Derivative of triazaspiro[5,5]undecane and pharmaceutical composition comprising its as active component

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

 

The technical FIELD

The present invention relates to a derivative of diazaspiro[5.5]undecane and pharmaceutical compositions comprising them as active ingredients.

More specifically it relates to a derivative of diazaspiro[5.5]undecane formula (I)

(where all the symbols have the same meanings as defined below in this description), their Quaternary ammonium salts, their N-oxides, and their non-toxic salts, processes for their preparation and pharmaceutical compositions comprising them as active ingredients.

PRIOR art

Chemokine known as the primary protein with endogenous chemotactic and activating action against leukocytes and high heparin-binding activity. Now consider that the chemokine is related not only to control the specific infiltration of leukocytes during inflammation and immune responses, but also to the development and homing lymphocytes under physiological conditions and migration of precursor cells of hemocytes and somatic cells.

Differentiation, proliferation and death of cells hemocytes are associated with different types of cytokines. In vivo inflammation find tapicerki, and differentiation, maturation, and the like lymphocytes occur on a certain set who run the sites. Thus, various necessary cells migrate in certain prescribed areas and accumulate in them, causing a number of inflammatory and immune responses. Accordingly, cell migration is also a necessary phenomenon in addition to differentiation, proliferation and death of cells.

Migration of hemocytes in a living organism begins initially at the stage of development when the offset hematopoesis, which began in the area AGM permanent hematopoesis in the bone marrow through the liver of the embryo. Further, precursor cells, T cells and dendritic cells of the thymus migrate from the liver of the embryo in the bone marrow and thymus gland and are cytodifferentiation in the environment of the thymus. T-cell, which is the selection of a clone, migrate to the secondary lymphoid tissue and is involved in the immune response in the periphery. Cell Langerhans skin, activated and differentiated capture of antigen migrates into the region of T-cells in the local lymph node and activates it early T-cell as a dendritic cell. T-cell memory exercises his way back again into the lymph node via the lymphatic and blood vessels. Also B-cell, T-cell in the epithelium of the intestine, γδ T-cells, NKT-cell and dendritic cell migrate from the bone marrow without passing through the gland thymus and undergo differentiation for making the Oia participate in an immune response.

Chemokine significantly associated with such migration of various cells. For example, MIP3β, SLC and their receptor CCR7 play an important role in the migration and return of immature T-cells, T-memory cells and Mature dendritic cells that have captured antigen in the local lymphoid tissue for efficient collision of dendritic cells with T-cells. T-cell and dendritic cell for monitoring antigen-specific immune responses, only slightly observed in the secondary lymph node PLT mice with deficient expression of SLC (J. Exp. Med., 189(3), 451 (1999)).

MDC, TARC and its receptor CCR4 play an important role in the migration of Th2 cells at local sites of immune and inflammatory responses, which is the ratio of Th2-cell. In the rat model fluminance hepatitis (P. acnes + LPS) antibodies against TARC inhibited the increase in the number of ALT in the blood and expressing increasing amounts of TNFα and FasL in the liver, as well as improved mortality in rats (J. Clin. Invest., 102, 1933 (1998)). Also antibodies against MDC reduced the number of eosinophils accumulated in the interstitium of the lung, and suppressed hypersensitivity pneumatic pathways in the mouse model of hypersensitivity pneumatic pathways induced OVA (J. Immunology, 163, 403 (1999)).

MCP-1 and its receptor CCR2 are related to the infiltration of macrophages at sites of inflammation. Antibodies of protium-1 showed the effect of suppressing the infiltration of monocytes and macrophages in the glomeruli in rat model of glomerular nephritis, caused by antibodies against Thy1.1 (Kidney Int., 51, 770 (1997)).

Thus, chemokine receptors significantly associated with the control of inflammatory and immune responses through a mechanism in which they expressed in certain specified periods in different specific cells and effector cells accumulate in the area of production of the chemokine.

Acquired immunodeficiency syndrome (named AIDS)caused by human immunodeficiency virus (hereinafter in this description and designated as "HIV") is one of the diseases for which treatments are the most seriously popular in recent years. Once completed HIV infection in CD4-positive cell, which is the main cell target, HIV reiterates its proliferation in the patient's body and, sooner or later, completely destroys T-cells, providing immunological function. During this process immunological function gradually decreases, which causes fever, diarrhea, enlarged lymph nodes and such different States of immunodeficiency, which cause complications with pneumonia caused by pneumocystis carinii and such various opportunistic infections. Such States are beginning AIDS, and it is well known that they cause and worsen Kaposi's sarcoma and the like placecast the military tumors.

As recent prophylactic and therapeutic methods against AIDS tried, for example, (1) to inhibit the growth of HIV by the introduction of nucleoside reverse transcriptase inhibitor or protease inhibitor and (2) to prevent or reduce opportunistic infections-medication with immunopotentional activity.

Cells T-helper cells, which play a Central role in the immune system, mainly becoming infected with HIV. Since 1985 it is known that HIV uses a membrane protein CD4 expressed on the membrane of T-cells during infection (Cell, 52, 631 (1985)). The CD4 molecule is composed of 433 amino acid residues, and its expression can be detected in macrophages, some B-cells, vascular endothelial cells, Langerhans cells in skin tissues, dendritic cells in lymphoid tissues, cells, glia of the Central nervous system and the like, in addition to Mature cells T-helper cells. However, since it has been shown that HIV infection is not completed only by the CD4 molecule, hypothesized the presence of factors other than the CD4 molecule, related to the infection of cells by HIV.

In 1996, as a factor related to HIV infection, other than the CD4 molecule, was identified protein of the cell membrane, called a Vaporetto (Fusin) (Science, 272, 872 (1996)). It was confirmed that this molecule Fusina represents the t of a receptor (that is, CXCR4), stromal derived factor-1 (hereinafter in this description and designated as "SDF-1"). Additionally, it was also confirmed in vitro that SDF-1-specific inhibits infection by T-cell tropic (X4) HIV (Nature, 382, 829 (1996), Nature, 382, 833 (1996)). It is believed that HIV infection is inhibited by the binding of SDF-1 with CXCR4, previous HIV, preventing, thus, HIV springboard for infection klette at the same time it was discovered that another receptor of the chemokine CCR5, which is a receptor for RANTES, MIP-1α and MIP-1βalso used during infection macrofoam tropic (R5) HIV (Science, 272, 1955 (1996)).

Accordingly, substances that can compete with CXCR4 and CCR5 for HIV or can contact HIV, leading, thus, to the inability of the virus to contact CXCR4 and CCR5 can be inhibitors of HIV infection. Also there is the case when low-molecular compound, originally discovered as an inhibitor of HIV infection, in fact, was a CXCR4 antagonist (Nature Medicine, 4, 72 (1998)).

Based on the above I believe that the chemokine/chemokine receptors significantly associated with inflammation, immune disease, or HIV infection. For example, believe that they are related to the inhibition of various inflammatory diseases, asthma, atopic dermatitis, urticaria, allergic dis is evani (allergic bronchopulmonary aspergillosis, allergic eosinophilic gastroenteritis, etc), glomerular nephritis, nephropathy, hepatitis, arthritis, chronic rheumatoid arthritis, psoriasis, rhinitis, conjunctivitis and ischemia-reperfusion injury, multiple sclerosis, ulcerative colitis, acute respiratory distress syndrome, shock accompanied by bacterial infection, diabetes mellitus, and autoimmune diseases, and transplant rejection, immunosuppression, prevention of metastatic disease and syndrome acquired immunodeficits the other hand, in the description WO97/11940, indicated that the compounds of formula (Z)

(where the atoms AiZand BjZindependently selected from carbon, nitrogen, oxygen and sulfur, provided that at least one atom of AiZrepresents a carbon, and at least one atom BjZis the carbon);

ring spirobicyclic formed AiZand BiZ, respectively, can be optionally partially unsaturated,

pZ and qZ are independently a number from 2 to 6,

mZ is a number from 0 to pZ,

R10Zis the same or different and is not the Deputy, is independently selected from hydrogen, alkyl, halogen-substituted of alkyl, alkenyl, quinil, cycloalkyl, =O and =S and so on,

nZ is a number from 0 to qZ,

R0Zis the same or different and is not the Deputy, is independently selected from hydrogen, alkyl, halogen-substituted of alkyl, alkenyl, quinil, cycloalkyl, =O, =S, and so on,

linking group -(LZ)- represents a single bond or a divalent substituted or unsubstituted chain, containing from 1 to 10 atoms selected from the group consisting of carbon, nitrogen, sulfur and oxygen,

QZrepresents a basic group containing one or more basic radicals, and

R3Zis acid group containing one or more acid radicals), applicable for the inhibition of platelet aggregation.

In the description of the application WO98/25605, it is shown that the compounds of formula (Y)

(where mY 1Y or each independently 0, 1, 2, 3, 4 or 5, R1Yrepresents hydrogen, C1-8alkyl, C2-8alkenyl, C2-8quinil etc., WYrepresents a single bond, C1-3alkyl or C1-3alkyl, substituted oxo etc., QYis-NR2-, -O-, -S-, -S(O)- OR-SO2-, XYrepresents a single bond, C1-3alkyl or C1-3alkyl, substituted oxo, etc., YY-ZYthe ring is a phenyl, naphthyl or heteroaryl, provided that the definition of each symbol is a partial sample), applies what we as modulators of chemokine receptors.

Description of the INVENTION

Studies have been conducted to detect compounds that regulate chemokine/chemokine receptors, and found that this goal was achieved by using derivatives of diazaspiro[5.5]undecane formula (I).

The present invention relates to

i) derived diazaspiro[5.5]undecane formula (I)

[where R1has the formula (1) or (2):

(where G represents a bond, C1-4alkylene, C2-4albaniles or-CO-,

ring A represents (1) C5-10-membered mono - or bikebicycle ring or (2) a 5-10 membered mono - or bicyclic a heterocycle containing 1-2 nitrogen atom and/or 1-2 oxygen atom)

R6is

(1) C1-4alkyl,

(2) halogen,

(3) nitrile,

(4) trifluoromethyl,

(5) -OR8,

(6) -SR9,

(7) -NR10R11,

(8) -COOR12,

(9) -CONR13R14,(10) -SO2NR15R16,

(11) -NR17SO2R18,

(12) -S(O)R19,

(13) -SO2R20,

(14) -N(SO2R21)2,

(15) C1-4 alkyl, substituted Deputy selected from (a) OR8(b) -NR10R11and (c) Cyc 1, or

(16) -NR27COR28,

where R8-R17each independently represent (1) hydrogen, (2) C1-4alkyl, (3) Cyc 1, (4) -OR22and (5) C1-4 alkyl, substituted Deputy selected from (a) OR22(b) -NR23R24(c) -COOR25and (d) Cyc 1, or

R10and R11, R13and R14or R15and R16, each independently, together with the nitrogen atom to which they are attached, form a 5-6-membered monocyclic heterocycle containing 1-2 nitrogen atom and/or oxygen atom (where 5-6-membered monocyclic heterocycle can be optionally substituted C1-4the alkyl or hydroxy),

R22-R25each independently represents (1) hydrogen, (2) C1-4alkyl or (3) C1-4alkyl, substituted C1-4alkoxy, or

R23and R24together with the nitrogen atom to which they are attached, form a 5-6-membered monocyclic heterocycle containing 1-2 nitrogen atom and/or oxygen atom (where 5-6-membered monocyclic heterocycle can be optionally substituted C1-4the alkyl or hydroxy),

R18-R21each independently represents C1-4alkyl,

R27represents (1) hydrogen, (2) C1-4alkyl, (3) Cyc 1, or (4) C1-4alkyl, substituted Deputy, optionally selected from (a) OR22(b) -NR23R24(c) -COOR25and (d) Cyc 1,

R28represents (1) C1-4alkyl, (2) Cyc 1, or (3) C1-4alkyl, substituted Deputy, optionally selected from (a) OR22(b) -NR23R24(c) -COORsup> 25and (d) Cyc 1,

Cyc 1 is (1) C5-6-membered monocarbocyclic ring or (2) a 5-6-membered monocyclic heterocycle containing 1-2 nitrogen atom and/or oxygen atom (where the carbocyclic ring or heterocycle can be optionally substituted C1-4alkoxy, halogen or-COOR29(where R29represents (1) hydrogen, (2) C1-4alkyl, (3) Cyc 1, or (4) C1-4alkyl, substituted Deputy selected from (a) OR22(b) -NR23R24(c) -COOR25and (d) Cyc 1).),

E represents a bond, -O-, -S-, -CO - or-CHOH-,

ring B is (1) C5-6 membered monocarbocyclic ring or (2) a 5-6-membered monocyclic heterocycle containing 1-2 nitrogen atom and/or oxygen atom

R7represents C1-4alkyl or halogen,

n is a number from 0 or 1 to 4 and m is a number from 0 or 1 to 4

R2represents (1) C1-4alkyl, (2) C2-4quinil or (3) C1-4alkyl, substituted Deputy, optionally selected from (a) OR30(b) -NR31R32and (c) Cyc 3 (where R30-R32each independently represents (1) hydrogen, (2) C1-4alkyl, (3) Cyc 3 or (4) C1-4alkyl, substituted Cyc 3, where Cyc 3 is (1) C5-6-membered monocarbocyclic ring or (2) a 5-6-membered monocyclic heterocycle containing 1-2 nitrogen atom and/or oxygen atom (where C5-6-clenn the e carbocyclic ring, or a 5-6-membered monocyclic heterocycle can be optionally substituted C 1-4alkoxy)),

R3and R4each independently represents (1) hydrogen, (2) C1-4alkyl or (3) C1-4alkyl substituted with 1-2 substituents selected from (a) Cyc 2 and (b) hydroxy (where Cyc 2 is (1) C5-6-membered monocarbocyclic ring or (2) a 5-6-membered monocyclic heterocycle containing 1-2 nitrogen atom and/or oxygen atom), or R3and R4together form

(where R26represents C1-4alkyl or Cyc 2), and R5represents hydrogen or C1-4alkyl],

its Quaternary ammonium salt, N-oxide or its non-toxic salt,

ii) to the compound of formula (I) in accordance with the above (i), where R3and R4represent hydrogen,

iii) to the compound of formula (I) in accordance with the above (i), where R3is hydrogen and R4represents (1) C1-4alkyl or (2) C1-4alkyl substituted with 1-2 substituents, optionally selected from (a) Cyc 2 and (b) hydroxy,

iv) to the compound of formula (I) in accordance with the above (i), where R3and R4each independently represents (1) C1-4alkyl or (2) C1-4alkyl, substituted Deputy, optionally selected from (a) Cyc 2 and (b) hydroxy,

v) to the compound of formula (I)described above, (i) in which R3and R4together form/img>

(where R26has the same meaning as defined in the above (i)),

vi) connection, representing

(1) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-benzyl-1,4,9-diazaspiro[5.5]undecane,

(2) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(6-phenoxypyridine-3-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(3) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methoxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(4) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(3-methoxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(5) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-torpedolike)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(6) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-chlorphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(7) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(phenylcarbamoyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(8) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(1-phenyl-1-hydroxymethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(9) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(morpholine-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(10) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(6-methylpyridin-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(11) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-HYDR is XI-2-methylpropyl)-9-(4-(pyridine-1-oxido-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(12) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-hydroxypiperidine-1-ylmethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(13) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(14) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(1,3,5-trimethylpyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(15) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-aminosulphonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(16) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylthiophenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(17) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(18) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-cyanovinylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(19) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(phenylthio)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(20) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-hydroxyphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(21) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylsulfonylamino)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(22) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)this is aminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(23) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(24) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(6-methylpyridin-1 oxido-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(25) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-hydroxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(26) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(6-(4-methoxybenzyloxy)pyridine-3-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(27) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(methylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(28) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-hydroxyethyl)aminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(29) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(30) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(31) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(morpholine-4-yl)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(32) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-methylpropyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(33) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(34) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(35) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(morpholine-4-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(36) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-aminosulphonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(37) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(38) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-were)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(39) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-diethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(40) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(41) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(5-chloro-3-methyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(42) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(morpholine-4-ylcarbonyl)phenyl)PI is the azole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(43) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(44) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(45) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(pyridine-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(46) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(47) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(48) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(2,4-differenl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(49) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(pyridine-2-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(50) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylaminophenol)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(51) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-cyclohexenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(52) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(3,4,5,6-tetrahydropyran-4-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(53) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydro is si-2-methylpropyl)-9-(4-(4-methoxyphenylethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(54) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(cyclohexanecarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(55) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(56)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-forfinal)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(57) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-phenylethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(58) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(1-benzyloxycarbonylamino-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(59) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(2-hydroxyethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(60) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(1-methylsulfonylmethane-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(61) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-hydroxyethyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(62) (3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-9-(6-phenoxypyridine-3-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(63) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane

(64) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(65) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(morpholine-4-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(66) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-methylsulfinylphenyl)-1,4,9-diazaspiro[5.5]undecane,

(67) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(68) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(morpholine-4-yl)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(69) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(70) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(71) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyridine-1-oxido-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(72) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(73) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(morpholine-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(74) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-diethylaminosulfur)Fe who yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(75) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(2-hydroxyethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(76) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(77) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(cyclohexanesulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(78) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(3-methoxypropylamine)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(79) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-methylsulfinylphenyl)-1,4,9-diazaspiro[5.5]undecane,

(80) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-propylpyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(81) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-aripirazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(82) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-cyclopentylphenol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(83) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(1,1-dimethylethyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(84) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(1-benzyloxycarbonylamino-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(85) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-((4-methoxyphenyl)methylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(86) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(3-methoxypropylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(87) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-ethoxycarbonylphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(88) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-methoxyphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(89) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(3-(morpholine-4-yl)propylaminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(90) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyrrolidin-1-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(91) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(piperidine-1-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(92) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(morpholine-4-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(93) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(N-methyl-N-(2-(pyridin-2-yl)ethyl)aminocarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(94) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(cyclohexanecarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(95) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(N,N-dimethylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(96) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-ethoxycarbonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(97) (3S)-1-butyl-2,5-dioxo-3-(2-methyl is ropyl)-9-(3,5-dimethyl-1-(1-methylpiperidin-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(98) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(1-methylsulfonylmethane-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(99) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(3-(N,N-dimethylamino)propylaminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(100) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(N,N-dimethylamino)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(101) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-(N',N'-dimethylamino)ethyl)aminosulphonylphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(102) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-((N,N-dimethylamino)methyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(103) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(104) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylaminophenol)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(105) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-((methoxycarbonyl)methylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(106) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-(3,5-dimethyl-1-phenylpyrazol-4-yl)-2E-propenyl)-1,4,9-diazaspiro[5.5]undecane,

(107) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(carboxymethylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(108) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-(3,5-dimethyl-1-phenyl shall irsol-4-yl)propyl)-1,4,9-diazaspiro[5.5]undecane,

(109) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(110) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(111) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(morpholine-4-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(112) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(113) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(morpholine-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(114) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-methylsulfinylphenyl)-1,4,9-diazaspiro[5.5]undecane,

(115) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(116) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(2-(morpholine-4-yl)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(117) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(118) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(119) (3S)-1-BU the Il-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(120) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(2-hydroxyethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(121) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(122) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(cyclohexanesulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(123) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(3-methoxypropylamine)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(124) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-methylsulfinylphenyl)-1,4,9-diazaspiro[5.5]undecane,

(125) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-propylpyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(126) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-aripirazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(127) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-cyclopentylphenol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(128) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(3-(morpholine-4-yl)propylaminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(129) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(N,N-dimethylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(130) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(pyrrolidin-1-ylcarbonyl)hair dryer is lmutil)-1,4,9-diazaspiro[5.5]undecane,

(131) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(N,N-dimethylamino)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(132) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(cyclohexanecarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(133) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-ethoxycarbonylphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(134) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(3-methoxypropylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(135) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(N-methyl-N-(2-(pyridin-2-yl)ethyl)aminocarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(136) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-((4-methoxyphenyl)methylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(137) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-ethoxycarbonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(138) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-methoxyphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(139) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1-methylpiperidin-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(140) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1-methylsulfonylmethane-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(141) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(3-(N,N-dimethylamino)cuts noalter)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(142) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-(N',N'-dimethylamino)ethyl)aminosulphonylphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(143) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(piperidine-1-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(144) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(morpholine-4-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(145) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-((N,N-dimethylamino)methyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(146) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-methylaminophenol)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(147) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1,1-dimethylethyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(148) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1-benzyloxycarbonylamino-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(149) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-hydroxyethyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(150) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-((methoxycarbonyl)methylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(151) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(carboxymethylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(152) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-shall unilaterally)-1,4,9-diazaspiro[5.5]undecane,

(153) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(6-phenoxypyridine-3-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(154) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-torpedolike)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(155) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-chlorphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(156) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-cyanovinylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(157) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(158) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(6-methylpyridin-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(159) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(1-methylethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(160) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(161) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(3,4,5,6-tetrahydropyran-4-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(162) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-phenylcarbonylamino)-1,4,9-diazaspiro[5.5]undecane,

(163) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(1-phenyl-1-hydroxy shall ethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(164) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(morpholine-4-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(165) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methylaminoethanol)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(166) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-hydroxyethyl)aminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(167) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(pyridine-2-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(168) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(169) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(1,3,5-trimethylpyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(170) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(171) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(N,N-biomethylation)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(172) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methylsulfonylamino)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(173) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylsulphamoyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(174) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(175) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(morpholine-4-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(176) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-aminocarbonylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(177) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-aminosulphonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(178) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-aminosulphonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(179) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(6-methylpyridin-1 oxido-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(180) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-hydroxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(181) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-hydroxyphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(182) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(183) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(pyrrole the n-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(184) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(5-chloro-3-methyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(185) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(186) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(3-methoxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(187) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(N,N-dimethylaminoethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(188) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(189) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-were)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(190) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-forfinal)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(191) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(6-(4-methoxybenzyloxy)pyridine-3-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(192) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(193) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(194) (3R)-1-buta is l-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(195) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(196) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-(morpholine-4-yl)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(197) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(morpholine-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(198) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(1,4-benzodioxan-6-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(199) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-diethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(200) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(pyridine-1-oxido-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(201) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(202) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(203) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(2,4-differenl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(204) (3R)-1-butyl-2,5-dioxo-3-(1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(205) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methylaminophenol)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(206) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(207) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-((4-methoxyphenyl)methylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(208) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(3-methoxypropylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(209) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(N-methyl-N-(2-(pyridin-2-yl)ethyl)aminocarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(210) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(211) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-chlorophenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(212) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-triptoreline)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(213) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methoxyphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(214) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-atile the azole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(215) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-propylpyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(216) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(1,1-dimethylethyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(217) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-cyclopentylphenol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(218) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(2-phenylethyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(219) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(1-benzyloxycarbonylamino-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(220) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(cyclohexanecarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(221) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(1-methylsulfonylmethane-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(222) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(2-hydroxyethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(223) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-hydroxyethyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(224) (3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfanyl is inoperate)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(225) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(226) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(227) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-(4-methoxyphenylethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(228) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(229) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(230) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(231) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(232) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(4-(4-(4-methoxyphenylethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(233) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(234) (3R)-1-butyl-2,5-deok is about-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(235) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(236) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(237) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methoxyphenylethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(238) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(239) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(240) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxyphenylethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(241) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(242) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(243) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-ethoxycarbonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(244) (3R)-1-propyl-2,5-dioxo-3-(1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[can,

(245) (3S)-1-propyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(246) (3S)-1-propyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(247) (3S)-1-propyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(248) (3S)-1-propyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(249) (3S)-1-propyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(250) 1-butyl-2,5-dioxo-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(251) 1-butyl-2,5-dioxo-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(252) (3R)-1-(2-butynyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(253) (3S)-1-(2-butynyl)-2,5-dioxo-3-((1S)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(254) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2-(4-phenoxyphenyl)ethyl)-1,4,9-diazaspiro[5.5]undecane,

(255) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-(4-phenoxyphenyl)ethyl)-1,4,9-diazaspiro[5.5]undecane,

(256) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-(4-methodology Setenil)ethyl)-1,4,9-diazaspiro[5.5]undecane,

(257) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-ethoxycarbonylphenyl)-1,4,9-diazaspiro[5.5]undecane,

(258) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-4-methyl-9-(4-vinyloxymethyl)-1,4,9-diazaspiro[5.5]undecane,

(259) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-methylpropylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(260) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-methoxyethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(261) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-phenylacetylamino)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(262) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-(4-forfinal)acetylamino)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(263) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxycarbonylaminophenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(264) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxyphenylacetylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(265) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(2-(4-methylaminoacenaphthylene)pyridine-5-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(266) (3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(267) (3S)-1-butyl-2,5-dioxo-3-(pyridine-3-ylmethyl)-9-(4-(4-methylaminorex is phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(268) (3S)-1-butyl-2,5-dioxo-3-phenylmethyl-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(269) (3S)-1-butyl-2,5-dioxo-3-(pyridine-2-ylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(270) (3S)-1-butyl-2,5-dioxo-3-hydroxymethyl-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(271) (3S)-1-butyl-2,5-dioxo-3-(pyridine-1-oxido-2-ylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(272) (3S)-1-butyl-2,5-dioxo-3-(pyridine-1-oxido-3-ylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(273) (3R)-1-(4-methoxyphenethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(274) (3R)-1-phenylmethyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(275) (3R)-1-(2-methoxyethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(276) (3R)-1-(pyridine-2-ylmethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(277) (3R)-1-(pyridine-3-ylmethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-treat the Spiro[5.5]undecane,

(278) (3R)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(279) (3S)-1-butyl-2,5-dioxo-3-(pyridine-1-oxido-2-ylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · 9-oxide,

(280) 1-butyl-2,5-dioxo-3-(morpholine-4-ylmethyl)9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(281) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(N-hydroxycarbamoyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(282) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylcarbamoyl)-1,4,9-diazaspiro[5.5]undecane, or

(283) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenyl)-1,4,9-diazaspiro[5.5]undecane,

its Quaternary ammonium salt, N-oxide or its non-toxic salt,

vii) a pharmaceutical composition comprising a derivative of diazaspiro[5.5]undecane formula (I)described in above (i), its Quaternary ammonium salt, N-oxide or its non-toxic salt as the active ingredient,

viii) the regulator of chemokine/chemokine receptor, including derived diazaspiro[5.5]undecane formula (I)described in above (i), its Quaternary ammonium salt, N-oxide or its non-toxic salt as active is the first ingredient, and (ix) the agent for the prophylaxis and/or treatment of asthma, atopic dermatitis, urticaria, allergic bronchopulmonary aspergillosis, allergic eosinophilic gastroenteritis, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, psoriasis, rhinitis, conjunctivitis, ischemic reperfusion disorder, multiple sclerosis, ulcerative colitis, acute respiratory distress syndrome, cytotoxic shock, diabetes, autoimmune diseases, transplant rejection, immunosuppression, metastases in cancer or acquired immunodeficiency syndrome, including derived diazaspiro[5.5]undecane formula (I)described in above (i), its Quaternary ammonium salt, N-oxide or its non-toxic salt as an active ingredient.

DETAILED description of the INVENTION

In the present invention, C1-4alkyl means methyl, ethyl, propyl, butyl or an isomer group.

C1-4alkoxy means methoxy, ethoxy, propoxy, butoxy or their isomeric groups.

Halogen represents chlorine, bromine, fluorine or iodine.

C1-4alkylene means methylene, ethylene, trimethylene, tetramethylene or their isomeric groups.

C2-4albaniles means vinile, propylen, butylen or their isomeric groups.

C2-4quinil means ethinyl, PROPYNYL, butynyl or the x isomeric groups.

C5-10-membered mono - or bikebicycle ring means cyclopentane, cyclohexane, Cycloheptane, cyclooctane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, inden, naphthalene, indan, tetrahydronaphthalen, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonan or bicyclo[4.4.0]decane, etc.

5-10-membered mono - or bi(condensed or Spiro)cyclic heterocycle containing 1-2 nitrogen atom and/or 1-2 oxygen atom means a 5-10 membered mono - or bi(condensed or Spiro)cyclic heteroaryl containing 1-2 nitrogen atom and/or 1-2 oxygen atom and a partially or fully saturated. For example, the above 5-10-membered mono - or bi(condensed or Spiro)cyclic heteroaryl containing 1-2 nitrogen atom and/or 1-2 oxygen atom and a partially or fully saturated include pyrrole, imidazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, azepine, diazepine, furan, Piran, oxepin, oxazol, isoxazol, furazan, oxadiazole, oxazin, oxadiazon, oxazepine, oxadiazon, indole, isoindole, benzofuran, isobenzofuran, indazole, quinoline, isoquinoline, phthalazine, naphthiridine, cinoxacin, hinzelin, cinnolin, benzoxazol, benzimidazole, benzofuran, benzotriazol, pyrrolin, pyrrolidin, imidazolin, imidazolidin, pyrazoline, pyrazolidine, dihydropyridines, tetrahedr is pyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxazolo, tetrahydrooxazolo, dihydroisoxazole, tetrahydrooxazolo, dihydroimidazole, tetrahydrooxazolo, tetrahydroimidazo, tetrahydroazepine, tetrahydroazepine, perhydroxyl, perhydroanthracene, morpholine, indoline, isoindoline, dihydrobenzofuran, perhydroanthracene, dihydroisobenzofuran, peligrosamente, dihydroindol, peritoneal, dihydroquinoline, tetrahydroquinoline, perhydroxyl, dihydroisoquinoline, tetrahydroisoquinoline, perhydrosqualene, dihydrophenazine, tetrahydrophthalate, PermitRootLogin, dihydronaphthalene, tetrahydronaphthalen, perhydroanthracene, dihydroquinoxaline, tetrahydroquinoxalin, perhydrophenanthrene, dihydroquinazolin, tetrahydroquinazolin, perhydrophenanthrene, dihydroindole, tetrahydroindole, permitiendoles, dihydroisoxazole, perhydroanthracene, dehydrobenzperidol, perhydroanthracene, dioxolane, dioxane, benzodioxole or benzodioxan etc.

5-6-membered m is neziklicescoy a heterocycle, containing 1-2 nitrogen atom and/or oxygen atom, which is formed by each Deputy, together with the attached nitrogen atom, means 5-6 membered monocyclic heteroaryl containing 1-2 nitrogen atom and/or oxygen atom, and partially or completely saturated. For example, in the above, 5-6-membered monocyclic heteroaryl containing 1-2 nitrogen atom and/or oxygen atom, and partially or completely saturated, includes pyrrole, imidazole, pyrazole, pyrrolin, pyrrolidin, imidazolin, imidazolidin, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, tetrahydrooxazolo, tetrahydrooxazolo, dihydroimidazole, tetrahydrooxazolo, tetrahydroimidazo or morpholine, etc.

5-6-membered monocarbocyclic ring specifically represents, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene or benzene, etc.

5-6-membered monocyclic heterocycle containing 1-2 nitrogen atom and/or oxygen atom means a 5-6-membered monocyclic heteroaryl containing 1-2 nitrogen atom and/or oxygen atom, and partially or completely saturated. For example, in the above, 5-6-membered monocycle is static heteroaryl, containing 1-2 nitrogen atom and/or oxygen atom, and partially or completely saturated, includes pyrrole, imidazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, furan, Piran, oxazol, isoxazol, furazan, oxadiazole, oxazin, oxadiazon, pyrrolin, pyrrolidin, imidazolin, imidazolidin, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxazolo, tetrahydrooxazolo, dihydroisoxazole, tetrahydrooxazolo, dihydroimidazole tetrahydrooxazolo, tetrahydroimidazo or morpholine, etc. In the present invention, each group represented by R1, R2, R3, R4or R5, is preferred. Particularly preferred are the groups described in the examples.

Unless otherwise agreed, in the present invention includes all isomers. For example, alkyl, alkoxy and alkylene groups include straight or branched chain. In addition, isomers on double bond, ring, fused ring (E-, Z-, CIS-, TRANS-isomer), isomers generated asymmetric carbon atoms (R-, S-, α-, β-isomer, ananti the measures the diastereoisomer), optically active isomers (D-, L-, d-, l-isomer), polar compounds generated by chromatographic separation (more polar compound, less polar compound), connection, balance, and mixtures thereof in any ratios and racemic mixtures are also included in the present invention.

[SALT]

Non-toxic salts of the present invention include all pharmaceutically acceptable salts, for example salts in a broad interpretation of this concept and salt accession acids.

Compounds of the present invention of formula (I) can be converted into the corresponding salts by standard methods. Non-toxic and water-soluble salts are preferred. Suitable salts, for example, include: salts of alkali metals (potassium or sodium etc), salts of alkaline earth metals (calcium or magnesium etc), ammonium salts and salts of pharmaceutically acceptable organic amines (Tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, Tris(hydroxymethyl)amine, lysine, arginine or N-methyl-D-glucamine etc).

Compounds of the present invention of formula (I) can be converted into the corresponding salt accession acids by standard methods. Soluble salts are preferred. Fit the Oli, for example, include salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, or nitrate; organic acid salts, such as acetate, triptorelin, lactate, tartrate, oxalate, fumarate, maleate, citrate, benzoate, methanesulfonate, aconsultant, bansilalpet, toluensulfonate, isetionate, glucuronate and gluconate.

Compounds of the present invention of formula (I) and their salts can be converted into the corresponding hydrates the conventional methods.

All the compounds of formula (I) or their non-toxic salts are preferred, specifically, compounds described in the examples or their non-toxic salts.

Quaternary ammonium salt compounds of formula (I) are compounds where the nitrogen compounds of formula (I) quaternion R0.

R0represents C1-4alkyl or C1-4alkyl substituted by phenyl.

N-oxides of compounds of formula (I) are compounds where the nitrogen compounds of formula (I) is oxidized.

[METHODS of making COMPOUNDS of the PRESENT INVENTION]

Compounds of the present invention of formula (I) can be obtained by the following methods or by methods described in the examples.

Among the compounds of the present invention of formula (I), the compound, where the nitrogen atoms are not included in the Quaternary ammonium salt or N-oxide, is from the Association of the formula (I-1)

(where R1-1, R2-1, R3-1, R4-1and R5-1are the same values that R1, R2, R3, R4and R5respectively, and N1is nitrogen, and where any nitrogen atom is not part of Quaternary ammonium salt or N-oxide), can be obtained in the following ways :

Among the compounds of the present invention of the formula (I-1), a compound in which any one of R1-1, R2-1, R3-1, R4-1and R5-1is not a group containing carboxyl, hydroxy, amino or thiol is a compound of formula (I-1A)

(where R1-1A, R2-1A, R3-1A, R4-1Aand R5-1Aare the same values that R1-1, R2-1, R3-1, R4-1and R5-1respectively, and where they are not a group that contains carboxy, hydroxy, amino or thiol, and the other symbols have the same meanings as defined above), can be obtained by cyclization of the compounds of formula (II)

(where T represents C1-4 alkyl, C5-6 monocarbocyclic ring or C1-4 alkyl, substituted Deputy selected from C5-6 monocarbocyclic ring and C5-6 monocyclic heterocycle containing 1-2 of nitrogen and/or oxygen).

Cyclization of the compounds of formula (II) is well known. For example, it is can be heated in an organic solvent (dichloroethane or toluene, etc. in the presence or absence of tertiary amine (triethylamine or diisopropylethylamine etc) or acid (acetic acid or triperoxonane acid, etc.) at 60-120°C. the cyclization reaction is completed simultaneously with the removal of group T.

In addition, the cyclization can be carried out with the compound in which R3or R4is a hydroxyl group.

The cyclization can be carried out with the compound in which the nitrogen in R1, R2, R3or R4oxidized to N-oxide.

If necessary, the translation in the desired non-toxic salts may be conducted by conventional methods after cyclization.

Among the compounds of formula (I-1A), the compound in which the group G in R1-1Arepresents a methylene or vinile, is a compound of formula (I-1A-1)

(where the group G1represents a methylene or vinile, R1-1A-1is

(where R6-1Ahas the same value as R6and where they are not a group that contains carboxy, hydroxy, amino or thiol, and the other symbols have the same meanings as defined above)can be obtained by reductive amination of compounds of formula (III)

(where all the symbols have the same meanings as defined above) or the compounds of formula (IV)

with the compound of the formula (V).

Recovery the amination is well known. For example, it may be carried out in an organic solvent (dichloroethane, dichloromethane, dimethylformamide, acetic acid or mixtures thereof, etc.) in the presence of a reducing agent (triacetoxyborohydride sodium or cyanoborohydride sodium, etc.) at 0-40°C.

In addition, reductive amination can be carried out with the compound in which the nitrogen in R1oxidized to N-oxide.

In addition, reductive amination can be carried out with the compound in which R3or R4represents a hydroxyl group.

Among the compounds of formula (I-1A), a compound in which the group G in R1-1Arepresents ethylene, is a compound of formula (I-1A-2)

(where all the symbols have the same meanings as defined above)can be obtained by the coupling of compounds of formula (VI)

(where all the symbols have the same meanings as defined above) with the compound of the formula (V).

This reaction is well known, for example, first, the reaction resin PS-TsCl-HL (trade mark catalog Argonaut Technologies, room 800366) with the compound of the formula (VI) can be carried out in an organic solvent (e.g. chloroform or dichloromethane, etc. in the presence of tertiary amine (isopropylethylene etc.) at 0-40°C, and then the reaction which may be carried out in an organic solvent (for example, chloroform or dichloromethane, etc.) with the compound of the formula (V) in the presence of tertiary amine (triethylamine or diisopropylethylamine etc.) at 40-100°C.

This reaction can be carried out with the compound in which the nitrogen in R1, R2, R3or R4oxidized to N-oxide.

Among the compounds of formula (I-1A), a compound in which the group G in R1-1Arepresents a single bond, is a compound of formula (I-1A-3)

(where all the symbols have the same meanings as defined above)can be obtained by the coupling of compounds of formula (VII)

(where X represents halogen and the other symbols have the same meanings as defined above)with the compound of the formula (V).

The reaction is well known, and it can be carried out, for example, in an organic solvent (dimethyl sulfoxide and so on) in the presence of an alkaline agent (potassium carbonate or sodium carbonate, etc.) at 100-150°C.

In addition, this reaction can be carried out with the compound in which the nitrogen in R1, R2, R3or R4oxidized to N-oxide.

Among the compounds of formula (I-1A), a compound in which the group G in R1-1Arepresents-CO-, is a compound of formula (I-1A-5)

(where all characters have the same C is achene, as defined above), can be obtained by amidation of the compounds of formula (XIII)

(where all the symbols have the same meanings as defined above), a compound of formula (V).

The amidation is well known, and it includes methods, for example,

(1) through gelegenheid acid,

(2) via a mixed acid anhydride,

(3) using a condensing agent.

These methods are explained as follows.

(1) the Way through gelegenheid acid, can be carried out, for example, the interaction of carboxylic acids with galogenangidridy acid (for example, oxalylamino or thionyl chloride etc. in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) or without a solvent at temperatures from -20°C to the boiling temperature under reflux. Next, the resulting derived gelegenheid acid can be subjected to interaction with the amine in an inert organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) in the presence of tertiary amine (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine) at 0-40°C. Alternative derived derived gelegenheid acid can be subjected to interaction with AMI who ohms in an organic solvent (for example, dioxane or tetrahydrofuran) using an alkaline aqueous solution (for example, sodium bicarbonate or sodium hydroxide) at 0-40°C.

(2) the Method via a mixed acid anhydride may be carried out, for example, the interaction of carboxylic acids with allelochemical (for example, revalorisation, mozillateam or methylchloride) or acid derivative (for example, etelcharge.com or isobutylparaben) in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) or without a solvent, in the presence of tertiary amine (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine) at 0-40°C. Next, the resulting derived mixed acid anhydride may be subject to interaction with the amine in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) at 0-40°C.

(3) the Method using a condensing agent may be carried out, for example, by the interaction of the carboxylic acid with amine in an organic solvent (e.g. chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran) or without a solvent, in the presence or absence of tertiary amine (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine) with use the of condensing agent (for example, 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1'-carbodiimide (CDI), iodide, 2-chloro-1-methylpyridine or cyclic anhydride 1-papapostolou acid) in the presence or absence of 1-hydroxybenzotriazole (HOBt) at 0-40°C.

To obtain the preferred result of the reaction described in (1), (2) and (3)may be conducted in an atmosphere of inert gas (e.g. argon or nitrogen)to avoid water ingress.

In addition, the amidation can be carried out with the compound in which R3or R4represents a hydroxyl group.

In addition, the amidation can be carried out with the compound in which the nitrogen in R1, R2, R3or R4oxidized to N-oxide.

Among the compounds of formula (I-1), a compound in which at least one group of R1, R2, R3, R4or R5represents a group containing carboxyl, hydroxy, amino or thiol, is a compound of formula (I-1B)

(where R1-1B, R2-1 B, R3-1B, R4-1Band R5-1Bare the same values that R1-1, R2-1, R3-1, R4-1and R5-1respectively, and where at least one group represents a group containing carboxyl, hydroxy, amino or thiol, and the other symbols have the same meanings as ODA is defined above), can be obtained by removing the protective groups containing carboxyl, hydroxy, amino and thiol, protected by a protective group, i.e. the compound of formula (I-1A-4)

(where R1-1A-4, R2-1A-4, R3-1A-4, R4-1A-4and R5-1A-4are the same values that R1-1, R2-1, R3-1, R4-1and R5-1respectively, and where at least one group represents a group containing carboxyl, hydroxy, amino or thiol, and the other symbols have the same meanings as defined above).

The protective group for carboxyl includes, for example, methyl, ethyl, tert-butyl, benzyl or allyl.

The protective group for the hydroxy-group includes, for example, methoxymethyl, 2-tetrahydropyranyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl or benzyl.

The protective group for the amino group includes, for example, benzyloxycarbonyl, allyloxycarbonyl, tert-butoxycarbonyl, TRIFLUOROACETYL or 9-fluorenylmethoxycarbonyl.

The protective group for Tilney group includes, for example, benzyl, methoxybenzyl, atsetamidometil, triphenylmethyl or acetyl.

Protective group carboxyl, hydroxy-group, amino group or Tilney group includes the above group, and, in addition to other protective group which can be selectively and easily removed, for example, a group described in T.W. Greene et al., Protective Groups in Orgic Synthesis, Third Edition, Wiley-Interscience, New York, 1999.

The removal of the protective group from the amino can be carried out by the method described above in this specification.

The removal of the protective group from carboxyl, hydroxy-group or Tilney group is well known, for example, it is a

(1) alkaline hydrolysis,

(2) removing the protective group in acidic conditions,

(3) removing the protective group by hydrogenolysis or

(4) removing the protective group containing silyl, or

(5) removing the protective group using complex metal etc.

Specific descriptions of these methods are as follows:

(1) removing the protective group under the conditions of alkaline hydrolysis (for example, trifluoracetyl group) can be carried out, for example, in an organic solvent (methanol, tetrahydrofuran or dioxane, etc.) hydroxide of alkaline metal (sodium hydroxide, potassium hydroxide or lithium hydroxide, etc.), hydroxide of alkaline earth metal (barium hydroxide or calcium hydroxide, etc.), a carbonate (sodium carbonate or potassium carbonate, etc. or their aqueous solution or their mixture at 0-40°C.

(2) removal of the protective group under acidic conditions (for example, tert-butoxycarbonyl group) can be carried out, for example, in an organic solvent (dichloromethane, chloroform, dioxane, is dilacerate or anisole etc) organic acid (acetic acid, triperoxonane acid or methanesulfonic acid, etc. or an inorganic acid (hydrochloric acid or sulfuric acid, etc. or mixtures thereof (hydrogen bromide/acetic acid etc) at 0-100°C.

(3) removing the protective group by hydrogenolysis (for example, benzyl, benzyloxycarbonyl or allyloxycarbonyl) can be carried out, for example, in a solvent (ether (tetrahydrofuran, dioxane, dimethoxyethane or diethyl ether, etc.), alcohol (methanol or ethanol etc), benzene (benzene or toluene, etc.), ketone (acetone or methylethylketone, etc.), a nitrile (acetonitrile etc), amide (dimethylformamide etc), water, ethyl acetate, acetic acid or mixtures thereof, etc. in the presence of a catalyst (palladium on carbon, palladium mobiles, palladium hydroxide, platinum oxide or Nickel of Renea etc), at atmospheric or pressure in the atmosphere of hydrogen or in the presence of ammonium formate at 0-200°C.

(4) removing the protective group containing silyl, can be carried out, for example, in an organic solvent (tetrahydrofuran or acetonitrile, etc.) tetrabutylammonium fluoride at 0-40°C(5) removing the protective group, by using a complex metal can be carried out, for example, in an organic solvent (dichloromethane, dimethylformamide or tetrahydrofuran, etc.) constituted the basis of a capture agent (anti-hydride or dimedone and so on) and/or organic acids (acetic acid, etc.) complex (metal complex of tetrakis(triphenylphosphine)palladium(0 and so on) at 0-40° C.

As is well known to the person skilled in the art, the target compounds of the present invention can be easily obtained by choosing among these options.

Among the compounds of formula (I), a compound in which at least one nitrogen atom is a Quaternary ammonium salt is a compound of the formula (I-2)

(where R1-2, R2-2, R3-2, R4-2and R5-2are the same values that R1, R2, R3, R4and R5,respectively, and where at least one nitrogen atom represents a salt of Quaternary ammonium, and where Q is a halogen), which can be obtained by the coupling of compounds of formula (XI)

(where R0represents C1-4alkyl or C1-4alkyl, substituted phenyl, and Q is a halogen).

The reaction is well known, and it can be done, for example, in an organic solvent (acetone, dimethyl sulfoxide or methyl ethyl ketone, etc.) at 0-40°C.

Among the compounds of formula (I) compound in which at least one nitrogen atom is N-oxide, is a compound of formula (I-3)

(where R1-2, R2-2, R3-2, R4-2and R5-2are the same values that R1, R2, R3, R4and R5according to the respectively, and where at least one nitrogen atom is N-oxide, and where Q is a halogen), which can be obtained by oxidation of compounds of formula (I-1).

Oxidation is well known, and it can be done, for example, in a suitable organic solvent (dichloromethane, chloroform, benzene, hexane or tert-butyl alcohol, etc. in the presence of excess oxidizing reagent (hydrogen peroxide, periodate sodium, acilitate, sodium perborate, peroksidaznoi acid (for example, 3-chloroperbenzoic acid or peracetic acid, etc), OXONE (trade mark, OXONE is an abbreviation for peroxymonosulfate potassium), potassium permanganate or chromic acid, etc.) at 20-60°C.

The compounds of formula (II) can be obtained in accordance with the following Scheme 1:

In the above Scheme 1, each reaction can be conducted by known methods. In addition, in the above Scheme 1, the starting materials for compounds of formula (IX), formula (X), formula (XI) or formula (XII) can be known as such, or can be obtained by known methods.

In the present invention in each of the reaction products obtained can be purified by standard methods. For example, purification can be carried out by distillation at atmospheric or decreased the pressure, high-performance liquid chromatography, thin-layer chromatography or column chromatography using silica gel or magnesium silicate, washing or recrystallization. Cleaning may be performed after each reaction or after several reactions.

Other source materials and each reagent in the present invention can be known as such, or can be obtained by known methods.

[PHARMACOLOGICAL ACTIVITY]

The effectiveness of compounds of the invention of formula (I) has been confirmed, for example, the following tests.

As described above, for screening compounds capable of inhibiting the binding of HIV CXCR4 or CCR5, which are receptors on CD4-positive cell, a more targeted way for it is an analytical system that uses the HIV virus. However, the use of a large number of HIV virus in screening is not practical due to the complexity of manipulation. On the other hand, as macrofamily tropic (R5) HIV-1 and ligands, which are RANTES, MIP-1α and MIP-1βcontact CCR5, we can assume that certain General characteristics are present in the sites of binding of CCR5 by HIV and by RANTES, MIP-1α and MIP-1βand in parts of the CCR5 binding to ligands, which is Vlada RANTES, MIP-1α and MIP-1βand for HIV. Accordingly, to find compounds capable of inhibiting adsorption of HIV virus cells with inhibitory mechanism that is used by the drugs currently used against AIDS, (reverse transcriptase inhibitors and protease inhibitors), you can use an analytical system that uses an endogenous ligand of CCR5, RANTES, MIP-1α or MIP-1β instead of HIV.

Specifically, for example, since CCR5 is associated with a G protein transmembrane receptor of the seven types, for screening compounds capable of inhibiting the binding of RANTES c CCR5 can be performed analytical system in which RANTES influences temporary increase in the concentration of Ca ion induced CCR5. Because T-cell tropic (X4) HIV and SDF-1 are associated with CXCR4, a similar idea can be taken into account when screening for compounds.

[TEST]

(1) Isolation of the gene of human CCR5

Placental cDNA person receive, using amplication set Marathon cDNA (Clontech). Primers for PCR hCCR5Xbal-F1:

5'-AGCTAGTCTAGATCCGTTCCCCTACAAGAAACTCTCC-3' (SEQ ID no:1) and hCCR5Xbal-R1:

5'-AGCTAGTCTAGAGTGCACAACTCTGACTGGGTCACCA-3' (SEQ ID no:2) were designed based on the sequence of GenBank U54994.

Using placental cDNA person as a matrix and using Ex Taq (Takara), Prov is completed reaction PCR (2 min at 95° C → (30 seconds at 95°C, 45 seconds at 60°C, 1 minute at 72° (C) x 35 times). Thus, amplificatory the PCR product is subjected to electrophoresis on 1% agarose gel, purified using the kit QIAquick Gel Extraction (QUIAGEN) and then treated with restriction enzymes Xbal. Processed fragments are ligated into the expression vector pEF-BOS-bsr using the set for ligating DNA Ver. 2 (Takara)and transformed into Escherichia coli DH5a. Obtaining the resulting plasmid pEF-BOS-bsr/hCCR5 control its DNA sequence.

(2) the Cultivation of CHO cells

CHO-dhfr(-) were cultured using HAM's F-12 (containing fetal bovine serum (FBS) (10%), penicillin (50 U/ml) and streptomycin (50 mg/ml)). Also, the transduced cells cultured by adding blasticidin (5 mg/ml) to the above environment.

(3) Transduction in CHO-cell

Plasmid pEF-BOS-bsr/hCCR5 transducer in CHO-dhfr(-) cell, using the reagent DMRIE-C (Gibco BRL). After 48 hours the medium is replaced by a medium containing 5 mg/ml blasticidin for breeding, setting, thus, stably over-expressing cell.

(4) Test for inhibition of binding of RANTES to CCR5 (RANTES activity by inducing a temporary increase in the concentration of Ca ion).

These cells SNO, stable sverkhekspressiya human CCR5 (CCR5/CHO cell), suspended in medium Ham's F-12 containing FBS (10%) and p is opredelyaut in 96-hole tablet portions 3,0x10 6cells/well. Through days of cultivation at 37°C, the supernatant of the culture select and environment Ham F-12 (containing Fura-2AM (5 μm), probenecid (2.5 mm) and HEPES (20 mm; pH 7,4)) allocate portions at 80 μl/well for 1 hour incubation at 37°C in terms of shading. After double wash solution 1x Hanks/HEPES (20 mm; pH 7,4) the same solution distribute portions of 100 μl/well. Each of the test compounds is added to thus Fura-2AM-embedded CCR5/CHO cell, and 3 minutes later there is added recombinant human RANTES (PeproTach), diluted with a solution of 1x Hanks/HEPES (20 mm; pH of 7.4) to a final concentration of 10 nm. A temporary increase in the concentration of intracellular Ca2+induced RANTES person, measured using the Ca2+detector for 96-well applications (Hamamatsu Photonics), and the ratio of inhibition (%) for test compounds are calculated according to the following calculation formula.

The ratio of inhibition=(Ec - Ea)/Ec x 100.

Ec: measured value, a temporary increase of Ca2+induced RANTES.

Ea: the measured value of the temporary increase of Ca2+induced RANTES adding the test compound.

In the compounds of the invention show the ratio of inhibition equal to 50% or more at 10 μm. For example, the compound of example 2 showed the value of the IC50equal to or 0.027 μm, and the compound of example 3 C is Uchenie IC 50equal to 0.37 μm. Analytical system for the detection of compounds with inhibitory activity against adsorption directional strain of HIV to CCR5 was described above, and it is obvious that it is possible to find a connection, is able to inhibit the activity of CCR5 or its ligand, using this system. In the same way, you can find a connection, is able to inhibit the activity of the receptor of the chemokine or its ligand. For example, can be designed a system for detecting compounds capable of inhibiting the activity of CCR2 or its ligand. Because CCR2 is a associated with G protein transmembrane receptor of the seven types, similar to CCR5, the system can be implemented by measuring the effect of the CCR2 ligand, for example, MCP-1 temporary increase in the concentration of Ca ion induced through CCR2.

(5) Test for inhibition of binding of MCP-1 and CCR2 (the activity of MCP-1 by inducing a temporary increase in the concentration of Ca ion).

CCR2-expressing human cells, for example monocyte human cell strain THP-1 (ATCC No. TIB-202), suspended in RPMI medium 1640 containing FBS (10%), Fura-2AM (5 μm), Probenecid (2.5 mm) and HEPES (20 mm, pH of 7.4) to a density of 5,0x106cells/ml and incubated at 37°C for 30 minutes in terms of shading. The obtained mixed with 4-8 volumes of 1x Hanks/HEPES (20 mm, pH 7,4)/Probenecid (2.5 mm) and then inquiry is at 37° C for 30 minutes in terms of shading. After washing solution 1x Hanks/HEPES (20 mm, pH 7,4)/Probenecid (2.5 mm), thus the washed cells resuspended in the same solution to a density of 2,0x106cells/ml and distributed in portions of 100 μl/well in 96-well plate. Each of the tested compounds add to it and 3 minutes later there is added recombinant MCP-1 person (PeproTach), diluted 1x Hanks/HEPES (20 mm; pH of 7.4) to a final concentration of 30 nm. A temporary increase in the concentration of intracellular Ca2+induced MCP-1 person, measured using the Ca2+detector for 96-well applications (Hamamatsu Photonics), and the ratio of inhibition (%) for test compounds are calculated according to the following calculation formula:

The ratio of inhibition=(Ec - Ea)/Ec x 100.

Ec: measured value, a temporary increase of Ca2+induced MCP-1;

Ea: the measured value of the temporary increase of Ca2+induced MCP-1 when adding the test compound.

[TOXICITY]

The toxicity of the compounds of the present invention is very low and therefore the connection can be considered safe for pharmaceutical use.

Industrial applicability

[APPLICATION TO PHARMACEUTICALS]

Compounds of the present invention of formula (I) regulate the effect of chemokine/chemokine is of eceptor animals including humans, especially humans, so that they are used for prevention and/or treatment of various inflammatory diseases, asthma, atopic dermatitis, urticaria, allergic diseases (allergic bronchopulmonary aspergillosis or allergic eosinophilic gastroenteritis, etc), nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, psoriasis, rhinitis, conjunctivitis, ischemic reperfusion disorder, multiple sclerosis, ulcerative colitis, acute respiratory distress syndrome, cytotoxic shock, diabetes, autoimmune diseases, transplant rejection, immunosuppression, cancer metastasis or acquired immunodeficiency syndrome.

For the purpose described above, the compounds of formula (I), their non-toxic salts, and their salts accession acids or their hydrates can accordingly be administered systemically or locally, usually by oral or parenteral administration.

Doses for administration determined, for example, the age, body weight, symptom, the desired therapeutic effect, the route of administration and duration of treatment. Adult personal dose usually ranges from 1 mg to 1000 mg, by oral administration, up to several times a day, and from 1 mg to 100 mg by parenteral administration (preferably inside venom introduction) up to several times per day or by continuous introduction from 1 to 24 hours a day in the veins.

As stated above, the dose to use depends on various conditions. Therefore, there are cases in which can be used doses at intervals smaller or larger than indicated above.

Compounds of the present invention can be administered, for example, in solid form for oral administration in liquid form for oral administration, injections, liniments or suppositories for parenteral administration.

Solid forms for oral administration include compressed tablets, pills, capsules, dispersible powders and granules. Capsules include hard capsules and soft capsules.

In such solid forms one or more active compounds can be mixed with carriers such as lactose, mannitol, glucose, microcrystalline cellulose, starch), binding agents (such as hydroxypropylcellulose, polyvinylpyrrolidone or metasilicate magnesium aluminate), disintegrants (such as cellulose-glycolic calcium), lubricating agents (such as magnesium stearate), stabilizing agents and auxiliary means dissolution (such as glutamic acid or aspartic acid) and obtained in accordance with methods well known in normal pharmaceutical practice. Solid forms may optionally be covered with a covering agents (this is how sugar, gelatin, hydroxypropylcellulose or phthalate of hydroxypropylmethylcellulose) or be covered by two or more films. Further, the coating can include the content inside the capsules of the adsorbed materials such as gelatin.

Liquid forms for oral administration include pharmaceutically acceptable solutions, suspensions and emulsions, syrups and elixirs. In such forms one or more active compounds may be dissolved, suspended or emulsified in the diluent normally used in this field (such as purified water, ethanol or mixtures thereof). In addition, such liquid formulations can also include additives, such as moisturizing agents, suspendresume agents, emulsifying agents, sweeteners, fragrances, flavors, preservatives or superimpose agent.

Injections for parenteral administration include sterile aqueous suspensions, emulsions and solid form, which is dissolved or suspended in solvents for injection immediately before use. When the injection of one or more active compounds may be dissolved, suspended or emulsified in a solvent. Solvents may include distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohol, for example, ETANA is, or mixtures thereof. Injections may include some additives, such as stabilizing agents, auxiliaries dissolution (such as glutamic acid, aspartic acid or POLYSORBATE 80 (registered trademark)), suspendresume agents, emulsifying agents, soothing agent, buferiruemoi agents, preservative. They can be sterilized in the final stage or can be obtained and compensated in accordance with a sterile way. They can also be made in the form of sterile solid dosage forms, such as freeze-dried products, which can be dissolved in sterile water or some other sterile diluent for injection immediately before use.

Other forms for parenteral administration include liquids for external use, ointments and undermydesk liniments, inhalations, sprays, suppositories and pessaries for vaginal administration, which include one or more active compounds and can be obtained by methods known as such.

Sprays can include additional substances other than diluents, such as stabilizing agents, such as sodium sulfate, isotonic buffers, such as sodium chloride, sodium citrate or citric acid. To obtain such sprays can be used, for example, the way the op is sliding in U.S. patent No. 2868691 or 3095355. The compound of the present invention of formula (I), its Quaternary ammonium salt, N-oxide or its non-toxic salt can be used together with at least one representative of the other means for the prevention and/or treatment of HIV infection (especially a remedy for the prevention and/or treatment of AIDS). In this case, the medicine, as such, can be mixed with pharmacologically acceptable excipients linking agent, dezintegriraat agent, lubricating agent, stabilizer, solubilizer, solvent, etc. either separately or simultaneously to obtain a pharmaceutical preparation that can be administered either orally or parenterally as a pharmaceutical composition for prevention and/or treatment of HIV infection.

The compound of formula (I), its Quaternary ammonium salt, N-oxide or its non-toxic salt possess inhibitory activity against HIV-1 infection, which acquired resistance to another agent for the prophylaxis and/or treatment of HIV infection (particularly, the means for prevention and/or treatment of AIDS). Therefore, they can also be used for HIV-infected patients for whom other means for the prevention and/or treatment of HIV infection is no longer effective. In this case, although the connection of this izopet the Deposit may be applied separately, it can also be used in conjunction with means for prevention and/or treatment of HIV infection, when the strain of HIV-1 acquires resistance, or together with other medicines.

The present invention covers the case where the compound of formula (I), its Quaternary ammonium salt, N-oxide or its non-toxic salt combined with medication, which did not inhibit HIV infection, whereby enhanced preventive and/or therapeutic effect against HIV infection compared with single-agent.

Examples of other agent for prevention and/or treatment of HIV infection used in combination with the compound of the present invention of formula (I), its Quaternary ammonium salt, N-oxide or its non-toxic salt, are nucleoside reverse transcriptase inhibitor, protease inhibitor, antagonist of a chemokine (such as CCR2 antagonist, CCR3 antagonist, CCR4 antagonist, CCR5 antagonist and antagonist of CXCR4), fusion inhibitor, antibody against surface antigen of HIV-1 and vaccine of HIV-1, etc.

Reverse transcriptase inhibitors are specifically (1) nucleoside/nucleotide reverse transcriptase inhibitors: zidovudine (brand name: Retrovir), didanosine (brand name: Videx), zalcitabine (brand: HIVID), stavudine (brand name: Zerit), lamivudine (brand name: Epivir), abacavir (brand name: Ziagen, adefovir, adefovir dipivoxil, emtricitabine (brand: Coviracil) or PMPA (brand: Tenofovir), etc. and (2) non nucleoside reverse transcriptase inhibitors: nevirapine (brand name: Viramune), delavirdine (brand: Rescriptor), efavirenz (brand name: Sustiva, Stocklin) or capravirine (AG1549) etc.

Protease inhibitors are specifically indinavir (brand name: Crixivan), ritonavir (brand name: Norvir), nelfinavir (brand name: Viracept), saquinavir (brand name: Invirase, Fortovase), APV (brand: Agenerase), lopinavir (brand name: Kaletra), or tipranavir, etc.

Antagonists of chemokine include internal ligands of the receptor of the chemokine, derivative, ones low-molecular compound or antibody against the receptor of the chemokine.

Examples of internal ligand receptor of the chemokine are specifically, MIP-1α, MIP-1β, RANTES, SDF-1α, SDF-1β, MCP-1, MCP-2, MCP-4, Eotaxin and MDC etc.

The derivatives of the internal ligand are specifically AOP-RANTES, Met-SDF-1α, Met-SDF-1β etc.

Antibodies to the receptor of the chemokine are specifically, Pro-140, etc.

Antagonists of CCR2 specifically described in the description WO99/07351, WO99/40913, WO00/46195, WO00/46196, WO00/46197, WO00/46198, WO00/46199, WO00/69432 or WO00/69815 or Bioord. Med. Chem. Lett., 10, 1803 (2000), etc.

Antagonists of CCR3 specifically described in the description DE19837386, WO99/55324, WO99/55330, WO00/04003, WO00/27800, WO00/27835, WO00/27843, WO00/29377, WO00/31032, WO00/31033, WO00/34278, WO00/35449,WO00/35451, WO00/35452, WO00/35453, WO00/35454, WO00/35876, WO00/35877, WO00/41685, WO00/51607, WO00/51608, WO00/51609, WO00/51610, WO00/53172, WO00/53600, WO00/58305, WO00/59497, WO00/59498, WO00/59502, WO00/59503, WO00/62814, WO00/73327 or WO01/09088, etc.

The CCR5 antagonists specifically described in the description WO99/17773, WO99/32100, WO00/06085, WO00/06146, WO00/10965, WO00/06153, WO00/21916, WO00/37455, EP1013276, WO00/38680, WO00/39125, WO00/40239, WO00/42045, WO00/53175, WO00/42852, WO00/66551, WO00/66558, WO00/66559, WO00/66141, WO00/68203, JP2000309598, WO00/51607, WO00/51608, WO00/51609, WO00/51610, WO00/56729, WO00/59497, WO00/59498, WO00/59502, WO00/59503, WO00/76933, WO98/25605 or WO99/04794, WO99/38514 or Bioord. Med. Chem. Lett., 10, 1803 (2000), etc.

The CXCR4 antagonists are specifically AMD-3100, T-22, KRH-1120 or compounds described in the description WO00/66112 etc.

Fusion inhibitors, specifically, are T-20 (Pentatonic) and T-1249, etc.

Assume that examples of means for combination therapy, described above, illustrate the present invention but do not restrict it.

Assume that typical examples of conventional dose levels for clinical trials of reverse transcriptase inhibitors or protease inhibitors, described below, illustrate the present invention but do not restrict it. Zidovudine: 100 mg capsule, 200 mg per dose, 3 times a day;

300 mg tablet 300 mg per dose, twice a day;

didanosine: 25-200 mg tablet, 125-200 mg per dose, twice a day;

zalcitabine: the 0.375-0.75 mg tablet of 0.75 mg per dose, 3 times a day;

stavudine: 15-40 mg capsule, 30-40 mg per dose, twice a day;

lamivudine: 50 mg tablet, 150 mg per dose, twice a day;

abacavir: 300 mg tablet 300 mg per dose, twice a day;

nevirapine is 200 mg tablet, 200 mg per dose, once a day for 14 days and then twice a day;

delavirdine: 100 mg tablet, 400 mg per dose, 3 times a day;

efavirenz: 50-200 mg capsule, 600 mg per dose, once a day;

indinavir: 200-400 mg capsule, 800 mg per dose, 3 times a day;

ritonavir: 100 mg capsule, 600 mg per dose, twice a day;

nelfinavir: 250 mg tablet 750 mg per dose, 3 times a day;

saquinavir: 200 mg capsule, 100, or 200 mg per dose, 3 times a day;

APV: 50-150 mg tablet, 100, or 200 mg per dose, twice a day.

The following reference examples and examples are intended to illustrate the present invention but do not restrict it.

The names of the solvents for chromatographic separations and TLC indicated in parentheses indicate eluting and showing solvents, and the ratio of the used solvents are three-dimensional.

Solvents, whose names are given in parentheses for the NMR data indicate that the solvents used for the measurement.

Reference example 1

(2R,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-4-methyl-N-butyl-N-[4-benzylaminocarbonyl-1-benzylpiperidine-4-yl]pentanone

To a solution of (2R,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-4-methylpentanoic is islote (10.5 g) in methanol (340 ml) is added n-butylamine (4,2 ml), N-benzyl-4-piperidone (7.9 ml) and benzylidene (5,2 ml). The reaction mixture was stirred overnight at 55°C. the Reaction mixture was concentrated. The resulting residue is purified column chromatography on silica gel(chloroform:methanol=100:1→75:1→50:1) to obtain specified in the connection header (19,8 g)having the following physical data.

TLC:Rf is 0.49 (chloroform:methanol=10:1);NMR (CD3OD): δ 7,38-to 7.15 (m, 10H), 4,58 (d, J=9.6 Hz, 1H), 4,39 (d, J=to 15.0 Hz, 1H), 4,23 (d, J=to 15.0 Hz, 1H), 3,70-3,30 (m, 3H), 3,50 (s, 2H), 2,79-of 2.30 (m, 6H), 2,08-of 1.88 (m, 2H), 1,88 is 1.70 (m, 3H), 1.50 is of 1.28 (m, 2H), to 1.38 (s, 9H), and 0.98 (t, J=7.2 Hz, 3H), of 0.96 (d, J=6.6 Hz, 3H), of 0.91 (d, J=6.6 Hz, 3H).

Reference example 2

(2R,3R)-2-amino-3-hydroxy-4-methyl-N-butyl-N-[4-benzylaminocarbonyl-1-benzylpiperidine-4-yl]pentanone

In a bath with ice to a solution of compound (19,8 g)obtained in reference example 1, in dichloromethane (65 ml) is added triperoxonane acid (50 ml). The reaction mixture is stirred for 1 hour at room temperature. To the reaction mixture dichloromethane, neutralized with an aqueous solution of sodium carbonate and extracted. The extract is washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated to obtain specified in the title compound having the following physical data. The obtained residue use in the following the reaction without further ochistki:Rf of 0.38 (chloroform:methanol=10:1).

Example 1

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-propyl)-9-benzyl-1,4,9-diazaspiro[5.5]undecane

To a solution of the compound obtained in reference example 2 in toluene (200 ml) is added acetic acid (15 ml). The reaction mixture is stirred for 45 minutes at 80°C. the Reaction mixture was diluted with ethyl acetate, neutralized with an aqueous solution of sodium carbonate and extracted. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (ethyl acetate:methanol=25:1) to obtain the specified title compound (12.9 g)having the following physical data.

TLC:Rf is 0.49 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 7.36-7,22 (m, 5H), 4,10 (d, J=2.7 Hz, 1H), 3,60 (s, 2H), 3,47 (m, 1H), 3,38-of 3.25 (m, 2H), 2,96 (m, 1H), 2,87-by 2.73 (m, 3H), 2,25-of 1.94 (m, 4H), equal to 1.82 (m, 1H), 1,64 (m, 1H), 1,53-of 1.27 (m, 3H), 0,96 (d, J=6.6 Hz, 6H), of 0.95 (t, J=7.5 Hz, 3H).

Reference example 3

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

In an argon atmosphere to a solution of compound (12,67 g)obtained in example 1 in methanol (160 ml) was added 20% palladium hydroxide on carbon (1.3 g). In hydrogen atmosphere, the reaction mixture is stirred for 12 hours at room temperaturereading the mixture is filtered through celite and the filtrate concentrated. The resulting residue is purified column chromatography on silica gel (chloroform:hexane=3:1 → chloroform:methanol=100:1→50:1→30:1→20:1→10:1). To the obtained connection add a solution of 4N hydrogen chloride/ethyl acetate and concentrated to obtain the compound indicated in heading (8.6 g)having the following physical data.

TLC:Rf of 0.16 (chloroform:methanol:acetic acid=20:4:1);

NMR (CD3OD): δ 4,15 (d, J=2.1 Hz, 1H), 3,95 (m, 1H), 3,71 (m, 1H), 3,52 (m, 1H), 3,42-of 3.31 (m, 2H), 3,21 (m, 1H), 3,21 (DD, J=a 9.6, 2.1 Hz, 1H), 2,48 of-2.32 (m, 2H), 2,23 (m, 1H), 2,14 is 1.96 (m, 2H), 1,72 (m, 1H), of 1.55 and 1.33 (m, 3H), 1,02 to 0.92 (m, 9H);

optical rotation:[α]D+13,9° (c 1,00, methanol, 28°C).

Reference examples 3(1)-3(9)

The following connections will receive is similar to the method described in reference example 1 → reference example 2, → example 1 → reference example 3, using the appropriate derivative of the amino acid instead of (2R,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-4-methylpentanoic acid, respectively, and using appropriate derivatives of amine instead of n-butylamine, respectively.

Reference example 3(1)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.18 (chloroform:methanol=4:1);

NMR (CD3OD): δ was 4.02 (DD, J=7,8, and 4.6 Hz, 1H), 3,82-3,70 (m, 2H), 3,39 (m, 4H), 2,34-of 2.09 (m, 4H), 1,88 of 1.50 (m, 5H), to 1.37 (m, 2H), 0,97 (t, J=5 Hz, 3H), of 0.95 (d, J=6.5 Hz, 3H), were 0.94 (d, J=6.5 Hz, 3H);

optical rotation:[α]D-38,8° (c 1,04, methanol, 23°C).

Reference example 3(2)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0,08 (chloroform:methanol:acetic acid=90:10:1);

NMR (CD3OD): δ of 4.05 (DD, J=7,8, and 4.8 Hz, 1H), 3,84-3,68 (m, 2H), 3.46 in-to 3.34 (m, 4H), 2.40 a-2,04 (m, 4H), 1,83 of 1.46 (m, 10H), of 1.39 (sextet, J=7.5 Hz, 2H), 1,05 is 0.86 (m, 2H), 0,97 (t, J=7.2 Hz, 3H);

optical rotation:[α]D-37,5° (c 1,04, methanol, 18°C).

Reference example 3(3)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.32 (butanol:acetic acid:water=4:2:1);

NMR (CD3OD): δ 4,16 (d, J=2.0 Hz, 1H), 3,95 (m, 1H), 3,70 (m, 1H), 3,52 (m, 1H), 3,37 (m, 1H), or 3.28 (m, 1H), 3,22-3,13 (m, 2H), 2,46-of 1.93 (m, 6H), 1,80-of 1.64 (m, 5H), 1,48-of 1.15 (m, 6H), of 1.02-0.87 (m, 5H);

optical rotation:[α]D+1,22° (c 1,04, methanol, 26°C).

Reference example 3(4)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.05 (chloroform:methanol=10:1);

NMR (CD3OD): δ 4,13 (d, J=2.0 Hz, 1H), 4,01-3,91 (m, 3H), 3,70 (m, 1H), 3,59-of 3.32 (m, 6H), 3,20 (m, 1H), 2,47-2,19 (m, 3H), 2,11 was 1.69 (m, 5H), 1,47-1,17 (m, 5H), 0,70 (t, J=7.0 Hz, 3H).

Reference example 3(5)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-g is droxy-1-cyclopentyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0,04 (chloroform:methanol=10:1);

NMR (CD3OD): δ 4,00 (d, J=2.0 Hz, 1H), 3,95 (m, 1H), 3,70 (m, 1H), 3,53 (m, 1H), 3,40-to 3.34 (m, 3H), 3,21 (m, 1H), 2,46-2,19 (m, 4H), of 2.08 (m, 1H), 1,92 of-1.83 (m, 2H), 1.70 to 1,50 (m, 6H), 1,45-of 1.26 (m, 5H), 0,97 (t, J=7.0 Hz, 3H).

Reference example 3(6)

(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.15 (chloroform:methanol:acetic acid=20:4:1);

NMR (CD3OD): δ 4,15 (d, J=2.1 Hz, 1H), 3.96 points (m, 1H), 3,71 (m, 1H), 3,56 is 3.25 (m, 3H), 3,20 (DD, J=a 9.6, 2.1 Hz, 1H), 3,13 (m, 1H), of 2.51-of 1.95 (m, 5H), of 1.75 (m, 1H), 1,49 (m, 1H), 0,99 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.95 (t, J=7.5 Hz, 3H).

Reference example 3(7)

(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.16 (chloroform:methanol:acetic acid=20:4:1);

NMR (CD3OD): δ 4,16 (d, J=2.1 Hz, 1H), 3,95 (m, 1H), 3,70 (m, 1H), 3,47 (m, 1H), 3,41-3,24 (m, 4H), of 3.12 (m, 1H), 2,44 (m, 1H), 2,33 (m, 1H), 2,19 (m, 1H), 2,08 (m, 1H), 2,03-1,89 (m, 2H), 1,84-of 1.62 (m, 4H), 1,50 (m, 1H), 1,40-1,10 (m, 3H), of 1.05 to 0.80 (m, 2H), of 0.95 (t, J=7.5 Hz, 3H);

optical rotation:[α]D-2,92° (c 1.06, methanol, 25°C).

Reference example 3(8)

(3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.16 (chloroform:methanol:acetic acid=20:4:1);

NMR (CD3OD): δ to 4.15 (d, J=2.1 Hz, 1H), 3,95 (m, 1H), 3,71 (m, 1H), 3,52 (m, 1H), 3,42-of 3.31 (m, 2H), 3,21 (m, 1H), 3,21 (DD, J=a 9.6, 2.1 Hz, 1H), 2,48 of-2.32 (m, 2H), 2,23 (m, 1H), 2,14 is 1.96 (m, 2H), 1,72 (m, 1H), of 1.55 and 1.33 (m, 3H), 1,02 to 0.92 (m, 9H);

optical rotation:[α]Dand 13.8° (c 1,00, methanol, 28°C).

Reference example 3(9)

(3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-1-cyclohexyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf to 0.17 (chloroform:methanol:acetic acid=20:4:1);

NMR (CD3OD): δ 4,16 (d, J=2.1 Hz, 1H), 3,95 (m, 1H), 3,70 (m, 1H), 3,52 (m, 1H), 3,42-of 3.25 (m, 3H), 3,17 (m, 1H), 2,49-of 2.38 (m, 2H), of 2.21 (m, 1H), 2,14-1,90 (m, 3H), 1,84-to 1.61 (m, 5H), 1.55V is 1.13 (m, 6H), 1.04 million is 0.81 (m, 2H), 0,97 (t, J=7.2 Hz, 3H);

optical rotation:[α]D-1,29° (c 1,09, methanol, 26°C).

Example 2

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(6-phenoxypyridine-3-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · 2 hydrochloride

To a solution of the compound obtained in reference example 3 (120 mg) in dimethylformamide (1 ml) is added acetic acid (59 ml). To the reaction mixture add triacetoxyborohydride sodium (146 mg) and 3-formyl-6-phenoxypyridine (89 mg). The reaction mixture was stirred over night at room temperature. To the reaction mixture is added methanol and concentrated. The resulting residue is purified column chromatography on silica gel (ethyl acetate→chloroform:methanol=25:1) and obtained the the group transferred to the cleaners containing hydrochloride salt, using the conventional way of obtaining specified in the title compound (118 mg)having the following physical data.

TLC:Rf of 0.48 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,35 (d, J=2.1 Hz, 1H), 8,12 (DD, J=8,7, and 2.1 Hz, 1H), 7,49-7,40 (m, 2H), 7,27 (t, J=7.8 Hz, 1H), 7,15 (d, J=7.8 Hz, 2H), 7,06 (d, J=8,7, 1H), 4,39 (s, 2H), 4,14 (d, J=2.1 Hz, 1H), 4,07-3,93 (m, 1H), 3,82-to 3.67 (m, 1H), to 3.58 is 3.40 (m, 3H), 3,30-3,15 (m, 1H), 3,19 (DD, J=a 9.6, 2.1 Hz, 1H), 2,60-of 2.28 (m, 3H), 2,18-2,05 (m, 1H), 2,05-1,90 (m, 1H), 1,80-of 1.55 (m, 1H), 1,50-1,25 (m, 3H), 0,99 (d, J=6,6 Hz, 3H), of 0.97 (d, J=6.6 Hz, 3H), of 0.95 (t, J=7.2 Hz, 3H);optical rotation:[α]D+10,8° (c of 1.05, methanol, 24°C).

Conditions of HPLC

Column: CHIRALCEL OJ-R, 0,46×15cm, DAICEL, OJR0CD-JB026:

flow rate: 0.7 ml/min;

Solvent

Solution A: 0,1M aqueous solution of potassium dihydrophosphate;

solution B: acetonitrile (A:B=76:24);

UV: 225 nm;

retention time: 11,53 minutes

Example 2(1)-2(59)

The following connections get the same methodology described in example 2, using the appropriate aldehyde derivatives instead of 3-formyl-6-phenoxypyridine.

Example 2(1)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methoxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ was 7.45 (d, J=8.7 Hz, 2H), 7,00-of 6.96 (m, 6H), 4,27 (s, 2H), 4,14 (d, J=2.1 Hz, 1H), 3,94 at 3.69 (m, 2H), 3,79 (s, 3H), 3,60 was 3.05 (m, 5H), 2,50-of 1.95 (m, 5H), to 1.70 (m, 1H), 1,50-of 1.30 (m, 3H), 1.00 and-0,93 (who, 9H).

Example 2(2)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(3-methoxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0,41 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 7,51 (d, J=8,4 Hz, 2H), 7,28 (t, J=8,4 Hz, 1H), was 7.08 (d, J=9.0 Hz, 2H), 6.75 in (m, 1H), 6,61-to 6.57 (m, 2H), 4,32 (s, 2H), 4,14 (d, J=2.1 Hz, 1H), 3,99-to 3.73 (m, 2H), of 3.77 (s, 3H), 3,60-3,10 (m, 5H), 2,55-of 1.95 (m, 5H), to 1.70 (m, 1H), 1,50-of 1.30 (m, 3H), 1.00 and with 0.93 (m, 9H).

Example 2(3)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-torpedolike)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.33(ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 7,50 (d, J=8.7 Hz, 2H), 7,17-7,03 (m, 6H), 4,30 (s, 2H), 4,14 (d, J=2.1 Hz, 1H), 3,97-3,71 (m, 2H), 3,60-3,10 (m, 5H), 2,55-of 1.95 (m, 5H), to 1.70 (m, 1H), 1,50-of 1.30 (m, 3H), 1.00 and with 0.93 (m, 9H).

Example 2(4)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-chlorphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.31 in (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 7,53 (d, J=8.7 Hz, 2H), 7,38 (d, J=9,3 Hz, 2H), to 7.09 (d, J=8.7 Hz, 2H), 7,02 (d, J=9,3 Hz, 2H), 4,32 (s, 2H), 4,14 (d, J=1.8 Hz, 1H), 3,98-and 3.72 (m, 2H), 3,60-3,10 (m, 5H), 2,55 is 2.00 (m, 5H), to 1.70 (m, 1H), 1,50-of 1.30 (m, 3H), 1.00 and with 0.93 (m, 9H).

Example 2(5)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(phenylcarbamoyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.57 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,87 (d, J=8,4 Hz, 2H), 7,83-7,72 (m, 4H), to 7.67 (m, 1H), to 7.59-of 7.48 (m, 2H), 4,48 (s, 2H), 4,14 (d, J=2.1 Hz, 1H), of 4.05 (m, 1H), 3,80 (m, 1H), 3,59-3,37 (m, 3H), 3,20 (m, 1H), 3,19 (DD, J=9,6 and 2.1 Hz, 1H), 2,60-of 2.28 (m, 3H), and 2.14 (m, 1H), 2,00 (m, 1H), 1,70 (m, 1H), 1,52 is 1.23 (m, 3H), 0,99 (d, J=6.6 Hz, 3H), of 0.97 (d, J=6.6 Hz, 3H), of 0.95 (t, J=7.2 Hz, 3H).

Example 2(6)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(1-phenyl-1-hydroxymethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.32 (chloroform:methanol=10:1);

NMR (CD3OD): δ a 7.62 7,40 (m, 4H), 7,40-to 7.18 (m, 5H), of 5.81 (s, 1H), 4,32 (s, 2H), 4,13 (d, J=2.1 Hz, 1H), 3,99 (m, 1H), to 3.73 (m, 1H), 3,55-to 3.38 (m, 3H), of 3.13 (m, 1H), 3,19 (DD, J=a 9.6, 2.1 Hz, 1H), 2,52 is 2.33 (m, 2H), 2,24 (m, 1H), 2,09 (m, 1H), up to 1.98 (m, 1H), 1,67 (m, 1H), 1,50-1,25 (m, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.96 (d, J=6.6 Hz, 3H), of 0.93 (t, J=7.2 Hz, 3H).

Example 2(7)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(morpholine-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.47 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.59 (d, J=8.7 Hz, 2H), of 7.48 (d, J=8.7 Hz, 2H), 7,14 (d, J=8.7 Hz, 2H), 7,10 (d, J=8.7 Hz, 2H), 4,35 (s, 2H), 4,14 (d, J=1.8 Hz, 1H), 3,99 (m, 1H), 3,85-to 3.35 (m, 12H), 3,23 (m, 1H), 3,19 (DD, J=9,3, 1.8 Hz, 1H), 2,55-to 2.41 (m, 2H), 2,32 (m, 1H), 2,12 (m, 1H), 2,01 (m, 1H), 1,68 (m, 1H), 1,50-1,25 (m, 3H), 0,99 (d, J=6.6 Hz, 3H), of 0.97 (d, J=6.6 Hz, 3H), of 0.95 (t, J=7.2 Hz, 3H).

Example 2(8)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(6-methylpyridin-3-yloxy)fenil the Teal)-1,4,9-diazaspiro[5.5]undecane · Hydrochloride

TLC:Rf to 0.19 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 8,58 (d, J=2.7, and 0.6 Hz, 1H), 8,17 (DD, J=9,0, 2.7 Hz, 1H), 7,89 (d, J=9.0 Hz, 1H), 7,74 (d, J=9.0 Hz, 2H), 7,31 (d, J=9.0 Hz, 2H), and 4.40 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), was 4.02 (m, 1H), 3,78 (m, 1H), 3,60-of 3.42 (m, 3H), 3,30-and 3.16 (m, 2H), was 2.76 (s, 3H), 2,64 of-2.32 (m, 3H), 2,18-of 1.94 (m, 2H), 1.70 to (m, 1H), 1,48-of 1.26 (m, 3H), and 1.00 (d, J=6.3 Hz, 3H), and 0.98 (d, J=6.3 Hz, 3H), of 0.96 (t, J=7.2 Hz, 3H).

Example 2(9)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(pyridine-1-oxido-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.54 (chloroform:methanol=5:1);

NMR (CD3OD): δ 8,56 (m, 1H), 8,45 (m, 1H), 7,81-to 7.68 (m, 2H), of 7.75 (d, J=8,4 Hz, 2H), 7,33 (d, J=8,4 Hz, 2H), to 4.41 (s, 2H), 4,15 (d, J=1.8 Hz, 1H), 4.00 points (m, 1H), 3,78 (m, 1H), to 3.58-3.42 points (m, 3H), 3,28-3,16 (m, 2H), 2,64-of 2.26 (m, 3H), 2,20-of 1.92 (m, 2H), by 1.68 (m, 1H), 1,52 of 1.28 (m, 3H), and 1.00 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.96 (t, J=7.2 Hz, 3H).

Example 2(10)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-hydroxypiperidine-1-ylmethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0,69 (chloroform:methanol:28% aqueous ammonia=100:10:1);

NMR (CD3OD): δ of 7.75 (d, J=8,4 Hz, 2H), to 7.67 (d, J=8,4 Hz, 2H), to 4.41 (s, 2H), to 4.38 (s, 2H), 4,14 (d, J=2.1 Hz, 1H), 4,14-of 3.94 (m, 2H), 3,78 (m, 1H), to 3.58 is 3.40 (m, 4H), 3,30-3,00 (m, 4H), 2,68-of 2.36 (m, 3H), 2,20 is 1.58 (m, 8H), 1,50-of 1.26 (m, 3H), 0,99 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.95 (t, J=6.9 Hz, 3H).

Example 2(11)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-methylpropyl)-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · Hydrochloride

TLC:Rf of 0.65 (chloroform:methanol=5:1);

NMR (CD3OD): δ 4,32 (m, 1H), 4,27 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4.00 points (m, 1H), 3,76 (m, 1H), 3,60-of 3.42 (m, 3H), 3,36-and 3.16 (m, 2H), 2,64-to 2.42 (m, 3H), 2.49 USD (s, 3H), of 2.44 (s, 3H), 2,18-1,22 (m, 16H), and 1.00 (d, J=6.6 Hz, 3H), 0,99 (d, J=6.6 Hz, 3H), of 0.95 (t, J=7.5 Hz, 3H).

Example 2(12)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(1,3,5-trimethylpyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.50 (chloroform:methanol=5:1);

NMR (CD3OD): δ 4,27 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4.00 points (m, 1H), 3,85 (s, 3H), 3,76 (m, 1H), 3,60-3,44 (m, 3H), 3,28-and 3.16 (m, 2H), 2,64 of-2.32 (m, 3H), of 2.44 (s, 3H), 2.40 a (s, 3H), 2,18-of 1.92 (m, 2H), 1.70 to (m, 1H), 1,48-of 1.26 (m, 3H), and 1.00 (d, J=6.6 Hz, 3H) 0,99 (d, J=6.6 Hz, 3H), of 0.95 (t, J=7.5 Hz, 3H).

Example 2(13)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-aminosulphonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.50 (chloroform:methanol=5:1);

NMR (CD3OD): δ to $ 7.91 (d, J=8.7 Hz, 2H), 7,60 (d, J=8.7 Hz, 2H), 7,19 (d, J=8.7 Hz, 2H), 7,14 (d, J=8.7 Hz, 2H), 4,35 (s, 2H), 4,15 (d, J=2.4 Hz, 1H), 3,98 (m, 1H), and 3.72 (m, 1H), to 3.58-to 3.38 (m, 3H), 3,28-3,18 (m, 2H), 2,56-of 1.92 (m, 5H), to 1.70 (m, 1H), 1,54 of 1.28 (m, 3H), and 1.00 (d, J=6.9 Hz, 3H), and 0.98 (d, J=6.9 Hz, 3H), of 0.96 (t, J=7.5 Hz, 3H).

Example 2(14)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylthiophenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.45 in (PI is reform:methanol=10:1);

NMR (CD3OD): δ 7,53 (d, J=9.0 Hz, 2H), 7,32 (d, J=9.0 Hz, 2H), 7,05 (d, J=9.0 Hz, 2H), 6,99 (d, J=9.0 Hz, 2H), 4,33 (s, 2H), 4,14 (d, J=2.1 Hz, 1H), 3,98 (m, 1H), and 3.72 (m, 1H), to 3.58 is 3.40 (m, 3H), 3,28-3,10 (m, 2H), 2,52-of 1.92 (m, 5H), 2,47 (s, 3H), of 1.70 (m, 1H), 1,50 of 1.28 (m, 3H), 1,02 is 0.86 (m, 9H).

Example 2(15)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.95 (d, J=9.0 Hz, 2H), 7,63 (d, J=8.1 Hz, 2H), 7.24 to to 7.18 (m, 4H), 4,39 (s, 2H), 4,14 (d, J=2.4 Hz, 1H), was 4.02 (m, 1H), 3,78 (m, 1H), 3,60-of 3.46 (m, 3H), 3,28-3,10 (m, 2H), 3,12 (s, 3H), 2,54-of 1.94 (m, 5H), to 1.70 (m, 1H), 1,50-of 1.30 (m, 3H), 1,02 is 0.86 (m, 9H).

Example 2(16)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-cyanovinylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,73 (d, J=8.7 Hz, 2H), to 7.64 (d, J=9.0 Hz, 2H), 7,21 (d, J=9.0 Hz, 2H), 7,14 (d, J=8.7 Hz, 2H), to 4.38 (s, 2H), 4,14 (d, J=2.1 Hz, 1H), was 4.02 (m, 1H), 3,76 (m, 1H), 3,60 is 3.40 (m, 3H), 3,28-3,14 (m, 2H), 2,54-of 2.26 (m, 3H), 2,20-1,90 (m, 2H), of 1.66 (m, 1H), 1,50 of 1.28 (m, 3H), 1,02-0,84 (m, 9H).

Example 2(17)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(phenylthio)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,50-7,34 (m, 7H), 7,30 (d, J=8,4 Hz, 2H), or 4.31 (s, 2H), 4,13 (d, J=2.1 Hz, 1H), 3,98 (m, 1H), and 3.72 (m, 1H), 3,56-,36 (m, 3H), 3,24-is 3.08 (m, 2H), 2,50-to 2.18 (m, 3H), 2,18-of 1.94 (m, 2H), by 1.68 (m, 1H), 1,50 of 1.28 (m, 3H), 1,10-to 0.88 (m, 9H).

Example 2(18)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-hydroxyphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · 2 hydrochloride

TCX:Rf 0,70 (chloroform:methanol=5:1);

NMR (CD3OD): δ 7,31 (d, J=8.7 Hz, 2H), 6,94 (d, J=8.7 Hz, 2H), 4,32 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), 3,80 (m, 1H), 3,64-of 3.48 (m, 3H), 3,38-3,18 (m, 2H), 2,70-of 2.30 (m, 3H), of 2.44 (s, 3H), 2,36 (s, 3H), 2,20-of 1.94 (m, 2H), by 1.68 (m, 1H), 1,50-of 1.26 (m, 3H), 1,02-0,84 (m, 9H).

Example 2(19)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylsulfonylamino)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · 2 hydrochloride

TLC:Rf to 0.72 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,47 (d, J=9.0 Hz, 2H), 7,41 (d, J=9.0 Hz, 2H), or 4.31 (s, 2H), 4,15 (d, J=1.8 Hz, 1H), was 4.02 (m, 1H), 3,78 (m, 1H), 3,62-of 3.48 (m, 3H), 3,38-3,18 (m, 2H), 3.04 from (s, 3H), 2,68-of 2.36 (m, 3H), 2,41 (s, 3H), 2,39 (s, 3H), 2,20-a 1.96 (m, 2H), by 1.68 (m, 1H), 1,50-of 1.30 (m, 3H), 1,02-to 0.88 (m, 9H).

Example 2(20)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0,12 (chloroform:methanol=5:1);

NMR (CD3OD): δ 8,07 (d, J=9.0 Hz, 2H), 7,78 (d, J=9.0 Hz, 2H), 4,30 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), was 4.02 (m, 1H), 3,76 (m, 1H), 3,62-of 3.48 (m, 3H), 3,40-3,18 (m, 6H), 2.95 and (s, 6H), of 2.64 (m, 1H), 2.49 USD(C, 3H), 2,42-of 2.36 (m, 2H), 2,41 (s, 3H), 2,18 is 1.96 (m, 2H), by 1.68 (m, 1H), 1,50-of 1.32 (m, 3H), 1,08-of 0.90 (m, 9H).

Example 2(21)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,01 (d, J=8.7 Hz, 2H), to 7.77 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,15 (d, J=1.8 Hz, 1H), Android 4.04 (m, 1H), 3,78 (m, 1H), 3,62-of 3.48 (m, 3H), 3,40-3,18 (m, 6H), to 2.66 (m, 1H), 2,54-of 2.38 (m, 2H), 2.49 USD (s, 3H), 2,42 (s, 3H), 2,20-of 1.94 (m, 2H), 1,82-of 1.62 (m, 5H), 1,50-of 1.30 (m, 3H), 1,02-to 0.88 (m, 9H).

Example 2(22)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(6-methylpyridin-1 oxido-3-ilexibility)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.26 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,58 (m, 1H), 7,81-7,71 (m, 2H), 7,73 (d, J=8,4 Hz, 2H), 7,30 (d, J=8,4 Hz, 2H), and 4.40 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4.00 points (m, 1H), 3,78 (m, 1H), 3,62 is 3.40 (m, 3H), 3,30-and 3.16 (m, 2H), 2,66-of 2.38 (m, 3H), of 2.66 (s, 3H), 2,18-of 1.94 (m, 2H), 1.70 to (m, 1H), 1,50 of 1.28 (m, 3H), and 1.00 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.96 (t, J=6.9 Hz, 3H).

Example 2(23)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-hydroxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.48 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 7,46 (d, J=8.7 Hz, 2H), 6,97 (d, J=8.7 Hz, 2H), to 6.88 (d, J=9.0 Hz, 2H), 6,80 (d, J=9.0 Hz, 2H), 4,30 (s, 2H), 4,13 (d, J=2.0 Hz, 1H), 3,98 (m, 1H), and 3.72 (m, 1H), 3,53-342 (m, 3H), 3,23-3,11 (m, 2H), 2,50-of 1.97 (m, 6H), to 1.70 (m, 1H), 1,39-of 1.30 (m, 3H), and 0.98 (d, J=6.5 Hz, 3H), of 0.96 (d, J=6.5 Hz, 3H), of 0.95 (t, J=7.0 Hz, 3H).

Example 2(24)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(6-(4-methoxybenzyloxy)pyridine-3-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochlorid

TLC:Rf is 0.42 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 8.41 (m, 1H), 8,18 (m, 1H), 7,13-6,99 (m, 5H), and 4.40 (s, 2H), 4,13 (d, J=2.0 Hz, 1H), 4.00 points (m, 1H), 3,82 (s, 3H), of 3.75 (m, 1H), 3,53 is-3.45 (m, 3H), 3,24 (m, 1H), 3,19 (DD, J=a 9.5, 2.0 Hz, 1H), 2,59-2,39 (m, 3H), 2,15-of 1.95 (m, 2H), 1.70 to (m, 1H), 1,40 to 1.31 (m, 3H), and 0.98 (d, J=6.5 Hz, 3H), of 0.97 (d, J=6.5 Hz, 3H), were 0.94 (t, J=7.5 Hz, 3H).

Example 2(25)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(methylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.29 (ethyl acetate:methanol=4:1);

NMR (CD3OD):δ 8,00 (d, J=9.0 Hz, 2H), 7,73 (d, J=9.0 Hz, 2H), 4,32 (s, 2H), 4.16 the (d, J=2.0 Hz, 1H), of 4.05 (m, 1H), 3,79 (m, 1H), 3,64-to 3.50 (m, 3H), 3,29-3,19 (m, 2H), 2,59 to 2.35 (m, 3H), 2,58 (s, 3H), 2,47 (s, 3H), 2.40 a (s, 3H), of 2.15 (m, 1H), 2,02 (m, 1H), 1,72 (m, 1H), 1.41 to about 1.35 (m, 3H), 0,99 (d, J=6.5 Hz, 3H), and 0.98 (d, J=6.5 Hz, 3H), of 0.96 (t, J=7.5 Hz, 3H).

Example 2(26)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-hydroxyethyl)aminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.21 in (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ 7,98 (d, J=8.5 Hz, 2H), 7.7 (d, J=8.5 Hz, 2H), or 4.31 (s, 2H), 4,15 (d, J=2.0 Hz, 1H), Android 4.04 (m, 1H), 3,79 (m, 1H), 3,69 (t, J=6.0 Hz, 2H), 3,61-3,51 (m, 3H), 3,23-3,17 (m, 4H), 2,87 (s, 3H), 2,58 is 2.44 (m, 3H), 2,48 (s, 3H), 2.40 a (s, 3H), of 2.15 (m, 1H), 2,02 (m, 1H), 1,71 (m, 1H), 1.41 to about 1.35 (m, 3H), 0,99 (d, J=6.5 Hz, 3H), and 0.98 (d, J=6.5 Hz, 3H), of 0.95 (t, J=7.0 Hz, 3H).

Example 2(27)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochlorid

TLC:Rf of 0.20 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ 8,03 (d, J=8.7 Hz, 2H), 7,72 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,15 (d, J=2.0 Hz, 1H), Android 4.04 (m, 1H), 3,79 (m, 1H), 3,63-3,51 (m, 3H), of 3.56 (t, J=6.0 Hz, 2H), 3,34 be 3.29 (m, 1H), 3,20 (DD, J=a 9.5, 2.0 Hz, 1H), 3,01 (t, J=6.0 Hz, 2H), 2,59 is 2.43 (m, 3H), 2,47 (s, 3H), 2.40 a (s, 3H), of 2.15 (m, 1H), 2,02 (m, 1H), 1,71 (m, 1H), 1.41 to about 1.35 (m, 3H), 0,99 (d, J=6.5 Hz, 3H), and 0.98 (d, J=6.5 Hz, 3H), 0,95 (t, J=7.2 Hz, 3H).

Example 2(28)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.35 (ethyl acetate:methanol=2:1);

NMR (CD3OD): δ a 7.62 (d, J=9.0 Hz, 2H), 7,58 (d, J=9.0 Hz, 2H), 4,32 (s, 2H), 4.16 the (d, J=2.0 Hz, 1H), of 4.05 (m, 1H), 3,79 (m, 1H), 3,61-to 3.49 (m, 3H), 3,34 be 3.29 (m, 1H), 3,20 (DD, J=a 9.5, 2.0 Hz, 1H), 3,13 (s, 3H), 3.04 from (s, 3H), 2,55-of 2.34 (m, 3H), 2,42 (s, 3H), 2,39 (s, 3H), 2,18 (m, 1H), 2,02 (m, 1H), 1,73 (m, 1H), 1.41 to of 1.34 (m, 3H), 0,99 (d, J=6.5 Hz, 3H), and 0.98 (d, J=6.5 Hz, 3H), of 0.96 (t, J=7.0 Hz, 3H).

Example 2(29)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(orphelin-4-yl)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · Hydrochloride

TLC:Rf of 0.33 (ethyl acetate:methanol=2:1);

NMR (CD3OD): δ of 8.06 (d, J=8.7 Hz, 2H), to 7.77 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,15 (d, J=2.0 Hz, 1H), 4,10-4,01 (m, 3H), 3,88 is 3.76 (m, 3H), 3,61-of 3.53 (m, 5H), 3,37-3,19 (m, 8H), 2,59-is 2.37 (m, 3H), 2,48 (s, 3H), is 2.40 (s, 3H), of 2.15 (m, 1H), 2,02 (m, 1H), 1,71 (m, 1H), 1,40-of 1.35 (m, 3H), 0,99 (d, J=6.5 Hz, 3H), and 0.98 (d, J=6.5 Hz, 3H), of 0.95 (t, J=7.0 Hz, 3H).

Example 2(30)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.41 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,72 (d, J=8.7 Hz, 2H), to 7.59 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), of 4.05 (m, 1H), 3,79 (m, 1H), 3,66-of 3.46 (m, 7H), of 3.25 (m, 1H), 3,21 (DD, J=a 9.6, 2.1 Hz, 1H), 2,65 to 2.35 (m, 3H), 2,43 (s, 3H), 2.40 a (s, 3H), of 2.16 (m, 1H), 2,09-to 1.87 (m, 5H), to 1.70 (m, 1H), 1,53-of 1.30 (m, 3H), and 1.00 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.95 (t, J=7.2 Hz, 3H).

Example 2(31)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf to 0.39 (chloroform:methanol=10:1);NMR (CD3OD): δ 7,74 (d, J=8.7 Hz, 2H), 7,60 (d, J=8.7 Hz, 2H), 7,22 (d, J=8.7 Hz, 2H), 7,17 (d, J=8.7 Hz, 2H), 4,37 (s, 2H), 4,14 (d, J=2.4 Hz, 1H), was 4.02 (m, 1H), 3,76 (m, 1H), to 3.58-3.42 points (m, 3H), 3.25 to 3,14 (m, 2H), 2,80 (s, 3H), 2,55-of 2.38 (m, 2H), to 2.29 (m, 1H), 2,15 (m, 1H), 2,01 (m, 1H), 1,70 (m, 1H), 1,50-of 1.27 (m, 3H), 1.04 million-of 0.90 (m, 9H).

Example 2(32)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9(3,5-dimethyl-1-(4-(N,N-dimethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · Hydrochloride

TLC:Rf 0.31 in (chloroform:methanol=10:1);

NMR (CD3OD): δ of 7.96 (d, J=8.7 Hz, 2H), to 7.77 (d, J=8.7 Hz, 2H), 4,32 (s, 2H), 4,15 (d, J=2.4 Hz, 1H), 4,06 (m, 1H), 3,79 (m, 1H), 3,64-of 3.46 (m, 3H), 3,29-3,14 (m, 2H), by 2.73 (s, 6H), 2,59 is 2.44 (m, 2H), 2,47 (s, 3H), 2,39 (s, 3H), 2,35 (m, 1H), 2,17 (m, 1H), 2,02 (m, 1H), 1,71 (m, 1H), 1,51-of 1.26 (m, 3H), of 1.05 to 0.89 (m, 9H).

Example 2(33)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(morpholine-4-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.25 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.95 (d, J=8.7 Hz, 2H), 7,78 (d, J=8.7 Hz, 2H), 4,32 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4,06 (m, 1H), 3,80 (m, 1H), 3,74-3,68 (m, 4H), 3,64-of 3.48 (m, 3H), 3,28-3,14 (m, 2H), 3,05 are 2.98 (m, 4H), 2,59 is 2.44 (m, 2H), 2,47 (s, 3H), 2,39 (s, 3H), 2,35 (m, 1H), 2,17 (m, 1H), 2,02 (m, 1H), 1,71 (m, 1H), 1,52-of 1.30 (m, 3H), 1,05-of 0.90 (m, 9H).

Example 2(34)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-aminosulphonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.22 (chloroform:methanol=10:1);

NMR (CD3OD): δ a 7.92 (d, J=8.7 Hz, 2H), 7.62mm (d, J=8.7 Hz, 2H), 7,16 (d, J=8.7 Hz, 2H), to 7.09 (d, J=8.7 Hz, 2H), 4,37 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4.00 points (m, 1H), 3,78 (m, 1H), 3,60-to 3.38 (m, 3H), 3,28-3,10 (m, 2H), 2,60-of 2.26 (m, 3H), 2,20-of 1.88 (m, 2H), by 1.68 (m, 1H), 1,54-1,22 (m, 3H), and 1.00 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.96 (t, J=7.5 Hz, 3H).

Example 2(35)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-metilaminopropionitrila the si)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.24 (chloroform:methanol=10:1);

NMR (CD3OD): δ a 7.85 (d, J=8.7 Hz, 2H), 7.62mm (d, J=8.7 Hz, 2H), 7,15 (d, J=8.7 Hz, 2H), was 7.08 (d, J=8.7 Hz, 2H), 4,37 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4.00 points (m, 1H), 3,76 (m, 1H), 3,56-of 3.42 (m, 3H), 3,26-3,18 (m, 2H), 2,92 (s, 3H), 2,60-of 2.28 (m, 3H), 2,18-of 1.94 (m, 2H), 1.70 to (m, 1H), 1,50-of 1.30 (m, 3H), and 1.00 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.96 (t, J=7.5 Hz, 3H).

Example 2(36)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-were)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochlorid

TLC:Rf and 0.46 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,41 (s, 4H), 4,34 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), 3,79 (m, 1H), 3,65-to 3.50 (m, 3H), 3,34 (m, 1H), 3,21 (DD, J=a 9.6, 2.1 Hz, 1H), 2,66 (m, 1H), 2,55-to 2.42 (m, 2H), 2,47 (s, 3H), of 2.45 (s, 3H), 2.40 a (s, 3H), and 2.14 (m, 1H), 2,01 (m, 1H), 1.69 in (m, 1H), 1,52-of 1.30 (m, 3H), and 1.00 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.95 (t, J=7.2 Hz, 3H).

Example 2(37)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-diethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.35 (chloroform:methanol=9:1);

NMR (CD3OD): δ to 7.99 (d, J=8.7 Hz, 2H), 7,72 (d, J=8.7 Hz, 2H), 4,32 (s, 2H), 4.16 the (d, J=2.1 Hz, 1H), 4,06 (m, 1H), 3,80 (m, 1H), 3,63-of 3.48 (m, 3H), 3,32-3,17 (m, 2H), 3,29 (kV, J=7.2 Hz, 4H), 2,54 and 2.13 (m, 4H), a 2.45 (s, 3H), 2,39 (s, 3H), 2,02 (m, 1H), 1,72 (m, 1H), 1,52-of 1.33 (m, 3H)and 1.15 (t, J=7.2 Hz, 6H), and 1.00 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.96 (t, J=6.9 Hz, 3H).

Example 2(38)

(3R)-1-butyl-2,5-diox the-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · Hydrochloride

TLC:Rf is 0.22 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,01 (d, J=8.7 Hz, 2H), 7,82 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,15 (d, J=1.8 Hz, 1H), 4,11-of 3.94 (m, 3H), 3,80 (m, 1H), 3,65-of 3.48 (m, 5H), 3,34-3,18 (m, 4H), 2.91 in (s, 3H), 2,86-2,70 (m, 2H), 2,68-of 2.36 (m, 3H), 2.49 USD (s, 3H), 2.40 a (s, 3H), of 2.15 (m, 1H), 2,02 (m, 1H), 1,70 (m, 1H), 1,50-of 1.27 (m, 3H), 1,05-of 0.90 (m, 9H).

Example 2(39)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(5-chloro-3-methyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.53(chloroform:methanol=10:1);

NMR (CD3OD): δ 7,63-of 7.48 (m, 5H), to 4.33 (s, 2H), 4,14 (d, J=1.8 Hz, 1H), 4,10 (m, 1H), 3,83 (m, 1H), 3,66 is-3.45 (m, 3H), 3,29-and 3.16 (m, 2H), 2,62 of-2.32 (m, 3H), of 2.44 (s, 3H), 2,17 (m, 1H), 2,01 (m, 1H), 1,71 (m, 1H), 1,52-1,11 (m, 3H), of 1.05 to 0.88 (m, 9H).

Example 2(40)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(morpholine-4-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf to 0.39 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,66-EUR 7.57 (m, 4H), or 4.31 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), of 4.05 (m, 1H), 3,88-3,39 (m, 12H), of 3.25 (m, 1H), 3,20 (DD, J=a 9.6, 2.1 Hz, 1H), 2,65-of 2.27 (m, 3H), 2,43 (s, 3H), 2.40 a (s, 3H), 2,17 (m, 1H), 2,02 (m, 1H), 1,71 (m, 1H), 1,54-of 1.27 (m, 3H), and 1.00 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.96 (t, J=7.2 Hz, 3H).

Example 2(41)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · GID klorid

TLC:Rf is 0.42 (chloroform:methanol=5:1);

NMR (CD3OD): δ 8,03 (d, J=8.7 Hz, 2H), to 7.61 (d, J=8.7 Hz, 2H), 4,32 (s, 2H), 4.16 the (d, J=1.8 Hz, 1H), Android 4.04 (m, 1H), 3,80 (m, 1H), 3,74 (t, J=5.7 Hz, 2H), 3,64-of 3.48 (m, 3H), of 3.54 (t, J=5.7 Hz, 2H), 3,30-3,16 (m, 2H), 2,64-of 2.34 (m, 3H), of 2.45 (s, 3H), 2,41 (s, 3H), 2,22-of 1.92 (m, 2H), 1,72 (m, 1H), 1,52-of 1.26 (m, 3H), 1,01 (d, J=6.6 Hz, 3H), 0,99 (d, J=6.6 Hz, 3H), of 0.96 (t, J=7.2 Hz, 3H).

Example 2(42)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf to 0.19 (chloroform:methanol=5:1);

NMR (CD3OD): δ to 7.93 (d, J=9.0 Hz, 2H), to 7.61 (d, J=8,4 Hz, 2H), 7.18 in-was 7.08 (m, 4H), 4,36 (s, 2H), 4,14 (d, J=1.8 Hz, 1H), 4.00 points (m, 1H), 3,80-3,70 (m, 3H), 3,54-of 3.42 (m, 3H), 3,38 (t, J=6.3 Hz, 2H), 3,26-3,18 (m, 2H), 2,98 (s, 6H), 2,60-of 2.30 (m, 3H), 2,18 is 1.96 (m, 2H), by 1.68 (m, 1H), 1,50-of 1.30 (m, 3H), 1.00 and-of 0.90 (m, 9H).

Example 2(43)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(pyridine-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.31 in (chloroform:methanol=10:1);

NMR (CD3OD): δ a total of 8.74 (m, 1H), to 8.62 (d, J=5.4 Hz, 1H), 8,24 (m, 1H), 8,14 (m, 1H), 7,76 (d, J=8,4 Hz, 2H), 7,34 (d, J=8,4 Hz, 2H), and 4.40 (s, 2H), 4,14 (d, J=2.1 Hz, 1H), 4.00 points (m, 1H), 3,76 (m, 1H), 3,60-3,44 (m, 3H), 3,30-and 3.16 (m, 2H), 2,60 (m, 1H), 2,50-to 2.40 (m, 2H), 2.26 and is 1.86 (m, 2H), of 1.66 (m, 1H), 1,50-of 1.30 (m, 3H), 1,02-to 0.88 (m, 9H).

Example 2(44)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-treat the Spiro[5.5]undecane · hydrochloride

TLC:Rf is 0.42 (chloroform:methanol=5:1);

NMR (CD3OD): δ of 8.04 (d, J=8.7 Hz, 2H), to 7.59 (d, J=8,4 Hz, 2H), 7,18 (d, J=8,4 Hz, 2H), 7,07 (d, J=8.7 Hz, 2H), 4,37 (s, 2H), 4,15 (d, J=2.4 Hz, 1H), was 4.02 (m, 1H), 3,76 (m, 1H), 3,60-3,44 (m, 3H), 3,24-is 3.08 (m, 2H), 2,56-of 1.92 (m, 5H), to 1.70 (m, 1H), 1,50-of 1.26 (m, 3H), 1,08-of 0.90 (m, 9H).

Example 2(45)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,49 (d, J=9.0 Hz, 2H), 7,20 (d, J=9.0 Hz, 2H), 7,02 (d, J=9.0 Hz, 2H), 6,92 (d, J=9.0 Hz, 2H), 4,32 (s, 2H), 4,14 (d, J=2.1 Hz, 1H), 3,98 (m, 1H), and 3.72 (m, 1H), to 3.58-to 3.36 (m, 3H), 3,26-is 3.08 (m, 2H), 2,52-to 1.82 (m, 5H), of 2.33 (s, 3H), by 1.68 (m, 1H), 1,50 of 1.28 (m, 3H), 1,02 is 0.86 (m, 9H).

Example 2(46)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(2,4-differenl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf to 0.63(chloroform:methanol=5:1);

NMR (CD3OD): δ 7,56 (m, 1H), 7,33-7,16 (m, 2H), 4,32 (s, 2H), 4.16 the (d, J=2.1 Hz, 1H), 4,06 (m, 1H), 3,80 (m, 1H), 3,62-3,44 (m, 3H), 3,28-and 3.16 (m, 2H), 2,62-of 1.84 (m, 5H), 2,39 (s, 3H), of 2.28 (s, 3H), 1,72 (m, 1H), 1,54 of 1.28 (m, 3H), 1,01 (d, J=6.6 Hz, 3H), 0,99 (d, J=6.6 Hz, 3H), of 0.97 (t, J=7.2 Hz, 3H).

Example 2(47)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(pyridine-2-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.28 in (choroform:methanol=10:1);

NMR (CD3OD): δ charged 8.52 (m, 1H), 8,01 (m, 1H), 7,81 (m, 1H), 7,41 (m, 1H), 4,33 (s, 2H), 4.16 the (d, J=1.8 Hz, 1H), 4,06 (m, 1H), 3,80 (m, 1H), 3,64-of 3.46 (m, 3H), 3,26-of 3.12 (m, 2H), 2,68 (s, 3H), 2,58-of 2.24 (m, 3H), is 2.41 (s, 3H), 2,18 (m, 1H), 2,04 (m, 1H), 1,70 (m, 1H), 1,54-of 1.26 (m, 3H), and 1.00 (d, J=6.6 Hz, 3H), 0,99 (d, J=6.6 Hz, 3H), of 0.96 (t, J=7.5 Hz, 3H).

Example 2(48)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylaminophenol)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.18 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.99 (d, J=8.7 Hz, 2H), to 7.61 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), 3,79 (m, 1H), 3,64-to 3.49 (m, 3H), 3,30-3,17 (m, 2H), equal to 2.94 (s, 3H), at 2.59 (m, 1H), of 2.51-2,36 (m, 2H), 2,44 (s, 3H), 2,41 (s, 3H), of 2.15 (m, 1H), 2,02 (m, 1H), 1,70 (m, 1H), 1,52-of 1.27 (m, 3H), 1,05-of 0.91 (m, 9H).

Example 2(49)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-cyclohexenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.44 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,44 (d, J=8.7 Hz, 2H), 7,01 (d, J=8.7 Hz, 2H), to 4.38 (m, 1H), 4,27 (s, 2H), 4,14 (d, J=2.1 Hz, 1H), 3.96 points (m, 1H), 3,70 (m, 1H), to 3.58-to 3.36 (m, 3H), 3,26-is 3.08 (m, 2H), 2,54-of 1.26 (m, 19H), 0,99 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.96 (t, J=7.5 Hz, 3H).

Example 2(50)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(3,4,5,6-tetrahydropyran-4-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.33(chloroform:methanol=10:1);

NMR (CD3 OD): δ 7,47 (d, J=8.7 Hz, 2H), 7,07 (d, J=8.7 Hz, 2H), with 4.64 (m, 1H), 4,29 (s, 2H), 4,14 (d, J=2.4 Hz, 1H), 4.04 the-3,86 (m, 3H), 3,80-to 3.36 (m, 6H), 3,26-is 3.08 (m, 2H), 2,52-1,90 (m, 7H), 1,80 is 1.58 (m, 3H), 1,50-of 1.26 (m, 3H), 0,99 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.96 (t, J=7.5 Hz, 3H).

Example 2(51)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methoxyphenylethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.37 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 7.96 (d, J=8,4 Hz, 2H), to 7.67 (d, J=8,4 Hz, 2H), 7,28 (d, J=8,4 Hz, 2H), to 6.88 (d, J=8,4 Hz, 2H), to 4.52 (s, 2H), 4,43 (s, 2H), 4,14 (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), of 3.77 (s, 3H), of 3.77 (m, 1H), to 3.58 is 3.40 (m, 3H), 3,26-3,10 (m, 2H), 2,54-2,22 (m, 3H), 2,20-1,90 (m, 2H), of 1.66 (m, 1H), 1,50-of 1.26 (m, 3H), 0,99 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.95 (t, J=7.5 Hz, 3H).

Example 2(52)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(cyclohexanecarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.44 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ to $ 7.91 (d, J=8,3 Hz, 2H), 7,66 (d, J=8,3 Hz, 2H), 4,42 (s, 2H), 4,13 (d, J=2.0 Hz, 1H), a 4.03 (m, 1H), 3,90-and 3.72 (m, 2H), 3,56-of 3.43 (m, 3H), of 3.25 (m, 1H), 3,18 (DD, J=a 9.6, 2.0 Hz, 1H), 2,53-2,4 0 (m, 2H), 2,30 (m, 1H), and 2.14 (m, 1H), 2.06 to a rate of 1.67 (m, 8H), of 1.50 and 1.33 (m, 7H), and 0.98 (d, J=6.6 Hz, 3H), of 0.96 (d, J=6.6 Hz, 3H), were 0.94 (t, J=7.5 Hz, 3H).

Example 2(53)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

/p>

TLC:Rf of 0.34 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ to 7.61-EUR 7.57 (m, 4H), 7,14 (d, J=8.7 Hz, 2H), to 7.09 (d, J=8.7 Hz, 2H), 4,36 (s, 2H), 4,14 (d, J=2.0 Hz, 1H), 4.00 points (m, 1H), 3,74 (m, 1H), 3,62 is-3.45 (m, 7H), 3,24 (m, 1H), 3,19 (DD, J=a 9.6, 2.0 Hz, 1H), 2,56-to 2.29 (m, 3H), 2,15-1,89 (m, 6H), to 1.70 (m, 1H), 1,40-of 1.33 (m, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.97 (d, J=6.6 Hz, 3H), of 0.95 (t, J=7.2 Hz, 3H).

Example 2(54)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-forfinal)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.37 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ 7,56-7,51 (m, 2H), 7,35-7,28 (m, 2H), or 4.31 (s, 2H), 4,15 (d, J=2.0 Hz, 1H), a 4.03 (m, 1H), 3,78 (m, 1H), 3,61-to 3.49 (m, 3H), 3,34 (m, 1H), 3,20 (DD, J=a 9.6, 2.0 Hz, 1H), 2,68-to 2.42 (m, 6H), 2,38 (, 3H), 2,17 (m, 1H), 2,02 (m, 1H), 1,70 (m, 1H), 1,50-of 1.35 (m, 3H), 0,99 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.95 (t, J=7.2 Hz, 3H).

Example 2(55)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-phenylethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0,13 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,32-7,20 (m, 3H), 7,11-was 7.08 (m, 2H), 4,45 (t, J=6.6 Hz, 2H), 4,20 (s, 2H), 4.16 the (d, J=1.8 Hz, 1H), 3,90 (m, 1H), 3,70-of 3.48 (m, 3H), 3,42-3,30 (m, 2H), 3,21 (m, 1H), 3,14 (t, J=6.6 Hz, 2H), was 2.76-of 2.38 (m, 3H), of 2.50 (s, 3H), 2,20-of 1.88 (m, 2H), of 1.97 (s, 3H), of 1.74 (m, 1H), 1.56 to of 1.34 (m, 3H), 1,01 (d, J=6.6 Hz, 3H), and 1.00 (d, J=6.6 Hz, 3H), of 0.97 (t, J=6.9 Hz, 3H).

Example 2(56)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(1-benzyloxycarbonylamino-4-yl)pyrazole-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · Hydrochloride

TLC:Rf 0,13(chloroform:methanol=10:1);

NMR (CD3OD): δ 7,44-of 7.24 (m, 5H), 5,16 (s, 2H), 4,54 (m, 1H), 4,40-4,20 (m, 2H), 4,25 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4.00 points (m, 1H), 3,82-of 3.42 (m, 5H), 3,30-is 2.88 (m, 3H), 2,64-of 2.30 (m, 3H), 2,47 (s, 3H), 2,37 (s, 3H), 2,20-of 1.84 (m, 6H), to 1.70 (m, 1H), 1,52-of 1.26 (m, 3H), and 1.00 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.95 (t, J=7.5 Hz, 3H).

Example 2(57)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(2-hydroxyethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.47 (chloroform:methanol=5:1);

NMR (CD3OD): δ 7,89 (d, J=9.0 Hz, 2H), to 7.61 (d, J=9.0 Hz, 2H), 7,16 (d, J=9.0 Hz, 2H), to 7.09 (d, J=9.0 Hz, 2H), 4,37 (s, 2H), 4.16 the (d, J=2.1 Hz, 1H), 4.00 points (m, 1H), 3,78 (m, 1H), 3,71 (t, J=5.7 Hz, 2H), 3,60 is 3.40 (m, 3H), 3,51 (t, J=5.7 Hz, 2H), 3,30-of 3.12 (m, 2H), 2,60-of 2.24 (m, 3H), 2,22-of 1.92 (m, 2H), 1.70 to (m, 1H), 1.56 to 1,24 (m, 3H), and 1.00 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.96 (t, J=7.5 Hz, 3H).

Example 2(58)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(1-methylsulfonylmethane-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.41 (chloroform:methanol=5:1);

NMR (CD3OD): δ of 4.44 (m, 1H), 4,25 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4,06-to 3.64 (m, 4H), 3,60-3,44 (m, 3H), 3,28-and 3.16 (m, 2H), 3,06 of 2.92 (m, 2H), 2,90 (s, 3H), 2,64-1,90 (m, 9H), 2,47 (s, 3H), is 2.37 (s, 3H), 1,68 (m, 1H), 1,50-of 1.24 (m, 3H), and 1.00 (d, J=6.6 Hz, 3H), 0,99 (d, J=6.6 Hz, 3H), of 0.95 (t, J=7.5 Hz, 3H).

Example 2(59)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylprop the l)-9-(4-(4-hydroxyethyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane

TLC:Rf of 0.32 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 7.36 (d, J=8,4 Hz, 2H), 7,35 (d, J=8,4 Hz, 2H), 6,97 (d, J=8,4 Hz, 4H), 4,58 (s, 2H), 4,12 (d, J=2.4 Hz, 1H), of 3.73 (s, 2H), 3,47 (m, 1H), 3,30-2,90 (m, 6H), 2,31 of-1.83 (m, 5H), of 1.64 (m, 1H), 1.55V is 1.23 (m, 3H), of 0.97 (d, J=6.6 Hz, 6H), of 0.95 (t, J=7.5 Hz, 3H).

Example 3

(3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-9-(6-phenoxypyridine-3-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

In accordance with the same procedure described in example 2 using the compound obtained in reference example 3, (8), instead of the compound obtained in reference example 3, get mentioned in the title compound (110 mg)having the following physical data.

TLC:Rf of 0.48 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,35 (d, J=2.1 Hz, 1H), 8,12 (DD, J=8,7, and 2.1 Hz, 1H), 7,49-7,40 (m, 2H), 7,27 (t, J=7.8 Hz, 1H), 7,15 (d, J=7.8 Hz, 2H), 7,06 (d, J=8,7, 1H), 4,39 (s, 2H), 4,14 (d, J=2.1 Hz, 1H), 4,07-3,93 (m, 1H), 3,82-to 3.67 (m, 1H), to 3.58 is 3.40 (m, 3H), 3,30-3,15 (m, 1H), 3,19 (DD, J=a 9.6, 2.1 Hz, 1H), 2,60-of 2.28 (m, 3H), 2,18-2,05 (m, 1H), 2,05-1,90 (m, 1H), 1,80-of 1.55 (m, 1H), 1,50-1,25 (m, 3H), 0,99 (d, J=6,6 Hz, 3H), of 0.97 (d, J=6.6 Hz, 3H), of 0.95 (t, J=7.2 Hz, 3H);

optical rotation:[α]D-10,1° (c 1,04, methanol, 25°C).

Conditions of HPLC

Column: CHIRALCEL OJ-R, 0,46×15 cm, DAICEL, OJR0CD-JB026:

flow rate: 0.7 ml/min

Solvent

Solution A: 0,1M aqueous solution of potassium dihydrophosphate;

solution B: acetonitrile (A:B=76:24);

UV: 225 nm;

in EMA retention: 8,65 minutes

Example 4

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

In accordance with the same procedure described in example 2 using the compound obtained in reference example 3(1), instead of the compound obtained in reference example 3, and using [4-(4-formyl-3,5-dimethylpyrazole)phenyl]-N,N-dimethylcarbamyl instead of 3-formyl-6-phenoxypyridine get mentioned in the title compound having the following physical data.

TLC:Rf and 0.62 (chloroform:methanol=5:1);

NMR (CD3OD): δ the 7.65 7,52 (m, 4H), to 4.33 (s, 2H), a 4.03 (DD, J=7,8, and 4.5 Hz, 1H), 3.96 points-and 3.72 (m, 2H), 3,64-of 3.54 (m, 2H), 3,50-to 3.36 (m, 2H), 3,14 (s, 3H), 3,05 (s, 3H), 2,60-to 2.42 (m, 2H), 2,44 (s, 3H), 2,41 (s, 3H), a 2.36-2,10 (m, 2H), 1,90-of 1.24 (m, 7H), of 0.97 (t, J=7.2 Hz, 3H), of 0.96 (d, J=6.6 Hz, 3H), of 0.95 (d, J=6.6 Hz, 3H).

Examples 4(1)-4(43)

In accordance with the same procedure described in example 4, using the appropriate aldehyde derivatives respectively instead of [4-(4-formyl-3,5-dimethylpyrazole)phenyl]-N,N-dimethylcarbamate receive the following compounds having the following physical data.

Example 4(1)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.56 to (chlorop the RM:methanol=5:1);

NMR (CD3OD): δ 7,73 (d, J=8.7 Hz, 2H), 7,60 (d, J=8.7 Hz, 2H), 4,33 (s, 2H), a 4.03 (DD, J=7,5, and 4.5 Hz, 1H), 3.96 points-3,74 (m, 2H), 3,66-to 3.36 (m, 8H), 2,58-to 2.40 (m, 2H), 2,44 (s, 3H), 2,41 (s, 3H), 2,34-2,12 (m, 2H,), 2.06 to 1.26 in (m, 11H), of 0.97 (t, J=7.2 Hz, 3H), of 0.96 (d, J=6.3 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H).

Example 4(2)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(morpholine-4-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.57 (chloroform:methanol=5:1);

NMR (CD3OD): δ to 7.64 (d, J=9.0 Hz, 2H), 7,60 (d, J=9.0 Hz, 2H), 4,33 (s, 2H), a 4.03 (DD, J=7,5, and 4.5 Hz, 1H), 3,98-to 3.36 (m, 14H), 2,58-of 2.36 (m, 2H), 2,44 (s, 3H), 2.40 a (s, 3H), 2,32 with 2.14 (m, 2H), 1,90-of 1.24 (m, 7H), of 0.97 (t, J=7.2 Hz, 3H), of 0.96 (d, J=6.3 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H).

Example 4(3)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-methylsulfinylphenyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.49 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 8.09 (d, J=8,4 Hz, 2H), a 7.85 (d, J=8,4 Hz, 2H), 4,48 (s, 2H), was 4.02 (DD, J=7,8, and 4.5 Hz, 1H), 3,92-3,70 (m, 2H), 3,56-to 3.36 (m, 4H), and 3.16 (s, 3H), 2,48-of 2.30 (m, 2H), 2,28-to 2.06 (m, 2H), 1,90-1,24 (m, 7H), is 0.96 (t, J=7.2 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H), were 0.94 (d, J=6.3 Hz, 3H).

Example 4(4)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.45 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 7.96 (d, J=8.7 Hz, 2H), 7,66 (d, J=8.7 Hz, 2H), 7.23 percent (d, J=8.7 Hz, 2H), 7,21 (d, J=8.7 Hz, 2H), and 4.40 (s, 2H), was 4.02 (who d, J=7,5, and 4.5 Hz, 1H), 3,94-and 3.72 (m, 2H), to 3.58-to 3.36 (m, 4H), of 3.12 (s, 3H), 2,54-of 2.36 (m, 2H), 2,18-of 2.08 (m, 2H), 1,88-of 1.26 (m, 7H), is 0.96 (t, J=6.9 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H), were 0.94 (d, J=6.3 Hz, 3H).

Example 4(5)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(morpholine-4-yl)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.60 (chloroform:methanol=5:1);

NMR (CD3OD): δ 8,07 (d, J=8,4 Hz, 2H), 7,78 (d, J=8,4 Hz, 2H), 4,32 (s, 2H), 4,16-3,98 (m, 3H), 3,94 is 3.76 (m, 4H), 3,64 is 3.40 (m, 6H), 3,38-3,18 (m, 6H), 2,62 is 2.44 (m, 2H), 2.49 USD (s, 3H), 2,41 (s, 3H), 2,36-2,12 (m, 2H), 1,90-of 1.24 (m, 7H), of 0.97 (t, J=6.6 Hz, 3H), of 0.96 (d, J=6.3 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H).

Example 4(6)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.50 (chloroform:methanol=5:1);

NMR (CD3OD): δ 8,02 (d, J=9.0 Hz, 2H), 7,83 (d, J=9.0 Hz, 2H), 4,32 (s, 2H), a 4.03 (DD, J=7,8, and 4.5 Hz, 1H), 4,03 is 3.76 (m, 4H), 3,68 of 3.56 (m, 4H), 3,54-of 3.42 (m, 2H), 3,30-3,20 (m, 2H), 2,92 (s, 3H), 2,86-2,72 (m, 2H), 2,64-2,48 (m, 2H), of 2.51 (s, 3H), 2,42 (s, 3H), 2,32-2,12 (m, 2H), 1,90-of 1.26 (m, 7H), of 0.97 (t, J=6.6 Hz, 3H), of 0.96 (d, J=6.3 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H).

Example 4(7)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.28 in (chloroform:methanol=10:1);

NMR (CD3OD): δ of 7.75 (d, J=9.0 Hz, 2H), 7.62mm (d, J=9.0 Hz, 2H), 7.23 percent (who, J=9.0 Hz, 2H), 7,18 (d, J=9.0 Hz, 2H), to 4.38 (s, 2H), was 4.02 (DD, J=7,5, and 4.5 Hz, 1H), 3,92-and 3.72 (m, 2H), to 3.58-to 3.36 (m, 4H), of 2.81 (s, 3H), 2,52-of 2.36 (m, 2H), 2,30 is 2.10 (m, 2H), 1,90-of 1.26 (m, 7H), is 0.96 (t, J=7,2 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H), were 0.94 (d, J=6.3 Hz, 3H).

Example 4(8)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyridine-1-oxido-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.48 (chloroform:methanol=5:1);

NMR (CD3OD): δ 8,66 (s, 1H), 8,53-charged 8.52 (m, 1H), 7,88 for 7.78 (m, 2H), to 7.77 (d, J=8.7 Hz, 2H), 7,34 (d, J=8.7 Hz, 2H), to 4.41 (s, 2H), a 4.03 (DD, J=7,5, and 4.5 Hz, 1H), 3,92-3,70 (m, 2H), 3,66 is 3.40 (m, 4H), 2,66-2,48 (m, 2H), 2.26 and-of 2.08 (m, 2H), 1,90-of 1.26 (m, H)to 0.96 (t, J=7.5 Hz, 3H), of 0.95 (d, J=6.6 Hz, 3H), were 0.94 (d, J=6.6 Hz, 3H).

Example 4(9)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.53(chloroform:methanol=5:1);

NMR (CD3OD): δ 8,03 (d, J=8,4 Hz, 2H), 7.62mm (d, J=8,4 Hz, 2H), 4,33 (s, 2H), a 4.03 (DD, J=7,8, and 4.5 Hz, 1H), 3,98 is 3.76 (m, 2H), 3,74 (t, J=5.7 Hz, 2H), 3,68-to 3.58 (m, 2H), 3,54 (t, J=5.7 Hz, 2H), 3,54 is 3.40 (m, 2H), 2,64-2,48 (m, 2H), 2,46 (s, 3H), 2,43 (s, 3H), 2,32 is 2.10 (m, 2H), 1,90-of 1.30 (m, 7H), of 0.97 (t, J=6.6 Hz, 3H), of 0.96 (d, J=6.3 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H).

Example 4(10)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(morpholine-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.55 (chloroform:methanol=5:1);

NMR (CD3OD): δ to 7.61 (d, J=8.7 Hz, 2H), 749 (d, J=8.7 Hz, 2H), 7,15 (d, J=8.7 Hz, 2H), 7,11 (d, J=8.7 Hz, 2H), 4,37 (s, 2H), was 4.02 (DD, J=7,8, and 4.8 Hz, 1H), 3,90-to 3.36 (m, 14H), 2,58-of 2.38 (m, 2H), 2,28-of 2.08 (m, 2H), 1,88 of 1.28 (m, 7H), is 0.96 (t, J=7.2 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H), were 0.94 (d, J=6.3 Hz, 3H).

Example 4(11)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-diethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf to 0.66 (chloroform:methanol=5:1);

NMR (CD3OD): δ 8,00 (d, J=8,4 Hz, 2H), 7,73 (d, J=8,4 Hz, 2H), 4,34 (s, 2H), Android 4.04 (DD, J=7,8, and 4.5 Hz, 1H), 3.96 points is 3.76 (m, 2H), 3,68 of 3.56 (m, 2H), 3,48-to 3.38 (m, 2H), 3,36-up 3.22 (m, 4H), 2,52-of 2.38 (m, 2H), 2,46 (, 3H), 2.40 a (s, 3H), 2,36 with 2.14 (m, 2H), 1,90 of 1.28 (m, 7H), 1,20-a 1.08 (m, 6H), of 0.97 (t, J=7.5 Hz, 3H), of 0.96 (d, J=6.3 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H).

Example 4(12)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(2-hydroxyethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,88 (d, J=8.7 Hz, 2H), 7,60 (d, J=8,4 Hz, 2H), 7,15 (d, J=8,4 Hz, 2H), 7,07 (d, J=8.7 Hz, 2H), 4,36 (s, 2H), 4,01 (DD, J=7,8, and 4.5 Hz, 1H), 3,90 is 3.76 (m, 2H), 3,70 (t, J=6.0 Hz, 2H), 3,56-3,36 (m, 4H), 3,50 (t, J=6.0 Hz, 2H), 2,52-of 2.38 (m, 2H), 2,24-of 2.08 (m, 2H), 1,88 is 1.16 (m, 7H), 1,02-to 0.88 (m, 9H).

Example 4(13)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.22 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ to 7.59 (d, J=8,4 Hz, 2), 7,58 (d, J=8,4 Hz, 2H), 7,16 (d, J=8,4 Hz, 2H), to 7.09 (d, J=8,4 Hz, 2H), to 4.38 (s, 2H), was 4.02 (DD, J=7,5, and 4.5 Hz, 1H), 3,92-and 3.72 (m, 2H), 3,64-to 3.36 (m, 8H), 2,48 is 2.10 (m, 4H), 2,04-of 1.26 (m, 11H), is 0.96 (t, J=6,9 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H), were 0.94 (d, J=6.3 Hz, 3H).

Example 4(14)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(cyclohexanesulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.42 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,02 (d, J=8,4 Hz, 2H), of 7.70 (d, J=8,4 Hz, 2H), or 4.31 (s, 2H), of 4.05 (DD, J=7,8, and 4.8 Hz, 1H), 3,92-and 3.72 (m, 2H), 3,68-to 3.58 (m, 2H), 3,56-3,44 (m, 2H), 3,06 (m, 1H), 2,68-of 2.50 (m, 2H), 2,47 (s, 3H), is 2.41 (s, 3H), 2,38-of 2.08 (m, 2H), 1,82 was 1.06 (m, 25H), 1,02 is 0.86 (m, 5H).

Example 4(15)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(3-methoxypropylamine)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.42 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,01 (d, J=8.7 Hz, 2H), 7,73 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), was 4.02 (DD, J=7,8, and 4.8 Hz, 1H), 3,94-and 3.72 (m, 2H), 3,68-to 3.58 (m, 2H), 3,56-of 3.46 (m, 2H), 3,39 (t, J=6.0 Hz, 2H), 3,26 (s, 3H), 2,98 (t, J=6.9 Hz, 2H), 2,72-of 2.58 (m, 2H), 2,48 (s, 3H), 2,42 (s, 3H), 2.26 and is 2.10 (m, 2H), 1,90 of 1.28 (m, 9H), 0,98-of 0.90 (m, 9H).

Example 4(16)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-methylsulfinylphenyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.13 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 7,88 (d, J=8.7 Hz, 2H), 7,81 (d, J=8.7 Hz, 2H), 4,47 (s, 2H), was 4.02 (DD, J=7,8, 4,8 the C, 1H), 3.96 points-3,74 (m, 2H), 3,56-to 3.36 (m, 4H), and 2.83 (s, 3H), 2,52-of 2.34 (m, 2H), 2,28-of 2.08 (m, 2H), 1,90-of 1.26 (m, 7H), of 0.95 (t, J=7.2 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H), were 0.94 (d, J=6.3 Hz, 3H).

Example 4(17)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-propylpyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.58 (chloroform:methanol=5:1);

NMR (CD3OD): δ 4.26 deaths (s, 2H), 4,10 (t, J=7.2 Hz, 2H), was 4.02 (DD, J=7,5, and 4.5 Hz, 1H), 3,90-3,68 (m, 2H), to 3.58-to 3.36 (m, 4H), 2,58-of 2.38 (m, 2H), 2,44 (s, 3H), of 2.38 (s, 3H), 2,30 is 2.10 (m, 2H), 1,92-of 1.24 (m, 9H), 0,96 (t, J=7.2 Hz, 6H), is 0.96 (d, J=6.6 Hz, 3H), of 0.95 (d, J=6.6 Hz, 3H).

Example 4(18)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-aripirazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.58 (chloroform:methanol=10:1);

NMR (CD3OD): δ 4,34-4,24 (m, 4H), to 4.01 (DD, J=7,8, and 4.5 Hz, 1H), 3,92-3,68 (m, 2H), 3,62-of 3.46 (m, 4H), 2,74-2,60 (m, 2H), 2,53 (s, 3H), of 2.50 (s, 3H), 2,24-to 2.06 (m, 2H), 1,88-of 1.26 (m, 10H), 1,02 is 0.86 (m, 9H).

Example 4(19)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-cyclopentylphenol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.53 (chloroform:methanol=10:1);

NMR (CD3OD): δ 5,00-4,82 (m, 1H), or 4.31 (s, 2H), 4,01 (DD, J=7,5, and 4.5 Hz, 1H), 3,92-3,70 (m, 2H), 3,62-of 3.46 (m, 4H), 2,78-of 2.58 (m, 2H), by 2.55 (s, 3H), of 2.53 (s, 3H), 2,32-2,04 (m, 4H), 2,04-of 1.26 (m, 13H), 0,98-0,84 (m, 9H).

Example 4(20)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(1,1-dimethylethyl)pyrazole-4-ylmethyl)-1,4,9-treat the Spiro[5.5]undecane · Hydrochloride

TLC:Rf of 0.15 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ to 4.23 (s, 2H), was 4.02 (DD, J=7,5, and 4.5 Hz, 1H), 3,90-3,68 (m, 2H), to 3.58-to 3.36 (m, 4H), of 2.56 (s, 3H), 2,56-of 2.38 (m, 2H), 2,32 (s, 3H), 2,32 is 2.10 (m, 2H), 1,88-of 1.26 (m, 7H), to 1.67 (s, 9H), is 0.96 (t, J=7.2 Hz, 3H), of 0.96 (d, J=6.3 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H).

Example 4(21)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(1-benzyloxycarbonylamino-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf to 0.17 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 7,42-7,26 (m, 5H), of 5.15 (s, 2H), 4,48-4,22 (m, 3H), 4,23 (s, 2H), was 4.02 (DD, J=7,8, and 4.5 Hz, 1H), 3,88-3,68 (m, 2H), to 3.58-to 3.36 (m, 4H), 3,12-2,90 (m, 2H), 2,50 of 1.28 (m, 15H), 2,42 (s, 3H), 2,30 (s, 3H), of 0.96 (t, J=6.9 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H), were 0.94 (d, J=6.3 Hz, 3H).

Example 4(22)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-((4-methoxyphenyl)methylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.50 (chloroform:methanol=9:1);

NMR (CD3OD): δ to 7.95 (d, J=8.7 Hz, 2H), to 7.67 (d, J=8.7 Hz, 2H), 7,27 (d, J=8.7 Hz, 2H), 6.87 in (d, J=8.7 Hz, 2H), 4,51 (s, 2H), 4,42 (s, 2H), 4,00 (DD, J=7,5, and 4.8 Hz, 1H), 3,91-and 3.72 (m, 2H), 3,76 (s, 3H), 3,53-to 3.35 (m, 4H), 2,50 to 2.35 (m, 2H), 2.26 and-of 2.08 (m, 2H), 1,87 of 1.28 (m, 7H), were 0.94 (t, J=7.5 Hz, 3H), were 0.94 (d, J=6.6 Hz, 3H), of 0.93 (d, J=6.6 Hz, 3H).

Example 4(23)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(3-methoxypropylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.48 (chloroform:methanol=9:1);

NMR (CD3OD): δ a 7.92 (d, J=8,4 Hz, 2H), to 7.67 (d, J=8,4 Hz, 2H), 4,43 (s, 2H), 4,00 (DD, J=7,8, and 4.5 Hz, 1H), 3,92 of 3.75 (m, 2H), 3,53-to 3.35 (m, 8H), to 3.34 (s, 3H), 2,50 to 2.35 (m, 2H), 2,27 is 2.10 (m, 2H), 1,92 of 1.28 (m, 9H), were 0.94 (t, J=7.2 Hz, 3H), were 0.94 (d, J=6.6 Hz, 3H), of 0.93 (d, J=6.6 Hz, 3H).

Example 4(24)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-ethoxycarbonylphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.29 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 8,19 (d, J=9.0 Hz, 2H), 7,63 (d, J=9.0 Hz, 2H), 4,28 (s, 2H), a 4.03 (m, 1H), 3,94 (s, 3H), 3.95 to 3,30 (m, 6H), 2,50-of 2.15 (m, 4H), of 2.44 (s, 3H), 2,39 (s, 3H), 1,90-of 1.30 (m, 7H), is 0.96 (t, J=7,2 Hz, 3H), of 0.95 (d, J=6.6 Hz, 3H) 0,94 (d, J=6.6 Hz, 3H).

Example 4(25)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-methoxyphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.31 in (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 7,37 (d, J=9.0 Hz, 2H), to 7.09 (d, J=9.0 Hz, 2H), or 4.31 (s, 2H), was 4.02 (m, 1H), 4,00-3,30 (m, 6H), 3,86 (s, 3H), 2,65-of 2.15 (m, 4H), 2,39 (s, 3H), of 2.34 (s, 3H), 1,90-of 1.30 (m, 7H), is 0.96 (t, J=7,2 Hz, 3H), of 0.95 (d, J=6.6 Hz, 3H) 0,94 (d, J=6.6 Hz, 3H).

Example 4(26)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(3-(morpholine-4-yl)propylaminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.18 (ethyl acetate:methanol=3:1);

NMR (CD3OD): δ 8,02 (d, J=8.7 Hz, 2H), 7,74 (d, J=8,7 the C, 2H), or 4.31 (s, 2H), 4,10-4,00 (m, 3H), 4,00 3.00 for (m, 16H), 2,70 is 2.10 (m, 4H), 2,48 (s, 3H), 2.40 a (s, 3H), 2,10-1,90 (m, 2H), 1,90-of 1.30 (m, 7H), is 0.96 (t, J=7.2 Hz, 3H), of 0.95 (d, J=6.6 Hz, 3H), were 0.94 (d, J=6,6 Hz, 3H).

Example 4(27)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyrrolidin-1-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.55 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,71-to 7.59 (m, 4H), to 4.41 (s, 2H), 4,01 (DD, J=7,8, and 4.5 Hz, 1H), 3,83-and 3.72 (m, 2H), 3,60 (t, J=6.9 Hz, 2H), 3,55-of 3.32 (m, 4H), of 3.45 (t, J=6.9 Hz, 2H), 2.57 m-is 2.37 (m, 2H), 2,27-of 2.08 (m, 2H), 2.05 is-1,44 (m, 9H), 1,44-of 1.27 (m, 2H), 0,99-of 0.90 (m, 9H).

Example 4(28)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(piperidine-1-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.60 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 7.69 (d, J=8,4 Hz, 2H), 7,50 (d, J=8,4 Hz, 2H), to 4.41 (s, 2H), 4,01 (DD, J=7,5, and 4.5 Hz, 1H), 3,93-and 3.72 (m, 4H), 3,55-3,30 (m, 6H), 2.57 m-2,39 (m, 2H), 2.26 and-2,07 (m, 2H), 1,90-of 1.44 (m, 11H), 1,44-1,26 (m, 2H), 0,98-of 0.90 (m, 9H).

Example 4(29)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(morpholine-4-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.59 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 7.69 (d, J=8.1 Hz, 2H), 7,55 (d, J=8.1 Hz, 2H), to 4.41 (s, 2H), 4,01 (DD, J=7,8, and 4.5 Hz, 1H), 3,93-3,55 (m, 8H), 3,55-to 3.34 (m, 6H), 2,55-of 2.36 (m, 2H), 2,27-of 2.08 (m, 2H), 1,88-of 1.44 (m, 5H), 1,44 of 1.28 (m, 2H), 0,98-of 0.90 (m, 9H).

Example 4(30)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(N-methyl-N-(2-(pyrid the h-2-yl)ethyl)aminocarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · Hydrochloride

TLC:Rf is 0.49 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,80 (d, J=6.0 Hz, 1H), 8,58 (m, 1H), 8,10 (d, J=8,4 Hz, 1H), 7,98 (m, 1H), of 7.70 (d, J=7.8 Hz, 2H), 7,41 (d, J=7.8 Hz, 2H), 4,39 (s, 2H), 4,05-3,95 (m, 3H), 3,94 at 3.69 (m, 2H), 3,60-3,37 (m, 6H), is 3.08 (s, 3H), 2,70 is 2.43 (m, 2H), 2.26 and-2,05 (m, 2H), 1,90-of 1.44 (m, 5H), 1,44-of 1.26 (m, 2H), 0,99-of 0.90 (m, 9H).

Example 4(31)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(cyclohexanecarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.33 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ a 7.92 (d, J=8.1 Hz, 2H), 7,69 (d, J=8.1 Hz, 2H), 4,43 (s, 2H), 4,01 (DD, J=7,5, and 4.5 Hz, 1H), 3.96 points-3,70 (m, 2H), to 3.58-to 3.36 (m, 4H), 2,58-of 2.38 (m, 2H), 2,28-to 2.06 (m, 2H), 2,04-of 1.12 (m, 18H), 0,95 (t, J=6,9 Hz, 3H), were 0.94 (d, J=6.3 Hz, 3H), of 0.93 (d, J=6.3 Hz, 3H).

Example 4(32)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(N,N-dimethylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.44 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ to $ 7.91 (d, J=8.7 Hz, 2H), 7,86 (d, J=8.7 Hz, 2H), 4,49 (s, 2H), was 4.02 (DD, J=7,5, and 4.8 Hz, 1H), 3.96 points is 3.76 (m, 2H), 3,56-to 3.38 (m, 4H), of 2.72 (s, 6H), 2,60-to 2.40 (m, 2H), 2,28-to 2.06 (m, 2H), 1,90 of 1.28 (m, 7H), of 0.95 (t, J=7.2 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H), were 0.94 (d, J=6.3 Hz, 3H).

Example 4(33)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-ethoxycarbonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.50 (ethyl acetate:methanol=10:1);

NMR (CD OD): δ of 8.04 (d, J=9.0 Hz, 2H), 7,63 (d, J=9.0 Hz, 2H), 7,19 (d, J=9.0 Hz, 2H), was 7.08 (d, J=9.0 Hz, 2H), to 4.38 (s, 2H), was 4.02 (DD, J=7,5, and 4.5 Hz, 1H), 3,90 (s, 3H), 3,88-and 3.72 (m, 2H), to 3.58-to 3.36 (m, 4H), 2,58-of 2.38 (m, 2H), 2,30-of 2.08 (m, 2H), 1,90 of 1.28 (m, 7H), is 0.96 (t, J=6.9 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H), were 0.94 (d, J=6.3 Hz, 3H).

Example 4(34)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(1-methylpiperidin-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.15 (chloroform:methanol=5:1);

NMR (CD3OD): δ 4,56 (m, 1H), 4,20 (s, 2H), 4,01 (DD, J=7,8, and 4.8 Hz, 1H), 3,86-of 3.42 (m, 8H), 3,30-3,20 (m, 2H), 2,93 (s, 3H), 2,64-2,48 (m, 2H), 2,44-of 2.28 (m, 2H), 2,44 (s, 3H), 2,31 (s, 3H), 2,22-to 2.06 (m, 4H), 1,86 of 1.28 (m, 7H), 0,98-to 0.88 (m, 9H).

Example 4(35)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(1-methylsulfonylmethane-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 4.46 (m, 1H), 4,25 (s, 2H), 4,01 (DD, J=7,8, and 4.8 Hz, 1H), 3,92-3,68 (m, 4H), 3,60-of 3.42 (m, 4H), 3.04 from-2,90 (m, 2H), 2,89 (s, 3H), 2,62 is 2.46 (m, 2H), 2,48 (s, 3H), of 2.38 (s, 3H), 2,24-to 1.98 (m, 6H), 1,90 of 1.28 (m, 7H), 0,98-of 0.90 (m, 9H).

Example 4(36)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(3-(N,N-dimethylamino)propylaminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.22 (chloroform:methanol:28% aqueous ammonia=100:10:1);

NMR (CD3OD): δ 8,02 (d, J=8.7 Hz, 2H), 7,74 (d, J=8.7 Hz, 2H) 4,30 (s, 2H), as 4.02 (DD, J=7,8, and 4.5 Hz, 1H), 3,84-to 3.73 (m, 2H), 3,66 of 3.56 (m, 2H), 3,55-3,44 (m, 2H), 3.27 to 3,18 (m, 2H), to 3.02 (t, J=6.3 Hz, 2H), 2,89 (s, 6H), 2,70-2,52 (m, 2H), 2,48 (s, 3H), 2.40 a (s, 3H), 2,28-2,11 (m, 2H), 2,00 of 1.28 (m, 9H), 1.00 and-of 0.90 (m, 9H).

Example 4(37)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(N,N-dimethylamino)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf and 0.61 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,68-of 7.60 (m, 4H), 7,21 (d, J=8.7 Hz, 2H), 7,14 (d, J=8.7 Hz, 2H), 4,35 (s, 2H), 4,00 (DD, J=7,8, and 4.8 Hz, 1H), 3,89-of 3.77 (m, 2H), 3,54 is 3.40 (m, 4H), of 3.28 (s, 6H), 2,62 is 2.44 (m, 2H), 2.26 and-2,07 (m, 2H), 1,90-of 1.26 (m, 7H), 1,00-of 0.90 (m, 9H).

Example 4(38)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-(N',N'-dimethylamino)ethyl)aminosulphonylphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.34 (chloroform:methanol:28% aqueous ammonia=100:10:1);

NMR (CD3OD): δ of 8.04 (d, J=8.7 Hz, 2H), 7,81 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), was 4.02 (DD, J=7,8, and 4.5 Hz, 1H), 3.95 to to 3.73 (m, 2H), 3,66-of 3.54 (m, 2H), 3,54-of 3.43 (m, 2H), 3,42 (s, 4H), 3,01 (s, 6H), 2,85 (s, 3H), 2,68-2,52 (m, 2H), 2,50 (s, 3H), 2,41 (s, 3H), 2,29 is 2.10 (m, 2H), 1,90 of 1.28 (m, 7H), 1,00-of 0.90 (m, 9H).

Example 4(39)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-((N,N-dimethylamino)methyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.29 (chloroform:methanol:28% aqueous ammonia=100:10:1);

NMR (CD3OD): δ a 7.62 (d, J=8.7 Hz, 2H), 7,53 (d, J=8.7 G is, 2H), 7.18 in-7,10 (m, 4H), 4,35 (s, 2H), 4,30 (s, 2H), 4,00 (DD, J=7,8, and 4.5 Hz, 1H), 3,88-3,68 (m, 2H), 3,54-to 3.38 (m, 4H), of 2.86 (s, 6H), 2,59-to 2.42 (m, 2H), 2.26 and-2,07 (m, 2H), 1,88-1,25 (m, 7H), 1,02-to 0.89 (m, 9H).

Example 4(40)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.25 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,03 (d, J=8.7 Hz, 2H), 7,58 (d, J=8.7 Hz, 2H), 7,16 (d, J=8.7 Hz, 2H), 7,05 (d, J=8.7 Hz, 2H), 4,32 (s, 2H), 4,01 (DD, J=7,8, and 4.5 Hz, 1H), 3,84-to 3.64 (m, 2H), 3,52-to 3.35 (m, 4H), 2,48 of-2.32 (m, 2H), 2,27 is 2.10 (m, 2H), 1,90-of 1.44 (m, 5H), 1,44-of 1.26 (m, 2H), 0,99-of 0.90 (m, 9H).

Example 4(41)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylaminophenol)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.35 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,01 (d, J=8.7 Hz, 2H), to 7.64 (d, J=8.7 Hz, 2H), 4,34 (s, 2H), a 4.03 (DD, J=7,8, and 4.8 Hz, 1H), 3.96 points-3,74 (m, 2H), 3,70-of 3.42 (m, 4H), 2,96 (s, 3H), 2,74-of 2.54 (m, 2H), 2,47 (s, 3H), of 2.46 (s, 3H), 2,30-2,10 (m, 2H), 1,92 of 1.28 (m, 7H), is 0.96 (t, J=6.9 Hz, 3H), of 0.96 (d, J=6.6 Hz, 3H), of 0.95 (d, J=6.6 Hz, 3H).

Example 4(42)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-((methoxycarbonyl)methylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane

NMR (CD3OD): δ for 7.78 (d, J=8.1 Hz, 2H), 7,42 (d, J=8.1 Hz, 2H), 6,70 (t, J=4,8 Hz, 1H), 6,40 (SHS, 1H), 4.26 deaths (d, J=4,8 Hz, 2H), 3.96 points (m, 1H), 3,81 (s, 3H), 3,62 (s, 2H), 3,50 of 3.28 (m, 2H), 3.00 and-2,48 (m, 8H), and 2.26-of 1.20 (m, 7H), 0,99-of 0.94 (m, 9H).

Example 4(43)

(3S)-1-butyl-25-dioxo-3-(2-methylpropyl)-9-(3-(3,5-dimethyl-1-phenylpyrazol-4-yl)-2E-propenyl)-1,4,9-diazaspiro[5.5]undecane · Hydrochloride

NMR (CD3OD): δ 7,56-to 7.32 (m, 5H), is 6.54 (m, 1H), 6,38 (SHS, 1H), 5,96 (m, 1H), 4.00 points (m, 1H), 3,76-2,90 (m, 8H), of 2.38 (s, 3H), of 2.34 (s, 3H), 2,14-1,22 (m, 11H), 1,00 is 0.86 (m, 9H).

Example 5

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(carboxymethylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

To a solution of the compound obtained in example 4(42), (106 mg) in methanol (3 ml) is added 5N aqueous sodium hydroxide solution (0.1 ml). The reaction mixture is stirred for 3 hours at room temperature. The reaction mixture was concentrated and the residue is dissolved in dioxane. To the solution was added a solution of 4N hydrogen chloride/ethyl acetate. The reaction mixture is concentrated and to the residue is added dioxane and filtered. The filtrate is concentrated and the obtained residue was washed with diethyl ether and dried to obtain specified in the title compound (62 mg)having the following physical data.

TLC:Rf 0.28 in (butanol:acetic acid:water=4:2:1);

NMR (CD3OD): δ to 7.99 (d, J=8.7 Hz, 2H), of 7.70 (d, J=8.7 Hz, 2H), of 4.44 (s, 2H), 4,11 (s, 2H), was 4.02 (DD, J=7,5, and 4.8 Hz, 1H), 3,94-3,74 (m, 2H), 3,56-to 3.36 (m, 4H), 2,48 of-2.32 (m, 2H), 2,28-of 2.08 (m, 2H), 1,88-of 1.30 (m, 7H), is 0.96 (t, J=7.2 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H), were 0.94 (d, J=6.3 Hz, 3H).

Example 6

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-(3,5-dimethyl-1-phenylpyrazol-4-yl)propyl)-1,4,9-diazaspiro[5.5]undecane · gidr the chloride

To a solution of the compound obtained in example 4(43), (85 mg) in methanol (10 ml) add a solution of 5% palladium on carbon (10 mg). The reaction mixture is stirred for 22 hours at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through Celite and the filtrate concentrated. The resulting residue is purified column chromatography on silica gel (ethyl acetate:methanol=15:1). To a solution of the obtained compound in methanol is added a solution of 4N hydrogen chloride/ethyl acetate. The reaction mixture was concentrated and the obtained residue was washed with diethyl ether and dried to obtain specified in the title compound (23 mg)having the following physical data.

TLC:Rf of 0.18 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,70 is 7.50 (m, 5H), is 4.03 (DD, J=7,2, 4,2 Hz, 1H), 3,86-3,68 (m, 2H), 3,66 is 3.40 (m, 4H), 3,30-and 3.16 (m, 2H), 2,74-2,48 (m, 4H), to 2.46 (s, 3H), of 2.35 (s, 3H), 2,28-to 1.98 (m, 4H), 1,90-of 1.24 (m, 7H), 0,97 (t, J=7.2 Hz, 3H), of 0.96 (d, J=6.6 Hz, 3H), of 0.95 (d, J=6.6 Hz, 3H).

Example 7

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in example 2 using the compound obtained in reference example 3(2), instead of the compound obtained in reference example 3, and using [4-(4-formyl-3,5-dimethylpyrazole)phenyl]-N-dimethylcarbamyl instead of 3-formyl-6-phenoxypyridine, get listed in the title compound having the following physical data.

TLC:Rf is 0.59 (chloroform:methanol=10:1);

NMR (CD3OD): δ a 7.62 (d, J=9.0 Hz, 2H), 7,58 (d, J=9.0 Hz, 2H), 4,32 (s, 2H), of 4.05 (DD, J=7,8, and 4.5 Hz, 1H), 3.96 points-of 3.78 (m, 2H), 3,66-to 3.58 (m, 2H), 3.46 in-to 3.34 (m, 2H), 3,13 (s, 3H), 3.04 from (s, 3H), 2,52-of 2.38 (m, 2H,), 2,42 (s, 3H), 2,39 (s, 3H), 2,32 with 2.14 (m, 2H), 1,82 is 1.16 (m, 15H), 1,02-0,88 (m, 5H).

Example 7(1)-7(41)

According to a similar method described in example 7 using the appropriate aldehyde derivatives respectively instead of [4-(4-formyl-3,5-dimethylpyrazole)phenyl]-N,N-dimethylcarbamate receive the following connections.

Example 7(1)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.53(chloroform:methanol=10:1);

NMR (CD3OD): δ 7,72 (d, J=8.7 Hz, 2H), 7,58 (d, J=8.7 Hz, 2H), 4,33 (s, 2H), of 4.05 (DD, J=7,5, and 4.5 Hz, 1H), 3,98-of 3.78 (m, 2H), 3,64 of 3.56 (m, 4H), 3,56-3,44 (m, 2H), 3,44-of 3.32 (m, 2H), 2,50 is 2.10 (m, 4H), 2,42 (, 3H), 2,39 (s, 3H), 2,10-of 1.88 (m, 4H), 1,88-1,10 (m, 15H), 1,10-of 0.90 (m, 5H).

Example 7(2)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(morpholine-4-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.53(chloroform:methanol=10:1);

NMR (CD3OD): δ the 7.65 7,56 (m, 4H), 4,32 (s, 2H), of 4.05 (DD, J=7,5, and 4.5 Hz, 1H), 3.96 points-3,30 (m, 14H), 2,54 of-2.32 (m, 2H), 2,43 (s, 3H), 2,39 (s, 3H), 2,32-2,12 (m, 2H), 1,84-1,10 (m, 15H), 1,02 is 0.86 (m, 5H).

Example 7(3)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.15 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,07 (d, J=8.1 Hz, 2H), to 7.64 (d, J=8.1 Hz, 2H), or 4.31 (s, 2H), of 4.05 (DD, J=7,2, 5,1 Hz, 1H), 3,94 is 3.76 (m, 2H), 3,79 (t, J=6.0 Hz, 2H), 3,66-of 3.54 (m, 2H), 3,54-to 3.36 (m, 2H), 3,41 (t, J=6.0 Hz, 2H), 3.00 and (s, 6H), 2,66-2,48 (m, 2H), 2,46 (s, 3H), 2,41 (s, 3H), 2,28 is 2.10 (m, 2H), 1,82-1,10 (m, 15H), 1,02 is 0.86 (m, 5H).

Example 7(4)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(morpholine-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.60 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.59 (d, J=8,4 Hz, 2H), of 7.48 (d, J=8.7 Hz, 2H), 7,22-to 7.09 (m, 4H), 4,36 (s, 2H), Android 4.04 (DD, J=7,5, and 4.8 Hz, 1H), 3,88-to 3.34 (m, 14H), 2,52-of 2.34 (m, 2H), 2,28-of 2.08 (m, 2H), 1,81-1,10 (m, 15H), 1,04-0,84 (m, 5H).

Example 7(5)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-methylsulfinylphenyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.57 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,08 (d, J=8,4 Hz, 2H), 7,87 (d, J=8,4 Hz, 2H), 4,50 (s, 2H), a 4.03 (DD, J=7,5, and 4.5 Hz, 1H), 3,94 is 3.76 (m, 2H), 3,52-to 3.36 (m, 4H), 3.15 in (s, 3H), 2,56-of 2.38 (m, 2H), 2.26 and-of 2.08 (m, 2H), 1,80-1,10 (m, 15H), 1,02 is 0.86 (m, 5H).

Example 7(6)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylsulfinylphenyl)phenylmethyl-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.57 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.95 (d, J=9.0 Hz, 2H), to 7.64 (d, J=8.7 Hz, 2H), 7,25-to 7.18 (m, 4H), 4,39 (s, 2H), Android 4.04 (DD, J=7,8, and 4.8 Hz, 1H), 3,90 is 3.76 (m, 2H), to 3.58-to 3.34 (m, 4H), of 3.12 (s, 3H), 2,50-of 2.36 (m, 2H), 2,30-2,10 (m, 2H), 1,82-1,10 (m, 15H), 1,02-0,88 (m, 5H).

Example 7(7)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(2-(morpholine-4-yl)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.43(chloroform:methanol=10:1);

NMR (CD3OD): δ of 8.06 (d, J=8.7 Hz, 2H), EUR 7.57 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,12-4,01 (m, 3H), 3,92 is 3.76 (m, 4H), 3,65 is 3.40 (m, 6H), 3,40-and 3.16 (m, 6H), 2,64 is 2.44 (m, 2H), 2,48 (s, 3H), 2,41 (s, 3H), 2,28-2,12 (m, 2H), 1,84-1,10 (m, 15H), 1,02 is 0.86 (m, 5H).

Example 7(8)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.43 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,01 (d, J=8.7 Hz, 2H), 7,83 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,08-3,95 (m, 3H), 3.95 to 3,74 (m, 2H), 3,68-of 3.46 (m, 6H), 3,28-3,20 (m, 2H), 2.91 in (s, 3H), 2,88-of 2.72 (m, 2H), 2,70-2,52 (m, 2H), of 2.51 (s, 3H), 2,42 (s, 3H), 2.26 and-of 2.08 (m, 2H), 1,82-1,10 (m, 15H), 1,02 is 0.86 (m, 5H).

Example 7(9)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.53 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,74 (d, J=9.0 Hz, 2H), 7.62mm (d, J=8.7 Hz, 2H), 7,25-7,14 (m, 4H), 4,37 (s, 2H), Android 4.04 (DD, J=7,5, and 4.5 Hz, 1H), 3,88-and 3.72 (m, 2H), 3,54-to 3.36 (m, 4H), 2,80 (s, 3H), 2,52-of 2.36 (m, 2H), 2.26 and is 2.10 (m, 2H), 1,80-1,10 (m, 15H), 1,02 is 0.86 (m, 5H).

Example 7(10)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.41 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,01 (d, J=8.7 Hz, 2H), 7,60 (d, J=8.7 Hz, 2H), 4,30 (s, 2H), of 4.05 (DD, J=7,5 and 4.2 Hz, 1H), 3,92-3,68 (m, 4H), 3,66-of 3.42 (m, 6H), 2,70-of 2.50 (m, 2H), of 2.45 (s, 3H), 2.40 a (s, 3H), 2,28-of 2.08 (m, 2H,), 1,82-1,10 (m, 15H), 1,02-0,84 (m, 5H).

Example 7(11)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(2-hydroxyethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,89 (d, J=9.0 Hz, 2H), 7,58 (d, J=8.7 Hz, 2H), 7,16 (d, J=8.7 Hz, 2H), was 7.08 (d, J=9.0 Hz, 2H), 4,37 (s, 2H), Android 4.04 (DD, J=7,5, and 4.5 Hz, 1H), 3,90-3,70 (m, 2H), 3,70 (t, J=6.0 Hz, 2H), to 3.58-3.46 in (m, 2H), 3,50 (t, J=6.0 Hz, 2H), 3,42-to 3.34 (m, 2H), 2,44-of 2.30 (m, 2H), 2,30-of 2.08 (m, 2H), 1,82-1,12 (m, 15H), 1,02-0,84 (m, 5H).

Example 7(12)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.25 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ to 7.59 (d, J=8.7 Hz, 2H), to 7.59 (d, J=8.7 Hz, 2H), 7,16 (d, J=8.7 Hz,2H), 7,10 (d, J=8.7 Hz, 2H), 4,37 (s, 2H), of 4.05 (DD, J=7,5, and 4.8 Hz, 1H), 3,90-3,74 (m, 2H), 3,62-to 3.36 (m, 8H), 2,48-of 2.08 (m, 4H), 2,04-1,08 (m, 19H), is 0.96 (t, J=7.2 Hz, 3H), 1.04 million-0,84 (m, 2H).

Example 7(13)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(cyclohexanesulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.42 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,03 (d, J=8.7 Hz, 2H), of 7.70 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), of 4.05 (DD, J=7,8, and 4.8 Hz, 1H), 3,92-and 3.72 (m, 2H), 3,68-to 3.58 (m, 2H), 3,56-3,44 (m, 2H), 3,06 (m, 1H), 2,68-of 2.50 (m, 2H), 2,47 (s, 3H), is 2.41 (s, 3H), 2,38-of 2.08 (m, 2H), 1,82 was 1.06 (m, 25H), 1,02 is 0.86 (m, 5H).

Example 7(14)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(3-methoxypropylamine)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.48 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,01 (d, J=8,4 Hz, 2H), 7,74 (d, J=8,4 Hz, 2H), or 4.31 (s, 2H), of 4.05 (DD, J=7,8, and 4.8 Hz, 1H), 3,92-and 3.72 (m, 2H), 3,68-to 3.58 (m, 2H), 3,56-of 3.46 (m, 4H), 3,39 (t, J=6.0 Hz, 2H), 3,26 (s, 3H), 2,98 (t, J=6.9 Hz, 2H), 2,72-of 2.56 (m, 2H), 2,48 (s, 3H), 2,43 (s, 3H), 2.26 and-of 2.08 (m, 2H), 1,82-1,10 (m, 15H), 1,02 is 0.86 (m, 5H).

Example 7(15)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-methylsulfinylphenyl)-1,4,9-diazaspiro[5.5]undecane· hydrochloride

TLC:Rf of 0.15 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ a 7.85 (d, J=8.7 Hz, 2H), 7,81 (d, J=8.7 Hz, 2H), 4,47 (s, 2H), of 4.05 (DD, J=7,2, 4.8 Hz, 1H), 3,94 is 3.76 (m, 2H), to 3.58-to 3.36 (m, 4H), and 2.83 (s, 3H), 2,54-,34 (m, 2H), 2,18-to 2.06 (m, 2H), 1,82-1,10 (m, 15H), is 0.96 (t, J=7.5 Hz, 3H), 1.06 a is 0.86 (m, 2H).

Example 7(16)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-propylpyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf and 0.61 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 4.28 (s, 2H), 4,13 (t, J=7.2 Hz, 2H), of 4.05 (DD, J=7,5, and 4.5 Hz, 1H), 3,88-and 3.72 (m, 2H), 3,60-to 3.38 (m, 4H), 2,62 of-2.32 (m, 2H), 2,46 (s, 3H), 2,42 (s, 3H), 2,28-of 2.08 (m, 2H), 1,94-1,08 (m, 17H), 0,96 (t, J=7.2 Hz, 6H), 1.06 a is 0.86 (m, 2H).

Example 7(17)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-aripirazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.51 (chloroform:methanol=10:1);

NMR (CD3OD): δ 4,34-4,20 (m, 4H), Android 4.04 (DD, J=7,8, and 4.8 Hz, 1H), 3,88-3,70 (m, 2H), 3,62-of 3.46 (m, 4H), 2,72-of 2.54 (m, 2H), 2,52 (s, 3H), 2,48 (s, 3H), 2,24-to 2.06 (m, 2H), 1,82-a 1.08 (m, 18H), 1,02 is 0.86 (m, 5H).

Example 7(18)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-cyclopentylphenol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.49 (chloroform:methanol=10:1);

NMR (CD3OD): δ 5,02-4,82 (m, 1H), 4,33 (s, 2H), Android 4.04 (DD, J=7,5, and 4.8 Hz, 1H), 3,90-3,70 (m, 2H), 3,64-of 3.48 (m, 4H), 2,80-2,60 (m, 2H), 2,58 (s, 3H), 2.57 m (s, 3H), 2,36-1,08 (m, 25H), 1,04-0,84 (m, 5H).

Example 7(19)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(3-(morpholine-4-yl)propylaminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.20 (ethyl acetate:methanol=3:1);

NMR (CD3OD): δ 8,02 (d, J=8.7 Hz, 2H), 7,74 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,10-4,00 (m, 3H), 4,00 3.00 for (m, 16H), 2,65 is 2.10 (m, 4H), 2,47 (s, 3H), 2.40 a (s, 3H), 2.05 is-of 1.95 (m, 2H), 1.85 to to 1.15 (m, 15H), 1,10-0,90 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 7(20)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(N,N-dimethylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.60 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 7.90 (d, J=8,4 Hz, 2H), to 7.84 (d, J=8,4 Hz, 2H), 4,48 (s, 2H), Android 4.04 (DD, J=7,5, and 4.5 Hz, 1H), 3,94 is 3.76 (m, 2H), 3,56-to 3.36 (m, 4H), 2,71 (s, 6H), 2,56-of 2.36 (m, 2H), 2,28-to 2.06 (m, 2H), 1,83-1,10 (m, 15H), 1,08-of 0.85 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 7(21)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(pyrrolidin-1-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.59 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.68 (d, J=8.7 Hz, 2H), 7,63 (d, J=8.7 Hz, 2H), to 4.41 (s, 2H), Android 4.04 (DD, J=7,5, and 4.5 Hz, 1H), 3,92-to 3.73 (m, 2H), 3,60 (t, J=6.9 Hz, 2H), 3,55-to 3.34 (m, 4H), of 3.45 (t, J=6.9 Hz, 2H), 2,56-of 2.36 (m, 2H), 2,27-2,07 (m, 2H), 2.06 to of 1.84 (m, 4H), 1,83-1,10 (m, 15H), 1,06-0,83 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 7(22)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(N,N-dimethylamino)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.51 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,70 to 7.62 (m, 4H), 7,22 (d, J=9.0 Hz, 2H), 7,14 (d, J=8,4 Hz, 2H), 4,36 (s, 2H), a 4.03 (DD, J=7,5, and 4.5 Hz, 1H), ,86-3,70 (m, 2H), 3,52 is 3.40 (m, 4H), 3,30 (s, 6H), 2,62 is 2.44 (m, 2H), 2,24-to 2.06 (m, 2H), 1,80-1,14 (m, 15H), 1,02 is 0.86 (m, 5H).

Example 7(23)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(cyclohexanecarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.38 (chloroform:methanol=10:1);

NMR (CD3OD): δ to $ 7.91 (d, J=8.1 Hz, 2H), 7,68 (d, J=8.1 Hz, 2H), 4,42 (s, 2H), a 4.03 (DD, J=7,5, and 4.5 Hz, 1H), 3,90-and 3.72 (m, 3H), 3,52-to 3.36 (m, 4H), 2,56-of 2.38 (m, 2H), 2,24-to 2.06 (m, 2H), 2,00-1,10 (m, 25H), 1,04-0,86 (m, 5H).

Example 7(24)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-ethoxycarbonylphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloridecan · hydrochloride

TLC:Rf of 0.33 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 8,18 (d, J=8.7 Hz, 2H), to 7.64 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), of 4.05 (m, 1H), 3,94 (s, 3H), 3,94 is-3.45 (m, 6H), 2,70-of 2.50 (m, 2H), 2,46 (s, 3H), 2,41 (s, 3H), 2,30 is 2.10 (m, 2H), 1.85 to 1,10 (m, 15H), 1,10-of 0.90 (m, 2H), of 0.95 (t, J=6.9 Hz, 3H).

Example 7(25)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(3-methoxypropylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloridecan · hydrochloride

TLC:Rf of 0.18 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ to 7.93 (d, J=8,4 Hz, 2H), 7,69 (d, J=8,4 Hz, 2H), of 4.44 (s, 2H), Android 4.04 (DD, J=7,5, and 4.8 Hz, 1H), 3,92-3,74 (m, 2H), to 3.58-to 3.36 (m, 10H), to 3.35 (s, 3H), 2,54-of 2.36 (m, 2H), 2,28-to 2.06 (m, 2H), 1,94-1,08 (m, 15H), 1,04-0,84 (m, 2H), of 0.95 (t, J=6.9 Hz, 3H).

Example 7(26)

(3S)-1-butyl-2,5-dioxo-3-CEC is heximer-9-(4-(N-methyl-N-(2-(pyridin-2-yl)ethyl)aminocarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · Hydrochloridecan · hydrochloride

TLC:Rf of 0.27 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 8,81 (m, 1H), 8,59 (m, 1H), 8,16-7,94 (m, 2H), 7,71 (d, J=7.8 Hz, 2H), 7,42 (d, J=7.8 Hz, 2H), and 4.40 (s, 2H), 4,06-3,70 (m, 5H), 3,60-to 3.36 (m, 6H), to 3.09 (s, 3H), 2,72-to 2.42 (m, 2H), 2.26 and-2,02 (m, 2H), 1,84-1,14 (m, 15H), 1,06-0,84 (m, 2H), of 0.95 (t, J=6.9 Hz, 3H).

Example 7(27)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-((4-methoxyphenyl)methylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloridecan · hydrochloride

TLC:Rf of 0.38 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 7.96 (d, J=9.0 Hz, 2H), 7,69 (d, J=9.0 Hz, 2H), 7,28 (d, J=9.0 Hz, 2H), to 6.88 (d, J=9.0 Hz, 2H), to 4.52 (s, 2H), 4,43 (s, 2H), Android 4.04 (DD, J=7,5, and 4.5 Hz, 1H), 3,92-of 3.78 (m, 2H), of 3.77 (s, 3H), 3,56-to 3.36 (m, 4H), 2,52-of 2.34 (m, 2H), 2.26 and e 2.06 (m, 2H), 1,82-1,10 (m, 15H), 1,06-0,84 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 7(28)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-ethoxycarbonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.54 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 8.04 (d, J=9.0 Hz, 2H), 7,63 (d, J=9.0 Hz, 2H), 7,19 (d, J=9.0 Hz, 2H), was 7.08 (d, J=9.0 Hz, 2H), to 4.38 (s, 2H), of 4.05 (DD, J=7,5, and 4.5 Hz, 1H), 3,90 (s, 3H), 3,88-and 3.72 (m, 2H), to 3.58-to 3.38 (m, 4H), 2,58-of 2.38 (m, 2H), 2,28-of 2.08 (m, 2H), 1,84-1,08 (m, 15H), 1,06 is 0.86 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 7(29)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-methoxyphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochl the reed

TLC:Rf of 0.40 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,42 (d, J=9.0 Hz, 2H), 7,12 (d, J=9.0 Hz, 2H), 4,33 (s, 2H), 4,06 (DD, J=7,5, and 4.5 Hz, 1H), 3.96 points is 3.76 (m, 2H), 3,88 (s, 3H), 3,68 is 3.40 (m, 4H), 2,68-2,48 (m, 2H), of 2.45 (s, 3H), of 2.38 (s, 3H), 2,32-of 2.08 (m, 2H), 1,84-1,12 (m, 15H), 1,06-0,84 (m, 2H), 0,97 (t, J=7.2 Hz, 3H).

Example 7(30)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1-methylpiperidin-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.18 (chloroform:methanol=5:1);

NMR (CD3OD): δ 4,58 (m, 1H), is 4.21 (s, 2H), a 4.03 (DD, J=7,5, and 4.5 Hz, 1H), 3,86-of 3.42 (m, 8H), 3,32-3,20 (m, 2H), 2,93 (s, 3H), 2,70-of 2.50 (m, 2H), 2,50-of 2.26 (m, 2H), of 2.45 (s, 3H), of 2.33 (s, 3H), 2,24-2,04 (m, 4H), 1,82 was 1.06 (m, 15H), 1,02 is 0.86 (m, 5H).

Example 7(31)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1-methylsulfonylmethane-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.41 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 4.44 (m, 1H), 4,24 (s, 2H), Android 4.04 (DD, J=7,8, and 4.8 Hz, 1H), 3,92-3,68 (m, 4H), 3,60 is 3.40 (m, 4H), 3,02-2,90 (m, 2H), 2,89 (s, 3H), 2,60-to 2.40 (m, 2H), 2,46 (s, 3H), of 2.36 (s, 3H), 2.26 and is 1.96 (m, 6H), 1,82-1,10 (m, 15H), 1,02 is 0.86 (m, 5H).

Example 7(32)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(3-(N,N-dimethylamino)propylaminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.22 (chloroform:methanol:28% aqueous solution and Miaka=100:10:1);

NMR (CD3OD): δ 8,02 (d, J=8.7 Hz, 2H), 7,74 (d, J=8.7 Hz, 2H), 4,30 (s, 2H), Android 4.04 (DD, J=7,5, and 4.5 Hz, 1H), 3,94-to 3.73 (m, 2H), 3,66 of 3.56 (m, 2H), 3,54-of 3.43 (m, 2H), 3.27 to 3,18 (m, 2H), 3,05-of 2.97 (m, 2H), 2,89 (, 6H), 2,68 is 2.51 (m, 2H), 2,48 (s, 3H), 2.40 a (s, 3H), 2,28-of 2.08 (m, 2H), 2.00 in a 1.88 (m, 2H), 1,84-1,10 (m, 15H), 1,04-0,88 (m, 5H).

Example 7(33)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-(N',N'-dimethylamino)ethyl)aminosulphonylphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.32 (chloroform:methanol:28% aqueous ammonia=100:10:1);

NMR (CD3OD): δ of 8.04 (d, J=8.7 Hz, 2H), 7,82 (d, J=8.7 Hz, 2H), 4,30 (s, 2H), Android 4.04 (DD, J=7,5, and 4.5 Hz, 1H), 3,94-3,74 (m, 2H), 3,67 of 3.56 (m, 2H), 3,55 is-3.45 (m, 2H), 3,42 (s, 4H), 3,01 (s, 6H), 2,85 (s, 3H), 2,72 of $ 2.53 (m, 2H), 2,50 (s, 3H), 2,41 (s, 3H), 2,27-of 2.08 (m, 2H), 1,84-1,11 (m, 15H), 1,06-0,84 (m, 5H).

Example 7(34)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(piperidine-1-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.56 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.68 (d, J=8.1 Hz, 2H), 7,50 (d, J=8.1 Hz, 2H), to 4.41 (s, 2H), Android 4.04 (DD, J=7,5, and 4.8 Hz, 1H), 3,92-the 3.65 (m, 4H), 3,56-3,30 (m, 6H), 2.57 m-a 2.36 (m, 2H), 2.26 and-2,07 (m, 2H), 1,83-of 1.10 (m, 21H), 1,06-0,83 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 7(35)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(morpholine-4-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.54 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 7.69 (d, J=8.1 Hz, 2H), 7,55 (d, J=8.1 Hz, 2H), to 4.41 (s, 2H), Android 4.04 (DD, J=7,5, and 4.5 Hz, 1H), 3,91-3,55 (m, 8H), 3,55-3,30 (m, 6H), 2.57 m-is 2.37 (m, 2H), 2,27-2,05 (m, 2H), 1,83-1,08 (m, 15H), 1,06-0,83 (m, 2H), 0,94 (t, J=7.2 Hz, 3H).

Example 7(36)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-((N,N-dimethylamino)methyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.37 (chloroform:methanol=10:1);

NMR (CD3OD): δ a 7.62 (d, J=8.7 Hz, 2H), 7,53 (d, J=8.7 Hz, 2H), 7,16-7,10 (m, 4H), 4,35 (s, 2H), or 4.31 (s, 2H), Android 4.04 (DD, J=7,5, and 4.5 Hz, 1H), 3,86-3,70 (m, 2H), 3,52-to 3.38 (m, 4H), of 2.86 (s, 6H), 2,62 is 2.46 (m, 2H,), and 2.26-to 2.06 (m, 2H), 1,82-1,12 (m, 15H), 1,06-0,88 (m, 5H).

Example 7(37)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-methylaminophenol)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.13 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 8,00 (d, J=8.7 Hz, 2H), to 7.61 (d, J=8.7 Hz, 2H), 4,33 (s, 2H), 4,06 (DD, J=7,8, and 4.8 Hz, 1H), 3,94 is 3.76 (m, 2H), 3,66 of 3.56 (m, 2H), 3,52 is 3.40 (m, 2H), 2.95 and (s, 3H), 2,62-of 2.38 (m, 2H), 2,50 (s, 3H), 2,42 (s, 3H), 2,32 is 2.10 (m, 2H), 1,84-of 1.18 (m, 15H), 1,06-0,84 (m, 2H), 0,97 (t, J=6.9 Hz, 3H).

Example 7(38)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1,1-dimethylethyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.38 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ of 4.25 (s, 2H), Android 4.04 (DD, J=7,8, and 4.8 Hz, 1H), 3,88-to 3.73 (m, 2H), 3,59-to 3.50 (m, 2H), 3,47-of 3.42 (m, 2H), 2,60 (s, 3H), 2.57 m at 2.45 (m, 2H), of 2.38 (s, 3H), 2.23 to-2,10 (m, 2H),1,80-of 1.15 (m, 24H), 1,02 to 0.92 (m, 5H).

Example 7(39)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1-benzyloxycarbonylamino-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.33 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ 7,39-7,29 (m, 5H), 5,14 (s, 2H), to 4.52 (m, 1H), 4,33-the 4.29 (m, 2H), 4,25 (s, 2H), Android 4.04 (DD, J=7,8, and 4.8 Hz, 1H), a 3.87-and 3.72 (m, 2H), 3,55-of 3.42 (m, 4H), 3,10-2,98 (m, 2H), 2,60 is 2.43 (m, 5H), a 2.36 (s, 3H), 2,23-of 1.95 (m, 6H), 1,80-of 1.15 (m, 15H), 1,02 to 0.92 (m, 5H).

Example 7(40)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-hydroxyethyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane

TLC:Rf is 0.24 (chloroform:methanol=20:1);

NMR (CD3OD): δ 7,34 (d, J=8.7 Hz, 2H), 7,31 (d, J=8.7 Hz, 2H), 6,95 (d, J=8.7 Hz, 2H), 6,94 (d, J=8.7 Hz, 2H), 4,57 (s, 2H), 4,00 (DD, J=7,5, and 4.5 Hz, 1H), 3,55 (s, 2H), 3,47-to 3.38 (m, 2H), 2,93-to 2.74 (m, 4H), 2,24-2,04 (m, 2H), 2.00 in to 1.83 (m, 2H), 1,83-1,08 (m, 15H), 1,05-0,84 (m, 2H), of 0.95 (t, J=7.5 Hz, 3H).

Example 7(41)

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-((methoxycarbonyl)methylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane

NMR (CDCl3): δ for 7.78 (d, J=8.1 Hz, 2H), 7,43 (d, J=8.1 Hz, 2H), of 6.71 (t, J=4,8 Hz, 1H), 6,32 (SHS, 1H), 4.26 deaths (d, J=4,8 Hz, 2H), 4.00 points (m, 1H), 3,81 (s, 3H), of 3.64 (s, 2H), 3,54 of 3.28 (m, 2H), 3,06-of 2.72 (m, 8H), and 2.26-1,10 (m, 15H), 1,06-of 0.82 (m, 2H), were 0.94 (t, J=6.9 Hz, 3H).

Example 8

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(carboxymethylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · GI is rochloride

According to the method described in example 5 using the compound obtained in example 7(41), instead of the compound obtained in example 4(42), get mentioned in the title compound having the following physical data.

TLC:Rf 0.36 and (butanol:acetic acid:water=4:2:1);

NMR (CD3OD): δ to 7.99 (d, J=8.1 Hz, 2H), of 7.70 (d, J=8.1 Hz, 2H), of 4.45 (s, 2H), 4,11 (s, 2H), Android 4.04 (DD, J=7,2, 4.5 Hz, 1H), 3,94-3,74 (m, 2H), to 3.58-to 3.36 (m, 4H), 2,56-of 2.34 (m, 2H), 2,30 e 2.06 (m, 2H), 1,84 is 1.16 (m, 15H), 1,06 is 0.86 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 9

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-vinyloxymethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in example 2 using the compound obtained in reference example 3(3), instead of the compound obtained in reference example 3, using 4-phenoxybenzaldehyde instead of 3-formyl-6-phenoxypyridine get mentioned in the title compound having the following physical data.

TLC:Rf and 0.46 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 7,50 (d, J=8.7 Hz, 2H), 7,42-7,37 (m, 2H), 7,18 (m, 1H), 7,07-7,01 (m, 4H), or 4.31 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 3,97 (m, 1H), 3,71 (m, 1H), 3,60 was 3.05 (m, 5H), 2,55-1,90 (m, 6H), 1,90-1,60 m, 5H), 1.60-to of 1.10 (m, 6H), 1,10-of 0.90 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Examples 9(1)-9(71)

According to the method described in example 9 using the appropriate aldehyde derivatives respectively instead of 4-phenoxybenzyl the guide, get the following compounds having the following physical data.

Example 9(1)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(6-phenoxypyridine-3-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ of 8.28 (d, J=2.7 Hz, 1H), 8,01 (DD, J=8,4, 2.7 Hz, 1H), 7,43 (t, J=8,4 Hz, 2H), 7,25 (t, J=8,4 Hz, 1H), 7,13 (d, J=8,4 Hz, 2H), 7,06 (d, J=8,4 Hz, 1H), to 4.38 (s, 2H), 4,15 (d, J=1.8 Hz, 1H), as 4.02 (m, 1H), of 3.77 (m, 1H), 3,60 was 3.05 (m, 5H), 2,55-1,90 (m, 6H), 1,90-to 1.60 (m, 5H), 1.60-to of 1.10 (m, 6H), 1,10-of 0.90 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 9(2)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-torpedolike)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.48 (chloroform:methanol=9:1);

NMR (CD3OD): δ 7,54-of 7.48 (m, 2H), 7,14 (DD, J=9,6, 8,1 Hz, 2H), 7,09-7,02 (m, 4H), to 4.33 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4.00 points (m, 1H), to 3.73 (m, 1H), 3,57 is 3.40 (m, 3H), 3.33 and-is 3.08 (m, 2H), 2,54-of 1.88 (m, 6H), 1,82-to 1.63 (m, 5H), 1,48 by 1.12 (m, 6H), 1,03-of 0.85 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 9(3)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-chlorphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.50 (chloroform:methanol=9:1);

NMR (CD3OD): δ 7,58-7,51 (m, 2H), 7,38 (d, J=9,3 Hz, 2H), 7,09 (sm, J=8,4 Hz, 2H), 7,02 (d, J=9,3 Hz, 2H), 4,34 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 3,99 (m, 1H), to 3.73 (m, 1H), to 3.58 is 3.40 (m, 3H), 3,32-to 3.09 (m, 2H), 2,53-1,89 (m, 6H), 1,81-of 1.62 (m, 5H), 1,48 is 1.13 (m, H), 1,03-of 0.82 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 9(4)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-cyanovinylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf value of 0.52 (chloroform:methanol=9:1);

NMR (CD3OD): δ 7,74 (d, J=9.0 Hz, 2H), of 7.64-7,58 (m, 2H), 7,21 (d, J=8,4 Hz, 2H), 7,13 (d, J=9.0 Hz, 2H), to 4.38 (s, 2H), 4.16 the (d, J=2.1 Hz, 1H), was 4.02 (m, 1H), of 3.77 (m, 1H), 3,57-of 3.43 (m, 3H), 3.33 and-is 3.08 (m, 2H), 2,54-1,90 (m, 6H), 1,80-to 1.63 (m, 5H), 1,48 is 1.13 (m, 6H), 1,03-of 0.82 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 9(5)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.41 (chloroform:methanol=9:1);

NMR (CD3OD): δ 7,53 (d, J=8.7 Hz, 2H), 7,29 (d, J=8.7 Hz, 2H), 7,06 (d, J=8.7 Hz, 2H), 7,03 (d, J=8.7 Hz, 2H), 4,33 (s, 2H), 4,15 (d, J=1.8 Hz, 1H), 3,98 (m, 1H), to 3.73 (m, 1H), to 3.58 is 3.40 (m, 3H), 3,32-3,03 (m, 2H), 2.95 and (s, 3H), 2,52-of 2.24 (m, 3H), 2,17-of 1.88 (m, 3H), 1,80-of 1.62 (m, 5H), 1,48-a 1.08 (m, 6H), 1,03-of 0.82 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 9(6)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(6-methylpyridin-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.21 in (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 8,54 (d, J=3.0 Hz, 1H), 8,08 (m, 1H), 7,82 (d, J=9.0 Hz, 1H), of 7.70 (d, J=9.0 Hz, 2H), 7,28 (d, J=9.0 Hz, 2H), 4,39 (s, 2H), 4,10 (d, J=2.1 Hz, 1H), 4,01 (m, 1H, in), 3.75 (m, 1H), 3,60-3,20 (m, 5H), by 2.73 (s, 3H), 2,70 to 2.35 (m, 3H), 2,20-1,90 (m, 3H), 1,90-1,60 (who, 5H), 1,50-of 1.15 (m, 6H), 1,10-of 0.90 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 9(7)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(1-methylethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0,41 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ was 7.45 (d, J=8.1 Hz, 2H), 7,37 (d, J=8.1 Hz, 2H), 4,30 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 3,98 (m, 1H), and 3.72 (m, 1H), 3,60 was 3.05 (m, 5H), 2.95 and (Quint, J=6,9 Hz, 1H), 2,50-1,90 (m, 6H), 1.85 to to 1.60 (m, 5H), 1,50-of 1.10 (m, 6H), 1,25 (d, J=6.9 Hz, 6H), 1,10-of 0.90 (m, 2H), of 0.95 (t, J=6.9 Hz, 3H).

Example 9(8)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.32 (chloroform:methanol=9:1);

NMR (CD3OD): δ 7,74 (d, J=9.0 Hz, 2H), to 7.61 (d, J=9.0 Hz, 2H), 7,22 (d, J=9.0 Hz, 2H), 7,17 (d, J=9.0 Hz, 2H), 4,36 (s, 2H), 4.16 the (d, J=2.1 Hz, 1H), 4,00 (dt, J=3,6, and 12.6 Hz, 1H, in), 3.75 (dt, J=3,6, and 12.6 Hz, 1H), to 3.58-3.42 points (m, 3H), 3,32-3,13 (m, 2H), 2,80 (s, 3H), 2,54 was 2.25 (m, 3H), 2,17-of 1.88 (m, 3H), 1,80-to 1.63 (m, 5H), 1,49 is 1.13 (m, 6H), 1,02-of 0.82 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 9(9)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(3,4,5,6-tetrahydropyran-4-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.43 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ was 7.45 (d, J=9.0 Hz, 2H), 7,06 (d, J=9.0 Hz, 2H), 4,63 (m, 1H), 4,28 (s, 2H), 4,15 (d, J=2.0 Hz, 1H), 4,01-3,90 (m, 3H), and 3.72 (m, 1H), 3,63-of 3.53 (m, 2H), 3,50-to 3.41 (m, 3H), of 3.27 (m, 1H), 3.15 in (m, 1H), 2,50 is 1.91 (m, 8H), 1,68-of 1.65 (m, 7H), 1,39-of 1.15 (m, 6H), 1,01-0.87 (m, 5H).

Example 9(10)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-phenylcarbonylamino)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.75 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ 7,87 (d, J=7.5 Hz, 2H), 7,81-7,72 (m, 4H), to 7.67 (t, J=7.5 Hz, 1H), 7,54 (t, J=7.5 Hz, 2H), 4,48 (s, 2H), 4.16 the (d, J=2.0 Hz, 1H), 4,07 (m, 1H), 3,81 (m, 1H), 3,53-3,47 (m, 3H), 3.33 and-3,17 (m, 2H), of 2.51-2,31 (m, 3H), 2,17-of 1.92 (m, 3H), 1,76 is 1.70 (m, 5H), 1,40-of 1.15 (m, 6H), 1,01-0.87 (m, 5H).

Example 9(11)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(1-phenyl-1-hydroxymethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.57 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ 7,53 (d, J=8.0 Hz, 2H), of 7.48 (d, J=8.0 Hz, 2H), 7,39-7,20 (m, 5H), of 5.81 (s, 1H), 4,33 (s, 2H), 4,14 (d, J=2.0 Hz, 1H), 4.00 points (m, 1H), 3,74 (m, 1H), 3.45 points-to 3.41 (m, 3H), 3,26 (m, 1H), 3,10 (m, 1H), 2,48 is 1.91 (m, 6H), 1,80-to 1.60 (m, 5H), 1,44-to 1.14 (m, 6H), 1.00 and is 0.86 (m, 5H).

Example 9(12)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(morpholine-4-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.49 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.95 (d, J=8.7 Hz, 2H), 7,79 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,17 (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), 3,79 (m, 1H), 3.75 to to 3.67 (m, 4H), 3,64-to 3.49 (m, 3H), 3,35-3,18 (m, 2H), 3,05-of 2.97 (m, 4H), 2,66-of 2.34 (m, 3H), 2.49 USD (s, 3H), 2.40 a (s, 3H), 2,20-to 1.87 (m, 3H), 1,84 is 1.60 (m, 5H), 1,52-of 1.10 (m, 6H), 1,05-080 (m, 2H), as 0.96 (t, J=7.2 Hz, 3H).

Example 9(13)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methylaminoethanol)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ 8,01 (d, J=8.7 Hz, 2H), 7,73 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4.16 the (d, J=2.0 Hz, 1H), of 4.05 (m, 1H), 3,80 (m, 1H), 3,63-of 3.53 (m, 3H), 3,34 is 3.23 (m, 2H), 2,59-of 2.34 (m, 3H), 2.57 m (s, 3H), 2,46 (s, 3H), 2,39 (s, 3H), of 2.16 (m, 1H), 2,05-of 1.93 (m, 2H), 1.77 in-of 1.66 (m, 5H), 1,45-1,17 (m, 6H), 1,01-0,88 (m, 5H).

Example 9(14)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-hydroxyethyl)aminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.44 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,98 (d, J=8.7 Hz, 2H), of 7.75 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,17 (d, J=2.0 Hz, 1H), Android 4.04 (m, 1H), 3,78 (m, 1H), 3,69 (t, J=5.7 Hz, 2H), 3,64-to 3.50 (m, 3H), 3,38-3,24 (m, 2H), 3,19 (t, J=5.7 Hz, 2H), 2,87 (s, 3H), 2,60-of 2.34 (m, 3H), 2,47 (s, 3H), 2.40 a (s, 3H), 2,20-of 1.88 (m, 3H), 1,82 is 1.60 (m, 5H), 1,50-of 1.12 (m, 6H), 1.04 million-of 0.82 (m, 5H).

Example 9(15)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(pyridine-2-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.40 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ 8,51 (d, J=4.5 Hz, 1H), 8,01 (m, 1H), 7,80 (d, J=8.0 Hz, 1H), 7,41 (m, 1H), 4,32 (s, 2H), 4.16 the (d, J=2.0 Hz, 1H), of 4.05 (m, 1H), 3,80 (m, 1H), 3,60-3,4 (m, 3H), 3.33 and-3,10 (m, 2H), to 2.67 (s, 3H), 2,53 to 2.35 (m, 3H), 2,41 (s, 3H), of 2.16 (m, 1H), 2,05-of 1.93 (m, 2H), 1,80-of 1.65 (m, 5H), 1,50-of 1.15 (m, 6H), 1,01-0,88 (m, 5H).

Example 9(16)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.34 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ 4,32 (m, 1H), 4,27 (s, 2H), 4,15 (d, J=2.0 Hz, 1H), 4.00 points (m, 1H), to 3.73 (m, 1H), 3,60-to 3.50 (m, 3H), 3,37-3,20 (m, 2H), 2,58-to 2.40 (m, 9H), 2.13 and is 1.70 (m, 15H), 1,58-of 1.15 (m, 9H), 1,01-0,88 (m, 5H).

Example 9(17)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(1,3,5-trimethylpyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.28 in (chloroform:methanol=10:1);

NMR (CD3OD): δ 4,27 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 3,98 (m, 1H), 3,85 (s, 3H), of 3.73 (m, 1H), 3,62 of 3.56 (m, 3H), 3,40-3,20 (m, 2H), 2,60 (m, 1H), 2,50-of 2.36 (m, 2H), of 2.45 (s, 3H), 2,41 (s, 3H), 2,16-of 1.88 (m, 3H), 1,84 is 1.60 (m, 5H), 1,50-of 1.10 (m, 6H), 1.04 million-0,80 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 9(18)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf to 0.19 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ a 7.62 (d, J=9.0 Hz, 2H), 7,58 (d, J=9.0 Hz, 2H), 4,32 (s, 2H), 4,17 (d, J=2.0 Hz, 1H), of 4.05 (m, 1H), 3,80 (m, 1H), 3,60-of 3.53 (m, 3H), 3.33 and-of 3.27 (m, 2H), 3,13 (s, 3H), 3.04 from (s, 3H), 2,53-2,35 (m, 3H), 2,42 (s, 3H), 2,39 (s, 3H), 2,17 (m, 1H), 2,05-of 1.92 (m, 2H), 1.77 in-of 1.65(m, 5H), 1,39-of 1.15 (m, 6H), 1,01-0,88 (m, 5H).

Example 9(19)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(N,N-biomethylation)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.47 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ of 7.69 (d, J=8,4 Hz, 2H), 7,60 (d, J=8,4 Hz, 2H), 4,42 (s, 2H), 4.16 the (d, J=2.1 Hz, 1H), 4,06 (m, 1H), 3,80 (m, 1H), 3,60-3,10 (m, 5H), 3.46 in (s, 6H), 2,55-1,90 (m, 6H), 1,90-to 1.60 (m, 5H), 1,50-of 1.10 (m, 6H), 1,10-of 0.90 (m, 2H), of 0.95 (t, J=6.9 Hz, 3H).

Example 9(20)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methylsulfonylamino)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.30 (chloroform:methanol=9:1);

NMR (CD3OD): δ of 7.48-7,38 (m, 4H), 4,30 (s, 2H), 4,17 (d, J=2.1 Hz, 1H), a 4.03 (m, 1H), 3,78 (m, 1H), 3,62-to 3.49 (m, 3H), 3,37-is 3.21 (m, 2H), 3.04 from (s, 3H), 2,62 to 2.35 (m, 3H), 2.40 a (s, 3H), of 2.38 (s, 3H), 2,18-1,90 (m, 3H), 1,83-to 1.63 (m, 5H), 1,48 is 1.13 (m, 6H), 1,03-of 0.82 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 9(21)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylsulphamoyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (chloroform:methanol=9:1);

NMR (CD3OD): δ of 7.96 (d, J=8.7 Hz, 2H), to 7.77 (d, J=8.7 Hz, 2H), 4,32 (s, 2H), 4,17 (d, J=2.1 Hz, 1H), of 4.05 (m, 1H), 3,79 (m, 1H), 3,63-of 3.48 (m, 3H), 3,34 is 3.15 (m, 2H), 2,74 (s, 6H), 2,58 of-2.32 (m, 3H), 2,47 (s, 3H), 2.40 a (s, 3H), 2.21 are 1,90 (m, 3H), 1,82-of 1.62 (m, 5H), 1,48 is 1.13 (m, 6H), 1,03-of 0.82 (m, 2H), 0,96 (t =7.2 Hz, 3H).

Example 9(22)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.38 (chloroform:methanol=9:1);

NMR (CD3OD): δ 7,72 (d, J=8.7 Hz, 2H), to 7.59 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,17 (d, J=2.4 Hz, 1H), Android 4.04 (m, 1H), 3,78 (m, 1H), 3,65-3,47 (m, 3H), 3,62 (t, J=6.6 Hz, 2H), 3,50 (t, J=6.6 Hz, 2H), 3.33 and-3,18 (m, 2H), 2,60 of-2.32 (m, 3H), 2,43 (s, 3H), 2,39 (s, 3H), 2,20-to 1.87 (m, 7H), 1,82-of 1.62 (m, 5H), 1,48 is 1.13 (m, 6H), 1,03-of 0.82 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 9(23)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(morpholine-4-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.38 (chloroform:methanol=9:1);

NMR (CD3OD): δ the 7.65 EUR 7.57 (m, 4H), or 4.31 (s, 2H), 4,17 (d, J=2.4 Hz, 1H), Android 4.04 (m, 1H), 3,85-of 3.46 (m, 12H), 3,34-3,17 (m, 2H), 2,60 of-2.32 (m, 3H), 2,43 (s, 3H), 2,39 (s, 3H), 2,20-1,90 (m, 3H), 1,82-of 1.62 (m, 5H), 1,48 is 1.13 (m, 6H), 1,03-of 0.82 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 9(24)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-aminocarbonylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.40 (ethyl acetate:methanol=3:1);

NMR (CD3OD): δ to 7.99 (d, J=8,4 Hz, 2H), of 7.70 (d, J=8,4 Hz, 2H), of 4.44 (s, 2H), 4.16 the (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), 3,78 (m, 1H), 3,60-to 3.38 (m, 3H), 3,30-is 3.08 (m, 2H), 2,60-of 2.24 (m, 3H), 2,20-to 1.86 (m, 3H), 1,82 is 1.58 (m, 5H), 1,50 was 1.06 (m, 6H), 1.04 million-0,80 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 9(25)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-aminosulphonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.25 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 7.90 (d, J=8.7 Hz, 2H), EUR 7.57 (d, J=8.7 Hz, 2H), 7,16 (d, J=8.7 Hz, 2H), 7,07 (d, J=8.7 Hz, 2H), 4,36 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), was 4.02 (m, 1H), 3,76 (m, 1H), 3,56-of 3.42 (m, 3H), 3.33 and-2,99 (m, 2H), 2,54-of 1.88 (m, 6H), 1,81-to 1.60 (m, 5H), 1,48 by 1.12 (m, 6H), 1.04 million-0,81 (m, 5H).

Example 9(26)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-aminosulphonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.28 in (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,89 (d, J=8.7 Hz, 2H), to 7.61 (d, J=8.7 Hz, 2H), 7,17 (d, J=8.7 Hz, 2H), 7,13 (d, J=8.7 Hz, 2H), 4,36 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4,01 (m, 1H, in), 3.75 (m, 1H), to 3.58-3.42 points (m, 3H), 3,32-3,14 (m, 2H), 2,55-to 2.40 (m, 2H), 2,32 (m, 1H), 2,13 (m, 1H), 2,07-1,89 (m, 2H), 1,82 is 1.60 (m, 5H), 1,50-of 1.12 (m, 6H), 1.06 a-0,80 (m, 5H).

Example 9(27)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(6-methylpyridin-1 oxido-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf and 0.62 (chloroform:methanol=5:1);

NMR (CD3OD): δ 8,51 (s, 1H), 7,80-7,56 (m, 2H), 7,72 (d, J=8.7 Hz, 2H), 7,29 (d, J=8.7 Hz, 2H), 4,39 (s, 2H), 4.16 the (d, J=2.1 Hz, 1H), 4.00 points (m, 1H), 3,78 (m, 1H), 3,62 is 3.40 (m, 3H), 3,36-3,18 (m, 2H), 2,64-of 2.30 (m, 3H), 2.63 in (s, 3H), 2,20-to 1.86 (m, 3H), 1,84 is 1.58 (m, 5H), 1,52-a 1.08 (m, 6H), 1.04 million-of 0.82 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H)

Example 9(28)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-hydroxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.35 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,46 (d, J=9.0 Hz, 2H), 6,97 (d, J=9.0 Hz, 2H), to 6.88 (d, J=9.0 Hz, 2H), 6,80 (d, J=9.0 Hz, 2H), 4,30 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 3,98 (m, 1H), and 3.72 (m, 1H), 3,67-3,39 (m, 3H), 3.27 to (m, 1H), 3.15 in (m, 1H), 2,53 to 2.35 (m, 2H), and 2.26 (m, 1H), 2,18-to 1.87 (m, 3H), 1,84 is 1.60 (m, 5H), 1,51-of 1.05 (m, 6H), 1.04 million-0,80 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 9(29)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-hydroxyphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.25 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,34 (d, J=8.7 Hz, 2H), of 6.96 (d, J=8.7 Hz, 2H), 4,34 (s, 2H), 4.16 the (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), 3,79 (m, 1H), 3,65-to 3.50 (m, 3H), of 3.32 (m, 1H), 3,29 (m, 1H), 2,64 (m, 1H), 2,55-to 2.42 (m, 2H), 2,48 (s, 3H), of 2.38 (s, 3H), 2,20-of 1.88 (m, 3H), 1,83 is 1.60 (m, 5H), 1,52-of 1.05 (m, 6H), 1.04 million-0,81 (m, 2H), of 0.96 (t, J=6.9 Hz, 3H).

Example 9(30)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.32 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,03 (d, J=8.7 Hz, 2H), 7,71 (d, J=8.7 Hz, 2H), 4,32 (s, 2H), 4,17 (d, J=2.1 Hz, 1H), 4,06 (m, 1H), 3,80 (m, 1H), 3,62-of 3.48 (m, 5H), 3,38-3,18 (m, 2H), 3,01 (t, J=5.7 Hz, 2H), 2,58-of 2.30 (m, 3H), the 2.46 (s, 3H) 2,39 (s, 3H), 2,20-of 1.88 (m, 3H), 1,82-of 1.62 (m, 5H), 1,50-of 1.10 (m, 6H), 1,02-of 0.82 (m, 5H).

Example 9(31)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.59 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,01 (d, J=8.7 Hz, 2H), of 7.75 (d, J=8.7 Hz, 2H), 4,32 (s, 2H), 4,17 (d, J=2.4 Hz, 1H), 4,06 (m, 1H), 3,80 (m, 1H), 3,62-of 3.48 (m, 3H), 3,38-3,18 (m, 6H), 2,60-of 2.30 (m, 3H), 2,47 (s, 3H), 2,39 (s, 3H), 2,20-of 1.88 (m, 3H), 1,82 is 1.60 (m, 9H), 1,50-of 1.10 (m, 6H), 1,02-of 0.82 (m, 5H).

Example 9(32)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(5-chloro-3-methyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf value of 0.52 (chloroform:methanol=10:1);

NMR (CD3OD): δ a 7.62 7,46 (m, 5H), 4,34 (s, 2H), 4,17 (d, J=1.8 Hz, 1H), 4,10 (m, 1H), 3,83 (m, 1H), 3,66-3,47 (m, 3H), 3,39-3,13 (m, 2H), 2,60-of 2.28 (m, 3H), of 2.44 (s, 3H), 2,18 (m, 1H), 2,09-of 1.88 (m, 2H), 1.85 to tariff-1.62 (m, 5H), 1,54-of 1.13 (m, 6H), 1,03 is 0.81 (m, 2H), 0,97 (t, J=7.2 Hz, 3H).

Example 9(33)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.50 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,49 (d, J=8.7 Hz, 2H), 6,98 (d, J=8.7 Hz, 2H), 7,02-6,92 (m, 4H), 4,30 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 3,97 (m, 1H), 3,79 (s, 3H), and 3.72 (m, 1H), to 3.58-to 3.38 (m, 3H), 3,30-3,13 (m, 2H), 2,55-is 2.40 (m, 2H), 2,32 (m, 1H), 2,16 is 1.86 (m, 3H), 1,81-to 1.60 (m, 5H), 1,50-of 1.10 (m, 6H), 1,030,80 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 9(34)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(3-methoxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.50 (chloroform:methanol=10:1);

NMR (CD3OD): δ rate of 7.54 (d, J=8.7 Hz, 2H), 7,28 (m, 1H), of 7.70 (d, J=8.7 Hz, 2H), 6.75 in (DDD, J=8,7, 2,1, 1.2 Hz, 1H), 6,63-6,56 (m, 2H), 4,33 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 3,98 (m, 1H), of 3.77 (s, 3H), of 3.75 (m, 1H), to 3.58 is 3.40 (m, 3H), 3,30-3,11 (m, 2H), 2,55-of 2.23 (m, 3H), 2,17-of 1.88 (m, 3H), 1,81-to 1.59 (m, 5H), 1,50 was 1.06 (m, 6H), 1,03-0,80 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 9(35)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(N,N-dimethylaminoethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.43 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,66 (d, J=8,4 Hz, 2H), 7,55 (d, J=8,4 Hz, 2H), to 4.41 (s, 2H), 4,15 (d, J=1.8 Hz, 1H), Android 4.04 (m, 1H), 3,78 (m, 1H), 3,59-of 3.42 (m, 3H), 3,30-3,10 (m, 2H), 3,11 (s, 3H), 2,99 (s, 3H), 2,53-2,20 (m, 3H), and 2.14 (m, 1H), 2,08-of 1.88 (m, 2H), 1,83 is 1.60 (m, 5H), 1,52-of 1.10 (m, 6H), 1.06 a-0,80 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 9(36)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.48 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,63-the 7.43 (m, 5H), 4,32 (s, 2H), 4,17 (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), 3,79 (m, 1H), 3,64-to 3.49 (m, 3H), 3,30-3,20 (m, 2H), 2,70-of 2.30 (m, 9H), 2,20-of 1.88 (m, 3H), 1,83 is 1.58 (m, 5H), 1,52 was 1.06 (m, 6H), 1.06 a-0,80 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

the example 9(37)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-were)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.48 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,37 (d, J=8.7 Hz, 2H), 7,34 (d, J=8.7 Hz, 2H), 4,30 (s, 2H), 4,17 (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), 3,79 (m, 1H), 3,63-3,47 (m, 3H), 3,35-of 3.06 (m, 2H), 2,63-of 2.26 (m, 3H), 2,43 (s, 3H), 2,38 (s, 3H), of 2.35 (s, 3H), of 2.16 (m, 1H), 2,09-of 1.88 (m, 2H), 1,83 is 1.60 (m, 5H), 1,55-of 1.10 (m, 6H), 1,08 is 0.80 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 9(38)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-forfinal)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.49 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.50 (DD, J=8,4, 4,8 Hz, 2H), 7,30 (DD, J=8,4, and 8.4 Hz, 2H), 4,30 (s, 2H), 4,17 (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), 3,78 (m, 1H), 3,63 is-3.45 (m, 3H), 3,30-of 3.12 (m, 2H), 2,61-of 2.30 (m, 3H), is 2.37 (s, 3H), a 2.36 (s, 3H), of 2.16 (m, 1H), 2,08-of 1.88 (m, 2H), 1,82 is 1.60 (m, 5H), 1,52-of 1.07 (m, 6H), 1.04 million-0,80 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 9(39)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(6-(4-methoxybenzyloxy)pyridine-3-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.38 (chloroform:methanol=10:1);

NMR (CD3OD): δ at 8.36 (m, 1H), 8,12 (m, 1H), 7,12-6,98 (m, 5H), 4,39 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4.00 points (m, 1H), 3,81 (s, 3H), 3,74 (m, 1H), 3,60-of 3.42 (m, 3H), 3,30-and 3.16 (m, 2H), 2,58-of 2.30 (m, 3H), 2,16-1,86 (m, 3H), 1,80-of 1.62 (m, 5H), 1,50-of 1.10 (m, 6H), 1,02-0,80 (m, 5H).

Example 9(40)

(R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf and 0.46 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.95 (d, J=9.0 Hz, 2H), 7,65 (d, J=8,4 Hz, 2H), 7,25-7,16 (m, 4H), to 4.38 (s, 2H), 4,15 (d, J=2.4 Hz, 1H), was 4.02 (m, 1H), 3,76 (m, 1H), 3,60-3,44 (m, 3H), 3,30-3,10 (m, 2H), 3,11 (s, 3H), 2,54-of 2.26 (m, 3H), 2,18-of 1.88 (m, 3H), 1,82-of 1.62 (m, 5H), 1,50-of 1.10 (m, 6H), 1,02-of 0.82 (m, 5H).

Example 9(41)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.15 (chloroform:methanol=5:1);

NMR (CD3OD): δ to 7.93 (d, J=9.0 Hz, 2H), 7.62mm (d, J=8,4 Hz, 2H), 7,20-was 7.08 (m, 4H), 3,98 (s, 2H), 4.16 the (d, J=2.1 Hz, 1H), 3,98 (m, 1H, in), 3.75 (m, 1H, in), 3.75 (t, J=5.4 Hz, 2H), to 3.58-3.42 points (m, 3H), 3,38 (t, J=a 5.4 Hz, 2H), 3,30-3,18 (m, 2H), 2,98 (s, 6H), 2,56-of 2.28 (m, 3H), 2,18-of 1.88 (m, 3H), 1,82-of 1.62 (m, 5H), 1,46-to 1.14 (m, 6H), 1,02-0,84 (m, 5H).

Example 9(42)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf and 0.46 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,01 (d, J=8.7 Hz, 2H), 7,60 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,17 (d, J=2.4 Hz, 1H), Android 4.04 (m, 1H), 3,80 (m, 1H), of 3.73 (t, J=6.0 Hz, 2H), 3.72 points-of 3.48 (m, 5H), 3,30-and 3.16 (m, 2H), 2,60-of 2.30 (m, 3H), 2,43 (s, 3H), 2,39 (s, 3H), 2,22-of 1.88 (m, 3H), 1,80-of 1.62 (m, 5H), 1,50-of 1.12 (m, 6H), 1.06 a-0,82 (m, 5H).

Example 9(43)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)is delaminations)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · Hydrochloride

TLC:Rf 0.14 (chloroform:methanol:28% aqueous ammonia=200:20:1);

NMR (CD3OD): δ 8,07 (d, J=8.7 Hz, 2H), to 7.64 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,17 (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), 3,79 (t, J=5.7 Hz, 2H), 3,78 (m, 1H), 3,63-to 3.49 (m, 3H), 3,41 (t, J=5.7 Hz, 2H), 3,32-3,20 (m, 2H), 3.00 and (s, 6H), 2.63 in to 2.35 (m, 3H), of 2.45 (s, 3H), 2,39 (s, 3H), 2,20-1,90 (m, 3H), 1,82-to 1.63 (m, 5H), 1,48 is 1.13 (m, 6H), 1,03-of 0.82 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 9(44)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-(morpholine-4-yl)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.42 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,07 (d, J=9.0 Hz, 2H), to 7.77 (d, J=9.0 Hz, 2H), 4,30 (s, 2H), 4,17 (d, J=2.4 Hz, 1H), 4,12-of 3.96 (m, 3H), 3,90-3,70 (m, 4H), 3,62-of 3.48 (m, 6H), 3,20-and 3.16 (m, 6H), 2,70-of 2.30 (m, 3H), 2.49 USD (s, 3H), is 2.41 (s, 3H), 2,20-of 1.88 (m, 3H), 1,82-of 1.62 (m, 5H), 1,50-of 1.10 (m, 6H), 1.04 million-0,84 (m, 5H).

Example 9(45)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(morpholine-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.31 in (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,58 (d, J=8,4 Hz, 2H), of 7.48 (d, J=8.7 Hz, 2H), 7.18 in-7,06 (m, 4H), 4,36 (s, 2H), 4.16 the (d, J=2.4 Hz, 1H), 4.00 points (m, 1H), 3,82 is 3.40 (m, 12H), 3,38-of 3.12 (m, 2H), 2,52-of 2.24 (m, 3H), 2,18 is 1.86 (m, 3H), 1,82-of 1.62 (m, 5H), 1,50-of 1.10 (m, 6H), 1,02-of 0.82 (m, 5H).

Example 9(46)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(1,4-benzodioxan--ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.38 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,05 (d, J=2.1 Hz, 1H), 7,00-of 6.90 (m, 2H), 4.26 deaths (s, 4H), to 4.23 (s, 2H), 4,15 (d, J=1.8 Hz, 1H), 3,94 (m, 1H), 3,68 (m, 1H), to 3.58-to 3.34 (m, 3H), 3,30-is 3.08 (m, 2H), 2,50 is 1.86 (m, 6H), 1,80-of 1.62 (m, 5H), 1,50 was 1.04 (m, 6H), 1,02-of 0.82 (m, 5H).

Example 9(47)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-diethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.99 (d, J=9.0 Hz, 2H), 7,73 (d, J=9.0 Hz, 2H), or 4.31 (s, 2H), 4,17 (d, J=2.1 Hz, 1H), 4,06 (m, 1H), 3,78 (m, 1H), 3,62-of 3.48 (m, 3H), 3,34-3,14 (m, 6H), 2,60-of 2.30 (m, 3H), of 2.45 (s, 3H), 2,39 (s, 3H), 2,20-of 1.88 (m, 3H), 1,82-of 1.62 (m, 5H), 1,50-a 1.08 (m, 6H)and 1.15 (t, J=7.5 Hz, 6H), 1,02-of 0.82 (m, 5H).

Example 9(48)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(pyridine-1-oxido-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.10 (ethyl acetate:methanol=3:1);

NMR (CD3OD): δ 8,48-of 8.37 (m, 2H), 7,73 (d, J=9.0 Hz, 2H), 7,73-of 7.60 (m, 2H), 7,31 (d, J=9.0 Hz, 2H), 4,39 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4,01 (m, 1H), 3,76 (m, 1H), 3,60-3,20 (m, 5H), 2,70-to 2.40 (m, 3H), 2,20-1,90 (m, 3H), 1,90-to 1.60 (m, 5H), 1.60-to of 1.10 (m, 6H), 1,10-0,80 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 9(49)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochl the reed

TLC:Rf of 0.34 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,01 (d, J=8.7 Hz, 2H), a 7.85 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,17 (d, J=2.4 Hz, 1H), 4,10-of 3.94 (m, 3H), of 3.78 (m, 1H), 3,66 of 3.56 (m, 5H), 3,40-3,20 (m, 4H), 2.91 in (s, 3H), 2,88-of 2.72 (m, 2H), 2,70-to 2.40 (m, 3H), of 2.50 (s, 3H), 2.40 a (s, 3H), 2,20-of 1.88 (m, 3H), 1,84 is 1.60 (m, 5H), 1.56 to of 1.10 (m, 6H), 1.04 million-of 0.82 (m, 5H).

Example 9(50)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.44 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.84 (d, J=9.0 Hz, 2H), to 7.59 (d, J=8.7 Hz, 2H), 7,15 (d, J=8.7 Hz, 2H), 7,07 (d, J=9.0 Hz, 2H), 4,36 (s, 2H), 4.16 the (d, J=2.1 Hz, 1H), 4.00 points (m, 1H), 3,74 (m, 1H), 3,60-3,44 (m, 3H), 3,28-3,16 (m, 2H), 2.91 in (s, 3H), 2,52-of 2.26 (m, 3H), 2,18-of 1.88 (m, 3H), 1,82-of 1.62 (m, 5H), 1,50-of 1.10 (m, 6H), 1,02-of 0.82 (m, 5H).

Example 9(51)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(2,4-differenl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf to 0.63 (chloroform:methanol=5:1);

NMR (CD3OD): δ 7,56 (m, 1H), 7,33-7,16 (m, 2H), 4,32 (s, 2H), 4,18 (d, J=2.4 Hz, 1H), Android 4.04 (m, 1H), 3,80 (m, 1H), 3,64-of 3.46 (m, 3H), 3,30-and 3.16 (m, 2H), 2,62-of 1.88 (m, 6H), 2,39 (s, 3H), of 2.28 (s, 3H), 1,84-1,60 (m, 5H), 1,52-of 1.10 (m, 6H), 1.06 a-0,82 (m, 2H), 0,97 (t, J=6.9 Hz, 3H).

Example 9(52)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]round the EN · hydrochloride-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.21 in (chloroform:methanol:28% aqueous ammonia=100:10:1);

NMR (CD3OD): δ 8,07 (d, J=8.7 Hz, 2H), 7,78 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4,17 (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), 3,80 (m, 1H), 3,64-to 3.50 (m, 3H), 3,40-up 3.22 (m, 6H), 2,96 (s, 6H), 2,74-of 2.38 (m, 3H), 2.49 USD (s, 3H), 2,41 (s, 3H), 2,22-of 1.88 (m, 3H), 1,84 is 1.60 (m, 5H), 1,52-of 1.10 (m, 6H), 1.06 a-0,82 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 9(53)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methylaminophenol)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.21 in (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,98 (d, J=8.7 Hz, 2H), 7,60 (d, J=8.7 Hz, 2H), or 4.31 (s, 2H), 4.16 the (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), 3,79 (m, 1H), 3,64-to 3.49 (m, 3H), 3,37-3,20 (m, 2H), equal to 2.94 (s, 3H), 2,63 is 2.33 (m, 3H), 2,43 (s, 3H), 2.40 a (s, 3H), of 2.16 (m, 1H), 2,09-1,90 (m, 2H), 1,83-of 1.62 (m, 5H), 1,50-of 1.12 (m, 6H), 1.04 million-of 0.82 (m, 5H).

Example 9(54)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.43 (chloroform:methanol=5:1);

NMR (CD3OD): δ with 8.05 (d, J=9.0 Hz, 2H), to 7.61 (d, J=9.0 Hz, 2H), 7,19 (d, J=9.0 Hz, 2H), was 7.08 (d, J=9.0 Hz, 2H), to 4.38 (s, 2H), 4,17 (d, J=2.1 Hz, 1H), was 4.02 (m, 1H), 3,78 (m, 1H), 3,60 is 3.40 (m, 3H), 3,30-3,10 (m, 2H), 2,56 is 1.86 (m, 6H), 1,82 is 1.60 (m, 5H), 1,52 is 1.16 (m, 6H), 1.06 a-0,82 (m, 2H), 0,97 (t, J=7.2 Hz, 3H).

Example 9(55)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohex lmutil)-9-(4-((4-methoxyphenyl)methylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.33 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 7.96 (d, J=8,4 Hz, 2H), 7,66 (d, J=8,4 Hz, 2H), 7,28 (d, J=8,4 Hz, 2H), to 6.88 (d, J=8,4 Hz, 2H), to 4.52 (s, 2H), 4,43 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), was 4.02 (m, 1H), of 3.77 (s, 3H), of 3.77 (m, 1H), to 3.58-to 3.38 (m, 3H), 3,30-3,10 (m, 2H), 2,54-2,22 (m, 3H), 2,18 is 1.86 (m, 3H), 1,82 is 1.60 (m, 5H), 1,50-a 1.08 (m, 6H), 1.04 million-0,80 (m, 2H), of 0.95 (t, J=6.9 Hz, 3H).

Example 9(56)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(3-methoxypropylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.27 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.93 (d, J=8.1 Hz, 2H), 7,68 (d, J=8.1 Hz, 2H), 4,43 (s, 2H), 4.16 the (d, J=1.8 Hz, 1H), Android 4.04 (m, 1H), 3,78 (m, 1H), 3,60 is 3.40 (m, 7H), to 3.35 (s, 3H), 3,30-3,10 (m, 2H), 2,58 is 1.60 (m, 13H), 1,52-a 1.08 (m, 6H), 1.06 a-0,80 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 9(57)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(N-methyl-N-(2-(pyridin-2-yl)ethyl)aminocarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.22 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,80 (m, 1H), to 8.57 (m, 1H), 8,08 (m, 1H), of 7.96 (m, 1H), 7,69 (d, J=8,4 Hz, 2H), 7,43 (d, J=8,4 Hz, 2H), and 4.40 (s, 2H), 4.16 the (d, J=2.1 Hz, 1H), 4,06-3,90 (m, 3H), 3,80 (m, 1H), 3,62-to 3.38 (m, 5H), 3,30-3,10 (m, 2H), is 3.08 (s, 3H), 2,64-of 2.30 (m, 3H), 2,18-of 1.84 (m, 3H), 1,82 is 1.60 (m, 5H), 1,50 was 1.06 (m, 6H), 1.04 million-0,80 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 9(58)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)is animetal)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0,41 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ to 7.59-7,56 (m, 4H), to 7.15 (d, J=8.7 Hz, 2H), to 7.09 (d, J=8.7 Hz, 2H), 4,36 (s, 2H), 4,15 (d, J=2.0 Hz, 1H), 4,01 (m, 1H, in), 3.75 (m, 1H), 3,60-of 3.46 (m, 7H), 3,30-3,13 (m, 2H), of 2.51-2,11 (m, 4H), 2,04-1,89 (m, 6H), 1,80-of 1.65 (m, 5H), 1,50-of 1.15 (m, 6H), and 1.00-0.87 (m, 5H).

Example 9(59)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-chlorophenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.51 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,58 (d, J=9.0 Hz, 2H), 7,49 (d, J=9.0 Hz, 2H), or 4.31 (s, 2H), 4,17 (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), 3,78 (m, 1H), 3,62-of 3.48 (m, 3H), 3,30-and 3.16 (m, 2H), 2,62 of-2.32 (m, 3H), 2.40 a (s, 3H), 2,39 (s, 3H), 2,22 is 1.86 (m, 3H), 1,84 is 1.60 (m, 5H), 1,54-of 1.10 (m, 6H), 1.06 a-0,82 (m, 2H), 0,97 (t, J=7.2 Hz, 3H).

Example 9(60)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-triptoreline)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.53 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,88 (d, J=8.7 Hz, 2H), 7,73 (d, J=8.7 Hz, 2H), 4,33 (s, 2H), 4,18 (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), 3,80 (m, 1H), 3,64-of 3.46 (m, 3H), 3,30-and 3.16 (m, 2H), 2,62-of 2.28 (m, 3H), of 2.46 (s, 3H), 2.40 a (s, 3H), 2,24-of 1.88 (m, 3H), 1,84 is 1.60 (m, 5H), 1.56 to the 1.06 (m, 6H), 1.06 a-0,82 (m, 2H), 0,97 (t, J=7.2 Hz, 3H).

Example 9(61)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methoxyphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.44 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,40 (d, J=8.7 Hz, 2H), 7,11 (d, J=8.7 Hz, 2H), 4,32 (s, 2H), 4,18 (d, J=2.4 Hz, 1H), Android 4.04 (m, 1H), 3,88 (s, 3H), 3,80 (m, 1H), 3,66-of 3.48 (m, 3H), 3,30-3,18 (m, 2H), 2,64-of 2.30 (m, 3H), 2,42 (s, 3H), of 2.36 (s, 3H), 2,22-of 1.88 (m, 3H), 1,84 is 1.60 (m, 5H), 1,54-of 1.10 (m, 6H), 1.06 a-0,82 (m, 2H), 0,97 (t, J=7.2 Hz, 3H).

Example 9(62)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-aripirazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.27 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 4.28 (s, 2H), 4,23 (kV, J=7.2 Hz, 2H), 4,17 (d, J=2.4 Hz, 1H), 4.00 points (m, 1H), 3,78 (m, 1H), 3,64-3,44 (m, 3H), 3,30-3,18 (m, 2H), 2,70-of 2.34 (m, 3H), 2,48 (s, 3H), 2,43 (s, 3H), 2,22 is 1.86 (m, 3H), 1,84 is 1.60 (m, 5H), 1,52-a 1.08 (m, 6H), USD 1.43 (t, J=7.2 Hz, 3H), 1.06 a-0,80 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 9(63)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-propylpyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.31 in (chloroform:methanol=10:1);

NMR (CD3OD): δ to 4.28 (s, 2H), 4.16 the (d, J=2.4 Hz, 1H), 4,15 (t, J=7.2 Hz, 2H), 4.00 points (m, 1H), 3,76 (m, 1H), 3,62-of 3.46 (m, 3H), 3,30-3,18 (m, 2H), 2,66-of 2.36 (m, 3H), 2,47 (s, 3H), 2,43 (s, 3H), 2,20-to 1.60 (m, 10H), 1,52-of 1.10 (m, 6H), of 1.18 (t, J=7.2 Hz, 3H), 1.06 a-0,80 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

Example 9(64)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(1,1-dimethylethyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.33 (chlorine the product:methanol=10:1);

NMR (CD3OD): δ 4.26 deaths (s, 2H), 4,17 (d, J=2.4 Hz, 1H), was 4.02 (m, 1H), 3,78 (m, 1H), 3,62-of 3.46 (m, 3H), 3,30-up 3.22 (m, 2H), 2,64-to 2.40 (m, 3H), 2.63 in (s, 3H), 2,42 (s, 3H), 2,20-to 1.86 (m, 3H), 1,84-of 1.62 (m, 5H), 1,72 (s, 9H), 1,54-of 1.16 (m, 6H), 1.04 million-of 0.82 (m, 2H), of 0.96 (t, J=6.9 Hz, 3H).

Example 9(65)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-cyclopentylphenol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.33 (chloroform:methanol=10:1);

NMR (CD3OD): δ 4,27 (s, 2H), 4.16 the (d, J=2.1 Hz, 1H), 4.00 points (m, 1H), 3,78 (m, 1H), 3,64-3,44 (m, 4H), 3,30-3,20 (m, 2H), 2,66-of 2.36 (m, 3H), 2,47 (s, 3H), 2,42 (s, 3H), 2,28 is 1.60 (m, 16H), 1,58-of 1.10 (m, 6H), 1,08-0,82 (m, 2H), of 0.96 (t, J=6.9 Hz, 3H).

Example 9(66)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(2-phenylethyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.25 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 7.36-7.18 in (m, 3H), 7,16-7,00 (m, 2H), 4,39 (t, J=6.3 Hz, 2H), 4,18 (s, 2H), 4,17 (d, J=2.4 Hz, 1H), 3,88 (m, 1H), 3.72 points-of 3.46 (m, 2H), 3,42-up 3.22 (m, 4H), of 3.12 (t, J=6.3 Hz, 2H), 2,66-of 2.34 (m, 3H), is 2.44 (s, 3H), 2,18 is 1.86 (m, 3H), of 1.92 (s, 3H), 1,84-of 1.62 (m, 5H), 1,54-of 1.10 (m, 6H), 1.06 a-0,82 (m, 2H), 0,97 (t, J=6.9 Hz, 3H).

Example 9(67)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(1-benzyloxycarbonylamino-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.40 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,42-7,25 (who, 5H), 5,14 (s, 2H), 4,56 (m, 1H), 4,36-of 4.25 (m, 2H), 4,25 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 3,98 (m, 1H), to 3.73 (m, 1H), 3,62 is-3.45 (m, 3H), 3,40-3,20 (m, 2H), 3,18-to 2.94 (m, 2H), 2,67-of 2.30 (m, 9H), 2,20-of 1.85 (m, 7H), 1,83 is 1.58 (m, 5H), 1,50-a 1.08 (m, 6H), of 1.05 to 0.80 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 9(68)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(cyclohexanecarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.45 (chloroform:methanol=10:1);

NMR (CD3OD): δ a 7.92 (d, J=8.7 Hz, 2H), to 7.67 (d, J=8.7 Hz, 2H), 4,42 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), was 4.02 (m, 1H), 3,92 at 3.69 (m, 2H), 3,60-3,39 (m, 3H), 3,30-of 3.12 (m, 2H), 2,56-of 2.26 (m, 3H), 2,17 is 1.58 (m, 14H)and 1.51-1,08 (m, 10H), 1,06 is 0.80 (m, 2H), of 0.95 (t, J=6.9 Hz, 3H).

Example 9(69)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(1-methylsulfonylmethane-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.26 (chloroform:methanol=10:1);

NMR (CD3OD): δ 4,48 (m, 1H), 4,25 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4,05-a 3.83 (m, 3H), 3,74 (m, 1H), 3,60-of 3.46 (m, 3H), 3,40-3,20 (m, 2H), 3,05 of 2.92 (m, 2H), 2,90 (s, 3H), 2,60 (m, 1H), 2,52-to 2.40 (m, 2H), 2.49 USD (s, 3H), 2,39 (s, 3H), 2.26 and-a 1.88 (m, 7H), 1,84 is 1.60 (m, 5H), 1,50-of 1.10 (m, 6H), of 1.05 to 0.80 (m, 2H), of 0.95 (t, J=6.9 Hz, 3H).

Example 9(70)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(2-hydroxyethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.50 (chloroform:methanol=5:1);

NMR (CD3OD): δ 7,89 (d, J=9.0 Hz, 2H), 7,60 (d, J=9.0 Hz, 2H), 7,16 (d, J=9.0 Hz, 2H), to 7.09 (d, J=9.0 Hz, 2H), 4,37 (s, 2H), 4,17 (d, J=2.1 Hz, 1H), was 4.02 (m, 1H), 3,78 (m, 1H), 3,71 (t, J=5.7 Hz, 2H), 3,60 is 3.40 (m, 3H), 3,51 (t, J=5.7 Hz, 2H), 3,30-3,10 (m, 2H), 2,58-of 1.84 (m, 6H), 1,82-of 1.56 (m, 5H), 1,54 was 1.06 (m, 6H), 1.04 million-0,80 (m, 2H), of 0.96 (t, J=6.9 Hz, 3H).

Example 9(71)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-hydroxyethyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane

TLC:Rf of 0.37 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,34 (d, J=8.7 Hz, 4H), 6,97 (d, J=8.7 Hz, 2H), of 6.96 (d, J=8.7 Hz, 2H), 4,57 (s, 2H), 4,13 (d, J=2.1 Hz, 1H), 3,71 (s, 2H), 3,47 (m, 1H), 3,35 (DD, J=9,0, 2.1 Hz, 1H), 3,30-is 2.88 (m, 5H), 2,31-is 1.81 (m, 6H), 1,81 is 1.58 (m, 5H), 1,55-of 1.05 (m, 6H), 1,05-0,83 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 10

(3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in example 2 using the compound obtained in reference example 3, (9), instead of the compound obtained in reference example 3, and using 4-(4-methylsulfonylmethane)benzaldehyde instead of 3-formyl-6-phenoxypyridine get mentioned in the title compound having the following physical data.

TLC:Rf of 0.54 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ rate of 7.54 (d, J=8,4 Hz, 2H), 7,29 (d, J=8.7 Hz, 2H), 7,06 (d, J=8,4 Hz, 2H), 7,03 (d, J=8.7 Hz, 2H), 4,32 (s, 2H), 4,15 (d, J=2.0 Hz, 1H), 3,98 (m, 1H), to 3.73 (m, 1H), 3,55-of 3.43 (m, 3H), 3,30-316 (m, 2H), 2.95 and (s, 3H), 2,52-of 2.28 (m, 3H), 2,14 is 1.91 (m, 3H), 1,76-of 1.65 (m, 5H), 1,50-of 1.15 (m, 6H), 1.00 and is 0.86 (m, 5H).

Example 11

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in example 2 using the compound obtained in reference example 3, (4), instead of the compound obtained in reference example 3, and using 4-formyl-3,5-dimethyl-1-phenylpyrazol instead of 3-formyl-6-phenoxypyridine get mentioned in the title compound having the following physical data.

TLC:Rf 0.31 in (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ to 7.67-7,56 (m, 5H), 4,37 (s, 2H), 4,13 (d, J=2.0 Hz, 1H), 4,06 (m, 1H), 3,98-3,91 (m, 2H), 3,80 (m, 1H), 3,64-of 3.53 (m, 4H), 3.46 in-3,37 (m, 3H), 2,80-2,52 (m, 5H), of 2.45 (s, 3H), 2,16 is 2.01 (m, 2H), 1,91-to 1.82 (m, 2H), 1,71 (m, 1H), 1,50-1,17 (m, 6H), of 0.95 (t, J=7.5 Hz, 3H).

Examples 11(1)-11(5)

According to the method described in example 11, using the appropriate aldehyde derivatives respectively instead of 4-formyl-3,5-dimethyl-1-phenylpyrazole receive the following compounds having the following physical data.

Example 11(1)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.28 in (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ to 7.84 (d, J=8.7 Hz, 2H), to 7.59 (d, J=8.7 Hz, 2H), 7,15 (d, J=8.7 Hz, 2H), 7,07 (d, J=8.7 Hz, 2H), 4,36 (s, 2H), 4,12 (d, J=2.0 Hz, 1H), 4,06-3,90 (m, 3H), of 3.75 (m, 1H), 3,56-to 3.34 (m, 5H), 3,30-3,20 (m, 2H), 2.91 in (with, 3H), of 2.51-of 2.28 (m, 3H), 2,16 was 1.69 (m, 5H), 1,50-of 1.15 (m, 5H), of 0.95 (t, J=7.0 Hz, 3H).

Example 11(2)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-(4-methoxyphenylethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ to 7.95 (d, J=8,3 Hz, 2H), 7,66 (d, J=8,3 Hz, 2H), 7,27 (d, J=8,8 Hz, 2H), 6.87 in (d, J=8,8 Hz, 2H), 4,51 (s, 2H), 4,42 (s, 2H), 4,11 (d, J=2.0 Hz, 1H), 4.04 the-3,91 (m, 3H), 3,76 (m, 1H), 3,76 (, 3H), 3,56-3,37 (m, 5H), 3,30-3,13 (m, 2H), 2,50 is 1.70 (m, 8H), 1,39-of 1.15 (m, 5H), of 0.95 (t, J=7.0 Hz, 3H).

Example 11(3)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.55 (chloroform:methanol=4:1);

NMR (CD3OD): δ 7,63 (d, J=9.0 Hz, 2H), 7,60 (d, J=9.0 Hz, 2H), 4,32 (s, 2H), 4,13 (d, J=2.0 Hz, 1H), 4,06 (m, 1H), 4,00-3,91 (m, 2H), 3,79 (m, 1H), 3,63-to 3.52 (m, 4H), 3.46 in-to 3.34 (m, 3H), of 3.13 (s, 3H), 3.04 from (s, 3H), 2,62-is 2.37 (m, 2H), 2,44 (s, 3H), 2,41 (s, 3H), of 2.15 (m, 1H), 2,03 (m, 1H), 1,90 is 1.70 (m, 3H), 1,50-of 1.15 (m, 6H), is 0.96 (t, J=7.0 Hz, 3H).

Example 11(4)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.30 (chloroform:methanol=4:1);

NMR (CD3OD): δ of 8.04 (d, J=9.0 Hz, 2H), 7,60 (d, J=8.5 Hz, 2H), 7,18 (d, J=8.5 Hz, 2H), 7,07 (d, J=9.0 Hz, 2H), 4,37 (s, 2H), 4,12 (d, J=2.0 Hz, 1H), 4,08-3,93 (m, 3H), of 3.75 (m, 1H), 3,57-to 3.34 (m, 5H), 3,30 is 3.15 (m, 2H), 2,52 was 1.69 (m, 8H), 1,50-of 1.18 (m, 5H), is 0.96 (t, J=7.2 Hz, 3H).

Example 11(5)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.35 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ 7,53 (d, J=8.7 Hz, 2H), 7,29 (d, J=8.7 Hz, 2H), 7,06 (d, J=8.7 Hz, 2H), 7,03 (d, J=8.7 Hz, 2H), 4,33 (s, 2H), 4,12 (d, J=2.0 Hz, 1H), 4.04 the-3,92 (m, 3H), and 3.72 (m, 1H), 3,54-to 3.38 (m, 5H), 3,30-3,13 (m, 2H), 2.95 and (s, 3H), of 2.51-of 2.26 (m, 3H), 2,16 is 2.00 (m, 2H), 1,89 is 1.70 (m, 3H), 1,50-of 1.15 (m, 5H), of 0.95 (t, J=7.0 Hz, 3H).

Example 12

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in example 2 using the compound obtained in reference example 3(5), instead of the compound obtained in reference example 3, and using 4-formyl-3,5-dimethyl-1-phenylpyrazol instead of 3-formyl-6-phenoxypyridine get mentioned in the title compound having the following physical data.

TLC:Rf of 0.45 (ethyl acetate:methanol=4:1);

NMR (CD3OD): δ to 7.64-7,51 (m, 5H), 4,34 (s, 2H), of 4.05 (m, 1H), 4,01 (d, J=2.0 Hz, 1H), 3,79 (m, 1H), 3,63-to 3.52 (m, 3), 3,39 (DD, J=9,9, 2.0 Hz, 1H), 3,30 (m, 1H), 2,64 (m, 1H), 2,48 (m, 1H), 2,47 (s, 3H), 2,42 (s, 3H), 2,37-2,12 (m, 2H), 1,90-to 1.82 (m, 2H), 1,74-of 1.15 (m, 11H), is 0.96 (t, J=7.5 Hz, 3H).

Examples 12(1)-12(3)

According to the method described in example 12, using the appropriate aldehyde derivatives respectively instead of 4-formyl-3,5-dimethyl-1-phenylpyrazole receive the following connections.

Example 12(1)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(4-(4-(4-methoxyphenylethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.35 (chloroform:methanol=10:1);

NMR (CD3OD): δ of 7.96 (d, J=8.7 Hz, 2H), 7,66 (d, J=8.7 Hz, 2H), 7,28 (d, J=8.7 Hz, 2H), to 6.88 (d, J=8.7 Hz, 2H), to 4.52 (s, 2H), 4,42 (s, 2H), was 4.02 (m, 1H), 4.00 points (d, J=1.8 Hz, 1H), of 3.77 (s, 3H), of 3.77 (m, 1H), 3,60-to 3.02 (m, 5H), 2,58-2,04 (m, 5H), 2,00 was 1.06 (m, 12H), is 0.96 (t, J=7.5 Hz, 3H).

Example 12(2)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.25 (chloroform:methanol=10:1);

NMR (CD3OD): δ a 7.85 (d, J=8.7 Hz, 2H), 7,60 (d, J=8.7 Hz, 2H), 7,16 (d, J=8.7 Hz, 2H), was 7.08 (d, J=8.7 Hz, 2H), 4,37 (s, 2H), was 4.02 (m, 1H), 4,01 (d, J=2.1 Hz, 1H), 3,78 (m, 1H), 3,40-of 3.12 (m, 5H), 2,92 (, 3H), 2,60 e 2.06 (m, 5H), 2.00 in a 1.08 (m, 12H), is 0.96 (t, J=7.2 Hz, 3H).

Example 12(3)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (chloroform:methanol=5:1);

NMR (CD3OD): δ with 8.05 (d, J=8.7 Hz, 2H), to 7.61 (d, J=8.7 Hz, 2H), 7,19 (d, J=8.7 Hz, 2H), was 7.08 (d, J=8.7 Hz, 2H), to 4.38 (s, 2H), was 4.02 (m, 1H), 4,01 (d, J=1.8 Hz, 1H), 3,78 (m, 1H), 3,62-is 3.08 (m, 5H), 2,60 e 2.06 (m, 5H), 2.00 in a 1.08 (m, 12H), is 0.96 (t, J=6.9 Hz, 3H).

Example 13

(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in example 2 using the compound obtained in reference example 3, (6), instead of the compound obtained in reference example 3, and using 4-(4-methylaminoacenaphthylene)benzaldehyde instead of 3-formyl-6-phenoxypyridine get mentioned in the title compound having the following physical data.

TLC:Rf of 0.35 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.84 (d, J=9.0 Hz, 2H), to 7.61 (d, J=8.7 Hz, 2H), 7,14 (d, J=8.7 Hz, 2H), 7,07 (d, J=9.0 Hz, 2H), 4,36 (s, 2H), 4,14 (d, J=1.8 Hz, 1H), 3,99 (m, 1H), 3,74 (m, 1H), 3,55 is 3.40 (m, 3H), 3,20 (m, 1H), 3,19 (DD, J=a 9.6, 1.8 Hz, 1H), 2.91 in (s, 3H), 2,59-to 2.29 (m, 3H), 2,12 (m, 1H), 2,00 (m, 1H), 1,74 (m, 1H), 1,46 (m, 1H), 0,99 (d, J=6.6 Hz, 3H), of 0.97 (d, J=6.6 Hz, 3H), of 0.93 (t, J=7.5 Hz, 3H).

Examples 13(1) and 13(2)

According to the method described in example 13 using the appropriate aldehyde derivatives respectively instead of 4-(4-methylaminoacenaphthylene)benzaldehyde receive the following connections.

Example 13(1)

(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-is imethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · Hydrochloride

TLC:Rf to 0.39 (chloroform:methanol=10:1);

NMR (CD3OD): δ and 4.40 (m, 1H), 4,30 (s, 2H), 4,14 (d, J=2.1 Hz, 1H), 4.00 points (m, 1H), 3,76 (m, 1H), 3,59-of 3.43 (m, 3H), up 3.22 (m, 1H), 3,20 (DD, J=a 9.6, 2.1 Hz, 1H), 2,66 (m, 1H), 2,53 (s, 3H), 2.49 USD (s, 3H), 2,50-of 2.38 (m, 2H), 2,15-1,10 (m, 14H), 0,99 (d, J=6.6 Hz, 3H), and 0.98 (d, J=6.6 Hz, 3H), of 0.93 (t, J=7.5 Hz, 3H).

Example 13(2)

(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methoxyphenylethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.41 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.95 (d, J=8.7 Hz, 2H), 7,69 (d, J=8.7 Hz, 2H), 7,27 (d, J=8.7 Hz, 2H), 6.87 in (d, J=8.7 Hz, 2H), 4,51 (s, 2H), 4,42 (s, 2H), 4,13 (d, J=2.1 Hz, 1H), 4,01 (m, 1H), 3,76 (m, 1H), 3,76 (s, 3H), 3,54-3,39 (m, 3H), 3,19 (m, 1H), 3,18 (DD, J=a 9.6, 2.1 Hz, 1H), 2,58-of 2.26 (m, 3H), 2,10 (m, 1H), 1,99 (m, 1H), 1,72 (m, 1H), 1,46 (m, 1H), and 0.98 (d, J=6.6 Hz, 3H), of 0.96 (d, J=6.6 Hz, 3H), of 0.92 (t, J=7,5 Hz, 3H).

Example 14

(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in example 2 using the compound obtained in reference example 3, (7), instead of the compound obtained in reference example 3, and using 4-(4-methylaminoacenaphthylene)benzaldehyde instead of 3-formyl-6-phenoxypyridine get mentioned in the title compound having the following physical data.

TLC:Rf of 0.38 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.84 (d, J=9.0 Hz, 2H), 7,60 (d, J=9.0 Hz, 2H), 7,15 (d, J=9.0 Hz, 2H), 7,07 (d, J=9.0 Hz, 2H), 4,36 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 3,99 (m, 1H, in), 3.75 (m, 1H), 3,54-3,39 (m, 3H), 3,30-3,10 (m, 2H), 2.91 in (s, 3H), 2,56-of 2.27 (m, 3H), 2,18-of 1.88 (m, 3H), 1,83 is 1.60 (m, 5H), of 1.46 (m, 1H), 1,37-1,11 (m, 3H), 1.04 million-0,80 (m, 2H), of 0.93 (t, J=7.5 Hz, 3H).

Examples 14(1)-14(5)

According to the method described in example 14, using the appropriate aldehyde derivatives respectively instead of 4-(4-methylaminoacenaphthylene)benzaldehyde receive the following connections.

Example 14(1)

(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.41 (chloroform:methanol=10:1);

NMR (CD3OD): δ 4,39 (m, 1H), 4,29 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4.00 points (m, 1H), 3,76 (m, 1H), 3,60-of 3.42 (m, 3H), 3,40-3,20 (m, 2H), 2,65 (m, 1H), 2,53 (s, 3H), 2.49 USD (s, 3H), 2,53 to 2.35 (m, 2H), 2,15-1,05 (m, 22H), of 1.05 to 0.80 (m, 2H), of 0.93 (t, J=7.2 Hz, 3H).

Example 14(2)

(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxyphenylethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf is 0.42 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,94 (d, J=8.7 Hz, 2H), 7,68 (d, J=8.7 Hz, 2H), 7,27 (d, J=8.7 Hz, 2H), 6.87 in (d, J=8.7 Hz, 2H), 4,51 (s, 2H), to 4.41 (s, 2H), 4,14 (d, J=1.8 Hz, 1H), 4,01 (m, 1H), 3,76 (m, 1H), 3,76 (s, 3H), 3,54-to 3.38 (m, 3H), of 3.27 (DD, J=a 9.6, 1.8 Hz, 1H), 3,18 (m, 1H), 2.57 m-of 2.26 (m, 3H), 2,16 to 1.6 (m, 3H), 1,82 is 1.60 (m, 5H), 1,54-of 1.05 (m, 4H), 1,03-0,80 (m, 2H), to 0.92 (t, J=7.5 Hz, 3H).

Example 14(3)

(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,63 (s, 4H), 4,32 (s, 2H), 4.16 the (d, J=2.1 Hz, 1H), Android 4.04 (m, 1H), 3,79 (m, 1H), 3,64-of 3.43 (m, 3H), 3,34-3,20 (m, 2H), 3,13 (s, 3H), 3.04 from (s, 3H), 2,62 (m, 1H), 2,53-2,39 (m, 2H), of 2.45 (s, 3H), is 2.44 (s, 3H), 2,19-of 1.88 (m, 3H), 1,83 is 1.60 (m, 5H), of 1.46 (m, 1H), 1,38-1,10 (m, 3H), of 1.05 to 0.80 (m, 2H), of 0.95 (t, J=7.5 Hz, 3H).

Example 14(4)

(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.21 in (chloroform:methanol:acetic acid=20:2:1);

NMR (CD3OD): δ of 8.04 (d, J=9.0 Hz, 2H), 7.62mm (d, J=8,4 Hz, 2H), 7,17 (d, J=8,4 Hz, 2H), 7,07 (d, J=9.0 Hz, 2H), 4,37 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4,01 (m, 1H, in), 3.75 (m, 1H), 3,55-to 3.38 (m, 3H), 3,30-3,09 (m, 2H), 2,55-of 2.26 (m, 3H), 2,18-of 1.88 (m, 3H), 1,83 is 1.60 (m, 5H), 1,57-1,10 (m, 4H), 1.04 million-0,80 (m, 2H), of 0.93 (t, J=7.5 Hz, 3H).

Example 14(5)

(3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-ethoxycarbonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.54 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,03 (d, J=8.7 Hz, 2H), 7.62mm (d, J=8.7 Hz, 2H), 7,17 (d, J=8.7 Hz, 2H), 7,07 (d, J=8.7 Hz, 2H), 4,37 (s, 2H), 4,15 (d, J=2.1 a is C, 1H), 4.00 points (m, 1H), 3,88 (s, 3H), of 3.75 (m, 1H), 3,54-to 3.41 (m, 3H), 3,30-3,10 (m, 2H), 2,58-of 2.27 (m, 3H), 2,18-to 1.87 (m, 3H), 1,84-to 1.61 (m, 5H), 1.56 to a 1.08 (m, 4H), 1.04 million-0,80 (m, 2H), were 0.94 (t, J=7.2 Hz, 3H).

Example 15

(3R)-1-propyl-2,5-dioxo-3-(1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in example 5 using the compound obtained in example 14(5), instead of the compound obtained in example 4(42), get mentioned in the title compound having the following physical data.

TLC:Rf is 0.42 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,03 (d, J=8.7 Hz, 2H), 7.62mm (d, J=8.7 Hz, 2H), 7,17 (d, J=8.7 Hz, 2H), 7,07 (d, J=8.7 Hz, 2H), by 5.87 (d, J=10.5 Hz, 1H), 4,37 (s, 2H), 3,78-3,62 (m, 2H), to 3.58-to 3.38 (m, 4H), 2,54-of 2.36 (m, 3H), 2,27-of 2.15 (m, 2H), 1,80-is 1.51 (m, 7H), 1,50-1,08 (m, 5H), of 0.93 (t, J=7.2 Hz, 3H).

Example 16

(3S)-1-propyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in reference example 1 → reference example 2, → example 1 → reference example 3, → example 2 using the appropriate derivative of the amino acid instead of (2R,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-4-methylpentanoic acid, derived using the appropriate amine instead of N-butylamine and using a corresponding aldehyde derivative instead of 3-formyl-6-dryers is oxypyridine, get listed in the title compound having the following physical data.

TLC:Rf of 0.51 (chloroform:methanol=10:1);

NMR (CD3OD): δ 4,39-4,27 (m, 1H), 4,28 (s, 2H), 4,01 (DD, J=7,8, and 4.5 Hz, 1H), 3,92-3,68 (m, 2H), 3,61-to 3.50 (m, 2H), 3,47-to 3.38 (m, 2H), 2,68-of 2.50 (m, 2H), 2.49 USD (s, 3H), of 2.45 (s, 3H), 2,25-2,05 (m, 2H), 2,03-1,20 (m, 15H), 0,98-to 0.89 (m, 9H).

Examples 16 (1)-16(6)

According to the method described in example 16 using the appropriate aldehyde derivatives respectively instead of 1-cyclohexyl-4-formyl-3,5-dimethylpyrazole receive the following compounds having the following physical data.

Example 16(1)

(3S)-1-propyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.53 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,53 (d, J=8.7 Hz, 2H), 7,29 (d, J=9.0 Hz, 2H), 7,07 (d, J=8.7 Hz, 2H), 7,03 (d, J=9.0 Hz, 2H), 4,34 (s, 2H), 4,01 (DD, J=7,8, and 4.8 Hz, 1H), 3,90 at 3.69 (m, 2H), 3,55-of 3.43 (m, 2H), 3,39-3,30 (m, 2H), 2.95 and (s, 3H), 2,48-to 2.29 (m, 2H), 2,28-of 2.09 (m, 2H), 1,90-of 1.44 (m, 5H), were 0.94 (d, J=6.6 Hz, 3H), of 0.93 (d, J=6.6 Hz, 3H), of 0.93 (t, J=7.5 Hz, 3H).

Example 16(2)

(3S)-1-propyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0,09 (chloroform:methanol:acetic acid=10:5:1);

NMR (CD3OD): δ 8,07 (d, J=9.0 Hz, 2H), 7,78 (d, J=9.0 Hz, 2H), or 4.31 (s, 2H), was 4.02 (DD, J=7,8, 4.5 G the, 1H), 3.95 to to 3.73 (m, 2H), 3,66 of 3.56 (m, 2H), 3,50 is 3.40 (m, 2H), 3,35-3,20 (m, 4H), 2.95 and (s, 6H), 2,72 of $ 2.53 (m, 2H), 2.49 USD (s, 3H), 2,41 (s, 3H), 2,30-of 2.08 (m, 2H), 1,92-of 1.45 (m, 5H), 0,99-to 0.89 (m, 9H).

Example 16(3)

(3S)-1-propyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.57 (chloroform:methanol=10:1);

NMR (CD3OD): δ 4,43-of 4.25 (m, 1H), 4,29 (s, 2H), Android 4.04 (DD, J=7,8, and 4.5 Hz, 1H), 3,92-3,70 (m, 2H), 3,60-to 3.50 (m, 2H), 3,48-to 3.38 (m, 2H), 2,70-of 2.50 (m, 2H), of 2.51 (s, 3H), 2,47 (s, 3H), 2,25-2,03 (m, 2H), 2,03-1,40 (m, 19H), 1,40-1,08 (m, 4H), 1,05-0,83 (m, 2H), of 0.93 (t, J=7.5 Hz, 3H).

Example 16(4)

(3S)-1-propyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.55 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,53 (d, J=9.0 Hz, 2H), 7,29 (d, J=9.0 Hz, 2H), 7,07 (d, J=9.0 Hz, 2H), 7,03 (d, J=9.0 Hz, 2H), 4,33 (s, 2H), Android 4.04 (DD, J=7,5, and 4.5 Hz, 1H), 3,89 at 3.69 (m, 2H), 3,54-of 3.43 (m, 2H), 3,39-3,30 (m, 2H), 2.95 and (s, 3H), 2,50-of 2.30 (m, 2H), 2,28-to 2.06 (m, 2H), 1,83-of 1.40 (m, 10H), 1,40-1,10 (m, 3H), of 1.05 to 0.85 (m, 2H), of 0.93 (t, J=7.5 Hz, 3H).

Example 16(5)

1-butyl-2,5-dioxo-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.48 (chloroform:methanol=10:1);

NMR (CD3OD): δ rate of 7.54 (d, J=8.7 Hz, 2H), 7,29 (d, J=8.7 Hz, 2H), 7,06 (d, J=8.7 Hz, 2H), 7,03 (d, J=8.7 Hz, 2H), 4,32 (s, 2H), of 3.97 (s, 2H), of 3.77-3,62 (m, 2H), 3,55-to 3.35 (m, 4H), 2.95 and (s, 3H), 2,48 is 2.33 (m, 2H), 2,33-2,22 (m, 2H), 1,0-of 1.46 (m, 2H), 1,43-of 1.26 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Example 16(6)

1-butyl-2,5-dioxo-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.50 (chloroform:methanol=10:1);

NMR (CD3OD): δ 4,34 (m, 1H), 4,27 (s, 2H), of 3.97 (s, 2H), 3,78-the 3.65 (m, 2H), 3,62-3,47 (m, 4H), 2,65-of 2.50 (m, 2H), 2,50 (s, 3H), of 2.45 (s, 3H), 2,31-of 2.20 (m, 2H), 2,04 is 1.70 (m, 6H), 1,65-of 1.42 (m, 4H), 1,42-1,20 (m, 4H), were 0.94 (t, J=7.2 Hz, 3H).

Example 17

(3R)-1-(2-butynyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in reference example 1 → reference example 2, → example 1 using (2R,3R)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-3-hydroxypropanoyl acid instead of (2R,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-4-methylpentanoic acid, 2-butenylamine instead of n-butylamine, N-(3,5-dimethyl-1-phenylpyrazol-4-yl)methyl-4-piperidone instead of N-benzyl-4-piperidone and n-utilitites instead of benzylideneamino get mentioned in the title compound having the following physical data.

TLC:Rf of 0.45 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,60 was 7.45 (m, 5H), of 4.44-to 4.28 (m, 3H), 4,21 (d, J=2.1 Hz, 1H), 4,10-of 3.94 (m, 2H), 3,79 (m, 1H), 3,66-of 3.54 (m, 2H), 3,32 (m, 1H), 2,74 (m, 1H), 2,56-of 2.34 (m, 8H), 2,24 (m, 1H), 2,08-1,90 (m, 2H), 1,84-of 1.62 (m, 7H), 1,44 by 1.12 (m, 3H), 1,05-of 0.82 (m, 2H).

Example 17(1)

(3S)-1-(2-butynyl)-2,5-deok is about-3-((1S)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · Hydrochloride

According to the method described in example 17, using (2S,3S)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-3-hydroxypropanoyl acid instead of (2R,3R)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-3-hydroxypropanoic acid, get mentioned in the title compound having the following physical data.

TLC:Rf of 0.45 (chloroform:methanol=10:1);

NMR (CD3OD): δ 7,60 was 7.45 (m, 5H), of 4.44-to 4.28 (m, 3H), 4,21 (d, J=2.1 Hz, 1H), 4,10-of 3.94 (m, 2H), 3,79 (m, 1H), 3,66-of 3.54 (m, 2H), 3,32 (m, 1H), 2,74 (m, 1H), 2,56-of 2.34 (m, 8H), 2,24 (m, 1H), 2,08-1,90 (m, 2H), 1,84-of 1.62 (m, 7H), 1,44 by 1.12 (m, 3H), 1,05-of 0.82 (m, 2H).

Example 18

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2-(4-phenoxyphenyl)ethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

To the resin PS-TsCl-HL (trade mark catalog Argonaut Technologies, room 800366) (305 mg) is added a solution of 2-(4-phenoxyphenyl)ethyl alcohol (112 mg) in dichloromethane (2 ml) and pyridine (2 ml). The reaction mixture is stirred for 5 hours at room temperature. The resin was washed with dichloromethane 3 times, dimethylformamide 5 times, with a mixture of dimethylformamide:water=3:1, 5 times, tetrahydrofuran 3 times with dichloromethane 3 times and acetonitrile 3 times. To the resulting resin add a solution of the compound obtained in reference example 3(2) (116 mg)in acetonitrile (5 ml) and diisopropylethylamine (0,366 ml). The reaction mixture is stirred during the course the e 18 hours at 70° C. After cooling the resin was washed with acetonitrile, obtained by leaching the concentrate fraction. The resulting residue is purified column chromatography on silica gel (ethyl acetate:methanol=20:1), the compound obtained is treated with hydrochloric acid to obtain specified in the title compound (82 mg)having the following physical data.

TLC:Rf of 0.54 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 7,37-7,29 (m, 4H), 7,11 (t, J=7.2 Hz, 1H), 6,97-to 6.95 (m, 4H), 4,06 (d, J=7,5, and 4.5 Hz, 1H), 3,88-of 3.77 (m, 2H), 3,65 (m, 2H), 3.46 in-to 3.36 (m, 4H), 3,13-of 3.07 (m, 2H), 2,48 (m, 2H), 2,28 with 2.14 (m, 2H), 1,80-to 1.21 (m, 15H), and 0.98 (t, J=7.0 Hz, 3H), 0,99-of 0.91 (m, 2H).

Examples 18(1) and 18(2)

According to the method described in example 18, using appropriate derivatives of alcohols respectively instead of 2-(4-phenoxyphenyl)ethanol and using the compound obtained in reference example 3(1), instead of the compound obtained in reference example 3(2), obtain the following compounds having the following physical data.

Example 18(1)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-(4-phenoxyphenyl)ethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.37 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 7,37-7,29 (m, 4H), 7,11 (t, J=7.5 Hz, 1H), 6,98-to 6.95 (m, 4H), a 4.03 (d, J=7,5, and 4.5 Hz, 1H), 3,89-of 3.77 (m, 2H), to 3.64 (m, 2H), 3,42-of 3.32 (m, 4H), 3,12-of 3.07 (m, 2H), 2,45 (m, 2H), 2,29-of 2.16 (m, 2H), 1,88-of 1.36 (m, 7H), and 0.98 (t, J=7.0 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H), were 0.94 (d, J=6.3 Hz, 3H).

Example 18(2)

(3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-(4-methoxyphenyl)ethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.37 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ 7,22 (d, J=9.0 Hz, 2H), make 6.90 (d, J=9.0 Hz, 2H), 4,01 (d, J=7,5, and 4.5 Hz, 1H), a 3.87-of 3.77 (m, 2H), of 3.77 (s, 3H), 3,63 (m, 2H), 3.43 points-of 3.32 (m, 4H), 3,03 (m, 2H), 2,44 (m, 2H), 2,28-of 2.15 (m, 2H), 1.85 to about 1.36 (m, 7H), of 0.97 (t, J=7.5 Hz, 3H), of 0.95 (d, J=6.3 Hz, 3H), were 0.94 (d, J=6.3 Hz, 3H).

Example 19

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-ethoxycarbonylphenyl)-1,4,9-diazaspiro[5.5]undecane· hydrochloride

To a solution of the compound obtained in reference example 3(2), (186 mg) in dimethyl sulfoxide (3 ml) is added ethyl 4-perbenzoate (164 mg) and potassium carbonate (141 mg). The reaction mixture is stirred for 24 hours at 140°C. To the reaction mixture are added water and tert-butyl methyl ether and extracted. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (hexane:ethyl acetate=4:1→3:1) and the compound obtained is treated with a solution of 4N hydrogen chloride/ethyl acetate to obtain specified in the title compound (67 mg)having the following physical data.

TLC:Rf of 0.27 (hexane:ethyl acetate=2:1);

NMR (CD3OD): δ 8,13 (d, J=8.7 Hz, 2H), to 7.59 (d, J=8.7 Hz, 2H), 4,37 (kV, J=7.2 Hz, 2H), from 4.3 to 4.15 (m, 2H), 4,07 (DD, J=7,5, and 4.5 Hz, 1H), 3,85 of 3.75 (m, 2H), 3,47-to 3.38 (m, 2H), 2,67-of 2.50 (m, 2H), 2,30-2,12 (m, 2H), 1.85 to a 1.46 (m, 10H), 1,44-1,19 (m, 5H), to 1.38 (t, J=7.2 Hz, 3H), of 1.05 to 0.88 (m, 2H), of 0.95 (t, J=7.2 Hz, 3H).

Reference example 4

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-benzyloxycarbonyl-1,4,9-diazaspiro[5.5]undecane

According to the method described in reference example 1 → reference example 2, → example 1, using (3S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropionic acid instead of (2R,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-4-methylpentanoic acid and N-benzyloxycarbonyl-4-piperidone instead of N-benzyl-4-piperidone get mentioned in the title compound having the following physical data.

TLC:Rf of 0.35 (hexane:ethyl acetate=1:1);

NMR (CD3OD): δ 7,39-7,31 (m, 5H), 6.48 in (SHS, 1H), 5,16 (s, 2H), 4,15 (CL, 2H), 4.00 points (DDD, J=9,6, to 4.8, 1.5 Hz, 1H), 3,76-and 3.16 (m, 4H), 2,02-1,12 (m, 19H), 1,08-0,88 (m, 2H), to 0.92 (t, J=7.2 Hz, 3H).

Reference example 5

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-4-methyl-9-benzyloxycarbonyl-1,4,9-diazaspiro[5.5]undecane · hydrochloride

When cooled in a bath with ice to a solution of the compound obtained in reference example 4 (1 g) in dimethylformamide (20 ml) is added 60% sodium hydride (164 mg). The reaction mixture is stirred for 1 hour at room temperature. In a bath with ice to the reaction mixture is added methyl iodide (0.3 ml). The reaction mixture is stirred over night at room temperature. To the reaction mixture is added ice water and extracted with ethyl acetate. The extract is washed with water and saturated aqueous sodium chloride, dried with anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain the specified title compound (1 g)having the following physical data.

TLC:Rf of 0.34 (hexane:ethyl acetate=1:1);

NMR (CD3OD): δ 7,40-to 7.32 (m, 5H), 5,16 (s, 2H), 4,12 (CL, 2H), 3,91 (t, J=5.7 Hz, 1H), 3,88 (SHS, 1H), 3,49 (m, 1H), 3,35 (m, 1H), 2,92 (s, 3H), 2,90 (m, 1H), 2,04-1,10 (m, 19H), 1,04-of 0.82 (m, 2H), to 0.92 (t, J=7.2 Hz, 3H).

Reference example 6

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-4-methyl-1,4,9-diazaspiro[5.5]undecane · hydrochloride

To a solution of the compound obtained in reference example 5 (1 g) in methanol (20 ml) is added 10% palladium on carbon (60 mg). In hydrogen atmosphere, the reaction mixture is stirred for 8 hours at room temperature. The reaction mixture was filtered through Celite and to the filtrate is added 4N solution of hydrogen chloride in ethyl acetate and concentrated to obtain specified in the connection header (799 mg)having the following physical data.

TLC:Rf 0.28 in (chloroform:methanol:acetic acid=90:10:1);

NMR (CD3OD): δ of 4.05 (DD, J=7,5 and 4.2 Hz, 1H), 4,01 (dt, J=4.2, and 12.9 Hz, 1H)and 3.59 (dt, J=3.3, which is 12.9 Hz, 1H), 3,51 (m, 1H), 3,40 (sm, J=5.4 Hz, 1H), ,36 (sm, J=5.4 Hz, 1H), 3,25 (m, 1H), 2,93 (s, 3H), is 2.37 (dt, J=5,4, 14.4 Hz, 1H), 2,32 (dt, J=5,4, 14.4 Hz, 1H), 2,11 (sm, J=14,4 Hz, 1H), 1,99 (sm, J=14,4 Hz, 1H), 1,86-1,14 (m, 15H), with 1.07-0.87 (m, 2H), 0,97 (t, J=7.2 Hz, 3H).

Example 20

(3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-4-methyl-9-(4-vinyloxymethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in example 2 using the compound obtained in reference example 6, instead of the compound obtained in reference example 3, get mentioned in the title compound having the following physical data.

TLC:Rf of 0.32 (ethyl acetate);

NMR (CD3OD): δ 7,53 (d, J=8.7 Hz, 2H), 7,39 (DD, J=8,7, 7.5 Hz, 2H), 7,18 (t, J=7.5 Hz, 1H), 7,09-7,01 (m, 4H), 4,34 (s, 2H), of 4.05 (m, 1H), Android 4.04 (DD, J=7,2, 3,9 Hz, 1H), 3,68-of 3.43 (m, 4H), of 3.27 (m, 1H), 2,93 (s, 3H), 2,48 (DD, J=14,4, a 5.4 Hz, 1H), 2,39 (DD, J=14,4, a 5.4 Hz, 1H), 2,16 (sm, J=14,4 Hz, 1H), 2,03 (sm, J=14,4 Hz, 1H), 1,86 is 1.58 (m, 8H), 1,53-1,14 (m, 7H), 1,07 is 0.86 (m, 2H), of 0.95 (t, J=7.5 Hz, 3H).

Example 21

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-methylpropylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in example 2 using the compound obtained in reference example 3(3), instead of the compound obtained in reference example 3, and using 4-(2-methylpropylamine)benzaldehyde instead of 3-formyl-6-phenoxypyridine get mentioned in the title compound, having the following Phi the practical data.

TLC:Rf 0.28 in (chloroform:methanol=10:1);

NMR (d6-DMSO): δ to 10.6 (s, 1H), 10.0 g (s, 1H), 8,02 (m, 1H), 7,68 (d, J=8.7 Hz, 2H), 7,52 (d, J=8.7 Hz, 2H), 5,24 (s, 1H), 4,22 (s, 2H), 3.96 points (m, 1H), 3,70 (m, 1H), 3,66-of 3.12 (m, 6H), 2,68-of 2.20 (m, 4H), 2,02-to 1.42 (m, 8H), of 1.40 to 1.00 (m, 6H), 1,10 (d, J=6.9 Hz, 6H), 0,98-of 0.64 (m, 2H), from 0.88 (t, J=6.9 Hz, 3H).

Example 21(1)-21(6)

According to the method described in example 21, using the appropriate aldehyde derivatives respectively instead of 4-(2-methylpropylamine)benzaldehyde, you receive the following compounds having the following physical data.

Example 21(1)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-methoxyethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.36 (chloroform:methanol=10:1);

NMR (d6-DMSO): δ and 10.5 (s, 1H), 9,95 (s, 1H), 8,02 (m, 1H), of 7.75 (d, J=8,4 Hz, 2H), 7,55 (d, J=8,4 Hz, 2H), 4.26 deaths (s, 2H), was 4.02 (s, 2H), 3.96 points (m, 1H), 3,80-3,10 (m, 7H), to 3.38 (s, 3H), 2,60-to 2.18 (m, 4H), 2,02-the 1.44 (m, 8H), of 1.40 to 1.00 (m, 6H), 0,98-of 0.64 (m, 2H), from 0.88 (t, J=7.2 Hz, 3H).

Example 21(2)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-phenylacetylamino)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.27 (chloroform:methanol=10:1);

NMR (d6-DMSO): δ to 10.6 (s, 1H), 10,4 (s, 1H), 8,01 (m, 1H), to 7.67 (d, J=9.0 Hz, 2H), 7,54 (d, J=9.0 Hz, 2H), 7,40-to 7.18 (m, 5H), 4,24 (s, 2H), 3.96 points (s, 1H), 3,84-3,10 (m, 8H), 2,62-to 2.18 (m, 4H), 2,04-of 1.42 (m, 8H), of 1.40 to 1.00 (m, 6H), 0,98-of 0.64 (m, 2H), from 0.88 (t, J=7.2 Hz, 3H).

Example 21(3)

(3R)-1-util-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-(4-forfinal)acetylamino)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.26 (chloroform:methanol=10:1);

NMR (d6-DMSO): δ to 10.8 (s, 1H), 10,4 (s, 1H), 8,01 (m, 1H), 7,66 (d, J=8,4 Hz, 2H), 7,54 (d, J=8,4 Hz, 2H), 7,37 (DD, J=8,4, a 5.4 Hz, 2H), 7,14 (t, J=8,4 Hz, 2H), 4,34-3,10 (m, 8H), 4,24 (s, 2H), 3.96 points (s, 1H), 2,66-to 2.18 (m, 4H), 2,02-of 1.42 (m, 8H), of 1.40 to 1.00 (m, 6H), 0,98-of 0.64 (m, 2H), from 0.88 (t, J=6.9 Hz, 3H).

Example 21(4)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxycarbonylaminophenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.35 (chloroform:methanol=10:1);

NMR (d6-DMSO): δ 10,90 (SHS, 1H), 10,70 (s, 1H), with 8.05 (m, 1H), 8,04 (d, J=8,4 Hz, 2H), 7,97 (s, 4H), 7,83 (d, J=8,4 Hz, 2H), 5,24 (m, 1H), 4,43 (s, 2H), 3,97 (m, 1H), 3,90-of 3.06 (m, 7H), of 3.84 (s, 3H), 2,62-2,20 (m, 3H), 2.06 to to 1.42 (m, 8H), 1,40-of 1.02 (m, 6H), 0,98-0,66 (m, 2H), 0,89 (t, J=6.9 Hz, 3H).

Example 21(5)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxyphenylacetylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.41 (chloroform:methanol=10:1);

NMR (d6-DMSO): δ to 10.6 (s, 1H), 8,03 (d, J=8.7 Hz, 2H), 8,02 (m, 1H), 7,78 (d, J=8.7 Hz, 2H), 7,42 (d, J=8.7 Hz, 2H), of 6.96 (d, J=8.7 Hz, 2H), and 5.30 (s, 2H), 5,24 (m, 1H), 4,42 (s, 2H), 3.96 points (m, 1H), 3,86-3,10 (m, 7H), 3,76 (s, 3H), 2,64-of 2.20 (m, 3H), 2,02-of 1.42 (m, 8H), of 1.40 to 1.00 (m, 6H), 0,96 of-0.68 (m, 2H), from 0.88 (t, J=6.3 Hz, 3H).

Example 21(6)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(2-(4-methylaminoacenaphthylene)pyridine-5-ylmethyl)-1,4,9-triaza the pyro[5.5]undecane · hydrochloride

TLC:Rf of 0.37 (chloroform:methanol=9:1);

NMR (CD3OD): δ 8,35 (d, J=2.5 Hz, 1H), 8,15 (DD, J=8,5, 2.5 Hz, 1H), 7,89 (d, J=8.5 Hz, 2H), 7.23 percent (d, J=8.5 Hz, 2H), 7,14 (d, J=8.5 Hz, 1H), 4,39 (s, 2H), 4,15 (d, J=2.0 Hz, 1H), 4.00 points (m, 1H, in), 3.75 (m, 1H), 3,57 is-3.45 (m, 3H), 3,30-up 3.22 (m, 2H), 2,92 (s, 3H), of 2.56 (m, 1H), 2,50-2,39 (m, 2H), 2,14 is 1.91 (m, 3H), 1,80-to 1.60 (m, 5H), 1,50-of 1.10 (m, 6H), and 1.00-0.87 (m, 2H), of 0.95 (t, J=7.0 Hz, 3H).

Example 22

(3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in example 2 using the compound obtained in reference example 3, (9), instead of the compound obtained in reference example 3, using 4-(4-carboxyphenoxy)benzaldehyde instead of 3-formyl-6-phenoxypyridine get mentioned in the title compound having the following physical data.

TLC:Rf of 0.45 (chloroform:methanol=5:1);

NMR (d6-DMSO): δ of 10.4 (s, 1H), with 8.05 (m, 1H), of 7.97 (d, J=8.7 Hz, 2H), 7,69 (d, J=8.7 Hz, 2H), 7,19 (d, J=8.7 Hz, 2H), to 7.09 (d, J=8.7 Hz, 2H), 5,28 (d, J=6,9 Hz, 1H), 4,35 (s, 2H), 3,97 (m, 1H), 3,88-3,12 (m, 7H), 2,64-of 2.20 (m, 3H), 2.06 to to 1.42 (m, 8H), of 1.40 to 1.00 (m, 6H), to 0.89 (t, J=6.9 Hz, 3H), 0,80 (m, 2H).

Example 23

(3S)-1-butyl-2,5-dioxo-3-(pyridine-3-ylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in reference example 1 → SS is Lochem example 2 → example 1 using N-tert-butoxycarbonyl-3-pyridyl-L-alanine instead of (2R,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-4-methylpentanol acid and using N-benzyl-4-piperidin-2-morfolinoetilrutin instead of N-(4-(4-methylaminoacenaphthylene)phenylmethyl)-4-piperidone get mentioned in the title compound having the following physical data.

TLC:Rf of 0.25 (chloroform:methanol=10:1);

NMR (CD3OD): δ 8,82-8,76 (m, 2H), 8,55 (d, J=8,4 Hz, 1H), of 8.06 (DD, J=7,8, 5.7 Hz, 1H), to 7.84 (d, J=9.0 Hz, 2H), 7,63 (d, J=8.7 Hz, 2H), 7,15-7,02 (m, 4H), 4,55 (t, J=5.4 Hz, 1H), 4,33 (s, 2H), 3,80 (m, 1H), 3,68 of 3.28 (m, 7H), only 2.91 (s, 3H), 2,56-to 2.40 (m, 2H), measuring 2.20 (m, 1H), 1,70 (m, 1H), 1,50-1,20 (m, 4H), to 0.92 (t, J=6.9 Hz, 3H).

Examples 23(1)-23(5)

According to the method described in example 23, using appropriate derivatives of amino acids, respectively, instead of N-tert-butoxycarbonyl-3-pyridyl-L-alanine, get the following compounds having the following physical data.

Example 23(1)

(3S)-1-butyl-2,5-dioxo-3-phenylmethyl-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.51 (chloroform:methanol:acetic acid=20:2:1);

NMR (CD3OD): δ to 7.84 (d, J=9.0 Hz, 2H), 7,56 (d, J=9.0 Hz, 2H), 7,30? 7.04 baby mortality (m, 9H), 4,36 (DD, J=4,5, 3.6 Hz, 1H), 4,25 (s, 2H), 3,78 (m, 1H), 3,50-to 3.02 (m, 6H), 3.00 and-2,84 (m, 4H), of 2.38 (m, 1H), 2,02 (m, 1H), to 1.86 (m, 1H), 1.60-to 1,24 (m, 4H), of 0.93 (t, J=6.9 Hz, 3H), 0,04 (m, 1H).

Example 23(2)

(3S)-1-butyl-2,5-dioxo-3-(pyridine-2-ylmethyl)-9-(-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · Hydrochloride

TLC:Rf and 0.46 (chloroform:methanol:acetic acid=20:2:1);

NMR (CD3OD): δ 8,78 (DD, J=7,5, 1.5 Hz, 1H), 8,57 (TD, J=7,8, 1.5 Hz, 1H), of 8.06 (d, J=8,4 Hz, 1H), 8,00 (m, 1H), to 7.84 (d, J=8,2 Hz, 2H), to 7.64 (d, J=6.6 Hz, 2H), 7,16? 7.04 baby mortality (m, 4H), and 4.68 (DD, J=6,9, 5.7 Hz, 1H), to 4.38 (s, 2H), 3,84 (m, 1H), 3,70-of 3.32 (m, 7H), only 2.91 (s, 3H), 2,64 is 2.44 (m, 2H), 2,16 (m, 1H), 2.06 to (m, 1H), 1,50-1,22 (m, 4H), of 0.91 (t, J=6.9 Hz, 3H).

Example 23(3)

(3S)-1-butyl-2,5-dioxo-3-hydroxymethyl-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.28 in (chloroform:methanol:acetic acid=20:2:1);

NMR (CD3OD): δ to 7.84 (d, J=9.0 Hz, 2H), to 7.61 (d, J=8.7 Hz, 2H), 7,14 (d, J=8.7 Hz, 2H), 7,07 (d, J=9.0 Hz, 2H), 4,36 (s, 2H), was 4.02-3,88 (m, 3H), 3,80-3,44 (m, 5H), 3,30 (m, 1H), 2.91 in (s, 3H), 2,60-of 2.36 (m, 3H), 2,18 (m, 1H), 1,64 (m, 1H), 1,50-of 1.26 (m, 3H), 1,02-of 0.90 (m, 3H).

Example 23(4)

(3S)-1-butyl-2,5-dioxo-3-(pyridine-1-oxido-2-ylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0,86 (chloroform:methanol:acetic acid=10:2:1);

NMR (CD3OD): δ to 8.70 (DD, J=5,4, 1.0 Hz, 1H), 8,05 (TD, J=6,6, 1.2 Hz, 1H), 7,92-7,72 (m, 4H), to 7.64 (d, J=9.0 Hz, 2H), 7,20-7,06 (m, 4H), of 4.67 (d, J=6.3 Hz, 1H), 4,36 (s, 2H), 3,86-3,18 (m, 8H), 2.91 in (s, 3H), 2,70-of 2.26 (m, 2H), 2,34-to 2.06 (m, 2H), 1.60-to the 1.44 (m, 2H), 1,44-1,24 (m, 2H), to 0.92 (t, J=7.5 Hz, 3H).

Example 23(5)

(3S)-1-butyl-2,5-dioxo-3-(pyridine-1-oxido-3-ylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.65 (chloroform:methanol:acetic acid=10:2:1);

NMR (CD3OD): δ a total of 8.74 at 8.60 (m, 2H), of 8.06 (d, J=7.8 Hz, 1H), 7,88 (m, 1H), to 7.84 (d, J=8.7 Hz, 2H), 7.62mm (d, J=8.7 Hz, 2H), 7,12 (d, J=8.7 Hz, 2H), 7,06 (d, J=8.7 Hz, 2H), to 4.52 (t, J=5,1 Hz, 1H), 4,33 (s, 2H,), of 4.00 (m, 1H), 3,78 (m, 1H), 3,60 (m, 1H), 3,56-3,18 (m, 5H), 2.91 in (s, 3H), 2,56-to 2.18 (m, 2H), measuring 2.20 (m, 1H), of 1.66 (m, 1H), 1,52-1,22 (m, 4H), of 0.93 (t, J=6.9 Hz, 3H).

Example 24

(3R)-1-(4-methoxyphenethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in reference example 1 → reference example 2, → example 1 using (2R,3R)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-3-hydroxypropanoyl acid instead of (2R,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-4-methylpentanoic acid, using 4-methoxybenzylamine instead of n-butylamine, using N-(4-(4-methylaminoacenaphthylene)phenylmethyl)-4-piperidone instead of N-benzyl-4-piperidone using 2-morfolinoetilrutin instead of benzylideneamino get mentioned in the title compound having the following physical data.

TLC:Rf is 0.24 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.84 (d, J=8.7 Hz, 2H), 7,56 (d, J=8.7 Hz, 2H), 7,18 (d, J=8.7 Hz, 2H), 7,13 (d, J=8.7 Hz, 2H), 7,07 (d, J=8.7 Hz, 2H), 6,85 (d, J=8.7 Hz, 2H), 4,48 (m, 1H), 4,33 (s, 4H), of 3.96 (m, 1H), of 3.75 (m, 1H, in), 3.75 (s, 3H), to 3.58-3,18 (m, 3H), of 2.92 (s, 3H), 2,6-of 2.28 (m, 3H), 2,16 is 1.58 (m, 7H), 1,40-of 0.82 (m, 5H).

Examples 24(1)-24(4)

According to the method described in example 24, using the corresponding amine instead of 4-methoxybenzylamine receive connections specified in the header.

Example 24(1)

(3R)-1-phenylmethyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.28 in (chloroform:methanol=10:1);

NMR (CD3OD): δ a 7.85 (d, J=8.7 Hz, 2H), 7,56 (d, J=8.7 Hz, 2H), 7,40-7,02 (m, 5H), 7,13 (d, J=8.7 Hz, 2H), 7,06 (d, J=8.7 Hz, 2H), 4,58 (m, 1H), 4,33 (s, 4H), of 3.96 (m, 1H), 3,76 (m, 1H), 3,54-3,18 (m, 3H), of 2.92 (s, 3H), 2,64-of 2.28 (m, 3H), 2,14 is 1.58 (m, 7H), 1,40-0,80 (m, 5H).

Example 24(2)

(3R)-1-(2-methoxyethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.35 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.84 (d, J=8.7 Hz, 2H), EUR 7.57 (d, J=8.7 Hz, 2H), 7,15 (d, J=8.7 Hz, 2H), 7,07 (d, J=8.7 Hz, 2H), 4,36 (s, 2H), 4,18 (d, J=2.1 Hz, 1H), 3,98 (m, 1H), 3,86-3,18 (m, 8H), and 3.31 (s, 3H), 2.91 in (with, 3H), 2,60 is 1.58 (m, 10H), 1,42-0,80 (m, 5H).

Example 24(3)

(3R)-1-(pyridine-2-ylmethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf 0.83(chloroform:methanol:acetic acid=10:2:1);

NMR (CD3OD): δ ,76 (DD, J=6,6, 1.8 Hz, 1H), 8,54 (TD, J=8,4, 1.8 Hz, 1H), 8,12 (d, J=8,4 Hz, 1H), to 7.93 (DD, J=8,4, and 6.6 Hz, 1H), 7,83 (d, J=9.0 Hz, 2H), 7,65 (d, J=8.7 Hz, 2H), 7,14-7,02 (m, 4H), 5,34-5,20 (m, 2H), to 4.38 (s, 2H), 4,30 (d, J=1.8 Hz, 1H), 3.96 points (m, 1H), 3,78 (m, 1H), 3,52-to 3.38 (m, 2H), 3,32 (m, 1H), 2,90 (s, 3H), 2,72-of 2.54 (m, 3H), 2,30 (m, 1H), 2.06 to (m, 1H), of 1.88 (m, 1H), 1,82 of 1.50 (m, 4H), 1,28 was 1.06 (m, 3H), 1.06 a-0,80 (m, 2H).

Example 24(4)

(3R)-1-(pyridine-3-ylmethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

TLC:Rf of 0.58 (chloroform:methanol:acetic acid=10:2:1);

NMR (CD3OD): δ 8,89 (s, 1H), 8,73 (d, J=5.7 Hz, 1H), 8,64 (d, J=8,1 Hz, 1H), 8,03 (DD, J=8,1, 5.7 Hz, 1H), 7,83 (d, J=8.7 Hz, 2H), 7,65 (d, J=8,4 Hz, 2H), 7.18 in-7,02 (m, 4H), 5,19 (d, J=18,0 Hz, 1H), 5,11 (d, J=18,0 Hz, 1H), 4,40-4.26 deaths (m, 3H), 3,90 (m, 1H), 3,78 (m, 1H), 3,50-to 3.38 (m, 2H), 3,30 (m, 1H), 2,90 (s, 3H), 2,74-to 2.42 (m, 3H), 2,20-of 1.88 (m, 3H), 1,82-of 1.56 (m, 4H), 1,32 was 1.06 (m, 3H), 1,02-0,80 (m, 2H).

Reference example 7

(3R)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in reference example 1 → reference example 2, → example 1 → reference example 3, using N-tert-butoxycarbonyl-D-cyclohexylamine instead of (2R,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-4-methylpentanoic acid, get mentioned in the title compound having the following physical data.

TLC:Rf 0.59 Is (N-butanol:acetic acid:H2O=4:2:1);

I is R (CD 3OD): δ of 4.05 (DD, J=7,5, and 4.8 Hz, 1H), 3,83 at 3.69 (m, 2H), 3,42-3,37 (m, 4H), 2,39-2,07 (m, 4H), 1,80-1,49 (m, 10H), 1,45-1,19 (m, 5H), 1,03-of 0.91 (m, 5H);

optical rotation:[α]D+35,5° (c of 1.05, methanol, 21°C).

Example 25

(3R)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in example 2 using the compound obtained in reference example 7, instead of the compound obtained in reference example 3, and using 4-(4-carboxyphenoxy)benzaldehyde instead of 3-formyl-6-phenoxypyridine get mentioned in the title compound having the following physical data.

TLC:Rf of 0.36 (chloroform:methanol=10:1);

NMR (d6-DMSO): δ 10,92 (SHS, 1H), to 8.41 (SHS, 1H), 7,95 (d, J=8.7 Hz, 2H), 7,69 (d, J=8.7 Hz, 2H), 7,17 (d, J=8.7 Hz, 2H), 7,07 (d, J=8.7 Hz, 2H), 4,32 (s, 2H), 3,91 (m, 1H), 3,59-to 3.35 (m, 6H), 2,56 to 2.35 (m, 2H,), 2,10 (m, 1H), up to 1.98 (m, 1H), 1,72-of 1.35 (m, 10H), 1,32-to 1.14 (m, 5H), 0,90-0,78 (m, 5H).

Example 26

(3S)-1-butyl-2,5-dioxo-3-(pyridine-1-oxido-2-ylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · 9-oxide

To a solution of the free form compound obtained in example 23(2), (117 mg) in chloroform (10 ml) is added dropwise a solution (4 ml) of 3-chloroperbenzoic acid (114 mg). After stirring the reaction mixture overnight at room temperature, p is storytell is evaporated. The resulting residue is purified column chromatography on silica gel (Fuji Silysia Chemical Ltd., NH-DM1020, chloroform) to obtain the specified title compound (100 mg)having the following physical data.

TLC:Rf of 0.23 (chloroform:methanol:acetic acid=20:2:1);

NMR (CD3OD): δ 8,81 (s, 1H), 8,28 (DD, J=6,0, 1.2 Hz, 1H), to 7.77 (d, J=8.7 Hz, 2H), 7,52-7,46 (m, 3H), 7,32-7,22 (m, 2H), 7,16-6,98 (m, 4H), 6,32 (m, 1H), 4,40-4,24 (m, 4H), a 3.87 (DD, J=11,0, 5,1 Hz, 1H), 3,66-3,34 (m, 4H), 3,16-of 2.86 (m, 4H), 3,01 (d, J=4.5 Hz, 3H), 1,84 is 1.20 (m, 6H), of 0.90 (t, J=7.2 Hz, 3H).

Reference example 8

1-butyl-2,5-dioxo-3-(morpholine-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in reference example 1 → reference example 2, → example 1 → reference example 3, using 2-(tert-butoxycarbonylamino)-3-(morpholine-4-yl)propanoic acid instead of (2R,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-4-methylpentanoic acid, get mentioned in the title compound having the following physical data.

TLC:Rf 0,07 (chloroform:methanol=10:1);

NMR (CD3OD): δ was 4.76 (DD, J=8,4, 4.8 Hz, 1H), 4,05-3,82 (m, 6H), 3,71 is 3.40 (m, 10H)to 2.41 (m, 1H), 2,31-of 2.21 (m, 3H), 1,98-and 1.54 (m, 2H), 1,46-of 1.36 (m, 2H), 0,97 (t, J=7.5 Hz, 3H).

Example 27

1-butyl-2,5-dioxo-3-(morpholine-4-ylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described Primera 2, using the compound obtained in reference example 8, instead of the compound obtained in reference example 3, and using 4-(4-methylaminomethyl)phenoxybenzaldehyde instead of 3-formyl-6-phenoxypyridine get mentioned in the title compound having the following physical data.

TLC:Rf of 0.41 (chloroform:methanol=10:1);

NMR (CD3OD): δ to 7.84 (d, J=9.0 Hz, 2H), 7,63 (d, J=8.5 Hz, 2H), 7,14 (d, J=8.5 Hz, 2H), 7,07 (d, J=9.0 Hz, 2H), 4,73 (DD, J=8,1, 5,1 Hz, 1H), 4,37 (s, 2H), 4,10-of 3.85 (m, 5H), 3,76-of 3.43 (m, 9H), 3,40-3,20 (m, 2H), 2.91 in (s, 3H), 2,63 is 2.43 (m, 2H), 2,33-of 2.24 (m, 2H), 1,65 of 1.50 (m, 2H), 1,44 is 1.34 (m, 2H), of 0.96 (t, J=7.0 Hz, 3H).

Example 28

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(N-hydroxycarbamoyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

To a suspension of the compound obtained in example 9(54), (120 mg) and (1-methoxyisobutyl)oxyamino (31 mg) in dimethylformamide (1.6 ml) add diisopropylethylamine (68 μl), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide · hydrochloride (56 mg) and 1-hydroxybenzotriazole (40 mg). The reaction mixture is stirred for 1 hour at room temperature. To the reaction mixture is added 1N hydrochloric acid (2 ml) and stirred for 15 minutes at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract is washed with water, saturated aqueous is carbonate sodium and saturated aqueous sodium chloride, the resulting residue is dried over anhydrous sodium sulfate and concentrated. To a solution of the obtained residue in methanol is added a solution of 4N hydrogen chloride/ethyl acetate and concentrated. The obtained residue is washed with ethyl acetate to obtain specified in the title compound (116 mg)having the following physical data.

TLC:Rf of 0.43(chloroform:methanol:acetic acid=20:4:1);

NMR (CD3OD): δ 7,79 (d, J=8.7 Hz, 2H), 7,60 (d, J=8.7 Hz, 2H), 7,14 (d, J=8.7 Hz, 2H), 7,06 (d, J=8.7 Hz, 2H), 4,36 (s, 2H), 4,15 (d, J=2.1 Hz, 1H), 4.00 points (m, 1H, in), 3.75 (m, 1H), 3,60 is 3.40 (m, 3H), 3,30-3,11 (m, 2H), 2,58-of 2.27 (m, 3H), 2,19 is 1.96 (m, 3H), 1.93 and is 1.60 (m, 5H), 1,50-of 1.09 (m, 6H), of 1.05 to 0.80 (m, 2H), were 0.94 (t, J=7.2 Hz, 3H).

Example 29

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylcarbamoyl)-1,4,9-diazaspiro[5.5]undecane

To a solution of 4-(4-methylaminoacenaphthylene)benzoic acid (53,8 mg) in dimethylformamide (4 ml) was added 1-hydroxybenzotriazole (34,9 mg) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide · hydrochloride (49.5 mg). The reaction mixture is stirred for 40 minutes at room temperature. To the reaction mixture are added the compound obtained in example 3(3), (100 mg) and stirred for 19 hours at room temperature. The reaction mixture was diluted with methylenechloride, add water and extracted with methylenechloride. The extract was washed with 10% is one citric acid solution and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (ethyl acetate:methanol=10:1) and washed with diethyl ether to obtain specified in the connection header (56,1 mg)having the following physical data.

TLC:Rf 0,41 (ethyl acetate:methanol=10:1);

NMR (CD3OD): δ to 7.84 (d, J=8.7 Hz, 2H), 7,49 (t, J=8.7 Hz, 2H), 7,13-7,06 (m, 4H), 3,70 (m, 1H), 4,16 (m, 1H), 4,12 are 2.98 (m, 6H), 2.91 in (s, 3H), 2,42-0,80 (m, 19H), is 0.96 (t, J=6.9 Hz, 3H).

Example 30

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenyl)-1,4,9-diazaspiro[5.5]undecane · hydrochloride

According to the method described in reference example 1 → reference example 2, → example 1 using (2R,3R)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-3-hydroxypropanoyl acid instead of (2R,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-4-methylpentanoic acid, using N-(4-(4-methylaminoacenaphthylene)phenyl)-4-piperidone instead of N-benzyl-4-piperidone and using 2-morfolinoetilrutin instead benzylideneamino get mentioned in the title compound having the following physical data.

TLC:Rf of 0.40 (ethyl acetate);

NMR (CD3OD): δ 7,87 (d, J=9.0 Hz, 2H), 7,78 (d, J=9.0 Hz, 2H), 7,25 (d, J=9.0 Hz, 2H), 7,10 (d, J=9.0 Hz, 2H)and 4.65 (m, 1H), 4,39 (m, 1H), 4,20 (d, J=1.8 Hz, 1H), of 3.73-the 3.65 (m, 3H), 3.43 points-of 3.27 (m, 2H), 2.91 in (s, 3H), 2,90-2,52 (m, 3H), of 2.25 (m, 1H), 2,1-1,90 (m, 2H), 1.85 to to 1.60 (m, 5H), 1.60-to of 1.10 (m, 6H), 0,99 (t, J=7.2 Hz, 3H), 1.00 and-of 0.82 (m, 2H).

The example of the pharmaceutical composition 1

The following components are mixed conventional method, pressed to obtain 100 tablets each containing 50 mg of active ingredient.

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(6-phenoxypyridine-3-ylmethyl)-
1,4,9-diazaspiro[5.5]undecane · hydrochloride5.0 g
calcixerollic (disintegrant)0.2 g
magnesium stearate (lubricating agent)0.1 g
microcrystalline cellulose4.7 grams

Example pharmaceutical compositions 2

The following components are mixed conventional method. The solution is sterilized by the conventional method, fill them ampoules of 5 ml each and lyophilizers a common method to obtain 100 ampoules each containing 20 mg of active ingredient.

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(6-phenoxypyridine-3-ylmethyl)-
1,4,9-diazaspiro[5.5]undecane · hydrochloride2.0 g
mannitol20 g
distil the new water 500 ml

1. Derived diazaspiro[5.5]undecane formula (I)

where R1has the formula (1) or (2)

where G represents a bond, C1-4alkylen, With 2-4 albaniles, or-CO-; ring a is a (1) C5-10-membered mono - or bikebicycle ring or (2) a 5-10 membered mono - or bicyclic a heterocycle containing 1-2 nitrogen atom and/or 1-2 oxygen atom;

R6is

(1) C1-4alkyl,

(2) halogen,

(3) nitrile,

(4) trifluoromethyl,

(5) -OR8,

(6) -SR9,

(7) -NR10R11,

(8) -COOR12,

(9) -CONR13R14,

(10) -SO2NR15R16,

(11) NR17SO2R18,

(12) -S(O)R19,

(13) -SO2R20,

(14) -N(SO2R21)2,

(15) C1-4alkyl, substituted Deputy selected from (a) OR8(b) -NR10R11and (c) Cyc 1, or

(16) -NR27COR28,

where R8-R17each independently represents (1) hydrogen, (2) C1-4alkyl, (3) WM 1, (4) -OR22and (5) C1-4alkyl, substituted Deputy selected from (a) OR22(b) -NR23R24, (s) -COOR25and (d) WM 1, or

R 10and R11, R13and R14or R15and R16, each independently, together with the nitrogen atom to which they are attached, form a 5-6-membered monocyclic heterocycle containing 1-2 nitrogen atom and/or oxygen atom, where 5-6-membered monocyclic heterocycle can be optionally substituted C1-4the alkyl or hydroxy,

R22-R25each independently represents (1) hydrogen, (2) C1-4alkyl or (3) C1-4alkyl, substituted C1-4alkoxy, or

R23and R24together with the nitrogen atom to which they are attached, form a 5-6-membered monocyclic heterocycle containing 1-2 nitrogen atom and/or oxygen atom, where 5-6-membered monocyclic heterocycle can be optionally substituted C1-4the alkyl or hydroxy,

R18-R21each independently represents C1-4alkyl,

R27represents (1) hydrogen, (2) C1-4alkyl, (3) WM 1 or

(4) C1-4alkyl, substituted Deputy, optionally selected from (a) OR22(b) -NR23R24(c) -COOR25and (d) Cyc 1,

R28represents (1)1-4alkyl, (2) Cyc 1, or (3) C1-4alkyl, substituted Deputy, optionally selected from (a) OR22(b) -NR23R24, (s) -COOR25and (d) Cyc 1,

Cyc 1 is (1) C5-6 membered monocarbocyclic or (2) a 5-6-membered monocyclic heterocycle, containing 1-2 nitrogen atom and/or oxygen atom (where the carbocyclic ring or heterocycle can be optionally substituted C1-4alkoxy, halogen or-COOR29where R29represents (1) hydrogen, (2) C1-4alkyl), (3) Cyc 1, or (4) C1-4alkyl, substituted Deputy selected from (a) OR22(b) -NR23R24, (s) -COOR25and (d) WM 1;

E represents a bond, -O-, -S-, -CO - or-NON-;

the ring represents (1) C5-6 membered monocarbocyclic ring or (2) a 5-6-membered monocyclic heterocycle containing 1-2 nitrogen atom and/or an oxygen atom;

R7represents C1-4alkyl or halogen;

n is a number from 0 or 1 to 4;

m is a number from 0 or 1 to 4;

R2represents (1) C1-4alkyl, (2) C2-4quinil or (3) C1-4alkyl, substituted Deputy, optionally selected from (a) OR30(b) -NR31R32and (C) WM 3 (where R30-R32each independently represents (1) hydrogen, (2) C1-4alkyl, (3) WM 3 or (4) C1-4alkyl, substituted WM 3 WM 3 is (1) C5-6 membered monocarbocyclic ring or (2) a 5-6-membered monocyclic heterocycle containing 1-2 nitrogen atom and/or oxygen atom, where C5 is a 6-membered carbocyclic ring or a 5-6-membered monocyclic heterocycle can be optionally C is medeni C 1-4alkoxy);

R3and R4each independently represents (1) hydrogen, (2) C1-4alkyl or (3) C1-4alkyl substituted with 1-2 substituents selected from (a) WM 2 and (b) hydroxy (where WM 2 is (1) C5-6 membered monocarbocyclic ring or (2) a 5-6-membered monocyclic heterocycle containing 1-2 nitrogen atom and/or oxygen atom), or R3and R4together form

where R26represents C1-4alkyl or WM 2;

R5represents hydrogen or C1-4alkyl, his Quaternary ammonium salt, N-oxide or its non-toxic salt.

2. The compound of formula (I) according to claim 1, where R3and R4represent hydrogen.

3. The compound of formula (I) according to claim 1, where R3is hydrogen and R4represents (1) C1-4alkyl or (2) C1-4alkyl substituted with 1-2 substituents, optionally selected from (a) WM 2 and (b) hydroxy.

4. The compound of formula (I) according to claim 1, where R3and R4each independently represent (1) C1-4alkyl or (2) C1-4alkyl, substituted Deputy, optionally selected from (a) WM 2 and (b) hydroxy.

5. The compound of formula (I) according to claim 1, where R3and R4together form

where R26has the meaning given in claim 1.

6. The is a group of representing

(1) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-benzyl-1,4,9-diazaspiro[5.5]undecane,

(2) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(6-phenoxypyridine-3-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(3) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methoxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(4) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(3-methoxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(5) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-torpedolike)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(6) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-chlorphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(7) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(phenylcarbamoyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(8) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(1-phenyl-1-hydroxymethyl)phenylmethyl)-1,4,9-diazaspiro[5,5]undecane,

(9) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(morpholine-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-three-azaspiro[5.5]undecane,

(10) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(6-methylpyridin-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(11) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(pyridine-1-oxido-3-ilexibility)-1,4,9-diazaspiro[5.5]undecane,

(12) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-hydroxypiperidine-1-ylmethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(13) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(14) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(1,3,5-trimethylpyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(15) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-aminosulphonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(16) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylthiophenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(17)(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(18) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-cyanovinylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(19) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(phenylthio)phenylmethyl)-1,4,9-diazaspiro[5,5]undecane,

(20) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-hydroxyphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(21) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylsulfonylamino)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(22) (3R)-1-butyl-2,5-diox the-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(23) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(24) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(6-methylpyridin-1 oxido-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5 ]undecane,

(25) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-hydroxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(26) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(6-(4-methoxybenzyloxy)pyridine-3-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(27) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(methylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(28) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-hydroxyethyl)aminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(29) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(30) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(31) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(morpholine-4-yl)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-triazene what about[5.5]undecane,

(32) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(33) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(34) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(35) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(morpholine-4-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(36) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-aminosulphonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(37) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(38) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-were)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(39) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-diethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(40) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(41) (3R)-1-butyl-,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(5-chloro-3-methyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(42) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(morpholine-4-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(43) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(44) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(45) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(pyridine-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(46) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(47) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(48) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(2,4-differenl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(49) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(pyridine-2-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(50) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylaminophenol)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(51) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-cyclohexyloxy is phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(52) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(3,4,5,6-tetrahydropyran-4-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(53) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methoxyphenylethylamine)phenylmethyl)-1,4,9-diazaspiro [5.5 ]undecane,

(54) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(cyclohexanecarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(55) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(56) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-forfinal)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(57) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-phenylethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(58) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(1-benzyloxycarbonylamino-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(59) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-(2-hydroxyethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(60) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-(1-methylsulfonylmethane-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(61) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-2-METI is propyl)-9-(4-(4-hydroxyethyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(62) (3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-2-methylpropyl)-9-(6-phenoxypyridine-3-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(63) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(64) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(65) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(morpholine-4-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(66) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-methylsulfinylphenyl)-1,4,9-diazaspiro[5.5]undecane,

(67) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(68) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(morpholine-4-yl)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(69) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(70) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(71) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyridine-1-oxido-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(72) (3S)-1-butyl-2,5-dioxo-3-(-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(73) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(morpholine-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(74) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N,N-diethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(75) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(2-hydroxyethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(76) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(77) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(cyclohexanesulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(78) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(3-methoxypropylamine)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(79) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-methylsulfinylphenyl)-1,4,9-diazaspiro[5.5]undecane,

(80) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-propylpyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(81) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-aripirazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(82) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-cyclopentylphenol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(83) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-(1,1-dimethylethyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(84) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(1-benzyloxycarbonylamino-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(85) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-((4-methoxyphenyl)methylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(86) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(3-methoxypropyl-aminocarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(87) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-ethoxycarbonylphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(88) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-methoxyphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(89) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(3-(morpholine-4-yl)propylaminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(90) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(pyrrolidin-1-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(91) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(piperidine-1-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(92) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(morpholine-4-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(93) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-N-methyl-N-(2-(pyridin-2-yl)ethyl)aminocarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(94) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-cyclohexylamino-carbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(95) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(N,N-dimethylamino-sulfonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(96) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methoxycarbonyl-phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(97) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(1-methylpiperidin-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(98) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(1-methylsulfonylmethane-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(99) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(3-(N,N-dimethylamino)propylaminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(100) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-(N,N-dimethylamino)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(101) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-(N',N'-dimethylamino)ethyl)aminosulphonylphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(102) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-((N,N-dimethylamino)methyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(103) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(104) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-methylaminophenol)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(106) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-(3,5-dimethyl-1-phenylpyrazol-4-yl)-2E-propenyl)-1,4,9-diazaspiro[5.5]undecane,

(107) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(carboxymethylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(108) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(3-(3,5-dimethyl-1-phenylpyrazol-4-yl)propyl)-1,4,9-diazaspiro[5.5]undecane,

(109) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-N,N-dimethylaminoethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(110) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(111) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(morpholine-4-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro [5.5 ]undecane,

(112) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(113) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(morpholine-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(114) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-methylsulfinylphenyl)-1,4,9-diazaspiro[5.5]undecane,

(115) (3S)-1-Buti is -2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(116) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(2-(morpholine-4-yl)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(117) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(118) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(119) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(120) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(2-hydroxyethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(121) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(122) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(cyclohexanesulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(123) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(3-methoxypropylamine)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(124) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-methylsulfinylphenyl)-1,4,9-diazaspiro[5.5]undecane,

(125) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-propeler the evil-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(126) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-aripirazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(127) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-cyclopentylphenol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(128) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(3-(morpholine-4-yl)propylaminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(129) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(N,N-dimethylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(130) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(pyrrolidin-1-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(131) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-(N,N-dimethylamino)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(132) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(cyclohexanecarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(133) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-ethoxycarbonylphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(134) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(3-methoxypropylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(135) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(N-methyl-N-(2-(pyridin-2-yl)ethyl)aminocarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(136) (3S)-1-butyl-2,5-dioxo-3-cyclohexyl the Teal-9-(4-((4-methoxyphenyl)methylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(137) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-ethoxycarbonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(138) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-methoxyphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(139) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1-methylpiperidin-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(140) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1-methylsulfonylmethane-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(141) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(3-(N,N-dimethylamino)propylaminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(142) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-(N',N'-dimethylamino)ethyl)aminosulphonylphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(143) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(piperidine-1-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(144) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(morpholine-4-ylcarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(145) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-((N,N-dimethylamino)methyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(146) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(4-methylaminophenol)pyrazole-4-ylmethyl-1,4,9-diazaspiro[5.5]undecane,

(147) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1,1-dimethylethyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(148) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-(1-benzyloxycarbonylamino-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(149) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-hydroxyethyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(150) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-((methoxycarbonyl)methylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(151) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(carboxymethylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(152) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-vinyloxymethyl)-1,4,9-diazaspiro[5.5]undecane,

(153) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(6-phenoxypyridine-3-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(154) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-torpedolike)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(155) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-chlorphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(156) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-cyanovinylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(157) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-illogicality)-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(158) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(6-methylpyridin-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(159) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(1-methylethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(160) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(161) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(3,4,5,6-tetrahydropyran-4-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(162) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-phenylcarbonylamino)-1,4,9-diazaspiro[5.5]undecane,

(163) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(1-phenyl-1-hydroxymethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(164) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(morpholine-4-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(165) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methylaminoethanol)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(166) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N-methyl-N-(2-hydroxyethyl)aminosulfonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(167) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-C is klagebilder)-9-(3,5-dimethyl-1-(pyridine-2-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(168) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(169) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(1,3,5-trimethylpyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(170) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(171) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(N,N-biomethylation)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(172) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methylsulfonylamino)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(173) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylsulphamoyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(174) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(175) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(morpholine-4-ylcarbonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(176) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-aminocarbonylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(177) (3R)-1-b the Teal-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-aminosulphonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(178) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-aminosulphonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(179) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(6-methylpyridin-1 oxido-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(180) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-hydroxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(181) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-hydroxyphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(182) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(183) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(pyrrolidin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(184) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(5-chloro-3-methyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(185) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(186) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(3-methoxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(187) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cycle is heximer)-9-(4-(N,N-dimethylaminoethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(188) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(189) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-were)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(190) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-forfinal)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(191) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(6-(4-methoxybenzyloxy)pyridine-3-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(192) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfinylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(193) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro [5.5 ]undecane,

(194) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-hydroxyethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(195) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(196) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-(morpholine-4-yl)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-is diazaspiro[5.5]undecane,

(197) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(morpholine-4-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(198) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(1,4-benzodioxan-b-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(199) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-diethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(200) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(pyridine-1-oxido-3-yloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(201) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(4-methylpiperazin-1-ylsulphonyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(202) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(203) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(2,4-differenl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(204) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(205) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methylaminophenol)pyrazole-4-ylmethyl)-1,4,9-diazaspiro the[5.5]undecane,

(206) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(207) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-((4-methoxyphenyl)methylaminomethyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(208) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(3-methoxypropylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(209) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(N-methyl-N-(2-(pyridin-2-yl)ethyl)aminocarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(210) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(pyrrolidin-1-ylcarbonyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(211) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-chlorophenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(212) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-triptoreline)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(213) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-methoxyphenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(214) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-aripirazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(215) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-C is klagebilder)-9-(3,5-dimethyl-1-propylpyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(216) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(1,1-dimethylethyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(217) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-cyclopentylphenol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(218) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(2-phenylethyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(219) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(1-benzyloxycarbonylamino-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(220) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(cyclohexanecarbonyl)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(221) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(1-methylsulfonylmethane-4-yl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(222) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(2-hydroxyethylaminomethyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(223) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-hydroxyethyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(224) (3S)-1-butyl-2,5-dioxo-3-((1S)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(225) (3R)-1-b the Teal-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(226) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-methylaminoacenaphthylene) phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(227) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-(4-methoxyphenylethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(228) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(229) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(230) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-(3,4,5,6-tetrahydropyran-4-yl)methyl)-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(231) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(232) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(4-(4-(4-methoxyphenylethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(233) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(234) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclopentylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-trizas the IIR[5.5]undecane,

(235) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(236) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(237) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-2-methylpropyl)-9-(4-(4-methoxyphenylethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(238) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(239) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(240) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxyphenylethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(241) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-(4-(N,N-dimethylaminoethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(242) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(243) (3R)-1-propyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-ethoxycarbonylphenyl)phenylmethyl)-1,4,9-diazaspiro[5.5 ]undecane,

(244) (3R)-1-propyl-2,5-dioxo-3-(1-cyclohexyl Liden)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(245) (3S)-1-propyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(246) (3S)-1-propyl-2,5-dioxo-3-(2-methylpropyl)-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(247) (3S)-1-propyl-2,5-dioxo-3-(2-methylpropyl)-9-(3,5-dimethyl-1-(4-(2-(N,N-dimethylamino)ethylaminomethyl)phenyl)pyrazole-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(248) (3S)-1-propyl-2,5-dioxo-3-cyclohexylmethyl-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(249) (3S)-1-propyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(250) 1-butyl-2,5-dioxo-9-(4-(4-methylsulfonylmethane)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(251) 1-butyl-2,5-dioxo-9-(3,5-dimethyl-1-cyclohexylprop-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(252) (3R)-1-(2-butynyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro [5.5]undecane,

(253) (3S)-1-(2-butynyl)-2,5-dioxo-3-((1S)-1-hydroxy-1-cyclohexylmethyl)-9-(3,5-dimethyl-1-phenylpyrazol-4-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(254) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(2-(4-phenoxyphenyl)ethyl)-1,4,9-diazaspiro[5.5]undecane,

(255) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-(4-phenoxyphenyl)ethyl)-1,4,9-treesap the ro[5.5]undecane,

(256) (3S)-1-butyl-2,5-dioxo-3-(2-methylpropyl)-9-(2-(4-methoxyphenyl)ethyl)-1,4,9-diazaspiro[5.5]undecane,

(257) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-ethoxycarbonylphenyl)-1,4,9-diazaspiro[5.5]undecane,

(258) (3S)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-4-methyl-9-(4-vinyloxymethyl)-1,4,9-diazaspiro[5.5]undecane,

(259) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-methylpropylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(260) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-methoxyethylamine)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(261) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-phenylacetylamino)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(262) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(2-(4-forfinal)acetylamino)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(263) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxycarbonylaminophenyl)phenylmethyl)-1,4,9-diazaspiro [5.5]undecane,

(264) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methoxyphenylacetylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(265) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(2-(4-methylaminoacenaphthylene)pyridine-5-ylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(266) (3S)-1-butyl-2,5-dioxo-3-((1S)-1-g is droxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(267) (3S)-1-butyl-2,5-dioxo-3-(pyridine-3-ylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(268) (3S)-1-butyl-2,5-dioxo-3-phenylmethyl-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(269) (3S)-1-butyl-2,5-dioxo-3-(pyridine-2-ylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(270) (3S)-1-butyl-2,5-dioxo-3-hydroxymethyl-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(271) (3S)-1-butyl-2,5-dioxo-3-(pyridine-1-oxido-2-ylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(272) (3S)-1-butyl-2,5-dioxo-3-(pyridine-1-oxide-3-ylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(273) (3R)-1-(4-methoxyphenethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(274) (3R)-1-phenylmethyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(275) (3R)-1-(2-methoxyethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(276) (3R)-1-(pyridine-2-ylmethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminomethyl is enyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(277) (3R)-1-(pyridine-3-ylmethyl)-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(278) (3R)-1-butyl-2,5-dioxo-3-cyclohexylmethyl-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(279) (3S)-1-butyl-2,5-dioxo-3-(pyridine-1-oxido-2-ylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane-9-oxide,

(280) 1-butyl-2,5-dioxo-3-(morpholine-4-ylmethyl)9-(4-(4-methylaminoacenaphthylene)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(281) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-(N-hydroxycarbamoyl)phenyloxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane,

(282) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenylcarbamoyl)-1,4,9-diazaspiro[5.5]undecane, or

(283) (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-methylaminoacenaphthylene)phenyl)-1,4,9-diazaspiro[5.5]undecane, its Quaternary ammonium salt, N-oxide or its non-toxic salt.

7. The pharmaceutical composition inhibiting HIV, including derived diazaspiro[5.5]undecane formula (I) according to claim 1, its Quaternary ammonium salt, N-oxide or its non-toxic salt as an active ingredient.

8. The regulator of chemokine/chemokine receptor, including PR is izvozna diazaspiro[5.5]undecane formula (I) according to claim 1, its Quaternary ammonium salt, N-oxide or its non-toxic salt as an active ingredient.

9. The remedy for the prevention and/or treatment of asthma, atomic dermatitis, urticaria, allergic bronchopulmonary aspergillosis, allergic eosinophilic gastroenteritis, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, psoriasis, rhinitis, conjunctivitis, ischemic reperfusion disorder, multiple sclerosis, ulcerative colitis, acute respiratory distress syndrome, cytotoxic shock, diabetes, autoimmune diseases, transplant rejection, immunosuppression, metastases in cancer or acquired immunodeficiency syndrome, including derived diazaspiro[5.5]undecane formula (I), paragraph 1, of its Quaternary ammonium salt, N-oxide or its non-toxic salt as an active ingredient.

10. The compound according to claim 1, which represents the (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane, its Quaternary ammonium salt, N-oxide or its non-toxic salt.

11. The compound according to any one of claims 1, 6 or 10, which represents a (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane hydrochloride.

12. The tool according to claim 9, where PR is iswalnum diazaspiro[5.5]undecane is (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane or its pharmaceutically acceptable salt.

13. (3R)-1-Butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane or its pharmaceutically acceptable salt.

14. (3R)-1-Butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane hydrochloride.

15. The pharmaceutical composition inhibiting HIV, comprising (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane or its pharmaceutically acceptable salt as an active ingredient.

16. The pharmaceutical composition inhibiting HIV, comprising (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenoxy)phenylmethyl)-1,4,9-diazaspiro[5.5]undecane hydrochloride as the active ingredient.

Priority from 19.03.2001: according to claim 1 with the exception of R6=-NR27COR28; WM 1=(1) substituted C5-6-membered monocarbocyclic ring or (2) a 5-6-membered monosilicate a heterocycle, substituted Deputy, other than With1-4alkoxy; R2=(3) substituted C1-4alkyl; claim 2 to 5, item 6), connection (1)-(258); claims 7 to 16.

The priority of 29.05.2001: 1 R6=-NR27COR28; WM 1=(1) substituted C5-6-membered monocarbocyclic ring or (2) a 5-6-membered monosilicate a heterocycle, substituted Deputy, other than With1-4and is coxi; item 6, the connection 259-283.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 ex

The invention relates to (DL)-1-hydroxy-3,7,7,9,9-pentamethyl-1,4,8-diazaspiro[4.5]decane-2-ONU formula (1)

The invention relates to new spirochetes formula I

< / BR>
where Ar is phenyl, substituted phenyl where the substituents are: alkoxy, alkyl, alkoxyalkyl, phenoxy, halogen, pyridyloxy, alkoxyalkane, halogenfree; R1- H; R2- H1-C4alkyl; W represents O or one or more1-C4alkyl fragments; Y is independently one or more members of the group consisting of H2, SR3, alkoxy; R3- H, alkyl; Z is a carbocyclic or heterocyclic Spiro-fragment with a 3-7 member ring system, where the heterocyclic fragment includes 2 oxygen atom or sulfur, or one nitrogen atom and spirits may be unsubstituted or substituted by hydroxy, C1-C4the alkyl, benzyloxy; n=1-3; optical isomers, diastereomers or enantiomers or pharmaceutically acceptable salts

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

The invention relates to new derivatives of pyrrolidinone possessing biological activity, in particular derivatives of 1H-3-aryl-pyrrolidin-2,4-dione

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

FIELD: medicine and veterinary.

SUBSTANCE: invention relates to method for prophylaxis of oncological diseases, or infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. In the first embodiment of invention blood extracellular DNA destroying agent, such as DNAase, is administered into blood. In the second embodiment agent, binding to blood extracellular DNA, such as anti-DNA antibody is administered into blood. According to the third embodiment enzyme altering of blood extracellular DNA chemical structure is administered into blood. According to the forth embodiment agent, stimulating synthesis and/or activity of endogenic deoxyribonuclease or agent stimulating synthesis of antibody binding to blood extracellular DNA are administered into blood.

EFFECT: effective method for treatment of abovementioned diseases without side effects when prolonged using of preparation affected on blood extracellular DNA.

7 cl, 11 tbl, 18 ex, 5 dwg

FIELD: medicine and veterinary.

SUBSTANCE: invention relates to method for treatment of diseases, associated with alterations of blood extracellular DNA, such as generalized infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. Method includes administering of blood extracellular DNA destroying agent into blood. As such agent DNAase is used, in particular in doses providing alteration of electrophoretic profile of blood extracellular DNA, detectable by pulse gel electrophoresis. DNAase may be administrated in doses and regimes providing exceeded levels of blood plasma DNA-hydrolytic activity, namely 150 Kuntz/l of plasma, during 12 h/day in total.

EFFECT: effective method for treatment of abovementioned diseases without side effects.

4 cl, 14 tbl, 15 ex, 5 dwg

FIELD: medicine, cardiology.

SUBSTANCE: the complex of medicinal therapy includes nibentane to be injected at the dosage of 0.125 mg/kg intravenously. Moreover, one should pre-inject magnesium sulfate solution at the dosage of 2.5 g about 10-15 min before nibentane injection. The innovation provides quick restoration of sinus rhythm in case of no therapeutic complications observed.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, medicine, cardiology, biochemistry.

SUBSTANCE: invention relates to benzoyl guanidines of the formula (I): wherein R1 means -CF3; R2 means -Y-para-(C6H4)-R11, -Y-meta-(C6H4)-R11 or -Y-ortho-(C6H4)-R11 wherein R11 means (C1-C9)-heteroaryl comprising two or more nitrogen atoms adjoining across nitrogen (N) atom; Y means oxygen atom; R3 means hydrogen atom; R4 means (C1-C4)-alkyl, and to their pharmaceutically acceptable salts. Indicated compounds elicit very high activity with respect to inhibition of Na+/H+ exchange and improved water solubility and therefore they can be used as anti-arrhythmic medicinal agents with cardioprotective component for prophylaxis of infarction and treatment of infarction and for treatment of stenocardia. Also, proposed compounds inhibit pathophysiological processes in arising disorders induced by ischemia, in particular, in treatment of cardiac arrhythmia induced by ischemia.

EFFECT: improved preparing method, improved treatment and prophylaxis, valuable medicinal properties of compounds.

17 cl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves applying intracoronary phosphocreatine introduction into infarction-responsible artery when carrying out coronary angioplasty. Phosphocreatine solution is injected after reperfusing the infarction-responsible artery at constant volume rate of 0.1-4 ml/s with introduced phosphocreatine dose being equal to 0.5-4 g.

EFFECT: reduced myocardium necrosis zone; prevented cardiac insufficiency and cardiac rhythm disorders.

4 cl

FIELD: organic chemistry, chemical technology, medicine, biochemistry.

SUBSTANCE: invention relates to quinuclidine compounds of the formula (I) , its salts or their hydrates wherein R1 represents hydroxyl group; W represents: (1) -CH2-CH2-; 2) -CH=CH-, or 3) -C≡C-; HAr represents 5-10-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom that in addition to the group -X-Ar can be substituted with 1-3 groups taken among: (1) halogen atom; (2) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl group substituted optionally with: (a) hydroxy-group; (b) (C1-C6)-alkoxycarbonyl; (c) (C1-C6)-alkanoyl optionally substituted with (C1-C6)-alkoxy-group; (d) hydroxylated (C3-C8)-cycloalkyl; (e) (C1-C6)-alkoxy-group; (f) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom, or (g) cyano-group; (3) (C1-C6)-alkoxy-group optionally substituted with: (a) hydroxy-group; (b) (C1-C6)-alkoxy-group optionally substituted with (C1-C6)-alkoxy-group; (c) halogen atom; (d) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (e) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (4) (C1-C6)-alkylthio-group optionally substituted with (C1-C6)-alkoxy-group or hydroxy-group; (5) 5-6-membered heterocyclyloxy-group comprising 1-2 oxygen atoms in heterocycle; (6) amino-group represented by the formula: -N(R3)R4 wherein R3 and R4 are similar or different and each represents hydrogen atom or group taken among: (a) (C1-C6)-alkyl group; (b) (C1-C6)-alkoxy-(C1-C6)-alkyl group; (c) carbonyl substituted with (C6-C14)-aryl; (d) (C6-C14)-arylsulfonyl or (e) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (7) (C3-C8)-cycloalkyl or cycloalkenyl hydrocarbon group optionally substituted with: (a) oxo-group or (b) hydroxy-group; (8) (C6-C14)-aromatic hydrocarbon ring optionally substituted with: (a) (C1-C4)-alkylene dioxy-group or (b) hydroxy-group; (9) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with: (a) cyano-group or (b) (C1-C6)-alkoxy-group; (10) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with one or some groups taken among: (a) hydroxy-group; (b) halogen atom; (c) cyano-group; (d) (C1-C6)-alkoxycarbonyl; (e) (C1-C6)-alkyl; (f) (C1-C6)-alkoxy-group that is optionally substituted with halogen atom or (C1-C6)-alkoxy-group; (g) (C1-C6)-alkanoyl; (h) (C1-C6)-alkoxy-(C1-C6)-alkyl; (i) oxo-group; (j) (C1-C4)-alkylenedioxy-group; (k) (C3-C8)-cycloalkylalkoxy-group or (C3-C8)-cycloalkenylalkoxy-group; (11) carbamoyl of the formula: -CO-N(R5)R6 wherein R5 and R6 can be similar or different and represent hydrogen atom, (C6-C14)-aryl wherein indicated aryl is optionally substituted with halogen atom, or (C3-C8)-cycloalkyl; or R5 and R6 form in common 3-6-membered ring; (12) carbonyl optionally substituted with (C1-C6)-alkoxy-group; X represents: (1) a simple bond; (2) (C1-C6)-alkylene chain; (3) (C1-C6)-alkenylene chain; (4) (C1-C6)-alkynylene chain; or (5) formula: -Q- wherein Q represents oxygen atom or sulfur atom; Ar represents: (1) (C6-C14)-aromatic hydrocarbon ring optionally substituted with one or some groups taken among: (a) halogen atom; (b) (C1-C4)-alkoxy-group or (c) (C1-C6)-alkylthio-group; or (2) 5-6-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom. Compounds of the formula (I) show inhibitory activity with respect to a squalene-synthesizing enzyme. Also, the invention relates to an inhibitor of squalene-synthesizing enzyme and the corresponding medicinal composition based on compound of the invention, a method for prophylaxis and treatment of disease wherein inhibition of squalene-synthesizing enzyme is effective. Also, invention proposes some methods for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable of medicinal and biochemical properties of com[pounds and composition.

25 cl, 10 tbl, 214 ex

FIELD: medicine.

SUBSTANCE: method involves administering a combination of an agent reducing cholesterol content in blood and reduced coenzyme Q10 of general formula .

EFFECT: enhanced effectiveness of treatment.

8 cl, 2 tbl

FIELD: medicine, cardiology.

SUBSTANCE: the present innovation deals with introducing nitrates, heparin, beta-blocking agents, calcium antagonists, aspirin. Additionally, one should intravenously inject dalargin once daily at the rate of about 5-7 mcg/kg/h at the dosage of 25-30 mcg/kg daily per 100 ml sodium chloride physiological solution for about 5-6 d against the onset of hospitalization period. The innovation provides favorable impact upon diastolic function of left ventricle by decreasing the risk of dangerous arrhythmias and coronary lethality.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising S-isomer of compound of the formula (I) or its pharmaceutically acceptable salts and solvates in common with a pharmaceutically acceptable vehicle. Also, invention relates to a method for synthesis of compound S-isomer of the formula (I), and to a method for treatment of disease relating to the group comprising respiratory diseases, allergic diseases, dermatological diseases, gastroenteric diseases and ophthalmic diseases. The composition provides avoiding adverse sedative effects in treatment of indicated diseases.

EFFECT: valuable medicinal properties of compounds.

14 cl, 6 ex

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