2,00 (s, 1H), 1,66 (s, 1H), 1,27-to 1.21 (m, 1H), and 0.98 (d, J=6.4 Hz, 3H), of 0.92 (t, J=7.2 Hz, 3H)
59459,103,101H NMR (500 MHz, DMSO-d6) 12,40 (s, 1H), 8,80 (t, J=6.3 Hz, 1H), 8,71 (d, J=2.4 Hz, 1H), 8.34 per (d, J=2,8 Hz, 1H), 8,29 (s, 1H), 8,27 (d, 1H), 7,58 (d, J=6.2 Hz, 1H), 4,57 (t, J=8.0 Hz, 1H), 4.04 the-3,98 (m, 1H), the 3.89-a 3.83 (m, 1H), 2.05 is of 1.99 (m, 1H), 1,65-to 1.60 (m, 1H), 1,33-of 1.23 (m, 1H), of 0.96 (d, 3H), from 0.88 (t, 3H)
60441,102,001H NMR (500 MHz, DMSO-d6) 13,0 (users, 1H), 8,98 (s, 1H), 8,66 (s, 1H), to 8.62 (s, 1H), to 8.41 (d, J=1.9 Hz, 1H), 8,17 (d, J=6.3 Hz, 1H), 6,84 (s, 1H), 4,90 (s, 1H), 4,08-4,07 (m, 1H), 3,88 (m, 2H), 2,11-of 2.08 (m, 1H), 1,50 (t, J=6,9 Hz, 1H), 1.27mm (m, 1H), and 1.00 (d, J=6.9 Hz, 3H), 0,92 (kV,.J=7.5 Hz, 3H)
61459,103,101H NMR (500 MHz, DMSO-d6) 12,38 (s, 1H), 8,76 (t, J=6.3 Hz, 1H), to 8.70 (d, J=2.4 Hz, 1H), 8,28 (m, J=4,2 Hz, 3H), of 8.28 (s, 1H), was 7.36 (d, J=5.7 Hz, 1H), 4.72 in (t, 1H), was 4.02-of 3.85 (m, 2H), 2.05 is (kV, J=6,8 Hz, 1H), 1,54-1,49 (m, 1H), 1,27-to 1.21 (m, 1H), 0,99 (d, J=6.8 Hz, 3H), 0,92 t, J=7.4 Hz, 3H)
62441,102,001H NMR (500 MHz, DMSO-d6) 13,01 (s, 1H), 9,05 (s, 1H), 8,78 (s, 1H), 8,64 (s, 1H), 8,42 (d, J=2.0 Hz, 1H), 8,16(d, J=6,4 Hz, 1H), 6,91 (s, 1H), 4,89 (d, J=8.0 Hz, 1H), 4,15-4,07 (m, 1H), 3,82-of 3.85 (m, 1H), only 1.08 (s, 9H)
63459,103,301H NMR (500 MHz, DMSO-d6) 12,41 (s, 1H), cent to 8.85 (t, J=6.3 Hz, 1H), total of 8.74 (d, J=2.4 Hz, 1H), 8,31 (d, 1H), 8,29 (s, 2H), 6,86 (d, J=7.8 Hz, 1H), 4,77 (d, J=8,8 Hz, 1H), 4.09 to as 4.02 (m, 1H), 3,88-3,82 (m, 1H), 1,08 (, 9H)
64429,102,391H NMR (CD3OD, 500 MHz): 2,45-2,52 (m, 1H), 2.91 in-3,00 (m, 1H), 3,89-to 4.14 (m, 2H), 4,50-br4.61 (m, 2H), 5.25-in, and 5.30 (m, 1H), 8,23-8,30 (m, 3H), 8,63 (s, 1H)
65373,401,90DMSO-d6: 12,9 (users, 1H); to 8.7 (s, 1H); and 8.6 (s, 1H); and 8.4 (s, 1H); to 8.3 (s, 1H); 8,15 (m, 1H); 6.8 cm (s, 1H); 4,6 (s, 1H); 3,1 (m, 1H); to 2.7 (m, 1H); to 2.25 (m, 1H); 1,1-of 0.95 (m, 9H)
66425,102,201H NMR (500 MHz, methanol-d4) 8,73 (d, J=2.0 Hz, 1H), 8,46 (s, 1H), 8,40 (s, 1H), 8,35 (d, J=2.1 Hz, 1H), 8,10 (d, J=7.2 Hz, 1H), 6.75 in (d, J=7.2 Hz, 1H), 3,85 (m, 2H), 3,01-of 2.97 (m, 2H), 2,44-2,39 (m, 2H), 2,16 (m, 2H)
67409,201,80DMSO-d6: 13,0 (users, 1H); is 8.75 (m, 1H); 8,65 (s, 1H); and 8.6 (s, 1H); and 8.4 (s, 1H); 8,15 (d, 1H); to 6.8 (m, 1H); 6,05 (t, 1H); 4.75 in (m, 1H); 3.75 to 3.5mm (m, 2H); to 2.25 (m, 1H); 1,1-of 0.95 (m, 6H)
68456,60 3,831H NMR (CD3OD, 500 MHz): 1,68-2,00 (m, 6H), 2.26 and is 2.33 (m, 1H), 3,49-to 3.58 (m, 1H), 3,84-was 4.02 (m, 2H), 4,45-a 4.53 (m, 1H), are 5.36-5,42 (m, 1H), of 6.71 (d, 1H), 8,11-8,39 (m, 4H), 8,86-of 8.92 (m, 1H)
69497,801,791H NMR (CD3OD, 500 MHz): 3,38 is 4.35 (m, 10H), of 4.67 (d, 1H), 5,19 is 5.54 (m, 1H), 6,80-7,07 (m, 1H), 8,23-8,80 (m, 4H)
70525,802,081H NMR (CD3OD, 500 MHz): of 1.29 (d, 6H), 3,43-4,30 (m, 7H), and 4.68 (d, 1H), 4,86-4,94 (m, 1H), 5,44 (with, of user., 1H), 7,01 (with, of user., 1H), 8,23-8,58 (m, 4H)
71523,802,051H NMR (CD3OD, 500 MHz): 3,40-4,30 (m, 7H), 4.53-in-4,74 (m, 3H), 5,19 is 5.54 (m, 3H), of 5.92-6,01 (m, 1H), 6,98 (with, of user., 1H), 8,24-to 8.57 (m, 4H)
72459,502,99the 10.5 (s, 1H), total of 8.74 (d, 1H), 8,39 (s, 1H), 8,35 (d, 1H), 8,28 (d, 1H), 7,20 (m, 1H), 6.73 x (s, 1H), 4,5-4,8 (s, 6H), 3,98 (m, 1H), 3,68 (m, 1H), 2,32 (m, 1H), 1,70 (s, 3H), 1,08 (DD, 6H) (CD3CN)
73441,201,80
74429,101,601H NMR (500 MHz, DMSO-d6) 12,95 (users, 1H), 8,78 (s, H), 8,65 (s, 1H), 8,59 (s, 1H), 8,39 (who, J=1.8 Hz, 1H), 8,17 (d, J=4,8 Hz, 1H), 6.90 to (s, 1H), and 5.30 (s, 1H), 4,74 (s, H), is 4.21 (s, 1H), 4.04 the-of 3.80 (m, 2H), 1,21 (d, J=5.7 Hz, 3H)
75423,001,801H NMR (500 MHz, DMSO-d6) 12,95 (users, 1H), 9,07 (s, H), 8,63 (s, 1H), at 8.60 (s, 1H), 8,40 (d, J=2.1 Hz, 1H), to 8.20 (s, 1H), 6.75 in (s, 1H), 4,99 (s, 1H), 4,05-a 3.83 (m, 2H), 2,98 (t, J=2.4 Hz, 1H), 2,80 (d, J=7,3 Hz, 2H)
76429,101,601H NMR (500 MHz, DMSO-d6) 12,96 (s, 1H), 8,79 (s, 1H), 8,65 (s, 1H), 8,61 (s, 1H), 8,40 (d, J=2.1 Hz, 1H), 8,20-8,17 (m, 1H), 6,91 (s, 1H), 5.25-inch (users, 1H), 4.75 in (s, 1H), 4,21 (s, 1H), 4.04 the-3,88 (m, 2H), 1,22 (d, J=6.2 Hz, 3H)
77482,401,691H NMR (CD3OD, 500 MHz): 2,08 (s, 3H), 3,18-equal to 4.97 (m, 9H), 6,87-was 7.08 (m, 1H), 8,24-8,59 (m, 4H)
78518,401,831H NMR (CD3OD, 500 MHz): at 2.93 (s, 3H), 3,18-equal to 4.97 (m, 9H), 7,00-7,10 (m, 1H), compared to 8.26-8,56 (m, 4H)
79526,502,001H NMR (CD3OD, 500 MHz): and 0.98 (t, 3H), 1,67-of 1.74 (m, 2H), 3,18-of 4.90 (m, 11H), 6,86-7,00 (m, 1H), 8,24-8,59 (m, 4H)
80540,502,121H NMR (CD3OD, 500 MHz): 0,97 (d,6H), 1,91 is 2.01 (m, 1H), 3,18-of 4.90 (m, 11H), 6,86-7,00 (m, 1H), 8,24-8,59 (m, 4H)
81482,501,611H NMR (CD3OD, 500 MHz): 2,08 (s, 3H), 3,18-equal to 4.97 (m, 9H), 6,87-was 7.08 (m, 1H), 8,24-8,59 (m, 4H)
82518,401,821H NMR (CD3OD, 500 MHz): at 2.93 (s, 3H), 3,18-equal to 4.97 (m, 9H), 7,00-7,10 (m, 1H), compared to 8.26-8,56 (m, 4H)
83441,201,50DMSO-d6: 12,85 (users, 1H); 9,05 (s, 0,3H); 8,9 (s, 0,7H); to 8.7 (m, 0,3H); 8,65 to 8.5 (m, 1,7H); 8,4-of 8.25 (m, 2H); 6.75 in (m, 0,7H); 6,2 (m, 0,3H)and 4.9 (m, 0,7H); 4,7 (m, 0,3H); 4,5 (m, 1H); 4,05 to 3.5 (m, 5H); is 2.05 (m, 1H)
84473,102,20DMSO-d6: 12,35 (users, 1H); to 8.7 (s, 1H); 8,35 to 8.1 (m, 4H); 6.4 (m, 1H); 4,7 (DD, 1H); 4.0 a (m, 2H); and 3.8 (m, 2H); 3.15 in (m, 1H); to 2.25 (m, 1H); 2.0 (m, 3H)
85459,102,00DMSO-d6: 12,3 (users, 1H); of 8.8 (s, 1H); to 8.7 (m, 1H); to 8.3 (m, 2H); 8,15 (m, 1H); is 4.85 (m, 1H); of 4.45 (m, 1H); 4,05 to 3.7 (m, 5H); 1,9 (m, 1H)
86413,202,301H NMR (500 MHz, DMSO) 12,63 (s, 1H), 8,87-8,86 (users, 1H), 8,61 (m, 2H), 8,35-8,31 (m, 2H), 7,25 (d, J=4,8 Hz, 1H), 5,39 (kV, J=7,1 Hz, 1H), 3.95 to 3,81 (m, 2H), 3,18 (s, 3), of 1.43 (d, J=6.9 Hz, 3H)
87431,202,701H NMR (500 MHz, DMSO) 12,38 (s, 1H), 8,70-8,65 (m, 2H), 8,32 (d, J=6,9 Hz, 1H), 8,29 (DD, J=2,4, 2,8 Hz, 2H), 5,16 (kV, J=7,0 Hz, 1H), 3.95 to 3,86 (m, 2H), 3,17 (d, J=4,2 Hz, 3H), of 1.46(d,J=7,0 Hz, 3H)
88400,102,30DMSO-d6: 12,6 (m, 1H); at 8.60 (m, 1H); and 8.50 (m, 1H); 8.30 to (m, 1H); of 8.25 (m, 1H); 4,50 (m, 1H); of 3.80 (m, 2H); to 1.42 (m, 3H)
89441,202,101H NMR (500 MHz, DMSO) 12,41 (s, 1H), 8,78 (t, J=6.3 Hz, 1H), 8,71 (d, J=2.4 Hz, 1H), at 8.36 (d, 1H), with 8.33 (d, 1H), 8,30 (d, J=2.4 Hz, 1H), a 4.86 (d, J=10.4 Hz, 1H),.98-3,88 (m, 2H), 3,20 (d, J=4.9 Hz, 3H), 2,44-to 2.40 (m, 1H), was 1.04 (d, J=6.5 Hz, 3H), of 0.90 (d, J=6,7 Hz, 3H)
90459,103,401H NMR (500 MHz, DMSO) 12,98 (s, 1H), 8,87 (users, 1H),.70 (s, 2H), 8,42 (d, 1H), scored 8.38 (d, 1H), 5,4 (users, 1H), 3,97-to 3.89 (m, 2H), 3,14 (users, 3H), of 2.51-to 2.42 (m, 1H), 1,03 (users, H)0,86 (d, J=6,7 Hz, 3H)
91459,402,9510,95 (s, 1H), 8,68 (s, 1H), 8,51 (s, 1H), at 8.36 (s, 1H), 8,28 (d, 1H), 7,25 (m, 2H), 4.1 and 4.5 (s, 8H), 3,95 (m, 1H), 3,69 (m, 1H), 2,39 (m, 1H), 1,72 (s, 3H), of 1.09 (DD, 6H) (CD3CN)
92445,40 2,7010,69 (s, 1H), to 8.70 (d, 1H), 8,48 (s, 1H), to 8.41 (d, 1H), 8,28 (d, 1H), 7,34 (s, 1H), 7.23 percent (m, 1H), 3.75 to 4,2 (m, 26H), of 2.20 (m, 2H), 1,72 (s, 3H), of 0.93 (t, 3H) (CD3CN)
93487,302,10DMSO-d6: 12,3 (users, 1H); cent to 8.85 (s, 1H); 8,65 (s, 1H); to 8.3 (m, 2H); 8,15 (s, 1H); 4.75 in (DD, 1H); 4.25 in (m, 1H); 4,05 to 3.8 (m, 4H); 3,6-of 3.45 (m, 3H); 2.0 (m, 1H); 1,1 (DD, 3H)
94499,402,20
95469,401,90DMSO-d6: 12,3 (users, 1H); from 9.1 to 8.3 (m, 5H); to 6.75 (m, 0,7H); 6,2 (m, 0,3H); 4,85 (m, 0,7H); 4,6 (m, 0,3H); 4,3 (m, 1H); of 4.1 and 3.5 (m, 7H); 2,1 (m, 1H); 1,1 (DD, 3H)
96481,402,00
97426,10of 2.51DMSO-d6: 12,6 (m, 1H); 8,82 (m, 0,5H); is 8.75 (s, 0,5H); to 8.62 (m, 1H); 8,58 (s, 0,5H); 8,48 (m, 1H); scored 8.38 (m, 0,5H); 8,35 (m, 0,5H); by 8.22 (m, 0,5H); 4,65-4,55 (m, 1H); 3,80-of 3.60 (m, 4H); 2,25 (m, 1H); 1,90 (m, 3H)
98414,102,52DMSO-d6: 12,6 (m, 1H); 8,95 (s, 0,5H); to 8.70 (m, 0,5H); and 8.50 (m, 0,5H); 8,40 (m, 0,5H); to 8.20 (m, 2,0H); 8,10-of 7.90 (m, 1H)
99 427,101,801H NMR (500 MHz, DMSO-d6) 13,07 (s, 1H), 9,17 (s, 1H), 8,69-8,66 (m, 3H), 8,61 (m, 1H), 8,39 (d, J=2.2 Hz, 1H), to 8.20 (d, J=7,1 Hz, 1H), 6,78 (d, J=6,9 Hz, 1H), 3,83-of 3.78 (m, 2H), 2,14-2,07 (m, 1H), 2,01-of 1.94 (m, 1H), 1,61 (s, 3H), from 0.88 (t, J=7.5 Hz, 3H)
100445,102,701H NMR (500 MHz, DMSO-d6) 12,36 (s, 1H), 8,68 (d, J=2.4 Hz, 1H), to 8.41 (t, J=6,4 Hz, 1H), 8,30-of 8.27 (m, 2H), 8,11 (s, 1H), 7,53 (s, 1H), 3,85-and 3.72 (m, 2H), 2,19-of 2.15 (m, 1H), 1,99-of 1.95 (m, 1H), 1.55V (s, 3H), 0,81 (t, J=7.5 Hz, 3H)
101473,212,55DMSO-d6: 12,3 (users, 1H); of 8.8 (s, 1H); to 8.7 (s, 1H); to 8.3 (m, 2H); 8,15 (m, 1H); is 8.75 (m, 1H); 4,15 (m, 1H); 4.1 and a 3.75 (m, 4H); to 3.45 (m, 4H); 2.0 (m, 1H)
102487,232,70DMSO-d6: 12,3 (users, 1H); of 8.8 (s, 1H); to 8.7 (s, 1H); to 8.3 (m, 2H); 8,15 (m, 1H); 4.75 in (m, 1H); 4,2 (m, 1H); 4,05-of 4.75 (m, 4H); 3,5 (m, 3H); 2.0 (m, 1H); 1,1 (DD, 3H)
103455,101,70
104500,101,90
105499,102,90DMSO-d6: 12,35 (users, 1H); cent to 8.85 (s, 1H); 8,65 (s,1H); to 8.3 (m, 2H); 8,15 (m, 1H); at 5.9 (m, 1H); 5,3 (d, 1H); further 5.15 (d, 1H); and 4.8 (m, 1H); 4,3 (m, 1H); of 4.05 (m, 2H); about 4.0 to 3.8 (m, 5H); 2.0 (m, 1H)
106455,101,70
107427,401,8010,07 (s, 1H), 8,83 (d, 1H), compared to 8.26 (d, 1H), they were 8.22 (d, 1H), 8,13 (d, 1H), 7,20 (m, 1H), 6,38 (d, 1H), 6,00 (s, 1H), 3,88 (m, 1H), of 3.77 (m, 1H), 1,95 (m, 2H), 1.57 in (s, 3H), of 0.91 (t, 3H) (CD3CN)
108359,401,65
109395,401,77
110441,401,91of 10.01 (s, 1H), 8,71 (d, 1H), 8,23 (d, 1H), 8,17 (d, 1H), 8,12 (d, 1H), 7,16 (m, 1H), 6,40 (d, 1H), 5,86 (s, 1H), 3,97 (m, 1H), 3,61 (m, 1H), 1,5,3 (s, 3H), of 1.02 (DD, 6H) (CD3CN)
111414,102,50DMSO-d6: 12,65 (m, 1H); 8,95 (s, 0,5H);,8,72 (m, 0,5H); to 8.70 (m, 0,5H); and 8.50 (m, 1H); 8,48 (m, 0,5H); 8,40 (m, 0,5H); 8,30 (m, 1H); 8,28 (m, 0,5H); 8,03 (m, 0,5H); of 4.45 (m, 1H); of 3.80 (m, 2H); to 1.75 (m, 2H); 1,00 (m, 3H)
112440,102,70DMSO-d6: 12,68 (m, 1H); 8,98 (s, 0,5H); 8,68 (s, 0,5H); ,58 (s, 0,5H); 8,48 (s, 0,5H); 8,43 (s, 0,5H); 8,35-8,15 (m, 3,5H); of 3.75 (m, 2H); to 2.15 (m, 2H); 2,02 (m, 2H); of 1.65 (m, 4H)
113426,102,60DMSO-d6: 12,55 (m, 1H); 8,95 (m, 0,5H); 8,68 (m, 0,5H); to 8.62 (m, 0,5H); 8,56 (m, 0,5H); charged 8.52 (m, 0,5H); to 8.45 (m, 0,5H); 8,40 (m, 0,5H); 8,35 (m, 1H); by 8.22 (0,5H); 8,16 (m, 1H); of 3.80 (m, 2H,); 2,70 (m, 1H); 2.40 a (m, 1H); to 2.25 (m, 2H); of 1.88 (m, 2H)
114512,101,80DMSO-d6: 12,5 (users, 1H); 8,95 (users, 1H); and 8.50 (m, 2H); 8,32 (m, 2H); to 6.80 (m, 1H); 4,50 (m, 1H); 4,00 is 3.40 (m, 10H); to 1.15 (t, 3H)
115540,102,10
116496,101,70DMSO-d6: 12,6 (m, 1H); 8,95 (m, 1H); and 8.50 (m, 2H); 8,32 (m, 2H); to 6.80 (m, 1H); 4,50 (m, 1H); 4,00 is 3.40 (m, 10H); to 1.15 (t, 3H)
117508,101,70
118522,201,90
119459,301,70DMSO-d6: 12,35 (users, 1H); 8,8 (m, 1H); 8,65 (s, 1H); to 8.3 (m, 2H); 8,15 (m, 1H); and 4.8 (m, 1H); 4,4 (m, 1H); 4,05 to 3.7 (m, 4H); 2,3 (m, 1H); 1,9 (m, 1H)
120441,401,70DMSO-d6: 12,9 (users, 1H); 9,05 (m, 0,3H); 8,9 (m, 0,7H); 8,7-8,5 (m, 2H); 8.4 to to 8.25 (m, 2H); 6.75 in (m, 0,7H); 6,2 (m, 3,3H); 4.95 points (m, 0,7H); 4,7 (m, 0,3H); 4,5 (m, 1H); 4,05 to 3.5 (m, 4H); 2.4 to (m, 1H); is 2.05 (m, 1H)
121425,002,03the 10.1 (s, 1H), 8,89 (s, 1H), 8,29 (m, 3H), 7,27 (s, 1H), 6,51 (d, 1H), 3,88 (m, 2H), 3,30 (s, 6H), to 1.86 (m, 1H), 1.57 in (m, 1H), USD 1.43 (m, 1H), 1,19 (m, 1H) (CD3CN)
122461,302,40
123443,301,90
124487,402,20
125479,402,30
126443,301,90
127439,171,841H NMR (500 MHz, MeOD) 8,79 (d, J=2.3 Hz, 1H), 8,51 t, J=6,4 Hz, 1H), 8,48 (s, 1H), 8,35 (d, J=2.3 Hz, 1H), of 8.06 (d, J=7.2 Hz, 1H), 6.73 x (d, J=7.2 Hz, 1H), a 3.87-3,81 (who, 2H), 2,56-2,52 (m, 2H), 2,25-of 2.20 (m, 2H), 1.93 and to 1.86 (m, 4H), 0,00 (TMS)
128441,402,201H NMR (500 MHz, DMSO) 8,66 (s, 1H), to 8.62 (s, 1H), 8,58 (s, 1H), scored 8.38 (d, J=2.0 Hz, 1H), 8,18 (d, J=7,0 Hz, 1H), for 6.81 (s, 1H), 4.09 to of 3.78 (m, 2H), 2,18-of 2.16 (m, 2H), 2,10 (m, 2H), of 0.77 (t, J=7.4 Hz, 6H), 0,00 (TMS)
129459,402,40
130461,302,40
131377,301,67
132441,091,651H NMR (500 MHz, MeOD) to 8.70 (d, J=2.2 Hz, 1H), 8,48 (s, 1H), at 8.36 (d, J=2.3 Hz, H)to 8.12 (d, J=7.2 Hz, 1H), to 7.59 (d, J=8,2 Hz, 2H*0.7 equiv. p-TsOH), 7,37 (d, J=8.0 Hz, 2H*0.7 equiv. p-TsOH), 6,76 (d, J=7.2 Hz, 1H), to 4.41 (d, J=9.6 Hz, 1H), 4,22 (d, J=9.5 Hz, 1H), 4,07-Android 4.04 (m, 2H), 3,88-a 3.83 (m, 2H), 2,88-2,82 (m, 1H), 2,52 is 2.43 (m, 1H), 2,43 (s, 3H*0.7 equiv. p-TsOH), 0,00 (TMS)
133443,302,86
134441,161,50
135 455,101,80DMSO-d6: 12,8 (users, 1H); 9,05 cent to 8.85 (m, 1H); 8,8-to 8.4 (m, 2H); 8,35 (m, 2H); 6.75 in (m, 0,8H); 6,2 (m, 0,2H); 4,85 (m, 0,8H); 4,6 (m, 0,2H); 4,2 (m, 1H); 4.0 a (m, 1H); 3,9-3,6 (m, 3H); 3,3 (s, 3H); 2,2 (m, 1H)
136455,101,80DMSO-d6: 12,9 (users, 1H); 8,75 is 8.25 (m, 5H); to 6.75 (m, 0,8H); to 8.45 (m, 0,2H); 4.95 points (m, 0,8H); at 4.75 (m, 0,2H); 4,2 (m, 1H); to 4.1 to 3.7 (m, 4H); 3,2 (s, 3H); 2,3 (m, 1H)
137473,102,00DMSO-d6: 12,35 (users, 1H); 8,65 (m, 1H); to 8.45 (DD, 1H); of 8.25 (m, 2H); 8,15 (m, 1H); and 4.8 (d, 1H); to 4.1 (m, 1H); 4.0 a (m, 1H); 3.9 to (m, 1H); of 3.85 (m, 2H); 3,2 (s, 3H); 2,2 (m, 1H)
138397,001,74(500 MHz, CD3OD) to 8.57 (t, J=6.2 Hz, 1H), and 8.50 (s, 1H), 8,48 (d, J=2.6 Hz, 1H), 8.3 (l, J=1.2 Hz, 1H), with 8.05 (d, J=7.2 Hz, 1H), 6,7 (d, J=7.2 Hz, 1H), 3,86 to 3.8 (m, 2H), 1,74 (s, 6H), 0 (TMS)
139445,103,301H NMR (500 MHz, DMSO) 12,24 (s, 1H), 8,69 (s, 1H),.32 (d, J=6,9 Hz, 1H), 8,24 (m, 2H), 8,15 (s, 1H), 3,68-3,63 (m, 2H), 3,20 (s, 1H)and 1.51 (s, 1H)
140427,101,801H NMR (500 MHz, DMSO) 12,7 (users, 1H), 8,82 (s, 1H),.34-8,30 (m, 2H), 8,16 (s, 1H), 8,07 (d, J=6.2 Hz, 1H), 5,63 (d, J=6.2 Hz, 1H), of 3.77-3,70 (m, 2H), 3,06 (s, 3H),.56 (s,6H)
141431,102,50DMSO-d6: 12,2 (m, 1H); at 8.60 (m, 1H); by 8.22 (s, 1H); 8,18 (s, 1H); 8,10 (s, 1H); of 7.70 (m, 1H); 5,16 (m, 1H); 4,18 (m, 2H); 3,3(s, 2,5H); 2,9 (s, 0,5H); of 1.35 (m, 3H)
142413,101,80DMSO-d6: 12,5 (m, 1H); to 8.70 (m, 1H); 8.30 to (m, 2H); 8,18 (m, 2H); 6.42 per (m, 1H); 5.25 in (m, 1H); 4,20 (m, 2H); 3.30 is (C, 2,5H); 2,90 (s, 0,5H); to 1.32 (m, 3H)
143413,101,84
144377,101,70
145395,101,74
146428,102,00
147411,102,00
148497,102,40
149554,002,20
150498,001,80DMSO-d6: 12,7 (m, 1H); of 8.92 (m, 1H); at 8.60 (m, 1H); 8,42 (m, 1H); 8,32 (m, 1H); 8,28 (m, 1H); to 6.80 (m, 1H); 5,20 (m, 1H); 4,30-of 3.60 (m, 8H); 3,55 (m, 3H)
151512,001,90DMSO-d6: 12,5 (m, 1H); 8,90 (m, 1H); 8,55 (m, 1H); 8,42 (m, 1H); 8,32 (m, 1H); 8.30 to (m, 1H); 6,70 (m, 1H); 5,20 (m, 1H); 4,35-3,55 (m, 10H); to 1.15 (t, 3H)
152526,102,00
153526,002,00
154540,102,10
155540,102,10
156532,803,10DMSO-d6: 12,35 (users, 1H); 8,9 (m, 1H); to 8.7 (s, 1H); and 8.4 and 8.1 (m, 3H); 4,85 (DD, 1H); 4.35, an increase of 4.1 (m, 2H); about 4.0 to 3.7 (m, 2H); 3,3 (m, 4H); to 2.85 (m, 1H); 2,4 (m, 1H)
157546,903,20DMSO-d6: 12,35 (users, 1H); 8,9 (m, 1H); to 8.7 (s, 1H); 8,35-of 8.15 (m, 3H)and 4.9 (DD, 1H); 4.1 and a 3.75 (m, 4H); of 3.1 and 2.9 (m, 5H); to 2.15 (m, 1H); 1,95 (who, 2H)
158493,901,70
159522,001,90
160524,001,90
161538,002,10
162511,001,70DMSO-d6: 12,8 (m, 1H); 8,90 (m, 1H); 8,55 (m, 2H); 8,35 (, 2H); to 6.80 (m, 1H); 5.25 in (, 1H); 4,20-of 3.60 (m, 8H); 2,62 (s, 6H)
163525,001,80
164560,002,20
165508,001,80
166443,001,60DMSO-d6: 12,8 (users, 1H); 8,95-8,65 (m, 1H); 8,65-to 8.45 (m, 2H); 8.4 to to 8.25 (m, 2H); 6.75 in (m, 0,7H); and 6.25 (m, 0,3H), and 5.5 (d, 1H); of 5.05 (m, 0,7H); 4,85 (m, 0,3H); from 4.2 to 3.7 (m, 4H); 2.8 to to 2.55 (m, 1H); 2,5 to 2.35 (m, 1H)
167460,901,80DMSO-d6: was 12.75 (users, 1H); 9,0 (m, 1H); 8,65 to 8.3 (m, 4H); 6,7 (m, 1H); further 5.15 (m, 1H); 4,2 (m, 2H); 4.0 a (m, 1H); of 3.85 (m, 1H); 3,1 (m, 1H); 2,6 (m, 1H)
168443,001,60DMSO-d6: 12,8 (users, 1H); 9,2-8,9 (m, 1H); 8,7-to 8.45 (m, 2H); and 8.4 to 8.3 (m, 2H); 6.75 in (m, 0,7H); and 6.25 (m, 0,3H); of 5.55 (d, 1H); 5,0 (m, 0,7H); and 4.8 (m, 0,3H); from 4.2 to 3.7 (m, 4H); 2,9-2,7 (m, 1H); 2,3-2,1 (m, 1H)
169403,102,20DMSO-d6: 12,45 (s, 1H); to 8.7 (s, 1H); to 8.3 (m, 2H); of 8.25 (m, 1H); 8.0 a (DD, 1H); 4.7 in (m, 1H); 3,95 (m, 1H); and 3.8 (m, 1H); 3,05 (m, 1H); 2.95 and (m, 1H); to 2.25 (m, 1H); 2.0 (m, 3H); 1,4 (m, 2H); 0.75 in (m, 3H)
170385,101,70DMSO-d6: 12,9 (users, 1H); to 8.7 and 8.6 (m, 2H); and 8.4 (m, 1H); to 8.3 (m, 1H); 8,15 (m, 1H); 6,7 (d, 0,7H); and 6.3 (d, 0,3H); 4,85 (d, 0,7H); 4,5 (0,3H); 4,05-3,6 (m, 2H); 3,2 was 3.05 (m, 1H); 2,9 (m, 1H); to 2.35 (m, 1H); is 2.05 (m, 3H); 1,5-1,3 (m, 2H); 0,8 (m, 1H); 0,7 (m, 2H)
171387,402,00DMSO-d6: 12,95 (users, 1H); to 8.7 (s, 1H); and 8.6 (s, 1H); and 8.4 (s, 1H); to 8.3 (s, 1H); 8,15 (m, 1H); 6.8 cm (s, 1H); 4,65 (s, 1H); 3,2 (m, 1H); 3,0 (m, 1H); to 2.25 (m, 1H); to 1.45 (m, 2H); 1,1-of 0.95 (m, 6H); 0,85 (m, 3H)
172457,102,40
173439,201,70DMSO-d6: 12,9 (users, 1H); 8,7-8,65 (m, 2H); 8,45 is 8.25 (m, 3H); 6.75 in (d, 0,8H); and 6.3 (d, 0,2H); 4,85 (d, 0,8H); 4,55 (d, 0,2H); 4,05-3,55 (m, 4H); 2,4-of 2.25 (m, 3H); 2.1 to 2.0 (m, 3H)
174441,402,00
175373,401,74
176427,301,87
177401,102,00DMSO-d6: 12,45 (s, 1H); to 8.7 (s, 1H); to 8.3 (m, 2H); of 8.25 (s, 1H); 8,15 (s, 1H); 4,6 (d, 1H); 3.9 to (m, 1H); and 3.8 (m, 1H); 2,6 (m, 1H); to 2.25 (m, 1H); 1,95 (m, 3H); 0,6 (m, 2H); 0,4 (m, 1H); 0,35 (m, 1H)
178383,101,60DMSO-d6: 13,0 (users, 1H); 8,65 (m, 1H); and 8.6 (s, 1H); and 8.4 (m, 1H); 8,35 to 8.2 (m, 2H); 6.75 in (d, 0,7H); and 6.3 (d, 0,3H); and 4.8 (d, 0,7H); 4,5 (0,3H); 4,05-3,6 (m, 2H); 2,7-to 2.55 (m, 1H); 2,35 (m, 1H); is 2.05 (m, 3H); 0,7-0,2 (m, 4H)
179385,401,90DM is About-d6: 12,95 (users, 1H); to 8.7 (s, 1H); and 8.6 (s, 1H); and 8.4 (s, 1H); 8,35 (s, 1H); 8,15 (m, 1H); 6.8 cm (s, 1H); 4,6 (s, 1H); to 2.7 (m, 1H); to 2.25 (m, 1H); of 1.05 to 0.95 (m, 6H); of 0.65 (m, 2H); to 0.45 (m, 2H)
180371,401,65

Table 5
Conn.No.M+HRtNMR
181473,11,9
182415,11,8(500 MHz, DMSO) 12,22 (s, 1H), 8,42 (DD, J=2,8, 9.9 Hz, 1H), of 8.37 (t, J=6,4 Hz, 1H), compared to 8.26-of 8.25 (m, 2H), 8,10 (d, J=2.5 Hz, 1H), 3,78-3,71 (m, 2H), 1.57 in (s, 6H), 0,00 (TMS)
183361,11,6(500 MHz, DMSO) 12,27 (s, 1H), of 8.47 (DD, J=2,8, or 9.8 Hz, 1H), 8,25 (d, J=3.0 Hz, 2H), 8,19 (d, J=2.2 Hz, 1H), of 7.75 (t, J=5.6 Hz, 1H), 7,56 (users, 1H), 3,02-to 2.99 (m, 2H), and 1.56 (s, 6H), of 0.77 (t, J=7,1 Hz, 3H), 0,00 (TMS)
184379,11,6(500 MHz, DMSO) to 12.3 (s, 1H), 8,45 (DD, J=2,8, or 9.8 Hz, 1H), 8,25 (m, 2H), 8,19 (users, 1H), with 8.05 (t,1H), 7,7 (users, 1H), 4.2V (dt, 2H, under water), 3,2 (DQC, 2), of 1.6 (s, 6H), 0,00 (TMS)
185397,11,7(500 MHz, DMSO) to 12.28 (s, 1H), 8,44 (DD, J=2,8, 9.9 Hz, 1H), 8,27 (d, J=4.4 Hz, 2H), 8,19 (t, J=5,9 Hz, 1H), 8,15 (d, J=2.5 Hz, 1H), 7,69 (users, 1H), 5,7 (TT, J=48 Hz, J=4.3 Hz, 1H), 3,39-of 3.31 (m, 2H), 1.57 in (C, 6H), 0,00
(TMS)
186375,11,7
187361,12,04
188379,1of 2.21
189343,12,04
190357,12,3
1914572,9(DMSO-d6) to 12.35 (s, 1H); to 8.7 (d, 1H); 8.4 to to 8.25 (m, 3H); 8,1 (s, 1H); to 4.1 (m, 1H); 3,95 (m, 1H); of 3.85 (m, 1H); 3,7 (m, 1H); is 2.05 (m, 4H); of 1.65 (s, 3H)
1924391,7(DMSO-d6) of 12.9 (s, 1H); 8,75-8,65 (m, 1,1H); 8,55 (m, 0,9H); 8,45-of 8.15 (m, 3H); 6,7 (m, 0,9H); 6,1 (m, 0,1H); 4,15 (m, 0,1H); 3,95 (m, 0,9H); and 3.8 (m, 3H); 2,2-205 (m, 4H); 1,75-1,6 (m, 3H)
193455,11,8(500 MHz, DMSO) to 12.95 (s, 1H), 8,71 (s, 1H), 8,59 (userd, 2H), at 8.36 (d, J=2.2 Hz, 1H), 8,23 (d, J=6,9 Hz, 1H), PC 6.82 (s, 1H), 3,82-of 3.77 (m, 4H), 3,66 (t, J=10.5 Hz, 4H), 2,27-of 2.20 (m, 2H), 2,20-of 2.08 (m, 2H), 0,00 (TMS)
194439,11,7(500 MHz, DMSO) 12,89 (s, 1H), 8,61 (m, 2H), 8,46 (d, J=9.6 Hz, 1H), at 8.36 (s, 1H), they were 8.22 (d, J=6,9 Hz, 1H), 6,82 (userd, 1H), 3,81-with 3.79 (m, 4H), 3,67-3,63 (m, 2H), 2,23 (t, J=10,2 Hz, 2H), 2,12 (m, 2H), 0,00 (TMS)
195409,11,8
196427,081,7
197528,92(DMSO-d6) 12,5 (users, 1H); 8,9 (m, 1H); 8,65 (m, 1H); and 8.4 to 8.3 (m, 3H); 6.75 in (m, 0,5H); 6,5 (m, 0,5H)and 4.9 (m, 1H); to 4.1 to 3.7 (m, 4H); of 3.1 and 2.9 (m, 5H); 2,2 (m, 1H); 1,95 (m, 2H)
198409,11,9(500 MHz, MeOD) 8,91 (d, J=2.2 Hz, 1H), 8,72 (s, 1H), 8,55 (d, J=8,3 Hz, 1H), scored 8.38 (d, J=2.2 Hz, 1H), 8,03 (t, J=7,6 Hz, 2H), 7,88 (d, J=8,3 Hz, 1H), 7,74 (t, J=7.8 Hz, 1H), 3,21 is 3.15 (m, 2H), 1,87 (s, 6H), 6,89 (t, J=7.2 Hz, 3H)
199447,1 1,79(500 MHz, MeOD) 8,73 (s, 1H), 8,63 (d, J=9.5 Hz, 1H), to 8.57 (m, 2H), with 8.33 (s, 1H), 8,03 (m, 1H), 7,89 (d, J=8,4 Hz, 1H), 7,74 (t, J=7.7 Hz, 1H), 3,82 (m, 2H), 2,66 (s, 1,3H), of 1.88 (s, 6H) (not identified peak at 2,66.)
200397,11,65(500 MHz, DMSO-d6) 12,90 (s, 1H), 9,05 (s, 1H), 8,66 (s, 1H), 8,40 (s, 1H), of 8.37 (s, 1H), 8,16 (d, J=6,4 Hz, 1H), 6.73 x (s, 1H), 4.75 in (s, 1H), 4,08-4,01 (m, 2H), a 3.87 (d, J=6,5 Hz, 1H), 1.93 and of-1.83 (m, 2H), 1.00 and (t, J=7.4 Hz, 3H), 0,00 (TMS)
2014451,7(DMSO-d6) was 12.75 (users, 1H); 9,0 (DD, 1H); 8,55 (s, 1H); 8,45 is 8.25 (m, 3H); 6,7 (m, 1H); 5,2 (m, 1H); 4,2 (m, 2H); 4,05 to 3.7 (m, 2H); 3,1 (m, 1H); 2,6 (m, 1H)
2024412,7(DMSO-d6) 12,25 (users, 1H); and 8.4 (d, 1H); 8,35 (DD, 1H); 8.3 (l, 1H); of 8.25 (s, 1H); 8,1 (s, 1H); to 4.1 (m, 1H); 3,95 (m, 1H); and 3.8 (m, 1H); 3,7 (m, 1H); 2.1 to 2.0 (m, 4H); of 1.65 (s,3H)
2034231,7(DMSO-d6) 12,8 (users, 1H); of 8.5 to 8.2 (m, 5H); 6,7 (m, 1H); about 4.0 to 3.7 (m, 4H); 2,2-2,0 (m, 4H); and 1.7 (s, 3H)
2044271,5(DMSO-d6) 12,85 (users, 1H); 9,2-9,0 (m, 1H); to 8.7 and 8.6 (m, 1H); and 8.4 (m, 3H); 6,85 (m, 0,8H); and 6.25 (m, 0,2H); of 5.55 (d, 1H); of 5.05 (DD, 0,8H); and 4.8 (m, 0,2H); from 4.2 to 3.6 (m, H); the 2.8 (m, 1H); 2,3-2,15 (m, 1H)
205423,12
206441,12
207459,12,1(500 MHz, DMSO) 13,17 (s, 1H), 8,87 (s, 1H), 8,80 at 8.60 (m, 2H), 8,40-8,30 (m, 2H), 8,05-7,94 (m, 1H), 7,89 (d, J=8,3 Hz, 1H), of 7.70 (m, 1H), 5,70 (TT, J=15,1, 3,9 Hz, 1H), 3,40-3,30 (m, 2H), 2,38-2,31 (m, 1H), 2,07 (m, 1H), 1,70 (s, 3H), of 0.89 (t, J=7.5 Hz, 3H)
208477,12,2(500 MHz, DMSO) cent to 8.85 (s, 1H), 8,67-8,55 (m, 3H), 8,39 (s, 1H), 7,99 (m, 1H), 7,89 (d, J=8,1 Hz, 1H), 7,69 (m, 1H), 3,86-3,71 (m, 2H), 2,40-of 2.34 (m, 1H), 2,10-to 2.06 (m, 1H), 1,70 (s, 3H), of 0.89 (t, J=7.5 Hz, 3H)
209359,11,6(500 MHz, MeOD) 8,48 (DD, J=2,8, and 9.3 Hz, 1H), 8,43 (s, 1H), 8,35-of 8.33 (m, 1H), 8,28-of 8.27 (m, 1H), 3,21 (kV, J=7.2 Hz, 2H), 1.77 in is 1.75 (m, 2H), 1,29 (m, 2H), 0,97 (t, J=7.2 Hz, 3H)
210395,11,7(500 MHz, DMSO) to 12.35 (s, 1H), to 8.57 (s, 1H), 8,39 (d, J=6,1 Hz, 2H), 8,31 (d, J=3,9 Hz, 1H), 8,27 is 8.25 (m, 2H), 5,95-5,71 (m, 1H), 3,45-3,37 (m, 2H), 1,53 (user., 2H), 1,16 (user., 2H)
211413 1,8(500 MHz, MeOD) 8,46-8,43 (m, 2H), of 8.37 (t, J=4,8 Hz, 1H), 8,27 compared to 8.26 (m, 1H), 3,90-a 3.83 (m, 2H), equal to 1.82 (m, 2H), 1,38 (m, 2H). Multiplet (0,47H) when 8,71 identified as not fully exchangeable proton, which is reduced to 0,38H after 1 hour.
212373,11,72(500 MHz, DMSO-d6) 13,04 (s, 1H), 9,16 (d, J=3.2 Hz, 1H), 8,82 (s, 1H), 8,66 (d, J=3.0 Hz, 1H), 8,39 (d, J=2.0 Hz, 1H), 8,15 (d, J=7,0 Hz, 1H), to 7.64 (d, J=7.2 Hz, 1H), of 6.68 (d, J=7,1 Hz, 1H), 3,88-a-3.84 (m, 1H), 1,60 (s, 6H), is 0.84 (d, J=6.2 Hz, 6H), 0,00 (TMS)
213405,11,6(500 MHz, MeOD) 8,83 (d, J=2.3 Hz, 1H), 8,58 (s, 1H), 8,35 (d, J=2.3 Hz, 1H), 8,18 (m, 1H), 4,21 (t, J=4,8 Hz, 1H), 4,11 (t, J=4,8 Hz, 1H), 3,37-of 3.32 (m, 2H), 2,58 (s, 3H), and 2.27 (s, 3H), 1,79 (s, 6H)
2144231,71(500 MHz, MeOD) 8,79 (d, J=2.3 Hz, 1H), 8,58 (s, 1H), at 8.36 (d, J=2.3 Hz, 1H), 8,29 (m, 1H), 5,67-5,43 (m, 1H), 3,48-to 3.38 (m, 2H), 2,58 (s, 3H), and 2.27 (s, 3H), 1,79 (s, 6H)
2154411,8(500 MHz, MeOD) 8,77 (d, J=2.3 Hz, 1H), 8,56 (s, 1H), 8,44-to 8.34 (TO, 1H), 8.34 per (d, J=2.2 Hz, 1H), 3,86-with 3.79 (m, 2H), 2,58 (s, 3H), of 2.28 (s, 3H), 1,79 (s, 6H)
2164712,9(500 MHz, DMSO) 12,32 (s, 1H), 8,69 (m,2H), 8,28-8,13 (m, 3H), 4,9-of 4.75 (m, 1H), 4,7-to 4.5 (m, 1H), 3.95 to a 3.75 (m, 3H), 2,15-of 1.95 (m, 1H), 1,87 (m, 2H), 1,6 (s, 1H), 1,44-of 1.41 (m, 1H), 1,1-of 0.85 (m, 3H)
2174391-8(500 MHz, MeOD) 8,77 (s, 1H), they were 8.22-8,19 (m, 3H), 6,40 (s, 1H), 4,69 (s, 1H), 4,32 (users, 1H), 4,01-3,91 (m, 2H), 2,43-of 2.38 (m, 1H), 2,27-of 2.16 (m, 2H), 1,86-to 1.82 (m, 1H), 1,45(d, J=6.0 Hz, 3H)
2184572,7(500 MHz, MeOD) 8,78-8,77 (m, 1H), to 8.20 (d, J=2.1 Hz, 1H), 8,15-8,10 (m, 2H), 4,90 (d, J=9.4 Hz, 1H), 3,94-3,82 (m, 2H), 2,58-to 2.40 (m, 1H), 2,24-of 2.21 (m, 1H), 2,0-2,1 (m, 1H), equal to 1.82 (m, 1H), 1,50 (d, 1H), 1,4-of 1.23 (m, 3H)
219452,92(500 MHz, MeOD) 8,76 (s, 1H), 8,21-8,17 (m, 3H), 6,40 (d, J=5,9 Hz, 1H), 4,90 (d, J=9.1 Hz, 1H), 4.04 the-3,88 (m, 2H), 3,63 (s, 1H), 2,53-2,39 (m, 1H), 2,22-2,11 (m, 3H), 2,01-of 1.92 (m, 1H), 1.60-to a 1.45 (m, 1H), 1,08 (t, J=7.2 Hz, 2H), 1,01 (t, J=7,1 Hz, 1H)
220469,11,84(500 MHz, DMSO) 13,52-13,35 (user., 1H), 13,12-12,96 (user., 1H), 9,07-8,61 (user., 1H), 8,93 (s, 1H), of 8.37 (s, 1H), 8.07-a rate of 7.54 (m, 2H), 7,40-7,27 (user., 1H), 3,02-of 2.97 (m, 2H), 1,71 (s, 6H), to 0.72 (t, J=7,1 Hz, 3H)
221487,11,85(500 MHz, MeOD) 8,93 (d, J=2.3 Hz, 1H), 8,61 (s, 1H), of 8.37 (d, J=2.2 Hz, 1H), 8,21 (m, 1H), 7,98 (s, 1H), 7,31 (s, 1H), 4,20 (t, J=4,8 Hz, 1H), 4,11 (t, J=4,9 is C, 1H), 4,07 (s, 3H), 4,06 (s, 3H), 3,36-to 3.35 (m, 2H), 1,87 (s, 6H)
222505,11,9(500 MHz, MeOD) 8,89 (d, J=2.3 Hz, 1H), 8,61 (s, 1H), of 8.37 (d, J=2.3 Hz, 1H), 8,33 (m, 1H), to 7.99 (s, 1H), 7,32 (s, 1H), 5,67-5,43 (m, 1H), 4,07 (s, 3H), 4,06 (s, 3H), 3,35-to 3.33 (m, 2H), 1,87 (s, 6H)
2234831,9(500 MHz, MeOD) 8,91 (d, J=2.3 Hz, 1H), to 8.62 (s, 1H), of 8.37 (d, J=2.3 Hz, 1H), 7,98 (s, 1H), 7,31 (s, 1H), 4,07 (s, 3H), 4,07 (s, 3H), 3,12-is 3.08 (m, 2H), to 1.86 (s, 6H), 1,33-1,25 (m, 2H), and 0.62 (t, J=7.5 Hz, 3H)
224329,051,4(500 MHz, MeOD) 8,49 (d, J=3.2 Hz, 1H), 8,45-to 8.40 (m, 1H), with 8.33 (d, J=1.5 Hz, 1H), 8,03 (d, J=7,1 Hz, 1H), 6,69 (d, J=6,9 Hz, 1H), 4,77-of 4.75 (m, 1H), 3,3 (m, overlapped signal Meon, 2H), 1.61 of (e, 7,1 Hz, 3H), 1,10 (t, J=7,2 Hz, 3H), 0,00 (TMS)
225346,931,4
2263651,4(500 MHz, MeOD) 8,49 (s, 1H), to 8.41 (d, J=7.9 Hz, 1H), 8,33-8,32 (m, 1H), 8,04 (d, J=6,9 Hz, 1H), 6,70 (d, J=6,6 Hz, 1H), of 5.84 (t, J=55,8 Hz, 1H), 3,74-3,44 (2m, 2H), and 1.63 (d, J=7.2 Hz, 3H), 0,00 (TMS)
2273831,6
228to € 391.12,3(500 MHz, DMSO) 12,96 (s, 1H), 8,65 (s, 1H), 8,42 is 8.38 (m, 2H), of 8.25 (s, 1H), to 8.20 (d, J=7,0 Hz, 1H), of 6.68 (d, J=6,8 Hz, 1H), USD 5.76 (t, J=56,1 Hz, 1H), 3,43-3,37 (m, 2H), 2,81-2,78 (m, 2H), 2,30 (DD, J=8,6, to 18.9 Hz, 2H), 2,01 (kv.n, J=8,1 Hz, 2H), 0,00 (TMS)
229409,12,4(500 MHz, DMSO) 12,91 (s, 1H), to 8.62 (s, 1H), 8,46 (s, 1H), to 8.41 (d, J=8,8 Hz, 1H), at 8.36 (s, 1H), to 8.20 (d, J=6,7 Hz, 1H), 6,66 (d, J=6,6 Hz, 1H), 3,82-with 3.79 (m, 2H), 2,84 (m, 2H), 2,32-of 2.28 (m, 2H), 2,02-1,95 m, 2H), 0,00 (TMS)
230369,21,6(500 MHz, DMSO) 12,92 (s, 1H), 8,63 (s, 1H), of 8.47 (d, J=8.5 Hz, 1H), of 8.37 (s, 1H), 8,18 (d, J=6,8 Hz, 1H), to 7.84 (s, 1H), 6,65 (d, J=6,5 Hz, 1H), 2,97 (m, 2H), and 2.79 (m, 2H), and 2.26 (m, 2H), 2,00 (m, 2H), 1,23 (DD, J=6,9, a 14.1 Hz, 2H), 0,54 (t, J=7,1 Hz, 3H), 0,00 (TMS)
231373,11,76(500 MHz, DMSO-d6) 13,02 (s, 1H), 8,99 (s, 1H), 8,76 (s, 1H), 8,63 (s, 1H), 8,39 (d, J=2.3 Hz, 1H), 8,16 (d, J=6,7 Hz, 1H), 7,92 (s, 1H), 6.75 in (d, J=4.9 Hz, 1H), 3,07 was 3.05 (m, 2H), 2,10-of 1.93 (m, 2H), 1,58 (, 3H), 0,86 (t, J=7.5 Hz, 3H), 0,81 (s, 3H), 0,00 (TMS)
232to € 391.11,77(500 MHz, DMSO-d6) 13,66-13,49 (m, 1H), 12,96-12,93 (m, 1H), 8,76 (s, 1H), to 8.57 (d, J=10,2 Hz, 1H), of 8.37 (s, 1H), 8,16-8,13 (m, 2H), of 6.68 (d, J=9.6 Hz, 1H), 4,21 (d, J=51.9 Hz, 2H), 3,28 (kV, J=5.4 Hz, 2H), 2,10-1,4 (m, 2H), 1.57 in (s, 3H), of 0.87 (t, J=7.5 Hz, 3H), 0,00 (TMS)
233409,11,87(500 MHz, DMSO-d6) 13,02 (s, 1H), 9,05 (s, 1H), to 8.70 (s, 1H), to 8.62 (s, 1H), 8,39 (d, J=2.2 Hz, 1H), 8,35 (s, 1H), 8,18 (d, J=7,0 Hz, 1H), 6.75 in (d, J=5.6 Hz, 1H), 5,86-5,64 (m, 1H), 3,43-3,37 (m, 2H), 2,12-1,93 (m, 2H), 1,59 (s, 3H), from 0.88 (t, J=7.5 Hz, 3H), 0,00 (TMS)
234387,11,87(500 MHz, DMSO-d6) of 13.56 (s, 1H), 12,89 (s, 1H), 8,89 (s, 1H), to 8.57 (s, 1H), at 8.36 (s, 1H), 8,16 (d, J=6,8 Hz, 1H), 6,63 (s, 1H), 3,24 (s, 3H), 2,94 (s, 2H), 2,20-to 1.87 (m, 2H), 1.57 in (s, 3H), of 0.87 (t, J=7,4 Hz, 3H), 0.75 in (s, 3H), 0,00 (TMS)
235523,11,9
236355,21,8
237373,11,8
2383982,6(DMSO-d6) 12,56 (m, 1H); 8,80 (m, 0,5H); 8,55 (s, 0,5H); and 8.50 (s, 0,5H); to 8.45 (m, 1,0H); 8,40-8,30 (m, 1,5H); 8,28 (m, 1,5H); 8,10 (m, 0,5H); of 3.80 (m, 2H); to 1.42 (m, 6H)
239410,91,7(500 MHz, DMSO) (heated to 100°C) and 12.2 (C, 1H), 8,84 (d, J=2.2 Hz, 1H), 8,43 (users, 1H), scored 8.38 (s, 1H), 8,29 (d, J=2.4 Hz, 1H), 8,23 (d, J=6.3 Hz, 1H), 8,13 (ushort, 1H), 6,46 (d, J=6.3 Hz, 1H), 3,93-a 3.83 (m, 2H), 1,62 is 1.60 (m, 2H), 1,23-1,17 (m, 2H), 0,0(TMS)
2403951,6(500 MHz, CD3OD, CT) to 8.8 (m, 0,6 H), 8,65 (ushort, 1H), 8,5 (s, 1H), 8,45 (userd, 1H), 8,25 (m, 1,3H), 8,1 (d, 0,8H), 6,7 (d, 1H), 3,9 (m, 2H), 1.8 m (osirm, 2H), 1,35 (osirm, 2H), 0 (TMS)
241371,11,76
242393,11,77
243411,1to 1.86
244341,11,5(500 MHz, MeOD, CT, contains conformers) 8,77 (DD, J=2,8, and 9.2 Hz, 0,29H), 8,54-8,49 (m, 1,66H), 831 (d, J=1.5 Hz, 1H), compared to 8.26-8,24 (m, 0,3H), 8,10 (DD, J=4,3, 7,2 Hz, 0,82H), 6,70 (d, J=7,3 Hz, 0,29H), of 6.66 (DD, J=4,3, 7,2 Hz, 0,71H), 3.27 to 3,18 (m, 2H), 1.77 in-1,72 (m, 2H), 1,28-1,24 (m, 2H), 1,09 (t, J=7,1 Hz, 0,98H), is 0.96 (t, J=7,1 Hz, 2,2H)
245359,11,6(500 MHz, MeOD, CT, contains conformers) 8,82-8,72 (m, 0,26H), and 8.50 (m, 1,67H), 8,43-8,31 (m, 1,84H), 8,25 (user., 0,26H), 8,10 (d, J=6,4 Hz, 0,72H), 6,70-of 6.65 (m, 1H), ,48-4,25 (m, 2H), 3,49-3,37 (m, 2H), 1,80 (m, 2H), 1.27mm (user., 2H)
246377,11,65(500 MHz, MeOD, CT, contains conformers) 8,77 (DD, J=2,8, and 9.1 Hz, 0,28H), to 8.57-to 8.45 (m, 2,29H), 8,32 (d, J=1.5 Hz, 1H), 8,27 compared to 8.26 (m, 0,29H), 8,11 (DD, J=4,0, 7,1 Hz, 0,74H), 6,72 (d, J=7,3 Hz, 0,29H), of 6.68 (d, J=7,1 Hz, 0,73H), of 5.89-the ceiling of 5.60 (m, 1H), 3,59-3,47 (m, 2H), 1,80 to 1.76 (m, 2H), 1,34-of 1.30 (m, 2H)
247355,11,6(500 MHz, MeOD, CT, contains conformers) 8,77 (DD, J=2,8, 9,3 Hz, 0,28H), 8,56-of 8.50 (m, 1,68H), 8,31 (d, J=1.5 Hz, 1H), compared to 8.26 (DD, J=4,4, 7,2 Hz, 0,28H), 8,10 (DD, J=4,4, 7,2 Hz, 0,75H), 6,72-6,70 (m, 0,29H), to 6.67 (m, 0,72H), 3,18-of 3.12 (m, 2H), 1.77 in-1,72 (m, 2H), 1,50 (m, 0,6H), to 1.38 (m, 1,57H), 1,29-1,24 (m, 2H), 0,87 (t, J=7,4 Hz, 0,92H), of 0.67 (t, J=7,3 Hz, 2,2H)
248are 460.92,7(DMSO-d6) of 12.4 (s, 1H); 8,9 (m, 1H); 8,65 (s, 1H); 8,35 (d, 1H); to 8.3 (s, 1H); or 8.2 (m, 1H), and 5.5 (d, 1H)and 4.9 (DD, 1H); from 4.3 to 3.8 (m, 4H); and 2.7 (m, 1H); 2,2-2,0 (m, 1H)
249478,92,9(DMSO-d6) of 12.4 (s, 1H); 8,9 (m, 1H); 8,65 (s, 1H); and 8.4 (d, 1H); to 8.3 (m, 1H); or 8.2 (m, 1H); of 5.05 (m, 1H); 4,3 (m, 2H); 3.9 to (m, 2H); 3,0 (m, 1H); 2,5 (m, 1H)
2503731,59(500 MHz, MeOD) 8,81 (d, J=2.1 Hz, 1H), 8,45 (s, 1H), at 8.36 (d, J=2.1 Hz, 1H), to 7.99 (s, 1H), 3,98 (s, 1H), 3,19 (kV J=7.2 Hz, 2H), 2,31 (s, 3H), 1,79 (s, 6H), of 0.90 (t, J=7.2 Hz, 3H)
2513911,61(500 MHz, DMSO) 13,07-of 12.73 (user., 1H), 8,83 (d, J=2.0 Hz, 1H), 8,55 (s, 1H), at 8.36 (d, J=1.8 Hz, 1H), 8,12 (s, 1H), 8,09 (user., 1H), 4,18 (t, J=5,1 Hz, 1H), 4,08 (t, J=5,1 Hz, 1H), 3.27 to (kV, J=5.3 Hz, 1H), 3,22 (kV, J=5.3 Hz, 1H), 2,24 (s, 3H), of 1.65 (s, 6H)
252409,11,69(500 MHz, MeOD) 8,79 (d, J=2.1 Hz, 1H), 8,44 (s, 1H), of 8.37 (d, J=2.0 Hz, 1H), 8,32 (user., 1H), 8,01 (s, 1H), 5,58 (m, 1H), 3,48-of 3.42 (m, 2H), 2,31 (s, 3H), 1,79 (s, 6H)
253427,11,77(500 MHz, MeOD) 8,78 (s, 1H), 8,46 (user., 1H), 8,42 (s, 1H), 8,35 (s, 1H), 8,01 (s, 1H), 3,85-3,82 (m, 2H), 2,32 (s, 3H), 1,79 (s, 6H). Identified peak at d 1,94.
2543871,66(500 MHz, MeOD) 8,81 (d, J=2.0 Hz, 1H), 8,45 (s, 1H), at 8.36 (d, J=2.0 Hz, 1H), 8,00 (s, 1H), 3,98 (s, 1H), 3,12-to 3.09 (m, 2H), 2,31 (s, 3H), 1,79 (s, 6H), of 1.33 (m, 2H), 0.67 and (t, J=7.4 Hz, 3H)
2553442(500 MHz, MeOD) 8,79 (user., 0,27H), 8,59 (d, J=8,9 Hz, 0,69H), 8,53 (s, 1H), of 8.47 (s, 1H), 8,24 (s, 1H), 3,17 (m, 2H), of 1.66 (s, 6H), 1,08 (user., 0,93H), of 0.91 (m, 2,14H)
256385 1,9
2574031,8
2584212
259399,12
2604282,7(500 MHz, MeOD) 9,07 (s, 0,33H), 8,78 (s, 0,56H), to 8.57-8,31 (m, 3,58H), 3,88 (m, 2H), 2,18 (m, 1H), 2,05-2,03 (m, 1H), of 1.66 (m, 3H), of 0.96 (t, J=7.4 Hz, 3H)
2614122,5(500 MHz, MeOD) 8,80 (m, 0,35H), 8,56-of 8.47 (m, 3,2H), 8,40 (m, 0,36H), compared to 8.26 (m, 1H), 3,85 (m, 2H), 2,18 (m, 1H), 2,04 (m, 1H), of 1.66 (m, 3H), of 0.96 (t, J=7.5 Hz, 3H)
2623602,1
2634452,4(DMSO-d6) 12,3 (users, 1H); 8,9 (m, 1H); and 8.4 (d, 1H); 8,35 (d, 1H); of 8.25 (s, 1H); or 8.2 (s, 1H), and 5.5 (d, 1H)and 4.9 (DD, 1H); 4,3-a 3.75 (m, 4H); and 2.7 (m, 1H); 2,2-2,0 (m, 1H)
2644632,8(DMSO-d6) 12,3 (users, 1H); 8,9 (DD, 1H); 8.4 to 8, (m, 2H); 8,25 to 8.2 (m, 2H); of 5.05 (d, 1H); of 4.35 (m, 2H); 3.9 to (m, 2H); 3,0 (m, 1H); 2,5 (m, 1H)
265432,22,6(CD3CN) the 10.40 (s, 1H), 8,80 (s, 1H), 8,29 (m, 3H), 6,97 (m, 1H), 5,22 (m, 1H), 4,79 (m, 1H), 4,43 (dt, 2H), 3,49 (dt, 2H), 2,54 (m, 1H), 2,43 (m, 1H), 2,39 (m, 1H), 2,22 (m, 1H)
266450,22,7(CD3CN) 10,48 (s, 1H), 8,79 (s, 1H), 8.30 to (m, 3H), 7,01 (t, 1H), 5,90 (TT, 1H), 5,24 (m, 1H), of 5.83 (m, 1H), 3,60 (m, 2H), 2,53 (m, 1H), 2,42 (m, 1H), a 2.36 (m, 1H), of 2.21 (m, 1H)
267468,22,86(CD3CN) 10,38 (s, 1H), 8,79 (s, 1H), 8,29 (m, 3H), 7,21 (t, 1H), total of 5.21 (m, 1H), a 4.83 (m, 1H), 3,99 (m, 1H), 3,86 (m, 1H), of 2.51 (m, 1H), 2,45 (m, 1H), 2,35 (m, 1H), measuring 2.20 (m, 1H)
268of 450.11,88
269of 450.11,93
270374,12,3(500 MHz, MeOD) 9,05 (s, 0,32H), 8,84 (s, 0,65H), 8,53 (s, 1H), 8,43 (s, 1H), 8,29 (s, 1H), 3.27 to-3,17 (m, 2H), 2,18 is 2.10 (m, 1H), 2,07 is 2.00 (m, 1H), 1,64 (m, 3H), of 1.08 (m, 1H), of 0.95 (t, J=7,4 Hz, 5H)
2713582,1 (500 MHz, MeOD) 8,78 (user., 0,33H), 8,58 (d, J=8.6 Hz, 0,81H), 8,53 (s, 1H), 8,46 (s, 1H), 8,24 (s, 1H), 3,26-and 3.16 (m, 2H), 2,17 and 2.13 (m, 1H), 2,01 (m, 1H), 1,71-of 1.57 (m, 3H), of 0.95 (t, J=7.5 Hz, 6H)
2724502,4(500 MHz, MeOD) 8,87 (s, 1H), 8,56 (ushort, 1H), 8,53 (s, 1H), 8,43 (d, J=6,9 Hz, 1H), 8,35 (d, J=2.2 Hz, 1H), 6,91 (d, J=6,7 Hz, 1H), 5,09 (apparent d, 1H), 4,86 (apparent d, 1H), was 4.02-of 3.96 (m, 1H), a 3.87-3,81 (m, 1H), 2,03 (m, 1H), 1,88 and 1.80 (m, 2H), 1,48 was 1.43 (m, 1H), 0,00 (TMS)
273464,12,5(500 MHz, MeOD) 8,86 (d, J=2.1 Hz, 1H), 8,44 (t, 1H), 8,40 (s, 1H), of 8.37 (d, J=6,6 Hz, 1H), 8,31 (d, J=2.2 Hz, 1H), 6,52 (users, 1H), around 4.85 (s, 2H), 3,93 (m, 2H), 2,86 (m, 2H), 2,72 (m, 2H, in), 2.25 (m, 1H), 2.06 to (m, 1H), 0,00 (TMS)
2744282,4(DMSO-d6) (mixture of rotatores approximately 1.3:1): 12,6 (m, 1H); 9,0 (DD, 0,6H); 8,8 (DD, 0,4H); 8,65 to 8.3 (m, 4H); 5,6-to 5.35 (m, 1H); 4,8 (t, 0,6H); 4,7 (t, 0,4H); 4.35 the (m, 0,4H); 4,2 (m, 0,6H) of 4.1 to 3.7 (m, 3H); 2,75-2,6 (m, 1H); 2,25-2,05 (m, 1H)
2754282,3(DMSO-d6) (mixture of rotatores approximately 1.3:1): 12,6 (m, 1H); 8,7-of 8.25 (m, 5H); 5,5-to 5.3 (m, 1H)and 4.9 (d, 0,6H); at 4.75 (d, 0,4H); to 4.1 to 3.7 (m, 4H); 2,75-2,6 (m, 1H); 2,4-2,3 (m, 1H)
2764442,52774732,3(DMSO-d6) 12,35 (m, 1H); 8,75 and 8.6 (m, 2H); 8,35-of 8.15 (m, 3H); 4.75 in (m, 1H); about 4.0 to 3.7 (m, 4H); 2,3 (m, 1H); 2.0 (m, 1H); to 1.35 (s, 3H)
2784872,5(DMSO-d6) 12,35 (m, 1H); 8,75 and 8.6 (m, 2H); 8,35-of 8.15 (m, 3H); 4.75 in (m, 1H); about 4.0 to 3.7 (m, 4H); 2,3 (m, 1H); 2.0 (m, 1H); 1,6 (m, 2H); 1,0 (m, 3H)
279468,11,59
2804551,5(DMSO-d6) of 13.05-12,9 (m, 1H); 8,8-of 8.25 (m, 5H); to 6.75 (m, 0,7H); 6,35 (m, 0,3H); 4.95 points (m, 0,7H); at 4.75 (m, 0,3H); 4,05-3,6 (m, 4H); 2,4-2,1 (m, 2H); 1,4 (m, 3H)
2814691,6(DMSO-d6) 13,0-12,9 (m, 1H); 8,8-of 8.25 (m, 5H); 6,7 (m, 0,7H); 6,3 (m, 0,3H); of 5.05-to 4.8 (m, 1H); of 4.1 and 3.6 (m, 4H); 2,4-2,05 (m, 2H); 1,75-1,6 (m, 2H); 1,05 to 0.9 (m, 3H)
282392,92,7(500 MHz, MeOD) 8,80 (d, J=2.3 Hz, 1H), 8,35 (s, 1H), with 8.33 (s, 1H), 8,28 (d, J=2.3 Hz, 1H), 3,19 (kV, J=7.2 Hz, 2H), 1,74 (s, 6H), of 0.93 (t, J=7.2 Hz, 3H)
283410,92,7(500 MHz, MeOD) 8,81 (d, J=2.3 Hz, 1H), 8,35 (s, 1H), with 8.33 (s, 1H), 8,28 (d, J=2.2 Hz, 1H), 8,19-8,17 (m, 0,33H), to 4.23 (dt, J=47,4, 5,1 Hz, 2H), 3,42 (dt, J=25,5, 5,1 Hz, 2H), of 1.75 (s, 6H)
284439,91,9(500 MHz, MeOD) 8,72 (s, 1H), 8,57 are 8.53 (m, 2H), to 8.45 (s, 1H), compared to 8.26 (s, 1H), 3,85-of 3.78 (m, 2H), of 1.75 (s, 6H)
2854282,8(500 MHz, MeOD) 9,07 (d, J=1.9 Hz, 0,53H), 8,81-8,78 (m, 0,84H), 8,55 (d, J=10.5 Hz, 1H), 8,45 (d, J=15.6 Hz, 1H), 8.30 to (s, 1H), 4,56-to 4.52 (m, 1H), 4,06-4,00 (m, 1H), 3,89-a-3.84 (m, 1H), 2,34-of 2.24 (m, 1H), 1,12-of 1.06 (m,6H)
286428,92,9(500 MHz, MeOD) 8,79 (d, J=2.3 Hz, 1H), at 8.36 (s, 1H), 8,33-of 8.28 (m, 2,8H), 5,64 (TT, J=56,5 and 4.2 Hz, 1H), 3,51-of 3.43 (m, 2H), 1,74 (s, 6H)
287446,93(500 MHz, MeOD) 8,78 (d, J=2.3 Hz, 1H), 8,45 (t, J=6,1 Hz, 1H), 8.34 per (s, 1H), 8,25 (d, J=3.3 Hz, 2H), 3,86-3,44 (m,2H), 1,73 (s, 6H)
288437,962,9(500 MHz, MeOD) 9,24 (m, 0,5H), 8,87-8,73 (m, 0,27H), 8,62-8,29 (m, 2,7H), 7,76-7,37 (m, 0,46H), 3,86 is 3.76 (m, 2H), 1,80 of 1.50 (m, 6H)
289403,5 2,9(DMSO-d6) 12,3 (users, 1H); to 8.7 (s, 1H); from 8.3 to 8.2 (m, 2H); 8,1 (s, 1H); the 7.65 (m, 1H); 4.1 and of 3.85 (m, 2H); 3.15 and is 2.9 (m, 2H); from 2.1 to 1.9 (m, 4H); 1,6 (s, 3H); 0,8 (m, 3H)
290421,52,9(DMSO-d6) 12,3 (users, 1H); to 8.7 (s, 1H); of 8.25 (m, 2H); 8,1 (s, 1H); to 7.95 (m, 1H); 4,35-of 4.05 (m, 3H); 3,95 (m, 1H); 3,35-3,2 (m, 2H); from 2.1 to 1.9 (m, 4H); 1,6 (s, 3H)
291439,53(DMSO-d6) 12,3 (users, 1H); to 8.7 (s, 1H); to 8.3 (m, 2H); 8,15-with 8.05 (m, 2H); 5,8 (DD, 1H); to 4.1 (m, 1H); 3.9 to (m, 1H); 3,4 (m, 2H); from 2.1 to 1.9 (m, 4H); 1,6 (s, 3H)
292417,12,7(DMSO-d6) 12,3 (s, 1H); to 8.7 (s, 1H); of 8.25 (m, 2H); 8,1 (s, 1H), and 7.7 (DD, 1H); to 4.1 (m, 1H); 3.9 to (m, 1H); 3.1 to the 2.8 (m, 2H); from 2.1 to 1.9 (m, 4H); 1,6 (s, 3H); 1,35-of 1.15 (m, 2H); 0,6 (m, 3H)
293455,12,09
294483,12,42
2954532,02
296410,31,75
297/td> 407,12,3(DMSO-d6): 12,45 (users, 1H); to 8.7 (s, 1H); and 8.4 to 8.2 (m, 4H), and 5.5 (d, 1H); 4.75 V (t, 1H); 4,25 to-3.9 (m, 2H); and 3.2 to 3.0 (m, 2H); 2,6-2,0 (m, 2H); 1,0 (m, 3H)
298UAH 421,22,5(DMSO-d6) 12,4 (users, 1H); to 8.7 (s, 1H); and 8.4 to 8.2 (m, 4H), and 5.5 (d, 1H); 4.75 V (t, 1H); 4,25 to-3.9 (m, 2H); and 3.8 (m, 1H); 3,0 (m, 1H); 2,3-2,0 (m, 2H); 1,45-1,2 (m, 2H); 0.75 in (m, 3H)
299425,12,3(DMSO-d6) 12,4 (users, 1H); to 8.7 (s, 1H); to 8.6 (m, 1H); 8,35 to 8.2 (m, 3H), and 5.5 (d, 1H); and 4.8 (t, 1H); of 4.45 (m, 1H); from 4.3 to 3.9 (m, 3H); 3,3 (m, 1H); to 2.7 (m, 1H); 2,3-2,0 (m, 2H)
300443,12,5(DMSO-d6) 12,4 (users, 1H); from 8.8 to 8.6 (m, 2H); and 8.4 to 8.2 (m, 3H); at 5.9 (DD, 1H), and 5.5 (d, 1H); is 4.85 (t, 1H); from 4.3 to 3.9 (m, 2H); 2,75-2,0 (m, 4H)
301441,12,6
302465,21,9
303411,21,8
304447,21,8
305425,21,9
306437,21,8
307to 455.22
308437,21,9
309457,11,8(DMSO-d6) 12,3 (users, 1H); is 8.75 (s, 1H); 8,35 to 8.2 (m, 3H); 8,1 (s, 1H); 6,45 (m, 1H); of 5.55 (m, 1H); from 4.2 to 3.7 (m, 4H); 2,4-2,2 (m, 2H); 1,7 (s, 3H)

Table 6
Conn.No.M+HRtNMR
310409,001,80DMSO-d6: 12,25 (users, 1H); 8,8 (m, 1H); to 8.7 (m, 1H); 8,35 to 8.3 (m, 2H); or 8.2 (m, 1H); to 7.2 (m, 1H); 4,85 (d, 1H); 4.0 a (m, 1H); 3.95 to to 3.8 (m, 3H); 2,35 (m, 1H); 2,1-of 1.85 (m, 3H)
311409,001,80DMSO-d6:12,25 (users, 1H); 8,8 (m, 1H); to 8.7 (m, 1H); 8,35 to 8.3 (m, 2H); or 8.2 (m, 1H); to 7.2 (m, 1H); 4,85 (d, 1H); 4.0 a (m, 1H); 3.95 to to 3.8 (m, 3H); 2,35 (m, 1H); 2,1-of 1.85 (m, 3H)
312444,902,20500 MHz DMSO-d6 at 60°C: 12,8 (osirm, 1H), cent to 8.85(m, 1H), 8,8(m, 1H), 8,65 (s, 1H), 8.3 (l, 1H), 8,25 (1H), 7,75 (osirm, 1H), and 7.3 (d, 1H), around 4.85 (m, 1H), 3,9 (m, 2H), 3.0 a (DM, 2H), 2,2 (s, 3H)
313495,002,30
314438,002,00500MHz MeOD-d4: 8,68 (m, 1H), 8,5 (s, 1H), 8,35 (s, 1H)and 8.1 (d, 1H), of 6.71 (d, 1H), Android 4.04 (m, 1H), 3,9 (m, 1H), and 2.7 (t, 2H), 2,4 (m, 1H), 2,24 (m, 1H)
315456,002,80500MHz MeOD-d4: 8,66 (s, 1H), and 8.4 (s, 1H), 8,35 (d, 1H), 8.3 (l, 1H), the 5.45 (m, 1H, partially exchange rate.), 5,04 (m, 1H), 4,01 (m, 1H), 3,93 (m, 1H), 2,73 (t, 2H), 2,5 (m, 1H), 2,32 (m, 1H)
316488,002,10500MHz MeOD-d4: 8,77 (s, 1H), 8,71 (s, 1H), and 8.5 (d, 1H), 8,35 (s, 1H), 8,02 (t, 1H), 7,88 (d, 1H), 7,71 (t, 1H), 5.25 in (m, 1H), was 4.02 (m, 1H), 3,90 (m, 1H), 2,73 (t, 2H), and 2.6 (m, 1H), 2,5 (m, 1H)
317482,002,70DMSO d5 12,8 (users, 1H); 8,7 (users, 1H); and-8.5 (m, 2H); and 8.4 (s, 1H), and 7.7 (s, 1H); 6,9 (C, 1); of 4.8 (m, 1H); and 3.8 (m, 2H); 3,6 (m, 3H); 29 (m, 2H); 2.0 (m, 2H); 1,2 (m, 2H)
318496,102,90DMSO d5 12,6 (users, 1H); 8,8 (users, 1H); to 8.7 (m, 2H); and 8.4 (s, 1H), and 7.7 (s, 1H); 6,9 (s, 1H); and 4.8 (m, 1H); and 3.8 (m, 2H); 3,6 (m, 2H); 3,5 (m, 5H); 2.0 (m, 2H); 1,2 (t, 3H)
319510,103,10DMSO d5 12,6 (users, 1H); 8,9 (users, 1H); to 8.6 (m, 2H); and 8.4 (s, 1H); 7,8 (s, 1H); 4.7 in (m, 1H); 3.9 to (m, 2H); 3,7 (m, 2H); 3,3 (m, 2H); 2.0 (m, 2H); 1,5 (m, 2H); 0,9 (t, 3H)
320508,103,00DMSO d5 12,6 (users, 1H); 8,8 (users, 1H); to 8.6 (m, 2H); and 8.4 (s, H), and 7.7 (s, 1H); 4.7 in (m, 1H); 4.0 a (m, 2H); and 3.8 (m, 2H); 2,9 (s, 1H); 2.0 (m, 2H); 1,9 (m, 3H); 0,8 (t, 2H); 0,6 (m, 1H)
321424,201,50(d4-methanol) 8,86 (d, 1H), 8,40 (d, 1H), 8,29 (d, 1H), of 8.25 (s, 1H), 7,30 (DD, 1H), 5,65 (users, 1H), to 4.62 (d, 1H), 4,03-.35 (m, 7H)
322403,102,10DMSO-d6: 12,5 (s, 1H); to 8.7 (s, 1H); to 8.3 (m, 3H); to 7.9 (d, 1H); with 4.65 (d, 1H); 3,95 (m, 1H); of 3.85 (m, 2H); to 2.25 (m, H); 2.0 (m, 3H); of 1.05 (m, 3H)
323395,101,70500 MHz, DMSO-d6) d 12,31 (s, 1H), 8,79 (s, 1H), 8,65 (d, J=7.8 for the C, 1H), 8,61 (t, J=6.3 Hz, 1H), scored 8.38 (d, J=4,1 Hz, 1H), 8,29 (DD, J=4,7, 1.5 Hz, 1H), 8,24 (s, 1H), 7,15 (DD, J=7,9, 4,7 Hz, 1H), 3,81 (m, 2H), 1.57 in (t, 2H), 1,19 (t, 2H)
324385,201,70DMSO-d6: 13,0 (users, 1H); to 8.7 and 8.6 (m, 2H); and 8.4 (m, 1H); to 8.3 (m, 1H); 8,15 (d, 0,3H); 8.0 a (l, 0,7H); to 6.75 (d, 0,7H); and 6.3 (d, 0,3H); 4,85 (d, 0,7H); 4,5 (0,3H); 4,0-of 3.85 (m, 1H); 3,8-3,6 (m, 2H); 2,35 (m, 1H); is 2.05 (m, 3H); 1,1 (DD, 2H); of 0.95 (DD, 4H)
325399,102,10DMSO-d6: 12,4 (users, 1H); 8,65 (s, 1H); 8,55 (m, 1H); to 8.3 (m, 2H); of 8.25 (s, 1H); 4.7 in (d, 1H); 3,95 (m, 1H); of 3.85 (m, 2H); and 3.8 (m, 1H); 3,0 (s, 1H); to 2.25 (m, 1H); 2.0 (m, 3H)
326452,393,60CD3OD/CDCl3: 1,68 (6H, s), and 2.14 (2H, m)to 3.38 (2H, m), 7,98 (1H, t), by 8.22 (1H, s), of 8.28 (1H, s), 8,54 (1H, s), 8,83 (1H, s)
327438,41of 3.56CD3OD/CDCl3: to 1.70 (6H, s), 3,81 (2H, m), to 7.59 (1H, m), by 8.22 (1H, s), compared to 8.26 (1H, s), to 8.45 (1H, t), 8,58 (1H, s), 8,81 (1H, s)
328404,343,23DMSO-d6/CD3OD/CDCl3: was 1.58 (6H, s), 3,12 (1H, in), 3.75 (2H, m), 7,21 (1H, m), 8,19 (1H, s), of 8.28 (1H, m), to 8.45 (1H, t), 8,69 (1H, s)8,71 (1H, d)
329470,353,24 MeOD of 1.75 (6H, s)of 2.16 (2H, m)to 3.35 (2H, m), a 8.34 (2H, s), 8,48 (1H, s), is 8.75 (1H, s), cent to 8.85 (1H, s)
330381,201,50DMSO-d6: 12,8 (s, 1H); 8,7-or 8.5 (m, 3H); 8,4-of 8.25 (m, 2H); 6,7 (m, 0,7H) 6,3 (m, 0,3H); and 4.8 (m, 0,7H); 4,6 (m, 0,3H); 4,0-3,6 (m, 4H); 2.95 and (m, 1H); 2,35 (m, 1H); is 2.05 (m, 3H)
331383,201,70DMSO-d6: 12,9 (users, 1H); of 8.8 (s, 1H); to 8.7 (s, 1H); and 8.6 (s, 1H); and 8.4 (s, 1H); 8,15 (m, 1H); 6.8 cm (s, 1H); 4.7 in (s, 1H); 4,05-of 3.85 (m, 2H); 3,1 (s, 1H); to 2.25 (m, 1H); 1,1-of 0.95 (m, 5H)
332387,402,00DMSO-d6: 12,95 (users, 1H); to 8.7 (s, 1H); and 8.6 (s, 1H); and 8.4 (C, H); 8,15 (m, 2H); at 6.8 (s, 1H); 4,6 (s, 1H); 3.9 to (m, 1H); to 2.25 (m, 1H); 1,1-of 0.95 (m, 12H)
333400,202,00DMSO-d6: 12,35 (users, 1H); 8,77 (DD, 1H); 8,65 (s, 1H); S.3 (m, 2H); or 8.2 (s, 1H); 4.7 in (d, 1H); to 4.1 (m, 2H); 3,95 (m, H); and 3.8 (m, 1H); to 2.25 (m, 1H); 2.0 (m, 3H)
334382,201,50DMSO-d6: 12,9 (users, 1H); 8,95 (DD, 1H); 8,75 (m, 0,4H); to 8.6 (m, 1,6H); and 8.4 to 8.3 (m, 2H); 6.75 in (d, 0,8H); 6,35 (d, D.2H)and 4.9 (d, 0,8H); the 4.65 (d, 0,2H); from 4.2 to 4.0 (m, 2H); and 3.8 (m, 1H); 3,6 (m, 1H); to 2.35 (m, 1H); 2.1 to 2.0 (m, 3H)
335387,402,00
336403,401,90
337385,401,80
338511,202,50DMSO-d6: at 8.60 (m, 2H); 8,30 (s, 1H); 8,23 (users, 1H); 5,50 (m, 2H); to 4.38 (m, 2H); 4,10 (m, 2H); to 3.38 (m, 4H); 2.50 each (m, 1H); 1,90-2,00 (m, 3H); 1.32 to (t, 3H)
339421,302,00
340455,202,10
341439,201,90DMSO-d6: 13,0 (users, 1H); 8,55 (m, 1H); to 8.45 (m, 1H); 8,35 (m, 1H); 6,72 (m, 1H); ceiling of 5.60 (m, 1H); 4,20-3,70 (m, 5H); 3,30 (s, 3H); 2,00 (m, 3H)
342457,102,40DMSO-d6: 8,30 (m, 1H); 8.30 to (m, 3H); of 7.70 (m, 1H); of 5.40 (m, 1H); 4,20-3,70 (m, 5H); 3,30 (s, 3H); 2,00 (m, 3H)
343379,202,04(500 MHz, DMSO) 12,83 (s, 1H), of 9.30 (s, 1H), 8,61 (t, J=7,6 Hz, 2H), of 8.37 (d, J=4.5 Hz, 1H), 8,17 (d, J=7,1 Hz, 1H), 7,27 (DD, J=4,7, ,7 Hz, 1H), 6,69 (d, J=6,9 Hz, 1H), 3,79 is 3.76 (m, 2H), and 1.63 (s, 6H)
344366,101,87DMSO-d6: 12,5 (m, 1H); 8,95 (m, 0.5 H); 8,78 (m, 0,5H); 8,65 (m, 0,5H); charged 8.52 (m, 0,5H); 8,48 (s, 1H); 8,32 is 8.25 (m, 2H); 8,30 (m, 1,5H); to 8.12 (m, 1H); 7,20 (m, 1H); of 4.54 (m, 1H); of 3.80 (m, 2H); 1.32 to (m, 3H)
345411,201,90(500 MHz, DMSO-d6) 12,20 (s, 1H), 8,67 (DD, J=1,4, 7.9 Hz, 1H), 8,43 (t, J=6.2 Hz, 1H), 8,32-of 8.28 (m, 2H), 8,10 (s, 1H), 7.5 (users, 1H), 7,20 (DD, J=4,7, 7.9 Hz, 2H), 3,81-to 3.73 (m, 2H), 2,20-of 2.16 (m, 1H), 1,99-1,95 (m, 1H), and 1.56 (s, 3H), of 0.82 (t, J=7.5 Hz, 3H)
346393,201,60(DMSO-d6, 300 MHz) 11,95 (users, 1H), and 8.7 (d, 1H), 8,25 (m, 2H), 8,12 (d, 1H), 8,02 (d, 1H), 7,28 (s, 1H), 7,13 (DD, 1H), 6,38 (userd, 1H, in), 3.75 (m, 2H), 2.06 to (m, 1H)and 1.83 (m, 1H), 1,46 (s, 3H), and 0.8 (t, 3H);
347425,272,25(500 MHz, MeOD) 8,87 (d, J=8,1 Hz, 1H), at 8.60 (t, 1H), at 8.36 (d, 1H), 8,27 compared to 8.26 (m, 2H), 7,39 (DD, J=5.0 and 8.0 Hz, 1H), 3,86 (m, 2H), to 2.29 (t, J=7.5 Hz, 4H), of 0.87 (t, J=7.5 Hz, 6H)
348407,201,67(500 MHz, DMSO-d6) d 12,81 (s,1H), of 8.92 (s, 1H), 8,68-to 8.57 (m, 3H), scored 8.38 (d, J=3.3 Hz, 1H), 8,17 (d, 1H), 7,30-7,27 (m, 1H), PC 6.82 (d, 1H), 3,82-3,74 (m, 2H), 2.26 and-a 2.12 (m, 2H), 2,12-2,05 (m, 2H), 0,82-0,78 (m, 6H)
349373,401,74
350407,401,72CD3CN: of 9.89 (s, 1H), 8,79 (d, 1H), 8,27 (m, 1H), 8,19 (d, H), 8,10 (d, 1H), 7,18 (m, 2H), of 6.49 (d, 1H), 5,80 (s, 1H), 3,97 (m, 1H)and 3.59 (m, 1H), 1,53 (s, 3H), of 1.02 (DD, 6H)
351425,401,40DMSO-d6: 12,2 (users, 1H); cent to 8.85 (m, 1H); to 8.7 (d, 1H); to 8.3 (m, 2H); 8,15 (m, 1H); to 7.2 (m, 1H)and 4.9 (DD, 1H); of 4.45 (m, 1H); 4,05 to 3.7 (m, 4H); 2,3 (m, 1H); 1,95 (m, 1H)
352407,401,40DMSO-d6: 12,8 (users, 1H); 9,1 (m, 1H); to 8.7 and 8.6 (m, 2H); 8,45 to 8.3 (m, 2H); to 7.4 (m, 0,3H); to 7.3 (m, 0,7H); 6,85 (d, 0,7H); 6,35 (d, 0,3H); 5,1 (DD, 0,7H); and 4.8 (DD, 0,3H); 4,5 (m, 1H); from 4.2 to 3.6 (m, 4H); 2,4 (m, 1H); 2,1 (m, 1H)
353401,401,95
354387,401,87
355369,301,69
356409,402,25
357423,301,90
358405,401,80
359399,101,80DMSO-d6: 12,7 (users, 1H); of 8.8 (s, 1H); 8,7-or 8.2 (s, 3H); 6,5 (m, 0,8H); 6,2 (m, 0,2H); 4,2 (m, 0,3H); 4.0 a (m, 0,7H); 3,8-3,6 (m, 2H); 3,4 (m, 1H); 3,2 was 3.05 (m, 1H); to 2.7 (m, 2H); 2,2 (m, 3H); is 2.05 (m, 1H); 1,7 (s, 2,7H); 1,6 (s, 0,3H); 1,0 (m, 0,3H); 0,7 (m, 2,7H)
360379,201,60DMSO-d6: 11,92 (m, 1H); 8,72 (users, 1H); by 8.22 (m, 1H); with 8.05 (m, 2H); 7,42 (m, 1H); 7.18 in (m, 1H); 6,32 (users, 1H); 5,22 (m, 1H); 4,20 (m, 2H); of 3.32 (s, 3H); of 1.35 (m, 3H)
361397,101,90DMSO-d6: 11,9 (m, 1H); 8,55 (m, 1H); of 8.25 (m, 1H); 8,18 (m, 1H); 7,98 (m, 1H); the 7.65 (m, 1H); to 7.15 (m, 1H); further 5.15 (m, 1H); 4,18 (m, 2H); 3.30 is (C, 2,5H); 2,90 (s, 0,5H); of 1.35 (m,3H)
362357,101,51
363343,101,40
364361,101,41
365391,101,85
366393,101,60(500 MHz, DMSO) 12,83 (s, 1H), 9,2 (users, 1H), 9,07 (s, 1H), 8,68 (d, J=7.8 Hz, 1H), 8,61 (s, 1H), 8,42 (d, J=4,6 Hz, 1H), 8,15 (d, J=7,1 Hz, 1H), 7,35 (DD, J=4,8, and 7.8 Hz, 1H), 6,86 (d, J=7.2 Hz, 1H), a 4.86 (t, J=6.3 Hz, 1H), 4,12-Android 4.04 (m, 1H), 3,90-of 3.85 (m, 1H), 2,31 (t, J=6,6 Hz, 1H), of 1.02 (d,6H)
367410,912,10(500 MHz, DMSO) 12,36 (s, 1H), 8,86 (t, J=6.3 Hz, 1H), 8,72 (DD, J=1,4, 7.9 Hz, 1H), 8,35-8,31 (m, 3H), 7,86 (s, 1H), 7,26 (DD, J=4,7, 7.9 Hz, 1H), 4,60 (t, J=7,6 Hz, 1H), 4.04 the-of 3.96 (m, 1H), 3,90-a 3.83 (m, 1H), 2,28 (TD, J=a 13.8, 6.9 Hz, 1H), of 1.02 (t, 6H),
368474,001,60
369490,001,80
370504,101,90
371477,001,50
372491,001,60
373409,001,40DMSO-d6: 12,9 (m, 1H); 8,95 cent to 8.85 (m, 1H); 8,8-8,65 (m, 2H); 8,55 to 8.3 (m, 2H); to 7.4 (m, 0,3H); to 7.3 (m, 0,7H); 6,85 (d, 0,7H); and 6.5 (d, 0,3H); of 5.55 (d, 1H); 5,2 (d, 0,7H); 5,0 (d, 0,3H); 4,3 to 3.8 (m, 4H); 2,8-2,6 (m, 1H); 2,5-2,4 (m, 1H)
374427,001,60DMSO-d6: 12,8 (users, 1H); 9,1 (m, 1H); 8,7-8,35 (m, 4H); and 7.3 (m, 1H); to 6.8 (m, 0,7H); 6,5 (m, 0,3H); 5,3 (m, 0,7H); 5,1 (m, 0,3H); 4,3 (m, 2H); 3.9 to (m, 2H); 3.15 in (m, 1H); to 2.65 (m, 1H)
375409,001,40DMSO-d6: 12,9 (m, 1H); 9,25 is 9.1 (m, 1H); 8,75 and 8.6 (m, 2H); 8,45-8,35 (m, 2H); to 7.4 (m, 0,3H); to 7.3 (m, 0,7H); 6,9 (d, 0,7H); and 6.3 (d, 0,3H); 5,6 (d, 1H); 5,1 (DD, 0,7H)and 4.9 (DD, 0,3H); 4,5 (m, 0,3H); 4,2 (m, 0,7H); from 4.3 to 3.6 (m, 3H); 2,8 (m, 1H); 2,3-2,1 (m, 1H)
376343,101,37
377361,101,48
378325,101,37
379339,101,49
380 397,101,60
381379,101,99
382429,351,70500 MHz, MeOD) 8,83 (d, J=8 Hz, 2H), 8,68 (s, 1H), 8,59-to 8.57 (m, 2H), 8,42-to 8.41 (m, 1H), 8.07-a 8,03 (m, 1H), of 7.90 (DD, J=4,4, 8,2 Hz, 1H), to 7.77-7,73 (m, 1H), 7,41 (m, 1H), 3,83 is 3.76 (m, 2H), of 1.88 (s, 6H)
383423,002,10DMSO-d6: 12,3 (s, 1H); to 8.7 (d, 1H); 8,45 is 8.25 (m, 3H); 8,15 (s, 1H); 7,25 (m, 1H); 4,15 (m, 1H); 4.0 a (m, 1H); of 3.85 (m, 1H); 3,7 (m, 1H); is 2.05 (m, 4H); a 1.75 (s, 3H)
384405,101,50DMSO-d6: 12,8 (s, 1H); from 8.8 to 8.2 (m, 5H); to 7.4 (m, 0,2H); 7,25 (m, 0,8H); to 6.8 (d, 0,8H); x 6.15 (d, 0,2H); 4,2 (m, 0,2H); 3,95 (m, 0,8H); and 3.8 (m, 3H); 2,2-2,0 (m, 4H); 1,8-1,6 (m, 3H)
385488,001,70
386380,001,90DMSO-d6: 12,4 (users, 1H); of 8.92 (m, 0,5H); to 8.62 (m, 0,5H); and 8.50 (s, 0,5H); 8,42 (s, 0,5H); 8,40-to 8.20 (m, 4H); 7,20 (m, 0,5H); to 7.15 (m, 0,5H); and 3.72 (m, 2H); to 1.45 (m, 6H)
387421,101,50/td> (500 MHz, DMSO) 12,81 (s, 1H), 8,65-8,56 (m, 3H), at 8.36 (d, J=4.4 Hz, 1H), they were 8.22 (d, J=6,9 Hz, 1H), 7,26 (DD, J=4,7, 7.9 Hz, 1H), 6,85 (d, J=6,4 Hz, 1H), 3,80 (osirm, 4H), 3,66-3,62 (m, 2H), 2.26 and-2,22 (m, 2H), 2,15 (m, 2H), 0,00 (TMS)
388453,301,68(500 MHz, MeOD) 8,88 (DD, J=1.5 and 8.1 Hz, 1H), at 8.60 (s, 1H), 8,40 (d, J=3.1 Hz, 1H), 8,32 compared to 8.26 (m, 1H), to 7.99 (s, 1H), 7,40 (DD, J=4,7, 8.0 Hz, 1H), 7,31 (s, 1H), 4,19 (t, J=1.8 Hz, 1H), 4,11-4.09 to (m, 1H), 4,07 (, 3H), 4,07 (s, 3H), 3,35-of 3.32 (m, 2H), 1,87 (s, 6H), 1,38-of 1.29 (m, 2H, unclean)
389489,001,78500 MHz, MeOD) 8,82 (DD, J=1,4, 8,1 Hz, 1H), 8,58 (s, H), charged 8.52 (m, 1H), 8,40 (d, J=3.2 Hz, 1H), 8,00 (s, 1H),.39 (DD, J=4,7, 8.0 Hz, 1H), 7,32 (s, 1H), 4,08 (s, 3H), 4,07 (s, 3H), 3,80-of 3.77 (m, 2H), 1,87 (s, 6H)
390471,101,70500 MHz, MeOD) cent to 8.85 (DD, J=1,4, 8,1 Hz, 1H), at 8.60 (s, H), 8,42-to 8.40 (m, 1H), of 8.37-8,30 (m, 1H), 8,00 (s, 1H), 7,40 (DD, J=4,7, 8.0 Hz, 1H), 7,32 (s, 1H), 5,64-5,41 (m, H)4,08 (s, 3H), 4,07 (s, 3H), 3,44 (m, 2H,), to 1.87 (s, 6H)
391449,201,70500 MHz, MeOD) 8,88-8,87 (m, 1H), 8,59 (s, 1H), 8,40 (d, J=3.3 Hz, 1H), 8,03-8,02 (m, 1H), to 7.99 (s, 1H), 7,40 (DD, J=4,7, 8,1 Hz, 1H), 7,31 (s, 1H), 4,07 (s, 3H), 4,07 (s, 3H), of 3.07 (m, 2H), to 1.86 (s, 6H), 1,29 (m, 2H), and 0.61 (t, J=7.5 Hz, 3H)
392339,10 1,45
393353,101,56
394357,101,47
395375,101,56
396427,001,90DMSO-d6: 12,25 (s, 1H); 8,95 (m, 1H); to 8.7 (d, 1H); 8,35 (d, 1H); to 8.3 (m, 1H); or 8.2 (m, 1H); to 7.25 (DD, 1H), and 5.5 (d, 1H); 4,95 (DD, 1H); 4,3-a 3.75 (m, 4H); and 2.7 (m, 1H); 2,2-2,0 (m, 1H)
397445,002,30DMSO-d6: 12,15 (s, 1H); 8,9 (m, 1H); 8,65 (d, 1H); 8,35 (d, 1H); to 8.3 (m, 1H); 8,15 (m, 1H); to 7.2 (m, 1H); 5,1 (m, 1H); 4,3 (m, 2H); 3.9 to (m, 2H); 3,0 (m, 1H); 2,5 (m, 1H)
398394,002,10(500 MHz, MeOD) 9,14 (m, 0,25H), of 8.95 (d, J=6,7 Hz, 0,66H), 8,59-to 8.41 (m, 3,64H), was 7.45 (m, 1H), 3,84 (m, 2H), 2.21 are to 2.18 (m, 1H), 2,05-2,02 (m, 1H), 1,67 (m, 3H), of 0.97 (t, J=7,3 Hz, 3H)
399325,901,60
400340,001,80 (500 MHz, MeOD) 9,07 (user., 0,24H), 8,54 (s, 1H), 8,46 (s, 1H), at 8.36 (d, J=4.3 Hz, 1H), 7,39 was 7.36 (m, 1H), 3.25 to 3.15 in (m, 2H), 2,19-2,00 (m, 2H), 1,65 (m, 3H), 0,97-of 0.90 (m, 6H)
401410,102,10DMSO-d6 (a mixture of rotatores approximately 1.3:1): 12,45 (m, 1H); 9,05 to 8.3 (m, 5H); and 7.3 to 7.2 (m, 1H); 5,6-to 5.4 (m, 1H); 4,8 (t, 0,6H); 4,7 (t, 0,4H); 4,45 of 3.75 (m, 4H); 2,8-2,6 (m, 1H); 2,25-2,1 (m, 1H)
402410,102,00DMSO-d6 (a mixture of rotatores approximately 1.3:1): 12,45 (m, 1H); from 8.8 to 8.3 (m, 5H); 7.3 to to 7.15 (m, 1H); 5,5 to 5.35 (m, 1H)and 4.9 (d, 0,6H); at 4.75 (d, 0,4H); 4,15 to 3.8 (m, 4H); 2,75-2,6 (m, 1H); 2,4-2,3 (m, 1H)
403392,102,00
404409,101,50
405409,001,50

Example 3: Testing for inhibition of JAK3

Organized the screening of compounds for their ability to inhibit JAK3, using the following test. The reaction was carried out in kinase buffer containing 100 mm HEPES (pH of 7.4), 1 mm DTT, 10 mm MgCl2, 25 mm NaCl and 0.01% BSA. Substrate concentration in the test was 5 μm ATP (200 µci/what KMOL ATP) and 1 μm poly(Glu) 4Tyr. The reaction was carried out at 25°C and 1 nm JAK3.

In each well of 96-well polycarbonate tablet was added to 1.5 ál candidate inhibitor of JAK3 with 50 μl of kinase buffer containing 2 μm poly(Glu)4Tyr and 10 μm ATP. Then they were mixed and added to 50 μl of kinase buffer containing 2 nm JAK3 enzyme to start the reaction. After 20 minutes at room temperature (25°C) the reaction was stopped by 50 μl of 20% trichloroacetic acid (TCA), which also contained 0.4 mm ATP. The full contents of each well are then transferred into 96-well plates with glass fiber filter using a harvester cells (TomTek Cell Harvester). After washing was added 60 μl of scintillation fluid were detected embedding33R on a Perkin Elmer TopCount.

Example 4: Testing for inhibition of JAK2

Testing was carried out as described in example 3, except that the used enzyme JAK-2, the final concentration of poly(Glu)4Tyr was 15 μm and the final concentration of ATP was 12 μm.

It was found that all compounds are presented in tables 1, 2 and 3 inhibit JAK3 with Kiless than 0.1 μm, with the exception of the compounds 22, 35, 56, 68, 177, 223, 310, 317, 318, 319, 320, 321, 322, 326, 336, 337, 338, 339, 340, 351, 356, 367, 369, 370, 388 and 390. All compounds of tables 1, 2 and 3 inhibited JAK3 with Kiless than 2.0 μm with the exception of compounds 68 and 319. It was found the, all compounds of tables 1, 2 and 3 inhibit JAK2 with Kiless than 0.5 microns, with the exception of the compounds 9, 22, 35, 56, 57, 68, 310, 317, 38, 319, 320, 321, 336, 338, 339, 340, 348, 351, 356, 367 and 372. All compounds of tables 1, 2 and 3 inhibited JAK2 with Kiless than 5.0 μm, with the exception of compounds 68, 318 and 319.

Example 5: Testing of JAK3 inhibition on cells

HT-2 clone A5E cells (catalog number ATCC CRL-1841) was grown and maintained at 37°C in a humid chamber in the medium for cell culture (RPMI 1640, supplemented with 2 mm L-glutamine, adapted for content of 1.5 g/l sodium bicarbonate, 4.5 g/l glucose, 10 mm HEPES, 1.0 mm sodium pyruvate, 0.05 mm 2-mercaptoethanol, 10% fetal calf serum and 10% T-STIM factor rats [Fisher Scientific, catalog number CB40115] concanavalin A). On the day of the experiment cells HT-2 were washed, resuspendable with a density of 5×106cells per ml in fresh medium for the culture of cells without T-STIM, and incubated for 4 hours without T-STIM. Four hours was added to each well of 96-hole tablet 50 μl of 0.25×106cells) resuspending cells. Serial dilution of the compounds were made in DMSO and then added RPMI. To each well was added 100 μl of the diluted compounds and incubated tablet for 1 hour at 37°C. was Added 50 μl of recombinant interleukin-2 mouse (rmIL-2) at 40 ng/ml (R&D systems Inc., catalog number 402-ML) and tablets in what was operovali for 15 minutes at 37°C.

Then the plates were centrifuged for 5 minutes at 1000 rpm, the supernatant was aspirated and added to 50 μl of 3.7% formaldehyde in phosphate buffered saline (PBS) per well. The plates were incubated for 5 minutes at room temperature on a plate shaker. Tablets centrifuged at 1000 rpm for 5 minutes. The supernatant was aspirated, was added to each well 50 μl of 90% methanol and the plate is incubated on ice for 30 minutes. The supernatant was aspirated and the plate washed with PBS. Added in tablets of 25 ál per well of 1:10 diluted PE(phycoerythrin)-conjugated antibodies against phospho-STAT-5(Y694) (PS-5 PE antibody; Becton-Dickinson, catalog number 61256) and the plates were incubated for 45 minutes at room temperature on a plate shaker. Added 100 μl of PBS and the plates were centrifuged. Was aspirated supernatant and cells resuspendable in 100 µl PBS. Then the tablet was read on a 96-well plate reader FACS (cell sorters with excitation fluorescence) (Guava PCA-96).

It was found that the compounds according to the invention inhibit JAK3 in this test.

Example 6: Testing of JAK2 inhibition on cells

TF-1 cells (catalog number ATCC CRL-2003) were grown and maintained at 37°C in a humid chamber in the medium for cell culture (RPMI 1640, supplemented with 2 mm L-glutamine, adapted for content of 1.5 GL of sodium bicarbonate, 4.5 g/l glucose, 10 mm HEPES, 1.0 mm sodium pyruvate, 10% fetal calf serum and recombinant granulocyte-macrophage colony-stimulating factor [rhGMCSF, R&D Systems Inc. catalog number 215-GM]). On the day of the experiment, TF-I cells were washed, resuspendable with a density of 5×106cells per ml in fresh medium for cell culture without rhGMCSF and incubated for 4 hours without rhGMCSF. Four hours was added to each well of 96-hole tablet 50 μl of 0.25×106cells) resuspending cells. Serial dilution of the compounds were made in DMSO and then added RPMI. To each well was added 100 μl of the diluted compounds and incubated tablet for 1 hour at 37°C. was Added 50 μl rhGMCSF at 10 ng/ml and the plates were incubated for 15 minutes at 37°C. Then, the tablets were subjected processed for FACS analysis as described in example 5. It was found that the compounds according to the invention inhibit JAK2 in this test.

Although described a number of embodiments of the present invention, it is obvious that basic examples can be modified for other embodiments that use compounds and methods according to this invention. Therefore, it should be understood that the scope of this invention defined by the claims, rather than specific options assests the tion, presented in the example above.

1. The compound of formula (I):

or its pharmaceutically acceptable salt,
where R3represents H;
X1represents N or CR4;
R2represents H, COOH, COOR', or CONHR';
R4represents H, F, R', HE, OR', COR', COOH, COOR', CONH2or CN;
or R2and R4taken together form a benzene ring, optionally substituted with 1-2 R10;
R' represents a C1-3alkyl or C2-3alkenyl, each of which is optionally substituted with 1-2 R5;
each R5independently selected from CN, unsubstituted With1-2the alkyl, or two groups R5together with the carbon to which they are attached, form cyclopropyl ring;
each R10independently selected from halogen, och3or HE;
R1represents a

R" is H or a C1-2alkyl, optionally substituted by 1-3 R11;
each R11independently selected from CN, or two groups R11together with the carbon to which they are attached, form cyclopropyl ring;
R6represents a C1-4alkyl, optionally substituted by 1-5 R12;
each R12independently selected from HE, SH or CN, unsubstituted With1-2of alkyl, not umestnogo 2the quinil, or two groups R12together with the carbon to which they are attached, form cyclopropyl ring;
ring a is a 4-6-membered saturated nitrogen-containing ring containing up to two additional heteroatoms, selected from N, O or S, and optionally substituted by 1-2 R13;
each R13independently selected from halogen, R', other', SR', HE, OR', NO2CN, CF3, COOR', COOH, COR', or NHC(O)R'; or any two groups of R13the same or different substituents together with the atom(s)to which the groups R13attached, form a 3-7-membered saturated, unsaturated or partially saturated carbocyclic or heterocyclic ring containing 1-2 sulfur atom, optionally substituted by 1-3 R5;
R8represents a C1-4alkyl, optionally substituted by 1-5 R12;
R9represents a C1-2alkyl; or
R8and R9taken together, form a 3-7-membered carbocyclic or heterocyclic saturated ring containing one oxygen atom, optionally substituted by 1-5 R12;
R14represents H or unsubstituted With1-2alkyl; and R7represents a C2-3alkyl or C3cycloalkyl, each of which is optionally substituted up to 6 F.

2. The compound according to claim 1, where the compound has formula I:

3. The compound according to claim 1 or 2, where R2represents H or CONHR'.

4. The compound according to claim 3, where R2represents N.

5. The compound according to claim 2, representing a compound of formula I-A, and R4represents H, F, R', HE or or'; or R2and R4taken together form a benzene ring.

6. The compound according to claim 5, where R4represents H or F.

7. The connection according to claim 6, in which R4represents F, R2represents N.

8. The connection according to claim 6, where R4and R2both represent N.

9. The compound according to any one of claims 1, 2 or 4-8, where R7represents CH2CH3CH2CF3CH2CHF2CH2CH2F, CH2CH2CH3CH2CH2CF3CH2CH2CH2F or CH2CH2CHF2.

10. The connection according to claim 9, where R7represents CH2CH3CH2CF3CH2CH2CH3or CH2CH2CF3.

11. The connection of claim 10, where R7represents CH2CF3.

12. The compound according to any one of claims 1, 2, or 4-11, where R" is H or CH3.

13. The connection section 12, where R" is N.

14. The compound according to any one of claims 1, 2, or 13, where R14represents N.

15. Connection p., where the compound has formula III:
,
where X1Arepresents N, CH or CF, and R1Arepresents a
.

16. The connection indicated in paragraph 15, where R7represents CH2CH3CH2CF3CH2CH2CH3or CH2CH2CF3.

17. Connection P16, where R7represents CH2CF3.

18. The compound according to any one of claims 1, 2, 4-11, 13, 15, 16 or 17, where R6and the carbon atom to which it is attached, represent a group selected from



19. Connection p, where R6and the carbon atom to which it is attached, represent a group selected from

20. The connection according to claim 19, where R6and the carbon atom to which it is attached, represent a group selected from
.

21. The compound according to any one of claims 1, 2, 4-11, 13 or 15-17, where the ring And is a

22. Connection item 21, where the ring And is a

23. Connection p.22, where ring a is a

24. Connection item 23, where R13is missing.

25. Connection item 23, where the ring And substituted with one R13.

26. Connection A.25, where R13HE is a, CH3, F, OR', or other'.

27. Connection p, where R' represents a C1-2alkyl or C2-3alkenyl.

28. Connection p, where R13is a HE.

29. The compound according to any one of claims 1, 2, 4-11, 13, 15, 16 or 17, where R8and R9taken together, form a ring selected from

where one carbon atom in the specified ring is optionally and independently replaced by O.

30. The compound according to any one of claims 1, 2, 4-11, 13, 15, 16 or 17, where R8, R9and the carbon atom to which they are attached, represent a group selected from

31. Connection item 30, where R8, R9and the carbon atom to which they are attached, represent a group selected from

32. Connection p, where R8, R9and the carbon atom to which they are attached, represent a group selected from

33. Connection item 21, where X1Arepresents CH or CF.

34. A compound selected from






35. The pharmaceutical composition exhibiting inhibitory activity against JAK-2 or JAK-3 kinase containing an effective amount of a compound according to any one of claims 1 to 34 and a pharmaceutically acceptable carrier, adjuvant or excipient.

36. A method of treating or reducing the severity of the pathological condition selected from a proliferative disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplantation, inflammatory disorders, or immunologically mediated disorder in a patient, comprising the stage of introduction of a given patient the compound according to any one of claims 1 to 34 or the composition of p.

37. The method according to p, where the disease or disorder is an Allergy or allergic reactions (type I), asthma, amyotrophic lateral sclerosis (als, the disease Lou Gehrig's disease (als), multiple sclerosis (PC), graft rejection, graft versus host, rheumatoid arthritis, solid tumor, hematological malignant disease, leukemia, lymphoma and myeloproliferative disorder.

38. The method according to clause 37, where the disease or disorder is an asthma.

39. The method according to clause 37, where the specified Zabol the existence or disorder is a rejection of the graft.

40. The method according to clause 37, where the disease or disorder is a rheumatoid arthritis.

41. The method according to clause 37, where the disease is a myeloproliferative disorder is selected from the group consisting of the true polycythemia, essential trombozitemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome and systemic mastocytosis.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to substituted imidazopyridine derivatives of general formula (I) or enantiomers, diastereomers and tautomers and pharmaceutically acceptable salts thereof, in which A denotes -NH-, -CH2-, -CH2-CH2- or a bond; X denotes phenyl, phenyl condensed with a saturated heterocyclic 5- or 6-member ring, where the heterocyclic ring can contain one or two heteroatoms selected from O and N, and where the heterocyclic ring can further be substituted with an oxo group, a 6-member saturated heterocyclyl containing O as a heteroatom, a 5-6-member heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, and where each phenyl and heteroaryl is possibly substituted with 1 to 2 R14 and/or 1 substitute R4b and/or 1 substitute R5; R1 and R2 are independently selected from the following groups: C1-6-alkyl and C1-6-alkylene-C3-7-cycloalkyl, and where each alkyl is possibly substituted with a OH group, or R1 and R2 together with the nitrogen atom with which they are bonded form a 5-6-member ring which is possibly substituted with one substitute selected from C1-6-alkyl and O-C1-6-alkyl; R4b denotes C(O)NH2, C(O)OH, C(O)NH-C1-6-alkyl, C(O)N-(C1.6-alkyl)2, SO2-C1-6-alkyl, oxo group, and where the ring is at least partially saturated, NH2, NH-C1-6-alkyl, N-(C1-6-alkyl)2; R5 denotes a 6-member heteroaryl containing N as a heteroatom; R3 denotes -(CR8R9)n-T; R8 and R9 are independently selected from the following groups: H and C1-6-alkyl; n equals 1, 2, 3, 4, 5 or 6; T denotes or NR12R13; R10 denotes H, NH2, OH, C1-6-alkyl, possibly substituted with one OH, a halogen atom, NH(C1-6-alkyl) or N(C1-6-alkyl)2; q equals 1 or 2; Y denotes CH2, NR11 or O; R11 denotes H, or C1-6-alkyl; R12 and R13 are independently selected from the following groups: H, C1-6-alkyl, C1-6-alkynyl, (CH2)0-2-C3-7-cycloalkyl, and C1-6-alkylene-O- C1-6-alkyl, where C1-6-alkyl is possibly substituted with one halogen; R14 denotes a halogen atom, CN, C1-6-alkyl, possibly substituted with 1-3 substitutes selected from halogen atom, OH, O- C1-6-alkyl, O-C(O)C1-6-alkyl, O- C1-6-alkyl, possibly substituted with one substitute selected from OH, O- C1-6-alkyl, and O-C(O) C1-6-alkyl, or OH. The invention also relates to a pharmaceutical composition based on the compound of formula (I).

EFFECT: novel imidazopyridine derivatives are obtained, which can be used as melanocortin-4 receptor modulators.

17 cl, 8 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new compounds of formula , wherein A represents residues of formulae

, , , X represents O; X1-X4 represents N, CH, CR1 or C-, X9-X12 represents N, CH, CR4 or C-, X13-X16 represents N, CH, CR or C-, wherein C represents an attachment point of the group A to a residue of the structure of formula (I); R' represents H or alkyl; R represents alkoxy, or Het; R1 represents F, CI, Br, I, OH, CN, carboxy, CONR6R7, NR2COR8, NR2COOR8, alkoxy, fluorinated alkoxy, Ar, Het or OHet; or R1 represents one of the following formulas: wherein n is equal to 2 and m is equal to 3; R2 represents H, alkyl, fluorinated alkyl, cycloalkyl, Het or Het-NH-CO-; R4 represents F, Cl, Br, I, OH, alkoxy, cycloalkoxy, Het or OHet; or R4 represents one of the following formulae: , wherein n is equal to 2 and t is equal to 3; each R6 and R7 independently represents alkyl, or cycloalkyl, or R6 and R7 together represent alkylene group containing 5-6 carbon atoms which forms a cycle with N atoms; R8 represent alkyl, or cycloalkylalkyl; R9 represents alkyl; Ar represents aryl group; Het represents heterocyclic group which is completely saturated, particularly saturated or completely unsaturated containing 5 to 10 ring atoms in which at least 1 ring atom represents N, O or S atom which is unsubstituted or substituted once or several times by the substituted specified in cl. 1; and their pharmaceutically acceptable salts or solvates or N-oxides, or solvates of their pharmaceutically acceptable salts, or solvates of N-oxides of their pharmaceutically acceptable salts wherein said compound can be presented in the form of a polymorph, wherein if said compound shows chirality, it can be presented in the form of a mixture of enanthiomers or a mixture of diastereoisomers, or can be presented in the form of single enanthiomer or single diastereoisomer; and wherein at least one of the groups R, R1 or R4 represents Het or OHet, wherein the group Het is specified in each case in substituted or unsubstituted azabicyclooctyl, oxaazabicycloheptyl, diazabicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hezahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. Also the invention refers to other compounds of formula (I), to specific compounds, to a pharmaceutical composition based on the compound of formula (I), to a method of selective activation/stimulation of α-7 nicotinic receptors, to application of the compound of formula (I) for making the drug.

EFFECT: there are produced new compounds showing effective biological properties.

53 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present application describes substituted bicyclic beta-lactams of formula I: which are class A and class C β-lactamase inhibitors wherein X, R1 and R2 are specified in the application, as well as a method for producing them. The compounds of formula I and their pharmaceutically acceptable salts are applicable for preparing a pharmaceutical composition and for producing a drug. The declared compounds are applicable for treating bacterial infections, optionally in a combination with a β-lactam antibiotic. Particularly, the compounds may be used with such β-lactam antibiotics, as e.g. imipenem, piperacillin or ceftazidime to control microorganisms resistant to β -lactam antibiotics due to the presence of β-lactamases.

EFFECT: preparing the composition for treating bacterial infections.

28 cl, 117 ex, 3 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae

and ,

which can be used to inhibit lipid kinase, including PI3K, and treat lipid kinase-mediated disorders. Values of radicals are given in claim 1.

EFFECT: improved properties of the compound.

11 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae and including their stereoisomers, as well as pharmaceutically acceptable salt, where X denotes O or S; R1 is selected from H, F, CI, Br, I, CN, -CR14R15-NR16R17, -CR14R15-NHR10, -(CR14R15)NR10R11, -(CR14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -(CR14R15)mOR10, -(CR14R15)nS(O)2R10, -C(OR10)R11R14, -C(R14)=CR18R19, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NHR12, -NR12C(=Y)R10, -S(O)2R10, -S(O)2NR10R11, C2-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C4 carbocyclyl, piperidinyl, thiopyranyl, phenyl or C5-C6 heteroaryl; R2 is selected from H, C2-C12 alkyl and thiazolyl; R3 denotes a condensed bicyclic heteroaryl selected from indazole, indole, benzoimidazole, pyrrolopyridine, imidazopyridine and quinoline; R10, R11 and R12 independently denote H, C2-C12 alkyl, C3 carbocyclyl, heterocyclyl selected from pyrrolidine, morpholine and piperazine, phenyl or heteroaryl selected from pyrazole, pyridine, benzothiophene; or R10 and R11 together with a nitrogen atom with which they are bonded possibly form a saturated C3-C6 heterocyclic ring, possibly containing one additional ring atom selected from N or O, where said heterocyclic ring is possibly substituted with one or more groups independently selected from oxo, (CH2)mOR10, NR10R11, SO2R10, C(=O)R10, NR12S(O)R11, C(=Y)NR10R11, C1-C12 alkyl and heterocyclyl selected from pyrrolidine; R14 and R15 are independently selected from H or C1-C12 alkyl; R16 and R17 independently denote H or phenyl; R18 and R19 together with a carbon atom with which they are bonded form a C3-C20 heterocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, phenyl, heteroaryl, piperidinyl and condensed bicyclic heteroaryl possibly substituted with one or more groups independently selected from F, CI, Br, I, CF3, -C(=Y)R10, -C(=Y)OR10, oxo, R10, -C(=Y)NR10R11, -(CR14R15)nNR10R11, -NR10R11, -NR12C(=Y)R10, -NR12C(=Y)NR10R11, -NR12SO2R10, OR10, SR10, -S(O)2R10, -S(O)2NR10R11, possibly substituted with carbocyclyl, selected from cyclopropyl, possibly substituted heterocyclyl selected from piperazine, possibly substituted with alkyl and alkylsulphonyl, pyrrolidine, morpholine, piperdine, possibly substituted CH3, phenyl and possibly substituted heteroaryl selected from imidazole and triazole; Y denotes O; m equals 0, 1 or 2; n equals 1 and t equals 2. The invention also relates to a pharmaceutical composition which modulates lipid kinase activity, based on said compounds.

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used to treat lipid kinase-mediated diseases, for example, cancer.

48 cl, 2 tbl, 372 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula where R1 is selected from H, F, CI, Br, CF3, C1-C6 alkoxy and OH; R2 is selected from H and C1-C6 alkyl; n equals 1-5; m equals 0 or 1; and Y is selected from CH2, NR3, (NR3R4)+X-, O and S; R3 and R4 are independently selected from H and C1-C4 alkyl; and X- is selected from pharmaceutically acceptable anions. The invention also relates to a method of producing said compound and to an antiviral pharmaceutical composition based on said compound of formula (I).

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used in medicine to treat a viral diseases such as herpes.

19 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: described is a compound of general formula: [1], where R1 denotes an optionally substituted C2-C12 alkyl, aryl or heterocyclic group which can be a mono- or bicyclic 5-11-member radical, where the heteroatoms can be nitrogen, oxygen or sulphur; X1 denotes C2-C4 an alkylene group; X2 denotes a bond; X3 denotes a group of general formula NR3 or CR4R5NR3 (where R3 denotes a hydrogen atom, optionally substituted lower alkyl group or imino-protective group) and R4 and R5 are identical or different, and each denotes a hydrogen atom or a lower alkyl group or bond; X4 denotes a lower alkylene or lower alkenylene or lower alkynylene group, which can be substituted with one or more oxo groups or a bond; X5 denotes a sulphur atom or bond; Y1 denotes an optionally substituted divalent 4-, 5- or 6-member alicyclic hydrocarbon residue or an optionally subsituted divalent 5- or 6-member alicyclic amine residue, where the heteroatoms can be nitrogen or oxygen; Z1, Z2, Z3, Z4, Z5 and Z6 are identical or different, and each denotes a nitrogen atom or a group of general formula CR7 (where R7 denotes a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted amino group, or an amino group substituted with one or more C1-6 alkyl groups, a lower alkyl group, a cycloalkyl, a lower alkoxy group or a monocyclic 5-member heterocyclic group which can be substituted with one or more halogen atoms, where the heteroatoms can be nitrogen, acid or sulphur or a group of general formula Q1CO2R10 (where R10 denotes a carboxyl-protective group and Q1 denotes a lower alkenylene group), provided that at least one of Z3, Z4, Z5 and Z6 denotes a nitrogen atom, or salt thereof. The invention also describes an antimicrobial agent based on said compound.

EFFECT: novel compounds which can be used as antimicrobial agents are obtained and described.

25 cl, 176 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of vinflunine ditartrate, production method thereof and use thereof in therapy, especially for cancer pathology treatment.

EFFECT: high stability and wide variety of galenic forms.

8 cl, 3 ex, 5 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a compound presented by formula (1), to its salt or hydrate where in formula R1 represents a methylene group, R2 represents a phenyl group which can contain a substitute(s), or a heterocyclic group which can contain a substitute(s), the cycle A represents a 6- or 7-members cycle (where cycle-making atoms of the cycle A different from a sulfur atom in position 6 are carbon atoms), and R3 represents a hydrogen atom, or 1-3 equal or different substitutes used to substitute the cycle A where the possible substitutes are specified in clause 1 of the patent claim. Also, the invention refers to a pharmaceutical composition exhibiting an anticancer activity, on the basis of the compound presented by formula (1).

EFFECT: there are produced new compounds and pharmaceutical composition on their basis which can find application in medicine for cancer treatment.

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds (la) of formula applied as tyrosine kinase c-Met inhibitors. , where: LA is selected from ,

or ; RA is selected from:

or each RA2 and RA6 represents hydrogen; RA3 represents RAr; or RA3, RA4 and carbon atoms whereto attached form 6-members aryl, optionally substituted, in the amount up to 4 by independent groups RAr, or a 5-6-members heterocyclyl or heteroaryl ring containing at least one O, N or S atom; R represents -OH; RA5 represents hydrogen or RAr; LB represents a covalent bond or -N(R*)-; RB represents halogen, NH2 or C1-8aliphatic group, optionally substituted by R; a 6-10-members aryl ring; a 3-7-members carbocyclyl ring, a 5-10-members heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms, where each said aryl or heteroaryl ring is optionally substituted, in the amount up to five by independent groups RAr; R represents halogen, -R°, -SR°, Ph, optionally substituted R° or -C(O)OR°; each RAr is independently selected from halogen, -R°, -OR°, -SR°, Ph, optionally substituted in the amount up to five by independent groups -R°, -CN, -N(R°)2 or -C(O)OR°; or two adjacent groups RAr taken together, represent 1,2-methylenedixy or 1,2-ethylenedixy; each R* represents hydrogen; and each R° represents independently hydrogen, an optionally substituted C1-6aliphatic radical or an unsubstituted 5-6-members heteroaryl or heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms.

EFFECT: invention refers to pharmaceutically acceptable compositions containing the compounds under the invention, and methods of application of the compositions in treatment of various proliferative disorders.

10 cl, 4 tbl, 548 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula , where R1 denotes OH, OPO3H2 or OCOR5; R2 denotes H, OH or OPO3H2; A denotes N or CR6; R3 denotes fluorine; R4 denotes H, C1-3alkyl or C3-6cycloalkyl; R5 denotes an alanine residue; R6 denotes H, C1-6alkoxy group or halogen; and n=0 or 1; and to pharmaceutically acceptable salts of compounds of formula I. The invention also relates to a pharmaceutical composition having antibacterial activity, and to use of compounds of formula I to obtain a medicinal agent for preventing or treating bacterial infections.

EFFECT: compounds of formula I, having antibacterial activity.

14 cl, 3 dwg, 2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound having chemical structure of formula II , all salts and stereoisomers thereof, where the value of radicals D, A2 and B are as described in paragraph 1 of the claim. The invention also relates to a composition having activity as a c-kit and c-fms modulator, a method of treating a subject suffering from a disease or condition mediated by c-kit and c-fms and a kit for modulating c-kit and c-fms.

EFFECT: novel compounds which can be useful in treating c-kit-mediated diseases or conditions and/or c-fms-mediated diseases or conditions are obtained and described.

21 cl, 44 ex

Polycyclic compound // 2451685

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a new polycyclic compound with general formula (I-1) and (1-3) or a pharmaceutically acceptable salt thereof where X1- -CR1 =CR2 - where R1 and R2 independently stand for hydrogen or C1-6 alkyl while Het stands for a radical of the following formulae: that may be substituted 1-3 times additionally described is a pharmaceutical composition containing such compound and intended for prevention or treatment of diseases caused by β-amyloid.

EFFECT: production of a pharmaceutical composition prevention or treatment of diseases caused by β-amyloid.

7 cl, 392 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to substituted imidazopyridine derivatives of general formula (I) or enantiomers, diastereomers and tautomers and pharmaceutically acceptable salts thereof, in which A denotes -NH-, -CH2-, -CH2-CH2- or a bond; X denotes phenyl, phenyl condensed with a saturated heterocyclic 5- or 6-member ring, where the heterocyclic ring can contain one or two heteroatoms selected from O and N, and where the heterocyclic ring can further be substituted with an oxo group, a 6-member saturated heterocyclyl containing O as a heteroatom, a 5-6-member heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, and where each phenyl and heteroaryl is possibly substituted with 1 to 2 R14 and/or 1 substitute R4b and/or 1 substitute R5; R1 and R2 are independently selected from the following groups: C1-6-alkyl and C1-6-alkylene-C3-7-cycloalkyl, and where each alkyl is possibly substituted with a OH group, or R1 and R2 together with the nitrogen atom with which they are bonded form a 5-6-member ring which is possibly substituted with one substitute selected from C1-6-alkyl and O-C1-6-alkyl; R4b denotes C(O)NH2, C(O)OH, C(O)NH-C1-6-alkyl, C(O)N-(C1.6-alkyl)2, SO2-C1-6-alkyl, oxo group, and where the ring is at least partially saturated, NH2, NH-C1-6-alkyl, N-(C1-6-alkyl)2; R5 denotes a 6-member heteroaryl containing N as a heteroatom; R3 denotes -(CR8R9)n-T; R8 and R9 are independently selected from the following groups: H and C1-6-alkyl; n equals 1, 2, 3, 4, 5 or 6; T denotes or NR12R13; R10 denotes H, NH2, OH, C1-6-alkyl, possibly substituted with one OH, a halogen atom, NH(C1-6-alkyl) or N(C1-6-alkyl)2; q equals 1 or 2; Y denotes CH2, NR11 or O; R11 denotes H, or C1-6-alkyl; R12 and R13 are independently selected from the following groups: H, C1-6-alkyl, C1-6-alkynyl, (CH2)0-2-C3-7-cycloalkyl, and C1-6-alkylene-O- C1-6-alkyl, where C1-6-alkyl is possibly substituted with one halogen; R14 denotes a halogen atom, CN, C1-6-alkyl, possibly substituted with 1-3 substitutes selected from halogen atom, OH, O- C1-6-alkyl, O-C(O)C1-6-alkyl, O- C1-6-alkyl, possibly substituted with one substitute selected from OH, O- C1-6-alkyl, and O-C(O) C1-6-alkyl, or OH. The invention also relates to a pharmaceutical composition based on the compound of formula (I).

EFFECT: novel imidazopyridine derivatives are obtained, which can be used as melanocortin-4 receptor modulators.

17 cl, 8 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to compounds that may be applied for HIV infection treatment or prevention or for AIDS or AIDS-associated complex treatment. According to the invention, the compounds represent compounds with formula I, where A stands for A1 , A2 , A3 or A4 and R1, R2, R3, R4a, R4b, R5, R6, Ar, X1, X2, X4, X4 and X5 having values specified in the patent claim. Additionally, this invention relates to a pharmaceutical composition containing the said compounds.

EFFECT: production of compounds possessing inhibition activity with regard to HIV reverse transcriptase.

22 cl, 3 tbl, 29 ex

Polymorphic form // 2448966

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is novel polymorphic form B N-[3-tret-butyl-1-(3-chlor-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-{2-[(2-hydroxyethyl)sulfanyl]phenyl}-[1,2,4]triazolo[4,3-a]pyridin-6-yl)sulfanyl]benzyl]}carbamide, method of its obtaining.

EFFECT: possibility to apply composition in treatment of various states, especially in treatment of inflammatory conditions, such as chronic obstructive lung disease.

4 cl, 12 ex, 9 tbl, 11 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 1-azabicycloalkyl derivatives of formula (I): wherein A represents O or N(R1); Y represents a group of formulas: or R represents substituted or unsubstituted phenyl or indolylradical, to their use as pharmaceutical agents, to pharmaceutical compositions containing them, to methods of treating and preventing mental and neurodegenerative diseases.

EFFECT: preparing pharmaceutical agents for treating and preventing mental and neurodegenerative diseases.

17 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrido[2,3-d]pyrimidines of formula (V) and use of compounds of formula (I), containing a compound of formula (V), to prepare a medicinal agent used for inhibiting HCV replication in mammals infected with HCV, as well as a pharmaceutical composition based on said compounds. In formula (I)

R1 denotes hydrogen, amino, mono- or disubstituted amino, where amino group substitute(s) can be selected from C1-6alkyl, C1-4alkyloxyC1-4alkyl, diC1-4alkylaminoC1-4alkyl/piperidin-1-ylC1-4alkyl, phenylC1-4alkyl, where the phenyl group can further be substituted with C1-4alkoxy; L denotes -NR8-; R2 denotes Het2, where said Het2 denotes an aromatic monocyclic 6-member heterocycle which contains one nitrogen atom and is optionally substituted with one or more substitutes selected from C1-4alkyl; polyhalogenC1-4alkyl, halogen, -COOR7, -CONR4aR4b, -OR7, -SR5, and where C1-4alkyl can further be substituted with -COOR7; R3 denotes phenyl which is optionally substituted with one or two halogen atoms; each of R4a and R4b independently denotes hydrogen, C1-4alkyl, hydroxyC1-4alkyl; each R5 independently denotes C1-4alkyl; each R7 independently denotes hydrogen or C1-4alkyl; and each R8 independently denotes hydrogen or C1-10alkoxycarbonyl. The values of radicals in formula (V) are given in the claim.

EFFECT: improved method.

18 cl, 4 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 2,3-substituted pyrazine sulphonamides of formula (I), use thereof in treating allergic diseases, inflammatory dermatosis, immonological disorders and neurodegenerative disorders, as well as pharmaceutical compositions, having CRTH2 receptor inhibiting action and inhibiting chemoattractant receptor, homologous to the molecule expressed on T-helpers 2. in general formula .

A is selected from a group consisting of

, n denotes an integer independently selected from 0, 1, 2, 3 or 4; m equals 1 or 2; B is selected from a group consisting of phenyl or piperazinyl; R1 denotes hydrogen; R2 denotes phenyl, where R2 is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl; R3 is selected from a group consisting of (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl, where each of said (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or where said aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl can be condensed with one or more aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl groups and can be substituted with one or more substitutes selected from a group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulphoxy, sulphonyl, sulphonamide and trihaloalkyl; R7 is selected from a group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, carboxyl, cyano, amino and hydroxy; aryl is selected from phenyl or naphthyl; and heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl, quinolizinyl.

EFFECT: high efficiency of using the compounds.

4 cl, 10 dwg, 46 ex

Up!