Heterocyclic dihydropyrimidine compounds

FIELD: organic chemistry, heterocyclic compounds, medicine.

SUBSTANCE: invention relates to dihydropyrimidine compounds of the formula (I*): their enantiomers, diastereoisomers and pharmaceutically acceptable salts wherein X1, X2 and X3 in common with atoms to which they are added form ring of the formula: or ; R1 represents hydrogen atom; R2, R3*, R4, R5, R6 and R7 have values given in cl. 1 of the invention claim. Also, invention relates to separate dihydropyrimidine compounds. Proposed compounds are inhibitors of calcium channel function being especially inhibitors of Kv1 subfamily of potential-overlapping K+-channels and especially inhibitors of Kv 1.5 that associated with super-rapid activating delayed cleaning K+-flow of Ikur and can be used in treatment of arrhythmia and Ikur-associated diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 589 ex

 

The scope of the invention

The present invention relates to heterocyclic dihydropyrimidine compounds useful as inhibitors of the function of the potassium channel (especially inhibitorsV1 subfamily potential overlap To+channels, more specifically inhibitorsV1.5, which were associated with sverhbystro activating delayed purifying K+stream IKURand to pharmaceutical compositions containing such compounds. The present invention further relates to methods of using such compounds for the treatment of arrhythmia, IKUR-related diseases and other diseases mediated by ion channel function.

Background of the invention

The importance of potassium channels was investigated for the first time about fifty years ago, when Hodgkin and Huxley found that potassium ions to flow into the flow, which stimulates the head of the giant axon. Research in this area, however, was hampered by the lack of selective, highly specific ligands for potassium channels. But with the advent of recombinant DNA technologies and technologies of compressed voltage of individual cells, and all cells of the slow pace of development in this area has changed. Indeed, the potassium channels that are functional, pharmacological characteristics and the characteristics and distribution of fabrics, were cloned. These cloned potassium channels are useful targets in tests to identify candidate compounds for treatment of various diseases. Potassium channels, as it turns out, are the most diverse family of ion channels that are currently open. They modulate a number of cellular interactions, such as muscle contraction, hormonal secretion, the frequency and duration of existing potentials, electrolyte homeostasis and residual membrane potential.

Potassium channels are expressed in eukaryotic and prokaryotic cells and are the elements that control electric and non-electric cell functions. Potassium channels are classified according to their biophysical and pharmacological characteristics. Subclasses of these channels are called on the basis of amino acid sequence and functional properties. Prominent among them are the potential-dependent potassium channels, such as the potential overlap potassium channels (e.g., Kv1, KV2, KV3, Kv4). Subtypes in these subclasses are characterized by their intended function, pharmacology and distribution in cells and tissues (Chandy and Gutman, "Voltage-gated potassium channel genes" in Handbook of Receptors and Channels - Ligand and Voltage-gated Ion Channels, ed. R.A. North, 1995; Doupnik and others, Curr. Opin. Neurobiol. :268, 1995). For example, Kv1 class of potassium channels is further subdivided depending on the molecular sequence of the channel, for example, KV1.1, KV1.2, KV1.3, KV1.4, KV1.5 ToV1.6 and KV1.7. Functional capacity-overlapping K+channels can exist as multimeric structures formed during the interaction of identical or different subunits. This phenomenon is believed, explains a wide variety To+the channels. However, the subunit composition of natural+channels and physiological role of the individual channels, in most cases, is still unclear.

Membrane depolarization KV1.3 inhibitors has been shown to be an effective way to prevent T-cell proliferation, and therefore is used in many autoimmune conditions. Inhibition of K+channels in the plasma membrane of human T lymphocytes was found to play a role when calling immunosuppressive responses in the regulation of intracellular CA++homeostasis, which, as it was discovered, is important in T-cell activation.

KV1.3 overlying voltage potassium channel found in neurons, blood cells, osteoclasts and T-lymphocytes. Chandy and Cahalan laboratory advanced hypotize that the lock is of K V1.3 channel causes immunosuppressive response (Chandy and others, J. Exp. Med. 160, 369, 1984; Decoursey and others, Nature, 307, 465, 1984). However, blockers of K+the channel used at these stages were non-selective. To test the peptide margatoxin, a peptide found in the venom of the Scorpion, there was no specific inhibitor of KV1.3 channel to test this hypothesis. Although laboratory (Price and others, Proc.Natl, Acad, Sci. USA, 86, 10171, 1989) showed that charybtotoxin blocks KV1.3 in human T-cells, charybtotoxin, as was later shown to be inhibited To four different+channel (KV1.3 and three other small conductance Ca+activated K+channel) in human T-lymphocytes, limiting the use of this toxin as a sample to determine the physiological role of KV1.3 (Leonard and others, the OEWG. Natl, Acad. Sci, USA, 89, 10094, 1992). Margatoxin, on the other hand, only blocks To theV1.3 in T-cells and has immunosuppressive activity both in in vitro and in vivo models (Lin and others, J. exp. Med, 177,637, 1993). therapeutic usefulness of these compounds, however, is limited by their strong toxicity. Recently reported on a class of compounds, which can be a good alternative to the above drugs, see, for example, US 5670504; 5631282; 5696156; 5679705 and 5696156. Although solved some problems activity/toxicity of these you who e drugs these compounds have high molecular weight and are usually synthetic in the way from a natural product, the allocation of which is burdensome and time-consuming.

Immunoregulatory disorders, has been shown to be present in a wide range of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosus, chronic rheumatoid arthritis, diabetes mellitus type I and II, inflammatory intestinal diseases, liver cirrhosis, uveitis, multiple sclerosis and other diseases, such as Crohn's disease, ulcerative colitis, bubble amphipod, sarcoidosis, psoriasis, ichthyosis, ophthalmopathy greivsa and asthma.

Although the underlying pathogenesis of each of these States may be different, they all appear different autoantibodies and polyreactive lymphocytes. This polyreactivity may be due in part to the lack of control of homeostasis, in which the normal functioning of the immune system. Also, using bone marrow transplantation or organ, the lymphocytes of the host recognize foreign tissue antigens and begin to produce antibodies, which lead to rejection of the transplanted organ.

On the one hand, the result of an autoimmune process, or the process of rejection is the rejection of tissue caused by inflammation of cells and release of mediators. EN vospalitelnye agents, such as NSAID's, act principally by blocking the action or secretion of these mediators, but do not alter the immunological basis of the disease. On the other hand, cytotoxic agents such as cyclophosphamide, act in a nonspecific way that isolate normal and autoimmune responses. Finally, patients who are treated with such nonspecific immunosuppressive agents probably are infected during their autoimmune diseases.

Cyclosporine A (CsA), which was approved by the US FDA in 1983, is currently the leading drug used to prevent rejection of transplanted organs. In 1993, FK-506 (Prograf) was approved by the US FDA to prevent rejection of liver transplantation. CsA and FK-506 inhibit the immune system from mobilizing its vast supply of natural protective agents to the exclusion of alien protein transplant. In 1994 CsA approved US FDA for the treatment of severe psoriasis and approved by European regulatory agencies for the treatment of superficial dermatitis. Although they are effective to combat rejection of the graft, CsA and FK-506 has been known to cause some unintended side effects, including nephrotoxicity, neurotoxicity, and gastrointestinal disorder. Therefore, there is still a need for gaining the selective immunosuppressant without these side effects. Inhibitors of potassium channel promise to solve the problem.

Atrial fibrillation (AF), and the oscillation of the Atria are the most common cardiac arrhythmia in clinical practice and grow in accordance with the age of the population. Currently, AF affects more than 1 million Americans annually, representing more than 5% of all cardiovascular diseases and causes more than 80,000 cases of paralysis in the United States. At that time, as AF is rarely fatal arrhythmia, it is responsible for high morbidity and can lead to complications such as the development of capsules heart failure or thromboembolism. Currently available antiarrhythmic drugs of class I and class III reduces the rate of recurrence of AF, but they are of limited use due to various potentially harmful effects, including prioritiy ventricle. Since this therapy is inadequate and fraught with side effects, there is a need to develop new therapeutic approaches.

Antiarrhythmic agents of class III are drugs that cause a selective prolongation of the duration of the action potential without significant cardiac depression. Available drugs in this class are limited. Examples, that is their as sotalol and amiodarone, been shown to have interesting properties class III (Singh B.N., Vaughan Williams, E.M. "A Third Class of Anti-Arrhythmic Action: Effects On Atrial And Ventricular Intracellular Potentials And Other Pharmacological Actions On Cardiac Muscle, of MJ 1999 And AH 3747" Br. J. Pharmacol 1970; 39:675-689, and B.N. Singh, Vaughan Williams E.M, "The Effect of Amiodarone, A New Anti-Anginal Dru g On Cardiac Muscle", Br J. Pharmacol 1970; 39:657-667), but they are not selective agents of class III.

Sotalol also has the action of class II, which can cause cardiac depression and is contraindicated in certain susceptible patients. Amiodarone is also not selective antiarrhythmic agent of class III, as he has accumulated electrophysiological effect and strictly limited due to side effects (Nademanee, K. "The Amiodarone Odessey". J. Am. Coll. Cardiol. 1992;20:1063-1065.) Drugs of this class, as expected, are effective to prevent ventricular fibrillation. Selective agents of class III, when the determination is deemed not to cause myocardiocytes depression or induction of arrhythmia caused by inhibition of conduction of current capacity, as shown for the antiarrhythmic agents of class I.

Agents of class III increase myocardiocytes stability by prolongation of the potential duration of cardiac action. Theoretically, extension of potential cardiac action can be achieved is by velichinam internal threads (that is, Na +or Sa2+threads; here and below, INaand ICarespectively) or a decrease in external repolarization potassium (K+)the threads. Prevent cleaning (IKTo+flow is the main external thread included in the total repolarization process during the action potential plateau, whereas temporary external (Itoand internal cleansing (IKI)K+flows are responsible for the fast initial and final phase of repolarization, respectively. The study of the cellular electrophysiology showed that IKconsists of two pharmacologically and kinetically different To+subtypes thread, Ikr(fast activation and deactivation) and Iks(slow activation and deactivation) (Sanguinetti and Jurkiewicz, Two Components Of Cardiac Delayed Rectifier K+Current: Differential Sensitivity To Block Class III Antiarrhythmic Agents, J Gen Physiol 1990, 96:195-215). Antiarrhythmic agents of class III, currently under development, including d-sotalol, dofetilide (UK-68798), elocuent (N/09), E-4031 and methanesulfonamide-N-[1'-6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl)-3,4-dihydro-4-hydroximino[2H-1-benzopyran-2,4'-piperidine]-6-yl]monochloride, mostly, if not completely block Ikr. Although amiodarone is a blocker of Iks(Balser J.R, Bennett, P.B., Hondeghem, L.M. and Roden, D.M. "Suppression Of Time-Dependent Outward Current In Guinea Pig Ventricular Myocytes: the Actions Of Quinidine And Amiodarone. Cic. Res. 1991, 69:519-529), it also blocks INaand ICaperforming thyroid function, as a non-specific adrenergic blocker and acts as an inhibitor of the enzyme phospholipase (Nademanee, K. "The Amiodarone Odessey" J. Am. Coll.Cardiol. 1992;20:1063-b). Therefore, this method of treating arrhythmias is uncertain. Most of the agents of class III, which, as you know, are in development, mainly block Ikr.

The incoming excitation (input), as shown, is a major mechanism underlying ventricular arrhythmias in humans. The incoming excitation requires a critical balance between slow conduction and short enough sustained periods, allowing the initiation and support folding incoming circuits for coexistence at the same time and support AF. An increase in cardiac stability in the prolongation of the potential duration (APD), prevents and/or completes inbound arrhythmia. The most selective antiarrhythmic agents of class III, currently under development, such as d-sotalol and dofetilide, mostly, if not completely block Ikrrapidly activating component of IKfound in the atrium and ventricle of a human.

As these Ikrblockers increase APD and sustainability both in the atrium and the ventricle, without the implementation of conductivity as such, theoretically, they are potentially useful agents for the treatment of arrhythmias, such as AF. These agents have a tendency to the fact that they increase the risk of proirity at slow speeds the heart. For example, Torsade de pointes ventricular fibrillation was observed when using these compounds (Roden, D.M. "Current Status of Class m Antiarrhythmic Drug Therapy", Am J. Cardiol., 1993; 72:44B-49). This exaggerated effect at slow speeds the heart is called "inverse frequency dependence", and it is the opposite of frequency-independent or frequency-dependent actions (Hondeghem, L.M. "Development of Class III Antiarrhythmic Agents". J.Cadiovasc.Cardiol. 20 (Suppl.2):S17-S22).

Slowly activating component, which prevents the cleaning (Ikc), potentially superior to some restrictions Ikrblockers associated with ventricular fibrillation. Because of their slow kinetics of activation, however, the role of Iksin the repolarization of the Atria may be limited due to the relatively short APD atrium. Therefore, although Iksblockers may provide a particular advantage in the case of ventricular arrhythmias, their ability to impact on SVT believed to be minimal.

Ultra-fast activation prevents cleaning To+flow (Ikur), as I believe, is a natural double CL is kirovenego potassium channel, marked Kv1.5 and, when present in the atrium of the man, it turns out, is not in the ventricle of a human. Moreover, because of the speed of activation and limited slow inactivation, Ikuras I believe, makes a significant contribution to the repolarization of the Atria of a human. Therefore, a specific blocker of Ikurthat is a compound that blocks Kv1.5, exceeds briefly came other connections to the prolongation of stability with slow depolarization in the atrium of a person without education obstacles in the repolarization of the ventricle, which becomes arrhythmogenic after depolyarizatsii and acquires long QT syndrome observed during treatment with these drugs class III.

In intact myocytes of the Atria person ultrafast activation prevents cleaning To+flow Ikuralso known as continuous external thread, Isusor Isoidentified and this thread has properties and kinetics identical to the properties and kinetics expressed by the clone To the+channel person (hKv1.5, HK2) in the allocation of the human heart and stably expressed in human (SOME-293) cell lines (Wang and others, 1993, Circ Res 73:1061-1076; Fedida and others, 1993, Circ Res 73:210-216; Snyders and others, 1993, J Gen Physiol 101:513-543) and usually is cloned from the brain is Rysy (Swanson and others, 10, Neuron 4:929-939). Although various antiarrhythmic agents are now available on the market, were not received agents with satisfactory efficiency and high reliability. For example, antiarrhythmic agents of class I in accordance with the classification scheme Vaughan-Williams ("Classification Of Antiarrhythmic Drugs: In: Cardiac Arrhythmias, edited by: E. ice pick stuck through, E. Flensted-Jensen, K. Olesen; Sweden, Astra, Sodertalje, pp449-472, 1981), which cause a selective inhibition of the maximum speed up existing capacity (max), are inadequate for preventing ventricular fibrillation. In addition, they are problematic in terms of safety, namely, they cause a depression of contraction of the myocardium and tend to cause arrhythmia caused by inhibition of conduction of the impulse. Beta adrenoreceptor blockers and calcium antagonists belonging to the class II and IV, respectively, have drawbacks in that their actions are either limited to a particular type of arrhythmia or have contraindications for their cardiac depressive properties in certain patients with cardiovascular disease. Their safety, however, is higher than the safety of antiarrhythmic agents of class I.

The invention

The present invention relates to heterocyclic dihydropyrimidine compounds of the following formula is I, including enantiomers, diastereoisomers and their salts, useful as inhibitors of the function of the potassium channel (especially inhibitorsv1 subfamily potential overlap To+channels, more specifically inhibitorsV1.5 associated with ultrafast activating delayed purifying K+stream IKUR) for the treatment of diseases, such as arrhythmia and IKUR-associated diseases:

where X1X2and X3independently selected from N, NR6, (CR7)q(CHR7)qor C=O, where the link connecting X1X2and X3with neighboring atoms can be simple or double bonds, forming a 5 to 7-membered saturated, partially unsaturated or aromatic ring;

R1, R2, R3, R4, R5, R6and R7are the same or different and independently selected from groups of the formula -(CR2)n-(Z1)m-(CH2)p-Z2or

R1, R2, R3, R4and R5may, in one or more pairs of two (such as R1and R2, R1and R3, R2and R3, R3and R4or R4and R5), together with the atoms to which they are attached, form a carbocyclic, substituted carbocyclic, heterocyclics the Yu or substituted heterocyclic group, or

R6and R7may, in one or more pairs of two (such as R6and R7, R6and R6or R7and R7), together with the atoms to which they are attached, form a carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocyclic group;

Z1represents-CZ3Z4-, -O-, -NZ3-, -S-, -SO-, -SO2-, -C(O)-, -C(O)Z3-, -C(O)NZ4, -C(S)-, -C(=NOZ3)-, alkyl, substituted alkyl, alkenyl, replaced alkenyl, quinil, substituted quinil, carbocycle, substituted carbocycle, aryl, substituted aryl, heterocycle or substituted heterocycle;

Z2represents hydrogen, -OZ5, -OC(O)Z5, -NZ5-C(O)-Z6, -NZ5-CO2-Z6, -NZ5(C=O)-NZ6Z7, -NZ5Z6, -NO2, halogen, -CN, -C(O)Z5, -CO2Z5, -C(S)Z5, -(C=NOZ5Z6, -C(O)NZ5Z6, -C(S)NZ5Zb, -SZ5, -SOZ5, -SO2Z5, -SO2NZ5Z6, alkyl, substituted alkyl, alkenyl, replaced alkenyl, quinil, substituted quinil, carbocycle, substituted carbocycle, aryl, substituted aryl, heterocycle (such as heteroaryl), or substituted heterocycle;

Z3, Z4, Z5, Z6and Z7independently represent hydrogen, halogen, alkyl, substituted alkyl, alkenyl, for ewenny of alkenyl, quinil, substituted quinil, carbocycle, substituted carbocycle, aryl, substituted aryl, heterocycle or substituted heterocycle or

Z3, Z4, Z5, Z6and Z7may, in one or more pairs of two (such as the Z3and Z4, Z5and Z6or Z6and Z7), together with the atom to which they are attached, form a carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocyclic group;

n and p are independently selected from integers from 0 to 10 when m is 0, p is 0;

m is an integer selected from 0 or 1, and

q is an integer selected from 1 to 3.

The present invention relates to new methods of prevention and treatment of arrhythmia and IKur-related diseases, by using one or more compounds of formula I, enantiomers, diastereoisomers or their pharmaceutically acceptable salts. Particularly the present invention relates to a new method of selective prevention and treatment of ventricular arrhythmias.

In addition, the compounds included in formula I, as well as enantiomers, diastereoisomers and their salts are new compounds, including the compounds of formula I and their salts:

where X1X2X3, R1, R2, R4and R5are what I like, as defined above;

R3* represents-OZ5, -OC(O)-Z5, -NZ5-C(O)2-Z6, -NZ5(C=O)-NZ6Z7, -NZ5Z6, -(C=NOZ5Z6, -C(O)NZ5*Z6*, -C(S)NZ5*Z6*, -SZ5, -SOZ5, -SO2Z5, -SO2NZ5Z6, -C(O)Z3*-Z2*, halogen, alkyl, substituted alkyl, alkenyl, replaced alkenyl, quinil, substituted quinil, carbocycle, substituted carbocycle, aryl, substituted aryl, heterocycle or substituted heterocycle;

Z2* is not hydrogen when Z3* represents heterocycle; Z3* represents heterocycle or substituted heterocycle;

Z5* is a substituted alkyl, alkenyl, replaced alkenyl, quinil, substituted quinil, carbocycle, substituted carbocycle, aryl, substituted aryl, heterocycle or substituted heterocycle and

Z6* represents hydrogen, alkyl, substituted alkyl, alkenyl, replaced alkenyl, quinil, substituted quinil, carbocycle, substituted carbocycle, aryl, substituted aryl, heterocycle or substituted heterocycle, provided that Z6* is not hydrogen when Z5* represents an unsubstituted cycloalkyl, unsubstituted aryl or unsubstituted benzyl,

or Z5* and Z6* together with the nitrogen atom to which they Preece is United, may form a heterocyclic group or substituted heterocyclic group, provided that Z5* and Z6* do not together form an unsubstituted piperidinyl, the unsubstituted pyrrolidinyl or an unsubstituted morpholinyl and further provided that when

(i) R1and R5each represents hydrogen, and

(ii) R2represents aryl or substituted aryl and

(iii) R4represents heterocyclizations aryl and

(iv) X1X2and X3form a ring

where R7* represents H or alkyl,

Z5* and Z6* together do not form an unsubstituted piperazinil or N-alkyl substituted piperazinil.

The preferred connection

The compounds of formula I and their salts in which one or more, especially all, of X1X2X3, R1, R2, R3, R4and R5selected from the following values are preferred compounds of the present invention:

R1represents hydrogen;

R2represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, carbocycle or substituted carbocycle;

R3represents -(CH2)nZ2, -(CH2)nC(O)Z3-(CH2)pZ2or -(CH2) C(O)NZ4-(CH2)R-Z2;

R4represents an alkyl or substituted alkyl;

R5represents hydrogen or -(CH2)nZ2and

X1X2and X3together with the atoms to which they are attached, form a ring selected from the

where R6and/or R7are the same or different, as defined above.

The compounds of formula I and their salts in which one or more, especially all, of X1X2X3, R1, R2, R3, R4and R5choose from the following values are preferred compounds of the present invention:

R1represents hydrogen;

R2represents aryl (especially if the aryl represents phenyl), substituted aryl, heterocycle, substituted heterocycle, carbocycle or substituted carbocycle;

R3represents -(CH2)nZ2, -(CH2)nC(O)Z3-(CH2)R-Z2or -(CH2)nC(O)NZ4-(CH2)pZ2where

Z2selected from-C(O)NZ5Z6, -CO2Z5, -SO2Z5, -NZ5Z6, -NZ5CO2Z6, -NZ5C(O)Z6, -OZ5, aryl, substituted aryl, heterocycle, substituted heterocycle, alkyl or substituted al the sludge;

Z3represents heterocycle or substituted heterocycle and n and p are independently selected from integers from 0 to 3;

R4represents an alkyl or substituted alkyl;

R5represents hydrogen or -(CH2)nZ2where Z2selected from-C(O)NZ5Z6, -CO2Z5, -NZ5Z6, aryl, substituted aryl, alkyl or substituted alkyl and

X1X2and X3together with the atoms to which they are attached, form a ring selected from the

The compounds of formula I and their salts in which one or more, especially all, of X1X2X3, R1, R2, R3, R4and R5choose from the following values are the most preferred compounds of the present invention:

R1represents hydrogen;

R2represents aryl (especially if the aryl represents phenyl), substituted aryl, heterocycle, substituted heterocycle, carbocycle or substituted carbocycle;

R3represents heterocycle or substituted heterocycle, -C(O)NZ5Z6, -C(O)Z3-CONZ5Z6, -C(O)Z3-Z2or-C(O)Z3-CO2Z5where Z3represents heterocycle or substituted heterocycle and Z2represents aryl or replace the military aryl;

R4represents alkyl (especially lower alkyl) or substituted alkyl (especially halogen-substituted alkyl or alkoxy-substituted alkyl);

R5represents hydrogen, alkyl or substituted alkyl and

X1X2and X3together with the atoms to which they are attached, form a ring selected from the

where R6represents H or C(O)Z5where Z5represents an alkyl or carbocycle, and

R7independently selected from H, alkyl, substituted alkyl (especially halogenating), halogen or CN.

Detailed description of the invention

The following are definitions of terms used in this description. The initial determination relating here to the group or the term applied to a group or term in the present description, separately or as part of another group, unless otherwise specified.

The terms "ALK" or "alkyl" refers to linear or branched chain hydrocarbon groups having from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl etc. Lower alkyl groups, such as alkyl groups with 1 to 6 carbon atoms are usually preferred. The term "substituted Ala is l" refers to alkyl groups, substituted by one or more groups (such as groups mentioned above in the definition of R1), which are preferably selected from aryl, substituted aryl, heterocycle, substituted heterocycle, carbocycle, substituted carbocycle, halogen, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkyl ester (optionally substituted), alleyra (optionally substituted), alkanoyl (optionally substituted), aryl (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane, sulfonyl etc.

The term "alkenyl" refers to a linear or branched chain hydrocarbon groups having from 2 to 12 carbon atoms, preferably from 2 to 4 carbon atoms, and at least one double carbon-carbon bond (CIS or TRANS), such as ethynyl. The term "substituted alkenyl" refers to alkenyl groups substituted by one or more groups (such as groups described above in the definition of R1), preferably selected from aryl, substituted aryl, heterocycle, substituted heterocycle, carbocycle, substituted carbocycle, halogen, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkyl ester (optionally substituted), alleyra (optionally substituted), alkanoyl is (optionally substituted), Ariola (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane, sulfonyl etc.

The term "quinil" refers to a linear or branched chain hydrocarbon groups having from 2 to 12 carbon atoms, preferably from 2 to 4 carbon atoms, and at least one triple carbon-carbon bond, such as ethinyl. The term "substituted quinil" refers to alkynylaryl groups substituted by one or more groups (such as groups described above in the definition of R1), preferably selected from aryl, substituted aryl, heterocycle, substituted heterocycle, carbocycle, substituted carbocycle, halogen, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkyl ester (optionally substituted), alleyra (optionally substituted), alkanoyl (optionally substituted), Ariola (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane, sulfonyl etc.

The terms "ar" or "aryl" refers to aromatic homocyclic (i.e. hydrocarbon) mono-, bi - or tricyclic ring groups, preferably having from 6 to 12 members, such as phenyl, naphthyl and biphenyl. Phenyl is a preferred aryl group. The term "substituted aryl" refers to a arilje is a diversified groups, substituted by one or more groups (such as groups described above in the definition of R1), preferably selected from alkyl, substituted alkyl, alkenyl (optionally substituted), aryl (optionally substituted), heterocycle (optionally substituted), halogen, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkanoyl (optionally substituted), Arora (optionally substituted), alkyl ester (optionally substituted), alleyra (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane, sulfonyl etc., where optionally one or more pair of substituents together with the atoms to which they are attached, form a 3-7 membered ring.

The terms "cycloalkyl" and "cycloalkenyl" refer to mono-, bi - or three homocyclic ring groups with 3 to 15 carbon atoms, which are respectively fully saturated and partially unsaturated. The term "cycloalkenyl includes bi - and tricyclic ring systems, which are not aromatic, but contain aromatic part (for example, fluorene, tetrahydronaphthalen, dihydroindeno and the like). Ring poliklinik cycloalkyl groups can be condensed, bridged and/or soedinenii through one or more of Seredenin. The terms "samewe the hydrated cycloalkyl" and "substituted cycloalkenyl" refer respectively to cycloalkyl and cycloalkenyl groups, substituted by one or more groups (such as groups described above in the definition of R1), preferably selected from aryl, substituted aryl, heterocycle, substituted heterocycle, carbocycle, substituted carbocycle, halogen, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkyl ester (optionally substituted), alleyra (optionally substituted), alkanoyl (optionally substituted), Ariola (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane, sulfonyl etc.

The terms "carbocycle", "carbocyclic" or "carbocyclic group" refers to cycloalkenyl and cycloalkenyl groups. The terms "substituted carbocycle", "substituted carbocyclic or substituted carbocyclic group" refers to carbocycle or carbocyclic groups substituted by one or more groups as defined in the definition of cycloalkyl and cycloalkenyl.

The terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine.

The terms "heterocycle", "heterocyclic", "heterocyclic group" or "heterocycle" refer to fully saturated or partially or fully unsaturated, including aromatic ("heteroaryl")or nonaromatic cyclic groups (for example, 3 to 13 member monocyclic, 7 - to 7-membered bicyclic or 10 - 20 membered tricyclic ring system, preferably containing a total of from 3 to 10 ring atoms)which have at least one heteroatom in at least one ring containing a carbon atom. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the heteroatoms nitrogen and sulfur may be optionally oxidized and the nitrogen heteroatoms may be optionally stereoselectivity. Heterocyclic group may join at any heteroatom or carbon atom of the ring or ring system. Ring poliklinik heterocycles can be condensed, bridged and/or connected via one or more of Seredenin.

Examples of monocyclic heterocyclic groups include azetidin, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolines, imidazoles, imidazolines, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, diazolidinyl, isothiazolin, isothiazolinones, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinil, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, 2-oxoazetidin, azepine, 4-piperidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrahydropyranyl, tetrazol, treat the sludge, morpholinyl, thiomorpholine, themorphological, themorphological, 1,3-dioxolane and tetrahydro-1, 1-DIOXOLANYL,

and similar to them.

Examples of bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothiazyl, hinokitiol, chinoline, tetrahydroisoquinoline, ethenolysis, benzimidazolyl, benzopyranyl, indolizinyl, benzofuran, benzofuranyl, dihydrobenzofuranyl, chromones, coumarinyl, benzodioxolyl, dihydrobenzofuranyl, benzodioxolyl, indolinyl, honokalani, indazoles, pyrrolopyridine, properidine (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoquinolyl, dihydroquinazolines (such as 3,4-dihydro-4-oxothiazolidine), tetrahydroquinoline, azabicycloalkanes (such as 6-azabicyclo[3.2.1]octane), azaspiracid (such as 1,4-dioxa-8 azaspiro[4.5]decane), imidazopyridine (such as imidazo[1,5-a]pyridine-3-yl), triazolopyridines (such as 1,2,4-triazole[4,3-a]pyridine-3-yl) and hexahydropyridine (such as 1,5,6,7,8,8A-hexahydrobenzo[1,5-a] pyridine-3-yl),

and similar to them.

Examples of tricyclic heterocyclic groups include carbazolyl, benzhydryl, phenanthrolines, acridines, phenanthridines, xantener and the like.

The terms "substituted heterocy the l", "substituted heterocyclic", "substituted heterocyclic group" and "substituted heterocycle" refer to heterocycle, geterotsiklicheskikh and heterostropha substituted by one or more groups (such as groups described above in the definition of R1), preferably selected from alkyl, substituted alkyl, alkenyl, oxo, aryl, substituted aryl, heterocycle, substituted heterocycle, carbocycle (optionally substituted), halogen, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkanoyl (optionally substituted), Arora (optionally substituted), alkyl ester (optionally substituted), alleyra (optionally substituted), cyano, nitro, amido, amino, substituted amino, lactam, urea, urethane, sulfonyl, etc. where optionally one or more pair of substituents together with the atoms to which they are linked, form a 3 to 7 membered ring.

The term "alkanoyl" refers to an alkyl group (which may be optionally substituted, as defined above)associated with the carbonyl group (i.e.- C(O)-alkyl). Similarly, the term "aroyl" refers to an aryl group (which may be optionally substituted as described above)associated with the carbonyl group (i.e.- C(O)-aryl).

Throughout the description of the group and the substituents can be selected from gaining the m stable groups and connections.

The compounds of formula I form salts, which are also included in the scope of this invention. It is clear that the reference to the compound of the formula I here include a link to his salt, if not stated otherwise. The term "salt(s)", as used here, denotes acidic and/or basic salts derived from inorganic and/or organic acids and bases. In addition, when the compound of formula I includes both basic and acid groups can be obtained zwitterions ("inner salts") and are included in the term "salt(s)"as used here. Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, although other suitable salt, for example, in the stages of separation or purification that may apply when you receive them. Salts of compounds of formula I can be obtained, for example, by the reaction of compound I with an amount of acid or base, such as an equivalent amount, in a medium in which the salt precipitates or in an aqueous medium followed by lyophilization.

The compounds of formula I, which include the main group, can form salts with various organic and inorganic acids. Examples of the acid additive salts include acetates (such as acetates formed with acetic acid or trigalogenmetany acid, for example triperoxonane to what slotow), adipate, alginate, ascorbate, aspartate, benzoate, bansilalpet, bisulfate, borates, butyrate, citrates, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, econsultancy, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (formed with hydrochloric acid), hydrobromide formed with bromoiodide), hydroiodide, 2-hydroxyethanesulfonic, lactates, maleate (educated maleic acid), methansulfonate formed with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrates, oxalates, pectinate, persulfates, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylates, succinate, sulfates such as the sulfates formed with sulfuric acid), sulfonates (such as sulfonates mentioned here), tartratami, thiocyanates, toluensulfonate, such as tozilaty, undecanoate and the like.

The compounds of formula I, including an acid group can form salts with various organic and inorganic bases. Examples of basic salts include ammonium salts, alkali metal salts, such as salts of sodium, lithium and potassium, salts of alkaline earth metals such as calcium salts and magnesium salts, salts with organic bases (for example, organic amines)such as benzathine, decollage ylamine, geranamine (formed with N,N-bis(dehydroabietyl)Ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamine, tert-butylamine and salts with amino acids such as arginine, lysine and the like.

Basic nitrogen-containing groups can be stereoselectivity agents, such as halides, lower alkyl (e.g. methyl, ethyl, propyl and butylchloride, bromides and iodides), diallylsulfide (e.g., dimethyl, diethyl, dibutil and dimycolate), long chain halides (e.g. decyl, lauryl, myristyl and sterilgarda, bromides and iodides), aralkylated (for example, benzyl and phenetermine) and others.

Prodrugs and the solvate of the compounds according to the invention are also presented here. The term "prodrug", as used here, refers to a compound that when administered to a subject undergoes a chemical transformation of metabolic or chemical processes to obtain the compounds of formula I or its salts and/or MES. The solvate of the compounds of formula I are preferably hydrates.

For the extension of the compounds of formula I and their salts that may exist in their tautomeric form, all such tautomeric forms are presented here as part of the present invention.

All stereoisomers of the present compounds, such as stereoisomers that may exist due to asymmetric of plastics technology : turning & the Doo with different R and Z substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbon) and diastereoisomeric form provided in the scope of this invention. Individual stereoisomers of compounds of the invention can, for example, be substantially free of other isomers, or may be mixed, for example, as racemates or with all other, or other selected stereoisomers. Chiral centers present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.

Here, the terms "including", "such as", "for example" and the like are exemplary embodiments and do not limit the scope of the present invention.

Schema

The compounds of formula I can be obtained using several stages below.

Compounds 1, 2 and 4 are used in this process are commercially available or readily obtained by methods well known to the specialist of this prior art. For example, the compounds of formula 1, where R3=CONZ5Z6can be obtained by way of Witzeman (JOC 1991, 56(5), 1713), which includes heating the amine in the pure tert-butoxy-β-ketoamide or in a suitable solvent (xylene, toluene, etc.)

Alternative compounds of formula 1, where R4 =methyl and R3=CONZ5Z6can be obtained by the reaction of the amine with diketene in a suitable solvent, such as dichloromethane, at temperatures between -100 -22°C.

The compounds of formula 3 can be obtained by modification of condensation on Knowingly. For example, the condensation of the compounds of formula 1 and compounds of formula 2 at temperatures between 22-170°in solvents, such as toluene or dimethylformamide, in the presence of acid, such as acetic acid, and bases, such as piperidine, while removing water formed during the use of 4Å dry molecular sieve or funnel, Dean-stark, leads to the production of the compounds of formula 3 in the form of a mixture of CIS - and TRANS - stereoisomers.

The compounds of formula I can also be obtained by condensation of compounds of formula 3 with compounds of formula 4 by heating at temperatures of between 30-150°an alcohol solvent such as ethanol or propanol, or by heating between 30-150°in a solvent such as dimethylformamide, in the presence of a base such as sodium acetate.

The compounds of formula I, where R=ether can be obtained by condensation of compounds of formula 1, formula 2 and the heterocycles of formula 4 by heating at temperatures of between 30-150° In the presence of bases, such as sodium carbonate or sodium bicarbonate, in a suitable solvent, such as dimethylformamide.

The compounds of formula I, where R3=amide can be obtained by treating compounds of formula I, where R3=ether, a suitable amine and trimethylaluminum in a solvent such as toluene, at temperatures between 0-150°C.

The compounds of formula I, where R3=amide, can be also obtained by condensation of compounds of formula I, where R3=COOH, with a suitable amine of ways amidation, a well-known specialist in this prior art. For example, treatment of compounds of formula I, where R3=COOH, the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI) and dimethylaminopyridine (DMAP) in a solvent such as dichloromethane, leads to the formation of compounds of formula I, where R3=amide.

The compounds of formula I, where R5is a Deputy who is not hydrogen, can be obtained by the reaction of compounds of formula 5 with a reactive substance M-R5so that the connection of the formula Ia, where M represents Cl, Br, OR, etc. and R5is as defined above (not hydrogen).

is soedineniya formula I, where X1X2and X3form a ring structure

where R6is a Deputy who is not hydrogen, can be obtained by the reaction of compounds of formula 7 with a reactive substance M-R6so that the connection of the formula Ib, where M represents Cl, Br, OR, etc. and R6is the same as defined above.

The compounds of formula Ic, where R3is an aminecontaining a heterocycle, can be prepared by condensation of compounds of formula I, where R3is an acid or ester with an amine, which is connected through a linker with M. M can be NH2That other SH or HE. The linker unit can be selected such that the obtained unsubstituted, substituted or condensed heterocycles.

R3=ester or acid.

Additional compounds within the scope of the present invention can be obtained from the compounds obtained by the above methods, the conversion of substitute groups into other functional groups by conventional means of chemical synthesis, as shown in the following examples.

The compounds of formula I, which contain chiral centers can be obtained in deracemization as deracemization synthesis or cleavage of ways, well-known specialist in this prior art. Nerezisca connection designated in the examples as "chiral".

In the examples described below, it may be necessary to protect reactive groups such as hydroxy, amino, thio or carboxypropyl where they are needed in the final product, to eliminate their unwanted participation in the reactions. The introduction and removal of protective groups are well known specialist in this prior art, for example, see (Green, .W. in "Protective Groups in Organic Synthesis", John Wiley and Sons, 1991).

Use

Connections in the scope of the present invention To inhibitv1 subfamily overlapping voltage K+channels and, therefore, are useful for the treatment and/or prevention of various diseases, such as cardiac arrhythmia, including ventricular fibrillation, atrial fibrillation, atrial fibrillation, atrial fibrillation, complications of cardiac ischemia, and are used as agents to control the speed of the heart; angina, including relief of the symptoms of Prinzmetal, vasospastic symptoms and similar symptoms; astrogeology disorders, including stream azapagic, functional dispersion, movement disorders (including constipation and diarrhea) and irritable bowel syndrome; disorders of the vascular and internal smooth muscle, including asthma, chronic and safety Deposit box is aktivnog pulmonary disease, Mature respiratory stress syndrome, peripheral vascular disease (including alternating lameness), venous insufficiency, impotence, cerebral and coronary paralysis and disease Raynaud; inflammatory and immunological diseases, including inflammatory bowel disease, rheumatoid arthritis, transplant rejection, asthma, chronic obstructive pulmonary disease, kidney fibrosis, and atherosclerosis; cell proliferative disorders, including restenosis and cancer (including leukemia); disorders of the auditory system; disorders of the visual system, including spotted degeneration and cataracts; diabetes, including diabetic retinopathy, diabetic nephropathy and diabetic neuropathy, diseases of the muscles, including myotonia and fatigue; peripheral neuropathy; disorders of perception; headache; memory loss, including Alzheimer's disease and dementia; CNS mediated motor dysfunction, including Parkinson's disease and ataxia; epilepsy and other disorders associated with ion channel.

As inhibitors Tov1 subfamily overlapping voltage To+channels of the connection of the present invention are useful for treatment of various disorders, including rejection of the organs of transplants or tissue, graft-versus-host disease caused transplantational brain, rheumatoid arthritis, systemic lupus erythematosus, thyroiditis Hashimoto's disease, multiple sclerosis, severe myasthenia gravis, uveitis diabetes type I, juvenile-initial or recent-initial diabetes, subsequent uveitis, allergic encephalomyelitis, glomerulonephritis, infectious diseases caused by pathogenic microorganisms, inflammatory and hyperproliferative skin diseases, psoriasis, superficial dermatitis, contact dermatitis, exanthematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bubble pemphigoid, epidermolysis bullosa, urticaria, giant urticaria, vasculitis, erythema, skin eosinophil, lupus erythematosus, acne, alopecia alopecia, keratoconjuctivitis, spring conjunctivitis, uveitis associated with disease Becket, keratitis, herpes zoster keratitis, conical cornea, the epithelial dystrophy of the cornea, lakomy cornea, ocular pemphigus, ulcerative scleritis Moray, ophthalmopathy greivsa syndrome Vogt-Koyanagi-Harada, sarcoidosis, pollen allergies, reversible obstructive disease of the Airways, bronchial asthma, allergic asthma, asthma, external asthma, asthma from dust, chronic or inveterate asthma, late asthma and hyperphosphorylate respiratory tract, bronchitis, stomach ulcers, vascular risk caused by ischemic diseases and thrombosis, ish the economic intestinal diseases, pulmonary, intestinal diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns, and leukotriene B4-mediated diseases, brunobeast diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis. Good-pasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis, Julian-Barr syndrome, a disease of Meniere, polyneura, multiple narit, Monomeric, radiculopathy, hyperthroidism. Graves ' disease, pure red cell aplasia, gipoplasticheskaya anemia, gipoplasticheskaya anemia, idiopathic thrombocytopenic purple, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, americaplay, osteoporosis, sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia, dermatitis, leucoderme of vulgaris, ichthyosis of vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, arteriosclerosis, atherosclerosis, arty syndrome, polyarteritis polyarteritis, micardis, scleroderma, granuloma's granulomatosis syndrome of Segren, adipose, eosinophilic fascit, damage to the gums, periodontitis, alveolar ossification, the real bone of dentis, glomerulonephritis, male systemic alopecia or aging is th alopecia in preventing epilation or hair and/or stimulating hair growth and hair growth, muscular dystrophy; Pyoderma and Sezary's syndrome, Addison disease, ischemia-reperfusion injury of organs which occurs upon preservation, transplantation or ischemic disease, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation, ischemic acute renal failure, chronic renal failure, toxemia caused by oxidation of the lungs or drugs, lung cancer, pulmonary emphysema, cataracts, sideros, retinitis, pigmentosa, senile spotted degeneration, vitreous scarring, alkaline burning of the cornea, multiforme dermatitic erythema, linear IgA bubble dermatitis and associated dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinoma and hypobaropathy, diseases caused by release of histamine or leukotriene-C4, disease Behcet, autoimmune hepatitis, primary cirrhosis, sclerosis cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock or anoxia, B-virus hepatitis, neither/nor, In hepatitis, cirrhosis, alcoholic cirrhosis, hepatic failure, fulminant hepatic failure, late hepatic failure, "acute-on-chronic" is Echinochloa failure, augentius chemotherapeutic actions, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, and chronic bacterial infection.

Compounds of the present invention are anti-arrhythmic agents, which are useful for prevention and treatment (including partial relief or cure) arrhythmia. As inhibitors of Kv1.5 connections volume present invention is particularly useful for the selective prevention and treatment of arrhythmia ventricular arrhythmia such as atrial fibrillation and fluctuations in the Atria. Under selective prevention and treatment of ventricular arrhythmias " understand the prevention or treatment of ventricular arrhythmias, where the ratio of the prolongation of the effective refractory period of the Atria and prolongation of the effective refractory period of the ventricle is greater than 1:1. This ratio is preferably greater than 4:1, more preferably greater than 10:1 and most preferably, the prolongation of the effective refractory response period of the Atria was achieved without much noticeable prolongation of the effective refractory period of the ventricle.

Moreover, the compounds in the scope of the present invention block the IKurand, therefore, may be useful for the prevention and treatment of all IKur-link to the data conditions. "IKur-associated condition " is a disease that can be prevented, partly alleviated or cured by the introduction of IKurblocker. Tov1.5 gene, as you know, is expressed in the tissue of the stomach, gastrointestinal tissue, pulmonary artery and pancreatic beta-cells. Therefore, the introduction of IKurblocker can provide treatment of diseases such as stream azapagic, functional dyspepsia, constipation, asthma and diabetes. In addition Tov1.5 is expressed in the anterior pituitary. Therefore, the introduction of IKurblockers can stimulate growth hormone secretion. IKurinhibitors may optionally be used in disorders of cell proliferation, such as leukemia and autoimmune diseases such as rheumatoid arthritis and rejection of the graft.

The present invention therefore relates to a method of prevention or treatment of one or more of the aforementioned disorders, comprising the stage of introduction to the subject in need of them, an effective amount of at least one compound of formula I. In these methods can be applied to other therapeutic agents, such as agents, described below, with the compounds according to the invention. In the methods of the present invention, such other therapeutic agent(s) may enter the I, simultaneously with or after introducing the compound(s) of the present invention.

The present invention also relates to pharmaceutical compositions comprising at least one of the compounds of the formula I or their salts, can prevent or treat one or more of these diseases in their effective amounts, and a pharmaceutically acceptable carrier or diluent. Compositions of the present invention can include other therapeutic agents as described below, and may be composed, for example, by conventional solid or liquid carriers or diluents, as well as pharmaceutical additives of the appropriate type for the method for the desired administration (for example, excipients, binders, preservatives, stabilizers, perfumes, etc.) methods well known in the prior art for pharmaceutical compositions.

The compounds of formula I may be introduced by suitable means, for example, orally in the form of tablets, capsules, granules or powders; sublingually; buccal; parenterally, subcutaneously, intravenously, intramuscularly, or vnutrigrudne injection or infusion methods (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasal, through inhalation spray; topically, in the form of creams or ointments, or rectally in the form of suppositories; in dotirovaniyah compositions, contains non-toxic pharmaceutically acceptable carriers or diluents. These connections may, for example, be in the form suitable for immediate release or extended release.

Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising compounds according to the invention or, especially in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. When the compounds of formula I is administered to prevent or treat arrhythmia, connections can be entered when performing chemical conversion to normal sinus rhythm, or can optionally be used in combination with an electric kardiochirurgia.

Examples of compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting volume, elganowo acid or alginate sodium as a suspending agent, methylcellulose as an amplifier viscosity and sweeteners or volatile agents known from the prior art, and tablets of immediate release, which may include, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other EXT is Cai, binders, fillers, disintegrant, diluents and lubricants known from the prior art. The compounds of formula I can also be delivered through the oral cavity with sublingual and/or buccal administration. Molded tablets, compression tablets or freeze-dried tablets are examples of formulas that can be used. Exemplary compositions include the compositions of the present compound(s) with rapidly dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. In such compositions can also include additives high molecular weight, such as cellulose (avicel) or polyethylene glycol (PEG). Such compositions can also include additives for supporting the mucosal adhesion such as hydroxypropylcellulose (LDCs), hypromellose (receiver array), sodium carboxymethyl cellulose (SCMC), a copolymer of maleic anhydride (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g., Carbopol 934). Lubricants, emollients, fragrances, dyes and stabilizers can also be added for free to manufacture and use.

Exemplary compositions for nasal aerosol or inhalation include saline solutions, which may include, for example, benzyl alcohol or other preservatives, absorb the ion promoters to enhance bioavailability, and/or other solubilizing or dispersing agents, known from the prior art.

Exemplary compositions for parenteral administration include injectable solutions or suspensions, which may include, for example, suitable non-toxic parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, ringer's solution, isotonic sodium chloride or other suitable dispersing or moisturizing and suspendresume agents, including synthetic mono - or diglycerides, and fatty acids, including oleic acid.

The approximate composition of rectal injection include suppositories, which may include, for example, suitable non-irritating excipient, such as cocoa butter, synthetic esters of glycerides or polyethylene glycols, which are solid at ordinary temperatures, but the process of dissolving and/or dissolve in the rectal cavity to release the drug.

Exemplary compositions for topical introduction include local media, such as Plastibase (mineral oil, deletirovanie with polyethylene).

An effective amount of the compounds of the present invention can be determined by a specialist in this prior art, and includes exemplary dosage amounts for an adult human of from about 0.001 to 100 mg/kg of body weight of active compound per day who can introduce the camping in a single dose or in the form of individual separate doses, such as from 1 to 4 times a day. It is clear that the specific dose level and frequency of the dose for each individual entity can be different and will depend on various factors including the activity of specific applicable connection metabolities stability and length of action of that compound, the type, age, body weight, General health, sex and diet of the subject, the mode and time of administration, rate of excretion, combination with medicines and complexity of the special conditions. Preferred subjects for treatment include animals, preferably mammals, such as human and domestic animals, such as dogs, cats and similar entities for the above diseases.

Compounds of the present invention can be used alone or in combination with each other and/or other suitable therapeutically active agents useful for the treatment of the above disorders or other diseases, including other antiarrhythmic agents, such as agents of Class I (e.g., propafenone), Class II agents (for example, carvedilol and propranolol), agents of Class III (e.g., sotalol, dofetilide, amiodarone, azimilide and ibutilide), Class IV agents (e.g., diltiazem and verapamil), NT antagonists (e.g., salamero, seralin and tropisetron), dandaron; blockers calcium channel (L-type, the T-type), such as diltiazem, verapamil, nifedipine, amlodipine and mibefradil; inhibitors of cyclooxygenase (i.e. SOH-1 and/or MOR-2 inhibitors), such as aspirin, indomethacin, ibuprofen, piroxicam, naproxen, celebrex, viox and NSAIDs; anti-thrombotic agents, such as GPIIb/IIIa blockers (e.g., abciximab, eptifibatide, and tirofiban), P2Y12antagonists (e.g., clopidogrel, ticlopidine and CS-747), antagonists of thromboxane receptor (e.g., ferroban), aspirin and PDE-III inhibitors (e.g., dipyridamole) with or without aspirin; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlormethiazide, polythiazide, benzthiazide, ticrynafen etakrinova acid, chlorthalidone, furosemide, muzolimine, bumetanide, triamterene, amiloride and spironolactone; antihypertensive agents, such as alpha blockers, beta blockers, calcium channel, diuretics, renin inhibitors, ACE inhibitors (e.g. captopril, zofenopril, fosinopril, enalapril, ceronapril, cilazapril, delapril, pentopril, inapril, ramipril, lisinopril), And II antagonists (such as losartan, irbesartan, valsartan), ET antagonists (for example, sitaxentan, Arsenal and compounds described in US 5612359 and 6043265), dual ET/AII antagonist (e.g., compounds described in WO 00/01389)inhibitors it is General endopeptidase (NEP), inhibitors vasopeptidase (dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), nitrates and combinations of such anti-hypertensive agents; anti-thrombotic/anti-thrombotic agents agents, such as tissue plasminogen activator (tPA), recombinant tPA, tenecteplase (TNK), lanoteplase (nPA), an inhibitor of factor VIIa inhibitors of factor XA, thrombin inhibitors (such as hirudin and argatroban), PAI-1 inhibitors (i.e inactivator inhibitors of tissue plasminogen activator), α2-antiplasmin inhibitors, streptokinase, urokinase, PUK, complex Antilibanus plasminogen activator, streptokinase and plasminogen activators animals or salivary glands; anticoagulants, such as warfarin and heparins (including nefrackzionirovannam and low molecular weight heparins, such as enoxaparin and dalteparin); inhibitors of HMG-CoA reductase inhibitor such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin or nicastrin or nicastrin) and ZD-4522 (a.k.a. rosuvastatin or itavastatin or visitation); other cholesterol/lepidophyma agents, such as inhibitors salanova synthetase, fibrates and biliary acids (for example, questran); antiproliferative agents, such as cyclosporine a, Taxol, FK 506, and adriamycin; anticancer agents such as Taxol, Adriatic is h, epothilones, cisplatin and carboplatin; anti-diabetic agents such as biguanides (e.g. Metformin), glucosidase inhibitors (e.g. acarbose), insulin, meglitinide (for example, Repaglinide), sulfonylureas (e.g., glimepiride, gliburid and glipizide), combination biguanid/gliburida (i.e. glucovance), thiazolidinedione (for example, troglitazone, rosiglitazone and pioglitazone), PPAR-gamma agonists, ar inhibitors and DP4 inhibitors; thyroid mimetics (including thyroid antagonists of receptors) (for example, thyrotropin, politizoid, KV-130015, and dronedarone); antagonists mineralocorticoid receptor, such as spironolactone, eplerenone; activators of growth hormone; antiosteoporosis agents (e.g., alendronate and raloxifene); agents hormones substituted therapy, such as estrogen (including conjugated estrogens in premarin) and estradiol; antidepressants such as nefazodone and sertraline; anti-stress agents, such as diazepam, lorazepam, buspirone and hydroxyzine, pamoat; oral contraceptives; antiozone agents and agents gastroesophogeal diseases, such as famotidine, ranitidine and omeprazole; agents against obesity, such as orlistat; cardiac glycosides, including digitalis and ouabain; inhibitors fosfodiesterasa, including PDE III inhibitors (e.g., Cilostazol) and PDE V inhibitors (e.g., sildenafil); inhib the Torah proteincontaining; steroid anti-inflammatory agents such as prednisone and dexamethasone, and other anti-inflammatory agents, such as Enbrel.

Other of the above therapeutic agents, when used in combination with the compounds of the present invention can be used, for example, in amounts indicated in the Physicians' Desk Reference (PDR) or otherwise determined by the specialist of this technology.

Tests to determine the degree of activity of the compounds as the IKurinhibitor are well known in the art and described in the literature, such as J. Gen. Physiol. Apr; 101(4):513-43, u Br. J. Pharmacol. 1995 May; 115(2):267-74.

Tests to determine the degree of activity of the compounds as inhibitors of other members Tov1 subfamily is also well known from the prior art. For example, inhibition of Kv1.1, KV1.2 and Kv1.3 can be measured using the techniques described Grissmer S, etc., Mol Pharmacol 1994 Jun; 45(6): 1227-34. Inhibition of Kv1.4 can be measured as described in Petersen KR and Nerbonne JM, Pflugers Arch 1999 Feb;437(3):381-92. Inhibition of Kv1.6 can be measured using the techniques described Bowlby MR and Levitan BB, J Neurophysiol 1995 Jun; 73(6):2221-9, and Inhibition of Kv1.7 can be measured using the techniques described To Kalman and others, J Biol Chem 1998 Mar 6; 273(10):5851-7.

Connections in the scope of the present invention are active inv1 tested the s, such as the tests described above.

All of these documents in the present description incorporated fully herein by reference.

The following examples and obtain describe the method of obtaining and using the invention and are illustrating, but not limiting. It is clear that there may be other embodiments that fall within the scope and the scope of the invention as described in the formula, is applied next. Abbreviations used here below.

CDI = carbonyldiimidazole

DCM = dichloromethane

DMAP = dimethylaminopyridine

DMF = dimethylformamide

DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone

EDCI (or EDC) = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

M+N = monoisotopic mass plus one proton

Et = ethyl

h = hours

HPLC = high performance liquid chromatography

NOUT = hydroxybenzotriazole

LC/MS = liquid chromatography /mass spectrometry

Me = methyl

minutes = minutes

MS = mass spectrometry

NaOAc = sodium acetate

The PPA = polyphosphoric acid

Pr = propyl

PY = pyridine

PyBrOP = bromo-Tris-pyrrolidinedithiocarbamate

RT = room temperature

Rt = delay

TEA = triethylamine

TFA = triperoxonane acid

TLC = thin layer chromatography

TMSOTf = trimethylsilyltrifluoromethane

Example 1

7(2,3-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxylic acid methyl ester

Method:

reflux = is heated at the boil under reflux

Phase A. the Mixture of methylacetoacetate 1 (5 ml, 46 mmol), 2,3-dichlorobenzaldehyde 2 (8,1 g, 46 mmol), piperidine (1.1 ml, 12 mmol) and acetic acid (0.6 ml, 11 mmol) in toluene (200 ml) is heated at boiling under reflux overnight with azeotropic removal of water using the apparatus of Dean-stark. The mixture is cooled to room temperature, zakolerovat water, transferred into a separating funnel, diluted with ethyl acetate, washed with aqueous solution of NaOH (1M), aqueous solution of HCl (1M), water, brine, and then concentrated in vacuo. The residue is purified using flash chromatography (silica gel, 33% ethyl acetate/hexane)to obtain 10.8 g (85% yield) of compound 3 in the form of a mixture of diastereoisomers. LS/MS reversed-phase: YMC S5 ODS 4.6×50 mm Ballistic column, UV determination at 220λ, 4 minute gradient (10% Meon/N2O with 0.1% TFA-90% Meon/N2O with 0.1% TFA), 4 ml/min Diastereoisomer A, Rt=3.51 min (53%). Diastereoisomer, Rt=3,70 minutes (45%). MS (M+H: 273).

Stage C. a Mixture of compound 3 (5 g, 18.3 mmol), 3-aminopyrazole 4 (1.5 g, 18.3 mmol) in 1-propanol (60 ml) is heated at boiling under reflux for 6 hours. The mixture is cooled to room temperature, then concentrated, and then recrystallized from ethyl is the Etat/hexanol, giving of 1.25 g (20%) of the target compound as a yellow solid. The mother liquid is concentrated and purified using flash chromatography (silica gel, 5% methanol/dichloromethane), which gives a further of 1.62 g (26%) of the named compound. Total yield 2,87 g (46%). LS/MS reversed-phase: YMC S5 ODS 4.6×50 mm Ballistic column, UV determination at 220λ, 4 minute gradient (10% Meon/N2O with 0.1% TFA-90% Meon/H2O with 0.1% TFA), 4 ml/min, Rt=3.38 min (96% purity). MS (M+H: 338). NMR (CDCl3, 400 MHz) 7.98 (1H, app. s), 7.15 (3H, m), 6.91 (1H, s), 5.52 (1H, app. s), 3.61 (3H, s), 2.39 (3H, s).

Examples 2 and 3

Compounds according to examples 2 and 3 shown in the table below, receive according to the method similar to example 1.

ExampleStructureName(M+H)
27-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxylic acid methyl ester338
37-(4-Chlorophenyl)-4,7-dihydro-5-methylpyrazole[ 1,5-a] pyrimidine-6-carboxylic acid methyl ester303

Example 4

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxylic acid 1,1 - dimethylethylene ether

p> Method 1:

Connection 1. Compound 1 is obtained by condensation of tert-butoxyethanol and 2,4-dichlorobenzaldehyde as described in example 1, step A.

Obtaining these compounds. A mixture of compound 1 (44.4 g, 141 mmol), 3-aminopyrazole 2 (17,6 g 212 mmol) and sodium acetate (46,3 g, 564 mmol) in dimethylformamide (300 ml) was stirred at 70°overnight (17 hours). The mixture is cooled to room temperature, transferred into a separating funnel, diluted with water and ethyl acetate, washed with water (add a small amount of methanol to break the emulsion, which are formed) and brine, dried over anhydrous sodium sulfate, and then concentrated. This forms a precipitate. It is washed with ethyl acetate, ethyl ether, hexane and dried, giving 8,93 g of substance. Uterine fluid concentrate that provides the second portion of sludge in number to 9.32, LC/MS analysis shows that sediment unclean. Precipitation combine, dissolve in dichloromethane and then concentrated with a sufficient quantity of silica gel, so to get slobodetski powder. The resulting powder was loaded on a chromatographic column filled with silica gel and dichloromethane. Elution of 100% dichloromethane to 3% methanol/dichloromethane gives a 15.1 g (29% yield) of the named compound. LS/MS education the military phase: YMC S5 ODS 4,6× 50 mm Ballistic column, UV determination at 220λ, 4 minute gradient (10% Meon/N2O with 0.1% TFA to 90% MeOH/H2O with 0.1% TFA), 4 ml/min, Rt=4,63 min (97% purity). MS (M+H: 380). NMR (CD3OD, 400 MHz) of 7.4 (2H, m), 7,33 (1H, d, J=2 Hz), was 7.08 (1H, m), 6,21 (1H, s), of 5.68 (1H, d, J=2 Hz), 2,43 (3H, s), 1,37 (N,C).

Method 2:

DMF=DMF

A mixture of tert-butoxyethanol 1 (22,6 g, 143 mmol), 3,4-dichlorobenzaldehyde 2 (25,0 g, 143 mmol), 3-aminopyrazole 3 (15,4 g, 185 mmol) and sodium hydrogen carbonate (36 g, 428 mmol) in dimethylformamide (250 ml) was stirred at 70°during the night (18 hours). The mixture is cooled to room temperature, zakolerovat with ethyl acetate and water, transferred into a separating funnel, washed with water and brine, dried over sodium sulfate, filtered, and then concentrated. The residue is recrystallized from ethyl acetate/hexane, giving 16,8 g (31% yield) of the target compound as a white solid. Data for the compounds are given in method 1.

Examples 5 and 6

Compounds according to examples 5 and 6, in the table below, receive according to the method similar to example 4, method 1.

ExampleStructureName(M+N)
57-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(reformer)pyrazole[1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethylethylene ether 448
67-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethylethylene ether448

Examples 7-11

Compounds according to examples 7 to 11 are shown in the table below, receive according to the method similar to example 4, method 2. Connection example 4, method 2 can be separated into the corresponding enantiomers a (example 8) and (example 9) preparative chiral HPLC (Chiralcel OD column (50 X 500 mm), elution 7% isopropanol/hexane containing 0.1% triethylamine amine at 50 ml/min), UV determination at 254λ. Analytical HPLC (Chiralcel OD column (a 4.6 X 250 mm), elution with 10% isopropanol/hexane containing 0.1% triethylamine amine at 1 ml/min), UV determination at 254λshows enantiomer A (Rt=6,98 min, 98% EE), enantiomer (Rt=9.22 min, 98% EE).

ExampleStructureName(M+N)
77-(2,3-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethylethylene ether380
87-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole [1-5]pyrimidine-6-ka is oil acid 1,1-dimethylethylene ether, enantiomer And380
97-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole [1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethylethylene ester, enantiomer In380
107-(3,4-Dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethyl - ethyl ester394
113-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a] pyrimidine-6-carboxylic acid 1,1-dimethylethylene ether380

Example 12

7-(2,3-Dichlorophenyl)-4,7-dihydro-4,5-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethylethylene ether

Method:

DMF=DMF

Connection 1. Compound 1 are as described in example 4, method 1. Obtaining these compounds. Sodium hydride (0.186 g, 7.76 mmol) is added at 0°With solution 1 (2.27 g, 5.97 mmol) in dimethylformamide (30 ml). After 10 minutes, add methyl iodide (0.41 ml, 6.57 mmol). Then after 85 minutes the mixture zakolerovat a saturated solution of ammonium chloride, diluted with ethyl acetate, transferred into a separating funnel, washed with a saturated solution of ammonium chloride, vodoyi brine, dried over anhydrous sodium sulfate, and then concentrated with a sufficient quantity of silica gel, so to get slobodetski powder. The resulting powder was loaded on a chromatographic column filled with 100% dichloromethane. Elution 0-10% ethyl acetate/dichloromethane gives of 1.16 g (49%) of the obtained compound in the form of a slightly yellow solid. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 minute gradient of 40-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=3.46 in minutes (96% purity), MS (M+H:394). NMR (CD3C1, 400 MHz) 7,39 (1 H, d, J=2 Hz), 7,35(1 H, m), 7.23 percent(1 H, m), 7,11(1 H, m)6,91(1 H, s), to 5.58(1 H, d, J=2 Hz), of 2.38 (3H, s), 2,62 (3H, s), 1.27mm (N,C).

Example 13

7-(3,4-Dichlorophenyl)-4,7-dihydro-4,5-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethylethylene ether

A named connection receive according to the method similar to the method of example 12, to obtain the compound (M+H): 394.

Example 14

4,7-Dihydro-5-methyl-7-(1-methylethyl)pyrazole[1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethylethylene ether

Method:

A sealed tube

DMF=DMF

High pressure tube is dried with heat gun in a stream of nitrogen. The tube h is anyone pressure load in the following order Isobutyraldehyde 2 (0,262 g, 3.63 mmol), dimethylformamide (3 ml), tert-butylacetoacetate 1 (0,574 g, 3.63 mmol), 3-aminopyrazole 3 (0,362 g, 4,36 mmol) and sodium acetate (1.22 g, 14.5 mmol). The mixture is blown with nitrogen. The tube is sealed, heated to 75°C and stirred overnight. The mixture is cooled to room temperature, diluted with ethyl acetate to a volume of 20 ml, washed with lithium chloride (2,4M, 10 ml) and brine, dried over anhydrous sodium sulfate, filtered, and then concentrated, giving 1,02 yellow oil. The oil is purified using flash chromatography (silica, 45% ethyl acetate/heptane), which gives 0,42 g (41% yield) of the named compound. HPLC with reversed phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2About 0.2% of PPA, solvent B: 90% MeOH/H2O with 0.2% PPA), 4 ml/min, Rt=3,83 min (100% purity). LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=3,06 min MS (EM, M+1: 278). NMR (CDCl3, 400 MHz): 7,37(1 H, d, J=2.2 Hz), 6.35mm (1 H, s)of 5.55(1 H, d, J=1,8 Hz), from 5.29 (1 H, d, J=2.2 Hz), is 2.41 (3H,s), 1,50 (N,C), 1,28-1,19 (1 H,m), with 1.07 (3H, d, J=7,0 Hz), 0,60 (3H, d, J=7,0 Hz).

Example 15

7-Cyclopropyl-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethylethylene ether

A named connection receive according to the method similar to the method of example 14, to obtain the compound (M+H): 275.

Example 16

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxylic acid

Method:

Connection 1. Compound 1 are as described in example 4.

Obtaining these compounds. At room temperature, HCL (4M in dioxane) is added to solid substance connection 1 (1.13 g, of 2.97 mmol). The solid is dissolved and sediment is deposited. The obtained thick reaction mixture is allowed to mix overnight, and then concentrated in vacuo, giving 1,14 g (120%, including dioxane) of the target compound as a white solid. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% MeOH/H2O with 0.1% TFA), 4 ml/min, Rt=3,54 minutes (93% purity). MS (M+H: 324). NMR (CD3OD, 400 MHz) Of 7.96 (1 H, d, J=3 Hz), 7,51 (2H, m), 7,21 (1 H, m), of 6.49 (1 H,s), 6,11 (1 H, d, J=3 Hz), of 2.51(3H, s). The named compound is used in the next stage without purification.

Example 17

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6 - carboxylic acid

Method:

Connection 1. Compound 1 (compound according to example 5) are obtained by the method similar to the method of example 4.

Obtaining these compounds. Trimethylsilyltrifluoromethane (0,873 ml, 4,82 mmol) is added at room temperature to a solution of compound 1 (1.08 g, is 2.41 mmol) in dichloromethane (50 ml). After 2 hours add triethylamine (0,672 ml, 4,82 mmol) and the reaction mixture is poured into water. The organic layer is separated and dried over Na2SO4concentrate and purify using flash chromatography (50% ethyl acetate/hexane to 100% ethyl acetate), giving 0.71 g (75% yield) of the target compound as a white solid. MS (M+H: 392).

Example 18

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl] carbonyl]-4-phenylpiperazin

Method 1:

Connection 1. Connection 1 receive, as described in example 1.

Obtaining these compounds. Trimethylaluminum (1.1 ml, 2.2 mmol, 2 M in toluene) is added dropwise at room temperature in a solution of 1-phenylpiperazine 2 (0.4 ml, 2.2 mmol) in toluene (7 ml). An hour later, the compound 1 (0.50 g, 1.5 mmol) is added and the resulting mixture was stirred at 100°C for 18 hours. The mixture is cooled to room temperature, zakolerovat water, dilute atilas what tatom, transferred into a separating funnel, washed with aqueous solution of HCl (1M), water and brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The residue is purified using flash chromatography (silica gel, 50% ethyl acetate/hexane, and then 5% methanol/dichloromethane) provides 0,22 g (32%) of a solid substance, which is then purified through recrystallization from methanol/ethyl ether, giving 0.15 g (22%) of the named compound. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% MeOH/H2O with 0.1% TFA), 4 ml/min, Rt=to 3.58 min, (92% purity). MS (M+H: 468). Additional data for the compounds given in the description of method 2, step C, option 1.

Method 2:

reflux = is heated at the boil under reflux,

DMF=DMF

Stage A, option 1. A mixture of N-phenylpiperazine 1 (6,7 ml, 41 mmol) and tert-butoxyethanol 2 (6.8 ml, 45 mmol) in toluene (50 ml) is heated at boiling under reflux overnight. The mixture is cooled to room temperature, transferred into a separating funnel, diluted with ethyl ether and extracted (3x) with an aqueous solution of HCl(1M). The HCl extracts are combined and washed with ethyl ether (2), alkalinized (pH 9) water rest the rum NaOH (50% V/V) and extracted with ethyl acetate. The ethyl acetate extracts are combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and then concentrated, giving 9,76 g (97,6%) of compound 4 in the form of a thick oil with a smell. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A:10% MeOH/H2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=1,65 minutes, (100% purity). MS (M+H: 247). NMR (CDCl3, 400 MHz) 7,28 (2H, m)6,91 (3H, m), 3,80 (2H, m), of 3.78 (2H, m)and 3.59 (4H, m), 3,19 (4H, M), IS 2.30 (3H, s).

Stage A, option 2. Diketene 3 (5.50 g, 65,5 mmol) is added slowly over 15 min at 0°to a solution of 4-phenylpiperazine 1 (5.31g, to 32.7 mmol) in dichloromethane (50 ml). TLC after 4 hours shows that compound 1 is not reacted completely. Add an extra amount of diketene (5.50 g, 65,5 mmol). Then after 1.5 hours the reaction zakolerovat 1N NaOH, transferred into a separating funnel, washed with 1N NaOH and brine, dried over sodium sulfate, concentrated, with a sufficient quantity of silica gel, so to get slobodetski powder. The resulting powder was loaded on a chromatographic column filled with silica and 50% ethyl acetate/hexane. Elution with 50-100% ethyl acetate/hexane yields of 8.2 g (100%) of compound 4 as a thick yellow oil. Data for compound 4 are shown in the description of the AI stage And, option 1.

Stage b: a Mixture of compound 4 (9,76 g, 40 mmol), 2,3-dichlorobenzaldehyde 6 (7,89 g, 45 mmol), piperidine (1.0 ml, 10 mmol), acetic acid (0,59 ml, 10 mmol) in toluene (100 ml) is heated at boiling under reflux overnight with azeotropic removal of water using the apparatus of Dean-stark. The mixture is cooled to room temperature, and then concentrated in vacuo, after which is usually used in a later stage without further purification. Compound 6 can be purified by chromatography on silica gel (30-40% ethyl acetate/hexane). LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=3,83 minutes (96% purity). MS (M+H: 404). NMR (CDCl3, 400 MHz) of 7.82 (1H, s), 7,55 (1H, DD, J=1,8 Hz), of 7.48 (1 H, DD, J=1,8 Hz), 7.23 percent(3H, m), 6.89 in(1 H, app. t, 7 Hz), 6,8(2H, d, J=8 Hz), of 3.78(2H, m)to 3.34 (1 H, m), 3,23 (2H, m), 2,96 (1 H, m), 2,85 (1 H, m)of 2.50 (3H, s), 2,42 (1 H, M).

Stage C, option 1. A mixture of compound 6 (16 g, 40 mmol), 3-aminopyrazole 7 (5,1 g 62 mmol) and sodium acetate (10.1 g, 123 mmol) in dimethylformamide (100 ml) was stirred at 70°overnight (17 hours). The mixture is cooled to room temperature, transferred into a separating funnel, diluted with water and ethyl acetate, washed with water (add a small amount of methanol to destroy the emulsion, which are formed) and brine, dried over anhydrous sodium sulfate, and then concentrated. The resulting residue is purified by chromatography on silica gel. Elution with 50% ethyl acetate/hexane, then 100% ethyl acetate to give 6.2 g (33% yield from compound 1) these compounds. The named compound is separated into the corresponding enantiomers a (example 28) and (example 29) preparative chiral HPLC (Chiracel OD column (50×500 mm), elution 30% isopropanol/hexane containing 0.1% triethylamine amine at 50 ml/min), UV determination at 254λ shows enantiomer A Rt=42 minutes, shows enantiomer Rt=54 minutes Analytical HPLC (Chiracel OD column (4,6×250 mm) elution 30% isopropanol/hexane, containing 0.1% triethylamine amine at 1 ml/min), UV determination at 254λ shows enantiomer And Rt=11,7 minutes, shows enantiomer Rt=17,6 minutes Data for enantiomer A: LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% MeOH/H2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=3,54 min (91% purity). MS (M+H: 468). NMR (HCL salt 8A, CD3OD, 400 MHz) 7,94 (1 H, d, J=3 Hz), 7,56 (8H, m), 7,38 1 H, m), equal to 6.05 (1 H, d, J=3 Hz)to 4.23 (1 H,m), 3,57 (7H, m), a 2.01(3H, s).

Stage C, option 2. A mixture of compound 5 (6.0 g, 15 mmol), 3-aminopyrazole 7 (1.24 g, 15 mmol) in n-propanol (50 ml) is heated the ri boiling under reflux overnight (19 hours). The mixture is cooled to room temperature, transferred into a separating funnel, diluted with ethyl acetate. When you try to wash the solution with saturated solution of ammonium chloride, a precipitate may form. It is dissolved in water and methanol. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The resulting residue is purified by chromatography on silica gel. Elution with 70% ethyl acetate/hexane, then 100% ethyl acetate to give 2.7 g (39% yield) of the target compound as a white solid. The compound obtained can be separated into the corresponding enantiomers a and b, as described in stage C, option 1.

Examples 19-27

Connection examples 19-27 shown in the table below, get the procedure described in example 18, method 1.

ExampleStructureName(M+N)
191-[[7-(3,4-Dichlorophenyl)-4,7 - dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-phenylpiperazin468
207-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-propylpyrazole[1,5-a] pyrimidine-6-carboxamide365
21 7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-phenylpyrazol[1,5-a]pyrimidine-6-carboxamide399
224-[[7-(2,3-Dichlorophenyl)-4,7 - dihydro-5-methylpyrazole [1,5-a]pyrimidine-6-yl]carbonyl]morpholine393
237-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-N-propylpyrazole[1,5-a]pyrimidine-6-carboxamide365
247-{2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-N-phenylpyrazol[1,5-a]pyrimidine-6-carboxamide399
257-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(2-phenylethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide427
267-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(2-phenylethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide427
277-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-3-pyridinylmethyl[1,5-a]pyrimidine-6-carboxamide400

Examples 28-82

Connection examples 28-82 shown in the table below, get the procedure described in example 18, method 2.

HPLC separation according to example 47, Chiralcel OD column is (50× 500 mm), elution 30% isopropanol/hexane containing 0.1% triethylamine at 50 ml/min UV determination at 254λ gives enantiomers a (example 50) and (example 51). Chiralcel OD column (4,6×250 mm) elution 30% isopropanol/hexane containing 0.1% triethylamine at 1 ml/min), UV determination at 254λ shows enantiomer A Rt=9,8 minutes, >99% EE. Enantiomer Rt=14,2 minutes, >99% EE.

HPLC separation according to example 70, Chiralpak AD column (50×500 mm), elution with 15% ethanol/hexane containing 0.1% triethylamine at 50 ml/min UV determination at 254λ gives enantiomers a (example 72) and (example 71). Chiralpak AD column (4,6×250 mm) elution with 15% ethanol/hexane containing 0.1% triethylamine at 1 ml/min), UV determination at 254λ shows enantiomer And Rt=6.9 min, >99% EE. Enantiomer Rt=13.4 min, >99% EE.

HPLC separation according to example 80, Chiralpak AD column (50 × 500 mm), elution with 25% isopropanol/hexane containing 0.1% triethylamine at 50 ml/min UV determination at 254 λleads enantiomers a (example 81) and (example 82). Chiralpak AD column (4.6×250 mm) elution 30% isopropanol/hexane containing 0.1% triethylamine at 1 ml/min), UV determination at 254λ shows enantiomer And Rt=5,3 minutes, >99% EE. Enantiomer Rt=7.1 min, >99% EE.

ExampleStructureName(M+N)
281-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidinyl]carbonyl]-4-phenylpiperazine, enantiomer And468
291-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine, enantiomer In468
301-[[7-(4-Chlorophenyl)-4,7-dihydro-5-methylpyrazole [1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin433
311-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(phenylmethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide413
324-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]morpholine393
331-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-methylpiperazin406
347-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(phenylmethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide413
35 7-(4-Chlorophenyl)-4,7-dihydro-5-methyl-N-(phenylmethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide378
364-[[7-(4-Chlorophenyl)-4,7-dihydro-5-methylpyrazole [1,5-a]pyrimidine-6-yl]carbonyl]morpholine358
371-[[7-(3,4-Dichlorophenyl)dihydro-5-methylpyrazole[ 1,5-a]pyrimidinyl] carbonyl]piperidine391
381-[[7-(2,3-Dichlorophenyl)dihydro-5-methylpyrazole[ 1,5-a]pyrimidinyl]carbonyl]piperidine391
397-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(3-phenylpropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide441
401-[[5-(3,4-Dichlorophenyl)-5,8-dihydro-7-methylimidazo[1,2-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin468
411-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(phenylmethyl)piperidine481
421-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N,N-dobropoljana[1,5-a]pyrimidine-6-ka is boxlid 482
437-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N,N-dobropoljana[1,5-a]pyrimidine-6-carboxamide407
441-[[7-(3-Chlorophenyl)-4,7-dihydro-5-aripirazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine451
451-[[7-(3,4-Differenl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine453
461-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl[1,2,4]triazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin469
471-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine486
481-(4-Forfinal)-4-[(4,7-dihydro-5-methyl-7-phenylpyrazol[1,5-a]pyrimidine-6-yl)carbonyl]piperazine417
491-[[7-(3,4-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin484
1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer And486

511-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer In486
521-[[5-(2,3-Dichlorophenyl)-5,8-dihydro-7-methylimidazo[1,2-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin468
531-(4-Forfinal)-4-[[7-(3-forfinal)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine435
541-[[7-(3,5-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine486
551-[(7-Cyclohexyl-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl)carbonyl]-4-phenylpiperazin405
561-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-[1,2,4]triazole[1,5-a]pyrimidine-6-yl)carbon is l]-4-phenylpiperazin 469
571-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin482
587-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-6-[(4-phenyl-1-piperazinil)carbonyl]pyrazole[1,5-a]pyrimidine-3-carboxylic acid ethyl ester540

591-[[4-(2,3-Dichlorophenyl)-4,6,7,8-tetrahydro-2-methyl-1H-pyrimido[1,2-a]pyrimidine-3-yl]carbonyl]-4-phenylpiperazin484
604-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1-piperazinecarboxamide acid 1,1-dimethylethylene ether492
611-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin482
621-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-phenylpyrazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin544
63 7-(3,4-Dichlorophenyl)-4,7-dihydro-2,5-dimethyl-N-(3-phenylpropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide455
641-[[7-(2,3-Dichlorophenyl)-2-(1,1-dimethylethyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin524

651-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperidine467
667-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-[[(3-phenylpropyl)amino]carbonyl]pyrazole[1,5-a]pyrimidine-3-carboxylic acid ethyl ester513
677-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-6-[(4-phenyl-1-piperazinil)carbonyl]pyrazole[1,5-a]pyrimidine-2-carboxylic acid ethyl ester540
681-[[3-Cyano-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine511
691-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)Piras the l[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine 554
701-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine554

711-[[7-(2,3-Dichlorophenyl)-4,dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer In554
721-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer In554
737-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(3-phenylpropyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide509
747-(3,4-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-2-carboxylic acid methyl ester544
75(2S)-1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)who irreligion 489
761[[7-(2,3-Dichlorophenyl)-2-fluoro-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine504

77(2S)-1-[[2-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin455
78(2S)-1-[[2-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin455
79(2S)-1-[[7-(2,3-Dichlorophenyl)-2-fluoro-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin439
801-[[7-3,4-Dichlorophenyl-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine500
811-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer And500
82 1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer In500

Example 83

7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-N,N-dobropoljana[1,5-a]pyrimidine-6-carboxamide

Method:

Connection 1. Compound 1 are as described in example 18, method 2, step A1, from tert-butoxyethanol and dipropylamine.

Obtaining these compounds. A mixture of compound 1 (0.2 g, 1.1 mmol), 2,3-dichlorobenzaldehyde 2 (0,23 g, 1.3 mmol), piperidine (of 0.015 ml, 0.27 mmol), acetic acid (0,027 ml, 0.27 mmol) and 4Å molecular sieves (on the tip of a spatula) in dimethylformamide (1 ml) was stirred at 70°With during the night. The mixture is cooled to room temperature. Add 3-aminopyrazole 3 (of 0.13 g, 1.6 mmol) and sodium acetate (0.28 g, 3.5 mmol) and then stirred overnight at 70°C. the Mixture is cooled to room temperature, transferred into a separating funnel, diluted with water and etilatsetatom, washed with water (add a small amount of methanol to break the emulsion, which are formed) and brine, dried over anhydrous sodium sulfate, and then concentrated.

The resulting residue is purified by chromatography on silica gel (50% ethyl acetate/hexane, then 100% ethyl is the Etat), to obtain 0.10 g (23% yield from compound 1) these compounds. LS/MS reversed-phase: YMC S5 ODS 4,6×10 to 50 mm Ballistic column, UV determination at 220λ, 4 minute gradient of 40-100% solvent b/a (solvent A:10% MeOH/H2O with 0.1% TFA, solvent B: 90% MeOH/H2O with 0.1% TFA), 4 ml/min, Rt=2,94 minutes (96% purity). MS (M+H: 407).

Examples 84-169

Connection examples 84-169 shown in the table below, get the technique similar to the method of example 83.

HPLC separation according to example 84, Chiralpak AS column (50×500 mm), elution 30% isopropanol/hexane containing 0.1% triethylamine at 50 ml/min), UV determination at 254λ defines the enantiomers a (example 166) and (example 167). Chiralpak AS column (4,6×250 mm) elution of 40% isopropanol/hexane containing 0.1% triethylamine at 1 ml/min). UV determination at 254λ shows enantiomer And Rt=of 5.53 minutes, >99% EE. Enantiomer Rt=12,0 min, 98% EE.

HPLC separation according to example 165, Chiralpak AD column (50×500 mm), elution with 20% isopropanol/hexane containing 0.1% triethylamine at 50 ml/min). UV determination at 254λshows enantiomers a (example 169) and (example 168). Chiralpak AD column (4,6×250 mm), elution with 20% isopropanol/hexane containing 0.1% triethylamine at 1 ml/min). UV determination at 254λ shows enantiomer And Rt=8,3 minutes, >99% EE, enantiomer Rt=12,8 min, 98% EE.

ExampleStructureName(M+N)
841-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine486
851-[[7-(2,3-Differenl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine453
864-[6-[[4-(4-Forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-7-yl]benzoic acid methyl ester;475
871-(4-Forfinal)-4-[[7-(2-forfinal)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine435
881-[[7-(2-Chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine451
891-[[7-(2,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine486

90
1-[[4,7-Dihydro-7-(2-methoxyphenyl)-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine447
911-[[7-(2,3-Acid)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl-(4-forfinal)piperazine477
921-[[7-(2,4-Acid)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl-(4-forfinal)piperazine477
931-[[7-(2,5-Acid)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl-(4-forfinal)piperazine477
941-[[4,7-Dihydro-5-methyl-7-[2-(trifluoromethyl)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine485

951-[[4,7-Dihydro-5-methyl-7-(2-were)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine431
961-[[4,7-Dihydro-5-methyl-7-(3-phenoxyphenyl)Piras the l[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine 509
971-[[7-(3,4-Acid)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine477
981-[[7-(3,5-Acid)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl-(4-forfinal)piperazine477
991-[[4,7-Dihydro-5-methyl-7-[3-(phenylmethoxy)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine523

1001-[[4,7-Dihydro-7-(3-hydroxyphenyl)-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine433
1011-[[4,7-Dihydro-5-methyl-7-[3-(trifluoromethyl)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine485
1021-[[4,7-Dihydro-5-methyl-7-(3-were)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine431
1031-[[7-(4-Cyanophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine 442
1041-(4-Forfinal)-4-[[7-(4-forfinal)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine435

105N-[4-[6-[[4-(4-Forfinal)-1 piperazinil]carbonyl]-4,7-dihydro-5-methylpyrazole[1,5-a] pyrimidine-7-yl]phenyl]ndimethylacetamide474
1061-[[7-[4-(Dimethylamino)phenyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine460
1071-[[4,7-Dihydro-7-(4-methoxyphenyl)-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine447
1081-[[4,7-Dihydro-5-methyl-7-[4-(phenylmethoxy)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine523
1091-[[7-(4-Butoxyphenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine489

110 1-[[4,7-Dihydro-5-methyl-7-(2-thienyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine423
1111-[[4,7-Dihydro-5-methyl-7-(3-thienyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine423
1121-[[4,7-Dihydro-5-methyl-7-[4-(trifluoromethyl)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine485
1131-[[4,7-Dihydro-5-methyl-7-(4-were)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine431
1141-[[4,7-Dihydro-5-methyl-7-(2-nitrophenyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine462

1151-[[4,7-Dihydro-5-methyl-7-(4-nitrophenyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine462
1161-[[7-(2,6-Differenl)-4,7-dihydro-5-methylpyrazole[ 1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-CFT is henyl)piperazine 453
1171-[[7-(2,4-Differenl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine453
1181-[[7-(2,5-Differenl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine453
1191-[[7-(3,5-Differenl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine453

1201-[[4,7-Dihydro-5-methyl-7-[2-(phenylmethoxy)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine523
1211-[[7-(3,4-Dimetilfenil)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine445
1221-[[4,7-Dihydro-5-methyl-7-[4-(triptoreline)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine501
123 501
1241-[[7-(3-Cyanophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine442

1251-[[4,7-Dihydro-7-(3-methoxyphenyl)-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine447
1261-[[7-(4-Chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine451
1271-[[4,7-Dihydro-5-methyl-7-(4-phenoxyphenyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine509
1281-[[4,7-Dihydro-5-methyl-7-(3-nitrophenyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine462
1291-[[4,7-Dihydro-5-methyl-7-(5-methyl-2-furanyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine421
1301-[[4,7-Dihydro-7-(1H-imida the ol-2-yl)-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine 407
1311-[[4,7-Dihydro-5-methyl-7-(1H-pyrrol-2-yl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine406
1321-[[4,7-Dihydro-5-methyl-7-(2-pyridinyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine418
1331-[[7-(3-Chloro-4-methoxyphenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine481
1341-[[4,7-Dihydro-7-(4-methoxy-1,3-benzodioxol-6-yl)-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine491

1351-[[4,7-Dihydro-7-[5-(hydroxymethyl)-2-furanyl]-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine437
1361-[[4,7-Dihydro-7-(1H-indol-3-yl)-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine456
1371-[[4,dihydro-5-methyl-7-(3-pyridinyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine 418
1381-[[4,7-Dihydro-5-methyl-7-(3-chinoline)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine468
1391-[[4,7-Dihydro-5-methyl-7-(4-chinoline)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine468

1401-[[7-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine475
1411-[[4,7-Dihydro-5-methyl-7-(2,3,5-trichlorophenyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine520
1421-[[7-(2,5-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine486
1431-(4-Forfinal)-4-[[7-(3-furanyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine407
1441-[[7-(2-Benzofuranyl)-4,7-dihydro-5-metalpar the ol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine 457

1451-[[4,7-Dihydro-5-methyl-7-(3-methylbenzo[b]thiophene-2-yl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine487
1461-[[4,7-Dihydro-5-methyl-7-(2-chinoline)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine468
1471-[[4,7-Dihydro-5-methyl-7-(2-thiazolyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine424
1481-(4-Forfinal)-4-[[7-(2-furanyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine407
1491-[[4,7-Dihydro-7-[3-methoxy-4-(phenylmethoxy)phenyl]-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine553

1501-[[4,7-Dihydro-7-[4-methoxy-3-(phenylmethoxy)phenyl]-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine553
151 1-[[4,7-Dihydro-5-methyl-7-(2-naphthalenyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine467
1521-[[7-[3,4-Bis(phenylmethoxy)phenyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine629
1531-[[7-(1,3-Benzodioxol-5-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine461
1541-[[7-[3,5-Bis(trifluoromethyl)phenyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine553

1551-[[4,7-Dihydro-5-methyl-7-[5-[1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl]-2-thienyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine571
1561-[[7-(5-Ethyl-2-furanyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine435
1571-[[7-(2,3-Dihydro-5-benzofuranyl)-4,7-dihydro-5-methylpyrazole[1,5-a]PI is kidin-6-yl]carbonyl]-4-(4-forfinal)piperazine 459
1581-[[7-(3-Bromophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine496
1591-[[4,7-Dihydro-5-methyl-7-[4-(1-pyrrolidyl)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine486

1601-[[4,7-Dihydro-5-methyl-7-(3-methyl-2-thienyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine437
1611-[[4,7-Dihydro-5-methyl-7-(5-methyl-2-thienyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine437
1621-[[7-(1,3-Benzodioxol-4-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine461
1631-[[7-(5-Chloro-2-thienyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine457
1641-[[7-(3, 5dimethylphenyl)-4,7-dihydro-5-methylp resol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine 445
1651-[[7-(2,3-Dichlorophenyl)-4,7 dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine500
1661-[[7-(3,4-Dichlorophenyl)-4,7 - dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer And486
1671-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer In486
1681-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer In500

1691-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer And500

Example 170

8-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,4-dioxa-8 azaspiro[4,5]Decan

Method:

Connection 1. Connection 1 on ucaut, as described in example 16.

Obtaining these compounds. Compound 2 (0,068 g, 0.47 mmol) are added to a suspension of compound 1 (0.10 g, 0.32 mmol), EDCI (0.09 g, 0.47 mmol), DMAP (0.004 g, 0.03 mmol) in dichloromethane (1 ml). After LC/MS shows that the reaction is complete, the mixture is loaded directly on Worldwide Monitoring CLEANING CARTRIDGE (silica gel, CUSIL12M6), which is charged 100% hexane. Elution is conducted 100% hexane (40 ml), and then 50% ethyl acetate/hexane (40 ml) and 100% ethyl acetate (70 ml). Purified fractions (TLC analysis) combine that gives 0,043 g (30% yield) of the target compound as a white solid. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 minute gradient of 40-100% solvent b/a (solvent A:10% MeOH/H2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=2,12 minutes (97% purity). MS (M+H: 449). NMR (DMSO-d6,400 MHz, 100° (C) Of 9.02 (1 H, broadened singlet), 7,49 (1 H, d, J=8 Hz), 7,26 (1 H, d, J=2 Hz), 7,14 (1 H, d, J=2 Hz), to 6.95 (1 H, d, J=8 Hz), between 6.08 (1 H, s)of 5.55 (1 H, d, J=2 Hz), a-3.84 (4H, m), 3,55 (2H,m), 3,20 (2H, m)to 1.86 (3H, s)to 1.37 (2H, m)of 1.26 (2H, m).

Examples 171-377

Connection examples 171-377 shown in the table below, receive according to the method described in example 170.

HPLC separation in example 194, Chiralpak AD column (50×500 mm), elution 30% isopropanol/hexane containing 0.1% triethylamine at 50 ml/min). UV determination at 254λ p is found enantiomers a (example 250) and (example 251). Chiralpak AD column (4,6×250 mm) elution 30% isopropanol/hexane containing 0.1% triethylamine at 1 ml/min). UV determination at 254λ shows enantiomer And Rt=5,32 min, 99% EE. Enantiomer Rt =8,59 min, 98% EE.

HPLC separation according to example 221, Chiralpak AS column (50×500 mm), elution with 50% isopropanol/hexane containing 0.1% triethylamine at 42 ml/min). UV determination at 254λ provides enantiomers a (example 328) and (example 329). Chiralpak AS column (4,6×250 mm) elution 30% isopropanol/hexane containing 0.1% triethylamine amine at 1 ml/min). UV determination at 254λ shows enantiomer And Rt=5,12 minutes, >99% EE. Enantiomer Rt=8,70 minutes, >99% EE.

HPLC separation according to example 288, Chiralpak AD column (50×500 mm), elution 30% isopropanol/hexane containing 0.1% triethylamine at 50 ml/min). UV determination at 254λ shows enantiomers a (example 376) and (example 377). Chiralpak AD column (4,6×250 mm) elution 30% isopropanol/hexane containing 0.1% triethylamine at 1 ml/min). UV determination at 254λ shows enantiomer A Rt=3,8 minutes, >99% EE. Enantiomer Rt=5,6 minutes, >99% EE.

HPLC separation according to example 333, Chiralpak AD column (50×500 mm), elution with 40% isopropanol/hexane containing 0.1% triethylamine at 50 ml/min). UV determination at 254λ provides enantiomers a (example 364) and (example 365). Chiralpak AD column (4,6×250 mm) e is the funding 40% isopropanol/hexane, containing 0.1% triethylamine at 1 ml/min). UV determination at 254λ shows enantiomer And Rt=4.92 in minutes, >99% EE. Enantiomer Rt=8,0 minutes, >97% EE.

Connection example 360 is divided into two pure diastereoisomer using a chromatographic column (silica gel elute 75% ethyl acetate, hexane). The more rapidly eluted isomer, which is diastereoisomer 1, more slowly eluted isomer, which is diastereoisomer 2. When separated using TLC (20% acetone in dichloromethane), diastereoisomer 1 has Rf0.26 and diastereoisomer 2 has Rf0,17. Diastereoisomer 2 then separated in the purity of chiral form using preparative chiral HPLC (Chiralpak AD 5 cm × 50 cm column, elute 13% ethanol in hexane with 0.1% TEA at 50 ml/min with UV determination at 254 nm). The more rapidly eluted isomer, which is an enantiomer A (HPLC the retention of 8.1 minutes, 4,6×250 mm Chiralpak AD column elute with 10% ethanol, hexane with 0.1% triethylamine in 2 ml/min, with UV determination at 254 nm) and more slowly eluted isomer, which is the enantiomer (HPLC the retention of 10.6 minutes, 4,6×250 mm Chiralpak AD column elute with 10% ethanol, hexane with 0.1% triethylamine in 2 ml/min, with UV determination at 254 nm). Diastereomer 1 can then be separated in the chiral purity of form similar to the method described is for diastereoisomer 2, above, to obtain the enantiomers C and D.

td align="left"> 498
ExampleStructureName(M+N)
1711-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(2-methoxyphenyl)piperazine498
1721-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]-pyrimidine-6-yl]carbonyl]-4-[3-(trifluoromethyl)phenyl]piperazine536
1731-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-nitrophenyl)piperazine513
1741-(4-Acetylphenyl)-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine510
1751-(2-Chlorophenyl)-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine502
1761-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl] -4-(4-methoxyphenyl)piperazine
1771 -(3,4-Dichlorophenyl)-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl] piperazine537
1781 -(3,5-Dichlorophenyl)-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl] piperazine537
1791-(4-Chlorophenyl)-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine502
1801 -(3-Chlorophenyl)-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro - 5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine502

1811-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(3-methoxyphenyl)piperazine498
1821-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-were)piperazine482
1831-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-metier is angry[1,5-a]-pyrimidine-6-yl]carbonyl]-4-[4-(trifluoromethyl)phenyl]piperazine 536
1841-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(2-forfinal)piperazine486

1851-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(3,4-dimetilfenil)piperazine496
1861-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(2-pyrimidinyl)piperazine470
1877-(3,4-Dichlorophenyl)-N-[2-[(4-forfinal)amino]ethyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide460
1884-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1-piperazinecarboxamide acid fenilmetilovy ether526
1897-(3,4-Dichlorophenyl)-N-ethyl-N-[(2-forfinal)methyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide459

190 N-[(3-Chloro-4-methoxyphenyl)methyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide477
1911-(1,3-Benzodioxol-5-ylmethyl)-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine526
1924-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1-piperazinecarboxamide acid ethyl ester464
1934-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(2-pyridinyl)piperazine469
1944-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin421

1951-[Bis(4-forfinal)methyl]-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine594
1961-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carb is Neil]-4-(2-fornicator)piperazine 486
1971-Cyclohexyl-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine474
1981-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(2-methoxyethyl)piperazine450
1991-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(N-fluoren-9-yl)piperazine556

200(2R)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin421
2011-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(2,3-dimetilfenil)piperazine496
2021-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-piperidinecarboxylic acid ethyl ester463
2031-[[7-(3,4-DIH arvanil)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-N,N-diethyl-3-piperidinecarboxylic 490
2041-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-piperidinecarboxylic acid ethyl ester463

2051-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-methylpiperidin405
2061-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl] - for 3,5-dimethylpiperidin419
2071-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-hydroxypiperidine407
2084-(4-Chlorophenyl)-1-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-hydroxypiperidine517
2091-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-piperidinecarboxylic acid ethyl ester463

210 1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-methylpiperidin405
2111-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,4-tetrahydroquinolin439
2121-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]-pyrimidine-6-yl]carbonyl]-decahydroquinoline445
2132-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,4-tetrahydroisoquinoline439
2142-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-propylpiperidine433

2152-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(hydroxydiphenylmethyl) piperidine573
2167-(3,4-Dichlorophenyl)-N-[(2-forfinal)methyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide431
2172-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole478
2187-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[2-(phenylamino)ethyl]pyrazole[1,5-a]pyrimidine-6-carboxamide442
219Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-[(phenylamino)methyl]pyrrolidin482

/tr>
220N-Cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydro-N,5-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxamide419
2213-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]thiazole395
2221-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]pyrrolidin377
2231-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3,4-dihydro-1H-indol425

2241-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]azetidin363
2251-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]hexahydro-1H-azepin405
2261-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]octahydrate419
2271-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole [1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,6-tetrahydropyridine389
2287-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[2-(2-pyridinyl)ethyl]pyrazole[1,5-a]pyrimidine-6-carboxamide442

229N-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-N-(phenylmethyl)glycine ethyl ester499
230TRANS-7-(3,4-Dichlorophenyl)-4,7-dig the draw-5-methyl-N-(2-vinylcyclopropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide 439
2311-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-methylpyrrolidine391
232N-[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-methylpiperidin363
2331-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-[[(2,6-dimetilfenil)amino]methyl]pyrrolidin510

2347-(3,4-Dichlorophenyl)-N-ethyl-4,7-dihydro-5-methyl-N-(4-pyridinylmethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide442
2357-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1R)-1-phenylethyl]pyrazole[1,5-a]pyrimidine-6-carboxamide441
2367-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1S)-1-phenylethyl]pyrazole[1,5-a]pyrimidine-6-carboxamide441
2376-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]Piri is one-6-yl]carbonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]Octan 459
2387-(3,4-Dichlorophenyl)-N-(hexahydro-1H-azepin-1-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide420

2397-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]aziridine349
2407-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]octahydro-1H-atonin433
241(2R-TRANS)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,5-bis(methoxymethyl)pyrrolidin465
242(2S-TRANS)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,5-bis(methoxymethyl)pyrrolidin465
243N-[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-L-prolinamide420

244 N-[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-D-prolinamide420
245N-[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,3-dihydro-2-methyl-1H-indol439
2461-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,3-dihydro-5-nitro-1H-indol470
2471-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,3-dihydro-6-nitro-1H-indol470
2484-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]thiomorpholine409

2494-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-L-prominetly ether435
2504-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin, enantiomer And421
251 4-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin, enantiomer In421
2524-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-L-Proline 1,1-dimethylethylene ether477
2534-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-N-(2-naphthalenyl)-L-prolinamide560

2541-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,4-tetrahydro-2-methylinosine453
2551-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-6-fluoro-1,2,3,4-tetrahydro-2-methylinosine471
2561-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-L-Proline fenilmetilovy ether511
2571-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylp Rotolo [1,5-a]pyrimidine-6-yl]carbonyl]-D-Proline fenilmetilovy ether 511
2581-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-hydroxy-L-Proline fenilmetilovy ether527

2591-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)-2-methylpiperazin500
2603-Chloro-N-cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydro-N,5-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxamide453
2614-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]thiomorpholine443
2621-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,3-dihydro-1H-indol459
2631-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]hexahydro-1H-azepin439

264 1-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]octahydrate453
2651-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,6-tetrahydropyridine423
2663-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1S)-1-phenylethyl]pyrazole[1,5-a]pyrimidine-6-carboxamide475
2673-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1R)-1-phenylethyl]pyrazole[1,5-a]pyrimidine-6-carboxamide475
2681-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]2-(methoxymethyl)piperidine435

269(3R)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-pyrrolidinyl]carboxylic acid 1,1-dimethylethylene ether492
270(3S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-pyrrolidinyl]carboxylic acid 1,1 dimethylethylamine ether 492
271(3R)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-(dimethylamino)pyrrolidin420
272N-[1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-pyrrolidinyl]ndimethylacetamide434
273N-[1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-pyrrolidinyl]-N-methylacetamide448

2747-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N,N-dipentylester[1,5-a]pyrimidine-6-carboxamide463
2757-(3,4-Dichlorophenyl)-N,N-dihexyl-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide491
2761-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperidine425
2773-Chloro-7-(3-chlorophenyl)-N-cyclohexyl-4,7-dihydro-N,5-dimethylpyrazolo[1,5-a]is eremein-6-carboxamide 419
278(2S)-1-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole [1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin455

2791-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]decahydroquinoline479
2802-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,4-tetrahydroisoquinoline473
2814-[[3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]thiomorpholine409
282N-Cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydro-N,5-dimethyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide487
2837-(3,4-Dichlorophenyl)-N,N-diethyl-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide379

N,N-Dibutil-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide
284435
2857-(3,4-Dichlorophenyl)-N,N-diheptyl-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide519
2861-[[7-(3,4-(Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-azacyclopentadecan489
2879-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-dodecahydro-1H-fluoren485
288(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole-[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin489

2891-[[3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperidine391
2901-[[3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]hexahydro-1H-azepin405
291 1-[[3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-octahydrate419
2921-[[3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,6-tetrahydropyridine389
2933-Chloro-7-(3-chlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1S)-1-phenylethyl]pyrazole[1,5-a]pyrimidine-6-carboxamide441

294(2S)-1-[[3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin421
2951-[[3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-decahydroquinoline445
2962-[[3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,4-tetrahydroisoquinoline439
2971-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]hexahydro-1H-azepin439
2981-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,6-tetrahydropyridine423

299(2S)-1-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin455
3001-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,3-dihydro-1H-indol493
3011-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]hexahydro-1H-azepin473
3027-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1S)-1-phenylethyl]-2-(trifter-methyl)pyrazole[1,5-a]pyrimidine-6-carboxamide509
3037-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1R)-1-phenylethyl]-2-(trifter-methyl)pyrazole[1,5-a]pyrimidine-6-carboxamide509

td align="left">
3047-(3,4-Dichlorophenyl)-4,7-dihydro-N,N-bis(2-methoxyethyl)-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide439
3057-(3,4-Dichlorophenyl)-N,N-bis(2-ethoxyethyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide467
3067-(3,4-Dichlorophenyl)-4,7-dihydro-N-(2-methoxyethyl)-N,5-dimethylpyrazolo[1,5-a}pyrimidine-6-carboxamide395
3077-(3,4-Dichlorophenyl)-4,7-dihydro-N-(2-methoxyethyl)-5-methyl-N-propylpyrazole[1,5-a]pyrimidine-6-carboxamide423
3081-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperidine425

3092-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,4-tetrahydroisoquinoline473
3101-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]octahydrate453
3113-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1 S)-1-phenylethyl]pyrazole[1,5-a]pyrimidine-6-carboxamide475
3123-Chloro-N-cyclohexyl-7-(2,3-dichlorophenyl)-4,7-dihydro-N,5-dimethylpyrazolo[ 1,5-a] pyrimidine-6-carboxamide453
3133-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methyl-N-(phenylmethyl)pyrazole[ 1,5-a]pyrimidine-6-carboxamide447

3147-(3,4-Dichlorophenyl)-N-ethyl-4,7-dihydro-N-(2-methoxyethyl)-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide409
315N-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-N-methylglycine ethyl ester423
316N-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-N-methylglycine 1,1-dimethylethylene ether451
317N-[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]PI is kidin-6-yl]carbonyl]-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester 495
3181-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(3-pyridinyl)piperidine468

3191-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,4-tetrahydro-6-methylinosine453
3201-[[7-(3,4-Dichlorophenyl)-4,7-,dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-propylpiperidine433
3211-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-[(diethylamino)methyl]piperidine476
3227-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(2-phenoxyethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide443
3231-[(7-Cyclopropyl-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl)carbonyl]-4-(4-forfinal)piperazine381

324 1-[[4,7-Dihydro-5-methyl-7-(1-methylethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine383
325(2S)-1-[[4,7-Dihydro-5-methyl-7-(1-methylethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin318
3261-[[4,7-Dihydro-5-methyl-7-(1-methylethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,3-dihydro-1H-indol322
3271-[[4,7-Dihydro-5-methyl-7-(1-methylethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,6-tetrahydropyridine286
3283-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]thiazolidin, enantiomer And395
3293-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]thiazolidin, enantiomer In395
3307-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-(phenylmethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide427
3317-(3,4-Dichlorophenyl)-4,-dihydro-N,5-dimethyl-N-(2-phenylethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide 441
3327-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(2-phenylethyl)-N-(phenylmethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide517
333(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(phenoxymethyl)pyrrolidin483

334(2R)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(phenoxymethyl)pyrrolidin483
335(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-[(4-pertenece)methyl]pyrrolidin501
336(2R)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-[(4-pertenece)methyl]pyrrolidin501
3377-(3,4-Dichlorophenyl)-N-ethyl-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide351
338N-Butyl-7-(3,4-dichlorophenyl)-4,7-is hydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide 379
3397-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-pentylphenol[1,5-a]pyrimidine-6-carboxamide393
3407-(3,4-Dichlorophenyl)-4,7-dihydro-N-(2-methoxyethyl)-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide381
341(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole [1,5-a]pyrimidine-6-yl]carbonyl]-2-(hydroxydiphenylmethyl) pyrrolidin559
342(2R)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(hydroxydiphenylmethyl)pyrrolidin559
3431-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(3-pyridinyl)pyrrolidin454
344(2S)-1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin421
3451-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-phenylpyrrole the Ying 453
3463-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-phenylthiazole471
3473-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-thiazolidinethione acid methyl ester453
3487-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-(3-phenylpropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide455
3497-(3,4-Dichlorphenol)-N-ethyl-4,7-dihydro-5-methyl-N-(3-phenylpropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide469
3507-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(3-phenylpropyl)-N-propylpyrazole[1,5-a]pyrimidine-6-carboxamide483
351N-Butyl-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-N-(3-phenylpropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide497
3522-(4-Chlorophenyl)-3-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]thiazole the Ying 505
353N(Cyclopropylmethyl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-N-propylpyrazole[1,5-a]pyrimidine-6-carboxamide419
3541-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(2,3-dihydro-2-oxo-1H-benzimidazole-1-yl)piperidine523
3558-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1-phenyl-1,3,8-diazaspiro[4.5]Decan-4-one537
3564-(4-Chlorophenyl)-1-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,6-tetrahydropyridine499
3571-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(2-phenylethyl)pyrrolidin481
3581-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(4-methoxyphenyl)pyrrolidin483
3591-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-metier is angry[1,5-a]pyrimidine-6-yl]carbonyl]-2-(2-methoxyphenyl)pyrrolidin 483
3601-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(4-forfinal)pyrrolidin471
361(3R)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro - 5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-phenoxypyridine469
362(2S)-2-[(Cyclohexyloxy)methyl]-1-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]pyrrolidin489
3631-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(phenylmethyl)pyrrolidin467
364(2S)-1-[[7-(3,4-(Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(phenoxymethyl)pyrrolidin, diastereoisomer And483

365(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-phenoxymethyl)pyrrolidin, diastereoisomer483
366 1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(3-methoxyphenyl)pyrrolidin483
367(2S)-2-(Butoxymethyl)-1-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]pyrrolidin463
3681-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(2-thienyl)pyrrolidin459
3691-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(4-pyridinyl)pyrrolidin454

370(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-[(methoxyethoxy)methyl]pyrrolidin451
371(2S)-2-(1H-Benzimidazole-1-yl)methyl)-1-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]pyrrolidinG
3721-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(3-wagon is Il)pyrrolidin 443
3731-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(2-pyridinyl)pyrrolidin454
374(3S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-phenoxypyridine469

375(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-phenoxypyridine488
376(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin, enantiomer And489
377(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]-pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin, enantiomer In489

Example 378

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl] carbonyl]-L-Proline

Method:

Connection 1. Connection 1 (the connection is the example 252) get method described in example 170.

A named connection. Hydrochloric acid (5 ml, 4M in dioxane) is added to compound 1 (0.05 g, 0.1 mmol). The resulting mixture was stirred at room temperature. After 3 hours the mixture was concentrated in vacuo. LC/MS analysis of the residue shows that the original product remains. Additionally, add hydrochloric acid (5 ml, 4M in dioxane). The resulting mixture was stirred at room temperature for 7 hours. TLC analysis shows that compound 1 was completely reacts. The mixture was concentrated in vacuo. The residue is purified using preparative HPLC with reversed phase, which gives a named connection in the form of a mixture of diastereoisomers. LC/MS shows that the connection remains contaminated (50% purity). LS/MS reversed-phase: YMC S5 CDS 4,6×50 mm Ballistic, UV determination at 220λ 4 min. gradient 0-100% solvent b/a (solvent A:10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min Diastereoisomer A Rt=3,34, diastereoisomer Rt=3,49 min MS (M+H: 421). The product is ground to powder with dichloromethane, giving of 0.014 g (32% yield) of the named compound (85% HPLC purity). LS/MS reversed-phase: YMC S5 4,6×50 mm combifilter, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A:10% MeOH/H2O with 0.2% N3PO4solvent B: 90% MeOH/H2O with 0.2% N3PO4), 4 ml/mi is. Diastereoisomer A Rt=2,82, diastereoisomer Rt=2,97 minutes

Example 379

7-(3,4-Dichlorophenyl)-4,7-dihydro-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-5-methyl-2 (trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide

Method:

Connection 1. Compound 1 are as described in example 17.

Obtaining these compounds. To a suspension of NOT deposited on polystyrene resin (NovaBiochem, >1.2 mmol/g, 50 mg, 1.0 equivalent) in anhydrous CH2Cl2(1.0 ml) is added compound 1 (47 mg, 2.0 equivalent), EDCI (23 mg, 2.0 equivalents) and DMAP (0.7 mg, 0.1 equivalent). The suspension is vigorously shaken using a VORTEX-GENIE2 for 1 hour. The solvent is then removed and the polymer is washed successively with DMF (3×2 ml), THF (3×2 ml) and CH2Cl2(3×2 ml), vigorously shaking. The polymer was again suspended in CH2Cl2(1 ml)and then added (R)-(-)aminoindan 2 (0,006 ml, 0.8 equivalent). The mixture is shaken for 2 hours. The solvent is removed and the polymer was washed with CH2Cl2(3×1 ml), vigorously shaking. All washings are combined and the solvent is removed under reduced pressure. The residue is purified through silikagelya cartridge, elwira 100% EtOAc, giving the compound obtained in the form of a white solid. LS/MS reversed-phase: YMC S5 ODS 4.6×50 mm Ballistic Colo is ke, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/H2About 0.2% of N3PO4solvent B: 90% Meon/H2About 0.2% of N3PO4), 4 ml/min, Rt=2,96 minutes (diastereoisomeric, 96% purity). MS (M+H): 507.

Examples 380-391

Connection examples 380-391 shown in the table below, get the procedure described in example 379.

ExampleStructureName(M+H)
3807-(3,4-Dichlorophenyl)-N-(2,3-dihydro-1H-inden-2-yl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide507
381N-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-D-phenylalanine methyl ester553
3827-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide521
3837-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[3-(2-oxo-1-pyrrolidinyl)about the yl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide 516
3847-(3,4-Dichlorophenyl)-N-(2-furylmethyl)-4,7-dihydro - 5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide471
3857-(3,4-Dichlorophenyl)-N-[(3,4-dichlorophenyl)methyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide550
3867-(3,4-Dichlorophenyl)-4,7-dihydro-N-[(2R)-2-(methoxymethyl)-1-pyrrolidinyl]-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide504
3877-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[(tetrahydro-2-furanyl)methyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide475
3887-(3,4-Dichlorophenyl)-4,7-dihydro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide507
3897-(3,4-Dichlorophenyl)-N-[2-(3,4-dichlorophenyl)ethyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide 564
3907-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)-N-[[4-[(trifluoromethyl)thio]-phenyl]methyl]pyrazole-[1,5-a]pyrimidine-6-carboxamide581
3912(S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(1-pyrrolidinyl)pyrrolidin666

Example 392

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(1-naphthalenesulfonyl)piperazine

Method:

Connection 1. Compound 1 (compound from example 60) are obtained by the method similar to the method of example 18, method 2.

Stage A. Hydrochloric acid (4M in dioxane) is added to a solid connection 1 (of 0.53 g, 1.1 mmol). Immediately formed a resinous precipitate. Add dichloromethane, resinous residue remains. The solvent is decanted and the residue is ground to powder with ethyl acetate (3x), concentrate, that gives 0,63 g (130%, contains residual dioxane) of the hydrochloride of compound 2 in the form of a slightly yellow powder. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 minute gradient of 40-100% solvent b/a (dissolve the ü A: 10% Meon/N 2O with 0.1% TFA, solvent B: 90% MeOH/H2O with 0.1% TFA), 4 ml/min, Rt=0,57 minutes (92% purity). MS (M+H): 392. Compound 2 is used without further purification.

Stage C. Compound 2 (0,077 g, 0.18 mmol) and compound 3 (0,049 g, 0.22 mmol) suspended in dichloromethane (1 ml). Then add triethylamine (0.05 ml, 0.36 mmol). The result is a clear solution. TLC after 30 minutes shows that all of the original product has slashdowns. The mixture is loaded directly onto the Worldwide Monitoring of CLEANSING.

CARTRIDGE (silica, CUSIL12M6), which is charged 100% hexane. Elution is conducted 100% hexane (40 ml), and then 50% ethyl acetate/hexane (40 ml) and 100% ethyl acetate (40 ml). Purified fractions (TLC analysis) combine that gives 0,068 g (65% yield) of the target compound as a white solid. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 minute gradient of 40-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/H2O with 0.1% TFA), 4 ml/min, Rt=3.46 in minutes (90% purity). MS (M+H: 582). NMR (CDCl3, 400 MHz): 8.60 (1H, d, J=8), 8.05 (2H, m), 7.95 (1H, m), 7.62 (4H, m), 7.35 (1H, d, J=2 Hz), 7.17 (1H, d, J=8 Hz), 7.06 (1H, d, J=2 Hz), 6.81 (1H, d, J=6 Hz), 6.17 (1H, m), 5.54 (1H, d, J=2 Hz), 3.23 (8H, m), 1.86 (3H, s).

Examples 393-396

Connection examples 393-396 shown in the table below, get the procedure described in example 392.

ExampleStructureName(M+H)
3931-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole [1,5-a]pyrimidine-6-yl]carbonyl]-4-[(4-ethylphenyl)sulfonyl]piperazine560
3941-[(4-Bromo-5-chloro-2-thienyl)sulfonyl]-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine651
3951-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-[[2-(triptoreline)phenyl]sulfonyl]piperazine616
3961-[(5-Chloro-3-methylbenzo[b]thiophene-2-yl)sulfonyl]-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine637

Example 397

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-[(3-methoxyphenyl)carbonyl]piperazine

Method:

Connection 1. Compound 1 are as described in stage a of example 392. Obtaining these compounds. Connection 1 (0,062 g, 0.15 mmol) and compound 2 (0,025 ml of 0.17 mmol) suspend the comfort in dichloromethane (1 ml). Then add triethylamine (0,040,0,29 mmol). The result is a clear solution. TLC after 30 minutes shows that the original product is fully entered into the reaction. The mixture was loaded directly on Worldwide Monitoring CLEANING CARTRIDGE (CUSIL12M6), which is charged 100% hexane. Elution is conducted 100% hexane (40 ml), and then 50% ethyl acetate/hexane (100 ml) and 100% ethyl acetate (100 ml). Purified fractions (TLC analysis) combine that gives 0,022 g (29% yield) of the target compound as a white solid. LS/MS reversed-phase: YMC S5 ODS 4.6×50 mm Ballistic column, UV determination at 220λ, 4 minute gradient of 40-100% solvent b/a (solvent A: 10% MeOH/H2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=2,69 minutes (90% purity). MS (M+H: 526).

Examples 398 and 399

Connection examples 398 and 399, shown in the table below, get the procedure described in example 397.

ExampleStructureName(M+H)
3981-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(1-oxo-3-phenyl-2-propenyl)piperazine522
3991-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]is eremein-6-yl]carbonyl]-4-(4-pyridylcarbonyl)piperazine 497

Example 400

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-4,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl] carbonyl] -4-phenylpiperazin

Method:

Connection 1. Compound 1 are as described in example 18.

Obtaining these compounds. Connection 1 (0.08 g, 0,17 mmol) dissolved in dimethylformamide (1.0 ml). Add NaH ( 0.005 g, 0.22 mmol, 60% oil) and the mixture stirred for 5 minutes Then add logmean (0,012 ml, 0.18 mmol). When TLC (5% methanol/dichloromethane) analysis shows that all of the original product came in reaction, her zakolerovat water, diluted with ethyl acetate, transferred into a separating funnel, washed with water and saturated brine solution, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by chromatography on silica gel, elwira 100% dichloromethane, and then 3% methanol/dichloromethane to obtain 0.06 g (75%) of the target compound as an amber oil. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 minute gradient of 40-100% solvent b/a (solvent A: 10% MeOH/H2O with 0.1% TFA, solvent B: 90% MeOH/H2O with 0.1% TFA), 4 ml/min, Rt=2,99 minutes (96% purity). MS (M+H: 482).

Examples 401-406

Connection examples 401-406 shown in the table below, get the method is written in the example 400. HPLC separation (example 403, Chiralpak AD column (50 × 500 mm), elution with 35% isopropanol/hexane containing 0.1% triethylamine at 50 ml/min). UV determination at 254λ shows enantiomers a (example 405) and (example 404). Chiralpak AD column (4,6 × 250 mm) elution 30% isopropanol/hexane containing 0.1% triethylamine at 1 ml/min). UV determination at 254λ shows enantiomer A Rt=14.4V minutes, >99% EE. Enantiomer Rt=28,7 minutes, >99% EE.

ExampleStructureName(M+N)
4011-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-4,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]piperidine405
4021-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-4,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine500
4031-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-4,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine500

4041-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-4,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl-4-(4-forfinal)piperazine, enantiomer In500
4051-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-4,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer And500
4061-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-2,4,5-trimethylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine514

Example 407

1-[[7-(2,3-Dichlorophenyl)-4-[(4-forfinal)methyl]-4,dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine

Method:

Connection 1. Connection 1 receive according to the method similar to the method of example 18, method 2.

Obtaining these compounds. Compound 1 (0.10 g, 0.21 mmol) dissolved in dimethylformamide (1.0 ml). Add NaH (0,007 g, 0.27 mmol, 60% oil) and the mixture is stirred for 5 minutes Then add 4-tormentilla (0,028 ml, 0.23 mmol). When TLC (5% methanol/dichloromethane) analysis shows the full entry in the initial reaction product, the reaction zakolerovat water, diluted with ethyl acetate, transferred into a separating funnel, washed with water and saturated brine solution, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by chromatography on si is imagele, elwira 100% dichloromethane, and then 3% methanol/dichloromethane to obtain 0.09 g (69%) of the named compound as an amber oil. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 minute gradient of 40-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=3,20 minutes (93% purity). MS (M+H: 608).

Example 408

7-(2,3-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-2,5-dimethylpyrazolo[1,5-a]pyrimidine-4(7H)-acetic acid ethyl ester

Method:

DMF=DMF

Connection 1. Connection 1 receive according to the method similar to the method of example 18, method 2.

Obtaining these compounds. Compound 1 (0.10 g, 0.21 mmol) dissolved in dimethylformamide (1.0 ml). Add NaH (0,006 g, 0.24 mmol, 60% oil) and the mixture stirred for 5 minutes Add ethylbromoacetate (0,029 ml, 0.26 mmol). When TLC (5% methanol/dichloromethane) analysis indicates full membership in the reaction raw product, its zakolerovat water, diluted with ethyl acetate, transferred into a separating funnel, washed with water and saturated brine solution, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by chromatography on silica gel, elwira 100% dichloromethane, and then 3% methanol the/dichloromethane to obtain 0,086 g (74%) of the named compound as a yellow glassy substance. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 minute gradient of 40-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=3,22 minutes (97% purity). MS (M+H: 586).

Example 409

7-(2,3-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-N,N,2,5-tetramethylspiro [1,5-a]pyrimidine-4(7H)-ndimethylacetamide

Method:

DMF=DMF

Connection 1. Connection receive according to the method similar to the method of example 18, method 2.

Obtaining these compounds. Compound 1 (0.05 g, 0.16 mmol) dissolved in dimethylformamide (0.8 ml). Add NaH (0.005 g, 0,19 mmol, 60% oil) and the mixture stirred for 5 minutes Add 2-chloro-N,N-dimethylacetamide (0,021 ml, 0.21 mmol). When TLC (5% methanol/dichloromethane) analysis indicates full membership in the reaction raw product, its zakolerovat water, diluted with ethyl acetate, transferred into a separating funnel, washed with water and saturated brine solution, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by chromatography on silica gel, elwira 100% dichloromethane, and then 3% methanol/dichloromethane to obtain 0,058 g (62%) of the named compound as a yellow oil. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic colon is E. UV determination at 220λ, 4 minute gradient of 40-100% solvent b/a (solvent A: 10% MeOH/H2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=2,63 minutes (93% purity). MS (M+H: 585).

Example 410

1-[[7-(2,3-Dichlorophenyl)-4-[2-(dimethylamino)ethyl]-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine

Method:

DMF=DMF

Connection 1. Connection 1 receive according to the method similar to the method of example 18, method 2.

Obtaining these compounds. Connection 1 (0.11 g, 0.21 mmol) dissolved in dimethylformamide (1.0 ml). Add sodium hydride (0,054 g, 0.47 mmol, 60% oil) and the mixture stirred for 5 minutes Add the hydrochloride of 1-chloro-2-dimethylaminoethanol (0,040 g, 0.27 mmol). After 25 minutes the reaction zakolerovat water, diluted with ethyl acetate, transferred into a separating funnel, washed with water and saturated brine solution, dried over anhydrous sodium sulfate, and then concentrated. LC/MS analysis of the residue shows that it contains mainly neproreagirovavshimi the original product. The residue is again cooled in dimethylformamide (1.0 ml). Add sodium hydride (0.10 g, 4.2 mmol) and the mixture stirred for 5 minutes Add the hydrochloride of 1-chloro-2-dimethylaminoethanol (0.15 g, 1.05 mmol). When TLC (5% methanol/dichloromethane) analysis shows is a comprehensive introduction into the reaction raw product, it zakolerovat water, diluted with ethyl acetate, transferred into a separating funnel, washed with water and saturated brine solution, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by chromatography on silica gel, elwira 100% dichloromethane, and then 3% methanol/dichloromethane to obtain 0,030 g (25%) of the named compound as a glassy substance. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 minute gradient of 40-100% solvent b/a (solvent A: 10% MeOH/H2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=1,72 minutes (92% purity). MS (M+H: 571).

Example 411

1-[[4-(Cyclopropylmethyl)-7-(2,3-dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine

Method:

DMF=DMF

Connection 1. Connection 1 receive according to the method similar to the method of example 18, method 2.

Obtaining these compounds. Connection 1 (0.11 g, 0.21 mmol) dissolved in dimethylformamide (1.0 ml). Add sodium hydride (0,006 g, 0.25 mmol, 60% oil) and the mixture stirred for 5 minutes Add (methyl bromide)cyclopropane (0,0251 ml, 0.27 mmol). When TLC (5% methanol/dichloromethane) analysis indicates full membership in the reaction raw product, its zakolerovat water, R is izbavlyayut with ethyl acetate, transferred into a separating funnel, washed with water and saturated brine solution, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by chromatography on silica gel, elwira 100% dichloromethane, and then 3% methanol/dichloromethane to obtain 0.104 g g (89%) of the named compound as a glassy substance. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 minute gradient of 40-100% solvent b/a (solvent A: 10% MeOH/H2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=2,99 minutes (95% purity). MS (M+H: 554).

Example 412

7-(2,3-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-N,N,2,5-tetramethylspiro[1,5-a]pyrimidine-4(7H)-carboxamide

Method:

THF=THF

Connection 1. Connection 1 receive according to the method similar to the method of example 18, method 2.

Obtaining these compounds. Connection 1 (0,22 g, 0.44 mmol) dissolved in tetrahydrofuran (3.0 ml). Add sodium hydride (0,106 g of 4.44 mmol, 60% oil) and the mixture stirred for 5 minutes Add N,N-dimethylcarbamoyl (0,12 ml of 1.33 mmol). The mixture is stirred over night. When TLC (5% methanol/dichloromethane) analysis indicates full membership in the reaction raw product, its zakolerovat water, diluted with ethyl acetate, the m transferred into a separating funnel, washed with water and saturated brine solution, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by chromatography on silica gel, elwira 100% dichloromethane, and then 3% methanol/dichloromethane to obtain 0,22 g (87% yield) of the named compound. LC/MS indicates that the connection is dirty. The compound obtained is then purified using chromatography on silica gel, elwira 10% ethyl acetate/hexane, then 50% ethyl acetate/hexane and 100% ethyl acetate to obtain the amount of 0.118 g (47% yield) of the named compound as a white glassy substance. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 minute gradient of 40-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=2,45 minutes (95% purity). MS (M+H: 571).

Example 413

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-4-methyl-5-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine

Method:

reflux = is heated at the boil under reflux,

DMF=DMF

Stage A. Acetic anhydride (0,77 ml, 8,14 mmol) are added dropwise to a solution of 4-(4-forfinal)piperazine 1 (1,17 g of 6.49 mmol) in dichloromethane (10 ml). TLC after 30 min shows that the reactions is completed. The mixture is transferred into a separating funnel, washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated, which gives 1.28 g (89% yield) of compound 2 as a light solid. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% MeOH/H2O with 0.1% TFA), 4 ml/min, Rt=1,58 minutes (92% purity). MS (M+H: 223). NMR (CDCl3, 400 MHz): of 6.96 (2H, m), 6.89 in (2H, m), of 3.77 (2H, m), 3,62 (2H, m), of 3.07 (4H, m), and 2.14 (3H, s). Compound 2 is used without further purification in the next stage.

Stage: Hexamethyldisilazide lithium (of 6.1 ml, 6.1 mmol, 1M in tetrahydrofuran) are added dropwise to a cooled to -78°With the solution of compound 2 (1.22 g, 5.5 mmol) in tetrahydrofuran (25 ml). After 40 minutes add 2,2,2-triftoratsetata (0.9 ml, 6.6 mmol) to the resulting yellow solution. The reaction changes the color from yellow to transparent. Then after another 10 minutes remove bath cooling and the mixture is allowed to warm to room temperature. After another 30 minutes the reaction zakolerovat a saturated solution of ammonium chloride, diluted with ethyl acetate, transferred into a separating funnel, washed with a saturated solution of ammonium chloride, water and brine, dried over bezvadnym sodium sulfate, and then concentrated with a sufficient amount of silicone is El, so, to get slobodetski powder. The resulting powder was loaded on a chromatographic column filled with silica gel, 30% ethyl acetate/hexane. Elution spend 30% ethyl acetate/hexane that gives is 0.998 g (57% yield) of compound 3 as a yellow solid. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 minute gradient of 40-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=2,87 minutes (90% purity). MS (M+H: 319). NMR (CDCl3, 400 MHz): (the specified connection exists in the enol form) to 7.00 (2H, m), 6.90 to (2N, m)5,80 (1 H, s), with 3.79 (4H, m), of 3.13 (4H, m).

Stage C. Compound 3 and compound 4 condensed, as described in example 18, method 2, step B, to obtain compound 5. Compound 5 is used in the next stage without further purification.

Stage D. Compound 5 and compound 6 condensed, as described in example 18, method 2, step 1, to obtain compound 7. LC/MS reversed-phase crude 6: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100%solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=4,12 minutes (58% purity). MS (M+H: 540). Compound 7 is cleaned by chromatography on silica gel, elwira 20-50% ethyl acetate/hexane, and C is the recrystallization from ethyl acetate/hexanol, that gives 0,084 g (6% yield) of compound 7 as a white solid. LC reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% MeOH/H2O with 0.2% N3PO4solvent B: 90% Meon/N2O 5 0.2% N3PO4), 4 ml/min, Rt=4,15 minutes (92% purity).

Stage E. the Connection 7 (0.05 g, 0.14 mmol) dissolved in dimethylformamide (1.0 ml). Add NaH (0.005 g, 0,19 mmol, 60% oil) and the mixture is stirred for 305 minutes Add logmean (0,010 ml, 0.16 mmol). The mixture is stirred for 2 hours and then zakolerovat a saturated solution of ammonium chloride, diluted with ethyl acetate, transferred into a separating funnel, washed with water and saturated brine solution, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified using preparative HPLC with reversed phase: YMC S5 ODS 20×100 mm Ballistic column, UV determination at 220λ, 10 minute gradient of 30-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% MeOH/H2O with 0.1% TFA), 20 ml/min, Rt=10,6 minutes, obtaining 0.037 g (45%) of the named compound. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/H2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=3.3V min MS (M+H: 568). LC reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2O with 0.2% N3PO4solvent B: 90% Meon/N2O with 0.2% N3PO4), 4 ml/min, Rt=4,37 minutes, 89% purity.

Examples 414-421

Connection examples 414-421 shown in the table below, get the procedure described in example 413.

HPLC separation of example 416, Chiralpak AD column (50×500 mm), elution with 50% isopropanol/hexane containing 0.1% triethylamine at 50 ml/min). UV determination at 254λ shows enantiomers a (example 418) and (example 417). Chiralpak AD column (4,6×250 mm) elution of 50% isopropanol/hexane containing 0.1% triethylamine at 1 ml/min). UV determination at 254λ shows enantiomer And Rt=14.4V minutes, 89% EE. Enantiomer Rt=28,7 minutes, 87% EE.

ExampleStructureName(M+N)
4141-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine554
4151-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-2-methyl-5-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-fluoro who enyl)piperazine 554
4161-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-2,4-dimethyl-5-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine568
4171-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-2,4-dimethyl-5-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer In568
4181-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-2,4-dimethyl-5-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl] -4-(4-forfinal)piperazine, enantiomer And568
4191-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine540
4201-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-2-methyl-5-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine554

Example 421

1-[[1-Benzoyl-7-(2,3-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin

Method:

Connection 1. Connection get method analogous to example 18, method 2.

Obtaining these compounds. The benzoyl chloride (0,007 ml, 0.06 mmol) and pyridine (0,008 ml, 0.10 mmol) is added to cooled to 0°With the solution of compound 1 (0.05 g, 0,17 mmol) in dichloromethane (5 ml). After 1 hour TLC shows that the reaction is complete. The reaction zakolerovat methanol, and then concentrated. The residue is purified by chromatography on silica gel, elwira 80% ethyl acetate/hexane to get 0,024 g (81%) of the named compound as a white solid. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=4,05 minutes (86% purity). (M+N: 588). NMR (CDCl3, 400 MHz): 8.08 (1 H, s), of 8.06 (1 H, s), 7,51 (1 H, m), 7,37 (2H, t, J=8 Hz), 7,28 (1 H, m), 7,18 (2H, m), was 7.08 (1 H, m), 6,9-6,7 (3H, m), 6,45 (1H, broadened singlet), the ceiling of 5.60 (1 H, broadened singlet), 4,15-2,8 (6N, m), 2,20 (1 H, broadened singlet), a 1.88 (3H, s)of 1.45 (1H, broadened singlet).

Examples 422-431

Connection examples 422-431 shown in the table below, get the procedure described in example 421.

ExampleStructureName(M+N)
4221-[[1-Benzoyl-7-(3,4-dichlor the Nile)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin 588
4231-[[1-Acetyl-7-(3,4-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin526
4241-[[7-(3,4-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxo-1-(1-oxobutyl)-pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin554
4251-[[1-(Cyclopropanecarbonyl)-7-(3,4-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin552
4261-[[1-(Cyclopropanecarbonyl)-7-(2,3-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine570

4271-[[7-(2,3-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-1-(3-methyl-1-oxobutyl)-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine586
4281-[[7-(2,3-Dichlorophenyl)-(2,2-dimethyl-1-oxopropyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]Carboni is]-4-phenylpiperazin 568
4291-[[1-(Cyclopropanecarbonyl)-7-(3,4-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine570
4301-[[1-(Cyclobutanecarbonyl)-7-(3,4-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine584
4311-[[7-(3,4-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-1-(2-methyl-1-oxopropyl)-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine572

Example 432

1-[[7-(2,3-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-1-[(1-methylethyl)sulfonyl]-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin

Method:

Connection 1. Connection 1 receive according to the method similar to the method of example 18, method 2.

Obtaining these compounds. Isopropylacetanilide (of 0.11 ml, 0.97 mmol) and pyridine (0,12 ml of 1.46 mmol) is added to cooled to 0°With the solution of compound 1 (0,234 g, 0,487 mmol) in dichloromethane (10 ml). The obtained mixture is allowed to warm to room temperature. After 5 hours, TLC shows that the reaction of the head is of rsen. The reaction zakolerovat methanol, and then concentrated. The residue is purified by chromatography on silica gel, elwira 5% methanol/ethyl acetate to obtain 0,095 g (33%) of the named compound as a pale yellow solid. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% MeOH/H2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=3,57 minutes (92% purity). (M+N: 590).

Example 433

1-[[7-(3,4-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-1-[(1-methylethyl)sulfonyl]-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine

This connection receive according to the method similar to the method of example 432. (M+H) 608.

Example 434

7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(1-methylethyl)-2-oxo-6-[(4-phenyl-1 piperazinil)carbonyl]pyrazole[1,5-a]pyrimidine-1(2H)-carboxamide

Method:

Connection 1. Connection 1 receive according to the method similar to the method of example 18, method 2.

Obtaining these compounds. Isopropyltoluene (0,034 ml, 0.35 mmol) and pyridine (0,057 ml, 0,706 mmol) is added to cooled to 0°With the solution of compound 1 (0,170 g, 0,350 mmol) in dichloromethane (50 ml). The obtained mixture is allowed to warm to room temperature After 5 hours, TLC shows that the reaction is complete. The reaction zakolerovat methanol, and then concentrated. The residue is purified by chromatography on silica gel, elwira 75% ethyl acetate/hexane to get 0,027 g (13%) of the named compound as a white solid. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/H2O with 0.1% TFA, solvent B: 90% MeOH/H2O with 0.1% TFA), 4 ml/min, Rt=3,68 minutes (95% purity). (M+N: 569).

Examples 435 and 436

Connection examples 435 and 436, shown in the table below, get the procedure described in example 434.

ExampleStructureName(M+N)
4357-(2,3-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-2-oxo-6-[(4-phenyl-1-piperazinil)carbonyl]pyrazole[1,5-a]pyrimidine-1(2H)-carboxamide541
4367-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-2-oxo-6-[(4-phenyl-1-piperazinil)carbonyl]pyrazole[1,5-a]pyrimidine-1(2H)-carboxamide527

Example 437

7-(3,4-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-N,N,5-trimethyl-2-oxadiazol[1,5-a]pyrimidine-1(2H)-carboxamide

Method:

Connection 1. Connection 1 receive according to the method similar to the method of example 18, method 2.

Obtaining these compounds. Dimethylcarbamoyl (0.10 ml, 1.1 mmol) is added to cooled to 0°With the solution of compound 1 (0.52 g, 1.0 mmol) in pyridine (5 ml). The resulting mixture was stirred at 0°C for 30 minutes, remove bath cooling and the mixture concentrated. The residue is dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by chromatography on silica gel, elwira 5% methanol/ethyl acetate to obtain 0,038 g (6%) of the named compound as a white solid. LS/MS reversed-phase: YMC S5 TurboPack Pro 4,6×33 column, UV determination at 220λ. 2 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=1,97 minutes (92% purity). MS (M+H: 573).

Example 438

1-[[1-(3-Butenyl)-7-(3,4-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine

Method:

Connection 1. Connection 1 receive according to the method similar to the method of example 18, method 2.

Obtaining these compounds. (Methyl bromide)cycle is propane (0,246 ml, 1.82 mmol) is added to a mixture of compound 1 (0,831 g of 1.66 mmol) and potassium carbonate in dimethylformamide (10 ml). The obtained mixture is allowed to mix at room temperature for 4 hours. The reaction is diluted with ethyl acetate, transferred into a separating funnel, washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by chromatography on silica gel, elwira 5% methanol/ethyl acetate to obtain 0,030 g (3%) of the named compound. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% MeOH/H2O with 0.1% TFA, solvent B: 90% MeOH/H2O with 0.1% TFA), 4 ml/min, Rt=2,99 minutes (87% purity). (M+N: 556).

Examples 439 and 4401-[[7-(3,4-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxo-1,4-bis -(2,2,2-triptorelin)pyrazole[-1,5-a] 6-yl]carbonyl]-4-(4-forfinal)piperazine
1-[[7-(3,4-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxo-1(2,2,2-triptorelin)pyrazole[1,5-a]pyrimidine--6-yl]carbonyl]-4-(4-forfinal) piperazine
Example 439

Method:
Example 440

DMF=DMF

Connection 1. With the Association 1 get method similar to the method of example 18, method 2.

A named connection. 2,2,2-Triftoratsetilatsetonom (0,49 g, 2.1 mmol) are added to a solution of compound 1 (0,967 g of 1.93 mmol) in dimethylformamide (10 ml). Then add sodium hydride (0.12 g, 2.89 mmol). When TLC (10% methanol/ethyl acetate) indicates full membership in the reaction of the compound 1, the mixture was diluted with ethyl acetate, transferred into a separating funnel, washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by chromatography on silica gel, elwira 100% ethyl acetate, then 10% methanol/ethyl acetate, giving a mixture of the above mentioned compounds. The compounds separated using preparative HPLC with reversed phase YMC S5 ODS 20×100 mm column, 25 ml/min, 15-min gradient elution of 50%-100% solvent b/a (solvent A: 10% MeOH/H2O with 0.1% TFA, solvent B: 90% MeOH/H2O with 0.1% TFA). Connection example 439 Rt=11,05 minutes, the compound of example 440 Rt=11,88 minimum Connection example 439: LS/MS reversed-phase: YMC S5 4,6×50 Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% MeOH/H2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=2,87 minutes, 95% purity). MS (M+H: 584). Connection example 440: LS/MS reversed-phase: YMC S5 4,6×50 Ballistic column, UV determination at 220λ, 4 is in. the gradient of 0-100% solvent b/a (solvent A: 10% MeOH/H2O with 0.1% TFA, solvent B: 90% MeOH/H2O with 0.1% TFA), 4 ml/min, Rt=3,25 minutes, 85% purity). MS (M+H: 666).

Example 441

7-(3,4-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-1(2H)-carboxylic acid 1-metaliteracy ether

Method:

Connection 1. Connection 1 receive according to the method similar to the method of example 18, method 2.

Obtaining these compounds. Isopropylcarbamate (1.0 ml, 1.0 mmol, 1M in toluene) is added to cooled to 0°With the solution of compound 1 (0,46 g to 0.92 mmol) in pyridine (5 ml). The resulting mixture was stirred at 0°C for 30 minutes and remove bath with cooling. After 2 hours add methanol to abruptly cool the reaction and the mixture concentrated. The residue is purified by chromatography on silica gel, elwira 5% methanol/ethyl acetate to obtain 0,057 g (11%) of the named compound as a light pink solid. LS/MS reversed-phase: YMC S5 ODS 4,6×50 column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/H2O with 0.1% TFA), 4 ml/min, Rt=3,67 minutes, 95% purity). (M+N: 573).

Example 442

1-[(4,7-Dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl)carbonyl]-4-f is nippersink

Method:

DMF=DMF

Connection 1. Connection 1 receive according to the method similar to the method of example 18, method 2.

Stage A. Compound 2 (0.6 ml, 4.4 mmol) and acetic anhydride (0,83 ml of 8.8 mmol) are added to a solution of compound 1 (0,72 g, 2.9 mmol) in dimethylformamide (10 ml). Mixture is allowed to mix overnight, then poured into water and then extracted with dichloromethane. The extracts are combined, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by chromatography on silica gel, elwira 50% ethyl acetate/hexane to 100% ethyl acetate/hexane that gives 0,290 g (38% yield) of compound 3 as a colorless syrup. (M+N: 259).

Stage C. the Condensation of compound 3 and compound 4 carried out as described in example 18, method 2, step C, leads to the named connection. LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=1,96 minutes (87% purity). (M+N: 323).

Example 443

7-(3,4-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-2-carboxylic acid

Method:

THF=THF

Connection 1. Connection 1 receive according to the method similar to the method of example 18, method 2.

Stage A. lithium Hydroxide (0,43 g, 1.8 mmol) dissolved in water (3 ml) and added slowly at room temperature to a solution of compound 1 in tetrahydrofuran (9 ml). The resulting mixture was stirred at room temperature for 3 hours. TLC shows that compound 1 has completely reacted. The mixture zakolerovat, adding an acidic resin Dowex. The resin is filtered off. The filtrate is diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated, giving 0,41 g (86% yield) of compound 2 in the form of a slightly yellow solid. LS/MS reversed-phase: YMC S5 ODS 4,6×50 column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=3,37 minutes, 96% purity). MS (M+H: 530).

Stage C. EDCI (0.025 g, 0.13 mmol), DMAP (0.003 g, 0.02 mmol) are added to a solution of compound 2 (0,0508 g, 0.1 mmol) and diethylamine (of 0.014 ml, 0.13 mmol) in dichloromethane (3 ml). The mixture is stirred over night. TLC shows that a number of the original product remained. The solvent is removed under reduced pressure. The resulting residue is purified by chromatography on silica gel, elwira 5% methanol/ethyl acetate, giving n is called a connection in the form of a white solid. LS/MS reversed-phase: YMC S5 4,6×50 Ballistic column, UV determination at 220λ, 4 min gradient 0 to 100% solvent b/a (solvent A: 10% MeOH/H2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=3,74 min, 91% purity). MS (M+H: 585).

Examples 444-449

Connection examples 445-450 shown in the table below, get the procedure described in example 443.

ExampleStructureName(M+H)
4447-(3,4-Dichlorophenyl)-N,N-diethyl-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-2-carboxamide585
4457-(3,4-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-hydro-N-(4-methylpyrazole[1,5-a]pyrimidine-2-carboxamide;621

4461-[[7-(3,4-Dichloro-phenyl)-4,dihydro-5-methyl-2-[[(28)-2-(1-pyrrolidinyl)-1-pyrrolidinyl]carbonyl]-pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine666
4477-(3,4-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]Carbo is Il]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-2-carboxamide 529
4487-(3,4-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-5-methyl-N-(phenylmethyl)pyrazole-[1,5-a]pyrimidine-2-carboxamide619
4497-(3,4-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-5-methyl-N-(2-phenylethyl)pyrazole[1,5-a]pyrimidine-2-carboxamide633

Example 450

1-[[2-Cyano-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine

Method:

Connection 1. Compound 1 (compound according to example 447) are obtained by the method similar to the method of example 443.

Obtaining these compounds. Anhydride triperoxonane acid (0.036 ml, 0.21 mmol) is added to cooled to 0°With the solution of compound 1 (0,103 g 0,19 mmol) and triethylamine (0,054 ml to 0.39 mmol) in dichloromethane (5 ml). After 10 minutes TLC (5% methanol/ethyl acetate) shows that compound 1 remained. Add newly anhydride triperoxonane acid (0.036 ml, 0.21 mmol) and triethylamine (0,054 ml to 0.39 mmol). After 10 minutes TLC (5% methanol/ethyl acetate) shows that compound 1 was still there. The mixture is heated to room temperature and stirred for a further 30 is in. The reaction was poured into a saturated solution of sodium bicarbonate, extracted with dichloromethane. The extracts are combined, dried over anhydrous sodium sulfate, and then concentrated. The resulting residue is purified by chromatography on silica gel, elwira 2% methanol/ethyl acetate to the input 0,018 g (19% yield) of the named compound as a white solid. LS/MS reversed-phase: YMC S5 4,6×33 column, UV determination at 220λ, 2 min gradient 0-100% solvent b/a (solvent A: 10% MeOH/H2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=3,60 minutes, 81% purity). MS(M+H:511).

Example 451

3-Bromo-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethylethylene ether

Method:

Connection 1. Compound 1 are as described in example 4.

Obtaining these compounds. Phenyltrimethylammonium (0,057 g,0.14 mmol) is added to cooled to 0°With the solution of compound 1 (0.05 g, 0.13 mmol) in dichloromethane (2 ml). Mixture is allowed to warm to room temperature for 4 hours. The solvent is removed under reduced pressure. The resulting residue is purified using preparative TLC (Analtech, silica gel, 20×20 cm, 1000 microns). Elution spend 25% acetone/hexane, resulting in 0,047 g (79% yield) of the named is soedineniya in the form of a white solid. HPLC with reversed phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2O with 0.2% N3PO4solvent B: 90% Meon/H2About 0.2% of N3PO4), 4 ml/min, Rt=4,67 minutes (95% purity). LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% MeOH/H2O with 0.1% TFA), 4 ml/min, Rt=4,19 min MS (EM, M+1: 458). NMR (COCl3, 400 MHz): 7,37 (1 H, d, J=2.0 Hz), was 7.36 (1 H, d, J=8.0 Hz), 7,33 (1 H, s), 7,12 (1 H, DD, J=2.2 and an 8.4 Hz), 6,38 (1 H, s), 6,27 (1 H, s)of 2.53 (3H, s), 1,36 (N, C).

Example 452

1-[[3-Bromo-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin

Connection example 452 receive according to the method similar to the method of example 451. (M+N) 547.

Example 453

1-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazin

Method:

Connection 1. Connection 1 receive according to the method similar to the method of example 18, method 2.

Obtaining these compounds. N-Chlorosuccinimide (0,0102 g, 0,076 mmol) is added to cooled to 0°With the solution of compound 1 (0,0343 g, 0,073 mmol) in dichloromethane (4 ml). MESI allowed to warm to room temperature for 2 hours. The solvent is removed under reduced pressure. The resulting residue is purified using preparative TLC (Analtech, silica gel, 20×20 cm, 1000 microns). Elution spend 50% acetone/hexane, which provides 0,0287 g (77% yield) of the named compound as a yellow oil, which solidified after standing. HPLC with reversed phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2About 0.2% of PPA, solvent B: 90% MeOH/H2O with 0.2% PPA), 4 ml/min, Rt=4,21 minutes (91% purity). LS/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% Meon/N2O with 0.1% TFA, solvent B: 90% Meon/N2O with 0.1% TFA), 4 ml/min, Rt=3,72 min MS (EM, M+1: 501).

Examples 454-463

Connection examples 454-463 shown in the table below, get the procedure described in example 453.

Connection example 456 get from one enantiomer In example 30, the compounds according to example 457 of one enantiomer And example 29. Chiralpak AD column (4,6×250 mm) elution 30% isopropanol/hexane, soderzhaschimi 0.1% triethylamine at 1 ml/min), UV determination at 254λ. Example 456 Rt=5,9 minutes, >99% EE. Example 457 Rt=6,3 minutes, >99% EE.

Connection example 458 get from one enantiomer And example 51, connection example a simple enantiomer In example 52. Chiralcel OD column (4,6×250 mm) elution 30% isopropanol/hexane containing 0.1% triethylamine at 1 ml/min), UV determination at 254λExample 458 Rt =7,8 minutes, >99% EE. Example 459 Rt=8,4 minutes, >99% EE.

Connection example 460 get from one enantiomer As in example 169, connection example 461 and simple enantiomer In example 168. Chiralpak AD column (4,6×250 mm), elution with 20% isopropanol/hexane containing 0.1% triethylamine at 1 ml/min), UV determination at 254λExample 461 Rt=9,2 minutes, >99% EE. Example 460 Rt=9,4 minutes, >99% EE.

Connection example 462 get from one enantiomer As in example 81, connection example 463 and simple enantiomer In example 82. Chiralpak AD column (4,6×250 mm), elution with 20% isopropanol/hexane containing 0.1% triethylamine at 1 ml/min), UV determination at 254λExample 462 Rt=8,25 minutes, >99% EE. Example 463 Rt=8,28 minutes, >99% EE.

ExampleStructureName(M+N)
4541-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine520
4551-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]CT is the IMT]-4-(4-forfinal)piperazine 520
4561-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine, enantiomer In502
4571-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine, enantiomer And502

4581-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole [1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer And520
4591-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer In520
4601-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer And534
4611-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer In534
4621-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer And534

4631-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine, enantiomer In534

Example 464

3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxylic acid 1,1-dimethylethylene ether

Method:

Connection 1. Compound 1 are as described in example 4.

Obtaining these compounds. The pyridine hydrochloride (0,020 g, 0,173 mmol) is added to cooled to 0°With the solution of compound 1 (to 0.060 g, 0,158 mmol) in dichloromethane (4 ml). After 2 minutes add N-chlorosuccinimide (0,0231 g, 0,174 mmol). Mixture is allowed to warm to room temperature and stirred for 13 hours. The solvent is removed under reduced pressure. The resulting residue is purified using preparative TLC (Analtech, silica gel, 20×20 cm, 1000 microns). Elution spend 20% acetone/hexane, resulting in 0,0092 g (14% yield) of the named compound as a yellow oil. HPLC with treatment is a major phase: YMC S5 ODS 4,6× 50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% MeOH/H2O with 0.2% PPA, solvent B: 90% Meon/N2O with 0.2% PPA), 4 ml/min, Rt=br4.61 minutes (94% purity). LC/MS reversed-phase: YMC S5 ODS 4,6×50 mm Ballistic column, UV determination at 220λ, 4 min. gradient 0-100% solvent b/a (solvent A: 10% MeOH/H2O with 0.1% TFA, solvent B: 90% MeOH/H2O with 0.1% TFA), 4 ml/min, Rt=4,71 min MS (EM, M+1: 414). NMR (CDCl3, 400 MHz): 7,37 (1 H,s)of 7.36 (1 H, d, J=1.7 Hz), was 7.36 (1 H, d, J=8,4 Hz), 7,12 (1 H, DD, J=2.0 and an 8.4 Hz), 6,45 (1 H, broadened singlet), 6,24 (1 H,s), 2,52 (3H,s), 1,36 (N,C).

Example 465

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-(5-phenyl-2-oxazolyl)pyrazole[1,5-a] pyrimidine

Method:

Connection 1. Compound 1 is synthesized as described in example 16.

The connection 3. Compound 1 (200 mg, of 0.62 mmol) are suspended in 2 ml of dichloromethane. Add triethylamine (300 μl, 2.2 mmol) and 2-aminoacetophenone 2 (116 mg, of 0.68 mmol), and then bromo-Tris-pyrrolidinedithiocarbamate (PyBrOP) (312 mg, of 0.68 mmol). All solids are dissolved with the addition of PyBrOP and the reaction mass is stirred for 4 hours. The mixture is loaded on silica gel and purified via flash chromatography on silica gel, elwira 40% acetone in hexane to yield 106 mg (39%) of a pink solid.1Mr. YAM is (400 MHz, CDCl3) 44180-148-16;1HCOSY (400 MHz, CD3OD);13With NMR (100 MHz, CDCl3); HPLC >99% when 4,0 min (YMC S5 ODS 4,6×50 mm column; 10-90% methanol, water with 0.2% phosphoric acid gradient over 4 min; 4 ml/min; UV determination at 220 nm).

Obtaining these compounds. Amide 3 (100 mg, 0.22 mmol) dissolved in 2 ml of phosphorus oxychloride and heated to 112°C for 2 hours. The mixture was then zakolerovat on ice and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered and the solvent is removed to obtain 339 mg of brown oil. The oil is purified using flash chromatography on silica gel, elwira 20-40% acetone, hexane to yield 50 mg (51%) of the titled compound as a white powder, TPL 229-231°C.1H NMR (400 MHz, CD3OD); MS (ESI) m/z 423 (MH+; HPLC >99% at a 4.7 min (YMC S5 ODS 4.6×50 mm column; 10-90% methanol, water with 0.2% phosphoric acid gradient over 4 min, then maintain at 90% methanol, water; 4 ml/min; UV determination at 220 nm).

Examples 466-469

Connection examples 466-473 shown in the table below, get the procedure described in example 465.

ExampleStructureName(M+N)
4667-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-(5-phenyl-1,3,4-oxadi the evils-2-yl)pyrazole[1,5-a]pyrimidine 424
4676-(1H-Benzimidazole-2-yl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine396
4686-(2-Benzothiazolyl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine413
4697-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-(1-methyl-1H-benzimidazole-2-yl)pyrazole[1,5-a]pyrimidine410

Example 470

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-[5-(trifluoromethyl)-1-propyl-1H-benzimidazole-2-yl]pyrazole[1,5-a]pyrimidine

Method:

Compound 2. To a solution of acid 1, obtained as described in example 16 (0.15 g, 0,463 mmol), is added 2-(n-propylamino)-5-triptorelin (0,141 g, 0,648 mmol) and DMAP (5 mg, cat.), then EDCI (0.124 g, 0,0648 mmol) and the solution stirred at room temperature for 2 hours. The reaction is treated with a saturated solution of sodium bicarbonate, the organic solution is dried over magnesium sulfate and the solvent evaporated. The crude product 2 is then used without further purification.

Obtaining these compounds. Compound 2 was dissolved in phosphorus oxychloride (4 ml) and heated to 80°St for 4 hours. TLC shows that the reaction is not completed fully. Add phosphorus oxychloride (2 ml) and the mixture is heated for 2 hours, then allowed to stand at room temperature overnight. The mixture was then zakolerovat on ice, alkalinized with ammonium hydroxide and extracted with ethyl acetate. The extracts are dried with magnesium sulfate, and then concentrated. The crude product is purified using preparative chromatography with reversed phase (YMC PACK ODSA S3 20×100 mm column 50-100 methanol, water with 0.1% TFA gradient over 10 min; 20 ml/min; UV determination at 220 nm.) The desired fractions are evaporated, the residue partitioned between saturated sodium hydrogen carbonate solution and ethyl acetate, the organic solution is dried and the solvent is removed under vacuum to obtain the product (27 mg, 11,5%) as a red glassy substance. [M+H] m/z 506; HPLC to 91.1% 4.6 min (YMC S5 ODS 4,6×50 mm column; 10-90% methanol, water with 0.2% phosphoric acid, gradient over 4 min; 4 ml/min; UV determination at 220 nm).

Examples 471-482

Connection examples 471-482 shown in the table below, get the procedure described in example 470.

HPLC divided by example 480, Chiralcel OD column (50×500 mm), elution with 25% isopropanol/hexane containing 0.1% triethylamine at 50 ml/min), UV determination at 254λ determine the enantiomers a (example 481) and (example 482). Analytical Chiralcel OD column (4,6× 250 mm) elution 25% isopropanol/hexane containing 0.1% triethylamine at 1 ml/min), UV determination at 254λshows enantiomer A Rt=7,2 minutes, >99% EE. Enantiomer Rt=10,0 minutes, >99% EE.

ExampleStructureName(M+N)
4716-(5-Butyl-1,3,4-oxadiazol-2-yl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine404
4721-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-(4-methyl-1H-benzimidazole-2-yl)pyrazole[1,5-a]pyrimidine410
4731-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-6-(1-methyl-1H-benzimidazole-2-yl)pyrazole[1,5-a]pyrimidine410
4747-(3,4-Dichlorophenyl)-4,7-dihydro-6-(imidazo[1,5-a]pyridine-3-yl)-5-methylpyrazole[1,5-a]pyrimidine510
4757-(3,4-Dichlorophenyl)-6-(1-ethyl-5-nitro-1H-benzimidazole-2-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine469

476 6-[5-Chloro-1-(1-methylethyl)-1H-benzimidazole-2-yl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine472
4776-(5-Chloro-1-ethyl-1H-benzimidazole-2-yl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine458
4787-(3,4-Dichlorophenyl)-6-(5-fluoro-1-propyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine456.35
4797-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-[1-(1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazole-2-yl]pyrazole[1,5-a]pyrimidine506
4807-(3,4-Dichlorophenyl)-6-(5-fluoro-1-methyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine428

428
4817-(3,4-Dichlorophenyl)-6-(5-fluoro-1-methyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine, enantiomer And428
4827-(3,4-Dichlorophenyl)-6-(5-fluoro-1-methyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine, enantiomer In

Example 483

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-[1-(phenylmethyl)-1H-benzimidazole-2-yl]pyrazole[1,5-a]pyrimidine

Method:

Connection 1. Receive, as described in example 16.

Compound 2. Produced from compound 1 and phenylenediamine according to the method similar to the method of example 470.

The connection 3. A suspension of 2 (50 mg 0,121 mmol), NaHCO3(50 mg, 0.6 mmol) and benzylbromide (20 mg, 0,121 mmol) in DMPU (0.5 ml) was stirred at room temperature overnight. Add the equivalent of benzylbromide to complete the reaction. The suspension is partitioned between water and ethyl acetate, the organic phase is dried (MgSO4) and the solvent evaporated. The remainder chromatographic using flash chromatography on silica, elwira hexane-acetone 2:1 to receive one or both compounds 3 and 3* (the exact structure has not been determined) (24,8 mg, 41%) as a white solid. TPL 135-140; [M+H]+m/z 504; HPLC 100% with 4,4 min (YMC S5 ODS 4,6×50 mm column; 10-90% methanol, water with 0.2% phosphoric acid, gradient over 4 min; 4 ml/ min; UV determination at 220 nm).

Obtaining these compounds. Connection(s) 3/3* dissolved in phosphorus oxychloride (1.5 ml) and heated to 80°C for 5 hours. Then the heating is stopped and the mixture is left to stand at room temperature overnight. The mixture zakolerovat on ice, alkalinized with ammonium hydroxide and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, and then concentrated. The residue is purified using flash chromatography (silica gel, 50% acetone/hexane), which gives 6.6 mg of the above compound in the form of a solid reddish-brown color. TPL 225-230; [M+H]+m/z 486; HPLC 100% when 3,8 min (YMC S5 ODS 4,6×50 mm column; 10-90% methanol, water with 0.2% phosphoric acid, gradient over 4 min; 4 ml/ min; UV determination at 220 nm).

Example 484

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-(methoxymethyl)-N-(2-pyridinylmethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide

Scheme:

Synthesis of 3. A solution of recrystallized (acetone, hexane) 2,2-dimethyl-1,3-dioxane-4,6-dione (1, 25,0 g 173.5 metric mmol) in dichloromethane (350 ml) is treated with pyridine (27.4 g, 346,9 mmol). The reaction mixture is cooled to -5,1°C. To the stirred solution was added a solution of methoxyacetanilide (2, 20.7 g, 190,8 mmol) in dichloromethane (150 ml) over 50 minutes, maintaining the reaction temperature above 1.5°C. the Reaction mixture turns orange and a precipitate. The reaction mixture is allowed to warm up to 17.5°for more than 40 minutes, the Reaction mixture becomes dark Burgundy and solids dissolve.

After TLC (100% ethyl acetate) shows the reaction is complete, it zakolerovat 3,7% aqueous solution of hydrochloric acid (500 ml) and the aqueous layer extracted with dichloromethane). The organic extracts are combined and washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The solvent is removed. The resulting oil is dried under high vacuum to constant weight, giving 3 (33,11 g) with 88.3 per cent of the output.

Synthesis of 4. To a solution of 3 (33.1 g, 153 mmol) in 100 ml of toluene is added 2-methyl-2-propanol (100 ml, 1.05 mol) and the reaction heated to boiling under reflux. After 1.5 hours the reaction mass is concentrated, which gives 4 (30,2 g) with 100% yield.

Synthesis of 5. To a solution β-keeeper 4 (30,2 g, 160,6 mmol) in dimethylformamide (120 ml) is added 3,4-dichlorobenzaldehyde (28,13 g, 160,6 mmol)and then 3-aminopyrazole (14,7 g, 176,7 mmol), then sodium hydrogen carbonate (54 g, 642,6 mmol). The reaction mixture is heated to 70°C for 48 hours. Then it is cooled to 35°and transferred into a rapidly stirred water (1.5 l) at room temperature. Obtained off-white solid filtered. The filtrate solids dilute with water (1 l) and filtered again. Raw pie (165 g) dissolved in ethyl acetate (1 l), which gives a two-phase mixture. The mixture was washed with saturated aqueous sodium chloride (500 ml). The organic layer is dried over anhydrous magnesium sulfate and filtered. The solvent in Aleut. The resulting crude material purified by chromatographic column using 40% ethyl acetate in hexane as eluent, giving 5 (22,6 g, 34,3%) as a white powder.

Synthesis of 6. To a solution of dihydropyrimidine tert-butyl ester 5 (10,13 g of 24.7 mmol) in dichloromethane (150 ml) add a solution trimethylsilyltrifluoromethane (11 g, a 49.5 mmol) in dichloromethane (11 ml). After 1 hour, slowly add hexane (300 ml) and the reaction concentrated to 250 ml of the Product constituting the resin and supernatant, decanted. Add hexane (250 ml) and the mixture is allowed to mix for 1 hour. The resin hardens to form powder. The supernatant decanted again and add another 250 ml of hexane. The mixture is stirred for 10 minutes and filtered. The obtained wet cake was washed with hexane (250 ml) and getting a good off-white powder 6, which is dried with suction.

Synthesis of 7. To a suspension dihydropyrimidinase acid 6 (100 mg, 0.28 mmol) in dichloromethane (10 ml) is added EDCI (76 mg, 0.39 mmol), and then a solution of 2-pyridylmethylamine (32.4 mg, 0,39 mmol) in dichloromethane (1 ml). After 2.5 hours, the reaction mass is evaporated to dryness and the crude mixture was purified using chromatography on silica gel using 10% methanol in dichloromethane as eluent, giving the compound obtained (90 mg, 72.4%) as off-white powder. Mass spectrum m/z (M+Na)+466.

Examples 485-496

With ewusie connection get method described in example 484.

ExampleStructureNameMS (m/z)
4857-(2,3-Dichlorophenyl)-4,7-dihydro-5-(methoxymethyl)-N-(2-pyridinylmethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide444 (M+N)*
4861-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(4-forfinal)pyrrolidin501 (M+H)+
4877-(3,4-Dichlorophenyl)-4,7-dihydro-5-(methoxymethyl)-N-(3-phenylpropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide471 (M+N)+

4881-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine516 (M+H)+
4891-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperidine421 (M+N)+
490(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-Digi the ro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin 451 (M+H)+
4917-(3,4-Dichlorophenyl)-4,7-dihydro-5-(methoxymethyl)-N,N-dobropoljana[1,5-a]pyrimidine-6-carboxamide437 (M+H)+
4925-Cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydro-N-(3-phenylpropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide509 (M+N)
4931-[[5-Cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine554 (M+N)

4941-[[5-Cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]piperidine459 (M+N)
495(2S)-1-[[5-Cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin489 (M+N)
4965-Cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydro-N,N-dobropoljana[1,5-a]pyrimidine-6-carboxamide475 (M+N)

Example 497

7-(3,4-Dichlorophenyl)-4,7-dihydro-6-(imidazo[1,5-a]pyridine-3-yl)-5(methoxymethyl)pyrazole[1,5-a]pyrimidine

Scheme

The synthesis of 1. The synthesis of 1 is the same as described in example 484.

Synthesis of 2. The named compound is synthesized according to the method similar to the method described in example 465. The product was then purified using preparative TLC in 10% methanol in dichloromethane. Mass spectrum m/z (M+H)+426.

Example 498

7-(2,3-Dichlorophenyl)-4,7-dihydro-6-(imidazo[1,5-a]pyridine-3-yl)-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine

The named compound synthesized by the method similar to the method of example 497. Mass spectrum m/z (M+H)+426.

Example 499

7-(3,4-Dichlorophenyl)-6-(5-fluoro-1-methyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine

On the basis of compound 6 of example 484 synthesize the compound obtained by the method similar to the method of example 470. MS m/z (M+H)+458. The named compound can be isolated in pure chiral form using preparative chiral HPLC (Chiralpak AD 5 cm ×50 cm column elute with 25% isopropanol in hexane with 0.1% TEA at 50 ml/min, UV determination at 254 nm). The more rapidly eluted isomer (example 503), which is an enantiomer A (HPLC retention time of approximately 6.8 minutes, 4,6×250 mm Chiralpak AD column elute 25% isopropanol, hexane with 0.1% triethylamine is ri 1 ml/min, UV determination at 220 nm) and slowly eluted isomer (example 504), which is an enantiomer (HPLC retention time of 12,0 minutes, 4,6×250 mm Chiralpak AD column elute 25% isopropanol, hexane with 0.1% triethylamine at 1 ml/min, UV determination at 254 nm).

Examples 500-504

Subsequent connection examples synthesized by the method similar to the method of example 499.

ExampleStructureNameMass spectrum
5007-(2,3-Dichlorophenyl)-6-(4-fluoro-1-methyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine458 (M+H)+
5017-(3,4-Dichlorophenyl)-6-(4-fluoro-1-methyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine458 (M+H)+
5027-(2,3-Dichlorophenyl)-6-(5-fluoro-1-methyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine458 (M+H)+
5037-(3,4-Dichlorophenyl)-6-(5-fluoro-1-methyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-(is ethoxymethyl)pyrazole[1,5-a]pyrimidine, enantiomer And458 (M+N)
5047-(3,4-Dichlorophenyl)-6-(5-fluoro-1-methyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine, enantiomer In458 (M+N)

Example 505

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-phenyl-N-(3-phenylpropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide

Scheme

THF=THF

The synthesis of 1. Solution betinol acid (3,05 g, 25 mmol) in tetrahydrofuran (25 ml) is treated with CDI (of 4.05 g, 25 mmol) at ambient temperature. In a separate flask generate sitedisability at -78°during the processing of a solution of tetrahydrofuran (40 ml), Diisopropylamine a (10.6 ml, 76,0 mmol) of 2.5 M n-butyllithium in hexane (30 ml, 75,0 mmol). Added dropwise tert-butyl acetate and the reaction stirred at -78°C for 1 hour. Enolate transferred at -78°to stir the solution imidazolidinone obtained previously. The resulting solution was cooled to -78°C. After adding enolate forming a thick slurry, which is destroyed when shaken. The reaction mixture is allowed to mix for 1 hour at -78°C. Add 1N aqueous solution of hydrochloric acid until the pH becomes equal to 4. The reaction mixture is allowed to warm up to the tempo of the atmospheric temperature environment under stirring. The reaction mixture was extracted with ditylum ether. The combined organic layers washed with aqueous solution IN hydrochloric acid, an aqueous solution of 10% sodium bicarbonate, saturated aqueous sodium chloride, dried over magnesium sulfate and filtered. The solvent is removed, giving 1 (5.0 g, 91%) as oil.

Synthesis of 2. Compound 2 synthesized by the method similar to the method of obtaining the compound 5 in example 484.

Synthesis of 3. Compound 3 synthesized by the method similar to the method of obtaining the compound 6 in example 484.

Synthesis of 4. The specified connection is synthesized by the method similar to the method of obtaining the compound 7 in example 484. Mass spectrum m/z (M+H)+503.

Examples 506-509

Subsequent connection examples 506-509 synthesized by the method similar to the method of example 505.

ExampleStructureNameMass spectrum
5061-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-phenylpyrazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine448 (M+H)+
5071-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-phenylpyrazol[1,5-a]pyrimidine-6-yl]carbonyl] piperidine459 (M+H)+
508(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-phenylpyrazol [1,5-a]pyrimidine-6-yl]carbonyl]-2-methoxymethyl)pyrrolidin483 (M+H)+
5097-(3,4-Dichlorophenyl)-4,7-dihydro-5-phenyl-N,N-dobropoljana[1,5-a]pyrimidine-6-carboxamide475 (M+N)

Example 510

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-phenylpyrazole

Scheme:

Getting 3. To a solution of dihydropyrimidinase acid 1 (0,336 g, 1 mmol) in dichloromethane (10 ml) was added 1-phenylpyrazoles 2 (0,215 g, 1.5 mmol, based on the method of obtaining described in Tempahedron, 1973,29,4045), and then 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0,278 g, 1.5 mmol) and the mixture is stirred at room temperature for 2 hours. The solvent is evaporated and the residue purified via chromatography on silica gel, elute with ethyl acetate, which gives compound 3 (0,184 g, 39%) as a white powder. (M+N)+=455.

Example 511

6-(1-Chloro-6,7-dihydro-5H-pyrrolo[1,2-C]imidazol-3-yl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine

Scheme:

Receiving the s Century At 20°WITH EDCI (100 mg, 0.52 mmol) is added to a stirred suspension of carboxylic acid (120 mg, of 0.37 mmol) in CH2Cl2. After 5 minutes add Proline amide (60 mg, 0.52 mmol) and the reaction mixture stirred at ambient temperature for 3 hours. The obtained yellow suspension is concentrated under reduced pressure, dissolved in 2 ml acetone and applied directly to preparative silicagel TLC plate (20×20 cm, 1 mm thickness, 254 nm UV light), elwira 10% Meon in CH2Cl2. The product is isolated in the form of diastereoisomers in the ratio of 1:1 (79 mg, 50% yield, as a pale yellow glassy substance.) HPLC: Rt 2,61 and 2,80 min (YMC S5 ODS 4,6×50 mm Ballistic column) 10-90% Meon/water with 0.2% PPA linear gradient over 4 min, 4 ml/min, UV determined at 220 nm. LCMS: Rt 2,63 and of 2.81 min (YMC S5 ODS 4,6×50 mm Ballistic column) 10-90% Meon/water with 0.1% TFA linear gradient over 4 min, 4 ml/min, UV determined at 220 nm. Mass spectrum m/z (M+H)+420.

Receiving C. phosphorus Oxychloride (4 ml) are added to diastereoisomerism In (190 mg, 0.46 mmol). The suspension is heated to 100°C for 12 hours after which the precipitate is dissolved to form a solution orange. The cooled reaction mixture was poured cautiously into saturated solution of K2CO3(about 20 ml) and extracted with EtOAc (3×30 ml). The combined organic portion with the shat over Na 2SO4, decanted, and then concentrate with the formation of an orange oil, which was purified directly by preparative HPLC: Rt 28,40 min (YMC S5 ODS 30×250 mm column with reversed phase 18) 30-90% Meon/water with 0.1% TFA linear gradient over 30 min, 25 ml/min, UV determined at 220 nm. The product (96 mg, 51% yield) are obtained in the form of a free base after removal of the Meon from HPLC fractions, addition of 1.0 M NaOH and extraction in CH2Cl2(3×30 ml). The enantiomers are separated chiral preparative HPLC: Rt 42,4 and 59,0 min (Chiral Pak OD 50×500 mm column with normal phase) 15% EtOH/hexane Isocratic, 50 ml/min, UV determined at 220 nm. Both enantiomers isolated as a pale yellow powder (34 mg of enantiomer a and 38 mg of enantiomer B). Chiral HPLC enantiomer In: (Chiral Pak OD 4,6×250 mm column with normal phase) 15% EtOH/hexane Isocratic, 2 ml/min, UV determined at 220 nm 100%. Chiral HPLC enantiomer And RT4,94 min (Chiral Pak OD 4,6×250 mm column with normal phase) 15% EtOH/hexane Isocratic, 2 ml/min, UV determined at 220 nm 100%.

Example 512

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-(1-methyl-1H-thieno[3,4-d]imidazol-2-yl)pyrazole[1,5-a]pyrimidine

Scheme:

reflux=heated at boiling with obratnyi fridge,

DMF=DMF

Getting connection 1, as described in example 16.

obtaining a connection 2. To a suspension of acid (152,9 mg, 0.47 mmol) in 5 ml of anhydrous dichloromethane add trichloroacetonitrile (57,0 μl, 0.67 mmol) and triphenylphosphine (186,2 mg, 0.71 mmol). The mixture becomes transparent and she is allowed to mix at room temperature for 1 hour. The reaction mixture is transferred into a solution of 3,4-diaminotoluene hydrochloride (88,5 mg, 0.47 mmol) and triethylamine (198,0 µl of 1.42 mmol) in 5 ml of dichloromethane. The reaction analyzed using TLC or LC/MS. After the interaction, the reaction mixture was loaded directly onto silica gel and elute with 5% methanol/dichloromethane to yield the desired amide as a white solid (132,3 mg, 67%).

Obtain compound 3. The suspension obtained amide (107 mg, 0.25 mmol) and pentachloride phosphorus (53,1 mg, 0.25 mmol) in chloroform (20 ml) is heated at boiling under reflux in an atmosphere of dry argon for 5 hours, after which the mixture is allowed to cool to room temperature, then stirred overnight. The solvent is removed under reduced pressure and the residue is again cooled in ethyl acetate and wash with saturated aqueous solution of sodium bicarbonate. The organic layer is separated, dried over sodium sulfate, and then concentrated, giving crude tanakadate, which is cleaned by flash chromatography using 100% ethyl acetate, giving a brown solid is e substance (73 mg, 71%).

The connection 4. To a solution of tanakadate (of 22.4 mg, 0.06 mmol) in 2 ml of anhydrous DMF is added by jodean (4,5 μl, 0.07 mmol) and potassium carbonate (15,4 mg, 0.11 mmol). Mixture is allowed to mix at room temperature over night. The reaction zakolerovat using methanol. The mixture is diluted with ethyl acetate, washed with 10% LiCl (3×10 ml) and brine (10 ml). The organic layer is separated, dried over sodium sulfate, and then concentrated, giving a residue which was further purified using flash chromatography (5% Meon/ethyl acetate) and (6% Meon/chloroform), giving a named connection in the form of a white solid (4.5 mg, 20%).

Example 513

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-(4-methyl-4H-imidazo[3,4-d] [1,2,5]thiadiazole-5-yl)pyrazole[1,5-a]pyrimidine

Scheme:

reflux=is heated at the boil under reflux,

DMF=DMF

The connection 5. To a suspension of acid (120 mg, of 0.37 mmol) in 5 ml of anhydrous dichloromethane add trichloroacetonitrile (55,9 μl, of 0.56 mmol) and triphenylphosphine (146,2 mg of 0.56 mmol). The mixture becomes transparent and she is allowed to mix at room temperature for 1 hour. The reaction mixture is transferred into a solution of 3,4-diamino-1,2,5-thiadiazole (51,7 mg, 0.45 mmol, obtained according to J. Heterocycl. Chem. 1976, 13, 13) and triethylamine (103,6 MK is, to 0.74 mmol) in 5 ml of dichloromethane. The reaction analyzed using TLC or LC/MS. After the interaction, the reaction mixture was loaded directly onto silica gel and elute with 50% ethyl acetate/hexane to yield the desired amide as a yellow solid (of 56.4 mg, 30%).

The connection 6. The suspension obtained amide (80 mg, 0,19 mmol) and pentachloride phosphorus (79 mg, 0.38 mmol) in chloroform (10 ml) was stirred at room temperature in an atmosphere of dry argon for one hour and then heated to boiling in a flask under reflux for 2 hours. The mixture is allowed to cool to room temperature and the solvent is removed under reduced pressure. The residue is again dissolved in ethyl acetate and wash with saturated aqueous solution of sodium bicarbonate. The organic layer is separated, dried over sodium sulfate, and then concentrated, giving crude thiadiazolidine, which is cleaned by flash chromatography using 80% ethyl acetate/hexane, giving a yellow solid (29 mg, 38%).

Obtain compound 7. To a solution of thiadiazolidine (29 mg, 0.07 mmol) in 2 ml of anhydrous DMF is added by jodean (4,9 μl, 0.08 mmol) and potassium carbonate (19.9 mg, 0.14 mmol). Mixture is allowed to mix at room temperature in an atmosphere of dry argon for 3 hours. The reaction zakolerovat using methanol,diluted with ethyl acetate, washed with 10% LiCl (3×10 ml) and brine (10 ml). The organic layer is separated, dried over sodium sulfate, and then concentrated, giving a residue that is purified using HPLC, giving the named compound as a white solid (1.6 mg, 5%).

Example 514

7-(3,4-Dichlorophenyl)-6-(1,6-dihydro-1,3,6-trimethylimidazo[4,5-C]pyrazole-5-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine

Scheme:

The connection 8. To a suspension of acid (150 mg, 0.46 mmol) in 5 ml of anhydrous dichloromethane add trichloroacetonitrile (69,8 μl, 0.70 mmol) and triphenylphosphine (182,7 mg, 0.70 mmol). The mixture becomes transparent and she is allowed to mix at room temperature for 1 hour. The reaction mixture is transferred into a solution of diaminophenol (receive in accordance with J. Med. Chem. 1995, 38, 3524) and triethylamine (129,5 μl, of 0.93 mmol) in 5 ml of dichloromethane. The reaction analyzed using TLC or LC/MS. After the interaction, the reaction mixture was loaded directly onto silica gel and elute with 10% methanol/ethyl acetate to yield the desired amide as a white solid.

The connection 9. The suspension obtained amide (39,5 mg, 0.09 mmol) in phosphorus oxychloride (10 ml) was stirred at 80°C in an atmosphere of dry argon over night. The mixture is allowed to cool to room temperature the tours and the solvent is removed under reduced pressure. The residue is again dissolved in ethyl acetate and wash with saturated aqueous solution of sodium bicarbonate. The organic layer is separated, dried over sodium sulfate, and then concentrated, giving a residue which was purified using flash chromatography using 10% methanol/dichloromethane, giving the desired product as light brown solid (13.9 mg, 37%).

Example 515

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(2-thienyl)pyrrolidin

Scheme:

Getting connection 1, as described in example 17.

Obtain compound 3. To a suspension of polystyrene, coated with HOBt reagent (5,2 g, 8.0 mmol) in 100 ml anhydrous dichloromethane, the reaction vessel which at the bottom is rittby glass filter, add acid (4.7 g, 12,0 mmol), 1-[3-(dimethylamino)propyl]-3 - ethylcarbodiimide hydrochloride (2.3 g, 12,0 mmol) and 4-dimethylaminopyridine (98 mg, 0.8 mmol). The mixture was shaken using an orbital vibrator for 3 hours at room temperature. The solvent is sucked off through filtration and the resin was washed with anhydrous DMF (3×30 ml), anhydrous THF (3×30 ml) and anhydrous dichloromethane (3×30 ml). The resin, which is applied to the activated ester, allowed to dry under vacuum overnight. About the third output is determined, based on the weight gain that stafleet 84%.

The connection 4. The resin containing Notre-activated ester (58 mg, 0.05 mmol) is placed in the reservoir into which pour in 2-(2'-thienyl)pyrrolidine (80 μl of 0.5 M, 0.04 mmol). The suspension is shaken at room temperature for 3 hours and then add the polystyrene coated with isocyanato reagent (83 mg, 0.08 mmol) and the suspension shaken for 2 hours. The solvent is removed through filtering and the resin washed with dichloromethane (2×0.5 ml). All the filtrates are combined and then concentrated under reduced pressure, giving the desired product as a white solid (18 mg). 100% cleaning product control using LC/MS, t/g becomes 527.

Examples 516-587

Subsequent connections synthesized by the method similar to the method of example 515. These compounds, which had a bad clean, purify using preparative HPLC, giving the corresponding desired products.

517
ExampleStructureNameMass spectrum
5161-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(4-methoxyphenyl)pyrrolidin551 (M+H)+
1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(3-furanyl)pyrrolidin511 (M+H)+
5181-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(2-pyridinyl)pyrrolidin522 (M+H)+

5191-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(pyridinyl)pyrrolidin535 (M+N)
5201-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(phenylmethyl)pyrrolidin535 (M+N)
5211-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(2-methoxyphenyl)pyrrolidin551 (M+N)
5221-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(2-phenylethyl)pyrrolidin549 (M+N)
5237-(3,4-Dichlorophenyl)-N-(2,3-dimethylcyclohexyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide501 (M+N)

5247-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[1-(1-naphthalenyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide545 (M+N)
5257-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[2-(1-piperidinyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide502 (M+N)
5267-(3,4-Dichlorophenyl)-N-(2,2-diphenylether)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide571 (M+N)
527N-[2-(1-Cyclohexen-1-yl)ethyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide499 (M+N)
5287-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[2-(phenylthio)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide527 (M+N)

tr>
529N-(1,1'-Bicyclohexyl]-2-yl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide555 (M+N)
5307-(3,4-Dichlorophenyl-N-[[(2,6-dichlorophenyl)methyl]thio]ethyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide610 (M+N)
531N-[(2-Chloro-6-were)methyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide629 (M+N)
532N(-(Bicyclo[2.2.1]heptane-2-yl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide485 (M+N)
533N-Cyclobutyl-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide445 (M+N)

534N-Cyclopentyl-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide458 (M+N)
535 N-Cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide473 (M+N)
5367-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(2-methylcyclohexyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide487 (M+N)
537N-(Cyclohexylmethyl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide487 (M+N)
538N-(2-Cyanoethyl)-7-(3,4-dichlorophenyl)-4,7-dihydro-N,5-dimethyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide458 (M+N)

5397-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide502 (M+N)
5407-(3,4-Dichlorophenyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide502 (M+N)
5417-(3,4-Dichlorophenyl)-4,7-is hydro-5-methyl-N-[2-(1-pyrrolidinyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide 488 (M+N)
542N-Cyclohexyl-7-(3,4-dichlorophenyl)-N-ethyl-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide501 (M+N)
543N-Cycloheptyl-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide487 (M+N)

5447-(3,4-Dichlorophenyl)-4,7-dihydro-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide491 (M+N)
5453-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]thiazolidin463 (M+N)
5461-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl] pyrrolidin445 (M+N)
5477-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(2-thienylmethyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide487 (M+N)

5481-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-methylpiperazin474 (M+N)
5498-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,4-dioxa-8 azaspiro[4.5]Decan517 (M+N)
5501-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(phenylmethyl)piperidine549 (M+N)
5517-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[4-(4-morpholinyl)phenyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide552 (M+N)

5527-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[3-(4-morpholinyl)propyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide518 (M+N)
5537-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[2-(2-pyridinyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide510 (M+N)
554 7-(3,4-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide525 (M+N)
5557-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(1-phenylethyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide495 (M+N)

5567-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(1-methylpropyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide447 (M+N)
5577-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(phenylmethyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide481 (M+N)
5587-(3,4-Dichlorophenyl)-N-[(2-forfinal)methyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide499 (M+H)
559N-[(2-Chlorophenyl)methyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide515 (M+N)
5607-(3,4-Dichlo is phenyl)-N-[(4-forfinal)methyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5 - a]pyrimidine-6-carboxamide 499 (M+N)

5617-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(2-phenylethyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide495 (M+N)
562N-[2-(4-Chlorophenyl)ethyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide530 (M+N)
5637-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N,N-bis(2-methylpropyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide503 (M+N)
5647-(3,4-Dichlorophenyl)-N-[(3,4-dichlorophenyl)methyl]-4,7-dihydro-N,5-dimethyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide564 (M+N)

565N-[(2-Chlorophenyl)methyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-N,5-dimethyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide530 (M+N)
5667-(3,4-Dichlorophenyl)-N-ethyl-4,7-dihydro-5-methyl-N-(1-methylethyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carbox the MFA 461 (M+N)
5677-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(phenylmethyl)-N-propyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide523 (M+N)
5687-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[[4-(1-methylethyl)phenyl]methyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide523 (M+N)

5697-(3,4-Dichlorophenyl)-N-[2-[ethyl(3-ethylphenyl)amino]ethyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide552 (M+N)
570N-(Cyclopropylmethyl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide445 (M+N)
5717-(3,4-Dichlorophenyl)-N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide552 (M+N)
572N-[2-(Butylamino)ethyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide518 (M+N
5737-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[1-(phenylmethyl)-3-pyrrolidinyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide550 (M+N)

5747-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[[4-(triptoreline)phenyl]methyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide565 (M+N)
5757-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[[3-(triptoreline)phenyl]methyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide565 (M+N)
5767-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[(1R)-1-(1-naphthalenyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide545 (M+N)
5777-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[(1S)-1-(1-naphthalenyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide545 (M+N)
578N-[(1S)-1-Cyclohexylethyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide501 (M+N)

5797-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(tricyclo[3.3.1.1 < 3,7]decane-1-ylmethyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide539 (M+N)
5807-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[(1R,2S,5R)-5-methyl-2-(1-methylethyl)cyclohexyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide511 (M+N)
5817-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[2-(4-phenoxyphenyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide529 (M+N)
5827-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[[4-(1,2,3-thiadiazole-4-yl)phenyl]methyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide565 (M+N)
5837-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(1-methyl-1-phenylethyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide509 (M+N)

5847-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[(5-methyl-2-furanyl)methyl]-2-(cryptomite is)pyrazole[1,5-a]pyrimidine-6-carboxamide 584 (M+N)
5857-(3,4-Dichlorophenyl)-N-[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide502 (M+N)
5867-(3,4-Dichlorophenyl)-N-(4,6-dimethyl-2-pyridinyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide596 (M+N)
5877-(3,4-Dichlorophenyl)-N-(1,1-dimethylethylene)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide447 (M+N)

Example 588

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin

Scheme:

Synthesis of 3. A mixture of N-(tert-butoxycarbonyl)-L-Proline 1 (0.5 g, 2.3 mmol), hydroxyamide 2 (0.172 g, 2.3 mmol, get, using the technique disclosed in J. Fluor. Chem. 1999, 95, 127) and hydrate of 1-hydroxybenzotriazole (0,323 g, 2.4 mmol) in 22% dimethylformamide in dichloromethane (9 ml) was stirred at room temperature for 0.5 hours. Then add 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0,757 g, 3.9 mmol) and the mixture is stirred at room temperature t is the treatment for another 2 hours, when HPLC shows that the reaction is complete. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer is washed successively with a saturated aqueous solution of sodium bicarbonate, saturated aqueous sodium chloride and dried over magnesium sulfate. Removal of the solvent yields a white solid (M+N)+272, constant for the associated product 3.

Getting 4. Solid 3 was dissolved in tetrahydrofuran (17 ml), add cesium carbonate (1.6 g) and the mixture is heated at 50-70°C for 18 hours, after which HPLC indicates complete metamorphosis 3. The reaction mass is diluted with water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated, giving a light green colored oil, which has (M+N)+254 corresponding to the desired oxadiazole 4, which is used without further purification.

Synthesis of 5. To a solution of 4 (in 0.288 g, 1.1 mmol) in dichloromethane (9 ml) add 0.9 ml triperoxonane acid and the solution stirred at room temperature for 18 hours, after which HPLC shows no 4. The reaction mixture was concentrated and the residue purified using ion-exchange chromatography (using BioRad AG-50W-X2 resin, 200-400 mesh, H+-form), elute 2N ammonia in methanol, giving off protection pyrrolidin 5 in which the asle (0,122 g,70%). (M+N)+=154.

Synthesis of 6. To a solution of dihydropyrimidinase acid (0.21 g, of 0.65 mmol) in dichloromethane (10 ml) add pyrrolidin 5 (0,139 g, 0.9 mmol)and then 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0,174 g, 0.9 mmol) and the reaction mass stirred at room temperature for 1.5 hours. The solvent is evaporated and the residue purified via chromatography on silica gel, elute with ethyl acetate, which gives two diastereoisomer: fast-moving, less polar diastereoisomer 1 and slow-moving, the more polar diastereoisomer 2, both in the form of a white amorphous solid (M+H)+460.

Example 589

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine

Scheme:

Synthesis of 4. A mixture of (+/-) N-(tert-butoxycarbonyl)pipecolinic acid 1 (0.8 g, 3.5 mmol), 1-hydroxybenzotriazole hydrate (1,14 g, 5.9 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0,49 g, 3.6 mmol) in 22% dimethylformamide in dichloromethane (20 ml) was stirred at room temperature for 0.5 hours. Then add hydroxyamide 2 (0.26 g, 3.5 mmol, get, using the technique disclosed in J. Fluor. Chem. 1999, 95, 127) and the mixture is stirred at room temperature for 18 hours when HPLC showing the pointed end of the reaction. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer is washed successively with a saturated aqueous solution of sodium bicarbonate, saturated aqueous sodium chloride and dried over magnesium sulfate. Distillation of the solvent gives a clear oil (M+N)+285 corresponding to the associated product 3. Oil 3 was dissolved in tetrahydrofuran (25 ml), add cesium carbonate (2.5 g) and the mixture is heated at 50-70°C for 18 hours, after which HPLC indicates complete metamorphosis 3. The reaction was diluted with water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated, giving a clear oil, which has (M+H)+267, corresponding to the desired oxadiazole 4, which is used without further purification.

Synthesis of 5. To a solution of 4 (0,82 g, 3.1 mmol) in dichloromethane (20 ml) add 2 ml triperoxonane acid and the solution stirred at room temperature for 18 hours, after which HPLC shows no 4. The reaction mixture was concentrated and the residue purified using ion-exchange chromatography (using BioRad AG-50W-X2 resin, 200-400 mesh, H+-form), elution 2N ammonia in methanol, giving pyrrolidin 5 is removed from protection in the form of oil (0,46 g, 89%). (M+N)+=167.

The synthesis of these compounds. To a solution of dihydropyrimidinase acid (0.64 g, 2.0 mmol)in dichloromethane (30 ml) add pyrrolidin 5 (0,462 g, 2.8 mmol)and then 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0,53 g, 2.8 mmol) and the reaction mass stirred at room temperature for 2.5 hours. The solvent is evaporated and the residue purified via chromatography on silica gel, ethyl acetate to elute, which gives two diastereoisomer: small amount and less polar diastereoisomer (diastereoisomer 1) and a greater number of more polar diastereoisomer (diastereoisomer 2), both in the form of a white amorphous solid (M+H)+473.

1. Dihydropyrimidinase the compounds of formula I*

its enantiomers, diastereoisomers and pharmaceutically acceptable salt,

where X1X2and X3together with the atoms to which they are attached form a ring

R1represents hydrogen;

R2represents hydrogen, lower alkyl, monocyclic cycloalkyl with 3-6 carbon atoms, mono - or bicyclic aryl, unsubstituted or substituted by 1-3 substituents selected from halogen, lower alkyl, hydroxy, cyano, nitro, lower alkoxy, optionally substituted phenyl, trifloromethyl, triptoreline, phenoxy, lower alkoxycarbonyl, pyridinyl and amino, optionally substituted lower ALK is nolam or lower alkyl groups, 5-6-membered heterocyclic or heteroaryl group containing 1-2 heteroatoms selected from nitrogen atoms, oxygen and sulfur, optionally condensed with a benzene ring and optionally substituted Deputy, selected from lower alkyl, optionally substituted by hydroxy, lower alkoxy, halogen, pyrazolyl substituted lower alkyl group, and trifluoromethyl;

R4represents lower alkyl, optionally substituted lower alkoxy, trifluoromethyl, cyclohexyl or phenyl;

R5represents hydrogen or the group -(CH2)nZ2where Z2selected from lower alkyl, phenyl, substituted by halogen, trifloromethyl, cyclopropyl, lower alkoxycarbonyl, di(lower alkyl)amino and di(lower alkyl)aminocarbonyl; n is chosen from integers from 0 to 2;

R6represents hydrogen, lower alkyl, unsubstituted or substituted by halogen atoms, lower alkenyl, lower alkanoyl, benzoyl,3-4cycloalkylcarbonyl, lower alkoxycarbonyl, carbarnoyl, optionally mono - or disubstituted by lower alkyl, lower alkylsulfonyl;

R7represents hydrogen, lower alkyl, phenyl, trifluoromethyl, cyano, halogen, CO2Z5or C(O)NZ5Z6;

Z5represents hydrogen or lower alkyl;

Z6represents hydrogen, lower alkyl, optionally substituted by phenyl, or phenyl substituted hydroxy, or

Z5and Z6together with the nitrogen atom to which they are attached, form pyrrolidino, substituted lower alkyl, which is substituted by pyrrolidino;

R3* represents a heterocyclic group selected from oxazolyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, imidazo[1,5-a]pyridinyl, 6,7-dihydro-5H-pyrrolo[1,2-C]imidazole, 1-H-thieno[3,4-d]imidazolyl, 4H-imidazo[4,5-C][1,2,5]thiadiazolyl and 1,6-dihydro-1H-imidazo[4,5-C]pyrazolyl, which may be substituted by 1-3 substituents selected from lower alkyl, optionally substituted by phenyl, halogen, trifloromethyl, nitro and phenyl; or

R3* represents a group C(O)NZ5*Z6*,

where Z5* represents lower alkyl substituted by 1-2 substituents selected from hydroxy, lower alkoxy, cyano, lower alkoxycarbonyl, phenoxy, phenylthio, lower alkylthio, substituted phenyl group, which is substituted by halogen atoms, amino substituted by 1-2 groups selected from lower alkyl and phenyl, optionally substituted with halogen or lower alkyl, monocyclic cycloalkyl or cycloalkenyl with 3-6 carbon atoms or tricyclo[3.3.1.13,7]APR is La, mono - or bicyclic aryl, unsubstituted or substituted by 1-2 substituents selected from lower alkyl, lower alkoxy, halogen, phenoxy, triptoreline, triptoreline and 1,2,3-thiadiazolyl, 5-6-membered monocyclic, heterocyclic or heteroaryl group containing 1-2 heteroatoms selected from nitrogen atoms, oxygen and sulfur, optionally substituted lower alkyl group or exography, bicyclic 9-membered heteroaryl groups containing a heteroatom of nitrogen, which is substituted with halogen; mono - or bicyclic aryl, unsubstituted or substituted by morpholinopropan; 3-12-membered saturated or partially unsaturated carbocyclic group which may be substituted by 1-2 lower alkyl groups or phenyl, pyridyl, unsubstituted or substituted 2 lower alkyl groups; 2,3-dihydrobenzo-1,4-dioxane; pyrrolidinyl, substituted phenyl(lower alkyl) or lower alkoxyalkyl; azepane;

Z6* represents hydrogen, lower alkyl which may be substituted by lower alkoxy, lower alkoxycarbonyl or phenyl;

or Z5*HZ6* together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated monocyclic or bicyclic, or tricyclic heterocyclic group containing from 3 to 13 atoms, t is including 1-3 heteroatoms, selected from nitrogen atoms, oxygen and sulfur, which is unsubstituted or substituted by 1-2 substituents selected from lower alkyl, optionally substituted by 1 to 3 substituents, which represents a hydroxy, phenyl, optionally substituted with halogen, lower alkoxy, optionally substituted lower alkoxy, phenoxy, optionally substituted with halogen, amino, mono - or disubstituted by a lower alkyl group or phenyl which may be substituted by lower alkyl groups, benzodioxolyl, pyrrolidinyl and benzimidazolyl; phenyl, optionally substituted with 1-2 substituents, represents lower alkyl, halogen, lower alkoxy, lower alkanoyl, trifluoromethyl, nitro, lower alkoxycarbonyl, optionally substituted phenyl, pyrimidinyl, pyridyl; fluorenyl or cyclohexyl; carboxyl or lower alkoxycarbonyl, optionally substituted by phenyl; heteroaryl selected from pyridyl, teinila, furil, oxadiazole, optionally substituted lower alkyl, benzimidazolyl, replaced by oxopropoxy; hydroxy or carbonyl group; nitro; amino, mono - or disubstituted by a lower alkyl group, lower alkanoyl or lower alkoxycarbonyl; phenoxy, optionally substituted lower alkoxygroup; carbamoyl, optionally substituted 1 or 2 groups selected from either the higher of alkyl or naphthyl; Betulinol groups, substituted lower alkoxygroup; the group-C(O)(heterocycle), where heterocycle represents pyridyl, furyl or piperidyl, or group-C(O)styryl; group - SO2(C6-10aryl), optionally substituted lower alkyl or triptoreline; group - SO2(heteroaryl), substituted by 1-2 halogen atoms, where heteroaryl is thienyl or sensational;

provided that Z5* and Z6* do not together form an unsubstituted piperidinyl, the unsubstituted pyrrolidinyl or an unsubstituted morpholinyl.

2. The compound according to claim 1, in which R4represents a lower alkyl or lower alkyl, substituted lower alkoxy.

3. The compound according to claim 1, in which

R1represents hydrogen;

R2represents aryl or substituted aryl or heterocyclic group or substituted heterocyclic group defined in claim 1;

R4represents a lower alkyl or lower alkyl, substituted lower alkoxy, or trifluoromethyl;

R5represents hydrogen, -(CH2)n-Z2where Z2selected from lower alkyl, trifloromethyl, cyclopropyl, lower alkoxycarbonyl, di(lower alkyl)amino and di(lower alkyl)aminocarbonyl and n is 0-2; and

R7represents lower alkyl.

4. The connection p is 1, which

R1represents hydrogen;

R2represents phenyl, phenyl substituted by 1 to 3 substituents as specified in claim 1, heterocyclic group or substituted heterocyclic as defined in claim 1;

R4represents a lower alkyl or lower alkyl, substituted lower alkoxy;

R5represents hydrogen, lower alkyl or lower alkyl, substituted phenyl, substituted with halogen; trifluoromethyl, cyclopropyl, lower alkoxycarbonyl, di(lower alkyl)amino and di(lower alkyl)aminocarbonyl; and

R7represents a lower alkyl, -CO2(lower alkyl), -CF3, -CN, F or Cl.

5. The compound according to claim 4, in which

R1represents hydrogen;

R2represents phenyl or substituted as indicated in claim 1, phenyl heterocyclic group or substituted heterocyclic group as defined in claim 1;

R4represents a lower alkyl or alkyl substituted lower alkoxy;

R5represents hydrogen, or lower alkyl,

R7represents lower alkyl.

6. The compound according to claim 5, in which

R1represents hydrogen;

R2represents phenyl substituted by 1 to 3 substituents as specified in claim 1, or heterocyclics the second group, defined in claim 1, substituted with the substituents specified in claim 1;

R4represents a lower alkyl or lower alkyl, substituted lower alkoxy;

R5represents hydrogen, lower alkyl or lower alkyl substituted by substituents as specified in claim 1; and

R7represents a lower alkyl, -CO2(lower alkyl), -CF3, -CN, F or Cl.

7. The compound according to claim 1, which represents the

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-(5-phenyl-2-oxazolyl)pyrazole[1,5-a]pyrimidine;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazole[1,5-a]pyrimidine;

6-(1H-Benzimidazole-2-yl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-(1-methyl-1H-benzimidazole-2-yl)pyrazole[1,5-a]pyrimidine;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-[5-(trifluoromethyl)-1-propyl-1H-benzimidazole-2-yl]pyrazole[1,5-a]pyrimidine;

6-(5-Butyl-1,3,4-oxadiazol-2-yl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine;

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-6-(1-methyl-1H-benzimidazole-2-yl)pyrazole[1,5-a]pyrimidine;

7-(3,4-Dichlorophenyl)-4,7-dihydro-6-(imidazo[1,5-a]pyridine-3-yl)-5-methylpyrazole[1,5-a]pyrimidine;

7-(3,4-Dichlorophenyl)-6-(1-ethyl-5-nitro-1H-benzimidazole-2-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine;

6-[5-Chloro-1-(1-meth is later)-1H-benzimidazole-2-yl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine;

6-(5-Chloro-1-ethyl-1H-benzimidazole-2-yl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine;

7-(3,4-Dichlorophenyl)-6-(5-fluoro-1-propyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-[1-(1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazole-2-yl]pyrazole[1,5-a]pyrimidine;

7-(3,4-Dichlorophenyl)-6-(5-fluoro-1-methyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-[1-(phenylmethyl)-1H-benzimidazole-2-yl]pyrazole[1,5-a]pyrimidine;

7-(3,4-Dichlorophenyl)-4,7-dihydro-6-(imidazo[1,5-a]pyridine-3-yl)-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine;

7-(2,3-Dichlorophenyl)-4,7-dihydro-6-(imidazo[1,5-a]pyridine-3-yl)-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine;

7-(3,4-Dichlorophenyl)-6-(5-fluoro-1-methyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine;

7-(2,3-Dichlorophenyl)-6-(4-fluoro-1-methyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine;

7-(3,4-Dichlorophenyl)-6-(4-fluoro-1-methyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine;

7-(2,3-Dichlorophenyl)-6-(5-fluoro-1-methyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine;

6-(1-Chloro-6,7-dihydro-5H-pyrrolo[1,2-C]imidazol-3-yl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine;

7-(3,4-Dichlorophenyl)-4,dihydro-5-methyl-6-(1-methyl-1H-thieno[3,4-d]imidazol-2-yl)pyrazole[1,5-a]pyrimidine;

and

8. The compound according to claim 1, which represents the

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine;

7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(2-phenylethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(2-phenylethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-3-pyridinylmethyl[1,5-a]pyrimidine-6-carboxamide;

1-[[7-(4-Chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-methylpiperazine;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N - (3-phenylpropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(phenylmethyl)piperidine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(phenylmethyl)piperazine;

1-[[7-(3-Chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(3,4-Differenl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-pyrazole[1,5-a]pyrimidine-6-yl] carbonyl]-4-(4-forfinal)piperazine;

1-(4-Forfinal)-4-[(4,7-dihydro-5-methyl-7-phenylpyrazol[1,5-a]pyrimidine-6-yl]carbonyl]piperazine;

1-(4-Forfinal)-4-[[7-(3-forfinal)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine;

1-[[7-(3,5-Dichlorophenyl)-4,7-dihydro-5-methyl-pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[(7-Cyclohexyl-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl)carbonyl]-4-phenylpiperazine;

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine;

7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-6-[(4-phenyl-1-piperazinil)-carbonyl]pyrazole[1,5-a]pyrimidine-3-carboxylic acid ethyl ester;

4-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1-piperazinecarboxamide acid 1,1-dimethylethylene ether;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-phenylpyrazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine;

7-(3,4-Dichlorophenyl)-4,7-dihydro-2,5-dimethyl-N-(3-phenylpropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

1-[[7-(2,3-Dichlorophenyl)-2-(1,1-dimethyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenyl-piperidine;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-6-[[(3-phenylpropyl)amino]carbonyl]pyrazole[1,5-a]pyrimidine-3-carboxylic acid ethyl ester;

7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-6-[(4-phenyl-1-piperazinil)-carbonyl]pyrazole[1,5-a]pyrimidine-2-carboxylic acid ethyl ester;

1-[[3-Cyano-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N - (3-phenylpropyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazine]carbonyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-2-carboxylic acid methyl ester;

(2S)-1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin;

1-[[7-(2,3-Dichlorophenyl)-2-fluoro-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

(2S)-1-[[2-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin;

(2S)-1-[[2-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimido the-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin;

(2S)-1-[[7-(2,3-Dichlorophenyl)-2-fluoro-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Differenl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

4-[6-[[4-(4-Forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-7-yl]benzoic acid methyl ester;

1-(4-Forfinal)-4-[[7-(2-forfinal)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine;

1-[[7-(2-Chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-7-(2-methoxyphenyl)-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Acid)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,4-Acid)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,5-Acid)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazin is;

-[[4,7-Dihydro-5-methyl-7-[2-(trifluoromethyl)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(2-were)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(3-phenoxyphenyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(3,4-Dimetilfenil)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(3,5-Acid)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-[3-(phenylmethoxy)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-7-(3-hydroxyphenyl)-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-[3-(trifluoromethyl)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(3-were)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forvever)piperazine;

1-[[7-(4-Cyanophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-(4-Forfinal)-4-[[7-(4-forfinal)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine;

N - [4-[6-[[4-(4-Forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-7-yl]phenyl]ndimethylacetamide;

1-[[7-[4-(L is methyl-amino)phenyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-7-(4-methoxyphenyl)-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-[4-(phenylmethoxy)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(4-Butoxyphenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(2-thienyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(3-thienyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-[4-(trifluoromethyl)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(4-were)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(2-nitrophenyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(4-nitrophenyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,6-Differenl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,4-Differenl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,5-Differenl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(3,5-Differenl)-4,7-dihydro-5-METI the pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-[2-(phenylmethoxy)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(3,4-Acid)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-[4-(triptoreline)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-[3-(triptoreline)phenyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(3-Cyanophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-7-(3-methoxyphenyl)-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(4-Chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(4-phenoxyphenyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(3-nitrophenyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(5-methyl-2-furanyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-7-(1H-imidazol-2-yl)-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(1H-pyrrol-2-yl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Digi the ro-5-methyl-7-(2-pyridinyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(3-Chloro-4-methoxyphenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-7-(4-methoxy-1,3-benzodioxol-6-yl)-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-7-[5-(hydroxymethyl)-2-furanyl]-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-7-(1H-indol-3-yl)-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(3-pyridinyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(3-chinoline)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(4-chinoline)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(2,3,5-trichloro-phenyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,5-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-(4-Forfinal)-4-[[7-(3-furanyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-piperazine;

1-[[7-(2-Benzofuranyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(2-chinoline)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(2-thiazolyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-(4-Forfinal)-4-[[7-(2-furanyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine;

1-[[4,7-Dihydro-7-[3-methoxy-4-(phenylmethoxy)phenyl]-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-7-[4-methoxy-3-(phenylmethoxy)phenyl]-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(2-naphthalenyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-[3,4-Bis(phenyl-methoxy)phenyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(1,3-benzodioxol-5-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-[3,5-Bis(trifluoromethyl)phenyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-[5-[1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl]-2-thienyl]pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(5-Ethyl-2-furanyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Dihydro-5-Benzofuranyl)-4,7-dihydro-5-methylpyrazole[1,5-a]is eremein-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(3-Bromophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-[4-(1-pyrrolidinyl)-phenyl]pyrazole]1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(5-methyl-2-thienyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(1,3-Benzodioxol-4-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

tert-[[7-(5-Chloro-2-thienyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(3, 5dimethylphenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

8-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,4-dioxa-8 azaspiro[4.5]decane;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(2-methoxy-phenyl)piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]-pyrimidine-6-yl]carbonyl]-4-[3-(trifluoromethyl)-phenyl]piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-nitrophenyl)piperazine;

1-(4-Acetylphenyl)-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazin is;

1-(2-Chlorophenyl)-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]-carbonyl]-4-(4-methoxyphenyl)piperazine;

1-(3,4-Dichlorophenyl)-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]-carbonyl]piperazine;

1-(3,5-Dichlorophenyl)-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]-carbonyl]piperazine;

1-(4-Chlorophenyl)-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine;

1-(3-Chlorophenyl)-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(3-methoxyphenyl)piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-were)piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5A]-pyrimidine-6-yl]carbonyl]-4-[4-(trifluoromethyl)-phenyl]piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(2-forfinal)piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(3,4-dimetilfenil)piperazine;

7-(3,4-Dichlorophenyl)-N-[2-[(4-forfinal)amino]ethyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide;

4-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1-piperazinecarboxamide acid fenilmetilovy ether;

7-(3,4-Dichlorophenyl)-N-ethyl-N-[(2-forfinal)methyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide;

N-[(3-Chloro-4-methoxyphenyl)methyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide;

1-(1,3-benzodioxol-5-ylmethyl)-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine;

4-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1-piperazinecarboxamide acid ethyl ester;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(2-pyridinyl)piperazine;

(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin;

1-[Bis(4-forfinal)-methyl]-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(2-furanyl-carbonyl)piperazine;

1-Cyclohexyl-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(2-methoxyethyl)piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]Piri is one-6-yl]carbonyl]-4-(N-fluoren-9-yl)piperazine;

(2R)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxy-methyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(2,3-dimethyl-phenyl)piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-piperidine-carboxylic acid ethyl ester;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-N,N-diethyl-3-piperidinecarboxylic;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-piperidine-carboxylic acid ethyl ester;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-methylpiperidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl] - for 3,5-dimethylpiperidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-hydroxypiperidine;

4-(4-Chlorophenyl)-1-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidin-6-yl]carbonyl]-4-hydroxypiperidine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-piperidinecarboxylic acid ethyl ester;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-methylpiperidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-the l]carbonyl]-1,2,3,4-tetrahydroquinolin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]-pyrimidine-6-yl]carbonyl]decahydroquinoline;

2-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,4-tetrahydroisoquinoline;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-propylpiperidine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(hydroxydiphenylmethyl)piperidine;

7-(3,4-Dichlorophenyl)-N-[(2-forfinal)methyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide;

2-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[2-(phenylamino)-ethyl]pyrazole[1,5-a]pyrimidine-6-carboxamide;

(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-[(phenyl-amino)methyl]pyrrolidin;

N-Cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydro-N,5-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxamide;

3-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]thiazole;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl] carbonyl]-3,4-dihydro-1H-indole;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]azetidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrim the DIN-6-yl]carbonyl]hexahydro-1H-azepin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]octahydrate;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,6-tetrahydropyridine;

7-(3,4-Dichlorophenyl)-4,dihydro-N,5-dimethyl-N-[2-(2-pyridinyl)-ethyl]pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-[[7-(3,4-Dichlorophenyl)-4,dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-N-(phenylmethyl)glycine ethyl ester;

TRANS-7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(2-vinylcyclopropyl)pyrazole[ 1,5-a]pyrimidine-6-carboxamide;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl] carbonyl]-2-methylpyrrolidine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-methylaziridine;

(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-[[(2,6-dimetilfenil)amino]methyl]pyrrolidin;

7-(3,4-Dichlorophenyl)-N-ethyl-4,7-dihydro-5-methyl-N-(4-pyridinylmethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1R)-1-phenylethyl]pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1S)-1-phenylethyl]pyrazole[1,5-a]pyrimidine-6-carboxamide;

6-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

7-(3,4-Dichlor the Nile)-N-(hexahydro-1H-azepin-1-yl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]aziridine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]octahydro-1H-atonin;

(2R-TRANS)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,5-bis(methoxymethyl)-pyrrolidin;

(2S-TRANS)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,5-bis-(methoxymethyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-L-prolinamide;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-D-prolinamide;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,3-dihydro-2-methyl-1H-indole;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,3-dihydro-5-nitro-1H-indole;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,3-dihydro-6-nitro-1H-indole;

4-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]thiomorpholine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-L-Proline methyl ester;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-L-Proline 1,1-dimethylethylene ether;

1-[[7-(3,4-Dichlorophenyl)-4,7-dig the draw-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-N-(2-naphthalenyl)-1-prolinamide;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,4-tetrahydro-2-methylinosine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-6-fluoro-1,2,3,4-tetrahydro-2-methylinosine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-L-Proline fenilmetilovy ether;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-D-Proline fenilmetilovy ether;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-hydroxy-L-Proline fenilmetilovy ether;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)-2-methylpiperazin;

3-Chloro-N-Cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydro-N,5-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxamide;

4-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]thiomorpholine;

1-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,3-dihydro-1H-indole;

1-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]hexahydro-1H-azepin;

1-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]octahydrate;

1-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a] pyrimidine-6-yl]carbonyl]-12,3,6-tetrahydropyridine;

3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1S)-1-phenylethyl]-pyrazole[1,5-a]pyrimidine-6-carboxamide;

3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1R)-1-phenylethyl]-pyrazole[1,5-a]pyrimidine-6-carboxamide;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]-carbonyl]-2-(methoxymethyl)piperidine;

[(3R)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-pyrrolidinyl]carboxylic acid 1,1-dimethylethylene ether;

[(3S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-pyrrolidinyl]carboxylic acid 1,1-dimethylethylene ether;

(3R)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-(dimethylamino)pyrrolidin;

N-[1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-pyrrolidinyl]ndimethylacetamide;

N-[1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-pyrrolidinyl]-N-methylacetamide;

3-Chloro-7-(3-chlorophenyl)-N-cyclohexyl-4,7-dihydro-N,5-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxamide;

(2S)-1-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin;

1-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]decahydroquinoline;

2-[[3-Chloro-7-(3,4-dichlorophenyl-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,4-tetrahydroisoquinoline;

4-[[3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]thiomorpholine;

N-Cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydro-N,5-dimethyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]azacyclopentadecan;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]dodecahydro-1H-fluoren;

(2S)-1-[[7-(3,4-Di-chlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole-[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin;

1-[[3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]hexahydro-1H-azepin;

1-[[3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]octahydrate;

1-[[3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,6-tetrahydropyridine;

3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1S)-1-phenylethyl]pyrazole[1,5-a]pyrimidine-6-carboxamide;

(2S)-1-[[3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin;

1-[[3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]decahydroquinoline;

2-[[3-Chloro-7-(3-chlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,4-tetrahydroisoquinoline;

1-[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]hexahydro-1H-azepin;

1-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,6-tetrahydropyridine;

(2S)-1-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,3-dihydro-1H-indole;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]hexahydro-1H-azepin;

7-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1S)-1-phenylethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1R)-1-phenylethyl]-2-(trifluoromethyl)pyrazole[1,5-a] pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-N,N-bis(2-methoxyethyl)-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N,N-bis(2-ethoxyethyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-N-(2-methoxyethyl)-N,5-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-N-(2-methoxyethyl)-5-methyl-N-propylpyrazole[1,5-a] pyrimidine-6-carboxamide;

2-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,4-tetrahydroisoquinoline;

1-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]chainreaction;

3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[(1S)-1-phenylethyl]pyrazole[1,5-a]pyrimidine-6-carboxamide;

3-Chloro-N-cyclohexyl-7-(2,3-dichlorophenyl)-4,7-dihydro-N,5-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-ethyl-4,7-dihydro-N-(2-methoxyethyl)-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide;

N-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl] carbonyl]-N-methylglycine ethyl ether;

N-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-N-methylglycine 1,1-dimethylethylene ether;

N-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(3-pyridinyl)piperidine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,4-tetrahydro-6-methylinosine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-propylpiperidine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl] carbonyl]-2-[(diethylamino)methyl]piperidine;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(2-phenoxyethyl)-pyrazole[1,5-a]pyrimidine-6-carboxamide;

1-[(7-cyclopropyl-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl)carbonyl]-4-(4-forfinal)piperazine;

1-[[4,7-Dihydro-5-methyl-7-(1-methylethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

(2S)-1-[[4,7-Dihydro-5-methyl-7-(1-methylethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin;

1-[[4,7-Dihydro-5-methyl-7-(1-methylethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2,3-dihydro-1H-indole;

1-[[4,7-Dihydro-5-methyl-7-(1-methylethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,6-tetrahydropyridine;

7-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-(phenylmethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-(2-phenylethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(2-phenylethyl)-N-(phenylmethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(phenoxymethyl)pyrrolidin;

(2R)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(phenoxymethyl)pyrrolidin;

(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1;5-a]pyrimidine-6-yl]carbonyl]-2-[(4-pertenece)methyl]-pyrrolidin;

(2R)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-[(4-pertenece)methyl]-pyrrolidin;

7-(3,4-Dichlorophenyl)-4,7-dihydro-N-(2-methoxyethyl)-5-methylpyrazole[1,5-a]pyrimidine-6-carboxamide;

(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(hydroxydiphenylmethyl)pyrrolidin;

(2R)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(hydroxydiphenylmethyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(3-pyridinyl)pyrrolidin;

(2S)-1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-phenylpyrrolidine;

3-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-phenylthiazole;

3-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-thiazolidinethione acid methyl ester;

7-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-(3-phenylpropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-ethyl-4,7-dihydro-5-methyl-N-(3-phenylpropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(3-phenylpropyl)-N-propylpyrazole[1,5-a]pyrimidine-6-carboxamide;

N-Butyl-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-N-(3-phenylpropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

2-(4-Chlorophenyl)-3-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]thiazolidin;

N-(Cyclopropylmethyl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-N-propylpyrazole[1,5-a]pyrimidine-6-carboxamide;

8-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1-phenyl-1,3,8-diazaspiro[4.5]Decan-4-one;

4-(4-Chlorophenyl)-1-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,2,3,6-tetrahydropyridine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(2-phenylethyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(4-methoxyphenyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(2-methoxyphenyl)pyrrolidin;

(3R)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-phenoxypyridine;

(2S)-2-[(Cyclohexyloxy)methyl]-1-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(phenylmethyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(3-methoxyphenyl)pyrrolidin;

(2S)-2-(Butoxymethyl)-1-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]Piri is one-6-yl]carbonyl]-2-(2-thienyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(4-pyridinyl)pyrrolidin;

(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-[(methoxyethoxy)-methyl]pyrrolidin;

(2S)-2-(1H-Benzimidazole-1-ylmethyl)-1-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(3-furanyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(2-pyridinyl)pyrrolidin;

(3S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-phenoxypyridine;

2S-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-3-phenoxypyridine;

7-(3,4-Dichlorophenyl)-4,7-dihydro-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-(2,3-dihydro-1H-inden-2-yl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-D-phenylalanine methyl ester;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dig the draw-5-methyl-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-(2-furylmethyl)-4,7-dihydro-5-methyl-2-(tri-permitil)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-[(3,4-dichlorophenyl)methyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-N-[(2R)-2-(methoxymethyl)-1-pyrrolidinyl]-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[(tetrahydro-2-furanyl)-methyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-[2-(3,4-dichlorophenyl)ethyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)-N-[[4-[(trifluoromethyl)thio]-phenyl]methyl]pyrazole-[1,5-a]pyrimidine-6-carboxamide;

(2S)-1-[[7-(3,4-Dichlorophenyl)-4,di-hydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(1-pyrrolidinyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(1-naphthalenesulfonyl)piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-[(4-ethylphenyl)sulfonyl]piperazine;

1-[(4-Bromo-5-chloro-2-thienyl)sulfonyl]-4-[[7-(3,4-dichlorophenyl)-4,7-digid is about-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-[[2-(triptoreline)phenyl]sulfonyl]piperazine;

1-[(5-Chloro-3-methyl-Benzo[b]thiophene-2-yl)sulfonyl]-4-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl] carbonyl]-4-[(3-methoxyphenyl)carbonyl]piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(1-oxo-3-phenyl-2-propenyl)piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-pyridylcarbonyl)piperazine;

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-4,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-4,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-4,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-2,4,5-trimethylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Dichlorophenyl)-4-[(4-forfinal)methyl]-4,dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

7-(2,3-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-2,5-dimethylpyrazolo[1,5-a]pyrimidine-4(7H)-acetic acid, Atila the initial broadcast;

7-(2,3-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-N,N,2,5-tetramethylspiro[1,5-a]pyrimidine-4(7H)-ndimethylacetamide;

1-[[7-(2,3-Dichlorophenyl)-4-[2-(dimethylamino)ethyl]-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[4-(Cyclopropylmethyl)-7-(2,3-Dichlorophenyl)-4,7-dihydro-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

7-(2,3-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-N,N,2,5-tetramethylspiro[1,5-a]pyrimidine-4(7H)-carboxamide;

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-4-methyl-5-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-5-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-2-methyl-5-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Dichlorophenyl)-4,7-dihydro-2,4-dimethyl-5-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[7-(3,4-Dichlorophenyl)-4,7-dihydro-2-methyl-5-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[1-Benzoyl-7-(2,3-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrim the DIN-6-yl]carbonyl]-4-phenylpiperazine;

1-[[1-Benzoyl-7-(3,4-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine;

1-[[1-Acetyl-7-(3,4-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine;

1 -[[7-(3,4-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxo-1-(1-oxobutyl)-pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine;

1-[[1-(cyclopropanecarbonyl)-7-(3,4-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine;

1-[[1-(cyclopropanecarbonyl)-7-(2,3-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-1-(3-methyl-1-oxobutyl)-2-oxadiazol[1,5-a]pyrimidin-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Dichlorophenyl)-(2,2-dimethyl-1-oxopropyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine;

1-[[1-(Cyclopropanecarbonyl)-7-(3,4-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[1-(Cyclobutanecarbonyl)-7-(3,4-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(3,4-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-1-(2-methyl-1-oxopropyl)-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbon is l]-4-(4-forfinal)piperazine;

1-[[7-(2,3-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-1-[(1-methylethyl)sulfonyl]-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine;

1-[[7-(3,4-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-1-[(1-methylethyl)sulfonyl]-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(1-methylethyl)-2-oxo-6-[(4-phenyl-1-piperazinil)carbonyl]pyrazole[1,5-a]pyrimidine-1(2H)-carboxamide;

7-(2,3-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-2-oxo-6-[(4-phenyl-1-piperazinil)carbonyl]pyrazole[1,5-a]pyrimidine-1(2H)-carboxamide;

7-(2,3-Dichlorophenyl)-4,7-dihydro-5-methyl-2-oxo-6-[(4-phenyl-1-piperazinil)carbonyl]pyrazole[1,5-a]pyrimidine-1(2H)-carboxamide;

7-(3,4-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-N,N,5-trimethyl-2-oxadiazol[1,5-a]pyrimidine-1(2H)-carboxamide;

1-[[1-(3-Butenyl)-7-(3,4-dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxadiazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(3,4-Dichlorophenyl)-1,2,4,7-tetrahydro-5-methyl-2-oxo-1-(2,2,2-triptorelin)pyrazole-[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[7-(3,4-Dichlorophenyl)-1,2,4,tetrahydro-5-methyl-2-oxo-1,4-bis(2,2,2-triptorelin)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

7-(3,4-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-5-methyl-2-oxadiazol[1,5-a]pyrim the DIN-1(2H)-carboxylic acid 1-metaliteracy ether;

1-[(4,7-Dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl)carbonyl]-4-phenylpiperazine;

7-(3,4-dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-2-carboxylic acid;

7-(3,4-Dichlorophenyl)-N,N-diethyl-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-2-carboxamide;

7-(3,4-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-N-(4-hydroxyphenyl)-5-methylpyrazole[1,5-a]pyrimidine-2-carboxamide;

1-[[7-(3,4-Dichlorophenyl)-4,dihydro-5-methyl-2-[[(2S)-2-(1-pyrrolidinyl)-1-pyrrolidinyl]carbonyl]-pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

7-(3,4-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-2-carboxamide;

7-(3,4-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-5-methyl-N-(phenylmethyl)pyrazole-[1,5-a]pyrimidine-2-carboxamide;

7-(3,4-Dichlorophenyl)-6-[[4-(4-forfinal)-1-piperazinil]carbonyl]-4,7-dihydro-5-methyl-N-(2-phenylethyl)-pyrazole[1,5-a]pyrimidine-2-carboxamide;

1-[[2-Cyano-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[3-Bromo-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-phenylpiperazine;

1-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]p is rimidine-6-yl]carbonyl]-4-phenylpiperazine;

1-[[3-Chloro-7-(2,3-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

1-[[3-Chloro-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-(methoxymethyl)-N-(2-pyridinylmethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(2,3-Dichlorophenyl)-4,7-dihydro-5-(methoxymethyl)-N-(2-pyridinylmethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(4-forfinal)pyrrolidin;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-(methoxymethyl)-N-(3-phenylpropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin;

5-Cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydro-N-(3-phenylpropyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

1-[[5-Cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

(2S)-1-[[5-Cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-phenyl-N-(3-phenylpropyl)pyrazole[1,5-a]PI is kidin-6-carboxamide;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-phenylpyrazol[1,5-a]pyrimidine-6-yl]carbonyl]-4-(4-forfinal)piperazine;

(2S)-1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-phenylpyrazol[1,5-a]pyrimidine-6-yl]carbonyl]-2-(methoxymethyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-phenylpyrazole;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(2-thienyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(4-methoxyphenyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(3-furanyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(2-pyridinyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(4-pyridinyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(phenylmethyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(2-methoxyphenyl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(2-phenylethyl)pyrrolidin;

7-(3,4-Dichlorophenyl)-N-(2,3-dimethylcyclohexyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[1-(1-naphthalenyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[2-(1-piperidinyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-(2,2-diphenylether)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-[2-(1-Cyclohexen-1-yl)ethyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[2-(phenylthio)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-([1,1-Bicyclohexyl]-2-yl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-[2-[[(2,6-dichlorophenyl)methyl]thio]ethyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-[(2-Chloro-6-were)methyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-(Bicyclo[2.2.1]heptane-2-yl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-Cyclobutyl-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxym is d;

N-Cyclopentyl-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-Cyclohexyl-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(2-methylcyclohexyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-(Cyclohexylmethyl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-(2-Cyanoethyl)-7-(3,4-dichlorophenyl)-4,7-dihydro-N,5-dimethyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[2-(1-pyrrolidinyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-Cyclohexyl-7-(3,4-dichlorophenyl)-N-ethyl-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-Cycloheptyl-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(2-thienylmethyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

1-[[7-(3,4-Dichlorophenyl)-4,dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-methylpiperazine;

8-[[7-(3,4-Dichlorophenyl)-4,dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-1,4-dioxa-8 azaspiro[4.5]decane;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-4-(phenylmethyl)piperidine;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[4-(4-morpholinyl)phenyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[3-(4-morpholinyl)propyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-N,5-dimethyl-N-[2-(2-pyridinyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(1-phenylethyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(phenylmethyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-[(2-forfinal)methyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-[(2-Chlorophenyl)methyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-[(4-forfinal)methyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(2-phenylethyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-[2-(4-Chlorophenyl)ethyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-[(3,4-dichlorophenyl)methyl]-4,7-dihydro-N,5-dimethyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-[(2-Chlorophenyl)methyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-N,5-dimethyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(phenylmethyl)-N-propyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[[4-(1-methylethyl)phenyl]methyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-[2-[ethyl(3-were)amino]ethyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-(Cyclopropylmethyl)-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-[2-(Butylamino)ethyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[1-(phenylmethyl)-3-pyrrolidinyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[[4-(triptoreline)phenyl]methyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[[3-(triptoreline)phenyl]methyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[(1R)-1-(1-naphthalenyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[(1S)-1-(1-naphthalenyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

N-[(1S)-1-Cyclohexylethyl]-7-(3,4-dichlorophenyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(tricyclo[3.3.1.13,7] decane-1-ylmethyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[(1R,2S,5R)-5-methyl-2-(1-methylethyl)cyclohexyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[2-(4-phenoxyphenyl)ethyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[[4-(1,2,3-Tiada the ol-4-yl)phenyl]methyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-(1-methyl-1-phenylethyl)-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methyl-N-[(5-methyl-2-furanyl)methyl]-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]-4,7-dihydro-5-methyl-2-(trifloromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

7-(3,4-Dichlorophenyl)-N-(4,6-dimethyl-2-pyridinyl)-4,7-dihydro-5-methyl-2-(trifluoromethyl)pyrazole[1,5-a]pyrimidine-6-carboxamide;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin;

1-[[7-(3,4-Dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine.

9. The compound according to claim 1, in which R3* selected from

or

or

10. The compound according to claim 1, in which R7selected from lower alkyl, -CO2(lower alkyl), trifloromethyl, cyano, fluorine or chlorine.

11. The compound 7-(3,4-dichlorophenyl)-6-(5-fluoro-1-methyl-1H-benzimidazole-2-yl)-4,7-dihydro-5-(methoxymethyl)pyrazole[1,5-a]pyrimidine, its enantiomer, solvate or salt.

12. The compound 1-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5-methylpyrazole[1,5-a]pyrimidine-6-yl]carbonyl]-2-(4-forfinal)pyrrolidin, its enantiomers, diastereoisomers, Almaty and salt.

13. Dihydropyrimidinase the compounds of formula

where R3selected from the

or

R4selected from H, -CH3or CH2Och3;

R5selected from H or lower alkyl;

R7selected from N, CH3, CF3, F, Cl or Br;

R8independently selected from H, HE, lower alkyl, -OR11where R11represents lower alkyl or phenyl, Cl, F, Br, CF3or CN, and r is an integer from 1 to 3;

R9is lower alkyl and R10represents F, Cl or Br.

14. The connection 13, in which R represents a

or

R4, R5and R7have the meanings as in clause 13, R8independently selected from F, Cl or Br, a r an integer from 1 to 3.

15. The connection 14, in which R8represents Cl and r is 2.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for improved synthesis of pharmacologically active compound of the formula (A): Method involves the following steps: (a) interaction of compound of the formula (I): with alkaline metal nitrite in the presence of suitable acid to yield compound of the formula (VII): (b) coupling compound of the formula (VII) with compound of the formula (VI): to yield compound of the formula (V): and (c) removal of protection from compound of the formula (V) to yield compound of the formula (A). Compound of the formula (A) possesses property of antagonist of R2T receptors, high metabolic stability and bioavailability. Also, invention relates to a novel intermediate substance of the formula (I) and methods for its synthesis, and to novel intermediate substances used in its synthesis.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

12 cl, 4 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to biologically active compounds and concerns the development of a novel substance - 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazine-7-(4H)-one sodium salt dihydrate of the formula: . This compound is designated for treatment and prophylaxis of diseases caused by viruses that are pathogenic form humans and animals. Proposed compound protects against infections caused by Rift Valley fever virus. Also, it shows activity against viruses of WEE(West Equine Encephalomyelitis), parainfluenza, respiratory-syncytium, Aujeszky's disease virus, avian infectious laryngotracheitis virus, avian influenza virus - totally against above 10 RNA- and DNA-containing viruses. The proposed compound is active in curative schedule of its using that is especially valuable.

EFFECT: valuable medicinal properties of compound.

1 cl, 6 tbl, 2 dwg, 7 ex

FIELD: organic chemistry, medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to novel 3,7-diazabicyclo[3.3.0]octanes of the formula (I): wherein wavy lines mean the possible relative cis- or trans-stereochemistry; R means (C1-C12)-alkyl (possibly substituted and/or terminating by one or more groups chosen from aryl, Het1, -C(O)R5a, -OR5b, -N(R6)R5c, -C(O)XR7, -C(O)N(R8)R5d and -S(O)2R9), Het2, -C(O)R5a, -C(O)XR7 or -S(O)2R9 wherein R5a - R5d in each case mean independently hydrogen atom (H), (C1-C6)-alkyl (possibly substituted and/or terminating by one or more substitute chosen from -OH, (C1-C6)-alkoxy-group, cyano-group, aryl, Het3 and -NHC(O)R10), aryl or Het4; R10means H, (C1-C4)-alkyl; R6 means H, aryl; X means oxygen atom (O); R7 means in each case (C1-C12)-alkyl (wherein alkyl group can be substituted and/or terminating by one substitute chosen from -OH, cyano-group, (C1-C6)-alkoxy-group, -SO2R13a, -C(O)R13b and Het5) wherein R13a and R13b mean independently (C1-C6)-alkyl; R8 means in each case H, (C1-C12)-alkyl, (C1-C6)-alkoxy-group (wherein two latter groups are substituted possibly and/or terminating by one substitute chosen from -OH, (C1-C4)-alkyl and (C1-C4)-alkoxy-group), -D-aryl, -D-Het6, -D-S(O)2R15a wherein R15a means independently aryl; D means a direct bond or (C1-C6)-alkylene; R9 means in each case (C1-C6)-alkyl (possibly substituted and/or terminating by one substitute chosen from aryl) or aryl; R2 means H, -E-OR16, -E-N(R17)R18 or in common with R3 represent =O; R3 means H or in common with R2 represent =O; R16 means H, (C1-C6)-alkyl or -E-aryl; R17 means H; R18 means H; E means in each case a direct bond or (C1-C4)-alkylene; A means -G-; B means -Z-, -Z-N(R22)-Z-, -Z-S(O)n-. -Z-O- (wherein in two latter groups Z is bound to carbon atom carrying R2 and R3); G means a direct bond or (C1-C6)-alkylene; Z means a direct bond or (C1-C4)-alkylene; R22 means independently H; R4 means aryl or het13 wherein both these groups are substituted possibly with one or more substitute chosen from -OH, cyano-group, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -C(O)R24c or -S(O)nR23c; Het13 means 5-6-membered heterocyclic group comprising one or more heteroatoms chosen from oxygen, nitrogen and/or sulfur; Het1 - Het6 in each case mean independently 5-6-membered heterocyclic groups comprising one or more heteroatoms chosen from oxygen, nitrogen and/or sulfur wherein these heterocyclic groups are substituted possibly with one or more substitutes comprising (C1-C6)-alkyl or -C(O)R24c wherein R23c means in each case independently (C1-C6)-alkyl; R24c means in each case H or (C1-C6)-alkyl; n means 0, 1 or 2 in each case; Ra - R1 mean independently H or (C1-C4)-alkyl wherein each aryl or aryloxy-group (if not indicated otherwise) is substituted possibly with one or more substitutes chosen from -OH, cyano-group, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -C(O)R24c or -S(O)nR23c; or it pharmaceutically acceptable derivative under condition that: (a) when R2 means -E-OR16 or -E-N(R17)R18 wherein E means a direct bond then: (1) A can't mean a direct bond; and (2) B doesn't mean -N(R22)-, -S(O)n-. -O- or -N(R22)-Z- (wherein in the latter group -N(R22) is bound to carbon atom carrying R2 and R3; (b) this compound is not 3,7-bis-(1-phenylethyl)-3,7-diazabicyclo[3.3.0]octane, 3-methyl-7-benzyl-3,7-diazabicyclo[3.3.0], 3-cyclohexyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(thiazol-2-yl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(2-pyrimidyl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(5,5-dimethoxy)pentyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane; (c) when R in common with R3 represent =O, and B means -Z-N(R22)- or -N(R22)-Z- then G is not a direct bond. Compounds of the formula (I) can be used as components of a pharmaceutical composition in treatment or prophylaxis of arrhythmia. Also, invention describes methods for its synthesis and intermediate compounds used in these methods.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

38 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel compound 4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)[1,5-a]-1,3,5-triazine of the formula (I):

, its steroisomeric forms or pharmaceutically acceptable salts, pharmaceutical composition comprising thereof and its using for preparing pharmaceutical composition used in treatment of anxiety in mammals.

EFFECT: valuable medicinal property of compound and pharmaceutical composition.

7 cl, 2 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and its pharmaceutically acceptable salts possessing properties of tumor necrosis factor (TNF-α) and to pharmaceutical composition based on thereof wherein R1 means substituted or unsubstituted phenyl wherein substitutes are chosen from halogen atoms or halide-(C1-C6)-alkyl; R4b is substituted or unsubstituted with 1-3 aryl substituted chosen from phenyl, naphthyl wherein substitutes are chosen from halogen atoms, (C1-C6)-alkyl, halide-(C1-C6)-alkyl, (C1-C6)-alkoxyl, cyano-, amino-, (C1-C6)-acylamino-group, (C1-C6)-alkanesulfonyl, or two adjacent substitutes in benzene ring form dioxol group, or unsubstituted or substituted 6-membered nitrogen-containing heteroaryl with 1-3 nitrogen atoms in ring wherein substitutes are chosen from halogen atoms.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 9 sch, 10 tbl, 15 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel pyrimidotriazines of the general formula (I):

wherein each R1 and R2 is chosen from the group comprising hydrogen atom, or R1 and R2 form in common chemical bond, -CH2-Ar and Ar is chosen from the group comprising unsubstituted phenyl, unsubstituted naphthyl, phenyl, mono- or disubstituted with (lower)-alkoxy-group and naphthyl mono- or disubstituted with (lower)-alkyl, or their pharmaceutically acceptable salts. Also, invention relates to a method for synthesis of these compounds, pharmaceutical composition based on thereof and to using novel pyrimidotriazines for prophylaxis and/or treatment of diabetes mellitus as these compounds possess the strong expressed inhibitory effect on activity of protein tyrosine phosphatase PTP1B.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 27 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: pharmaceutical industry, in particular method for production of lappaconitine hydrobromide.

SUBSTANCE: claimed method includes extraction of aconite grass with sulfuric acid aqueous solution at certain conditions; alkalization up to weak-acid reaction; alkaloid isolating with organic solvent; purification with activated carbon; chromatography on alumina; precipitation of lappaconitine base with acetone; and brominating in alcohol solution.

EFFECT: method of high yield; lappaconitine hydrobromide of improved purity.

5 cl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anthranilic acid amides with a by-side heteroarylsulfonyl chain. Invention describes compounds of the formula (I): wherein R1 means compounds of formulae: or wherein A means -CnH2n- wherein n = 0, 1, 2, 3, 4 or 5; D means a bond or -O-; E means -CmH2m- wherein m = 0, 1, 2, 3, 4 or 5; R8 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or -CpH2p-R14 wherein p = 1, 2, 3, 4 or 5; R14 means phenyl or heteroaryl wherein phenyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting fluorine (F), chlorine (Cl), bromine (Br) and iodine (J) atom, alkyl with 1, 2, 3 or 4 carbon atoms; R9 means hydrogen atom or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; R10 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon toms, phenyl, naphthyl or heteroaryl wherein phenyl, naphthyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R11 means cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl, furyl, pyridyl, pyrazinyl wherein phenyl, furyl, pyridyl, pyrazinyl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms; R12 means alkyl with 1, 2, 3 or 4 carbon atoms, alkynyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl or heteroaryl; R13 means -CpH2p-R14 wherein p = 0, 1, 2, 3, 4 or 5; R15 means cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms; R2 means hydrogen atom; R3 means heteroaryl wherein heteroaryl is unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R4, R5, R6 and R7 mean independently of one another hydrogen atom, F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms, and their pharmaceutically acceptable salts also. Also, invention describes pharmaceutical composition containing compounds of the formula (I) possessing the effect blocking Kv1.5-channel. Proposed compounds can be used in treatment and prophylaxis of diseases mediated by K+-channel.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

20 cl, 4 tbl, 70 ex

FIELD: organic chemistry, medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to novel 3,7-diazabicyclo[3.3.0]octanes of the formula (I): wherein wavy lines mean the possible relative cis- or trans-stereochemistry; R means (C1-C12)-alkyl (possibly substituted and/or terminating by one or more groups chosen from aryl, Het1, -C(O)R5a, -OR5b, -N(R6)R5c, -C(O)XR7, -C(O)N(R8)R5d and -S(O)2R9), Het2, -C(O)R5a, -C(O)XR7 or -S(O)2R9 wherein R5a - R5d in each case mean independently hydrogen atom (H), (C1-C6)-alkyl (possibly substituted and/or terminating by one or more substitute chosen from -OH, (C1-C6)-alkoxy-group, cyano-group, aryl, Het3 and -NHC(O)R10), aryl or Het4; R10means H, (C1-C4)-alkyl; R6 means H, aryl; X means oxygen atom (O); R7 means in each case (C1-C12)-alkyl (wherein alkyl group can be substituted and/or terminating by one substitute chosen from -OH, cyano-group, (C1-C6)-alkoxy-group, -SO2R13a, -C(O)R13b and Het5) wherein R13a and R13b mean independently (C1-C6)-alkyl; R8 means in each case H, (C1-C12)-alkyl, (C1-C6)-alkoxy-group (wherein two latter groups are substituted possibly and/or terminating by one substitute chosen from -OH, (C1-C4)-alkyl and (C1-C4)-alkoxy-group), -D-aryl, -D-Het6, -D-S(O)2R15a wherein R15a means independently aryl; D means a direct bond or (C1-C6)-alkylene; R9 means in each case (C1-C6)-alkyl (possibly substituted and/or terminating by one substitute chosen from aryl) or aryl; R2 means H, -E-OR16, -E-N(R17)R18 or in common with R3 represent =O; R3 means H or in common with R2 represent =O; R16 means H, (C1-C6)-alkyl or -E-aryl; R17 means H; R18 means H; E means in each case a direct bond or (C1-C4)-alkylene; A means -G-; B means -Z-, -Z-N(R22)-Z-, -Z-S(O)n-. -Z-O- (wherein in two latter groups Z is bound to carbon atom carrying R2 and R3); G means a direct bond or (C1-C6)-alkylene; Z means a direct bond or (C1-C4)-alkylene; R22 means independently H; R4 means aryl or het13 wherein both these groups are substituted possibly with one or more substitute chosen from -OH, cyano-group, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -C(O)R24c or -S(O)nR23c; Het13 means 5-6-membered heterocyclic group comprising one or more heteroatoms chosen from oxygen, nitrogen and/or sulfur; Het1 - Het6 in each case mean independently 5-6-membered heterocyclic groups comprising one or more heteroatoms chosen from oxygen, nitrogen and/or sulfur wherein these heterocyclic groups are substituted possibly with one or more substitutes comprising (C1-C6)-alkyl or -C(O)R24c wherein R23c means in each case independently (C1-C6)-alkyl; R24c means in each case H or (C1-C6)-alkyl; n means 0, 1 or 2 in each case; Ra - R1 mean independently H or (C1-C4)-alkyl wherein each aryl or aryloxy-group (if not indicated otherwise) is substituted possibly with one or more substitutes chosen from -OH, cyano-group, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -C(O)R24c or -S(O)nR23c; or it pharmaceutically acceptable derivative under condition that: (a) when R2 means -E-OR16 or -E-N(R17)R18 wherein E means a direct bond then: (1) A can't mean a direct bond; and (2) B doesn't mean -N(R22)-, -S(O)n-. -O- or -N(R22)-Z- (wherein in the latter group -N(R22) is bound to carbon atom carrying R2 and R3; (b) this compound is not 3,7-bis-(1-phenylethyl)-3,7-diazabicyclo[3.3.0]octane, 3-methyl-7-benzyl-3,7-diazabicyclo[3.3.0], 3-cyclohexyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(thiazol-2-yl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(2-pyrimidyl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(5,5-dimethoxy)pentyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane; (c) when R in common with R3 represent =O, and B means -Z-N(R22)- or -N(R22)-Z- then G is not a direct bond. Compounds of the formula (I) can be used as components of a pharmaceutical composition in treatment or prophylaxis of arrhythmia. Also, invention describes methods for its synthesis and intermediate compounds used in these methods.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

38 cl, 6 ex

FIELD: medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to an anti-arrhythmic medicament in combination with amiodarone that comprises thiotriazoline in the ratio to amiodarone = 1:2 by dry matter. Proposed medicament possesses the more expressed anti-arrhythmic effect as compared with prototype (preparation amiodarone).

EFFECT: enhanced and valuable medicinal property of agent.

2 cl, 4 tbl, 4 dwg, 2 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to derivatives of benzopyrane of the formula (1)

or the formula (2) ,

wherein each R1 and R2 means independently of one another hydrogen atom; R3 means hydroxyl group; R4 means hydrogen atom; R5 means (C1-C6)-alkyl group substituted with (C6-C14)-aryl group wherein indicated (C1-C6)-group can be substituted optionally with hydroxyl, methyl group and indicated (C6-C14)-aryl group can be substitute optionally with 1-3 radicals R7 (wherein R7 represents halogen atom or amino-group) or linear (C5-C8)-alkyl group; R6 means (C1-C6)-alkyl group (wherein indicated alkyl group can be substituted optionally with hydroxyl or amino-group), halogen atom, nitro-group or -C(O)NH2 but excluding compound of the formula (1) wherein R means -NO2 at position 6; R5 means -CH2CH2Ph, and R1 and R2 mean methyl group, and compound of the formula (1) wherein R6 means bromine atom at position 6; R5 means benzyl and R1 and R2 mean methyl group, or their pharmaceutically acceptable salts, and a pharmaceutical preparation based on thereof. Proposed compounds are useful as anti-arrhythmic agents.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 7 tbl, 26 ex

FIELD: medicine.

SUBSTANCE: invention relates to application of Acizol, namely bis(1-vinylimidazole) zinc diacetate as coronary active anti-ischemia and anti-arrhythmia agent. Acizol makes it possible to limit development of necrosis zone in acute myocardium ischemia, to reduce frequency of complications and fatal cases, to normalize antrioventricular and intraventricular electrical conductivity , to prevent ciliary arrythmia.

EFFECT: improved anti-ischemia and anti-arrhythmia agent.

15 tbl, 7 dwg, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel solid formulation of anti-arrhythmic medicinal agents. Invention describes crystalline formulation of 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)-benznitrile, tert.-butyl-2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-dizabicyclo[3.3.1]non-3-yl}ethylcarbamate, tert.-butyl-2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate or tert.-butyl-2-{7-[(25)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate and their pharmaceutically acceptable salts. Also, invention describes methods for their synthesis, a pharmaceutical preparation based on thereof, a method for prophylaxis or treatment of arrhythmia and their using.

EFFECT: valuable medicinal properties of compounds and pharmaceutical preparation.

73 cl, 22 dwg, 22 tbl, 23 ex

FIELD: pharmaceuticals, organic chemistry.

SUBSTANCE: invention relates to anthranilic acid amides of general formula I , wherein R1 represents or

R2 represents hydrogen or alkyl; R3 represents dialkoxyphenyl; R4, R5, R6, R7 represent hydrogen, halogen alkyl. Pharmaceutical composition based on compounds of formula I and uses thereof in pharmaceutical agent production. Abovementioned compounds are useful as antiarrhythmic biologically active agents in particular for prevention and prophylaxis of arrhythmias.

EFFECT: new agents for prevention and prophylaxis of arrhythmias.

13 cl, 152 ex

FIELD: medicine, cardiology.

SUBSTANCE: invention relates to prophylaxis of disorders of the cardiac activity rhythm. Method involves simultaneous administration of para-aminobenzoic acid β-diethylaminoethylamide and 3-(2,2,2-trimethylhydrazinium)propionate dihydrate, 30-40 min before the suggested development of disorders of cardiac activity rhythm. Such performance of method allows carrying out the effective prophylactic of disorders of cardiac rhythm caused by arhythmogenic factor of different etiology.

EFFECT: improved method of prophylaxis.

2 cl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bis-aryl compounds of the formula (I): wherein one among A1-A4 means nitrogen atom and others mean -CH or -CR5; A5-A8 mean -CH or -CR5; R5 means halogen atom or (C1-C)-alkyl; R(1) means -C(O)OR(9), -COR(11); R(9) and R(11) mean CxH2x-R(14); x means 0, 1,2, 3 or 4 and x can't mean 0 if R(14) means -OR(15); R(14) means (C1-C6)-alkyl or phenyl; R(15) means (C1-C5)-alkyl; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y means 0, 1, 2, 3 or 4 and y can't mean 0 if R(16) means -OR(17); R(16) means (C1-C6)-alkyl, phenyl or pyridyl; R(17) means hydrogen atom, (C1-C5)-alkyl, phenyl or pyridyl, or R(3) means -CHR(18)R(19); R(18) means hydrogen atom or CzH2z-R(16) wherein R(16) means abovementioned values; z means 0, 1, 2 or 3; R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and to their pharmaceutically acceptable salts also. Compounds of the formula (I) possess anti-arrhythmic activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

11 cl, 30 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

Up!