SA05260424B1 - fused pyrazole derivatives and methods of treatment - Google Patents

Abstract

Abstract: The present invention relates to certain fused pyrazole derivatives having the formula (Ia), and pharmaceutically acceptable salts thereof, showing useful pharmacological properties as auxiliaries, for example, for the RUP25 receptor. Through the present invention, pharmaceutical formulations containing the compounds of the invention and methods for using the compounds and compositions of the invention in the treatment of Metabolic disorders, including dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, type 2 diabetes, Syndrome X and the like. In addition, the present invention also provides for the use of compounds of the invention in combination with active agents such as those belonging to the class of ɑ-glucosidase inhibitors, aldose reductase inhibitors, biguanides, HMG-CoA reductase inhibitors, squalene and fibrate synthesis inhibitors, LDL catabolism enhancers, and ACE inhibitors. angiotensin) and insulin secretion enhancers, DP receptor antagonists and the like. Number of Claims (71) Number of Claims (71)

Description

Fused Pyrazole Derivatives and Methods of Treatment of Metabolic-Related Disorders Thereof Useful as eg adjuvants for RUP25 acid receptor 01016l0. The present invention Lad provides pharmaceutical compositions containing one or more compounds of the invention and methods for using compounds and compositions of the invention in the treatment of metabolic disorders; These include dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, type 2 diabetes, X= syndrome, and the like. In addition; The present invention also provides for the use of the compounds of the invention in combination with Aled agents such as those belonging to the class of -” glucosidase inhibitors, aldose reductase inhibitors, 5180801068, HMG-CoA reductase inhibitors, and squalene fibrates synthesis inhibitors. and enhancers of catabolism — LDL, angiotensin converting enzyme (ACE) inhibitors, thiazolidinedione s insulin enhancers, DP receptor antagonists, and the like. Compounds of the invention as anti-lipolysis agents: vo atherosclerosis and stroke are the No. 1 and No. 1 cause of death in both men and women in the United States. Type 2 diabetes is a serious public health problem that is widespread and on the rise. F

tuck

Elevated levels of low-density lipoprotein (LDL) cholesterol, or levels

low for HDL cholesterol (1101); Severally; dangerous factors

For atherosclerosis and its associated cardiovascular disease manifestations. In addition;

Elevated levels of free fatty acids in plasma have been associated with insulin resistance and type 2 diabetes. One of the esters is to lower LDL-cholesterol and increase it

Cholesterol - HDL and reduce free fatty acids in plasma in inhibition

Lipolysis in adipose tissue. This method involves regulating the hormone-sensitive lipase enzyme;

which is the rate-limiting enzyme in lipolysis. Increases lipolysis factors

Cellular levels of cAMP that lead to activation of the hormone-sensitive lipase enzyme within 0 fat cells. And on the contrary; Factors that lower levels of Jala cAMP can

To be anti-lipolysis.

What is also worth noting when this is skipped is the increase in cellular levels of cAMP

lead to a controlled decrease in the secretion of 80100080000 fatty acids LOAD :

ML et al.

Biochem J (2002) July]. Low levels have been accompanied

Lal adiponectin 10 in food-related disorders, J Ball; Including atherosclerosis

atherosclerosis, coronary heart disease, insulin resistance, and diabetes

: Type II (= diabetes

[Matsuda, M et al.

J Biol Chem (2002) July and reviewed therein]

Nicotinic acid (niacin, pyridine-3-carboxylic acid) is a water-soluble Sls vitamin.

© It is needed by the human body for health, growth and reproduction; It is part of the vitamin 5 complex. And it is considered

_— $ _ Lad nicotinic acid is one of the oldest drugs used in the treatment of blood lipid imbalances. It is considered a valuable drug in that it effectively and appropriately affects each of the lipid-influencing agents described previously. Goodman and Gilman's Pharmacological Basis of Therapeutics, editors Harmon JG [[and Limbird LE, Chapter 36, Mahley RW and Bersot TP (2001) pages 971-1002 0 The benefits of nicotinic acid in the treatment or prevention of atherosclerotic cardiovascular disease have been documented in six major clinical trials: [Guyton JR (1998) Am J Cardiol 1 8U-23U] and it has been recently discussed nicotinic acid and related derivatives; Lorenzen, A et al (2001) Molecular Pharmacology Jacipimox 59:349-357]. The synthesis and synthesis of additional nicotinic acid analogues and derivatives] at each position in the sMerck index are discussed in An Encyclopedia of Chemicals, Drugs, and Biologicals, Tenth “Edition (1983) which is fully incorporated herein by reference. nicotinic acid inhibits the production and release of free fatty acids from adipose tissue; Possibly by inhibiting adenylyl cyclase and decreasing intracellular levels of cAMP yo with a concomitant decrease in the activity of HSL+ and aids in a controlled decrease in HSL activity. It leads to ait in plasma free fatty acid levels and potentially has therapeutic value. The result is a reduction of free fatty acids in the plasma for two reasons. First, it completely lowers IDL-cholesterol levels and raises HDL-cholesterol levels = Yvaa.

Thus, independent risk factors are reduced; and the risk of death due to the occurrence of cardiovascular disease after the formation of pastyoma. cals because it also provides an increase in insulin sensitivity in individuals who have insulin resistance or who have type 2 diabetes. Unfortunately;" The use of acid is partially reduced by its manufacture - with a number of associated adverse side effects. These include irritability, free fatty acid reflux, and liver toxicity. The rationale for nicotinic acid receptor agonists that have few side effects is valuable in this regard. However, this has been hampered to date by the inability to molecularly identify the nicotinic acid receptor. Furthermore; It is possible that other receptors of the same (Ail) 0 on the surface of fat cells lead to a decrease in the activity of the hormone-sensitive enzyme lipase enzyme diagonally through a reduction in the level of the cell Jala cAMP, but without showing adverse effects such as irritation; Thus, promising new therapeutic targets are presented. The present work suggests that acid 01010016 potentially functions through a qualitative GPCR: [Lorenzen A, et al (2001) Molecular Pharmacology 59:349-357 and reviewed therein] Effects of nicotinic acid on macrophages, on the spleen, and possibly on adipocytes by this specific GPCR. Lorenzen A, et al. (2002) Biochemical Pharmacology 64:645-648 and reviewed [therein]

General description of the invention The present invention is then directed towards compounds that bind with and activate receptor 110025; and its uses. The term RUP25 as used herein includes human sequences in GenBank accession number 1184-177551 for the nucleotide and in GeneBank © accession number NP-808219 for the polypeptide and for naturally occurring conjugate variants and genes of common origin and the products of mutations thereof to the product of genetic recombination. An aspect of the present invention relates to certain fused pyrazole derivatives as represented by the formula (Ia) Rj X. N—H Q ie Rs Rg (Ia) 01, salt, or hydrates or solubles thereof are acceptable raw, where: X is 07 and 72 is B5©; Or X is “CRy” and 2 is “N” Ry, and each of them is chosen separately from the group that is from acyl Cres H with acyloxy and alkoxy cis alkenyl and alkyl m from alkylamino Yemen alkynyl Cj alkylthiocarboxamide C,.¢ alkylcarboxamide 0 and alkylsulfonamide Yvasa

Cis alkylthioureyl Cis alkylthio Cis alkylsulfinyl Cie alkylsulfinyl Cig and alkylsulfinyl Cis amino alkylamido Cs amino alkylureyl and carboxy carboxamide s alkoxy — C,¢ — carbo alkylthioamido from and kylcarboxamide ware dialkylamino C65 cycloalkyl C575 cy ano and haloalkyl C,¢s haloalkoxy ware halogens dialkylthiocarboxamide Cig © cyclic 4c gana haloalkyl thio Cys haloalkyl sulfinyl and haloalkylsulfinyl Cj. ¢ thiol 3 sulfonamides nitro s hydroxyls heterocyclic heterocyclic

Ciss acyl Cres H and each of them is selected separately from the group that consists of Ry Yemen alkylamino Ces alkyl Cis alkoxy Cies alkenyl Cig acyloxy alkylsulfonamide C;¢s alkynyl and mo alkylthiocarboxamide and 0 alkylcarboxamide 0

Cis alkylthioureyl Cs alkylthio C4 alkylsulfinyl from alkylsulfinyl Cg and alkylsulfinyl from amino alkylamido C;¢s amino alkylureyl carbo 3 carbamidoyl s arylthio ys arylsulfonyl s arylsulfinyl sy alkylthioamido bitter and cycloalkyl cvanoy carboxy carboxamide alkoxy — Cg — and dialkylcarboxamide Cis dialkylamino Cy. cycloalkyloxy M atmosphere and dialkylthioamido C4 dialkylamido - C4 dialkylthiocarboxamide M and haloalkylsulfinyl Cis haloalkyl Css haloalkoxy C;ss halogen M"

- m heterocyclic and haloalkyl thio heterocyclic group m haloalkyl sulfinyl heterocyclic sulfonyl and heterocyclic oxy group and heteroaryl s heterocyclic group and group homologous carbonyl and heterocyclic group patterns; Where the sulfonic acids sulfonamides and the aforementioned heteroaryl carbonyl compounds have substitution groups to be selected from alkyl ©, there is an optional substitution in the group of ©, alkylamine, alkoxy, acyloxy, and acyl Cig The group consisting of - and their positions - yin amino alkylthio whey alkylsulfinyl whey alkylsulfinyl mer cycloalkyloxy 0 cycloalkyl gene cyanos carboxys carboxamide alkoxy haloalkyl cis haloalkylsulfinyl C;¢s haloalkoxy C;4s dialkylamino Maine or ¢ phenyl and phenoxy nitro s hydroxyls haloalkyl thio and sulfinyl 0 ¢ cycloalkyl ye dc sana of them have JS d and 18 form with the carbon atom that acyl Cres H is bonded with And with each of them being selected separately from the group consisting of Rs, alkylamine, alkyl, alkoxy, alkynyl, acyloxy alkylsulfonamide, C,4 alkynyl, alkylthiocarboxamide, and M0 alkylcarboxamide

Cis alkylthioureyl Cs alkylthio Cis alkylsulfinyl Cis alkylsulfinyl Cis Vo

C375 cyano carboxys carboxamide alkoxy Cy — carbos amino alkylureyl dialkylcarboxamide Cis dialkylamino cycloalkyl

and b halogens dialkylthiocarboxamide m haloalkoxy n haloalkyl rum haloalkylsulfinyl or haloalkyl thio C 4s haloalkyl sulfinyl and a heterocyclic group thiol 3 sulfonamide s nitro s hydroxyl s heterocyclic ¢ and b alkoxy group Crs - carbo, carboxy, or tetrazol-5-yl.

0 and in some embodiments; Ras Ry is sis to each other. Another aspect of the present invention relates to pharmaceutical compositions which comprise a compound of the present invention in combination with a pharmaceutically acceptable carrier. Another aspect of the present invention 2 relates to pharmaceutical formulations as described herein; It also includes one or more agents selected from the group consisting of an a-glucosidase inhibitor

0 bday biguanides aldose reductase inhibitor HMG-CoA reductase inhibitor squalene fibrates synthesis inhibitor catabolism LDL metabolism booster angiotensin converting enzyme inhibitor thiazolidinedione s insulin secretion booster DP receptor antagonist Another aspect of the present invention relates to methods of treating Jad je metabolic disorder involving giving a person in need of such treatment a therapeutically effective amount of the compound of the invention

1 the current drug or a pharmaceutical formulation thereof. Another aspect of the present invention relates to methods for reducing VLDL or VLDL levels in a particular person; It includes giving the aforementioned person who is in need of that treatment a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition thereof.

Ve = - Another aspect of the present invention relates to methods for reducing serum triglyceride levels in a given person; It includes giving the aforementioned person in need of that treatment a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition thereof. An aspect of the AT of the present invention relates to methods for reducing serum LP(a) levels in a given individual; It includes giving the aforementioned person in need of that treatment a therapeutically effective amount of

The compound of the present invention or a pharmaceutical composition thereof. An aspect of the AT of the present invention relates to methods for treating a metabolic disorder; involves administering to a person in need of such treatment a therapeutically effective amount of the compound of the present invention and an antagonist of the DP receptor

0 Another aspect of the present invention relates to methods to modify the receptor RUP2S involving receptor contact and an aspect jal of the invention all relates to methods to modify the receptor 8171725 for the treatment of a disorder associated with an active amount Ladle of a compound of the present invention.

Another aspect of the invention Mal relates to compounds; where the compound is an adjuvant. Another aspect of the present invention relates to compounds; where the compound is a partial adjuvant.

YYa4q

The DAT profile of the present invention relates to methods for treating atherosclerosis in which it is effective in treating atherosclerosis. Another aspect of the present invention relates to methods of treating dyslipidemia oe in a human patient in need of such treatment; It involves giving the patient the choice 2 compound in the amount that is effective in treating blood lipid imbalances. Another appearance is related to Select | Current methods for raising HDL in a person “pia” include giving that person a therapeutically effective amount of the compound of the present invention. Another aspect of the present invention relates to compounds of the present invention for use in a method for therapeutic treatment of the human or animal body. Another aspect of the present invention relates to compounds of the present invention for use in a method of therapeutically treating a disorder associated with the metabolism of the human or animal body. Another aspect of the present invention relates to the use of compounds of the present invention in the production of a drug for use in the treatment of a metabolic disorder. Vo and in some Zila the present invention; The metabolic disorder is from the group consisting of dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, obesity, impaired glucose tolerance, and intolerance. atheromatous disease

Hypertension, stroke, Syndrome 1, and heart disease

Heart disease and diabetes 01806168 _ of the second type. and in some embodiments; He is

A metabolic disorder is an imbalance of blood lipids or atherosclerosis

Or coronary heart disease, or insulin resistance, and type 2 diabetes mellitus.

and in some models; A metabolic disorder is an imbalance of lipid profile

in the blood. and in some embodiments; A metabolic disorder is hardening

My porridge. and in some embodiments; A metabolic disorder is a disease

Coronary heart. and in some embodiments; Metabolic disorder 01 is insulin resistance. and in ax forms; The associated perturbation Jal

Diet is type 2 diabetes.

Some embodiments of the present invention relate to ways in which an individual is a mammal.

Some embodiments of the present invention relate to ways in which a mammal is a human being.

The jal aspect of the present invention relates to methods for producing a pharmaceutical composition involving the mixing of at least one vo compound of the present invention and a pharmaceutically acceptable carrier or excipient.

In this document, the aspects of the invention that are disclosed are indicated in addition to other aspects

Appearances are further elaborated as the Innocence unfolds.

_ \ v —

Detailed description:

Practical references have adopted several conventions for consistency and clarity; will be used

The following definitions are everywhere in this patent document.

The expression “ae lad” means the parts that overlap and activate the receptor, such as the receptor 10025 [lass©] the physiological or pharmacological response characteristic of that receptor. This is when the parts activate, for example

For example, the response within a cell when it binds with a receptor or when it enhances TTP binding with a receptor

membranes.

The term atherosclerosis in this document is intended to contain arterial disorders

Large and medium-sized cells that lead to the gradual accumulation within the deep endothelium of fat and smooth muscle cells.

Chemical group, part or moiety:

The term “© acyl” denotes an alkyl moiety bonded to a carbonyl where the definition of an alkyl is

Same meaning as given in this ARDY Some examples include but are not limited to t-butanoyl, Sec-butanoyls iso-butanoyl, n-butanoyls propionyls acetyl

Vo (ie; Ly pentanoyl ( pivaloyl) cognate.

The expression 'acyloxy Cie' refers to an acyl moiety bonded to an oxygen atom; where the acyl has

Same definition as given in this Aa and some examples include but are not limited to

on:

— ¢ 3 _ acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy, sec-butanoyloxy, t-butanoyloxy and the like. The term alkenyl Cog' refers to moieties containing ? to ge SANT where at least one carbon-carbon double bond exists; And be in some models of? to ; 0 carbon atoms and some embodiments include 2 carbon atoms. Both isomers 5 and 2 are contained by the expression “alkenyl”. Furthermore, the expression “alkenyl” includes .di-enes. Accordingly, if more than one double bond is present; Maid bonds can They are all 8 or 7 or mixtures of Zs E and the abd of the alkenyl includes: vinyl, propenyl, allyl, isopropenyl, 2-methyl-propenyl1-methyl-propenyl, but-1-enyl, but- 01 2-enyl, but-3-enyl, buta-1,3-dienyl, etc. The expression “©,” alkoxy denotes an “alkyl moiety” as defined herein that is directly bonded to an atom of oxygen Examples include: methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy, secondary 1 sec-butoxy and the like. A straight or branched carbon radical containing a number of carbon atoms as shown for example in some embodiments, where the alkyl is a flux

— mg \ — alkyl ©" " and the set contains 1 to ; carbon atoms. The alkyl in some embodiments contains 1 to 0 carbon atoms; It contains in some embodiments 1 to ¥ of carbon atoms and in some embodiments contains 1 carbon atom. Examples of alkyls include, but are not limited to:

methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, sec-butyl 0 and the like. The expression 'carboxamide alkyl Cig'" refers to one alkyl Cig group bonded to the 08 atom of the amide group where the alkyl is the same as defined herein.

The group alkylcarboxamide Cig can be represented by: 0 QA N Cis alkyl H. 0 Examples include, but are not limited to: N-methylcarboxamide, N-ethylcarboxamide, N-n-propylcarboxamide, N-iso - propylcarboxamide, N-n-butylcarboxamide, N-sec-butylcarboxamide, N-iso- butylcarboxamide, N-t-butylcarboxamide and the like. 1 © alkylsulfingl ' refers to a ©, alkyl moiety associated with a sulfoxide moiety of the formula: -(8)0 - where the alkyl moiety has the same definition as given herein. Examples include, but are not limited to:

methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, iso-propylsulfiny], n-butylsulfinyl, sec- butylsulfinyl, iso-butylsulfinyl, t-butyl and the like. To the group: “alkylsulfonamide Cj.” Expression indicates

A

It has SI N C4 68 alkyl

H. ° The same definition that was then mentioned in this document. alkyl cis, where the group - has the formula: sulfone bonded with the alkyl Crs moiety to the 'alkylsulfinyl Cig' moiety, and the expression refers to the same definition that was Mentioned in this document Examples for an alkyl where the S(0) moiety is: include but are not limited to methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, sec- 01 butylsulfonyl, iso -butylsulfonyl, t-butylsulfonyl and the like. It has the formula: sulfide ic gana bonded with alkyl cis to the moiety "alkylthio Cig" and the term refers to the same definition mentioned in this document. Examples include The alkyl moiety of the Cus -8- moiety is: but not limited to 1 and (CH;S-) (i.e.; methylsulfanyl

Yyasa

1 7 —_ _ ethylsulfanyl, n-propylsulfanyl, iso-propylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl, iso-butylsulfanyl, t-butyl and the like. The term 'carboxamide alkylthio' denotes a single alkyl Ci group bonded to a de gana atom! Subsequently:

Ore alkyl has H. Examples include, but are not limited to: N-methylthiocarboxamide, N-ethylthiocarboxamide, N-n-propylthiocarboxamide, N-iso- propylthiocarboxamide, N-n-butylthiocarboxamide, N-sec-butylthiocarboxamide, N -iso- 01 butylthiocarboxamide, N-t-butylthiocarboxamide and the like. The expression “alkylthioureyl Cg” denotes a dc gana of the formula: “NC(S)N—where in one or both nitrogen atoms there is a substitution of similar or different alkyl Cp groups and the alkyl is 0 Same definition as mentioned in this document. Examples of alkylthioureyl include, but are not limited to: Yyas

«(CH3),N(S)NH- «(CH3),N(S)NH- «NHyC(S)NCH;s-5 «CH3NHC(S)NH-

CH3;CH,NHC(S)NCH;3- “CH3CHNHC(S)NH- 5 “(CH3),N(S)NCH3- 5 and the like. Where there is a substitution in “NC(O)N = to a group having the formula: "alkylureyl Cig" and the term alkyl Cig denotes similar or different where the alkyl Ci is with a nitrogen group of one or both of the atoms for example not alkylureyl same definition as mentioned in this document. Examples include: Restriction “(CH;3);N(O)NH-5 “(CH3,N(O)NH-3 {NH,C(O)NCH;-3 “CH3NHC(O)NH) - “CH3;CHNHC(O)NCH;3- 5 « CH3CHpNHC(O)NH- 5 «(CH,3),N(O)NCHj3- 4 and the like. ' to a moiety containing ? to 16 carbon atoms and at least one carbon-carbon triple bond; and is in some embodiments of Os SAY UY and in some embodiments contains two carbons. Examples include alkynyl but not Limit to: ethynyl, prop-1-ynyl, 3-prop-2-ynyl, but-1-ynyl, 1-methyl-prop-2-ynyl, buta-1,3-diynyl, and the like. The term "alkynyl" includes di-ynes Vo, "amino" denotes the "NH" group; "alkylamido Chg'" denotes the "acyl Cr" group as defined herein; associated with The NH group and the 1-6 0 alkylamido group can be represented by the following formula:

0 alky! milliSN H . Examples of the alkylamido group include but not pa all ~NHCOMe, -1100171, and the like. The term alkylsulfinyl Cig - amino' " stands for alkylsulfiny! de sane as defined in © herein; associated with an NH group The amino group = bitter alkylsulfinyl can be represented by the formula: B” Cg alkyl chem SN H 1-6 alky Jo amide alkylthio group examples include but are not limited to ~NHCSMe —NHCSEt and the like.

0 “alkylamino cig’” refers to a single alkyl moiety associated with an amino moiety where the alkyl moiety has the same meaning as given herein. Some examples of it include but are not limited to:

methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino, sec- butylamino, iso-butylamino, t-butylamino

.” alkylamino Cj” and the like. Some embodiments of vo have carbon atoms in the ring. 01 to 1 to an aromatic ring moiety containing the aryl! Expression indicates. naphthyl phenyl and its examples include

= nor and the expression arylsulfinyl "" denotes an aryl group bonded to a sulfoxide moiety of the formula: (5)0 - where the aryl moiety has the same definition as given in this document. The expression "0(0[1]) denotes to an aryl de gene bonded to a sulfonyl moiety having the formula: - «(5)0- where the aryl moiety has the same definition as given herein. oo The term arylthio” denotes the aryl group bonded to a thio moiety of the formula: -8- where the aryl moiety has the same meaning as mentioned in this document. The expression “carbamimidoyl” denotes de gana with the following chemical formula: NH Ns and in some rial Pla) is substituted for one or two hydrogen atoms by another group . For example 1 for a hydroxyl group Jad can replace one hydrogen atom to get an N-hydroxycarbamidoyl group or it can substitute for alkyl de sane replaces one hydrogen atom to obtain: N-methylcarbamidoyl, N-ethylcarbamidoyl, N-propylcarbamimidoyl, N- butylcarbamimidoyl Vo and the like.

Y \ — _ 'alkoxy Cig - carbo' denotes the alkyl ester Cig of a dua carboxylic acid being an alkyl group as defined herein. Examples of these include, but are not limited to: carbomethoxy, carboethoxy, carbopropoxy, carboisopropoxy, carbobutoxy, carbo-sec- butoxy, carbo-iso-butoxy, carbo-t-butoxy ° etc. The term “carboxamide” refers to the group .—~CONH; The expression 'carboxy' or 'carboxyl' denotes the group –COLH and lea a) is denoted as the carboxylic acid group. 0, “cyano” denotes the group ~CN, and “cycloalkyl cap” denotes a saturated ring moiety containing ? to 6 carbon atoms; Some embodiments contain JY© carbon atoms; Some models contain to ; carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the term “.0 cycloalkyloxy” refers to a WS cycloalkyl moiety defined herein that is directly bonded 1 to an oxygen atom. Examples include: cyclopropyloxy, cyclobutyloxy, cyclopentoxy and the like. YYaq

Cause Y Y b_ and “dialkylamino Cog” denotes an amino _ substituted with the same or different alkyl moieties Cua The alkyl moiety has the same definition as given herein. The dialkylamino group can be represented by the following groups: Cia alkyl S—N, Cia alkyl . o Some embodiments include oo dialkylamino Coe such as (alkyl Crs) ~N and the dialkylamino moiety includes For example but not limited to: dimethylamino, methylethylamino, dithylamino, methylpropylamino, methylisopropylamino and the like. 0 The expression 'dialkylamido Cig' ' denotes two alkyl moieties that are the same or different and related to an amido group where the alkyl is the same definition given herein. The group dialkylamido Cig can be represented by the following group : ;o > en alkyl

C16 alkyl dialkylamido Same definition as given in this document. Examples include Crip where is -N(CH3)COCH,CH; and “-N(CH3)COCH;3 to name a few on vo

Y Ay — _ "©" dialkylthioamido denotes two 0 alkyl moieties that are the same or different and are associated with group 10800100; Cua is an alkyl the same definition given in this document. The group dialkylthioamido Cig can be represented by the following group: S $ ce alkyl ~ C45 alkyl . where Crp has the same definition as that given herein. The dialkylthioamido complex includes but is not limited to the methylated Jue “N(CH3)CSCH; (de, -N(CH3)CSCH,CH; and so on. The term dialkylcarboxamide Cig “ ” refers to an alkyl moiety; they are the same or different; they are attached to an amide + group where the alkyl is Same definition as given in this document. dialkylcarboxamide including but not limited to: N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide, N,N-diethylcarboxamide, N- methyl-N-isopropylcarboxamide 0 and the like.

A - The expression 't' dialkylthiocarboxamide refers to JUS 'alkyl moieties that are similar or different; they are attached to a thioamide group where the alkyl is the same definition mentioned in this document. The group sdialkylthiocarboxamide Cg can be represented by the following group :

alkyl 5 to Cig alkyl 0 e, and the compounds of Je dialkylthiocarboxamide include, for example: N,N-dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide | .and the like. The term 'haloalkoxy Cig' ' denotes the WS haloalkyl defined herein; which is directly bonded to an oxygen atom. Examples include but are not limited to: difluoromethoxy, trifluoromethoxy, 2,2,2- trifluoroethoxy, pentafluoroethoxy and the like. in which there is a substitution in all positions of the formula L Cus «Cplone the 'h' 5 halogen represents the number of carbon atoms 0 and when there is more than one halogen position then the halogen 1 positions can be are similar or different and are chosen from the group consisting of F and 01 Bry Ig It is known that the terms 'alkyl' halogens have the same definition as in this document. In some embodiments, haloalkyl is a haloalkyl Cra'" and a set containing 1 z to ; carbon atoms; Some models contain 1 to On SAY ; And some contain

- Yo —

Embodiments contain 1 to 2 carbon atoms and some embodiments contain only one carbon atom. And when there is a substitution in all places of haloalkyl atoms of halogen ; This group is referred to in this document as a haloalkyl, and one of its models is an alkyl replaced in all positions by fluorine atoms, and it is referred to in this document as “perfluoroalkyl”. and in some embodiments; include bd

: but not limited to haloalkyl ° difluoromethyl, fluoromethyl, 2,2,2-trifluoro-ethyl, 2,2-difluoro-ethyl, 2-fluoro-ethyl, 1,2,2-trifluoro-ethyl, 1 ,2-difluoro-ethyl, 1,1-difluoro-ethyl, 1,1,2-trifluoro-ethyl, 3,3,3- trifluoro-propyl, 2,2-difluoro-propyl, 3,3-difluoro-propyl , 3-fluoro-propyl, 2,3,3- trifluoro-propyl, 2,3-Difluoro-propyl, 2,2,3,3,3-pentafluoro-propyl, 2,2,3,3-tetrafluoro-propyl , 2,2,3-trifluoro-propyl, 1,2,3,3-tetrafluoro-propyl, 1,2,3-trifluoro-propyl, 3,3- Ve difluoro-propyl, 1,2,2,3- tetrafluoro-propyl, 4,4-difluoro-butyl, 3,3-difluoro-butyl, 4,4,4- trifluoro-butyl, 3,3-difluoro-butyl, and the like.

In some embodiments, examples of a perfluoroalkyl include, but not limited to, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, 1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl,

1 and the like. The term “haloalkylsulfinyl bitter” refers to a haloalkyl moiety attached to a sulfoxide group having the formula: -(8)0- where the haloalkyl moiety has the same definition as mentioned in this document. The expression “© haloalkyl sulfinyl” denotes a haloalkyl moiety attached to a sulfone group of the formula: – —S(0), where haloalkyl is the same definition given herein.

The term “haloalkyl thio Cig” refers to a haloalkyl moiety directly bonded to a sulfur atom wherein haloalkyl has the same meaning as herein. "halogen" or "halo" denotes fluorine de sana and or chloro or bromo or .iodo 0 and aryl' hetero" denotes an aromatic ring system; it can It is one or two fused rings or three fused lila where at least one carbon atom is replaced by a heterocyclic atom in the ring and the heterocyclic atom is chosen for example but not limited to the group consisting of 0 and 5 (Ns where there can be Optional substitution in the N by hydrogen or by acyl or alkyl Cra Examples of aryl heterocyclic groups include, but are not limited to: pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, isoquinolinyl, quinazolinyl, quinoxalinyl etc. In ary embodiments the heteroaryl aryl atom is 0 or 5 or “NH vo examples include but are not limited to pyrrolyl and Loy indolyl etc. The expression de sana 'heterocyclic' denotes an aromatic ped carbon ring (i.e. cycloalkyl or WS cycloalkenyl is defined herein); where Jad is a heterocyclic atom with one, two, or three carbon atoms replaced in the ring; And the heteroatom is selected for example but not limited to the group consisting of ©, 8 and 11 where Sa is to be present

Optional substitution in the 11th with hydrogen, acyl bitter, or alkyl Cry, and there is an optional substitution in the carbon atoms of the ring with an oxy group or 01000, and thus it is a carbonyl group or a thiocarbonyl group. A heterocyclic group is a ring containing -or, −, ©-, >- or -17 atoms. Examples of M heterocyclic groups include, but are not limited to: aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, piperidin-1-yl , piperidin-4-yl, morpholin-4-yl, piperzin-1-yl, piperzin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, [1,3]-dioxolan-2 -yl. and the like. 0 and the term heteroaryl carbonyl' ' denoted a heteroaryl group as defined herein; it is directly bonded to a carbonyl de sana carbon (i.e. 0 (C=) Examples of aryl groups include Carbonyl heterocyclics include, for example, but not limited to: pyridyl-carbonyl, benzofuranyl-carbonyl, pyrazinyl-carbonyl, pyridazinyl-carbonyl, pyrimidinyl-carbonyl, triazinyl-carbonyl, quinolinyl-carbonyl, benzoxazolyl-carbonyl, benzothiazolyl-carbonyl, 1H-benzimidazolyl-carbonyl, isoquinolinyl-carbonyl, \o quinazolinyl-carbonyl, quinoxalinyl-carbonyl, pyrrole-carbonyl, indolyl-carbonyl and the like.

The term 'carbonyl' heterocyclic' refers to a heterocyclic group as defined herein that is directly bonded to a carbon of the carbonyl group (ie, C=©0). In some embodiments; The ring nitrogen atom of the heterocyclic group is bonded to the carbonyl group forming an amide Examples include but are not limited to: 0 0 0 N oP N but 7 N to Lo 0 , , etc. Oxy' heterocyclic denotes de sana heterocyclic; as defined herein; It is directly bonded to an oxygen atom. Examples include Os 0 0 0 0 sahonlondes HN 0 TN . H , 7 3 > (I> (Tv HN ) 5 : va : 0 and so on. The expression “Als sulfonyl heterocyclic” denotes a heterocyclic group “as defined in This document, together with the ring nitrogen atom, is directly bonded to the SO; group forming a sulfonamide. Examples include but are not limited to Vo: YYaq

and mmh p INT ar add Lo

and the like.

The term “hydroxyl” refers to the -011 group.

"between Als alkyl - oxy" refers to the cycloalkyl bech as defined herein; 0 where carbonyl replaces one of the carbon atoms of the ring. abd includes the oxy gene -

: including but not limited to cycloalkyl

2-0x0-cyclobutyl, 3-oxo-cyclobutyl, 3-oxo-cyclopentyl, 4-oxo-cyclohexyl ¢ and the like

It is represented by the following structural formulas, in order:

0 7 + 5 OQ z ; O b and 0 0 0 ' 0

.~NO; to the group "nitro" and the expression 0

The expression 'phenoxy' refers to the group 0:11,0-.

The term phenyl' refers to the group and 11m0-.

The term 'sulfonamide' stands for -SO;NH; group

The term “sulfonic acid” refers to group 50011-. Vo and the expression “thiol” refers to group 511-.

Yv44

-©. “thicacyl Cig” denotes an alkyl moiety associated with a thiocarbonyl; the definition of alkyl has the same meaning as given herein; some examples include but are not limited to -CSCH,CH. 5-CSCH; and a pharmaceutically acceptable carrier.'Activity of a compound' means a measure of the ability of a compound to inhibit or excite receptor function against the binding affinity of the receptor. -B means "1 I< a ] EE Jad formative" subordinate to Jad | v - a formative. 0 The expression 'configurational receptor activation'' means stabilization of the receptor in the active state by means other than binding of the receptor to its internal ligand group (Lana) or a chemical equivalent thereof. The expressions 'Gad' or 'to come into contact with' mean to bring the parts shown together whether in a system in a laboratory or a system in a living organism. Thus 'contacting' receptor 1817725 with the compound of the invention includes giving the compound of the present invention to an individual such as a human being It includes the receptor compound 16 800025 and also the introduction of the compound of the invention, for example, into a sample containing one or more pure cellular preparations that contain the receptor RUP25. “'Coronary heart disease' in this document means the definition of disorders that include narrowing of the tiny blood vessels that supply blood oxygens to the heart. Coronary heart disease usually results from a buildup of YYaq

Ay \ — — plates and fatty materials. when stenosis of the coronary arteries; The blood flow to the heart can slow or stop. Coronary heart disease can cause chest pain (such as stable angina), shortness of breath, heart attack, or other symptoms. The expression "decrease" is used to mean a reduction in a measurable amount and is used synonymously with the expressions 'tall 0', 'reduce' and 'decreasing' and n A 0 . Uae “diabetes” as used herein means the normal diagnosis of diabetes made by any of the methods including, but not limited to the following list: Symptoms of drunkenness (such as urination, excessive thirst, bulimia) In addition, if the incidental levels of glucose in the plasma are equal to or more than 100 mg/dl, the incidental level of glucose in the plasma is determined at any time during the day, regardless of the times of consumption of meals or drinks, and the glucose levels are determined in Fasting plasma A sad hours equal to or less than 177 mg/dL; determination of plasma glucose levels equal to or greater than 100 mg/dL two hours after administration of Vo g glucose no mani dissolved in water orally. On disorders involving any elevated plasma free fatty acid level or elevated YY44 cholesterol level

Plasma OR High cholesterol = LDL OR Low cholesterol = HDL OR High plasma triglycerides. The expression “in need of treatment” as used herein refers to the decision made by the caregiver (eg doctor, nurse, nurse-worker, etc. in the case of humans; and the veterinarian in All Animals, which includes non-mammals). human) that the individual or animal needs treatment or can benefit from treatment This decision is made depending on a combination of factors within the provider's field of expertise, including knowledge that the person is ill or will be ill as a result of the disease, condition or disorder that is Furthermore, the term “in need of treatment” refers to the “prevention” of an individual, which is the decision by the caregiver that that individual will become ill.In this context, the compounds of the invention are used in a preventive manner Accordingly, “in need of treatment” refers to the caregiver's determination that the individual is or will become ill and that the compounds of the present invention may be used in the mitigation, inhibition, or prevention of disease, condition, or disorder. The term 'individual' as used herein refers to any animal; it includes mammals such as mice1, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, and human beings in an embodiment. In relation to the term 'response', the response is reduced or inhibited in the presence of the compound compared to the response in the absence of the compound. YY4q

The term “insulin resistance” as used herein means the standard diagnosis of insulin resistance that is performed by any number of methods including, but not limited to: an intravenous tolerance test 810060588 or insulin level measurement It is well known that there is an excellent relationship between the high level of insulin during fasting and the degree of insulin resistance.Based on this, we can use the high insulin levels during fasting as an alternative indicator of insulin resistance in order to identify normal people with tolerance. (NGT) glucose in people with insulin resistance A diagnosis of insulin resistance can also be made using the normal blood glucose engagement test The term 'inverted adjuvants' means the parts that bind or bind the endogenous image of the receptor With the constitutively activated form of the receptor that inhibits the baseline intracellular response that fag is the active form of the receptor below the normal baseline level of activity observed in no cofactors, partial cofactors, or reduced GTP binding to membranes.In some embodiments the response is minimally inhibited. inside the cell in the presence of a reverse adjuvant of at least 770; and in other embodiments by at least Ton; and in other models Lad by at least 7975 1 compared to the lower aad response in the absence of the reverse assist. Ae pend' ligand means 'naturally occurring endogenous molecule; determinant of a naturally occurring endogenous receptor. 'Metabolism-related disorders' in this document is intended to include, but is not limited to, lipid imbalances in dyslipidemia axl YYaq obesity, obesity, insulin resistance, coronary heart disease, coronary heart disease, atherosclerosis baa, high atheromatous disease, glucose tolerance, poor tolerance to heart disease, heart disease X, and syndrome stroke stroke, stroke, hypertension, type 2 diabetes, and diabetes mellitus 'modify' or 'modify' as used herein; denotes an increase or decrease in the amount, quality, response, or in the effect of a particular activity, function, or molecule. A “partial cofactor” as used herein means the part that activates a response within the cell, but to a lesser extent compared to RUP25 when bound to a receptor (such as a receptor). The complete helper The expression of the partial helper is a relative expression, where the partial helper produces a partial response compared to the response of the total helper. It is known that when new 0 compounds are discovered, over time, the compound can be changed later once it is described as a total adjuvant to a partial compound, depending on the discovery of a new total adjuvant. Disease or condition; A composition for the prophylaxis, treatment or control of a compound of the present invention comprising Jie salts and comprising at least one active compound thereof and one carrier on pharmaceutically acceptable hydrates and/or solutes and/or 0 The term 'pharmaceutically acceptable carrier or excipient' means any essentially inert substance used as a diluent or any excipient of a compound of the present invention.

— MG 7 -_ The term 'Ladle effective amount' as used herein refers to the amount of an active compound or pharmaceutical agent that induces a biological or medical response in a tissue, system, animal, individual or human body of interest to the researcher , veterinarian, attending physician, or other clinical physician and includes one or more of the following: ° (1) Patient prevention such as preventing a disease, condition or disorder in an individual who may have a predisposition to the disease, condition or disorder but has not suffered (7) Disease suppression”; i.e., inhibition of a disease, condition, or disorder in an individual who suffers or manifests a pathogen or combination of symptoms of a disease, condition, or disorder (Ve) looking at further developments of the aetiology and/or set of symptoms of the disease); and (las -©) the disease; such as improvement of the disease, condition, or disorder in an individual who has or manifests the aetiology or set of symptoms of the disease, condition, or disorder (ie; Reflection of the aetiology and/or combination of symptoms of the disease). B Rs Rs (Ia).

Ris and 2X are pharmaceutically acceptable. Where the groups have 55 5 hydrates J or a salt and the same definitions mentioned in this document previously and later. Rss Ry 5 Rss Ros specific incorporators as represented by the formula pyrazole One aspect of the present invention relates to derivatives or solubles thereof pharmaceutically acceptable; Where: hydrates or salt Ia

N is CRy is X or “CR; and 7 be iN m * be acyl rmen, each of which is selected separately from the group that consists of 04.11 Ras Ry

Ciss alkylamino Cigy alkyl Cig alkoxy Ces alkenyl Cis acyloxy alkylsulfonamide Cj. alkynyl Cys alkylthiocarboxamide and alkylcarboxamide

Cis alkylthioureyl rum alkylthio Cig alkylsulfinyl from alkylsulfinyl rumen and alkylsulfinyl M0 amino alkylamido rumen amino 3 alkylureyl 0 cyanos carboxy carboxamide alkoxy — Cig — carboy alkylthioamido M s dialkylcarboxamide Cisky diallamino Cy. s cycloalkyl joule Criss haloalkyl Cig haloalkoxy m halogen s dialkylthiocarboxamide from and a non-cyclic group haloalkyl thio Cj haloalkyl sulfinyl m haloalkylsulfinyl ¢ thiol y sulfonamide 5 nitro s hydroxyl s heterocyclic congener 1 of acyl and 18 are selected separately from the group that consists of 04.11 Ry Roman alkylamino C4 alkyl M alkoxy Ciss alkenyl Cig acyloxy alkylsulfonamide repair alkynyl Cos alkylthiocarboxamide ware alkylcarboxamide

YYdsd

Cres alkylthioureyl C45 alkylthio yemen alkylsulfinyl Cis alkylsulfinyl and alkylsulfinyl from amino alkylamido Cs amino y alkylureyl and carbamidoyl 3 arylthio s arylsulfonyl arylsulfinyl and alkylthioamido 5 cycloalkyl c ren cyano carboxy alkoxy carboxamide = Cj — carbo, dialkylcarboxamide, and dialkylamino Cy. cycloalkyloxy mjo and dialkylthioamido romen dialkylamido - C and dialkylthiocarboxamide mrmen haloalkylsulfinyl mm haloalkyl bitter© haloalkoxy Cis halogen heterocyclic and heterocyclic group haloalkyl thio Cis haloalkyl sulfinyl heterocyclic sulfonyl heterocyclic group oxy heterocyclic group heteroaryl s heterocyclic group carbonyl heterocyclic 0 phenyl group phenoxy cycloalkyl - oxy and g nitro hydroxyl 3 heteroaryl carbonyl alkyl C16 Optional substituent in group Cua ¢ thiol 5 sulfonic acids sulfonamide

Cres acyl Crs substitution is chosen from the group consisting of the mentioned Cle ganas, alkylsulfinyl and alkylsulfinyl Cj. alkylamino ramine alkoxy roy acyloxy

Cyanoy carboxy s alkoxy carboxamides — Cq — carbo y amino alkylthio Cj 00

Ci.” haloalkoxy C4 dialkylamino Cas cycloalkyloxy gene cycloalkyl resin nitro hydroxyl y haloalkyl thio where haloalkyl sulfinyl cis haloalkylsulfinyl m or ¢ phenyl and phenoxy

YA — — Res Rs selected separately from the group consisting of Cres acyl Cres H Cis alkylamino Cis alkyl Cries alkoxy Cie alkenyl Cy 5 acyloxy alkylcarboxamide mer alkynyl Cj. alkylthiocarboxamide rum alkylsulfonamide cres alkylthioureyl Cg alkylthio Cj. alkylsulfinyl Cs alkylsulfinyl Cs carbo amino alkylureyl © — Mi Css cyanos carboxy g carboxamide 5 alkoxy dialkylcarboxamide Cie dialkylamino Ca. cycloalkyl and Ciss haloalkyl C4. haloalkoxy Cis halogens dialkylthiocarboxamide Cis haloalkyl sulfinyl Cs haloalkylsulfinyl m haloalkyl thio heterocyclic group thiol 5 sulfonamide 5 nitro 3 hydroxyl 5 heterocyclic ¢ and 0 87 is an alkoxy group Cis - carbo or carboxy That is, tetrazol-5-yl. It is known that the present invention includes every subsequent or previous compound and general formulas; Where the groups are 8, 8 and 8 sis with respect to each other. Ji states that certain properties of the invention described in a race of preferred embodiments may also be provided for illustration in combination with a monolithic embodiment. And on the contrary; Lad can provide various ve properties of the invention that are briefly described in the context of a monomeric embodiment separately or in any subcombination and the expression 'has a substitution' as used herein indicates that a substituent group or groups that do not contain an atom are substituted hydrogen is the substitute for at least one hydrogen atom of the chemical group. When 'there is a substitution' for the chemical group in this document; it can

dos -

includes substitution to the fullest extent permitted by SS e.g. there can be a substitution in a methyl group with one or two substituents or AD and a substitution in a methylene group can have one or two substituents and a substitution can exist in a phenyl group with one replacement group or ? or © or; or ©; and the like. and in some embodiments; 0 “has substitution” denotes 1 substitution sets or “ or * ; or © or 1 . or 5. and in some embodiments; 'Has a substitution' refers to single substitution groups OR ?, © or . In some embodiments, 'Has a substitution' refers to groups of a single OR ? or '. In some embodiments, 'Has a substitution' refers to One or two replacement sets.

0 and in some embodiments; The expression 'with a substitution' refers to a single substituent group. It is known and understood that compounds of formula (Ta) can contain one or more chiral centres; they can therefore exist as homologues and/or homodimers. It is known that the invention extends and includes All these isomers and dimers and mixtures thereof include, without limitation, racemics.Accordingly, one embodiment of the present invention relates to compounds having the formula (Ta) 1 and the formulas used in each place of this discovery which are allotropes. Accordingly, asl embodiments of the present invention relate to compounds having the formula (Ta) and the formulas used in each position of this discovery which are homologues 8. In another embodiment, the compounds of the present invention have two stereochemical centers and both are Roe In another embodiment, the compounds of the invention have two stereochemical centers, both of which are SY, and in another embodiment, the compounds of the invention all have three stereochemical centers, where they are

YY44

all are 1. In the eal embodiment, the compounds of the present invention have three stereochemical centers where two of them are 1# and the third is 8. In a third embodiment; The compounds of the present invention have three stereochemical centres, two of which are 8 and the third is 8. It is known that compounds having formula (la) and formulas 0 used in each position of this discovery are meant to represent all the isomers and mixtures unless otherwise indicated or indicated. The compounds of the present invention can be found in different synthetic forms. Those who are skilled in this field will be well aware that tetrazole compounds can exist in at least two synthetic forms, and yet they are represented in certain formulas mentioned in this document in one form; However, all xenomorphs are contained in the present invention; ad explanatory note; when X is N and 7 is B08; where Ry is tetrazol-5-yl ; Then, Lad follows two possible compounds for the tetrazole ring: R2 Ry R2 Ry Rs _N Rs _N Re 9 'NH LR — 'NH IT NT ZI NE N vr N.

H and similarly; It is known that when X is “CRy where Ry is tetrazol-5-yl + and 7 is N that Vo can also exist compounds of the tetrazole ring. In addition; Those skilled in the art will be well aware that pyrazole heterocycles can also be present in at least two nucleotide forms and although the formulas mentioned in these

_ $ \ —

The document represents a single image; However, it is known that with the invention, Jal, all anatomical images are included. In the following, as an illustration, two possible cyclic compounds of the pyrazole ring are indicated (when C is N and 72 is {(CRy)

R 1 H and about and

1 and 8 Rs _N R4 | 7 N with a solution > B Rs Re R7 H Rs Re 0 and similarly; Solar compounds can exist when X is CRy, 7 is N, and furthermore

that; It is known that when Ry is tetrazol-5-yl ring; It is then possible to have homologous compounds for both the pyrazoleJ ring and also for ring 56 in a recombinant group. It is known that all of the compounds that can exist for the compounds that are disclosed in this document are within the scope of the invention.

0 It is also known that the isoforms can include a corresponding label for each enantiomer. Accordingly; The present invention includes all anatomical images and the different nomenclature meanings of all anatomical images. Some embodiments of the present invention relate to compounds where X is [8; And 7 is “CRy, Baa, Baal, carbo-mi alkoxy or carboxy.

1 Some embodiments of the present invention relate to compounds where X is ON and 7 is B8©; be carboxy. Some models can be represented by the formula (Io) as shown below:

R 1 and Rj _ N, Re __N-H Rs Rg COM (Ie) where each variable in the formula (©1) has the same meaning as previously and later in this document. Some embodiments of the present invention relate to compounds where X is 8 Zs is B8©; And to be, Sass. tetrazol-5-yl Some embodiments are represented by the formula (Te) as shown below: 1 8 and Rj _N Re NH Rg R 8 Ble NH -\ (Te) 0 Where each variable in the formula (Te) has the same meaning mentioned in this document previously and later. Some embodiments of the present invention relate to compounds where X is ¢CRy and B is Cis — carbo alkoxy — or carboxy; and 72 be N. Some embodiments of the present invention relate to compounds where X is ¢CRy and then is carboxy; 7 , 0 is N and some models can be represented by the form (Ig) as shown below: Ry 0021 ie Rs N—H © (Ig) where each variable in the formula has (Ig) has the same meaning as herein; previously and later.

v — $ — and some embodiments of the present invention relate to compounds where X is ¢CRy, some is tetrazol-5-yl ¢, and 7 is N. Some embodiments can be represented by the formula ((1) as shown hereinafter : N- NSH = N b Ra _ and 8 N—H 0 > bih Rs Rg (Ii) where each variable in formula (I) The same meaning mentioned in this document, previously and subsequently. Ry Cus compounds are 11 i.e. halogen Some models of the invention relate to compounds where Ry is H and some models of the invention relate to compounds where both Ry and b are 11. 1 Some models relate to z | choose J 2 with alias components of the form (Ik) as shown below: and Rj X (ON-H 2 what Rs' (IK) where Each variable in formula (Ik) shall have the same meaning as previously and subsequently stated herein.Some embodiments of the invention relate to compounds where Rs is 11 or a halogen.

_— $ $ — Some of the invention models are related to compounds where Rs is H and some of the invention models relate to Rg Cus compounds where H is a halogen . Some embodiments of the invention relate to compounds where Rg is Some embodiments of the present invention pertain to compounds where each of the Res Rs is 11. e and some embodiments of the present invention pertain to compounds represented by the formula (Im) as shown hereinafter: R 1 and “XI N— H OQ H (Im) Where each variable in the formula (Im) has the same meaning mentioned in this document previously and later. Some embodiments of the present invention relate to compounds where both Res Rss Res Ry are 11. Some embodiments can be represented by the formula (e) as shown Lod after: and * and two solutions of Zz (To) 01 where Each variable in the formula (To) has the same meaning mentioned in this document previously and later. Some embodiments of the present invention relate to compounds where each of the 142 Ris is selected separately from the group consisting of alkyl Cros H halogens; Cua There is an optional substitution in said alkyl Cig de sans with substituent groups chosen from the group consisting of an alkoxy cis Vo, an alkoxy, an alkylamine, an alkylsulfinyl, and a

mug $_—

amino alkylthio Cis alkylsulfinyl cycloalkyloxy atmosphere, mo-dialkylamino and haloalkyl Cis haloalkyl sulfinyl Cis haloalkylsulfinyl Cs haloalkoxy Ci hydroxyls thio and phenyl 5 phenoxy .

Some embodiments of the present invention relate to compounds where R and O form with the carbon atom being

0 each bonded to it cycloalkyl Cs . a) The embodiments of the present invention relate to compounds where H is or alkyl Cis; H is halogens alkyl Cres; Where there is an optional substitution in the mentioned alkyl Ci. with substituent groups that are not selected from the group consisting of 1-6 alkoxy C 1-69 acyloxy C 63-] 0 alkylsulfinyl Cys alkylamino, alkylsulfinyl flexible, and amino alkylthio And between cycloalkyloxy 00 and min haloalkylsulfinyl Css haloalkoxy Ci. dialkylamino and

,. phenyl and phenoxy hydroxyls haloalkyl thio Cis haloalkyl sulfinyl Ci.

Some embodiments of the present invention relate to compounds where Ry is 11 or Rss ¢ alkyl Cig is H or Min alkenyl that of alkyl Rmin cyclo or halogen or phenyl; Where there is an optional substitution in the alkyl passes mentioned by substituent groups then they are selected from the group that composes

01 of phenoxy hydroxyls alkylthio cis alkoxy cis and phenyl ; Or Ris Ro with atom 05080 All of which JS is bonded to form a cyclopropyl , cyclopentyl or cyclohexyl group . Some embodiments of the present invention relate to compounds where Ry is H or Rss (CH; is 11 or:

or allyl Or cyclopropyl carbon atom to which each of them is bonded to form a Ris group. cyclohexyl or cyclopentyl

H be Ras ¢ alkyl Crs of H be Ry and some embodiments of the present invention relate to compounds where; where there is an optional substitution in phenyl, halogen, alkyl Ci, alkenyl, or cities

Cris are listed with substituent groups chosen from the group consisting of the alkyl © . phenyl, phenoxy and alkoxy hydroxyls 0

JH be Rss ¢CHy be 11- or Ry and some embodiments of the present invention relate to compounds where . benzyl or CH; Some embodiments of the present invention relate to compounds where methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, 5 hydroxymethyl, .methoxymethyl, benzyl, phenyl or phenoxymethyl.Vo Some embodiments of the invention relate to compounds where: ; carboxyl and be “CR; be X

Rss Rus Ry which are 11 each; may be 11 or 5¢CH;R; be H or CH; or benzyl Or: salt, hydrates, or leta solubles that are pharmaceutically acceptable. z 0 and some embodiments of the present invention relate to compounds where: X is N and 2 is B016; where Ry is carboxyl or 0,86©-R tetrazol-5-yl ; or X is 8©; Cua can be carboxyl or —CO,Et or tetrazolyl ; and 2 is 1; 1 Res Rss of 11 each; It can be H or 'CH; and

: JH is 8 0 methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl or phenoxymethyl

Or salt or hydrates or solubles thereof are pharmaceutically acceptable. Some embodiments of the present invention relate to compounds where: N and 7 are “CR7” and then are carboxyl or CO,Et or tetrazol-5-yl ; YYa4q

Rss Ray Ry and each of which is a 1]; It can be H or ¢CH; and M1 is 11 or: methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl or phenoxymethyl ° or salt or hydrates or dissolved thereof are pharmaceutically acceptable. Some embodiments of the present invention relate to compounds selected from the group consisting of: 3b,4,4a,5-Tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carbox- ylic acid; 1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carb- oxylic acid; 1-Benzyl-1a,3,5,5a-tetrahydro-1H-2 ,3 -diaza-cyclopropa[a]pentalene-4-carbo- xylic 01 acid; and 1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropafa]pentalene-4- carboxylic acid; Some embodiments of the present invention relate to compounds selected from the group consisting of: 4-(2H-Tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropalajpenta- lene; Vo 1,1-Dimethyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3 -diaza--

— $9 b ‎cyclopropafa]pentalene; and 1 -Benzy!l-4-(2H-tetrazol-5-y1)-1a,3,5,5 a-tetrahydro-1H- 2,3-diaza-cycloprop- a[a]pentalene; or Salt or hydrates or solubles thereof are acceptable for Ly. Some embodiments of the present invention relate to compounds where the stereochemistry of each of the two carbon atoms specified as 7i and 4 or 1e and 2 is R and some embodiments of the invention IN relate to compounds where the stereochemistry of each of the two carbon atoms specified as 57 and 85 or 81 and 82 are 8. Some embodiments of the present invention relate to compounds where the stereochemistry of each of the carbon atoms specified as 81 and 80 is 8. 0 Some embodiments of the present invention relate to compounds where the stereochemistry of the specified carbon atom is k a) is R and the stereochemistry of the carbon atom defined as ad is

Some embodiments of the present invention relate to compounds where the stereochemistry of the carbon atom defined as a) is 5 and the stereochemistry of the carbon atom defined as at is R yo. Some embodiments of the present invention relate to compounds where the stereochemistry is of the priority group bonded to the carbon atom identified as 1 internal. It is known that de pend has the same meaning as that which was specified by: Yyaa

—_ c - . “The Cahn, Ingold and Prelog System” by application of sequence rules, for a general review of the CIP system see R.S. Cahn, C.K. Ingold and V. Prelog, Angew. Chem.

Internat. Ed. Eng. 5, 385-415, (1966) ; and V. Prelog and G. Helmchen, Angew. Chem.

Internat. Ed. Eng. 21, 567-583 (1982). Some embodiments of the present invention relate to compounds in which the stereochemistry of the priority group © is extrinsic. Internal and external conventions apply to

IN and 7 being CRy when D is for example

Rendo R 1 with R7 7 ft

Ry — Nt Place = N—H mant B =N 8 N Placement Rg

Reg Re

CR; and 7 is N is X or when 0

Rendo 8

Rexo Rg

R =N, and 2b N—H

Rg == R =

EndoR. Rs 86 m 5 Rg Ry i bY then the two carbon atoms defined as (N be Z 5 “CRy be X) and in general; when below: (Ila) as shown in the formula at

Qo \ — —_— Ry B Ra Ry—\t_[3b AU, Hala - 4a Ry 3 Rs Rs (I1a): It is known that it is for the compounds of the present invention Stereochemistry where the two groups are RusRycis relative to each other. In general, these compounds can be represented by the formula (IC) and the formula (110): R2 Ri R; m Rs Rs Rr md) ; 5 ms Re and in some embodiments; The carbon atoms identified as af 5 bY have stereochemical designations as represented by formula (110): Ry Ry and Ry—_J3b 3, N-H 2 Rs SN Rs Rg (IXc). A some models; The carbon atoms identified as af 3 bY have stereochemical designations as 0 is represented by the formula (Id) after Ra Ri Rab 3 4a = _ N H > for Rs 3 Rg R may | 9 and in the form (fla when X is “N and 7 is CRy” then the two carbon atoms specified as a0 are 5a) as shown in the formula (Ile) below :

Lag Ro 8 Rs; XT 5a = Ne N—-H 4 > yb RS Rs Ry (Ie) It is known that the compounds of the present invention have stereochemistry where the two groups are Ry and B8 cis with respect to each other. In general, these compounds can be represented by the formula (p11), and the formula is: Rz Ry ni Rj I Sia n> Rj L Jia n> Sa) = NaH Sa = 'NH Ra = 4 > Rj Rg Ry Rs Rg Ry (Mg) (ITh): ° and in some embodiments; The carbon atoms designated as al have a stereochemical designation position as represented by the formula (Ig) y 2 and 1 8 Sa =N 3 3 N—-H ~~ of Ry 1 RS Rs Ry (Ig) and in Lar) models; The carbon atoms identified as 1 8 and 8 have stereochemical designations as 0 is represented by the formula: (ITh) Ro, Ry d Sa N—H ,(~ yg Rs Rg Ry (ITh). s in the two formulas (G11) 5 (Th) varies depending on the different groups present.In some examples for example "when Ry to Rg are all hydrogen atoms" then the stereochemistry vo is specified as Indicated in formulas (LIK) 5 (I).

— o Ae —

H

4 a R7 Da =N

SE AE

N 8 011) (11k) : may be hydrogen and may be all atoms of Rss Ras Ras Ry and in some embodiments; when or (0)1; Then a C (4) group is selected so that the carbon atom of the group is bonded directly with: from Ry and (110). Examples of (Im) stereochemistry may be chosen as given in the formulas methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, ° methoxymethyl, benzyl, phenyl and phenoxymethyl; or R.sub.3 can be selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, hydroxymethyl, methoxymethyl, benzyl, phenyl, phenoxymethyl, methylsulfanylmethyl, ethoxymethyl, cyclopropyl, 1- but-2-enyl, and allyl:

H

R34 D R7 5 Vi No SE H SET N Re (IIm) (In). 01 It is also known that all other possible stereochemical designations and representations are included in the invention below.

_ m $ — (1) Formula table Chemical name 3b,4,4a,5-Tetrahydro-2H- 5 cyclopropa[3,4]cyclopenta[1,2- 1 c]pyrazole-3- carbo-xylic acid — OH \ NH

N - 4-(2H-Tetrazol-5-yl)-1a,3,5,5a- n=, tetrahydro-1H-2,3-diaza- _NH cyclopropafa]pentalene = N Y \-NH 1a,3,5 ,5a-Tetrahydro-1H-2,3- 0 diaza-cyclopropa[a]pentalene-4- carboxylic acid = OH 7 <8 Ba 0 aR,5aR)-4-(2H-Tetrazol-5-yl) - H n= 1a,3,5,5a-tetrahydro-1H-2,3-diaza-NH cyclopr-opa[a]pentalene = N¢

H N ~NH exo-1-Benzyl-1a,3,5,5 a-tetrahydro- 1H-2,3-diaza- o cyclopropala]pentalene-4- carboxylic acid H ( OH yum NH 1,1-Dimethyl- 1a,3,5,5 a-tetrahydro- 1H-2,3-diaza- ° cyclopropa[a]pentalene-4-- 1 carboxylic acid = OH \ -NH 1,1-Dimethyl-4-(2H-tetrazol- 5-y1)- 1a,3,5,5a-tetrahydro-1H-2,3 -diaza-N

N="cycl- opropafa]pentalene _NH \-NH exo-1-Benzyl-4-(2H-tetrazol-5-yl)- n= 1a,3,5,5a-tetrahydro-1H-2,3-diaza - NH cycl- opropala]pentalene H 4 Z A NH : ( Y ) Models c Compounds of the present invention are related to compounds in table an and in ( Y ) table 7 7 7 the name Alkisiti ‎ etd 1-Methyl-1a,3,5,5a-tetrahydro- 1H-2,3-diaza- 0 cyclopropa[a]pentalene-4-carb- ~~ OH 9 oxylic acid \ _NH 1-Isobutyl-1a,3 ,5,5a-tetrahydro- o 1H-2,3-diaza- \ cyclopropa[a]pentalene-4-ca- ( OH rboxylic acid 1-Butyl-1a,3,5,5a-tetrahydro- 0 1H-2,3-diaza- ~ OH 11 cyclopropafa]pentalene-4-carbo- 4 xylic acid N- NH 1-Methyl-4-(2H-tetrazol-5-yl)- n= 1a,3,5,5a -tetrahydro-1H-2,3- NH b" diaza-cyclopro- pa[a]pentalene = N 8 and 1-Ethyl-4-(2H-tetrazol-5-yl1)- .1a, 3,5,5a-tetrahydro-1H-2,3- N MN H diaza-cycloprop- a[a]pentalene yama N VY

N\ H NH : 1-Pentyl-1a,3,5,5a-tetrahydro- o 1H-2,3-diaza- cyclopropa[a]pentalene-4-carb- ( OH 5 oxylic acid m NH

— ZH 4 _ 1-Propyl-4-(2H-tetrazol-5-yl)- 1a,3,5,5a-tetrahydro-1H-2,3- N . N = diaza-cyclopro-pa[a]pentalene NH \o = N

N\-NH 1-Propyl-1a,3,5,5a-tetrahydro- o 1H-2,3-diaza- cyclopropafa]pentalene-4-carb- ( OH 11 oxylic acid lime 1-Isobutyl-4- (2H-tetrazol-5-yl)- n= 1a,3,5,5a-tetrahydro-1H-2,3- NH diaza-cyclop-ropa[ajpentalene — N VV \ NH

N - 1-Methoxymethyl-1a,3,5,5a- 0 tetrahydro-1H-2,3-diaza- 0 cyclopropala]pentalene- -4- L “OH YA carboxylic acid acid 1-Ethyl-1a ,3,5,5a-tetrahydro- 0 1H-2,3-diaza- cyclopropa[a]pentalene-4-carbo- 4 OH 3 xylic acid 1-mother 1-Phenyl-4-(2H-tetrazol-5) -yl)- n= 1a,3,5,5a-tetrahydro-1H-2,3- NH . diaza-cyclopro-pa[a]pentalene = N but “N - ]-Benzyl-4-(2H-tetrazol-5-y1)- 1a,3,5,5a-tetrahydro-1H-2,3- N

N="diaza-cyclopro-pa[a]pentalene NH = N

\N

— B_ 7 zm 1-Benzyl-1a,3,5,5a-tetrahydro- 1H-2,3-diaza- o cyclopropafa]pentalene-4-carb- . : OH YY oxylic acid =

N\-NH 1-Benzyl-1a,3,5,5a-tetrahydro- 1H-2,3-diaza- o talene-4-carb- 0 a m alene-4-car sucking - oxylic acid ethyl ester 01 bal “N - 1,1-Dimethyl-1a,3,5,5a- 0 tetrahydro-1H-2,3-diaza- p cyclopropa[a]pentalene-4-- ( Y¢ carboxylic acid ethyl ester N-NH 1,1-Dimethyl-1a,3,5,5a- 0 tetrahydro-1H-2,3-diaza- cyclopropal[a]pentalene-4-- ( Yo carboxylic acid ethyl ester lime 1-Phenyl-1a,3,5,5a-tetrahydro- 0 1H-2,3-diaza- cyclopropa[a]pentalene-4-carb- \ _NH Yi oxylic acid ethyl ester 1 -Phenyl-1a,3,5,5a-tetrahydro- n= 1H-2,3-diaza- - NH cyclopropafa]pentalene-4-carb- L “N L oxylic acid lyme |- Pentyl-4-(2H-tetrazol-5-yl)- n= la,3,5,5a-tetrahydro-1H-2,3- NH diaza-cyclopro- pa[a]pentalene = N\NH YA

N-

— 0 A _ 1-Butyl-4-(2H-tetrazol-5-y1)- o 1a,3,5,5a-tetrahydro-1H-2,3- I~ diaza-cycloprop- a[a]pentalene = © Y4

N\-NH 1-Ethyl-1a,3,5,5a-tetrahydro- o 1H-2,3-diaza- p cyclopropa[a]pentalene-4-carbo- 4 7 Ve xylic acid ethyl ester ester ‎ 1-Methyl-1a,3,5,5a-tetrahydro- 1H-2,3-diaza- o cyclopropa[a]pentalene-4-carb- I~ y oxylic acid ethyl ester == © \ NH

N - 1-Pentyl-1a,3,5,5a-tetrahydro- n= 1H-2,3-diaza- NH cyclopropala]pentalene-4-carb- ( N YY oxylic acid ethyl ester 1-Isopropyl- 4-(2H-tetrazol-5- yD)-1a,3,5,5a-tetrahydro-1H-2,3- { Ho NH oy diaza-cyclo- propa[a]pentalene = N

N~NH

N - 1-Phenoxymethyl-4-(2H- 0 tetrazol-5-yl)-1a,3,5,5a- tetrahydro-1H-2,3-diaza-c- Co OH Y¢ yclopropafa]pentalene alim 1-Isopropyl-1a,3,5,5a- 0 tetrahydro-1H-2,3-diaza- <Q H vo cyclopropa[a]pentalene-4-c- \ _NH arboxylic acid 1-Vinyl-1a,3 ,5,5a-tetrahydro- \ 0 1H-2,3-diaza- <=" OH = cyclopropala]pentalene-4-carbo- \- NH xylic acid ethyl ester

: - od - 1-Vinyl-1a,3,5,5a-tetrahydro- n= 1H-2,3-diaza- \ wu cyclopropafa]pentalene-4-carbo- 0 N b xylic acid n-NH 4 -(2H-Tetrazol-5-yl)-1 -vinyl- 0 1a,3,5,5a-tetrahydro-1 H-2,3- diaza-cycloprop-a[a]pentalene = YA \- NH 1-Fthyl-1a,3,5,5 a-tetrahydro- o 1H-2,3-diaza- —Q, p cyclopropala]pentalene-4-carbo- ( va xylic acid ethyl ester yum NH 1-Methoxymethyl-1a,3,5,5a- NZ N, tetrahydro-1H-2,3-diaza- —0 NH .cyclopropa[a]pentalene- -4- ( N carboxylic acid ethyl N-NH 1-Hydroxymethyl- 1a,3,5,5a- 0 tetrahydro-1H-2,3-diaza- HO p 0 cyclopropa[a]pentalene- -4- 0 carboxylic acid ethyl ester lime 1 -Hydroxymethyl-1a,3, 5,5a- o tetrahydro-1H-2,3-diaza- HO I. cyclopropa[a]pentalene- -4- 4 OH carboxylic acid Tull =N, [4-(2H-Tetrazol-5-y1) )-1 a,3,5,5a- HO N NH tetrahydro-1H-2,3-diaza- ~ =N - cyclopropa[a]pen- talen-1 -yl}- \ NH methanol iF) The compounds of the invention relate With the compounds in Table Eel and in some

- and Table (¥ ) 1-Methylsulfanylmethyl-1a,3,5,5a- 0 tetrahydro-1H-2,3-diaza- 5 cyclopropala]pe-ntalene-4- 4 = OH ¢ Mother carboxylic acid 1-Ethoxymethyl-1a,3,5,5a- 0 tetrahydro-1H-2,3-diaza- —S cyclopropa[a]pentalene-- 4- ( OH ¢ carboxylic acid n- NH 1-Cyclopropyl-1a,3,5,5 a-tetrahydro- 0 1H-2,3-diaza- cyclopropala]pentalene-4- ( OH £7 yme carboxylic acid Cyclopropyl-4-(2H-tetrazol-5-yl)- 1 1a,3,5,5a-tetrahydro-1H-2,3-diaza- NH cyclopropa[a]pentalene ( = N gv NH bundles 1-Vinyl-1a,3,5 ,Sa-tetrahydro-1H- o 2,3-diaza-cyclopropa[a]pentalene-4- \ carbo- xylic acid ( OH ¢A NH yum 4-(2H-Tetrazol-5-yl)-1-vinyl- n= 1a,3,5,5a-tetrahydro-1H-2,3-diaza- \ NH cycloprop- a[a]pentalene 4 = N 4 NH ha 1-Spirocyclopropyl-1a,3,5,5a- o tetrahydro-1H-2,3-diaza- cyclopropa[a]pental - ene-4- 4 = OH carboxylic acid N- NH

- vy = 1 -spirocyclopropyl-4-(2H-tetrazol-5- 1a,3,5,5a-tetrahydro-1H-2,3-diaz- a- = oy cyclopropala]pentalene 0 NH bundles (E)-1-Propenyl-1a,3,5,5a- 0 tetrahydro-1H-2,3-diaza- \ on oY cyclopropa[a]pentalene- 4- 1 L carboxylic acid lyme ( Z)-1-Propenyl-1a,3,5,5a- 0 tetrahydro-1H-2,3-diaza- oF cyclopropa[a]pentalene-- 4- rR H carboxylic acid lime (E)-1- Propenyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-L0H0diaza-cy-clopropa[ajpentalene 1] M I!lem NH (Z)-1-Propenyl-4-(2H-tetrazol-5- n= yl)-1a,3,5,5a-tetrahydro-1H-2,3- NH diaza-cy - clopropa[a]pentalene rR N 1m NH 1-Methoxymethyl-1a,3,5,5a- o tetrahydro-1H-2,3-diaza- 0 cyclopropala]pentalene- -4- <= OH ol carboxylic acid ‏ lyme 1-Methoxymethyl-4-(2H-tetrazol-5- macrophages yb)-1a,3,5,5a-tetrahydro-1H-2,3- 0 _ NH diaza-c- yclopropafa]pentalene < =" N ov dream NH 1-Phenoxymethyl-1a,3,5,5a- tetrahydro-1H-2,3-diaza- cyclopropa[a]pentalene- -4- l 0 0 oA carboxylic acid <=" OH 8 Bala Yvyas

Spiro[la,3 ,5,5a-tetrahydro-1H-2,3- 0 diaza-cyclopropala]pentalene-1,1'- 4 cycl- opentan]-4-carboxylic acid = 011 bal “N - 5 -(Spiro-{1a,3 ,5,5a-tetrahydro-1H- n= 2,3-diaza-cyclopropala]pentalene- NH 1,1'-- cyclopentan]-4-yl)-1H- to “N Te tetrazole L Spirof1a,3,5,5 a-tetrahydro-1H-2,3- o diaza-cyclopropa[a]pentalene-1,1'- 11 cycl- ohexan]-4-carboxylic acid 01 OH \ NH

N - 5-(Spiro-[1a,3,5,5 a-tetrahydro-1H- N= 2,3-diaza-cyclopropa[a]pentalene- NH 1,1'-- cyclohexan]-4-yl)- 1H- ( N TY tetrazole n= NH 1-Allyl-1a,3,5,5 a-tetrahydro-1H- o 2,3-diaza-cyclopropa[a]pentalene-4- = b carbo- xylic acid = OH Pal 1-Allyl-4-(2H-tetrazol-5-y1)- n=, 1a,3,5,5a-tetrahydro-1H-2,3-diaza- = NH cycloprop-a[a]pentalene = N +6 <8 bal 4-Methyl-3b,4,4a,5 -tetrahydro-2H- cyclopropa[3,4]cyclopental 1,2- o ¢]pyrazol- e-3-carboxylic acid lo = Oh

N\-NH 1-Cyclopropylmethyl-1a,3,5,5a- 0 tetrahydro-1H-2,3-diaza- ~ OH 4 cyclopropa[a]penta- lene-4- Y, _NH carboxylic acid

Yvaa

_ 7 1" _ In addition, the compounds of the present invention include; hydrates thereof are pharmaceutically acceptable.It is known that the present invention includes each dimer and all isomers and mixtures thereof for each © compound and general formulas which are disclosed herein as if each of them were disclosed individually with the specific stereochemical designation for each chiral carbon atom.It includes An embodiment of the invention for example on a compound with stereochemical properties (4aS “3bS) or 0 (5aS “1 aS) and one embodiment of the present invention is chosen from the group consisting of: (3bS, 4a8S)-3b ,4,4a,5-Tetrahydro-2H-cyclopropa(3 ,4]cyclopenta[1,2-c]pyrazol- e-3- Ve carboxylic acid; (1aS, 5aS)-4-(2H-Tetrazol- 5-yl)-1a,3,5 ,5a-tetrahydro-1H-2,3-diaza- cyclopropa[a)- pentalene; and (1aS, 5as)-1a,3,5,5a-Tetrahydro-1H -2,3-diaza- cyclopropa[a]pentalene-4-carboxyli- ¢ acid. Alternatively, one embodiment of the present invention comprises a compound with the stereochemical properties 10 (4aR 3bR) or 0 ( 5aR «1 aR) and an embodiment of the present invention is chosen from the group consisting of: (3bR, 4aR)-3b,4,4a,5-Tetrahydro-2H-cyclopropa(3 ,4]cyclopenta[1,2-c] [pyrazol-e-3-carboxylic acid; (1aR,5aR)-4-(2H-Tetrazol-5-yl)-1a,3 ,5,5a-tetrahydro-1H-2,3-diaza-

p cyclopropa[a]-pentalene; and (1aR, 5aR)-1a,3,5,5a-Tetrahydro-1 H-2,3-diaza- cyclopropa[ajpentalene-4-carboxyli- ¢ acid. An embodiment of the present invention comprises a compound with the intrinsic stereochemical properties (¢laR 585). An embodiment of the present invention is selected from the group consisting of: - endo-(1aR, 5aS)-1-Methyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pe - ntalene- 4-carboxylic acid; endo-(1aR, 5aS)-1-Isobutyl-1 a,3,5,5a-tetrahydro-1H-2,3-diaza- cyclopropala]pentalene-- 4-carboxylic acid; endo-(1aR, 5aS)-1 -Butyl-1a,3,5,5a- tetrahydro-1 H-2,3-diaza-cyclopropa[a]pentalene-4-c- arboxylic acid; endo-(1aR, 5aS)-1- Methyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cycl-opropala]pentalene ; 0 endo-(1aR, 5aS)-1-Ethyl-4-(2H-tetrazol-5 -yl)-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclo-propa [a]pentalene; endo-1 aR, 5aS)-1-Pentyl-1a,3,5 ,Sa-tetrahydro-1H-2,3-diaza- cyclopropafa]pentalene-4-- carboxylic acid; endo-(1aR, 5aS)-1 -Propyl-4-(2H-tetrazol-5- yl)-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cycl- opropa[a] pentalene; endo-(1aR, 5aS)-1- Propyl-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pentalene-4-- carboxylic acid; Vo endo-1aR, 5a)-1-Isobutyl-4-(2H-tetrazol-5 -yD)-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyc-lopropa[ a]pentalene; endo-(1aR, 5aS)- 1-Methoxymethyl-1a,3,5,5a-tetrahydro-1H-2,3- diaza-cyclopropa[a]penta-lene-4-carboxylic acid; endo-(1aR, 5aS)-1-Ethyl-1a,3,5,5a- tetrahydro- 1H-2,3-diaza-cyclopropa[a]pentalene-4-c- arboxylic acid; endo-(1aR, 5aS) endo-(1aR, 5aS)-1 -Phenyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3- diaza-cycl- Y. YYaa

~vo - opropa[a]pentalene; endo-(laR, 5aS)-1-Benzyl-4-2H-tetrazol-5-yl)-1a,3 ,5,5a-tetrahydro- 1H-2,3-diaza-cyclo-propafa}pentalene; endo-(1aR, 5aS)-1-Benzyl-1a,3 ,5,5a-tetrahydro- 1H-2,3-diaza-cyclopropa[a]pentalene-4-- carboxylic acid; endo-(1aR, 5aS)-1 -Benzyl- 1a,3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa[a]pentalene-4-- carboxylic acid ethyl ester; endo-(1aR, 5aS)-1-Phenyl-1 a,3,5,5a-tetrahydro-1H-2,3-diaza- ° cyclopropala]pentalene-4-- carboxylic acid ethyl ester; endo-(1aR, 5aS)-1-Phenyl- 1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropala]pentalene-4-- carboxylic acid; endo- (1aR, 5aS)- 1-Pentyl-4-(2H-tetrazol-5-yl)-1a,3,5 ,5a-tetrahydro-1H-2,3-diaza-cycl- opropa[a]pentalene; endo-(1aR, 5aS)-1 -Butyl-4-(2H-tetrazol-5-y1)-1a,3.5,5a-tetrahydro- 1H-2,3-diaza-cyclo-propa[a]pentalene; endo-(1aR, 5aS)-1-Ethyl-1a,3 ,5,5a-tetrahydro- 01 1H-2,3-diaza-cyclopropa[a]pentalene-4-c- arboxylic acid ethyl ester; endo-(1aR, S5aS)-1-

Methyl-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pentalene-4-- carboxylic acid ethyl ester; endo-(1aR, 5aS)-1 -Pentyl-1a,3,5,5a-tetrahydro-1H-2, 3-diaza- cyclopropala]pentalene-4-- carboxylic acid ethyl ester; endo-(1aR, 585(- 1-Isopropyl-4- (2H-tetrazol-5-yl)-1a,3,5 ,5Sa-tetrahydro-1H-2,3-diaza-c- yclopropa[a]pe includes a \o compound with the ntalene; endo-(1aR, 5aS)-1 -Phenoxymethyl-4-(2H-tetrazol-5-yl)- 1a,3,5,5a-tetrahydro-1H-2,3-dia- za-cyclopropa[a]pentalene;endo-(1aR, 5aS)-1-

Isopropyl-1a,3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa[a]pentalene- -4-carboxylic acid, endo-(1aR, 5aS)-1-Vinyl-1a,3,5 ,Sa-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pentalene-4-c- arboxylic acid ethyl ester; endo-(1aR,5aS)-1-Vinyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-Y.

- 1 cyclopropafa]pentalene-4-c-arboxylic acid; endo-(1aR, 5a8)-4-(2H-Tetrazol-5-y!)-1- vinyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclo-propa[a] pentalene; endo-(1aR, 5aS)- 1-

Ethyl-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropala]pentalene-4-c- arboxylic acid ethyl ester; endo-(1aR, 5aS)-1 -Methoxymethyl-1a,3,5,5a-tetrahydro-1H-2,3 -diaza- cyclopropala]penta-lene-4-carboxylic acid ethyl ester; endo-(1aR, 5aS)-1- 0

Methoxymethyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-dia-za-cyclopropala]pentalene; endo-(1 aR, 5a8)-1-Hydroxymethyl-1a,3,5,5a-tetrahydro-1H-2,3- diaza-cyclopropa[a]penta-lene-4-carboxylic acid ethyl ester; endo-(1aR, 5aS)-1-

Hydroxymethyl-1a,3,5 _Sa-tetrahydro-1H-2,3-diaza-cyclopropa[a]penta-lene-4-carboxylic acid; and endo-(1aR, 5aS)-[4-(2H-Tetrazol-5-yl)-1 a,3,5,5a-tetrahydro-1H-2,3- 00 diaza-cyclopropa[a-Jpentalen-1- yl] -methanol. Another embodiment of the present invention is selected from the group consisting of: endo-(1aR, 5S)-1-Methylsulfanylmethyl-1 a,3,5,5a-tetrahydro-1H-2,3-diaza- cyclopropala- [pentalene-] 4-carboxylic acid; endo-(1aR, 5aS)-1-Ethoxymethyl-1a,3,5,5a- tetrahydro-1H-2,3 -diaza-cyclopropa[a]pental-ene-4-carboxylic acid; endo-(1aR, 5aS)-1- Vo

Cyclopropyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentale-ne-4-carboxylic acid; endo-(1aR, 5aS)-1 -Cyclopropyl-4-(2H-tetrazol-5-yl)-1a,3,5 ,Sa-tetrahydro-1H-2,3- diaza- -cyclopropa[a]pentalene; endo-(1aR, 5aS)-1-Vinyl-1a,3,5,5a-tetrahydro-1H-2,3- diaza-cyclopropa[a]pentalene-4-c- arboxylic acid; endo-(1aR, 5aS)-4-(2H-Tetrazol-5-yl)- 1-vinyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclo-propala]pentalene; endo-1aR, 5aS)- 1- A

YYa4

_vy—

Spirocyclopropyl-1a,3,5,5 a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pe-ntalene-4- carboxylic acid; endo-(1aR, 5aS)-1 _spirocyclopropyl-4-(2H-tetrazol-5-y1)- 1a,3,5,5a- tetrahydro-1H-2,3-- diaza-cyclopropala]pentalene; endo-1aR, 5aS)-(E)-1-But-2-enyl- 1a,3,5,5a-tetrahydro-1H-2 ,3-diaza-cyclopropafa]pent-alene-4-carboxylic acid; endo- (1aR, 5aS)-(Z)-1 -But-2-enyl-1a,3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropala]pent- ° alene-4-carboxylic acid ; endo-(1aR, 5aS)-(E)-1 -Propenyl-4-(2H-tetrazol-5-yl)- 1a,3,5,5a- tetrahydro-1H-2,3-diaz-a-cyclopropa[ a]pentalene; endo-(1aR,5aS)-(Z)-1-Propenyl-4- (2H-tetrazol-5-y1)-1a,3,5,5a-tetrahydro-1H-2,3-diaz-a- cyclopropala]pentalene; endo- (1aR, 5aS)-1 -Methoxymethyl-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropala]penta-lene-4-carboxylic acid; endo-(1aR, 5aS)- 1 -Methoxymethyl-4-(2H-tetrazol-5-yl)- 1 1a,3,5,5a-tetrahydro-1 H-2,3-dia-za-cyclopropa[a] pentalene; endo-(1aR, 5aS)-1-

Phenoxymethyl-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]penta-lene-4-carboxylic acid; endo-(1aR, 5aS)-Spiro| 1a,3,5,5a-tetrahydro- 1H-2,3-diaza- cyclopropala]pentalene-1, l'-- cyclopentan]-4-carboxylic acid; endo-(1aR, 5aS)-5-(Spiro-[1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-1- ,1'-cyclopentan]-4- yl)-1H-\o tetrazole; endo-(1aR, 5aS)-Spiro[la,3 ,5,5a-tetrahydro- 1H-2,3-diaza- cyclopropala]pentalene-1, 1'-- cyclohexan]-4-carboxylic acid; endo-(1aR, 5aS)-5-(Spiro-[1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-1-,1'-cyclohexan]-4- yl)-1H-tetrazole; endo-(1aR, 5aS)-1-Allyl-1a,3 5,5a-tetrahydro-1H-2,3-diaza- cyclopropa[a]pentalene-4-c- arboxylic acid; endo-(1aR, 5a8)-1-Allyl-4-(2H-tetrazol-5-Y.

A —_ 1" _ yl)-1a,3,5 ,5a-tetrahydro-1 H-2,3-diaza-cyclo- propala]pentalene; and endo-(1aR, 5aS)-1- Cyclopropylmethyl- 1a,3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropala]p- entalene-4- carboxylic acid. It is known that the compound as described in this document has external stereochemical properties - 1aR) © ; (5aS) and inner - (5aS «1a8) and outer - (Say (Sa 18S) written similarly. N =N, NH | 8 N = N \ N= NH and in some gz dail the compound of the present invention has the structural formula: H NEN NH 8 2 LQ~" N and a salt or a soluble or 5 of it is pharmaceutically acceptable. 0 In some embodiments, the compound of the present invention has the structural formula: with meat H NH = H N NH, salt, solute, or J sie 43 pharmaceutical hydrates.In some embodiments, the compound of the present invention has the structural formula: 0 SQ or N\NH Ham yyaa

0 salt or soluble or 585 thereof J sie fishing uy and in ran forms; The compound of the present invention has the structural formula: H 0 OH non-living sea or salt or soluble 0 5 of it J side Ly. 0 and in some models; The compound of the present invention has the structural formula: 1 OH sea salt Ho salt or soluble or 98 of it is acceptable for fishing. and in some embodiments; The compound of the present invention shall have the structural formula: No NH “N => 01 8 or salt or solutes or hydrates 43 acceptable Ly and in some oz Sah the compound of the present invention shall have the structural formula: =N, NH 1 " N => I WJ or salt or soluble or pharmaceutically acceptable 43s hydrates.

‎VY. - — and in some embodiments; The compound of the present invention has the structural formula: =N, N NH “>I” N H N ~NH or a salt or a solubility or 5 thereof that is pharmaceutically acceptable. and in some embodiments; The compound of the present invention has the structural formula: 0 OH ~~ dl, salt, solubility, or 43a hydrates that are pharmaceutically acceptable. and in some embodiments; Compound 1 to choose 2 present has the structural formula: H 0 H 0 OH or 1 =~ OH "~~ lacy qo lahi go or salt or solubility or 5 of it is acceptable Sayd Lania ' 0 In some embodiments, the compound of the present invention has the structural formula: H 0 H 0 OH or mn =~ OH ~~ Ho NH qo NH or salt or solutes or aie hydrates that are pharmaceutically acceptable. The compound of the present invention has the structural formula: mg OH = dar

Or salt or soluble or hydrates 43 pharmaceutically acceptable. and in some embodiments; The compound of the present invention shall have the structural formula: 9 2 AH 9 2 AH LA, salt, solubility, or 8 of it is acceptable for fishing. ° and in some models; The compound of the present invention has the structural formula: ? ~ WH 9 3 WH -NH for the salts of Ho, salt, solubles, or aia hydrates that are pharmaceutically acceptable. and in some embodiments; The compound of the present invention has the structural formula: 0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,000 salt, or solubility, or 98 of it, is acceptable to fish because of it, and in some embodiments.” The compound of the present invention has the structural formula: H 0 H 0 or Nin Lr or Ha lassi go l or salt or solubility or 5 of it is acceptable for fishing. and in some embodiments; The compound of the present invention has the structural formula:

VY Y — b_ H 0 H 0 ly L HoH or salt or solubilities or hydrates 430 Sat Ly Chemical properties of the present invention: Synthetic procedures for the preparation of compounds 1 of the present invention:

oo Some aspects of the present invention relate to synthetic processes for the preparation of new fused pyrazole compounds having the formula (la) and the compounds of the present invention can easily be prepared according to these new processes using a variety of commercially available or readily prepared starting materials Synthetic systems that may be familiar to a person skilled in this field. In the synthesis shown ean Lag Lgl the numbered substitution groups have the same definitions

0 mentioned in this document unless otherwise indicated. One of the methods that can be used in the preparation of the compounds of the invention where X be 27 Zs be C-tetrazol-5-yl are intermediate compounds derived from cyclic ketone having formula (A) as shown In interaction diagram No. (1) below:

— YY - :() ) Chart No. 0

Ra Rs Rg Rs Re Rs Re 020

Rs Ra 046 m _ — R live R wy 3 0 0 3 > NH

R R N

Ri © 2 Ry 2 Ry (A) B) | ©

Ns for ~ N

Rs Re on Balsala Rs Re on Rs Re CONH, Yeh _ H Ra __ Yeh _

Rs « NH = Rs ~ NH Rs ~ NH

N N N

R2 Ry R2 Ry R2 Ry (Ta) (E) (D) with (A) which has the formula cyclic ketone by reaction (la) compounds with the formula can be prepared in the presence of an alkyl Cig base Rpg has the form 02 (0)0); Wherein dialkyloxalate or pentanol or butanol or ethanol or methanol or alkanol Cig and an analogous polar solvent and the like as DMF or THF or isopropanol or -2 methoxyethanol or © hexanol Appropriate bases include (B) the formula Al Ketoester for example ¢ for potassium, sodium ethoxide and sodium methoxide enclosed alkali metal alkoxides alkali metal amides 5 similar; lithium hexamethyldisilazide 0; hydrazine can be made with (B) Ketoester Jeli and can be protected or unprotected hexamethyldisilazide bases; under suitable conditions to obtain hydrazine use either

4l - pyrazole esters have the formula (CO) and optionally 6 can be protected using benzyl group for example and the like 0 and thus converting the J amide J ester of formula (D) using methods known to a person skilled in the art to process eg with ammonia in a polar solvent at a temperature between room temperature and the boiling point of the solvent. © (D)amide is reacted with a dehydrator; as phosphorous oxychloride or thionyl chloride phosphorous pentoxide or trifluoroacetic anhydride and the like either pure or in the presence of a non-proton donor solvent; acetonitrile Jie or “DMF” and the like to obtain (BE) nitrile and (B) nitrile is reacted with an azide (ie; (N5) or an azide equivalent such as sodium azide or potassium azide or trimethylsilyl azide (i.e. (((CH3)SiNg and the like) 0 to obtain compounds of formula (Ta) where X is Al and 2 is C-tetrazol- 5-yl It may be useful in some cases to include the presence of a Lewis acid AICI Jie or :70 and the like in a suitable solvent DMF Jie etc. Other compounds of the invention may be prepared where X is 87 Zs is C-COMH or 2 is L and 5 is C-COH from the intermediate compound (©) by hydrolysis of the corresponding acids of the formula lithium hydroxide (Ic) 0 or sodium hydroxide or potassium hydroxide Or potassium trimethylsilanoate or similar 0 and this process is explained Lad after for models in which X is iN and 7 is C-COH Drum Rs Re Ammo 1 Rs Re 5 Sh N A 82 R, N 2" (C) (Ic) YY44

Vo - -— A process similar to embodiments of the present invention can also be illustrated where X is (C-COH), 7 is Z Raz, and Rom Ri is 080 "Rs NH" B > — NH “ YH N N Rs Re Rs Re (Ig))© And it is possible in a manner similar to what was mentioned in Scheme No. ( \ ) to prepare the compounds of the present invention ¢ dus 0 2 to be neither nor to be ©- tetrazolyl or C-COH or :0-00 -m alkyl using (F) ketone oe 0 R plus R, 1 R, R, Scheme 1 0 Rj = SS Rs NH \= Yeh Rs Re mk Rg Re (Ti) 00 (Say) Preparation of (F) ketone compounds by cyclopropanation of the appropriate cyclopentenol by treatment with Suitable carbene and precursor — carbenoid degraded diiodoethane with 0 | Ry and y can be converted directly to (F) ketone or by the introduction of group(s) (i.e., malformed by (Riss Rj;) which can subsequently convert to Ry groups using methods known in the art. Cyclopentyl alcohol can be oxidized to cyclic ketone with factors

_ “7 3 —

Jl sc 5 tetrapropylammonium perrhuthenate or pyridinium chlorochromate is an oxidant such as a chelating oxidant. This process is described below. 8 on CH, Rs OH TPAP Ri 0 Henpet —

Et, Zn NMO Raz

R R -1

Rs and R, Ry © Lahi Rap i.e. CRp2R312 XK): Et;Zn 7

Rs OH Ri OH

IP R2

R R

Ris Rs Rs 8 Rs Rs Rs 8 is appropriately substituted with 1,2-epoxy-5,6-alkene by preparing compounds by treating (Sa: this is a strong base such as lithium tetramethylpiperazide, lithium diisopropylamide, lithium hexamethyldisilazane, Sodium hexamethyldisilazane, potassium hexamethyldisilazane: See “(M) Alcohol and similar rules for converting to Alcohol (Says Hodson, etal. J. Am. Chem. Soc. 2004, 126, 8664): As dans] using Ketone factor (1) 00 for example tetrapropylammonium perrhuthenate pyridinium chlorochromate but not limited to and the like. 8 R 8 8 Rs 6 Rs 6

R Pd Ra Ra 2-7 to _—

Rs Rs Re 0 Rs OH Rs 0

R2 Ri and 5 9 001) 5

— VY - of the invention by separation for hydrolysis Motion Chiral (non-racemic) compounds can be prepared: using the method published in Epoxide (G) (Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunga, M. Hansen, K.B.; Gould, A.

E.: Furrow, M.E.; Jacobsen, E.N.J Am. Chem. Soc. 2002, 124, 1307) produced by the reaction of anion by adding another Jan ul to it (1) ketones and alternatively it is possible to prepare © potassium hydride 0 sodiuim hydride Jie and a suitable base trimethylsulfoxonium iodide and the like with cyclo 9 I 0 2720040 or R 2 B O

I ZnR Br 1 501161 — parenthesis _— pyridine PdCl,Ph; NaH

Rs Rg Rs Rg Ry = alkyl Rs Rg Rs Rg DESCRIPTION OF ANOTHER METHOD THAT CAN BE USED IN THE PREPARATION OF THE COMPOUNDS OF THE present invention; JX where 00 and this method is illustrated 0 without the need to use multiple steps or tetrazol-5-yl azide: c-tetrazol-yl is no and 7 is X in the following diagram where

PG. _N 0 m Re 1 nmla PG

N LG Ney M (P) Ra Rs Rs MN 0

Rs 0 Base Rs Uh R, Ra 0 (A) Ri 0 (0)

N “N PG

N

Re. Ro | " y = pi H,oN-NH;

Rs N

R

2 Ri

VA - - Ketone (A) 42 can be suitably substituted into (0) Diketone using tetrazole (P) in the presence of a base, where 70 is an appropriate protecting group or metal cation. A suitable base to use in the reaction is one that is ALG soluble in the solvent and can remove a proton from cyclopentanone but does not otherwise participate in the reaction.Organic strengthening 0 bases are particularly useful DBU Jie or <DBN i.e. tetramethylguanidine or alkali or alkaline earth metal bases » such as: sodium or magnesium alkoxides, especially potassium butoxide. tetrazole (©) or Diketone (0) produced; some examples include (C4) alkoxy esters or 107 by 00. Suitable solvents include (DMF) dimethylformamide and (DMAC) dimethylacetamide and (DMSO) dimethylsulfoxide and N-methylpyrrolidinone HMPT (NMP) plus tetrahydrofuran (THF) in the same reaction or as an additional step after isolation; Diketone (O) is converted to (Q) tetrazole using hydrazine . The protection group is thus extracted to provide the compounds of the present invention. No and Lad can demonstrate a process similar to embodiments of the present invention where X is Cetetrazol-5-yl and 7 is N

_ 9 7 Sb N 0 Dream PG. NAL Ry N.\-PG M _ N=N LG Rs Ri N B Ro Rs (P) Ra Ry ° Base Rs 0 R Rs Rg Ney' PG 6 0 N i Ro 81 =N . R n-l2i| B 3 N’ = y

Rs Re service in this ual) Various transformations of the organic group and protection groups can be performed in a position with several procedures other than the previously mentioned procedures. For example, references may be found to other synthetic procedures that may be used in the preparation of intermediate compounds or: compounds disclosed herein in oo

Smith, 11. B.; 1March, J,, Advanced Organic Chemistry, 5 Edition, Wiley-

Interscience (2¢ 1); Larock, R.C., Comprehensive Organic Transformations, A Guide to

Functional Grease Preparations, 2™ Edition, VCH Publishers, Inc. (1 999), or Wuts, P.

G.M.; Greene, i. W.; Protective Groups in Organic Synthesis, 3" Edition, John Wiley and Sons, (1999). Photoactivation and liberation of the photoactive amine compound by treatment using a base or separation of doubic salts using a photoactive base ve and thus liberation of the acid by treatment with acid.Another method is adopted to separate racemic

- .m - to optically pure isoforms on a chromatograph on a photoactive substrate or AS carrier and certain racemic compounds of the present invention can thus be separated into their photoisomers; For example, if the partial crystallization of salts is: or 1-(tartrates, mandelates, or camphorsulphonate) -l, for example. These compounds of the present invention can be separated by forming amides or esters, doubic monomers (Jeli) compounds of the present invention with a photoactive amine or alcohol such as (+) or (-) “- methylbenzylamine” (+ ( or )- ( methylbenzylalcohol —a but not limited to and the like) and separated by fractional crystallization, chiral chromatography, or similar and thus hydrolyzed. Additional methods may be used to separate optical isomers known to those skilled in the art and 0 can be demonstrated to the person of ordinary skill In this field, 0 and these methods include the methods that Hale researched by: J.

Jaques, A.

Collet, and 5. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1 981). It is known that the chemical properties mentioned in this document are representative and are not intended to be 1 limiting any way. Methods and uses: The compounds of the present invention are useful in inhibiting the production of free fatty acids. The compounds of the present invention are also useful in inhibiting the production of 1 free fatty acids when

AY - - lead to significant reduction or no measurable side effects of irritation in some cases. zed is a side effect commonly associated with the administration of niacin, and the compounds of the present invention do not usually cause vasodilation at higher doses of about Toe-M as measured using methods known in the art; Jie method shown in example AV) and in some embodiments; The compounds of the present invention do not result in a substantially measurable flushing of the face in the individual compared to an essentially equal dose of Alladll niacin. and in some embodiments; Compounds of the present invention result in less than about 788, 65, 296, ne 110, 150, 146, 140, 170, 276, 210, 201 Jive, 75, or 1 measurable facial flushing in person compared to an equally effective dose of niacin essentially ye. Compounds of the present invention can modulate receptor activity (RUP2S) and 'modulate' is intended to indicate the ability to increase or decrease receptor activity 0 In some embodiments, compounds of the invention can be used in ways to modulate the receptor 5 by contacting the receptor with any one or more of the compounds mentioned in this document. Also in another embodiment, the compounds of the invention can be used in 1 Methods of receptor modulation method 8100025 in the treatment of a metabolic disorder in an individual in need of such modification, which involves contacting the receptor with a therapeutically effective amount of a compound of the formula (Ta) In some embodiments, the compounds of the invention enhance receptor activity 80025. In another embodiment, the compounds of the invention are receptor adjuvants 5. The term 'adjuvant' as used herein refers to agents that can activate (i.e.; activate) the receptor such as

AY - - receiver RUPDS and in some embodiments; The compounds of the invention are partial adjuvants to the RUP25 receptor. Another aspect of the present invention relates to methods of treating a metabolic disorder ea Giving an individual in need of such treatment a pharmacologically effective amount of a compound having the formula (Ta) 0. Another aspect of the present invention relates to methods To raise HDL in a specific individual' involves giving said individual a therapeutically effective amount of a compound of formula (Ta) Another aspect of the present invention relates to compounds of formula (la) for use in a method of treating the human or animal body with a drug; It is also mentioned in this document. Another aspect of the present invention relates to compounds having the formula (Ta) for use in a method for treating 0 a disorder related to the metabolism of the human or animal body with a drug as described herein. Another aspect of the present invention relates to compounds having the formula (fa) for use in a method of treating with a drug a disorder associated with the metabolism of the human or animal body as herein stated wherein said metabolic disorder is selected from the group 0 consisting of an impairment The percentage of lipids in dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, obesity, poor tolerance, atherosclerosis, hypertension, stroke, and Syndrome X = And heart disease, and type 2 diabetes.

Another aspect of the present invention relates to compounds having the formula (Ta) for use in a method for treating a metabolic disorder of the human or animal body with a drug as herein mentioned wherein said metabolic disorder is selected from the group consisting of a lipid imbalance In dyslipidemia pal), atherosclerosis, coronary heart disease, insulin resistance, and type 2 diabetes mellitus. Another aspect of the present invention relates to compounds of formula (la) for use in a method for treating atherosclerosis 5 of the human or animal body with a drug as described herein. The AT manifestation of the present invention relates to compounds of formula (Ta) for use in a method of raising HDL 0 in the human or animal body with a drug as described herein. Another aspect of the present invention relates to uses of compounds of formula (la) in the production of a drug for use in the treatment of a metabolic disorder as described herein. Another aspect of the present invention relates to uses of compounds of formula (Ta) in the production of a drug for use in the treatment of a metabolic disorder as described herein; It is chosen from the group consisting of dyslipidemia, atherosclerosis, coronary heart, insulin resistance, obesity, poor tolerance, disease 5, and high blood pressure. Stroke, Crohn's syndrome, heart disease, and Type 85 diabetes.

Ym - Another aspect of the present invention relates to uses of compounds of formula (Ta) as mentioned herein; In the production of a drug for use in the treatment of atherosclerosis. Another aspect of the present invention relates to uses of compounds of formula (la) as mentioned herein; In producing a drug for use in raising an individual's HDL.

0 Some embodiments of the present invention relate to methods for treating metabolic disorders. and in some embodiments; The metabolic disorder is from the group consisting of dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, obesity, poor tolerance, atherosclerosis 8 and high blood pressure hypertension, stroke, and syndrome

X— 0 0 heart disease and diabetes 85 type 2 0 and in some embodiments; A metabolic disorder is dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, or type 2 diabetes mellitus. In some embodiments the metabolic disorder is a lipid imbalance in pid and in some

models.” The metabolic disorder is atherosclerosis. and in some embodiments; The metabolic disorder is coronary heart disease and in some embodiments; The metabolic disorder is resistant (A.08) some embodiments; the metabolic disorder is type 2 diabetes mellitus.

— A A _ and the individual in some embodiments related to the methods of the present invention is a tensile object. In other embodiments, the mammal is a human being. The AT manifestation of the present invention relates to methods for producing a pharmaceutical composition involving mixing or incorporation of a compound of formula (fa) as described herein; and a pharmaceutically acceptable carrier. Compositions of the Present Invention: Some embodiments of the present invention include a method for producing a pharmaceutical composition involving the mixing of at least one compound according to any of the embodiments of compounds disclosed herein and a commercially acceptable carrier. Formulations may be prepared by any suitable method by uniformly mixing the active compound(s) usually with 0 liquids or finely divided solid carriers or both in proportions required and the resulting mixture thereafter and if necessary formed into the required form. a Conventional excipients such as binders, fillers, acceptable wetting agents, tablet-forming lubricants and disintegrants in tablets and capsules for oral administration can be used. Liquid preparations for oral administration can be in the form of solutions 1, emulsions 5, idle suspensions or ay) and syrups. alternatively; Preparations for oral administration may be in the form of a dry powder which may be reconstituted with water or another suitable aqueous carrier prior to use. And it can! Jia Additives Suspending or emulsifying agents, non-aqueous carriers (including edible oils), preservatives, flavorings and coloring materials to liquid formulations. Pictures can be prepared

A 4 — — doses for non-gastrointestinal administration by dissolving the compound of the invention in a suitable liquid carrier and sterilizing the solution by filtering prior to packaging and sealing it in a suitable vial or ampoule. These are only a few examples of the many suitable methods that are well known in the art for preparing dose forms. 0 The compound of the present invention can be formulated into pharmaceutical formulations using emetic methods well known to those skilled in this art. Suitable carriers are pharmaceutically acceptable. that fall outside the material mentioned in this document; well known in this field; See, for example: Remington, The Science and Practice of Pharmacy, 20" Edition, 2000, Lippincott.

Williams p Wilkins, (Editors: Gennaro, A. R., ef al.) 0 While an Une substitute - a compound for use in the treatment of the present invention may be made as a crude or pure chemical; However, it is preferred that the compound or "active ingredient" be presented as a pharmaceutical formulation or formulation that also includes a pharmaceutically acceptable carrier. Accordingly; One of the aspects of the invention includes containing pharmaceutical formulations that include a pharmaceutically acceptable carrier in combination with at least one compound according to formula (la) 1. One or more Pharmaceutically Acceptable 0 carriers The carrier(s) must be 'acceptable'; ie compatible with the other components of the formulation and not excessively harmful to its receptor.

m - Pharmaceutical formulations include formulations suitable for oral, nasal, or nasal administration, topical administration (which includes buccal and sublingual administration), vaginal administration, or through the alimentary canal (which includes intramuscular, subcutaneous, and intravenous administration) or in the form of Suitable for administration by inhalation, administration, or as a transdermal patch. The transdermal patch discharges the drug at a measured rate, providing the drug for effective absorption with minimal drug degradation. The transdermal patches typically include an impermeable backing layer, one pressure-sensitive adhesive, and an ALE protective removal layer with a release liner. Willem acquaints a person with ordinary skill in the art with the appropriate techniques to produce the effective patch required for transdermal application based on the needs of the person skilled in the art.

0 The compounds of the invention can therefore be formulated with a conventional adjuvant, carrier or diluent in the form of pharmaceutical formulations and dosage units thereof and in the form in which they may be used as solids; such as tablets or capsules filled or as liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with this and all for oral administration; Or in the form of suppositories for rectal administration or in the form of

0 Sterile injectable solutions for non-gastrointestinal administration (including injection into the skin). These pharmaceutical formulations and dosage forms may include traditional ingredients in traditional proportions; With or without additional active compounds or agents, these particular dosage unit forms may contain any appropriate effective amount of the active ingredient proportional to the range of daily doses required for use.

YY44

mm - for oral administration; The pharmaceutical composition can be, for example, in the form of a tablet, capsule, suspension or liquid. It is preferable that the pharmaceutical composition be made in the form of dosage units containing a specific amount of the active ingredient. The models of dosage units are capsules, tablets, powders, granules or suspension with Asal additives such as lactose 0, mannitol, corn starch or potato Li and with binders such as cellulose lie, cellulose derivatives, gum arabic, corn starch or gelating; and with crumbling materials Jue corn starch or potato starch or carboxymethyl-cellulose 3; With lubricants such as talc or magnesium stearate, the active ingredient can also be given parenterally as a formulation where, for example, saline, dextrose or water can be used as a pharmaceutically acceptable carrier.

0 Compounds of the present invention, salt, hydrates or solubles thereof that are pharmaceutically acceptable may be used as active ingredients in pharmaceutical formulations; Specifically as receptor adjuvants/partial auxiliaries 5. The term 'active ingredient' is defined under 'pharmaceutical formulation'; it means the component of the pharmaceutical formulation that provides the initial therapeutic effect as opposed to the 'inactive ingredient' which is generally characterized by not providing essentially pharmaceutical benefit.

Ve The dose can vary when using the compounds of the current invention within wide limits, and as usual and known to the attending physician, it is determined according to the cases of individuals and according to each Allah alone. It depends, for example, on the nature and severity of the disease being treated, on the condition of the patient, on the compound used, on whether treatment is being undertaken for an acute or chronic condition, or on whether active compounds are also given in addition to the compounds of the present invention. Dosages included

0 typical of the present invention but not limited to about 0.001 mg to approx

m - Oe plural; from about 000 to about 1500 mg; from about 0.001 to about 0 mg; from about 009 to about 0060 mg; and from about 1001 mg to about YO mg; and from about 0 + 0 to about 100 mg; from about 0.001 to about 0 mg; and from about 1000 to about yo mg. ll multiple doses may be given per day; 0 especially when relatively large amounts are thought to be required; And that paralyzed? or or ; doses. Depending on the individual Alla and what is considered appropriate by the physician or caregiver (a sal) it may be necessary to deviate up or down from the dosages stated in this document. The amount of active ingredient, lad, hydrates or solubility varies Pharmacologically acceptable required ye for use in treatment not only depends on the specific salt that is chosen, but also according to the method of administration, the nature of the condition being treated, and according to the age and condition of the patient. In general, a person skilled in the art understands how data are interpolated in an organism by analogy obtained in one model system to another such as an animal to human model. As described in the subsequent (1) example 0 the mouse atherosclerosis model as described in the subsequent (Y) example or the animal atherosclerosis model in the organism as described in the subsequent (0) example In some circumstances, these interpolations may be approximately based on the weight of the animal model compared to another such as a mammal and preferably a human. However Wes also; These 0 interpolations depend not simply on weight differences but also on the inclusion of a different set of factors. YYaa

f. Typical factors include gender, age, weight, sex, diet, medical condition of the patient, severity of disease, route of administration, and therapeutic considerations such as activity, efficacy, pharmacokinetic and toxicological profiles of the specific compound used; whether a drug delivery system is used and whether the condition being treated is acute or chronic and whether active 0 compounds are also administered in addition to the compounds of the present invention as part of a combination therapy. The dosing regimen for treating a diseased condition with the compounds and/or formulations of this invention is chosen according to a combination of factors such as those previously mentioned. Thus, the actual dosing regimen used can vary greatly and thus may be deviated from the preferred dosing regimen and a person skilled in the art will realize that doses and dosing regimen outside of these typical ranges may be tested and may be used as appropriate in the methods of this invention. The required dose may conveniently be given as a single dose or in divided doses given at appropriate intervals such as two, three, four or more secondary doses per day. The same secondary dose may also be divided eg into several separate administrations at partial intervals. The daily dose can be divided; Especially when relatively large volumes of Vo are given as appropriate amounts; Jie into multiple doses, two, three, or four doses, or partial administrations. as appropriate and depending on individual behaviour; It may need to deviate up or down from the indicated daily dose. The compounds of the present invention can be administered in a wide range of oral and non-gastrointestinal dosage forms. And it becomes clear to those skilled in this field that Tire can

ay - - the following doses of either the compound of the invention or a pharmaceutically acceptable salt of the compound of the invention as the active ingredient. and to prepare pharmaceutical formulations from the compounds of the present invention; add A pharmaceutically acceptable carrier can be either a solid or a liquid. Solid formulations include powders, tablets, tablets, capsules, rivets, suppositories, and ALE granules for dispersion. The solid carrier can be one or more substances that can act as diluents, flavoring agents, solvents, lubricants, dispersing agents, binders, preservatives, disintegrating agents for tablets, textures, and in powders; The carrier shall be a finely divided solid which is in admixture with Active Component 0 Finely Fractionated. and in discs; The active ingredient is mixed with the carrier having the necessary binding capacity in appropriate proportions and combined in the required shape and volume. Powders and tablets can contain varying amounts and percentages of the active compound. A typical amount in a powder or tablet can contain from 16 to about 798 ve of active ingredient; However, a skilled person in this field knows when quantities outside this range are required. The appropriate carrier materials for powders and tablets are: magnesium carbonate, magnesium stearate, talc, sugar, lactose, or pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, low fusing wax, JSS butter and the like.

av - _ 'preparation' means the inclusion of the formulation of the active compound with an encapsulated material as a carrier providing a capsule in which the active ingredient is enclosed with or without the carrier material with which it is therefore in association. Rivets and lozenges are similarly included. Tablets, powders, capsules, tablets, lozenges and lozenges may be used as solid forms suitable for oral administration.

and to prepare suppositories; A low-melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is homogeneously dispersed in it by stirring. The homogeneous molten mixture is then poured into molds of suitable sizes and allowed to set

by cooling and thus harden.

0 Suitable formulations for vaginal administration can be offered as viscous, vasopressors, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, carriers such as those known to be suitable for this field. Liquid formulation preparations include solutions, suspensions, Jie emulsions in water or propylene glycol solutions in water. And can

1 For example, formulation of liquid preparations for non-intestinal injection. As solutions in a solution (Says le polyethylene glycol) Formulation of injectable preparations Jie Suspensions - sterile aqueous or oily injectable suspensions according to what is known in this field using suitable dispersing or wetting agents or suspending agents. The sterile injectable preparation can also It shall be a sterile injectable solution or suspension in a non-toxic diluent or solvent

Dsggo - Acceptable Non-GI Jie solution in -1,3-butanediol Acceptable carriers and solvents that may be used include water, Ringer's solution and isotonic sodium chloride solution. In addition to odd, fixed oils have traditionally been used as a solvent or suspension medium. For this purpose any emollient stable oil including synthetic mono- and oe-5*e glycerides may be used in addition; Oleic acid is used in the preparation of injectable formulations. Compounds of the present invention may therefore be formulated for non-gastrointestinal administration (such as parenterally; such as by implantation or by continuous infusion) and may be delivered as a unit dose in ampoules, pre-filled syringes, small volume infusions, or in multi-dose vessels. With an added preservative. The formulations can take forms such as suspensions, solutions, emulsions, oily carriers, or dil, and may contain formaly agents such as suspending and/or stabilizing agents. alternatively stabilizing and/or dispersing; (Say) for the active ingredient to be in the form of a powder obtained by pure isolation of the sterile solid material or by freeze-drying 0 of a solution for composition with a suitable Alda substance such as sterile water without heat before use. Ail solutions can be prepared Suitable for oral use by dissolving the active ingredient in water and adding appropriate colouring, flavoring, stabilizing and thickening agents as required.

Aqueous suspensions suitable for oral use may be made by dispersing the finely divided active ingredient in water with a viscous substance such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other known Jaa suspensions. Also included are preparations in the form of a solid which are prepared for conversion shortly before use into liquid formulations for oral administration 0 These liquid forms include 5 solutions, suspensions and emulsions. Such preparations may contain, in addition to the active ingredient, colourings, flavourings, stabilizers, pH EIR regulators, artificial and natural sweeteners, dispersants, thickeners, dissolving agents and the like. 0 and for topical administration on the epidermal layer; The compounds according to the invention may be formulated as ointments, creams, lotions, or as transdermal patches. Ointments and creams may for example be formulated with a water or oil base and with the addition of suitable thickening and/or gelling agents. Washings may be formulated with a water or oil base and generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. .coloring Formulations suitable for topical oral administration include lozenges containing the active agent in a flavoring base; They are usually sucrose and gum arabic or tragacanth ¢ and medicinal sweetener tablets that contain the active ingredient in an inactive base such as glycerin 5 gelatin or AR

mu - sucrose and gum arabic; and mouthwashes containing the active ingredient in a suitable A Lda liquid carrier. Solutions and 5E suspensions are administered directly into the nasal cavity by conventional means, such as using a dropper, pipette, or spray. The formulations can be supplied as single doses or as multiple doses. In the latter case of dropper or pipette; This can be done by the patient taking an appropriate, predetermined volume of solution or suspension. In the case of a machine gun; This can be done for example with a metering pump for mist spraying. Intranasal administration may also be made by means of an aerosol formulation in which the active ingredient is supplied in a pressurized bottle with a suitable propellant. and if compounds of formula (Ta)0 or pharmaceutical compositions containing them are administered as by a sprayer, nebulizer, pump nebulizer, inhaler, metered inhaler, or dry powder inhaler. Pharmaceutical forms may be prepared to give compounds of formula (I) as aerosols by processes well known to one skilled in the art. For their preparation, for example, solutions of dispersions of compounds of formula (la) in water and/or mixtures of alcohol [ela] or suitable brine solutions using ordinary additives Jie may be used, for example. benzyl alcohol other suitable preservatives or absorption enhancers to increase bioavailability or solubilities or dispersants etc. and ordinary propellants as appropriate comprising for example CO2, 6705 such as dichlorodifluoromethane and

q 4 _ _ trichloroflucromethane and dichlorotetrafluoroethane « and the like. The aerosol can also conveniently contain a surfactant, lecithin Jie, and the dose of the drug can be controlled by providing a metering valve. and in a are intended for administration via the respiratory tract; Intranasal formulas include the compound having generally a small particle size of the order of eg 01 micron or less Sa 0 Obtaining the particle size by means known in the art as by conversion to microparticles. Adapted formulations may be used if required to obtain an extended release of the active ingredient. As an alternative, the active ingredients can be provided in the form of a dry powder, such as mixing the compound powder in a suitable powder base, lactose Jie, starch, or starch derivatives such as: hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). appropriately; The powder carrier forms a gel in the nasal cavity. The powder formulation may be presented as a unit dose such as in capsules, eg gelatin cartridges or small pill cassettes from which the powder can be administered via an inhaler device. Vo and pharmaceuticals are preferably in Sle yall Clas . In this form, the formulation of the preparation is subdivided into dosage units that contain appropriate quantities of the active ingredient 0 and the form of the dose unit can be a preparation in a package; The package contains separate quantities of the preparation such as packed tablets, capsules and powders in vials or ampoules.

_ 7 9 — The dosage form may also be a capsule, rivet or lozenge in itself, or it may be the appropriate number of any of those in the packaged form. Oral tablets and capsules and non-gastrointestinal fluids are the preferred formulations. These tablets and capsules usually contain about 0 (Le) mg to about 110 g; or from about vy 1 mg to about a mg; or from about 1 4 mg to about yo. mg of the compound of formula (Ia). The compounds of the present invention can be converted into dle' pro-drugs. pro-drugs "to compounds that have been modified with certain chemical groups known in this field and those groups, when administered to an individual, undergo a biotransformation to obtain the original compound 0. Thus, prodrugs can be viewed as compounds of the invention containing one or more of Specialized non-toxic protective combinations that are used in a temporary manner to alter or remove a property of a compound.In general, the “pro-drug” method is used to facilitate oral absorption0 A thorough discussion is provided in: T.

Higuchi and V.

Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed.

Edward B.

Roche, Vo American Pharmaceutical Association and Pergamon Press, 1987. Both are incorporated in full by reference herein.

Combination Therapy: Whereas 1 compounds of the present invention can be administered as a single active pharmaceutical agent (ol) as monotherapy); However, it may also be used in combination with other pharmaceutical agents (ie; combination therapy) as for the treatment of the diseases/conditions/disorders mentioned in this document. Accordingly the AT aspect of the present invention includes methods for treating metabolic diseases involving administration to the individual in need of such treatment a therapeutically effective amount of a compound of the present invention in combination with one or more of the additional pharmaceutical agents mentioned herein. Suitable pharmaceutical agents that can be used in combination with compounds of the present invention71 include anti-Je agents, apolipoprotein-8 secretion inhibitors/micro-triglycerides (apo-B/MTP) and adjuvants. MCR-4 and choleretic agonists (CCK-A) and serotonin and norepinephrine reuptake inhibitors (eg; sibutramine) and sympathomimetic agents and adrenergic Bs receptor agonists and dopamine agonists (such as bromocriptine) and melanocyte stimulating hormone receptor agonists \o and cannabinoid Cah 1 receptor antagonists such as: N-(piperidin-1-yl)-5 -(4-chlorophenyl)-1-(2 4-dichlorophenyl)-4-methyl-1H-- pyrazole-3- carboxamide], leptons 5 melanin concentrate (OB) antagonists, leptin ¢ homologues, leptin receptor agonists, galanin antagonists and lipase inhibitors (such as tetrahydrolipstatin, ie

AQ - Jal se 5) Orlistat Anorexia (such as bombesin adjuvants), Neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone analogues, glucocorticoid receptor antagonists or orexin receptor antagonists glucagon-like peptide-1 receptor cofactors and oo-neutrophil trophic factors (such as Axokine™ from Regeneron Pharmaceuticals, Inc., Tarrytown, (NY and Procter & Gamble) Company, Cincinnati, OH, human gout-related proteins (AGRP), receptor 0 antagonists, histamine receptor 3 antagonists or reverse agonists, receptor 2 17 agonists, noradrenergic anorectic agents phentermine, mazindol (fis) agents and the like) and appetite suppressants (bupropion Ji). In some embodiments, selecting anti-obesity agents from the group consisting of Otlistat, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine. In conjunction with exercise and sensitive diets. It is known that the field of combination therapy for the compounds of the current invention with other anti-obesity and appetite-suppressing agents and related agents is not limited to the previously mentioned agents; but include who

: Coy. In principle, any combination with any pharmaceutical agent or pharmaceutical composition is useful in the treatment of overweight. obesity and treatment of obese individuals and in addition to anti-obesity agents; Other suitable pharmaceutical agents that may be used in combination with compounds of the present invention include agents useful in the treatment of comorbid disorders. The treatment of such disorders involves the use of one or more pharmaceutical agents known in the field and belonging to the drug classes indicated to name a few the following: »- 6 AS yey meglitinides inhibitors, 15 CLS peroxisome peroxisomes, receptor cofactors 6, HMG-CoA reductase drugs and analogues; and inhibitors | insulin s (PPAR-y) (i.e. fenofibrate, bezafibrate, gemfibrozil, which includes: cholesterol-lowering fibrate (eg 0-cholestyramine, etc.) and bile acid fragmentation agents which include: 1001 © oJ antagonists) and anti-platelet agents (niacin and the like; colestipol and the like; ticlopidine and clopidogrel which include: adenosine diphosphate aspirin receptor . adiponectin 3 angiotensin II and angiotensin receptor antagonists thereof) and converting enzyme inhibitors According to one aspect of the present invention; a present compound may be used in combination with a pharmaceutical agent or ve agents belonging to one or more of the drug classes described herein. The field of combination therapy of the compounds of the present invention with other pharmaceutical agents does not, but includes in principle any lin limited to those set out in this document previously or

- 1.1 A combination with any pharmaceutical agent or pharmaceutical composition useful in the treatment of diseases, conditions or disorders that are associated with disorders related to metabolism. Some models of the current invention include methods for treating a disease, disorder, or condition as mentioned in this document, which include giving the individual in need of that treatment a therapeutically effective amount or a dose of the current compound in association with at least one pharmaceutical agent. Meglitinides and sulfonylureas, choosing from the group consisting of: compounds and receptor agonists - +- activator of o-glucosidase reproduction, biguanide enzyme inhibitors, HMG- compounds, insulin enzyme inhibitors and insulin analogues (PPAR) -y (i.e. peroxisome bodies 5 fenofibrate including: fibrate, statins (eg CoA reductase, etc.; clofibrate, gemfibrozil, bezafibrate) 0 and agents (niacin and the like” and Lay colestipol 5 cholestyramine: bile that includes adenosine diphosphate 5 aspirin receptor antagonists (Jia) anti-platelet angiotensin and the like) and converting enzyme inhibitors ticlopidine s clopidogrel includes: In some embodiments;

HMG-CoA reductase, biguanides aldose reductase inhibitor, glucosidase angiotensin inhibitor, LDL converting enzyme inhibitor, fibrate ys squalene catabolism enhancer, synthesis inhibitor

DP, a thiazolidinedione insulin receptor antagonist, and a secretion enhancer. An aspect of the present invention includes pharmaceutical compositions containing at least one compound as mentioned herein. and in some embodiments; It also includes the all-invention © formula

unless. 1 Pharmaceutical drug One or more agents selected from the group consisting of, for example, an a-glucosidase inhibitor, a biguanides aldose reductase inhibitor, an HMG-CoA reductase inhibitor, and a fibrate s squalene synthesis inhibitor LDL catabolism enhancer, angiotensin converting enzyme inhibitor, and thiazolidinedione 5 insulin secretion enhancer. © Suitable pharmaceutical agents that may be used in combination with compounds of the present invention include -6-enzyme inhibitors. O-glucosidase inhibitors belong to a class of drugs that competitively inhibit digestive enzymes such as amylase-a, maltase, dextrinase-a, enzyme-6, etc. in the pancreas and/or small intestine. Reversible inhibition with o-glucosidase inhibitors delays, reduces, or otherwise lowers 0-glucose levels in the blood by delaying the digestion of starch and sugars. Some representative examples of a-glucosidase PA inhibitors include acarbose, N-(1,3dihydroxy-2-propyl)valiolamine (with generic name: voglibose) and miglitol and the 0-glucosidase inhibitors known in this the field. Suitable pharmaceutical agents that can be used in combination with compounds of the present invention include sulfonylureas, and (SU) sulfonylureas are drugs that 1 enhance insulin secretion from pancreatic cells =p by sending signals for insulin secretion by through SU receptors in cell membranes. HD includes sulfonylureas, glyburide, glipizide, glimepiride, and other sulfonylureas known in this field.

Ask

They include suitable pharmaceutical agents that may be used in combination with the compounds of the invention

The current study contains meglitinides, and meglitinides are derivatives of benzoic acid.

Jud is a new class of insulin triggers that target the increase in blood sugar after food

It shows effectiveness compared to 5 compounds in reducing 0 / 10. Examples of meglitinides© include nateglinide 5 repaglinide and other meglitinides known in

this field.

They include suitable pharmaceutical agents that may be used in combination with the compounds of the invention

current on biguanide compounds. The 8 biguanides represent drugs that activate glycolysis

Abiotic glucose and increase sensitivity to insulin in peripheral tissues and inhibit ABA I.D

Ge glucose 0 in the small intestine, suppresses the neoformation of glucose and inhibits the oxidation of fatty acid.

Forms of biguanide compounds include:

Phenformin, metformin, buformin, and other biguanides are known in this field.

They include suitable pharmaceutical agents that may be used in combination with the compounds of the invention

Current on enzyme inhibitors ©0-105106. competitively; These inhibitors inhibit digestive enzymes

Je vo enzyme maltase my amylase —a, enzyme ©- dextrinase, sugar enzyme... etc. in

Pancreatic and/or small intestine cells. Reversible inhibition with a-glucosidase inhibitors

To delay, reduce, or otherwise lower blood glucose levels by delaying starch digestion

and sugars. Some examples of a-glucosidase X inhibitors include:

- 1.40 miglitol and (voglibose): (with the generic name acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine known in this field. o-glucosidase and enzyme inhibitors, including pharmaceutical agents suitable that can be used in combination with the compounds of the invention (PPAR —y (i.e.; peroxisome activator of antibody y= present on the receptor adjuvants e) and these adjuvants represent 45 compounds that activate <7gm/00 of the nuclear receptor and thus regulate Transcription, transmission, and utilization of glucose involved in controlling the production of insulin-responsive genes Factors in the category also facilitate regulation of fatty acid metabolism Examples include rosiglitazone, pioglitazone, tesaglitazar, netoglitazone PPAR—y Well-known aids in this field. PPAR—y and aids GW-505116 5 GW-409544

0 The appropriate pharmaceutical agents that can be used in combination with the compounds of the present invention include DP receptor antagonists, and these antagonists include those mentioned in international patents No. 1791569 or 1177 / | Tv and 0176/2 and EC No. 13067850 and AT 944876/7<; and the like. Other compounds can be found as DP antagonists

Vo is typical in International Application No. 4/0770 .. Examples of compounds that are particularly useful for selectively antagonizing the DP receptor include:

- 1. — )( Compound (c) Compound (b) of compound _b MeO,S 1 . “COM each” CO the _S. 2S 0 alk TL oy TL © Mri- 3 ol CHa Fg (3) Compound (f) Compound (e) Compound 5 F N

IN 5 a ny CO,H = 1526 COM Tr ~ Sos COM b I 5 07 -) a © ml TL ma 3 cl 0 compound (i) component (h) compound ( g) 08 SMe cl

SO) ar What is NTN CO, H NTN Naron | >

N° ON COH Compound (L) Compound (K) Compound (Z) 0 SO,Me 0 oe al A se SOMe 0 1 ] | for | NT59

NTN CO,H 01,00 O No Ps

N

COH

Compound (o) Compound (n) Compound (m) cl SO,Me ci

SO;Me sc" 502/6 ed Os

N° PZ oS > | NN CO,H for a

NCOHNTNCOM

(5) Compound (R) Compound (F) Compound

SO,Me © Cl Cl 50/6 (re x XX):

AO BO Squirt NTN CO,H | J N° ON CO,H

NT ON COLH

- Va = (3) Compound (U) Compound (R) Compound

SO,Me s<_) Cl, SO,Me \ 7 SO,Me = ~~ 01 a a l [ 0 ] ) m 0 NAS CO,H

NT ONT CO,H ’ (2) Compound (x) Compound (w) Compound

SO;Me — 5-) Mr 005 Fe A “7 0 COM. 2 COH i | N XN

N Os >

CO, H 2 TL 0, and tune TL cl CH, Cl for compound (1) compound (Z) compound (X) core of MTerb

N F 0 Mona Lane Or

O=s_ “TL N 2

CHs > N 0 Ad Compound A Compound Ab 0 COzH 0 - C 0 &

N N NH H

. © ae! "

OO Zero Ah: L (LJ) and Compound (Az) Compound (or) Compound (A E)

F N F A L J “%_-COH N MOTHER 0 0 9 cl ~( 0 0

N

CH,

Yvyasa

- 1.7 (cl) Compound (A) Compound (A) Compound Sni “Harin” Svat © (Oe CH40, S ge) is pharmaceutically acceptable. Compound (Ab) lei hydrates 5 can be synthesized and salts are included and solutes of September 1” published on 10-A1-13678 according to the description shown in the international application No. 77814-. Compounds (A) and (AH) as described in Yor ¥ Mar 01 published on 0 vie 3009 September YO published in 0784609/17_17 set out in International Application No. and include suitable pharmaceutical agents that It can be used in combination with the compounds of the invention

CoAhe. The current HMG-CoA reductase inhibitors are the agents also referred to as statins that belong to the (HMG-CoA) reductase class: drugs that lower blood cholesterol levels by inhibiting enzyme 0. Hydroxymethylglutalyl CoA (HMG-CoA) reductase is the rate-limiting enzyme in CoA (HMG-CoA) reductase biosynthesis and is considered an enzyme involved in a controlled increase in the activity of LDL and statin cholesterol concentrations. And reduce compounds from the blood. Some typical examples of LDL and are responsible for LDL clearance include their simvastatin s receptor sodium gles pravastatin s rosuvastatin the statin compounds 0, pitavastatin, ccrivastatin, antiviral 107, and atorvastatin g lovastatin 3

YY44

NA — - superstatin " for BMS and other known CoA (HMG-CoA) reductase inhibitors in the field. Suitable pharmaceutical agents that may be used in combination with compounds of the present invention include converting enzyme inhibitors 0 (ACE) angiotensin These inhibitors belong to class 0 drugs that partially lower blood glucose levels in addition to lowering blood pressure by inhibiting angiotensin converting enzymes Examples of angiotensin converting enzyme inhibitors include: captopril, enalapril, alacepril, delapril; ramipril, lisinopril, imidapril, benazepril, ceronapril, cilazapril, enalaprilat, fosinopril, moveltopril, perindopril, quinapril, spirapril, temocapril, trandolapril 0 and ACE-0 inhibitors known in this field. suitable pharmacological compounds that can be used in combination with compounds of the invention Ja on angiotensin -11 receptor antagonists.These antagonists target the angiotensin II (AT) receptor -1 subtype and show a beneficial effect on hypertension. pl Examples of angiotensin 1 receptor antagonists include losartan (the potassium salt form) and angiotensin-11 receptor antagonists known in the field. Other treatments for one or more of the diseases described in this document include the use of one or more of the pharmaceutical agents known in this field, which belong to the drug classes referred to, for example, but not limited to, as follows:

- 11.89!

GLP-1 (eg insulin aids and releasers) pramlintide;” Ju) amylin NVP-DPP-adjuvants (eg dipeptyl peptidase and exendin-4 inhibitors; insulinotropin (NN2211 and NN2211) Ezetimibe (eg CoA acyl cholesterol acetyltransferase and reductase 8 inhibitors), Ezetimibe and similar compounds) and cholesterol absorption inhibitors (eg ¢ eflucimibe

CP-529414 cholesterol (as ester and similar compounds), converting enzyme inhibitors 08018006800 0 triglycerides and similar compounds), torcetrapib converting protein inhibitors, 111-705, 0511-1, and Atlas modifiers (eg 10011180106 and compounds microsomal triglyceride microparticles

GT 103- and similar compounds) and bile acid modifiers (eg. 10-6 (Jie) cholesterol | .118-11501, squalene synthase inhibitors, ladies' enzyme, and similar compounds) squalene synthesis inhibitors are dependent on squalene and examples of squalene synthesis inhibitors include . squalene by inhibiting the synthesis of (S)-.alpha.-[Bis[2 ,2-dimethyl-1 -oxopropoxy)methoxy]phosphinyl] -3-phenoxyb- enzenebutanesulfonic acid, mono potassium salt (BMS-188494) is known in this squalene and synthesis inhibitors 1 and according to the present invention 0 the combination can be used by mixing the corresponding active ingredients either all together or independently with a pharmaceutically acceptable Alla or with an excipient, binder, diluent, etc. ; As previously described in this Aah, giving the mixture or mixtures as a pharmaceutical composition, either orally or non-orally. When a compound of the present invention is administered as a treatment combination with an active compound, Al, the therapeutic agents may be formulated as formulations

Ta is a pharmaceutical given at the same time or at different times Giving therapeutic agents: as a monocomplex. According to the present invention; A combination of the compound of the present invention and a pharmaceutical agent may be prepared by mixing the corresponding active ingredients either together or independently with a pharmaceutically acceptable carrier or with a binder, diluent, etc.; As described herein; Administering the Elem© mixture or mixtures as a pharmaceutical composition either orally or non-orally. and when a compound or mixture of compounds of the present invention is administered as a therapeutic combination with another active compound; It can craft! Therapeutic agents as pharmaceutical formulations that are given at the same time or at different times, or they can be used as a single formulation. Useful only in radiography, but also in laboratory and in vivo evaluation methods; To determine the position and quantities of 5 in tissue samples including humans and to determine the binding groups of receptor 5 by blocking the binding of a radiolabeled compound. Another objective is to include those radioactively numbered compounds. The RUP2S of this invention is to contain new evaluations of vo and any of its subtypes (ta). The present invention includes radioisotope-numbered compounds of formula (10) to (la) Formulas of Je in this document and 'isotopes' or 'radio-numbered' compounds are those that are identical to the compounds disclosed herein; were it not for the fact that one or more atoms are substituted for Or there is a replacement

-011a - contains a seed that has an atomic mass or mass number different from the naturally occurring atomic mass or mass number (gl ale) that occurs naturally). Suitable radionuclides that may be included in the compounds of the present invention include, but are not limited to, PH (also written 0 for deuterium Res (also written T for PN Cs PCs HC 5 (tritium ria ) Bly, 1251 4 1241 12314 Br 4 "Br Br 82Br Cl 3g BE 4 BO 0 4 50° : The radionuclide that is included in existing radionuclide compounds depends on the specific use of that radionuclide. For example, compounds that include 311 5 190 S251, PS PM PL In general, very useful for competitive evaluations and for RUP2S numbering in the laboratory. Bry 0 L It is known that the 'radio-numbered' or 'numbered compound' is the empty compound of the invention in which at least one radionuclide is included; in some embodiments the radionuclide is selected from the group consisting of 31 Hes 1251 338 and is Certain compounds of the present invention numbered with isotopes are useful in assessments of the texture distribution of the composite As 101. In some embodiments, the isotope 311 and/or © are useful in these studies. Substitution with the heavy isotope Jie deuterium (ie, CH) can yield certain therapeutic benefits due to greater stability of metabolism (eg, increase in half-life in the organism or in reduced dose requirements) and thus may be favored in some cases. Conditions 0 The isotope-numbered compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the preceding schemes and in the examples Gia

WY - - by replacing the isotope-labelled material with a non-isotope-labeled material. Other potentially useful synthetic methods are discussed later. Furthermore; It should be recognized that each of the atoms represented in the compounds of the invention can be either a very commonly occurring SI AB isotope, a very rare radioactive isotope, or a radioactive isotope. 0 Synthetic methods for the incorporation of radioisotopes into organic compounds are applicable to the compounds of the invention and are well known in this field. These synthetic methods include, for example, levels of Tritium activity in target molecules. They are as follows: Catalytic Reduction with Tritium Gas - This procedure usually produces high quality activity products and requires halogenated or unsaturated precursors. 0 reduction with Sodium Borohydride [H] - This procedure is also cheap and requires precursors containing reducible functional groups such as aldehydes, ketones s lactones, 5168, etc. J nal using Lithium Aluminum Hydride PH] - This procedure often gives products with specific theoretical activities. It also needs producing materials that contain a reducible functional group 0 such as ketones aldehydes and its anhydrous 1, Las esterss and the like. Exposure numbering — © Tritium Gas This procedure involves exposure of proton exchangeable precursors to Tritium Gas in the presence of a suitable catalyst.

MY - - Introducing a Methylation group using 16 [PH] Methyl - This procedure is usually used in the preparation of O-methyl or N-methyl [PH] products by treating with suitable precursors with Methyl Iodide [ 311] with high specific activity. This method generally allows for a high specific activity of about Yr - 50 curie/mmol for example. 0 Synthetic methods for incorporating activity levels of L125 into target molecules include: analogous Ley Sandmeyer reactions - this procedure converts an aryl or heteroaryl amine to a diazonium salt; Jia tetrafluoroborate salt and thus to a compound numbered B [125] using Na'PT and a similar procedure has been demonstrated by: Zhu, D.-G. and co-workers in J.

Org.

Chem. 2002, 67, 943-948 0 Inclusion of a 25 odination on the phenols position - This procedure allows the inclusion of the 257 at the phenol position as demonstrated by: Collier, 1. 1. and co. -workers in J.

Labeled Compd Radiopharm. 1999, 42, 5264-6 Replace heteroaryl and aryl with 125 - this is generally a two-step process. The first step is to convert the heteroaryl or aryl heterocycle to the corresponding tri-alkyltin intermediate 0 using for example a catalyzed reaction with Pd [ie; pd [(phsp)s or through aryl or heteroaryl lithium ¢ in the presence of -tri-alkyltinhalide or hexaalkylditin [eg [(CH3)s] SnSn (CHs)s. Similar by : .Bas, M.-D. and co-workers at J Labeled Compd Radiopharm. 2001, 44, 5280-2

1115 - - R-numbered compound 10025 with formula (Ta) can be used in an evaluation test to identify/evaluate 0 compounds and in general; A compound that has been resynthesized or identified (i.e., a test compound) can be evaluated for its ability to reduce the binding of the radiolabelled compound of formula (la) to receptor 5. According to coll) the ability of the test compound to compete with the 'labelled compound' Radioactively 'which 0 denotes formula (e1)' to bind with receptor 5 is directly related to its affinity for binding. The numbered compounds of the present invention are associated with the receptor 5. In one embodiment; The numbered compound has ICs of less than about oer micromolar ; In another example; The compound numbered m1 is less than about 0 micromolar; In another embodiment, the compound numbered 90 and 10 have less than about 10 micromolar, and in another embodiment, the inhibitor numbered ICsp is less than about 1.1 00 micromolar. Other uses of the receptors and the ways in which they are revealed to those working in this field are evident based on a review of this discovery, among other things. The steps of the methods of the present invention need not be performed any particular number of times or in any particular sequence as they will be done. Additional objectives, benefits, and new properties of this invention will become apparent to those skilled in this field when examining their examples; which are prepared to be illustrative and are not intended to be restrictive. z

— C / 1 _ Examples: The following examples are provided for illustrative purposes and not as a means of identification. A person with ordinary skill in this area may be able to design equivalent assessments and methods based on the discovery made in this document; They all form part of the present invention. Example (\ ): Diabetes in rodent models: Diabetes 595 of the second type associated with obesity and resistance to insulin was induced in rodent models. Ob/ob s db/db Jie genetic models have been shown, see: 1-6 31 (1982) 5 in rats fa/fa s 6: To understand the pathophysiology 01 of the disease and to test candidate therapeutic compounds: [Diabetes (1983) 32:830-838; Annu Rep Sankyo Res Lab (1994) 46:1-57] The homozygous animals in 8 CSTBL/ Ksl-db/db oJ developed by the Hajakson laboratory are obese, have high blood sugar, are resistant to insulin, and have a high level of insulin in the blood. [85:962-967 (1990) of Clin Invest, where homozygotes are scanty, Vo and normal blood sugar are 0, and in the eda model “db/db mice, insulin levels decrease gradually with age, and they are A feature observed in late stages of type 2 diabetes in humans when glucose levels are not adequately controlled.As this pattern is similar to type 2 diabetes “gs pad”, the compounds of the present invention are tested

AY = - for activities including but not limited to lowering splasma glucose triglycerides The (fa/fa) Zucker rats are severely obese and have elevated pall insulin and are resistant to: {Coleman, Diabetes (1) 982) 31:1; E Shafrir in Diabetes Mellitus, H Rifkin and insulin ‎D Porte, Jr, Eds [Elsevier Science Publishing Co, New York, ed. 4, ( 1990), p. 299- Co }3401 and the fafa mutation can be the rat equivalent of the mouse mutation [Friedman et al, Cell db Truett et al, Proc Natl Acad Sci USA (1991) 88:7806]:69:217- 220 (1992); The mouse (tub/tub) Tubby is characterized by obesity, moderate insulin resistance, and a high blood insulin level without a significant increase in blood sugar: [Coleman et al, Heredity (1 990) 81: 424] The present invention includes the use of compounds of the invention in reducing resistance8 and elevation of glycemia in any or all of the earlier mouse models of diabetes and in humans with ye diabetes type 2 or other preferred metabolic or eo-related disorders Lipid metabolism mentioned earlier or in models based on other mammalian organisms. Plasma glucose s insulin levels will be tested as well as other factors including but not limited to free amino acids and triglycerides.

VV - Evaluation of the anti-hyperglycemic activity of the compounds of the invention in vivo: obese, diabetic (db/db) transgenic (db/db) (male; 5-7 weeks old) were kept under standard laboratory conditions at YY m, relative humidity 750, and keeping her eating a mouse meal of Purina and water when she likes it. Prior to treatment, blood is collected from the xylem vein of each animal and blood glucose concentrations are determined using a single duals glucose monitor (Lifescan) basic device. Phthrans with plasma glucose levels between 0 and 00 mg are used. / dl. Each treatment group consisted of seven items distributed so that an average of 6 levels was equivalent in each group at the beginning of the study. Rats are dosed with small osmotic pumps administered using the anesthetic isoflurane to give lS eV of the invention, saline solution or an unsuitable compound Gl subcutaneously (5.0). Blood samples are taken from the tail vein at intervals and then analyzed for blood glucose concentrations. ps Evaluation of significant differences between the group (by comparing the compounds of the invention with the groups treated with saline) using the Student-t test. Example: (1) 1 Model of atherosclerosis in a mouse: Two mice with a deficiency in adiponectin were shown. produced by deactivating the adiponectin gene to make it susceptible to atherosclerosis and insulin resistance Mice are also a suitable model for localized ischemic heart disease (Matsuda, M et al J Biol Chem (2002) July] and references indicated therein; whose discoveries are fully included by reference in this document].

Gama- and adiponectin-deactivated vaginas (1-5 Jo) Fg) are held under standard laboratory conditions at YY-RH AO and dosing of vulvas is done with small osmotic pumps; Inserted using the anesthetic isoflurane to give compounds of 1 of the invention, saline solution or compound not suitable for rats subcutaneously (©.8). Neoplastic endothelial thickening and local ischemic heart disease are determined for different groups of mice that are killed at different time intervals. Significant differences between the groups (by comparing the compounds of the invention with the groups treated with saline) were evaluated using the Student-t test. Example (): Bioactivity in the laboratory: 0 de sana Amodified Flash Plate™ adenylyl enzyme was used cyclase (from New (England Nuclear; Cat.

No.

SMP004A for the direct identification of candidate compounds as adjuvants to according to the following system 0 and expression 0025 includes the human sequences located in the GenBank with accession number NM-177551 for the nucleotide and with accession number 9 1 in the GenBank for the polypeptide and allelic variants that occur Normally and mammalian genes of 0 common origin and their mutation products from recombination. Stably hypoinfected CHO cells were harvested using an expression vector encoding HRUP2S and cultured under permitting conditions to express transgenic surfaces of the 5m-encoded Wa receptor harvested from flasks by non-enzymatic means. Cells were washed in 5 and resuspended in buffer solution for product experiment. Live Wal was counted using a scale

- a = cell/ 01 XY _ban; The concentration of the cells was adjusted until Trypan blue cells in the blood were excluded, a standard and a reagent buffer solution (containing ? microcuries of the tracer CAMP and 0 mL of the reagent buffer were prepared) and maintained according to 11 μl ) to 0 ) cAMP - [#1] per product instructions. Candidate compounds specified as above (thawed at room temperature 41°C if frozen) were added to their corresponding eyes (preferably eyes in a plate with 0 micromolar VY eye) at increasing concentrations (¥ μl/eye; With a final concentration of the experiment, its value is microliters of the buffer solution for the experiment, 000 cells in 0, and a minute was added to those eyes at room temperature; with slight agitation. Ye the mixture was then incubated for 1 μl of detection buffer into each well followed by 1001 and after incubation; Added using Wallac MicroBeta 1 hour. Plates were counted in a plate reader 14-7 sad incubation 0 (according to product instructions). "Prot. # 31"

Yo has a value of about cAMP in the whole cell method of ECso, and certain compounds of the invention have micromolar or less. Example (9): Bioactivity in the laboratory: 358 - 010758 W 1 linkage assessment that crosses Stably from Chinese Hamster Ovary [C1-(0110) cells prepared from 100 mM (μg/experiment) membranes were diluted in buffer solution for evaluation V) or a vector control niacin receptor PH with pH MgCl 01 mM, NaCl 001 mM, HEPES pH and pre-incubated with reduced test compounds in Wallac Scintistrip 5 solution in plates (4).

YYaq

Y . —- \ — regulator of the experiment containing te micromolar GDP (the final [GDP] was 0.1 µm) for about 10 minutes before adding 0775-379 at a concentration of 0,1 nM. to avoid possible precipitation of the compound; All compounds were first prepared in DMSO 7000 and then diluted with experimental buffer to a final concentration of DMSO LY at rating 0 and binding 0 was allowed to persist for 1 hour before centrifuging the plates at 5006 rpm per minute for VO min at room temperature and a subsequent Se at dae flashed. TopCount and a nonlinear regression analysis of the binding curves was performed in GraphPad Prism software. Membrane preparation: Materials: 0 medium Wal's culture 0110-16[1: Kaighn's modified cell culture medium 1-12 with FBS/00, mM of [-glutamine, 1 mM of sodium pyruvate, 06? µg/mL G418. Film scraping buffer: 0 mM HEPES 0 mM Vo; With a pH of 4,/A. Membrane washing buffer: 01 mM HEPES 01 mM EDTA pH behind a mixture of P-8340: Protease inhibitor (from Sigma, St.louis, Mo 4S) yi

YY - - To perform: - aspiration of cell culture media from dishes with a surface area of V0 cm; Rinse with ¾ ml of cold PBS and aspirate. - Add © ml abrasive buffer solution to the cells and abrasive cells. The scrape was transferred to a 000 mL centrifuge tube. And add 000 microliters of Protease inhibitor mixture. Spinning at 70,000 rpm for 11 minutes at 4 um. Aspirate the supernatant and resuspend the pellet in 70 ml of membrane washing solution. And add 0 μl of the protease inhibitor mixture. Spinning at 70,000 rpm for 17 minutes at 4 m. . - Aspirate the supernatant from the membrane pellet 0 and the pellet can be frozen at -80°C for later use or it can be used immediately. Rating: Materials: - “GDP) Guanosine 5'-diphosphate sodium salt Sigma catalog — Aldrich Vo No. 0 (AV \YY - triethylammonium salt of 5' [**S] GTPyS) thiotriphosphate [y** S] Guanosine Amersham Biosciences Catalog #0 80; about 0001 curie/mmol).

YY - - - AT eye flash plates (number 6 =)© from Perkin - Elmer - binder buffer solution: 01 mM HEPES pH 4, for 0 mM NaCl yo mM MgCl, - Boke's buffer solution (GDP) from a binder buffer solution plus GDP ranging from 0.4 to 56 μM; work well before experiment. J to perform: (total experiment volume = 100 μm by eye) YO - μl GDP buffer solution with or without compounds GDP) at a final concentration of 10,01 μm; drawn from a stock of te micromolar). gly Swoon - membranes in 0.4 (mg protein/mL) binder buffer. Te - 061775 [7S] in buffer solution. This is done by adding © μl of stock GTPyS [5?] to 0 mL of binder buffer solution (this buffer does not contain GDP) - the plates to be examined are dissolved (reducing dishes with μl of compound at ?mM in DMSO 700

177 - - - Are the compounds in it diluted? mM at a ratio of (0 00) μl to μml Yio GDP buffer solution at 77 050. Thaw frozen membrane pellet on ice. - Homogenize the films briefly to suspension using 13100 Poly TRON (with PT- probe DA 3007/2° at 000 rpm setting). The membrane protein concentration was determined by the Bradford evaluation and the membranes were diluted to protein concentrations of 460 mg/mL in a J buffer (note: the final evaluation concentration was 1 μg/sample). Add 1 μl of YO compounds to the GDP buffer solution in each eye of the flash plate. 1- Add 00 μl membranes to each eye in a flash plate. Pre-incubation for 08 minutes at room temperature. Addition of YO μl of GTPYS [2598]. Incubation was done on a reflux device (Lab-Line device, model number grate, and shaken on the fourth position) for 50 minutes at room temperature. vo - The experiment is stopped by rotating the dishes with the lids sealed at You rpm for yo min at yy m. - Reading on flash dae —TopCount NXT System 355.

And 11 - in the -SFA-CHO meal, and the animals are divided into two groups: a group (with number A=) is fed SFA-CHO meal and is treated with sham doses, and another group (with number = A) is fed with the 0110-878 meal and treated with the compound (©mg/kg').The control animals are fed standard food for 0 days.dy Blood samples are collected at the beginning (2 days after receiving the animals) and after *0 days of Meals start to be given.Blood lipids are analyzed.Animals are perturbed and dissected.Alternatively, the previous analysis includes several groups, each of which is treated with a different dose of the compound.The mentioned preferred doses are selected from the group consisting of: 01 mg/ Teas And 71 mg/kg 'and 1 mg/kg' and mg/kg Vos mg fae Fog aa 0 kg' and 100 mg/Daas Alternatively, the above analysis is performed at several time points. Selection of the preferred time points mentioned from the set consisting of 01 weeks, 10 weeks, 1" weeks, and 56 weeks 00 weeks. Cholesterol [101]-.1:Blood collected in trisodium citrate (AVA) at a ratio of 10:1 Plasma 1 is obtained after centrifugation (8 00 for 15 minutes) and processed immediately. Total cholesterol, L-1101 cholesterol, and L-1101/7 cholesterol are measured using a Kodak Ektachem DT Automated Analyzer (0 Corporation) (Rochester, NY, USA). Samples with variants in excess of the range are diluted with the solution provided by the producer and reanalyzed after The percentage of total cholesterol/cholesterol 111 (017) is determined

HDL cholesterol = 0 between groups and a comparison is made of the ratio of total cholesterol/cholesterol 11017 between groups. And the ratio of raising HDL cholesterol or lowering total cholesterol / cholesterol-11017 is taken when the compound is given as an indication for the compound that contains the aforementioned benefit. Atherosclerosis 0 The thoracic and abdominal aorta arteries are extracted intact, opened longitudinally along the abdomen, and fixed in a neutral and orderly manner after excision of samples from standard sites in the aorta formalin in the thorax and abdomen for tissue examination studies and the composition and synthesis of fat. fixation; They are stapled and stapled to a flat surface; Whole Sudan IV aorta obtained using dye on digital images using a telephoto camera connected to a computer image analysis system 0 surface dy shall ratio determination (Image Pro Plus; Media Cybernetics, Silver Spring, MD)

Gerrity RG et al, Diabetes [Atherosclerosis of the Aorta Involved in Atherosclerotic Injuries (2001) 50:1654-65; Comhill JF et al, Arteriosclerosis, Thrombosis, and Vascular whose full disclosures are included herein by reference]. Biology (1985) 1 5-6 Vo makes a comparison between the dy sill groups of the aortic surface covered by atherosclerosis injuries. And the reduction in the percentage of the aortic surface covered by atherosclerosis injuries is taken when that compound is given as an indication for the compound that has the previously mentioned benefit.

1171 - - Example (*): Receptor Binding Assessment Another method of evaluating the test compound in addition to the other methods mentioned in this document is to determine the binding affinity of the receptor 817025. This type of assessment generally requires a radioactively numbered ligand © group with The receptor RUP2S and in the absence of the use of known ligand groups of the receptor 5 and radiolabeling from it, it is possible to digitize compounds with the formula (Ta) with a radioactive isotope and use it in an experiment to evaluate the affinity of the test compound with the receptor RUP25 and compound 810025 with the radionumber of the formula can be used (Ia) in an assay experiment to identify/evaluate compounds.In general, a specific or newly re-synthesized compound (i.e., a test compound) can be evaluated 0 Known for its ability to reduce radiolabeled CS all of formula (la ) with receptor 5. Accordingly, the ability to compete with 'radio-numbered compound of formula (La) or radio-numbered RUP2S ligand for binding to receptor 117725 is directly related to its binding affinity of the test compound to the receptor RUP25 Evaluation System for Receptor Binding Determination 1817025: A- Preparation of the receptor 'RUP25' Ya y cell (human kidney; (ATCC ¢) Jd was transiently infected with 5 μg human Ye receptor and 10 μl Lipofectamine (per 0 cm plate) in a dish for 4 7 hours (975/swarm) with spacing and removal. media using 01 ml/dish of

- \YA- (01 mM EDTA + 01 mM Hepes) and Hepes/201 buffer solution consisting of

Beckman and centrifuged in a centrifuge (7.4 pH) and then recycled (JA-25.50 rotor) rpm 17.0000 min; up to 01 for a period of Coulter 7.4 with a pH of 1 mM EDTA + Hepes 01 mM to suspend the pellet and centrifuge it a second time. 6 homogenizer and make it homogenous using + -8 ml © After removing the float; Pellets are stored at - 80 m;» Until used in the evaluation of binding. ml of 10 minutes and then added to the membranes on ice for AY and when used in the evaluation is 001 mM MgCl 1 mM Hepes mM Yr) The buffer solution of the incubation and the membranes are stirred to resuspend the raw membrane pellets and make them (PH) with a pH (NaCl) for 10 seconds at 01 for a period of time using a Brinkmann PT-3100 Polytron homogenizer using a BRL Bradford 0 device. Membrane protein concentration using the proteomic assay 1. Mode B-Assessment of binding: µl of membranes appropriately diluted 00 for total binding add a volume of (pH) Tris HCL in a buffer solution containing on 0 mM Adis (μg protein) to 04705 (1 mM EDTA and 6.MgCl) and 10 mM 0 001 followed by the addition of ¢ polypropylene 97 well titer plates of labeled RUP25 μL of test buffer and 05 μL of a micro-ligand kit 11-78 are scanned.The plates are then incubated at room temperature for

Microplate Devices End of the binding reaction by filtering the experimental dishes through the filter dish eye followed by washing using Brandell-AT with GF/C Unifilter 0 plate harvester

179 - - 0 mM Tris HCL cold; with a pH of Vt pH of 76009 NaCl and the bottom of the filter dish is then sealed; 50 µL of Optiphase Supermix is added to each plate; The top of the dishes is sealed” and the dishes are counted on the blinker 11008618 “1A11. And for competitive studies of the compound; It is done instead of adding (100) μl of the buffer solution for the experiment; add Yao μl of suitably diluted test compound to appropriate eyes; followed by the addition of 00 µL of the radiolabeled ligand pool. C- Calculations: The test compounds are initially evaluated at 1 and 11 micromolar and then at the chosen concentration range 0 so that (Ray) for the average dose induces an inhibition of about 750 for the binding of the radioactive RUP2S ligand (i.e.; Specific binding in the absence of the test compound (Bo) is the total binding difference (Br) minus the nonspecific binding (NSB) and similarly the specific binding (in the presence of the test compound) is (B) is the difference of the binding displacement (Bp) minus the nonspecific binding (0455). 10.0 is determined from the inhibition response curve” of the scaling plot of the logarithm of the ve ratio of the two probabilities 0 against the concentration of the test compound. Kj is calculated by :Cheng transform and Prustoff transformation (McA/ZnLA + K;=ICso/(1), where [1] is the concentration of the radioactive bonding group used in the evaluation, and the hills constant of the radioactive bonding group 5 determined independently under the same binding conditions.

SG-D - An alternative procedure for binding evaluation: a 311-Nicotinic acid binding competition experiment

0110-1651 cells stably expressing the niacin receptor in membranes were used for binding analysis. Cells were grown in cultures of about 7860 in a growth medium (modified F-12 Kaighn ATCC) oo No. Yo-100) containing (GIBCO) FBS 71010 rum H1+ (Y1). (GIBCO) G418 Js [pa Vs No. (P-0871 Sigma) 1X Pen-Streps (+YV = 0101), harvested by scraping and centrifuged at 1700 with W?m for 10 minutes.

Suspend the cell pellets in 01 harvesting buffer (01 mM Hepes 10 mM EDTA, pH 7.4) and homogenize it using 4 01 x jets/sec at

0 homogenizer VY Polytron ml; at position 0. The decomposition product was centrifuged at X 0”; and at 4 m for 0 min to remove non-dissolved cells and nuclei; The resulting supernatant was centrifuged at 34,000 x ag at 4 um for 0 £ min to pellet membranes. And done

Resuspend the resulting pellet in washing buffer (Tr) mM HEPES and 12 mM

molar EDTA with a pH of 7.4) and homogenize it using ? 01 x bursts/sec

g X 3422060 ml at position 4; Centrifugation re-work at VY Polytron on Ve

and at m for a period of © min. The resulting pellet was resuspended in the wash buffer and stored

in 00 liquid before use. The concentration of membrane proteins in this preparation was determined

Using Pierce's evaluation of protein BCA with BSA as standard.

191 - - A balanced linkage of 317-Nicotinic acid was carried out in dishes with AT sample of polypropylene and the reactions contained 040 μl films diluted in the buffer solution of the experiment (Yo) mM HEPES with pH Vet pH, 1 mM MgCl, 70.01 Yo = 11, “CHAPS (μg membrane protein/experiment) and 10 μl o test compounds diluted in experiment buffer (compound stocks were in DMSO 7000 The final concentration of DMSO in the experiment was 720.75 (5 pounds 0) μl of You nanomolar niacin containing tritiated ([© 1- [[PH] acid) from American Radiolabeled Chemicals, Inc. and 10 micromoles in ethanol ¢ and the concentration of Aled ethanol in each experiment was determined. A non-specific association was determined in the presence of YOu micromolar of unlabeled nicotinic acid. And after mixing for a period of ? hours at room temperature Reaction components were filtered through 017/0 Packard Unifilter plates using a Packard harvester and washed with XA 001 μL of binding buffer solution chilled on ice The plates were dried overnight and sealed back Using PerkinElmer ribbon designed for dishes ©017/0. 6 µL of PerkinElmer Microscint-20 scintillator fluid was added to each well, the tops were sealed, the plates were analyzed in a Packard TopCount scintillation counter, and calculations were performed as in the previous step (7). certain of the invention and 20 in the competitive evaluation of the binding of nicotinic acid—'H' within the range of about 01 to about 01 µm. Very usefully, the compounds of the invention have value ECs in this evaluation within the range of about 1 to About 01 micromolar.

YY - - and very usefully for chad the compounds have a BCsp value in this evaluation of less than about 1 micromolar. Example 7: Irritation by Laser Doppler Procedure: Male rat 057816 is anesthetized (approximately YO g) with 01 mg/[de kg] Nembutal sodium 0 . And when antibiotics are given; It is injected in combination with the anesthetic Nembutal. After 10 minutes, the animal is placed under the laser beam, and the ear is folded back to reveal the ventral side. The laser is placed in the center of the ear and focused at 4 - 8.4 volts (usually about 8 cm above the ear). Data detection is initiated using the Vo Yo X size image design, auto interval, 01 image count, 0 second time delay with media separation. 0._test compounds are administered after the tenth image by injection into the peritoneal space. Images 01 - 1 are considered to be the primary images of the animal and the data is normalized to the lowest average intensity rating. J gal and methods: niacin » Laser Doppler Pirimed Pimil (from Nembutal 5 company) Sigma (1a) coefficient (Abbott: Jie _ 1 (8): inhibition of free fatty acid production acid all in vivo from SPA catheterized Sprague-Daly rats: Non-esterified free-fatty acid (NEFA) assessments performed on serum derived from live, freely moving rats. jugular veins in jugular veins and animals are allowed to recover for at least $A hour after surgery.food is removed from vy.animals approximately sixteen hours prior to experiment.approximately Yoo microliters of blood are withdrawn from

YY - - The catheter represents a basic NEFA serum sample. The drug is administered intraperitoneally (IP) at various concentrations to rats individually and approximately 10,010 µl blood is then withdrawn from the catheter at the time points indicated for further NEFA analysis. NEFA experiments are performed according to product specifications (Wako Chemicals, USA; NEFA C) and free fatty acid concentrations are determined by regression analysis of a known standard curve (range of free fatty acids information). The data is analyzed using Graph 5 Excel 11570 software. Example (4): Synthesis of the compounds selected for the invention: The compounds of the invention and their synthesis are also illustrated by the following examples. However, the following examples are provided to identify the invention Lad without being restricted to the details provided In these examples, the compounds mentioned earlier and later in this document are named according to: Chem Draw Ultra Version 7.0.1 or AutoNom 2000 05. In certain cases, common names are used, and it is known that these common names can be distinguished by those skilled in this field For the examples below, the standard designation '(+)' is generally used immediately before the chemical name 1 to indicate the racemic mixture. The chemical structural formulas shown in the examples are provided for illustrative purposes only and are not intended to be restrictive unless the chemical name is indicated. For example, in another way.

- AYE - Chemical properties:

Varian Mercury VX400 Proton NMR (111118) was recorded on a Bruker Avance-400 equipped with a probe with ; Automatically switchable kernels and a scale of -7 or a scale of -72. A BBD or GNP is given with a four-core probe with the residual solvent signal used as a reference. Chemical displacements are done (ppm) in parts per million 0 as follows: 5 - single; wu - double; The 00-second double NMR uses wide abbreviations. A multiple = bry = my triple f = quadruple = ty triple double = di and exposure to microwave radiation (Personal Chemistry) Emyrs was done using a synthesis device and silica gel (Merck) was performed. 60 Fass on (TLC) thin layer chromatography procedure 1 mm 608 plates silica gel pk6F on a preparative (prep TLC) thin layer chromatography 0” 60 Kiesel gel using 51168 gel and Column-on-Column (Whatman) rotational chromatography. Buchi was done and vacuum evaporation was carried out on a (Merck) 1.700 - ... 7 evaporator. palladium Recommendations UE 454© celite Using LCMS specs: 1) PC: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC system 1 controller: SCL-10A VP, Shimadzu Inc; UV Detector: SPD-10A VP, Shimadzu Inc; yo

Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API 150EX with

Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2. 2) Mac: HPLC-pumps:

LC-8A VP, Shimadzu Inc.; HPLC system controller: SCL-10A 77, Shimadzu Inc. UV-

Detector: SPD-10A VP, Shimadzu Inc.; Autosampler: 215 Liquid Handler, Gilson Inc.;

Mass spectrometer: API 150EX with Turbo Ion Spray source, AB/MDS Sciex Software: Masschrom 1.5.2. Example: (1-9) Compound preparation: (1aR, 5aR)- (+)-4-(2H-Tetrazol-5-yl)-1a,3,5,5a-tetrahydro- 1H-2,3-diaza-cycloprop-a[a]pentalene° (compound ¢ i Step 0: Prepare bicyclo[3.1.0]hexan-2-0] Li N H TK 1 AK R 1 0 t-BuOMe . OH LITMP was produced by adding n-BULi (JY sa Y.0) in TOA “Ja VEY » hexanes mmol) to a volatile solution of TMP (©4.V) + g; 04 mmol) in 1 (tBUOMe L) at -p YA and solution 1111/10 light yellow was slowly warmed to 0 °C over £0 min. The LITMP solution was added dropwise via a bore needle to a volatile solution of: (R)-2-but-3-enyl-oxirane ) 5 G 179 mmol Schaus, 5. E.; et al.

J Am.

Chem.) 2002 , 124 , 1307 .506” in (Jo 04+) t-BuOMe at 0 °C during Or 10 min. a Reducing the resulting mixture at ambient temperature for YA hours and then quenching it with (Ja 2 ) MeOH. The reaction mixture was then concentrated to a total volume of 0 mL and done

17 - Washing the solution with 1) Standard HCl. You x V ml eq) and brine (Yeo ml). The organic layers were dried at 14850, filtered, and concentrated (0 mmHg; at 0°C bath) to yield bicyelo[3.1.0]hexan-2-0l as a light yellow oil. The spectral data for bicyclo[3.1.0]hexan-2-0l were similar to those reported in references; Ex: -Hodgson, 10. 1/.: Chung, Y.

K.; Paris, J.-M.

J.

Am.

Chem.

Soc. 2004, 126, 8664 0 : Step B: Preparation of Bicyclo[3.1.0]hexan-2-one H H TPAP, NMO <AAA —_— A 4A MS, CH,Cl, A (V.AA) TPAP added g; 0.70 mmol) to a volatile solution of: 001*(bicyclo[3.1.0]hexan-2-ol g 0117 mmol) and 1040 70 can YON (mmol) 01 and supplement with 5 angstrom powder) A g) in (Ja 9.6 ) CH,Cl, at ambient temperature. Then the mixture was stirred for two and a half hours and filtered through Ae (silica gel 11 cm x 1 cm) and filtered with CHCl BGO (1:1 ratio). The organic solvent was carefully evaporated in vacuum (100 mm Hg). ; at a soldering temperature, Yo) to obtain: 0«H-0-2H»5:07010]3.1.010. The spectral data were similar to those shown previously for 1 for rac-bicyclo[3.1.0]. hexan-2-one . (Newman-Evans, R.

H.; Simon, R.

J.; Carpenter, B.

XK.

J.

Org.

Chem. 1990, 55, 695).

- 117 - Step (2): Preparation of 1a,2,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester

H o 1) KOt-BU/THF 9

EtOH H 086 + 2 L __

EO 2) HNNH HC b _NH

H © 0 0 HN 443 solution of Kot-Bu in THF (7 mL of 1 M 011 mmol solution) was reduced to M bicyclo[3.1.0Jhexan-2-one (4 1.7 g) 961 mmol) and V¢.V) diethyl oxalate g; 011 mmol) in You (EtOH ml) at room temperature below Np and the reaction mixture was stirred for three and a half hours and at that time hydrazine hydrochloride (76 g) was added; 110 mmol) in 0:11 (2 ml). The reaction mixture was then stirred for 10 hours at room temperature and acidified to a pH of ¥ by the addition of HCI (0 N 1 aqueous). The volatiles were removed in vacuum and the resulting solid was diluted with EtOAc (+ +© ml) 5 HO (+4 © ml). The layers were separated and the aqueous phase was re-extracted using To + (BOAC mL). The organic co-layers were washed with brine (do £11), dried at ,14880, filtered, and concentrated to crude oil which was determined to be ester of approximately Veo - 7280 purity (w/w) by 11107078'. The title compound was used in 1 immediately following reaction (for amino degradation) without further purification.

M1 - “HNMR (400 MHz, CDCL3): § 10.55 (1H, bs), 4.32 (2H, q, J = 6.8 Hz), 2.96 (1H, dd, J Hz), 2.80 (1H, d ,J= 17.2 Hz), 2.23-2.13 (2H, m), 1.35 3H, t, J = 7.2 Hz), 6.0 ,16.8 = (1H, m), 0.34 (1H, m).'C APT NMR (partial) (100 MHz, CDCLs): § up: 127.4, 1.15 § down: 23.0, 15.4, 14.5 ; 61.2, 26.8, 16.8 ; MS/HPLC column: Alltech® Prevail C18 (© Micro) » CH3CN 70 5 (aa 0.1 X © 0 vol/v (containing 71 TFA vol/v) at 11:0 (containing 71 TFA vol/v) stepping up to 799 CHRON vol / volume in 11: .0; 5© mL/min; t = 0.17, min = ESI" (M + H) 193.1. Step (d): Preparation: 2.2.5 ,5a-Tetrahydro- 1 H1-2,3-diaza-cyclopropalalpentalene-4-carboxylic acid amide 1 01 H — OEt NH4OH, dioxane H _ NH; H H (de Yor (HO NH; YA) added ) ammonium hydroxide to ester solution from step (c) (1 407 can 77.9 mmol) in VE (dioxane mL). The mixture was placed in a 0001 mL Pyrex flask and stirred on the gainer plate for 77 hours at room temperature. The mixture was concentrated in vacuum to a total volume of 100 ml and at that time the resulting yellow precipitate was clear. The mixture was filtered and the solid was washed with H.0.001 XY (0.1 mL). Additive drying of the solid in vacuum resulted in obtaining:

18 - - 1a,2,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pentalene-4-carboxylic acid amide (HPLC/ MS] (Discorery® C18 column) +0 μCH3CN 70 “(aa X 1.1 vol/v (containing 7 TFA vol/v) in H,O (containing 7 TFA vol/v) gradually up to 794 CHRON Volume/Volume in 1720 (HO ml/min; tp = 0.14) NUE - ESI [(H +M)© as LL alia in white. : step (e): Preparation: 2-Benzyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa|a]pentalene-4-carbo-nitrile N H 4 0 BnBr, NaOH , ) 1 H NH; dioxane / N N 8 Ha —_— and xX, NH 2) SOCl,, DMF L ) N H then partially dissolving the amide from step ) 9 ( q TA) g 07.4 mmol) in (J— Yo. ) dioxane 0 and (N) Jl) NaOH added”; 119 (Jo YY mmol) followed by benzyl bromide 0 g; 00.7 mmol). The mixture was slowly cleared and the reaction mixture reduced for 51 hours at room temperature. The mixture was calcined to a pH of approximately ? By adding 1) standard HCI; aqueous) and concentrate to dryness in vacuum. The resulting light yellow solid was washed with NaHCO3 (saturated aqueous; (Ja 0 ) HO (Je 001). Further drying of the solid in Fara 2 resulted in obtaining the treated product (b) to benzylated. YYas

M61 - 2-benzyl-1a,2,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pentalene-4-carbo- xylic acid amide as a white solid. A flask was filled with a drying tube under an atmosphere of: 31b anhydrous DMF (deer), the flask was cooled to 0 °C, and thionyl chloride (84, 05 mmol) was added dropwise over a period of 2 minutes. . and after reducing for an additional 10 minutes; Added suspension of: 2-benzyl-1a,2,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pentalene-4-carbo- xylic acid amide. can 4 ) 00.7 mmol) in (Je 4+) DMF over © minutes using an addition funnel. The mixture was slowly 0 warmed to room temperature and stirred for 71 minutes at which time additional thionyl chloride (0.05 (Ja 41.5 mmol) was added as a premixed solution in DMF (71). ml). The reaction mixture was stirred for an additional 1 min and NaHCO (saturated aqueous; 0 mL) was added, followed by application of 1120 001 (0 mL). The mixture was stirred for 10 minutes and concentrated to near dryness in vacuum. The remainder was diluted with Yo + (EtOAc mL) and You (11.0 mL). The layers were separated and the aqueous phase was extracted (sale) using You (EtOAc ml). The combined layers were washed with NaHCO; (saturated aqueous; 400 mL) and brine (400 mL), dried at 14850 i, and concentrated to obtain: : pH 7

- VEN - as 2-benzyl-1a,2,5,5a-tetrahydro-11-2,3 -diaza-cyclopropala]pentalene-4- carbonitrile brown solid. 'H NMR (400 MHz, CDCl3) : 8 7.37 (3H, m), 7.25 (2H, m), 5.31 (1H, d, J= 14.8 Hz), 5.24 (1H, d, J= 14.8 Hz), 2.86, (1H, dd, J= 16.4 , 6.4 Hz), 2.72 (1H, d, J= 16.0 Hz), 2.19 (1H, m), 1.87 (1H, m), 1.07 (1H, m), 0.32 (1H, m). C APT NMR (100 MHz, °

CDCls): Sup: 154.4, 135.3, 130.0, 118.9, 114.3, 55.9, 26.2, 16.9; down: 129.2, 128.6, 128.1, 24.2, 14.4. and 78 011:01 volume/¢ (aa 1.1 X 04 µm”©) Alltech® Prevail C18 column: MS/HPLC volume/volume A (contains HO volume/volume ) in TFA 1/7 volume (containing

ESI" = min; YYW volume/volume in whitl 0 mL/min; CH;CN 744 step by step up to 236.1 01 M +H): For step (f): * Preparation of J 2-Benzyl -4-(2H-tetrazol-5-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cycloprop-ala]pentalene .

N1

H 7 N N 1 H N / N NaN3, ZnBr, 1 A M /

H DMF, 120 °C m a p Vo Yyaa

147 - - A, ¢ ) ZnBr, \ g 1 , nor mmol) followed by VY 1 7 (NaN; g ra mmol) was added to a solution of : 2-benzyl-1a,2 ,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pentalene-4-carbo- nitrile £V,Y aa (11.1 mmol in Y YO) DMF ml). The mixture was heated to 5 0011 J C for VA h under Ny atmosphere and the reaction mixture was cooled to room temperature and the DMF was CAN in vacuum. The crude residue was diluted with 01 (EtOAc mL) HCl (aqueous ¥ N”; approximately 001 Ja) and stirred for 10 minutes. The layers were separated and the aqueous phase was re-extracted with 0 (EtOAc mL) . The organic co-layers were washed with NaOH (aqueous (Ja You XY « OY 5a 1) and then the organic layers were discarded. The 0 basic methyl phase was acidified using 1N HCI to a pH of 11M around Y and extracted using (You XY) EtOAc mL). The extracts were washed using saline (Vor ml) and dried over MgSO4, filtered and concentrated to obtain: 2-benzyl4-(2H-tetrazol-5-yl)-1a,2,5,5a-tetrahydro- 1H- 2,3-diaza-cyclopropa-[a]pentalene as a light brown solid. 'H NMR (400 MHz, MeOD): 87.33 (SH.m), 5.42 (IH, d,J= 14.8 Hz), 5.35 (1H, d, J Vo =152Hz),3.01 (1H, dd, J= 16.4, 6.4 Hz), 2.88 (1H, d, J = 17.6 Hz), 2.28 (1H, m), 2.11 (1H, M), 1.14 (1H, m), 0.33 (1H, m). MS/HPLC: 018 X © 0 "5 Sua © (Alltech® Prevail 4.1 mm); and 70 CH3CN v/v (containing 71 TFA v/v) in 11:0 (containing TFA 71 v/v)

VEY - - incrementally up to 794 011:01 volume/volume in [Ua ¥,0 (HO min; 1 = 1.14 min = ESI" (M + H) 279.3. Step ( g): Preparation: (1aR,5aR)-4-(2H-Tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopro-pa[a] pentalene ° (compound ¢) No ! - Air bubbles were released during stirring of a solution of: 2-benzyl-4-(2H-tetrazol-5-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cycloprop- a[a]pentalene Vs 016 (g; 0/6 mmol) and VE KOt-Bu mL of a solution of 1 M in 176 mmol (THF) in (Jo Yoo ) DMSO for Vo hours at room temperature, the remaining THF in Fara 2 was removed and the reaction mixture was acidified to pH Y = pH by adding HCl (aqueous v molar) 0 and the mixture was concentrated in Ell to near dryness. The residue was dissolved in HCI vo (1 M aqueous; Jo You) and extracted with 51086 (0 YOu X ml). The organic layers were dried in MaSO, and filtered The product was then purified and converted into salt

Veg - - ammonium is filled with a substance (such as a solution in (MeOH) in a column containing Bondesil SCX SPE resin (about You g). The column is washed with (Je 001) MeOH to remove The product is filtered with NH, 7 N/MeOH (Yoo ml, approx.) The sale concentration of basic purification resulted in obtaining the ammonium salt of compound (4;) as a white solid. ‘H NMR (400 MHz, MeOD): 6 3.02 (1H, d, J= 16.4, 6.0 Hz), 2.90 (1H, d, J = 16.0 Hz), 2.19 (2H, m), 1.17 (1H , m), 0.33 (1H, m). MS/HPLC: 018 Alltech® Prevail (© micro” 7.1 x 00 mm); CH;CN Jo vol/v (contains 7 TFA vol/v) at 11:0 (contains 71 TFA vol/v) 0 increments [ana 011:07 799 ia vol at 1:0 0,¥ ml/min; - 71 minutes; = BSI" M + H) 189.0. Example (7-9): Preparation of compound: -Dimethyl-4-(2H-tetrazol-5-yl)-1a,3,5 ,Sa-tetrahydro-1H -2,3-diaz- a- 1,1-)* cyclopropa[a]pentalene 10 (compound (V .

Dc ¢ \ — Step 0: (£)-2-(4-Methylpent-3-enyl)oxirane plain stirred: 1(0r”-2-801-3 0001) g; 01 mmol) and 01(2-methylbut-2-ene g; 10 mmol) at room temperature for 1 hour in a sealed Jaall flash flask with catalyst 0 8 Y) \ Zhan (Tn mmol) 0. Then the solvent was removed under reduced pressure and the rest was purified by column chromatography ((EtOAc/n-hexane/silica V+ - 0) to obtain: 2-4-methylpent-3-enyl)oxirane. As a colorless oil. , 1H J;=5.0, 1,=2.8), 2.15 (2H, q, J=7.4), 1.70 (s, 3H), 1.63 (s, 3H), 1.60-1.50 2.48 (m, 2H). Va Step (b): Prepare (#)-6,6-Dimethyl-bicyclo[3.1.0]hexan-2-0l 0 H Hon 0 patched (9,Y+) 2,2, 6,6-Tetramethylpiperidine g » 4 mmol) in 001 mL MTBE and cooled to - VA m. Carefully 1,1 de 47(n-Butyllithium molar) was added in: n-hexane Vo ¢ 49 mmol) and the resulting solution was allowed to stir at -VA m for Fe min. The pale yellow solution was added by a tubular transition to the cooled die (0°C) solution of 2-(4-methyl- pent-3-enyl)-oxirane (4.77 g; 4.7 mmol) (1413) +

hg - - ml) over 1 minute and allowed to warm slowly to room temperature and stirred under argon for VA 1 hour. The solution was then added to 1 M hydrochloric acid (50 ml) and extracted in ©1415 Additional Yor ml).The solvent was removed under reduced pressure and the resulting oil was purified by column chromatography (40-0 7 EtOAc/n-hexane, silica) to obtain 6,6-Dimethyl-bicyclo[3.1.0 [Jhexan-2-0l © (£) as yellow oil. 'H NMR (CDCl3): 6 4.15-4.10 (m, 1H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 1H), 1.80-1.70 (m, 1H), 1.62 (br s, OH), 1.56 (ddd, 1H, J;=12.9, J,=9.5, J;=2.9), 1.48 (br s, 1H), 1.14 (dd, 1H, 1126.3, J,=1.2), 0.99 (s, 3H), 0.93 (s, 3H). Step (c): Preparation of 6,6-Dimethyl-bicyclo[3.1.0]hexan-2 -one (+) z H 01" A cooled solution (at 0°C) of N-methylmorpholine N-oxide was prepared (wet can 17.5 mmol) +,YA +) (VII) tetrapropylammonium perrethenate G 15 la mmol) in DOM (£4 mL) contains a molecular retarder of €Ag (~17+ g). A solution of (),1Y () - 6,6-dimethyl-bicyclo[3.1.0]Jhexan-2-0] 10,11 gm (Use in (Je 01) was added dropwise. DOM and allowed the solution to warm to room temperature and stirred for dela time under argon The solution was filtered through a silica stopper and the solvent was removed under reduced pressure and the resulting oil was purified by column chromatography (DCM/n-hexane, silica ZY ++ - 0 (- 6,6-Dimethyl-bicyclo[3.1.0]Jhexan-2-one was obtained as brown oil.

1697 - - 'H NMR (CDCl): 8 2.35-2.15 (m, 2H), 2.10-2.00 (m, 1H), 1.97-1.85 (m, 2H), 1.66 (d, 1H, J =4.7), 1.16 (s, 3H), 1.12 (s, 3H). Step D: Prepare: 1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza -cyclopropa[a]pental- enc-4- -)+( carboxylic acid ethyl ester ° H 0 ~~ re Bala Ho 6,6-Dimethyl-bicyclo[3.1] was stirred .0Thexan-2-one - 0 ) 4 g; oe VY mol) V,£7) diethyl oxalate g VLA mmol) 1 5 “Je YA) potassium t-butoxide molar in YA (THF mmol) in (Je 2 ) ethanol at room temperature for two hours Cd 0 Note: (6,6-dimethyl-2-oxo-bicyclo[3.1.0]hex-3-yl)-oxo-acetic acid ethyl ester required by (m/z (ES): 247 [M+Na]®, 225 [M+H]") 1.0145 but not isolated. VTA) Hydrazine monohydrochloride + g 54.4 mmol (in water) was added (? mL) and the solution was heated to 88 °C for VA h. The solvent was removed under reduced pressure and the resulting oil ve was decanted in 11 M (©0 mL) aqueous hydrochloric acid and extracted in 001 DCM (mL). The solvent was removed under reduced pressure and the residue was purified by column chromatography (m-lov EtOAc/n-hexane, silica) to obtain:

- YEA - (#) - 1,1-dimethyl-1a,3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa[a]pental-ene-4-carboxylic acid ethyl ester as pale yellow oil Solidifies at stability. m/z (ES). 243 [M+Na]", 221 [M+H]", 175 11-0807: 'H NMR (CD;OD): 6 4.4-4.3 (mm, 2H, OCH), 2.90 (dd, 1H, J; =17.5, J,=6.9), 2.65 (d, 1H, J=17.5), 2.1-2.0 (m, 1H), 1.95 ) o 1H, J=12.9), 1.37 (td, J)=7.1, J, =2.0), 1.13 (s, 3H, exo-CH3), 0.74 (d, 3H, J=2.0, endo-

CH;). Step E: Prepare (£)-1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pental-ene-4-carboxylic acid Vo

H0

H\)l : (+.)-1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pentale-ne-4 is raised - carboxylic acid ethyl ester in a vial (Je 1+) methanolic ammonia Molar V mmol) at 5.80 can), 0 (0 hrs). The resulting suspension was collected by vacuum filtration VA for m for 001 Close the lock and heat it up: To obtain

18 - - (£)-1,1-dimethyl-1a,3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa[-a]pentalene-4-carboxylic acid amide As a pale yellow solid. m/z (ES"). 192 [M+H]", 175 [M-NH,]"; 1H, J=19.9),2.0-1.8 (m, 2H), 1.03 (s, 3H), 0.63 (s, 3H).° Step (f): Prepare: (£)-1,1- Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pental- ene-4- carbonitrile Raised: (%)-1,1-Dimethyl-1a ,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentale- ne-4- 01 carboxylic acid amide (Y,V can + (07) mmol) in ( J— (10+) THF and the addition of trifluoroacetic anhydride and (0.875 g mmol). Then the resulting solution was stirred at room temperature under argon for an hour. (Je©) Ethyl acetate was added and the solvent removed under reduced pressure. 1 The resulting pale yellow oil was diluted in (100 DCM ml) and washed with a bicarbonate solution of £4 (Je) and the solvent removed under reduced pressure. The resulting white solid was lifted as a suspension in Yo DCM ml) and filtered to obtain:

Qo, — \ — (%.)-1,1-dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropala]pental-ene-4-carbonitrile m/z (ES"): 174 [M+H]" Step (g): Preparation: (£)-1,1-Dimethyl-4-(2H-tetrazol-5-yl)-1a,3, 5,5a-tetrahydro-1H-2,3-diaz- a- ° cyclopropala]pentalene (compound VY followed by H N NH N = cyclopropala H has been removed: (#)-1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentale- ne-4- 01 carbonitrile : ) 64 vol. mmol) in 10 (1,4-dioxane mL) with zinc dibromide (Y, YY ipa) (8 mmol) 0 A ) sodium azide c. 1717 mmol) in 3 thick-walled glass tubes . Then Aud for two solution Jd induced by microwave radiation up to Yoo Am for 1 hour. The solution was poured into 1 M 01 (ml) aqueous hydrochloric acid and extracted in (Je©+) Ethyl acetate. The solvent was removed under reduced pressure and the resulting oil was purified by preparative HPLC to obtain:

1 o \ — b (£)-1,1-dimethyl-4-(2H-tetrazol-5-y1)-1a,3,5,5a-tetrahydro-1H-2,3-diaz- a- cyclopropalapentalene NMR (CD;0D): § 2.87 (dd, 1H, J,;=16.5, No m/z (ES): 217 [M+H]", 189 [M-N,+H] "; J,=5.6), 2.67 (dd, 1H, J,=16.5, J,=0.8), 2.1-2.0 (m, 2H), 1.08 (s, 3H), 0.69 (s, 3H). ‏

© Example (9-?): Preparation: (£)-1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pental-ene-4- carboxylic acid (compound 1( H 0 N-D 0 0) then reduce: (£)-1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3- diaza-cyclopropa[a]pentale- ne-4- carboxylic acid ethyl ester (AVY Ca 4 ra. ) mmol) for YA h for YA h at room temperature in a solution of 1 Sl lithium hydroxide:THF: methanol 10:8: (molar VE) ml). 1 the solvent was removed under reduced pressure; The remainder was raised in 1 M aqueous hydrochloric acid (©mL) and extracted in ethyl acetate (£4mL). The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to obtain a white solid pala.

— m a Y —_ m/z (ES'): 215 [M+Na]", 193 [M+H]*, 175 [M-OHJ"; 11 NMR (CDsCN): 8 2.91 (dd, 1H, 17.4, ]1,=6.8), 2.66 (d, 1H, J=17.4), 2.11 (dd, 1H, J,=6.3, J,=1.2), 2.05-1.95 (m, 1H), 1.19 (s, 3H, exo-CH3), 0.77 (d, 3H, J=2.0, endo-CH3). Example (4-9): Preparation of (£)-exo-1-Benzyl-4-(2H-tetrazol-5-yl)1a,3,5,5a-tetrahydro-1H-2,3-diaza- 0 cyclopropala]pentalene (A) (compound : In a manner similar to that in Example (9-?) starting with (A) the compound was synthesized and the intermediate compounds were characterized as shown below. ( E)-2-(5-phenyl-pent-3-enyl)-oxirane For the corresponding steps. 0 (+£)-ex0-6-Benzyl-bicyclo[3.1.0]hexan-2-o0] : 0 H step (7-9); step (b). Jha The title compound was prepared in a manner similar to that of 'H NMR (CDCls): § 7.35-7.25 (m, 2H), 7.25-7.15 (m, 3H), 4.25 (d, 1H, J=4.7), 2.54 (d, 2H, J=6.9), 2.00-1.85 (m, 1H), 1.74 (dd, 1H, J;=12.5, J, =8.0), 1.65-1.50 (m, 1H), 1.45- \o 1.35 (m, 1H), 1.35-1.30 (m, 1H), 0.71 (septet, 1H, J=3.3).

YYaq

- yoy — . (%)-endo-6-benzyl-bicyclo[3.1.0]hexan-2-o0l. / Yo contains (+)-ex0-6-Benzyl-bicyclo[3.1.0Thexan-2-one dangerous (b):

H

§ H N (1) The title compound was prepared in a manner similar to the method mentioned in Example (1-4); By step HNMR (CDCl): 8 7.35-7.28 (m, 2H), 7.25-7.20 (m, 3H), 2.78 (dd, 1H, J,=14.9, °

J2=6.1), 2.60 (dd, 1H, J,=14.9, J,=7.2), 2.20-2.10 (m, 1H), 2.10-2.00 (m, 4H), 1.74 (dd, 1H, J;=5.2 , J,=2.4), 1.65-1.55 (m, 1H). (+)-endo-6-benzyl-bicyclo[3.1.0]hexan-2-one / © contains: (2) 3 hall (+)-exo-1-Benzyl-1a,3,5, 5a-tetrahydro-1H-2,3-diaza-cyclopropa[a-Jpentalene-4-01 carboxylic acid ethyl ester

H 0 ~ Hoss 8 H Neighborhood NH . (2) 5 shally Y—9 ) Then prepare the title compound in a manner similar to the method mentioned in the example

_— \ 0 ¢ — 'H NMR (CD;0D): 8 7.35-7.10 (m, 5H), 4.31 (q, 2H, J=7.1, OCH>), 2.97 (dd, 1H, 5=17.2,J ,76.2), 2.90-2.75 (m, 2H), 2.59 (dd, 1H, J;=15.0, J,=7.5), 2.20-2.15 (m, 1H), 2.15-2.05 (m, 1H), 1.34 ( t, 3H, J=7.1), 1.00 (septet, 1H, J=3.5). 710 contains (+)-endo-1-benzyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropala]penta-lene-4- ° carboxylic acid ethyl ester

MS m/z (ES"): 305 [M+Na]", 283 [M+H]", 237 [M-OEt]". Step (d): (*)-exo-1-Benzyl- 1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a-Jpentalene-4-carboxylic acid amide Vo

H0 ~ NH, . H \- NH The title compound was prepared in a manner similar to that in Example (9-?); By step (e). NMR (CD;0D): 6 7.4-7.1 (m, 5H), 2.95 (dd, 1H, J,=16.5, J,=5.4), 2.87 (d, 1H,

J=15.6), 2.8-2.6 (m, 2H), 2.25-2.15 (m, 2H), 1.05-0.90 (m, 1H). From JAY: contain Vo

— \ 00 - (+)-endo-1-benzyl-1a,3,5,5a-tetrahydro-1H-2 3-diaza-cyclopropala]penta-lene-4- carboxylic acid amide

MS m/z (ES): 276 [M+Na]", 254 [M+H]", 237 [M-NH,]" Step (e): (+)-exo-1-Benzyl-1a ,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a-|pentalene-4-|° carbonitrile

H

AN

~~

H \ ~NH . ( ) by step 0 (Y -9 ) and then prepare the address compound in a similar way to the method mentioned in the example

MS m/z 2E 0:236 [M+H]" : contains 719 of 0(+£)-endo-1-benzyl-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]penta-lene-4-carbonitrile .9) step (x)-exo-1-Benzyl-4-(2H-tetrazol-5-yl)1a,3,5,5a- tetrahydro-1H-2,-3-diaza-cyclopropa[a]pentalene Vo

- lol -

AA (compound H N= N, _ NH

S.N

Ho \-NH in step (g). (Y=) The title compound was prepared in a manner similar to that in the example of 'H NMR (CD;0D): 6 7.6-7.5 (m, 4H), 7.5-7.4 ( m, 1H), 3.29 (dd, 1H, 1216.2, J,=6.0), 3.18 (d, 1H, J=16.2), 3.01 (dd, 1H, J,;=14.7, J,=6.6), 2.90 ( dd, 1H, 1214.7, J,=7.4), 2.55- » 2.45 (m, 2H), 1.35-1.25 (m, 1H). MS m/z (ES”): 301 [M+H]”, 279 [M+H]”, 251 [M-

No+H]'. Example (9-9): preparation of (+)-exo-1-Benzyl-1a,3,5,5a-tetrahydro- 1H-2,3-diaza-cyclopropa[a]pental-ene-4- carboxylic acid Ve (0 (compound H 0 b OH

Non-H: Compound (0) was synthesized from (£)-exo-1-Benzyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pental-ene -4- carboxylic acid ethyl ester \o

— \ o 7 _ using a method similar to that in Example (9-?). MS m/z 65 L: 277 [M+Na]", 255 [M+H]", 237 [M-OH]; 'H NMR (CD;CN): § 7.3- 7.1 (m, 5H), 2.83 (dd, 1H, J,=17.0, ,=5.8), 2.66 (d, 1H, J=17.0), 2.57 (dd, 2H, J,=7.0,

J,=4.2), 2.05-1.95 (m, 2H), 0.82 (septet, 1H, J=3.5). : from 1 on TREE 5 (+)-endo-1-benzyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]penta-lene-4- carboxylic acid Example (1-9): Preparation of (+)-3b,4,4a,5-Tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c|pyrazole-3- -carboxylic acid | Ve. 1 (compound .Bicyclo[3.1.0]hexan-3-one Step A): Preparation

H0

Or 1) EtoZn, CHyly, DCM XT rere J 2) PCC, basic alumina

H cyclopentene-4-0l to the CHI solution, using a syringe pump, add 01 “01” under atmosphere (Je YO) DCM mmol) at 111 “da (1,4 mM EtyZng) mol) 09.0 can 5 (vo) at 0 °C. The reaction mixture was slowly warmed to room temperature over Ny of then 0 dilute (ben ml) HCL overnight and then at that time opened Air the mixture and dampen it slowly by adding

A — 0 / — mixture was diluted with (Je 001) EtOAc and filtered. The organic layer was separated and washed with (Je 0 ) H,0 then brine (Jo Yoo). The organics were dried on MgSO, filtered and concentrated to oil purified by IY chromatography) silica gel EtOAc in xl hexanes # to 770 EtOAc in hexanes to obtain 0e cyclopropyl alcohol as a clear oil. Alcohol (from the above) in (Ja YOu) DCM and sequentially treated with 001 (basic alumina) 17) PCC g; mmol) at room temperature. and after stirring for VA 1 hour; The solution was filtered through a celite pad on top of silica gel using EO/DCM (ratio ?:1) as an elufiltration. The solvent was removed in a vacuum (You) \ mbar ¢ and a bath temperature of 90 °C, and the product was purified by distillation from the AY vessel at low pressure (1 mbar) to obtain Ketone as a clear oil. Hz), 1.54 (2H, m), 20.0 Glc' H NMR (CDCl, 400 MHz): 6 2.60 (2H, m), 2.16 (2H, (1H, dt, J= 6.0, 1.6 Hz) ), -0.05 (1H, dt, J = 6.0, 4.0 Hz).0.90 b shall 3,4[0610-eg 5-1b35,4,48-() acid ethyl ester H o H ~ © 7 / N dream H

— \ o 9 —

The title ester was prepared in a manner similar to the method mentioned in Example (-0); by step (c

using .bicyclo[3.1.0]Thexan-3-one

Step (c): Prepare: (£)-3b,4,4a,5-Tetrahydro-2H-cyclopropa[3,4]cyclopenta[ 1,2-c]pyrazole-3- -carboxylic acid ° ( Compound () Hoo H OH == N\ N= NH then at room temperature add 11:0 YA) LioH mg; 0 mmol) to a solution of ester (¥ ¢ mg mmol) in (Ja 1 ) H,0 (Je Y ) THF . The reaction mixture was heated to 0 © C for an hour and a half. After cooling to room temperature; The mixture was acidified to pH = 1 using HOI (aqueous; 76 N). Reverse phase filtration of 0 ) Phenomenex® Luna C18 2 saad] HPLC micro (YYV X You mm) Lo 011:0 (vol/v) (containing 7 TFA v/v) in H,O (containing 1 TFA (p>[ana]) gradually up to 40[01 (H,0 mL/fl; A = 714 nmol] to obtain 1 free acid As a white solid after lyophilization.: MS/ HPLC Column 018 Alltech® Prevail (5 µm; x00 4.1 mm); 10 11:07 vol/v (containing TFA 71 vol/v ) in 11:0 (has TRA 711 volume/volume) YYaq

- 11. - = EST min; -9( Jha(£)-4-(2H-Tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[-a]pentalene (Y) (compound ° - N,

H N™ NH

J J=y ~~

Ho NH using: (V9) in a manner similar to the method mentioned in Example (Y) The compound was prepared. racemic 2-but-3-enyl-oxirane: Example (8-9): Preparation (£) -1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropafa]pentalene-4-carboxy-lic acid 0

AY (compound H 0

NO

HN ~NH

NE ester mL) to a 1 N solution of Yo (aqueous NaOH at room temperature was added and the reaction mixture was reduced throughout 0 (Je 1 ) dioxane mmol) in YT cane 0 ( ) x) analogues and they performed 0 mani) “sole 1) HCl using 1 - pH night and acidifying it to pH vo

1111 7 - Reverse Phase Purification for HPLC [With You Column (0 gS) Phenomenex” Luna C18 CHCN 05 (ae YY X (vol/vol) (containing TFA 11 v/v) in HO (containing TFA /1 v/v) gradually until [da 10 HO a0 min; TYE = A nmol] until free acid is obtained as a white solid after freeze drying: MS/ HPLC 0 Column “Phenomenex” C18 © (© Micro XO rt fo ima 11:01 vol/v (containing 1 TFA vol/v) in HO (containing 71 TFA volume/volume) incrementally up to 154 min volume/volume in [Ja 8 HO min; 0.1 tr = 4 tr min (H+M) VEN = EST” Example: Preparation: intermediate compound (£)-6,6-dichloro-spiro[bicyclo[3 .1.0]hexane-2 ,2'-[1 ,3]dioxolane] H 4 NaOH 50% 0 Ci 4 —_— 0 oJ CHCl3, 0602 H TEBAC 7 | 0 ) triethylbenzylammonium chloride mg) and a solution of Jo 00 / 5. NaDh | a solution of YOON { 4-dioxa-spiro[4,4]non-6-ene g 701 g mol) in ( Je Yoo) CHCl, and 0205 (Je Yoo). This solution was strongly reduced at H; m within ? days. The reaction mixture was diluted with Yoo (HO ml) and extracted using 0 m (Je Vou * Y) CHCl;, the organic co-layer was concentrated in vacuo and the residue Aan was electrophoresed by column chromatography 0:5 (+ = CHCl Joe in 85) to the title compounds as a colorless liquid.

AY - - (m, 4 H), 2.25-2.01 (m, 5H), 1.89-1.83 (m, 4.06-3.93 E): H NMR (400 MHz, 1H). Example (8-01): Preparation of the intermediate compound: ()-exo-6-chloro-spiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolane] and (+)- endo-6-chloro- spiro[bicyclo[3.1.0]Thexane-2,2'-[1,3]dioxolane] ° H H H Ci oD me sh 9 H + b — _— Cl Ci 0 H EtOH 0 H 0 oO for NP 80 °C and then at room temperature add 71 ca + A (the mol) to a solution of: (£ )-6,6-dichloro-spiro[bicyclo[3.1.0]Thexane-2,2'-[1,3]dioxolane] (No 1 g; AY mmol) YA) KoH g ; 1.5 mol) in 001 (EtOH mL). The reaction mixture was heated at Av 0 C under vigorous stirring overnight. After cooling the reaction mixture to room temperature; Then it was filtered through a 16:06 packing and the filtrate was treated with acetic anhydride (7.77; 0.5 “Ja mol) under an ice bath. And after concentrating in the soil, then extracting the residue in Yoo (hexanes ml) and washing it with Yeo XY (H, O ml) and then saline solution (Ja You). A 5102 column chromatogram (CHCl ZV = Yo) was performed at 065 h. »©1) to obtain: exo-chloride and endo-chloride Vo YYaq

- AY - Exo-chloride: Exo-chloride NMR (400 MHz, y: § 4.07-3.90 (m, 4 H), 2.94 (t, 1H,J = 1.9 Hz) 1.95-1.90 ( m, 2H), 1.88-1.74 (m, 2H), 1.68-1.62 (m, 1H), 1.45-1.36 (m, 1H). § 4.02-3.91 (m, 4 H), 3.42 (t, 1H, J = 7.5 Hz) 2.22-2.12 ° (m, 1H), 2.05-1.74 (m, SH): Preparation of the intermediate compound: (11- 8 ) Ex. (+)-endo-6-chloro-exo-6-methyl-spiro[bicyclo[3.1.0]hexane-2,2'-[1,3]di-oxolane]

H H

Cl <> 1.'BuLi, -10096 Cl > ? M < 0 ~ 0 e” b 0

H oJ 2. Mel H J) ml of a solution of 70.35 mM TV, YY) t-butyl lithium add 1 001 - to be done dropwise at 0: to a solution of Molar pentane in 17 mM YAY 1.00 g ) (£)-6,6-dichloro-spiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolane] mL; Y, YY) Methyl Iodide min; 10 mol THF (in 6 mL mmol) was added dropwise to the solution and slowly warmed to room temperature. 771 was extracted and the solvent was removed under reduced pressure. He performed a column chromatograph. n-hexane 8 vo yields the title compound as oil. (hexane —n/ EtOAc ZY + - +) SiO;

- AAA 'H NMR (400 MHz, BL: 4.01-3.91 (m, 4H), 2.20-2.07 (m, 2H), 1.96-1.82 (m, 2H). 1.63 (dd, 1H, J, =6.8 Hz, J, =5.3 Hz), 1.61 (s,3 H), 1.54 (dd, 111, 1, =7.6 Hz, J, = 1.0 Hz). -4( Ex. (+)-6-methylene-spiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolane] e0

Cl Hy, Hy, + KO'Bu >] A & —— S

H 0 DMSO H 0 o_J 60 °C oJ) to a solution of 1 molar THF (in 1 mL of 10 Ko'Bu) add a 00 g (£)-6-chloro Coad solution -6-methyl-spiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolane] ml). The solution was heated at 60 °C overnight. And after £4 (DMSO mmol) in YO i and 0 0 n-hexane and then extract the product in Ad yall the reaction mixture was cooled to a temperature of 01 -/ EtOAc 778 = 1? (SiO; The solvent is under reduced pressure. Column chromatography led to obtaining the title compound as oil. (hexane "H NMR (400 MHz, Oak): 5.55 (s, 1H), 5.42 (t, IH, J = 1.0) Hz), 4.08-3.91 (m, 4H), 2.07-1.97 (m, 2H), 1.90-1.84 (m, 2H), 1.65-1.54 (m, 2H).

119 - = Example (7-91a): Preparation of the intermediate compound: (%.)-6-spirocyclopropyl-spiro[bicyclo[3.1.0Jhexane-2,2'-[1,3]dioxolane] H 'yy CH, No Hy, —_ 3 H 3 Pd(OAc), iS 0 for yy 0 pd (Cac), (about 01 mg) is added to a solution of: (+ )-6-methylene-spiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolane] ° ) 7 g 10 m (Use in CHoNps (Je Yo) ERO (approximately mmol) in EO and additional CHyN (approximately ∼mmol) in 10 was dropwise added to the solution within an hour at room temperature. After concentration, a SiO column chromatography (0 * - 790 leads to 01 in hexanes ) to get: (£)-6-spirocyclopropyl-spiro[bicyclo[3.1.0]Thexane-2,2'-[1,3]dioxolane] 1 NMR ( 400 MHz, CDCl3): [14.02-3.94 (m, 1H), 3.92-3.86 (m, 3H), 1.96-1.89 (m, 1H), 1.75-1.62 (m, 5H), 0.82-0.86 ( m, 2H), 0.79-0.76 (m, 1H), 0.73-0.70 (m, 1H). Example (9-11): Preparation of intermediate compounds with intrinsic substitution.

Vit - - general reaction scheme: cl <0 1. LiDBB, -78 °C ~O Cady ae TUR =H or CHs R, = electrophile P =H or CH; Lithium wire (0 equivalent) cut into small pieces at room temperature into a solution of 4,4'-di-tert-butyl-biphenyl (0 equivalent) in THF vigorously stirred at 0 0°C for 7 hours and cooled to - VA m. External or internal - (2) mono-chloride (1 equivalent) dissolved in THF was added to a dark green solution. After 10 minutes; Electrophilic solution (0 equivalent) to the solution; it was slowly warmed to room temperature; the resulting solution was rapidly poured into a mixture of highly volatile saturated [NHC]hexane solution under an ice bath. The separated organic layer was concentrated and a 0 column chromatography performed 58:02 to get the product in which there is an internal substitution.z Example (13-4): (%)-ex0-4-Methyl-spiro[bicyclo[3.1.0]hexane-2,2' -[1,3 dioxolane] H H, XO 0088, -78 °C xO | EtOH MES J .2 to 6' H NMR (400 MHz, CDCl3): § 4.05-3.87 (m, 4H), 1.90-1.80 (m, 1H), 1.76 (dd, 1H, J, = Hz, J, = 8.0 Hz), 1.61 (dd, 1H, J, = 13.8 Hz, J, = 8.4 Hz) , 1.45 (ddd, 1H,J, = 13.8 1 12.3

- Viv -

Hz, about 11.8 Hz, J; =8.2 Hz), 1.18-1.14 (m, 1H), 1.10 (ddd, 1H, J, 2 61 Hz, J, =2.9

Hz, J; =1.1 Hz), 1.00 (d, 3H, J = 6.0 Hz), 0.88 (qdd, 1H, J; - 6.0 Hz, J, =3.0 Hz, J; = 3.0 Hz). : : ab v-4) eg (#)-endo-6-Methyl-spiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolane] °

H z H cl ~2 1. LIDBB, -78 °C = O aaa 3 3 0 1 b 0

H2.CHslH

A 'EN' H NMR (400 MHz, CDCl;): § 3.98-3.88 (m, 4H), 2.10-2.00 (m, 1H), 1.91 (dd, 1H, J, = 14.3 Hz, J, = 10.7 Hz ), 1.69 (ddd, 1H, J, = 13.2 Hz, J, = 9.3 Hz, J; = 1.4 Hz), 1.59-1.45 (m, 2H), 1.38 (ddd, 1H, J; =8.6 Hz, J, = 6.5 Hz, J3 = 1.3 Hz), 1.15 (d, 3H, J = 6.6 Hz), 0.97 (qdd, 1H, J; = 6.6 Hz, J, = 7.5 Hz, J; = 7.5 Hz). Ve c): 1 eg (y-(+)-endo-6-Methyl-spiro[bicyclo[3.1.0Thexane-2,2'-[1,3]dioxolane]

H

Z i 0 Hy, cl ~ 1. LiDBB, -78 °C z i > —_— & 5 0 H 3 0

H 2.51 H

NG for

- VTA - 'H NMR (400 MHz, CDCls): 6 3.99-3.88 (m, 4H), 2.09-1.91 (m, 2H), 1.73-1.50 (m, 4H), 1.45-1.35 (m, 2H), 1.15 (t, 3H, J = 7.4 Hz), 0.78 (qdd, 1H, J; = 7.4 Hz, J, = 7.5 Hz,

J; = 7.5 Hz). (2 example) : 4-?(%)-endo-6-Ethyl-spiro[bicyclo[3.1.0]hexane-2,2"-[1,3]dioxolane] ° " 0 H,, cl 2 1. 088, -78 °C TN 3 _—— SN 0 2. DMF H nN 0

Ho J 3. NH,CI for 'H NMR (400 MHz, CDCls): § 9.60 (d, 1H, J = 6.3 Hz), 4.05-3.93 (m, 4H), 2.34-2.19 (m, 2H ), 2.15-2.06 (m, 3H), 1.91-1.76 (m, 2H). e): 1-4) Ex. (+)-endo-6-Formyl-spiro[bicyclo[3.1.0Thexane-2,2'-[1,3]dioxolane] Vo $) H, and ‎ H 7 cl ~~ 1. LIDBB, -78 °C Hos x —_— 3 \

S70 2. DMF 0 wk be oJ 3. H,0 0" oJ 'H NMR (400 MHz, 086 9.27 (d, 1H, J = 4.0 Hz), 4.08-4.02 (m, 1H), 3.99-3.91 (m, 3H), 2.13-1.99 (m, 4H), 1.90 (dd, 1H, J; = 12.7 Hz, J, =8.0 Hz), 1.72 (dd, 1H, J, = 14.0 Hz, J, = 8.7 Hz), 1.59-1.50 (m, 1H).\o

- 1098 - Example:(15-49) Preparation of intermediate compound: (+)-endo-6-vinyl-spiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolane] 0

H, + - 7

HN Ph3PCH5BrN

HY = 0 aye hn > > . > 0

Hn-BuLiH

A A

ml of a solution of ¢ y 86 l mmol, V¢ (n-Butyllithium) at room temperature add 1.90 g) methyltriphenylphosphonium bromide to a solution of (molar hexane at 0.1 © : 2 hours later” a solution of JTHE (mM) was added in 0?mL of 4 g; 0.90 mmol) 1) endo-6-formyl-spiro[bicyclo[3.1.0thexane-2] ,2'-[1,3]dioxolane] was added to the reaction mixture at room temperature and stirred overnight. THF was dissolved in mL A and the solvent was removed under reduced pressure. And he has led. n-hexane J Extract the product to obtain the title compound (hexane —n/EtOAc 77-1) SiO; column chromatography 0 as oil. HNMR (400 MHz, tile: § 5.87) ddd, 1H, J, = 17.0 Hz, J, = 10.2 Hz, J; = 8.6 Hz), 5.30 (ddd, 1H, J; =17.0 Hz, J, =2.0 Hz, J; = 1.0 Hz), 5.18 ( ddd, 1H, J, = 10.2 Hz, J, = 2.0 Hz, J; = 1.0 Hz), 4.00-3.88 (m, 4H), 2.12-2.02 (m, 1H), 1.90 (dd, 1H, J; = 14.5Hz,

J, =10.3 Hz), 1.80-1.56 (m, SH). Vo

— \ 7 Sa f : Example (9-?1a): Preparation of intermediate compound (£)-ex0-6-vinyl-spiro[bicyclo[3.1.0}hexane-2,2'-[1,3] [dioxolane]

H, + ~ H,

He PhsPCHsBr "a

H Nl \ ——,———— —_ ~ > 0 _ : b 0 o H d_J n-Bul.i H o_J . ( 10-4 ) The title compound was prepared in a manner similar to that in the example '” H NMR (400 MHz, CDCl3): 8 5.35 (ddd, 1H, J; = 17.0 Hz, J, = 10.2 Hz, J; = 8.6 Hz) (m, 1H), 3.99-3.88 (m, 3H), 1.98-1.88 (m, 1H), 1.84 (dd, 1H, J, = 12.1 Hz, J, = 8.1 Hz), 1.66 (dd, 1H, J , = 14.2 Hz, J, = 8.8 Hz), 1.56-1.43 (m, 4H). Example: 2-9 ab: preparation of the intermediate (+)-endo-6-(1-propenyl)-spiro[ bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolane- [ Ve 7 H, .la H,

XD PrePehachis & 0

H o 0 : H o 0

H oJ n-BuLi H d_J . ( 10-8 ) Then prepare the title compound in a manner similar to the method mentioned in the example '" H NMR (400 MHz, CDCls): 6 5.75-5.68 (m, 1H), 5.52-5.47 (m, 1H), 3.99-3.88 (m, 4H), 2.06-1.96 (m, 1H), 1.89-1.70 (m, 5H), 1.68-1.52 (m, 4H).

YY4q:

1/1 = - eg (z 01-4): Preparation of the intermediate compound: (£)-endo-6-cyclopropyl-spiro[bicyclo[3.1.0]hexane-2,2'-[1, 3]dioxolane] H .CH 2 N 2 H ”, 2) Cd Hd) Nd 0 m f-0)um 0 HN for Et,0 H for H The title compound was prepared in a manner similar to that in Example (7-491a). (400 MHz, CDCl3): 3H), 1.48-1.39 (m, 2H), 1.22-1.17 (m, 1H), 0.78-0.71 (m, 1H), 0.65-0.52 (m, 2H), -0.33 (m, 2H). 0.26 Example (0-9 1(V) Preparation of Ketone Intermediates General reaction scheme: Ra <C > TSOH rR, R SN —_—— SO Ry © 8 0 1 H Acetone/H,0 | 2 0 and 0 A dallas The ketone solution protected in acetone / 11:0 (in ratio (V/¢) was done using a catalyst of TSOH at room temperature.The solution was stirred overnight.808008 was removed in vacuum and the product extracted using hexanes (7 times).The organic co-layer was washed with a solution of 70 NaHCO;brine and dried on (MgS04) and concentrate it in vacuo to obtain the resulting ketone.

(¥)-exo0-6-Methyl-bicyclo[3.1.0]hexane-2-one H, H,

H \ % TsOH ah “aa o we mM”

H o_ Acetone/H,0 H > "HNMR (400 MHz, CDCl): 6 2.14-1.98 (m, 4H), 1.85 (q, 1H, J =4.8 Hz), 1.52 (dd, 1H, J, =5.0 Hz, J, = 2.5 Hz), 1.36-1.30 (m, 1H), 1.12 (d, 3H, J = 6.0 Hz).°(+)-endo-6-Methyl-bicyclo[3.1.0]hexane-2 -one :(Yo—1}) Example: H Me “, Me 2

N TsOH Q the ———— 0 H oJ} Acetone/H,0 H 0 'H NMR (400 MHz, CDCl): 6 2.32-2.21 (m, 2H), 2.13-2.08 (m, 1H), 1.97-1.84 (m, 3H), 1.55-1.48 (m, 1H), 1.15 (d, 3H, J = 6.6 Hz). : (+)-endo-6-Ethyl-bicyclo[3.1.0]hexane-2-one :(z)0-4) Jha0

H, H,

RN TsOH T H oS 0 —_- Be for Acetone/H,0 H 0 'H NMR (400 MHz, CDCly): § 2.34-2.20 (m, 2H), 2.15 (q, 1H) , J = 6.0 Hz), 2.00-1.87 (m, 3H), 1.48-1.36 (m, 3H), 1.04 (1, 3H, J = 6.5 Hz).

- AVY - (x)-endo-6-Vinyl-bicyclo[3.1.0]hexane-2-one :)D1 0-1) Example H, 2

RN TsOH \

H a ) o x H nN ) o_J Acetone/H,0 0 'H NMR (400 MHz, CDCl3): § 5.67 (ddd, 1H, J, = 17.0 Hz, J, = 10.3 Hz, J; = 8.5 Hz), 5.37 (dt, 1H, J; = 17.0 Hz, J, = 1.4 Hz), 5.27 (dt, 1H, J, = 10.3 Hz, J, = 1.5 Hz), 2.32- 2.21 (m, 3H), 2.20-2.14 (m, 1H), 2.10-2.07 (m, 1H), 2.03-1.93 (m, 2H). ° (£)-6-Spirocyclopropyl-bicyclo[3.1.0]hexane-2-one : (—2 1 Example (4-e)

H, H, >] ) TsOH - > “«Am Acetone H 70 Acetone/H,0 a for 2 H 5 ace NMR (400 MHz, : 12.33 (t, 1H, J = 5.0 Hz), 2.26-2.04 (m, 4H), 1.99-1.91 (m, 1H), 1.03 (t, 2H, J = 7.2 Hz), 0.88-0.78 (m, 2H).(£)-ex0-6 -Vinyl-bicyclo[3.1.0]hexane-2-one : (5 0-9 ) Jie 0

H H

Hy J TSOH Ho 4 = J o The core of J

H d_J Acetone/H,0 H 5 '"H NMR (400 MHz, CDCl3): 5.35 (ddd, 1H, J; = 17.0 Hz, J, = 10.2 Hz, J; = 8.5 Hz), 5.15( ddd, 1H, J, =17.0 Hz, J, = 1.2 Hz, J; = 0.4 Hz), 4.99 (dd, 111, J, = 10.2 Hz, J, = 1.1 Hz), 2.20-2.05 (m, SH) , 1.95-1.91 (m, 1H), 1.83 (q, 1H, J, = 2.5 Hz).

- 11786 - Example (3-ah-lz): `sah-2-`sah »[3.1.0] what nat - (aleem 1-010)-2000-6- ()

Hy, ra “NY) TSOH . Nm HL for Acetone/H,0 HS 0 cetone/H, 0 11 (400 MHz, CDCl;): § 5.82-5.75 (m, 1H), 5.33-5.26 (m, 1H), -2.30 1.89 (m, 7H), 1.76-1.70 (m, 3H). (+)-endo-6-cyclopropyl-bicyclo[3.1.0Jhexane-2-one :(z)o=4)m Ex 27 TsOH Ha, > 03

HS 0 Acetone/H,0 0 8 Y NMR (400 MHz, radius: 2.32-2.09 (m, 5H), 1.86-1.82 (m, 1H), 1.16-1.09 (m, 1H), 0.71 Preparation: (V1) Joe (+)-exo-1-methyl-1a,3,5, 5a-tetrahydro- 1 H-2,3-diaza-cyclopropa[a]pental- ene-4- 01 carboxylic acid ethyl ester 0 : ehran x = 08

Me SD

H 0 . (2) The title compound was prepared in a manner similar to the method mentioned in Example (7-9); by step

YYaq

— \ 7 mg —

MS m/z (EST): 207.2 [M+H]", 229.4 [M+Na]"; Ta NMR (400 MHz, CDCl3): § 4.37-4.31 (m, 2H), 2.97 (dd, 1H, J, = 17.1 Hz, J, =5.7 Hz), 2.86 (d, 1H, J = 17.1 Hz ), 2.01-1.97 (m, 2H), 1.36 (t, 3H, J = 7.1 Hz), 1.13 (d, 3H, J = 6.1 Hz), 0.78-0.72 (m, 1H). Example (17-49): preparation of (£)-exo-1-methyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pental-ene-4- ° carboxylic acid to man NH 3 = OH

Me aS 5 (¥-9) The title compound was prepared in a manner similar to that in the example

MS m/z (EST): 179.1 [M+H]", 201.5 [M+Na]"; ‘” H NMR (400 MHz, :((dd, 1H, J, = 18.5 Hz, J, =6.3 Hz), 291 (d, 111.12 18.5 112), 2.09 (dd, 1H, J; =5.6 Hz, dl = Ve 2.2 Hz), 1.78 (dd, 1H, J, =9.7 Hz, J, =5.9 Hz), 1.17 (d, 3H, J = 6.0 Hz), 0.74 (qdd, 1h,

J1 =6.0 Hz, J, =3.0 Hz, J; = 3.0 Hz). : preparation (VA) eg (£)-exo-1-methyl-4-(2H-tetrazol-5-yl)1a,3,5,5a-tetrahydro-1H-2,3-diaza- - cyclopropa[a]pentalene: Vo

Yvasa

- 171 - : Step 0( : preparation (x)-exo-1-methyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropala]pental-ene-4- carboxylic acid amide

N~ 1 H,, y NH

Q = NH;

Me > .

H 0 . (2) In step 0 (0-8) the title compound was prepared in a manner similar to that in the example

MS m/z 565: 178.1 [M+H], 200.1 [M+Na]"; 11 NMR (400 MHz, 1150-40: 2.84 (dd, 1H, J; = 18.0 Hz, J, =6.4 Hz), 2.69 (d, 1H, J = 18.0 Hz), 1.97 (dd, 1H, J, = 5.8 Hz,

J, =2.3 Hz), 1.68 (dd, IH, J; =9.5 Hz, J, = 6.0 Hz), 1.08 (d, 3H, J = 6.0 Hz), 0.63 (qdd, 1H, J, = 6.0 Hz, J, = 3.0 Hz, J; = 3.0 Hz). Step B: Preparation of 0(+)-exo-1-methyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pental-ene-4-carbonitrile

N<

H, 4 “NH

H, _

XX g “CN

Me™ by H in step (f). (Y=) The title compound was prepared in a manner similar to that in the example

- No -

MS m/z 55: 160.2 [M+HT], 319.1 [2M+H]"; 11 NMR (400 MHz, 01150-00: 8 0 (dd, 1H, J; = 15.9 Hz, J. =4.4 Hz), 2.71 (d, IH, J] = 15.9 Hz), 2.04-1.97 (m, 2H ), 1.05 (d, 3H, J = 6.1 Hz), 0.72–0.65 (m, 1H).: Step (c): Preparation of (£)-exo-1-methyl-4-(2H-tetrazol-5) -yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaz- a- ° cyclopropala]pentalene A Hy, 5 1 1 = N

ZN

Me & NH

H N= (0) The title compound was prepared in a manner similar to that in Example (7-9); by step

MS m/z (ES*): 203.5 [M+H]", 225.4 [WANDA] : 'H NMR (400 MHz, DMSO-ds): § 2.89 (ddd, 1H, J, = 16.2 Hz, J , =4.7 Hz, J; = 1.6 Hz), 2.81 (d, 1H, J = 16.2 Hz), 2.02-1.98 0.1 (m, 2H), 1.08 (d, 3H, J = 6.1 Hz), 0.70 ( Example (9-14) Preparation of (£)-endo-1-methyl-1a,3,5,5a -tetrahydro-1H-2,3-diaza-cyclopropa[a]penta- lene- carboxylic acid ethyl ester Le: H NH "OA

A 08 >

H HHS 0 . (9) In step 0 (Y -9 ) the title compound was prepared in a manner similar to that in the example

- \YVYA =

MS m/z 55: 207.1 [M+H]", 229.2 [M+Na]"; No NMR (400 MHz, CDCl;): § 4.37-4.30 (m, 2H), 2.92 (dd, 1H, J, = 17.5 Hz, J, = 6.8 Hz), 2.65 (d, 1H, J = 17.5 Hz), 2.33 ) 1H,

J=6.8 Hz), 2.33 (dd, 1H, J; =15.0 Hz, J, = 6.8 Hz), 1.38 (t, 3H, J = 7.1 Hz), 1.39-1.30 (m, 1H), 0.71 (d, 3H, J = 6.5 Hz). Example (?-10): preparation of 0 (+)-endo-1-methyl-1a-3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropafa]penta-lene-4- carboxylic acid No Me Ra / NH Ah | ak 0): SN

HnN0

CT) The title compound was prepared in a manner similar to that in the example

MS m/z (EST): 179.1 [M+H]", 357.1 [2M+H]"; ‘” H NMR (400 MHz, CD;0D): § 2.89 Ve (dd, 1H, J, = 17.3 Hz, J, = 6.7 Hz), 2.64 (d, 1H, J = 17.2 Hz), 2.30-2.18 ( m, 2H)), 1.34 (qdd, 1H, J, =6.4 Hz, J, =7.0 Hz, J; = 7.0 Hz). ): preparation of (£)-endo-1-methyl-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza- - cyclopropa[a]pentalene Vo

- 179 - : Step A: Prepare (#)-endo-1-methyl-1a-3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a] penta-lene-4- carboxylic acid amide

N~

H, God “NH

M2

CN NH; . H nN 0 . In step (e) 0 (Y-4) the title compound was prepared in a manner similar to that in Example 0

MS m/z 55: 178.1 [M+H]", 355.2 [2M+H]"; NMR (400 MHz, CD;0D): § 2.88 (dd, 1H, J, = 16.5 Hz, J, =4.8 Hz), 2.66 (d, 1H, J = 16.8 Hz), 2.30-2.22 (m , 2H)), 1.32 (qdd, 1H, J, = 6.4 Hz, J, = 7.0 Hz, J3 = 7.0 Hz). 0.69 (d, 3H, J = 6.4 Hz). Step B: Prepare (£)-endo-1-methyl-1a-3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]penta-lene-4-01 carbonitrile No NH S CN “b H H The title compound was prepared in a manner similar to that in the example (Y=) in step (f). MS m/z (EST): 160.1 [M+H]", 319.4 [2M-+H]"; ‘”H NMR (400 MHz, CD;0D): § 2.84 (dd, 1H, J, = 16.6 Hz, J, = 6.7 Hz), 2.59 (d, 1H, J = 16.6 Hz), 2.36-2.27 (m, 2H)), 1.39 \o (qdd, 1H, J, = 6.4 Hz, J, = 7.0 Hz, J; = 7.0 Hz). 0.69 (d, 3H, J = 6.4 Hz). Yyas

- yama: step (=): preparation of (+)-endo-1-methyl-4-(2H-tetrazol-5 -yl)-1a,3,5,5a-tetrahydro-1H-2, 3-dia-za-cyclopropa[a]pentalene

N = = N > ZN

He & NH

H N = . (0) by step ‘ (Y -9 ) and then prepare the title compound in a manner similar to the method mentioned in Example 0

MS m/z (ES): 203.4 [M+H]", 405.4 [2M+H]"; ‘H NMR (400 MHz, CDCl3): 8 3.18 (dd, 1H, J, =17.3 Hz, J, = 6.5 112, 2.95 (d, IH, J = 17.4 Hz), 2.60-2.53 (m, 2H)) , 1.67 (qdd, 1H, J; = 6.5 Hz, J, = 7.0 Hz, J; = 7.0 Hz). 0.82 (d, 3H, J = 6.5 Hz). Preparation:)” Y-4) Example: (+)-endo-1-ethyl-1a-3,5,5a-tetrahydro- 1H-2,3-diaza-cyclopropa[a]pental-ene -1- 01 carboxylic acid ethyl ester Rat MN “NH > .(2) By step ¢ ( Y-4 ) of the method mentioned in the alles example, then prepare the title compound in a manner

MS m/z (ES'): 221.3 [M+H]", 243.3 [M+Na]"; ‘” H NMR (400 MHz, CDCly): § 4.38-4.30 (m, 2H), 2.92 (dd, 1H, J; = 17.5 Hz, J, = 6.9 Hz), 2.65 (d, 1H, J = 17.5 Hz ), 2.35 (dddd, Vo

- YAN - 1H, J, - 7.6 Hz, J, = 6.2 Hz, J3= 1.3 Hz), 2.21 (dd, 1H, J, = 4 Hz, J, = 6.7 Hz), 1.37 ) 3H, J = 7.1 Hz ), 1.23-1.17 (m, 1H), 1.11-1.01 (m, 1H), 0.91-0.83 (m, 4H). Preparation (YF) eg (+)-endo-1-ethyl-1a-3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pental-ene-4- carboxylic acid ° no sah OH

H oS 8 . -?) q ) Then prepare the title compound in the manner mentioned in an example

MS m/z (EST): 193.0 [M+H]", 215.0 [M+Na]"; ‘” H NMR (400 MHz, DMSO-ds): 6 2.80 (dd, 1H, J; = 17.2 Hz, J, = 6.8 Hz), 2.49 (d, 1H, J = 17.2 Hz), 2.24 (ddd, 1H , J, = 7.6 Hz,

J,=6.2 Hz, J; =1.0 Hz), 2.15 (dd, 1H, J; = 14.4 Hz, J, = 6.4 Hz), 118-1. 11 (m, 1H), 01 1.03-0.93 (m, 1H), 0.81 (t, 3H, J = 6.9 Hz), 0.77-0.68 (m, 1H). Example: (4-£): preparation of (+)-endo-1-ethyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3- diaz-a-cyclopropala]pentalene : step 0( : preparation of 1(+)-endo-1-ethyl-1a-3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pental- ene-1-carboxylic acid amide

YAY - - A H, CA NH, SN H oS 0 The title compound was prepared in a manner similar to the method mentioned in Example (0-4) » in step D. [M+H] 192.0 for 35 MS m/z Step B: Preparation: (+)-endo-1-ethyl-1a-3,5,5a-tetrahydro-1H -2,3 -diaza-cyclopropa[a]pental- ene-1- ° carbonitrile N ~ H, y NH — 7 b H H The title compound was prepared in a manner similar to that mentioned In example (Y-1) in step (5). MS m/z (ES”): 174.1 [M+H]”, 347.4 [2M+H]”. 01 Step (z) Synthesis: (*)-endo-1-ethyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaz-a-cyclopropa[ a]pentalene Ho NNH 7 for 1 m Then prepare the title compound by alas method for the method mentioned in Example (0-9) 'by step (g.

-VAT-

MS m/z (ES): 217.1 [M+H]", 433.1 [2M+H]"; H NMR (400 MHz, CD;0D): § 2.91 (dd, 2H, J; = 14.6 Hz, J, = 6.1 Hz), 2.07-2.03 (m, 1H), 1.88-1.79 (m, 1H), 1.66-1.57 (m, 1H), 1.17 (dd, 1H, J, = 7.7 Hz, J, =4.7 Hz), 1.09 (t, 3H, J = 7.4 Hz), 0.56 (dd, 1H, J, = 4.2 Hz, J, =3.2 Hz). -cyclopropa[a]pental-ene-4-carboxylic acid ethyl ester

N~ = Oet

N.A

(2) In step 0 (7-9) the title compound was prepared in a manner similar to the method mentioned in the example

MS m/z (ES): 219.2 [M+H]", 241.1 [M+Na]"; ‘” H NMR (400 MHz, CDCl3): 6 5.31-5.23 Ve (m, 1H), 5.05-4.95 (m, 1H), 4.39-4.31 (m, 2H), 2.99 (dd, 1H, J, = 17.5 Hz, J, = 6.7 Hz), 2.76 (d, 1H, J = 17.5 Hz), 2.60 (ddd, 1H, J, =7.6 Hz, J, = 6.0 Hz, J; = 1.2 Hz), 2.42 (dd, 1H, J; = 15.0 Hz, J, = 6.0 Hz), 1.99 (ddd, 1H, J, =8.0 Hz, J, = 8.0 Hz, J; = 8.0 Hz), 1.37 (t, 3H, J = 7.1 Hz ).

Yyaa

- wa - : Example (-7): preparation of (+)-endo-1-vinyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pental-ene-carboxylic acid

H, J NH “HN OH 2 H a 0 : . (v- q ) M The title compound was prepared in a manner similar to the method mentioned in the example

MS m/z (ES): 191.2 [M+H]", 381.3 [2M+H]*; "TH NMR (400 MHz, DMSO-dg): 6 5.25 (dd, 1H, J, = 16.9 Hz, J = 2.3 Hz), 4.99 (dd, 1H, J; = 10.4 Hz, J, = 2.4 Hz), 4.85 (dd,

IH, J1 =16.9 Hz, J, =10.4 Hz, 11- 9.2 Hz), 2.88 (dd, 1H, J, = 17.3 Hz, J, = 6.6 Hz), 2.57-2.50 (m, 2H), 2.39 (dd , 1H, J; = 14.5 Hz, J, = 6.2 Hz), 1.94 (ddd, 1H, J, = 8.4 Hz, 1 = 84 Hz, 3 = 8.4 Hz). 11: Example (4-77): preparation of (%)-endo-1-vinyl-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropala]pental-ene-4-carboxylic acid amide no H \ nal L

H iS 0 . (2) By step 0 (0-9) and then prepare the title compound in a manner similar to the method mentioned in example ve

— \ A m —

MS m/z (ES¥): 190.2 [M+H]", 379.2 [2M+H]"; 'H NMR (400 MHz, DMSO-de): § 5.25 (dd, 1H, J, = 16.9 Hz, J, = 2.3 Hz), 4.98 (dd, 1H, J, = 10.4 Hz, J, = 2.4 Hz) , 4.90-4.81 (m, 1H), 2.88 (bd, 1H, J = 13.6 Hz), 2.64-2.49 (m, 2H), 2.40 (dd, 1H, J, = 13.7 Hz, J, = 6.9 Hz), 1.92 (ddd, 1H, J, =8.4 Hz, J, =8.4 Hz, J; = 8.4 Hz). Step B: Prepare ©(+)-endo-1-vinyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pental-ene-4-carbonitrile lm H, 4 NH 7 —

ACACN

H 0 . By step f 0 ( 7-9 ) the title compound was prepared in a manner similar to the method mentioned in the example

MS m/z: L6) 172.3 [M+H]", 343.3 [2M+H]"; 11 NMR (400 MHz, CDCl): § 5.30 (dd, Ve 1H, J, = 16.9 Hz, J, =2.0 Hz), 5.08 (dd, 1H, J, = 10.4 Hz, J, =2.0 Hz), 4.93 (ddd, 1H, J, =16.9 Hz, J, = 10.4 Hz, J; = 8.5 Hz), 2.96 (dd, 1H, J, = 16.9 Hz, J, = 6.7 Hz), 2.73 (d, 1H, J = 16.9 Hz), 2.60-2.49 (m, 2H), 2.03 (ddd, 1H, J; =8.3 Hz, J, = 8.3 Hz, J; = 8.3

Hz). Step (2): Preparation of \o (+)-endo-4-(2H-tetrazol-5-yl)-1-vinyl-1a,3,5,5a-tetrahydro-1H-2,3-diaz - a-cyclopropa[a]pentalene

-VAT-

N~ = N 8 ZN

SN NH

H HS N = y . By step (f) 1 0-8) then prepare the title compound in a manner similar to the method mentioned in an example

MS m/z 55: 215.2 [M+H]", 429.3 [2M+H]"; ‘”H NMR (400 MHz, CD;0D): 6 5.30-5.25 (m, 1H), 5.07-4.99 (m, 2H), 3.05 (dd, 1H, J, = 16.6 Hz, J, = 6.6 Hz) , 2.82 (d, 1H, J =16.6 Hz),2.62 (dd, 1H, J, =7.5Hz, J, =6.1 Hz), 2.55 (dd, 1H, J; = 13.5 Hz, J, = 7.0°

Hz), 2.06-2.00 (m, 1H). Example (7/8-9): preparation of ()-endo-1-Benzyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3- dia-za-cyclopropala]pentalene

H

H N- MN

N

1 Lr N \ oRAt 11 From the mixture of the stereoisomers mentioned in the HPLC example, the title compound was obtained by purifying R (f) by step (f).

MS: m/z (ES+): 301 [M+Na]", 279 [M+H]", 251 [M-N2+H]"; 11117116 (CD;0D): § 7.2-7.05 (m, 2H) ), 7.03 (t, 1H, J=6.8), 6.97 (d, 2H, J=7.4), 3.0-2.8 (m, 1H), 2.77 (d, 1H,

J=16.7), 2.5-2.3 (m, 3H), 2.02 (dd, 1H, J,=14.5, J,=8.9), 1.55-1.45 (m, 1H). Vo

- YAY - : Example (9-79): Preparation of (+)-exo-1-Propyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pental-ene- 4- carboxylic acid ethyl ester (+)-ex0-6-Propyl-bicyclo[3.1.0Thexan-2-0l Step A: Preparation

H

H 0 by step (b).0 (Y-1 ) and then prepare the title compound in a manner similar to that in the example. , 1H), 1.67 (dd, 1H, 1112.5

J;=8.2),1.53 (dd, 1H, 1214.2, ],=8.3), 1.48-1.28 (m, 4H), 1.20-1.05 (m, 3H), 0.88 (t, 3H,

J=7.3), 0.37 (septet, 1H, J=3.3). (+)endo-6-n-propyl-bicyclo[3.1.0Jhexan-2-0l /Y contains approx. 0 (#)-ex0-6-Propyl-bicyclo[3.1.0]hexan-2-one Step B: Preparation

H

© . (©) For the method mentioned in Example (4-7); by step Alles the title compound was prepared by the 'H NMR (CDCl) method: 8 2.15-5 (m, 4H), 1.9-1.8 (m, 1H), 1.53 (d, 1H, J=5.0), 1.50-1.35 (m, 2H), 1.35-1.25 (m, 3H), 0.91 (t, 3H, J=7.3).

= yra(+)endo-6-n-propyl-bicyclo[3.1.0jhexan-2-one ZY contains approximately: step (c): preparation of (%)-exo-1-propyl- 1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pental-ene-4-carboxylic acid ethyl ester

H 0 mR

H \ paracentesis. (2) In step 0 (7-9) the title compound was prepared in a manner similar to that in the example

MS: m/z (ES+): 257 [M+Na]", 235 [M+H]", 189 [M-OEt]"; TNA NMR))00: 4.25 (9, 2H, J=7.1 , OCH2), 2.86 (dd, 1H, J|=17.1, J,=6.2), 2.74 (d, 1H, J=17.1), 1.95-1.90 (m, 1H), 1.87-1.80 (m, 1H), 1.40-1.10 (m, 7H, including 1.27 (t, 3H, J=7.2)), 0.85 (t, 3H,

J=7.2), 0.60 (septet, 1H, J=3.4). Ve : 7271 contains approximately (#)-endo-1-n-propyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a- Jpentalene-4- carboxylic acid ethyl ester Preparation: 0-1(example: (+)-exo-1-Propyl-1a,3,5,5a-tetrahydro- 1H-2,3-diaza-cyclopropa[a]pental-ene- 4- Your carboxylic acid

- YA4 - 0 0 L -NH (Y=) The title compound was prepared in a manner similar to that in the example

MS: m/z (ES+): 229 [M+Na]*, 207 [M+H]", 189 [M-OH]"; ‘” H NMR (CD;0D): § 2.95- 2.85 (m, 1H), 2.79 (d, 1H, 1-16.8), 2.00-1.90 (m, 2H), 1.47 (m, 2H, J=7.1) , 1.40-1.25 (m, 2H), 0.96 (t, 3H, J=7.3), 0.63 (m, 1H, J=3.4).° : Example (9-1?): Preparation of (£)-exo -1-Propyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaz-a-cyclopropala]pentalene : Step (a): Preparation of ( )-exo-1-Propyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pental-ene-4- yo carboxylic acid amide

H 0 B J I~ NH,

H Lahi. (—=) Then prepare the title compound in a manner similar to the method mentioned in Example (7-4 1) by step

MS: m/z (ES+): 206 [M+H]", 189 [M-NH2]*; "TH NMR (CD;0D): 6 2.92 (dd, 1H,

J1=16.4, J,=5.8), 2.82 (d, 1H, J=16.5), 2.05-1.90 (m, 2H), 1.47 (pentet, 2H, J=7.1), 1.38- Vo 1.28 (m, 2H) , 0.96 (t, 3H, J=7.3), 0.66 (septet, 1H, J=3.3).

Yyaa

- Ya. - : Step (b): Preparation of (x)-exo0-1-Propyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pental-ene-4- carbonitrile

H.

N

- 0 \-NH . (9) 3 shally 0 (the title compound was prepared in a manner similar to that in the example) 9-? 0

MS: m/z (ES+): 188 [M+H]"; no NMR (CD;OD): § 2.88 (dd, 1H, 6.3 µJ,=6.0), 2.76 (d, 1H , J=16.2), 2.1-2.0 (m, 2H), 1.47 (pentet, 2H, J=7.3), 1.40-1.28 (m, 2H), 0.96 (t, 3H,

J=7.3), 0.71 (septet, 1H, J=3.3). Step (c): Prepare (+)-exo-1-Propyl-4-(2H-tetrazol-5-yl-1a,3,5,5a-tetrahydro- 1H-2,3-diaza- - Ve cyclopropa[a]pentalene

H

H N-- for 9. NN = N

H Lahi. (0) 5 ghaally ¢ ( 7-48 ) The title compound was prepared in a manner similar to that in the example

Yyas

-Va-

MS: m/z (ES+): 231 [M+H]", 203 [M-N2+H]"; 'H NMR (CD;0D): E 3.00 (dd, 1H,

J,=10.1, J,=6.1), 2.91(d, 1H, J=16.2), 2.07 (m, 2H), 1.50 (sextet, 2H, J=7.3), 1.35 (septet, 2H, J=7.0) , 0.99 (t, 3H, J=6.1), 0.74 (septet, 1H, J=3.3). Ex. carboxylic acid 1 I~" OH

H by using a mixture (Y=) the title compound was prepared in a manner similar to the method mentioned in Example: (9-49?); In step (c). Jha dimorphisms mentioned in

MS: m/z (ES+): 229, 207 [M+H]", 189 [M-OH]". 0 : Example (4-): Preparation of (+)-endo-1-Propyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-dia - za-cyclopropala]pentalene! Step 0: Preparation of (+)-endo-1-Propyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropala]penta-lene-4- Vo carboxylic acid amide

- 197 -

H0

JH bitter NH;

Ho no. (—2) By step » ( Y—-1 ) The title compound was prepared in a manner similar to the method mentioned in an example

MS: m/z (ES+): 206 [M+H]", 189 [M-NH2]"; 'H NMR (CDCl;): 8 6.45 (br s, 1H), 5.95 (brs, 1H), 2.93 (dd, 1H, J,=16.6, J,=6.6), 2.68 (d, 1H, J=16.6 ), 2.4-2.3 (m, 2H), 1.4-1.2 (m, 3H), 1.15-1.00 (m, 1H), 0.88-0.78 (m, 4H). ° : Step B: Prepare (£)-endo-1-Propyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]penta-lene-4-carbonitrile

H N

2

ANIL I~"

Ho except in step (F). 0 (Y-1) The title compound was prepared in a manner similar to that in Example 0

MS: m/z (ES+): 188 [M+H]*; TNA NMR (CD;OD): § 2.85 (dd, 1H, J,=16.6, J,=6.6), 2.60 (d, 1H, J=16.6), 2.4-2.3 (m, 2H), 1.45 1.20 (m, 3H), 1.15-1.05 (m, 1H), 0.90-0.80 (m, 3H), 0.78-0.65 (m, 1H). Step C: Prepare (#)-endo-1-Propyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-dia-za - \o cyclopropa[a]pentalene

- yay —

H

HNN,

IN

IIH I~"N

H for the title compound was prepared in a manner similar to the method mentioned in Example (4-7); With step (g).

MS: m/z (ES+): 231 [M+H]", 203 [M-N2+H]"; 11 NMR (0:00): § 2.97 (dd, 1H, 1210.2, J,=6.4), 2.72 (d, 1H, J=18.3), 2.40-2.34 (m, 2H), 1.42-1.28 (m, 3H ), 1.20-1.11 (m, 1H), 0.86-0.77 (m, 4H including 0.85 (t, 3H, J=7.4)).° : Example (4-9 7): preparation of (£)-exo- 1-Butyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a] pentale- ne-4- carboxylic acid ethyl ester (£)-(E)-2-(Oct-3 -enyl)oxirane: step (1): preparation of 1 lo 1: 011 milli-can (5.17 mmol) and p-1-0*g 017 00 (2-) were stirred But-3-enyl)oxirane h in a sealed flash vial with YE sad catalyst (mmol) at room temperature (mmol). The solvent was removed under reduced pressure and the residue 187 g purified; (+, OY) 1-78 : to obtain (silica [hexane aphate/H-ZY += +) by column chromatography 1 1e-2 -p.«0-6-8171-0197010]3.1.0[8»©-(+) as colorless oil.

YYaq

- Vag - “HNMR (CDCl3): 6 5.5-5.4 (m, 2H), 3.0-2.9 (m, 1H), 2.8-2.7 (m, 1H), 2.5-2.45 (m, 1H), 2.2-2.1 ( m, 2H), 1.99 (q, 2H, J=5.7), 1.65-1.55 (m, 2H), 1.35-1.25 (m, 4H), 0.95-0.85 (m, 3H).(£)-endo- 6-n-butyl-bicyclo[3.1.0]hexan-2-ol IY contains approximately (+)-ex0-6-Butyl-bicyclo[3.1.0]hexan-2-one : step (b) Preparation: 0

H

/ H 4 . In step (b) 1 Y-4) the title compound was prepared in a manner similar to that in the example O. NMR (CDCl3): 6 4.21 (d, 1H, J=4.8), 1.95-1.80 (m, 1H ), 1.69 (dd, 1H, 1212.6,

J,=8.0),1.54 (dd, 1H, J,=11.6, J,=5.7), 1.48-1.25 (m, 6H), 1.25-1.05 (m, 3H), 0.95-0.85 (m, 3H), 0.36 (septet, 1H, J=3.3). Ve. (£)-endo-6-n-butyl-bicyclo[3.1.0]hexan-2-ol. : 7701 contains approximately (+)-2« 0-6-3 Step (c): Prepare 167610[3.1.0[56:20-2-0086i-Aloa0 . / H 3 (©) By step ' (0-1) and then prepare the title component in a manner similar to the method mentioned in an example

_ \ 8 mg — 'H NMR (CDCly): 8 2.15-1.95 (m, 4H), 1.9-1.8 (m, 1H), 1.54 (t, 1H, J=2.4), 1.45-1.20 (m, 7H), 0.95-0.85 (m, 3H). (%)-endo-6-n-butyl-bicyclo[3.1.0]hexan-2-one 701 contains approximately: Step (d): Preparation of (+)-exo-1-Butyl-1a, 3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a] pentale- ne-4- ° .carboxylic acid ethyl ester

H 0 a \ . H the mother. (9) By step ‘ (Y-9) of the method mentioned in the example of alae, then preparing the title compound in a way

MS: m/z (ES+): 249 [M+H]", 203 [M-OEt]"; ‘” H NMR (CDCl): 6 4.30 (q, 2H, J=7.2,

OCH2), 2.91 (dd, 1H, J,=17.0, J,=6.2), 2.79 (d, 1H, J=17.0), 1.98-1.93 (m, 1H), 1.89 01 (dd, 1H, J,= 9.8, J,=6.0), 1.45-1.10 (m, 9H, including 1.32 (t, 3H, J=7.1)), 0.87 (t, 3H,

J=6.8), 0.70-0.60 (m, 1H). : of 771 contains approximately (2)-6000-1-1-0171-18,3,3,5a-tetrahydro-1H-2,3-diaza-cyclopropala]pent-alene-4-carboxylic acid ethyl ester \o yYv4a4a

- Vat - : Example (3-9?): Prepare (£)-exo-1-Butyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropala]pentale-ne-4 - carboxylic acid

H 0 = OH

Hy-NH. (*- 9) M. The title compound was prepared in a manner similar to the method mentioned in the example

MS: m/z (ES+): 221 [M+H]", 203 [M-OH]"; 11 NMR (CD;0D): 6 2.95-2.85 (m, 1H), 2.78 (d, 1H, J=16.9), 2.00-1.90 (m, 2H), 1.5-1.25 (m, 6H), 0.93 (t , 3H, J=7.0), 0.62 (septet, 1H, J=3.3). Example (7-9?): Preparation of (£)-exo- 1-Butyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3- diaza- - 01 cyclopropala]pentalene : Step 0( : Prepare (%)-exo-1-Butyl-1a,3,5,5a-tetrahydro- 1 H-2,3-diaza-cyclopropa[a]pentale- ne-4-carboxylic acid amide

H0

H ? -NH yo agreed

- 197 - In step (e). 0 (7-3) the title compound was prepared in a manner similar to the method mentioned in an example.

MS: m/z (ES+): 220 [M+H]", 203 [M-NH2]*; "TH NMR (CD;OD): § 2.92 (dd, 1H,

Ji=16.4, 1,-5.9), 2.82 (d, 1H, J=16.0), 2.05-1.90 (m, 2H), 1.50-1.30 (m, 6H), 0.93 ) 3H,

J=7.0), 0.65 (septet, 1H, J=3.3). Step b: Prepare oo(+)-exo-1-Butyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentale-ne-4-carbonitrile

H

IN

=~ sine H N - NH . (9) Then prepare the title compound in a manner similar to the method mentioned in Example (9-7) in the step

MS: m/z (ES+): 202 [M+H]"; 'H NMR :(0,0) 8 2.89 (dd, 1H, J1=16.3, J,=6.0), Ve 2.76 (d, 1H , J=16.2), 2.1-2.0 (m, 2H), 1.50-1.30 (m, 6H), 0.93 (t, 3H, J=7.0), 0.70 (septet, 1H, J=3.3). Preparation: (z) step (£)-exo-1-Butyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3- diaza- - cyclopropafa]pentalene \o

- 1 pm

H

H didn't N,

N

S.S.N

Ho to (0) The title compound was prepared in a manner similar to the method mentioned in Example (4-7); by step

MS: m/z (ES+): 245 [M+H]+, 217 [M-N2+H]"; NMR (CD;0D): 6 2.99 (dd, 1H,

J,=10.2, 1,=6.0), 2.90 (d, 1H, J=16.2), 2.10-2.00 (m, 2H), 1.49-1.32 (m, 6H), 0.93 (t, 3H,

J=7.0), 0.72 (septet, 1H, J=3.3). ° : Example (7-9?): Preparation (x)-endo-1-Butyl-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pental-ene-4 - carboxylic acid

H 0 "i I ~ OH / H nonlinear using mixture (F-9) and then prepare the title compound in a manner similar to the method mentioned in Example 0 stereoisomers mentioned in Example (4-9); by step (d) ..

MS: m/z (ES+): 221 [M+H]", 203 [M-OH]". Ex. - a-cyclopropala]pentalene \o

YY4q

- 188 - : Step A: Prepare (+)-endo-1-n-Butyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropala]pent-alene-4- carboxylic acidamide

H 0 i = NH, / | H \- NH The title compound was prepared in a manner similar to that in Example (7-9); In step (e).

MS: m/z (ES+): 220 [M+H]", 203 [M-NH2]"; ‘”H NMR (CD;OD): 6 2.87 (dd, 1H, 1216.7, 1,=6.3), 2.66 (d, 1H, J=16.7), 2.35-2.20 (m, 2H), 1.35-1.15 (m , 5H), 1.15-1.05 (m, 1H), 0.85-0.70 (m, 4H).: Step (b): Preparation of (+)-endo-1-Butyl-1a,3,5,5a-tetrahydro -1H-2,3 -diaza-cyclopropaa]pental-ene-4- \ carbonitrile m N nn I~" / Ho) -NH . (1) 8 shally ((Y-4 ) The title compound was prepared in a manner similar to that in the example

MS: m/z (ES+): 202 [M+H]"; ), 2.4-2.3 (m, 2H), 1.4-1.1 (m, 6H), 0.85-0.79 (m, 3H), 0.78-0.68 (m, 1H). \o

= Wala Step (c: Preparation: (+)-endo-1-Butyl-4-(2H-tetrazol-5-yl)-1a,3,5,Sa-tetrahydro-1H-2,3-diaz- a- cyclopropala]pentalene H H N~ N, N in I~ N A H N- NH / 0 The title compound was prepared in a manner similar to that in example ( 7-9); by step (g). MS: m/z (ES+): 245 11+11 217 [M-N2+H]"; 'H NMR (CD;0D): 8 2.97 (dd, 1H, J,=6.4), 2.78 (d, 1H, J=16.6), 2.38 (pentet, 2H, J=5.4), 1.40-1.14 (m, 6H), 0.85- ,1210.0 (m, 3H) , 0.88-0.79 (m, 4H including 0.81 ) 3H, J=7.2) 0.79 Example (9-9?): Preparation: (+)-endo-1-Pentyl-1a,3,5,5a- tetrahydro-1H-2,3 -diaza-cyclopropa[a]penta-lene-4- 01 carboxylic acid ethyl ester Step 0: Preparation of (+)-endo-6n-Pentyl-bicyclo[3.1.0]Jhexan -2-0l H a Hi KR H 00 The title compound was prepared in a manner similar to the method mentioned in Example (0) Y-4 in step (=). RARE:

— YN - 'H NMR (CDCls): 8 4.17 (dd, 1H, 1125.0, J>=1.0), 2.15-2.00 (m, 1H), 1.80-1.45 (m, 3H),1.40-1.25 (m , 8H), 1.22-1.15 (m, 3H), 0.95-0.85 (m, 3H), 0.75 (pentet, 1H, J=8.4). (+)-endo-6-Pentyl-bicyclo[3.1.0Thexan-2-one Step B: Preparation

H

H © . (2) By step 6 ( Y—14 ) and then prepare the title compound in a manner similar to that in the 0 'H NMR example: (J020) 6 2.35-2.20 (m, 2H), 2.14 (dd, 1H, J,=11.8, J,=5.9), 2.05-1.85 (m, 3H), 1.50-1.20 (m, 9H), 0.95-0.85 (m, 3H). Step C: Prepare (+)-endo-1-Pentyl-1a,3,5,5a-tetrahydro-1H-2 ,3-diaza-cyclopropa[a]penta-lene-4- carboxylic acid ethyl ester 01

H 0 111 Hess bitter ad Ho sah. (2) The title compound was prepared in a manner similar to the method mentioned in Example (7-9) by step

MS: m/z (ES+): 263 [M+H]", 217 [M-OEt]"; 11 NMR (CDCl): § 4.40-4.30 (m, 2H), 2.91 (dd, 1H, 1217.5, 1,=6.8), 2.66 (d, 1H, J=17.5), 2.33 (dd, 1H, J,= 7.7, J,=6.2,

J;=1.2), 2.20 (dd, 1H, J;=14.6, J,=6.5), 1.35-1.15 (m, 10H), 1.10-0.95 (m, 1H), 0.87 (t, Vo 3H, J= 6.9).

YYas

- Y.Y - : Example (9-40): Preparation of (+)-endo-1-Pentyl-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropala]penta-lene-4- carboxylic acid

H0

Hi I~" CH ad H . (3- a ) Joa The title compound was prepared in a manner similar to that for 0 m/z (ES+): 235 [M+H]", 217 [M-OH ]"; 'H NMR (CD;0D): § 2.86 (dd, 1H, J,=17.2, 1,=6.7), 2.40 (d, 1H, J=17.2), 2.33-2.28 (m, 1H), 2.28-2.20(m, 1H), 1.40-1.15 (m, 7H), 1.13-1.05(m, 1H), 0.88-0.82 (m, 3H), 0.82-0.73(m, 1H). Example: 4-19( preparation (+)-endo-1-Pentyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-dia-za-01 cyclopropala]pentalene : step (a): prepare (+)-endo-1-Pentyl-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]penta-lene-4- carboxylic acidamide

H 0 1111 I~" NH; ad Ho M Lahi 1.3

—- YY - . (—2) by step “(Y-14) and then prepare the title compound in a manner similar to the method mentioned in an example

MS: m/z (ES+): 234 11,7 [M-NH2]”; J=16.8), 2.35-2.25 (m, 2H), 1.40-1.15 (m, 7H), 1.15-1.05 (m, 1H), 0.90-0.70 (m, 4H). Step (b): Prepare oo(+)-endo-1-Pentyl-1a,3,5,5a-tetrahydro- 1H-2,3-diaza-cyclopropa[a]penta-lene-4-carbonitrile" N 1) I~" ~~ H N ~-NH . (9) In step 0 (7-4) the title compound was prepared in a manner similar to the method mentioned in the example

MS: m/z (ES+): 216 [11711]. 0: Preparation: (z) step (+)-endo-1-Pentyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2, 3-dia-za-cyclopropala]pentalene

H

H to N,

N

HnI~N

Wad Ho Earl . (0) by step 0 (Y -9 ) and then prepare the title compound in a manner similar to the method in the Vo example

_ Y 0 $ —

MS: m/z (ES+): 260 [M+H]", 232 [M-N2+H]"; 'H NMR (CD;0D): § 2.96 (dd, 1H, J, =16.5, J.=6.4), 2.75 (d, 1H, J=16.5), 2.40-2.33 (m, 2H), 1.40-1.12 (m, 8H), 0.86-0.78 (m, 4H). Example (9-47): preparation of (+)-exo-1-Isopropyl-1a,3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropala]pen-talene-4- ° carboxylic acid ethyl ester (+)-exo0-6-Isopropyl-bicyclo|3.1 .Olhexan-2-0l : Step A: Preparation

H

7, HOH. (<) Then prepare the title compound in a manner similar to the method mentioned in Example (4-7) in step 'H NMR (CDCls): 6 4.19 (d, 1H, J=4.8), 1.94-1.85 (m, 2H), 1.65 (dd, 1H, J;=12.5, 1 12-8.2,1.53 (dd, 1H, J;=14.2, J,=8.4), 1.36-1.26 (m, 1H), 1.22-1.20 (m, 1H), 1.14- 1.12(m, 1H), 0.95-0.87 (m, 7H), 0.37 (m, 1H).(+)-ex0-6-Isopropyl-bicyclo[3.1.0]hexan-2-one step (b) ).

H

H © . (©) Then prepare the title compound in a manner similar to the method mentioned in Example (4-7) «by step Ne

—- Y.o — 'H NMR (CDCl3): 8 2.07-1.93 (m, 4H), 1 86-1.84 (m, 1H), 1.53 (d, 1H, J=5.2), 1.05- 1.02 (m, 2H) , 0.98(d, 3H, J=5.1), 0.93(d, 3H, 1 : Step (c): Preparation of (+)-exo-1-Isopropyl-1a,3,5,5a-tetrahydro-1H -2,3-diaza-cyclopropa[a]pen-talene-4-carboxylic acid ethyl ester °

H 0 a /

HN~N

H

(2) By step ((Y-4) and then prepare the title compound in a manner similar to the method mentioned in an example

MS: m/z (ES+): 235 1 189 [M-OEt]"; 'H NMR (CDCl): 8 4.33 (q, 2H, J=5.9), 2.90 (dd, 1H, J;=17.1, J ,=5.3), 2.77 (d, 1H, J=17.1), 1.91-1.89 (m, 1H), 1.30 (t, 3H, I= 10.1), 1.24-1.19 (m, 1H), 1.06-1.03 (m , 1H), 0.97 (d, 6H, J=11.5), 0.45 (m, 1H). 5 a-tetrahydro-1H-2,3-diaza-cyclopropa[ajpen-talene-4-carboxylic acid

H0

Oh

> 17

H N ~ N oo H . (v- 9 ) Then prepare the title compound in a manner similar to the method mentioned in the example of Ve

a for MS: m/z (ES+): 207 [MH], 189 [M-OH]"; "H NMR (0:0): 8 2.95-2.93 (m, 1H), (d, 1H, J=16.7), 2.00 (m, 2H), 1.08- 1.03(m, 7H (including d, 6H, J=12.4)), 0.43 2.90 (septet, 1H, J=4.1). Example) £6( Preparation: (£)-exo-1 Jsopropyl-4-(2H-tetrazol-5 -yl)-1a,3,5,5a-tetrahydro-1H-2,3-d-iaza-° cyclopropal[a]pentalene H H NEN N atomic number Ho dissolved 0.159 cpa vy Yoo) (+)-ex0-6-Isopropyl-bicyclo[3.1.0] hexan-2one mmol) and salt (v, YYA) 1 H-tetrazole-5-carboxylic acid ethyl ester sodium mg; 0.45 mmol) 0 in (Je©) DMEF and cooled to 0°C. Potassium tert-butoxide (1 M) in 1.01 “THF mL YY. mmol) was added slowly and the resulting solution was stirred at 0 °C Baal h. Subsequently, hydrochloric acid (?Number “Y,4+”Je 0.01 mmol) was added slowly; followed by the addition of hydrazine monohydrate dropwise (0080 ml; 0 VY mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The DMF \o was removed under reduced pressure and the reaction mixture alJ in o (DMSO ml) was removed and purified by HPLC to yield: (£)-ex0-1 -isopropyl-4-(2H- tetrazol-5-y1)- 1a,3,5,5a-tetrahydro-1H-- 2,3-diaza- cyclopropala]pentalene

As a white to yellowish solid.

MS: m/z (ES+): 231 [M+H]", 203 11-21 'H NMR (CD;0D): 8 2.83 (dd, 1H,

J,=14.6, J,=5.6), 2.65(d, 1H, J=16.1), 1.95-1.86 (m, 2H), 0.81-0.88(m, 7H (including d, 6H, J=12.9)), 0.31(septet, 1H, J=3.3). Example (9-95;): preparation of oo(+)-exo-1-Isobutyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pent-alene- 4- carboxylic acid ethyl ester (£)exo-Isobutyl-bicyclo[3.1.0Thexan-2-0l (Step 0): Preparation ( H

HoH Then prepare the title compound in a manner similar to the method mentioned in Example (7-4) in step (b). 1 .72-1.45 (m, 4H,),1.40-1.20 (m, 1H), 1.20-1.16(m, 1H), 1.15-1.00(m, 2H), 0.97-0.83 (m, 6H) 0.37 (septet , 1H). ()endo-6-isobutyl-bicyclo[3.1.0]hexan-2-ol Ye contains approximately (£)exo-6-isobutyl-bicyclo[3.1.0]hexan-2-one step (b) Preparation: (H

H 0 1

_ Y 0 A — . ( ) by step oY -9 ) and then prepare the title compound in a manner similar to the method mentioned in the example of 0' H NMR) and: Leah 8 2.13-1.97 (m, 4H), 1.88-1.82 (m, 1H), 1.74 -1.66 (m, 1H), 1.55- 1.51(d, 1H, J=5.1), 1.32-1.23(m, 2H), 1.15-1.07(m, 1H) 0.95(d, 3H, J=2.5), 0.92 (d, 3H,

J=2.5). (+)endo-6-isobutyl-bicyclo[3.1.0]hexan-2-one Ye contains approximately 0 : Step (c): Preparation of (+)-exo-1-Isobutyl-1a,3, 5,5 a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pent-alene-4-carboxyiic acid ethyl ester

H 0 0 ' 17 I

HN~N

H

(9) 3 shally ((Y-4 ) The title compound was prepared in a manner similar to that in Example 0

MS: m/z (ES+): 249 [M+H]", 203 [M-OEt]"; 'H NMR (CDCl): 5 4.30 (q, 2H, J=7.1), 2.91 (dd, 1H, 1217.0, J,=6.2), 2.77 (d, 1H, J=17.0), 1 .98-1.93 ( m, 2H), 1.59-1.49 (m, 1H), 1.43-1.34(t, 3H, J=6.9), 1.24-1.15 (m, 1H), 0.85(m, 7H) , 0.64-0.57 (m, 1H ). : 7780 contains approximately (+)-endo-1-Isobutyl-1a,3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropala]pen- talene-4- \o carboxylic acid ethyl ester .

— Y 0 9 _ : Example (57-49): Preparation of (£)-exo-1-Isobutyl-1a,3,5,5 a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pent - alene-4-carboxylic acid

H0

Oh

1 7 m N

H

. )- q ) The title compound was prepared in a manner similar to that in Example 0

MS: m/z (ES+): 221 [M+H], 203 [M-OH]"; NMR (CD;OD): 6 2.95-2.90 (m, 1H), 2.80 (d, 1H, J=16.9), 1.96(m, 2H), 1.78-1.72 (m, 1H), 1.26-1.23(m, 2H), 0.98-0.94 (m, 6H), 0.62 (septet, 1H, J=3.3). Example: (3-;): Synthesis of (+)-exo0-1-Isobutyl-4-(2H-tetrazol-5-yl)-1a,3, 5,5a-tetrahydro-1H-2,3-di - aza- The cyclopropala]pentalene

H

H N-N

N

S.S.N

Ho Balhi. (2-49) the compound of the title in a manner similar to the method mentioned in the example of paca] then 74 a

— Lala —

MS: m/z (ES+): 245 [M+H]", 217 [M-N2+H]"; '"H NMR (CD;0D): § 2.99 (dd, 1H, 1216.2, J,=5.6), 2.91 (d, 1H, J=16.0), 2.10-2.00 (m, 2H), 1.78-1.71(m , 1H),1.30- 1.23(m, 2H), 0.96 (m, 6H), 0.73(septet, 1H, J=3.2). Example (9-48): Preparation (+)-endo-1- Isobutyl-1a,3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa[ajpen-talene-1-° carboxylic acid

H 0 ni 7 OH

H M N

H

For the method mentioned in Example (9 -?) using an alas mixture, then preparing the title compound by the method of the homoisomers mentioned in Example (5-4 1 in step (c).

MS: m/z (ES+): 221 [M+H]", 203 [M-OH]"; 'H NMR (CD;0D): 6 2.94-2.88 (dd, 1H, 01

J=6.7), 2.65 (d, 1H, J=17.5), 2.35-2.24 (m, 2H), 1.63-1 54 (m, 1H), 1.34-1.27(m, 1H), 1.07-0.98(m, 1H) 0.90(d, 3H, J=6.6), 0.84(d, 3H, J=6.6), 0.66 (septet, 1H, J=3.1). Example (9-49): Preparation of (+)-endo-1-Isobutyl-4-(2H-tetrazol-5-yl)1a,3,5 ,Sa-tetrahydro-1H-2,3-di- aza-cyclopropafa]pentalene \o

H

H for 8

N ni I~" N

Ho -NH

Yyasa

111 - Then prepare the title compound in a manner similar to the method mentioned in Example (9-2).

MS: m/z (ES+): 245 [M+H]", 217 [M-N2+H]"; ‘”H NMR (CD;0D): § 2.84 (dd, 1H, 1,=16.5, 1,=6.6), 2.62 (d, 1H, I=16.6), 2.38 (m, 2H), 1.50-1 43 (m, 1H), 1.22-1.18(m,

1H), 1.00-0.94(m, 1H), 0.76(d, 3H, J=6.6), 0.70(d, 3H, J= 6.6), 0.59-0.52(m, 1H).

Example: (4-00) preparation of oe (+)-endo-1-Phenyl-4-(2H-tetrazol-5 -yl)-1a,3,5,5a-tetrahydro-1H-2,3- dia-zocyclopropan[a]pentalene (Z)-Ethyl 5-phenylpent-4-enoate Step 0: Preparation

0 then patches AN) 3-Ethoxycarbonylpropyltriethylphosphonium bromide 4 g; 1700 mmol) and (0) benzaldehyde (1.00 mmol g) potassium t-butoxide (40 6

g 77.06 mmol in 0 (MTBE ml) at room temperature and stirred overnight.

The reaction mixture was washed with (de 001 XY) water, the aqueous phase was extracted with (Je 001 XY) MTBE, and the solvent was removed from the co-organic phase under pressure.

( EtOAc/n-hexane, silica 7101-0 ) Low VO AEH column chromatography oil

to obtain (Z)-ethyl 5-phenylpent-4-enoate as a pale yellow oil.

Pyr NMR (CDCls): 6 7.36-7.31 (m, 2H), 7.28-7.21 (m, 3H), 6.47 (d, 1H, J=11.6, Ph-CH), 5.63 (dt, 1H, J, =11.6, J,=7.2), 4.14 (q, 2H, J=7.2), 2.66 (dq, 2H, J;:=7.3, J,=1.7), 2.43 (t, 2H, J=7.6), 1.24 ) 3H, J=7.1). (E)-ethyl 5-phenylpent-4-enoate JASE containing current (Z)-5-Phenylpent-4-enal Step B: Preparation 0 od (J =o ATT g ) (2 )-Ethyl 5-phenylpent-4-enoate \) DIBAL was raised and . 1 YA - and cooled to Ny under (Je 001 (dichloromethane M for ? VA — mmol) and the reaction mixture was stirred at 0 ml 4 ¢ hexanes molar in ml). The resulting solution (YO) was slowly decanted with excess methanol by adding DIBAL and 0 hours additional hexane was inactivated and 0 (Je £+ +) sodium/potassium tartarate was added in a saturated solution of The mixture was stirred at room temperature overnight. The organic phase (Je 0) was collected.

LX v=) and remove the solvent under reduced pressure. The resulting oil was purified by column chromatography as a pale yellow oil. (Z)-5-phenylpent-4-enal (EtOAc/n-hexane, silica 'H NMR (CDCl): 59.77 (s, 1H) was obtained. 7.36-7.29 (m, 2H), 7.25-7.21 (m, 3H), 6.49 (d, 1H, Vo

J=11.5), 5.62 (dt, 1H, J,=11.6, J,=7.2, Ph-CHCH), 2.70-2.62 (m, 2H), 2.60-2.55 (m, 2H).

(E)-5-phenylpent-4-enal 7/11 contains approximately. (Z)-5-Phenylpent-4-enal )© no gm 1.97 mM (J s— and dibromomethane m aa 1 Yi) 7.10 mmol) in (Je Yo ) THF and cooled down to - 1 VA under 60 (6 T 2) and 1 (molar n-Butyllithium in chexane? to room temperature and stirred overnight.Then the reaction mixture was poured into 201.01 saturated aqueous T+ (ml) and extracted using MIBE (2007 7 ml) and the Cad solvent was removed under reduced pressure. Cad purified the resulting oil with an F-column chromatogram (AR / EtOAc/n-hexane, silica 0) to obtain (Z)-2-(4-Phenylbut-3-enyl)oxirane as a pale yellow oil. . (m, 2H), 7.25-7.19 (m, 3H), 6.47 (d, 1H,J=11.7), 5.68 7.32-7.27 8:(O00) “HNMR (J1=11.6, J,= 7.3),2.97-2.93 (m, 1H), 2.77-2.74 (m, 1H), 2.55-2.52 (m, 1H), 2.53-2.48 (m, 2H), 1.76-1.67 (m, 2H). (E)-2-4-phenylbut-3-enyl)oxirane IA. Step D: Preparation of (+)-endo-6-Phenylbicyclo[3.1.0]hexan-2 -0l : H H "oH Yvaq

- 106 - By step (b). f(Y-1 ) and then prepare the title compound in a manner similar to the method given in Example 'H NMR (CDCls): 8 7.31-7.17 (m, 5H), 4.20 (d, 1H) , J=5.2). 2.20 (t, 1H, J=8.6), 2.13- 2.03 (m, 2H), 1.92-1.79 (m, 2H), 1.78-1.63 (m, 2H), 0.51-0.40 (m, 1H, Ph-CH) . (£)-endo-6Phenylbicyclo[3.1.0Jhexan-2-one Step E: Preparation 1:

H 0 o . (2) The title compound was prepared in a manner similar to that in Example 7-9 1 by step 'H NMR :(YL0020) 8 7.32-7.24 (m, 5H), 2.80 (t, 1H, J=8.6) , 2.45-2.36 (m, 1H), 2.32-2.15 (m, 2H), 2.08-1.82 (m, 2H), 0.98-0.86 (m, 1H, Ph-CH). Step (5): Preparation of (+)-endo-1-Phenyl-4-(2H-tetrazol-5-yl)1a,3,5,5 a-tetrahydro-1H-2,3-diaz- 01 ocyclopropan{a]pentalene

Og "1 T NH

IN

WO7

N—NH. (6-9) For the method mentioned in the example of Alles, the title compound was prepared using a method

_ 7 3 o —

MS: m/z (ES+): 265 [M+H] +, 237 [M-N2+H]; No NMR (CD;0D): § 7.50-6.90 (im, 5H), 3.05-2.96 (dd, 1H, 3216.4, J,=6.3), 2.84-2.76 (m, 1H), 2.76-2.67 (m , 1H), 2.64 (t, 1H, J=8.1), 1.40-1.25 (m, 1H). —- ( tetrazol-5-yl -HY ) a methyl phenoxy - - m ( : preparation 0 — exogenous 0-1 ) eg pentalene. [a] di-aza-cyclopropa =F oY -111- tetrahydro al © «Fad oo Silane. - (oxy 7e-ranyl-pent-?-enyl TO ) - Step 0: -butyl-dimethyl

B50" NF <> 0 in step (a). (Y=9) The title complex was prepared in a manner similar to that in the example '" H NMR (400 MHz, CDCls): 6 5.65 (1H, dt, J= 15.3, 6.2 Hz), 5.57 (1H, dt, J= 15.3, 4.9

Hz), 4.11 (2H, m), 2.91 (1H, m), 2.73 (1H, m), 2.46 (1H, dd, J=5.0,2.7 Hz), 2.19 (2H, \m), 1.61 (2H, m), 0.89 (9H, 5), 0.05 (6H, 5). -methyl (oxy-butyl-dimethyl-silanyl) —t) 717 Step (b): Prepare (£) -external first. -7-hexane [+ 0 «¥] bicyclo

Li

N

1

TBS 0 NI — TBS AA t-BuOMe H OH (mmol) to 114 “Ja©) « molar hexanes in Y,0) n-BuLi by adding LITMP then producing 0 278 - In 800 148 (£01 ml) at TMP (Use 17.5 mVTE g; 17.5 g) a volatile solution of

Yv44

711 - - The light yellow LITMP solution was slowly warmed to 0°C. The LITMP solution was added dropwise to a volatile solution of: 17 p > 01 ( tert-butyl-dimethyl-(5-oxiranyl-pent-2-enyloxy)-silane mmol) in t- BuOMe (Ja Yeo) ° . Then the resulting mixture was stirred at ambient temperature for YA 1 hour and then quenched with 10 (MeOH ml). The reaction mixture was concentrated to a total volume of 300 mL and the solution was dialyzed with 10 110 (saturated aqueous; ¥ 056” mL) then saline (Ja Yoru). The organic layers were dried at 14850, filtered, concentrated and vomited on an EtOAc/70” silica gel column in hexane gradually up to 70 EtOAc in (0 hexane) to obtain the title compound as a light yellow oil. (1H) , d, J = 4.8 Hz), 3.49 (1H, dd, 72 10.8, 6.2 Hz), 4.25 e: give H' NMR (400 MHz, (1H, dd, J = 10.8, 6.4 Hz), 1.93 (1H, m), 1.72 (1H, dd, J= 12.6, 8.1 Hz), 1.57 (1H, 3.44 dd, J= 14.5, 8.4 Hz), 1.38-1.24 (4H, m), 0.89 (9H , s), 0.71 (1H, m), 0.04 (6H, s). Step (c): Preparation: +-.)-ex0-6-(tert-Butyl-dimethyl-silanyloxymethyl)-bicyclo [3.1. 0]hexan-2-one Vo ( H H TPAP, NMO ~~ TBSO —— > TBSO 4A MS, CH,Cl, H OH H 0 then TPAP added) a 0 g « Y 0, » mmol) to a volatile solution of YYaq

V, 5( (.+-.)-exo-6-(tert-Butyl-dimethyl-silanyloxymethyl)-bicyclo[3.1.0Jhexan-2- -ol g;0"mmol) Y,8 ) NMOS g; 707 mmol (£5 angstroms MS (¥ g) in CHCl (Ja 0 +) at ambient temperature. The mixture was stirred for − hours, filtered through celite, and poured over silica gel and filtered using CHCl ERO (1:1 ratio).

0 organic solvent in vacuo to obtain the title compound. ° NMR (400 MHz, CDCl3): & 3.69 (1H, dd, J= 10.8, 4.8 Hz), 3.58 (1H, dd, J= 10.8, 5.3) Hz), 2.15 (1H, m), 2.05 (4H, m), 1.72 (1H, m), 1.51 (1H, m), 0.87 (9H, s), 0.04 (6H, 59)

Step (d): Prepare (.+-.)-exo-1-Hydroxymethyl-1a-3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a- 01 |pentalene-4 -carboxylic acid ethyl ester 0 OEt 0 SOG D H 0 KOr-Bu, EtOH 08 H yi TBSO = "NH H,NNH, HCI HO =) ) 2 0 3 A solution of Kot-Bu in 011 THF (THF 1 M 01101 mmol) was added to CAN 7,7 (Ketone 9.7 mmol) 0,7© ( diethyl oxalate s g; 9.7 mmol) in (Je YO) 20011 ho at room temperature below Np and the reaction mixture was stirred for ; hours Dla hydrazine hydrochloride (207,©) was added g; 11 mmol) at 11:0); (Je and Tm

-YVA-

PH hours at room temperature and acidified to a pH of 0 The reaction mixture was stirred for a period The volatile substances were removed in vacuum and 0 N) 1 (aqueous HCl about ?) was diluted by adding the resulting solid using 6C20 (+0 mil) and 11.0 (04 mil). The layers were separated, and the joint organic layers were re-washed with EtOAc using SL phase extraction: brine, dried at +1850, filtered, and concentrated to obtain the title compound. The compound 0 was used directly in the following reaction without further purification. ,5.9

Hz), 3.28 (1H, dd, J= 11.4, 6.8 Hz), 2.84 (1H, dd, l 16.9, 6.2 Hz), 2.69 (1H, d, J = 16.9 Hz), 2.05 (2H, m) , 1.26 3H, t,J 7.1 Hz), 0.78 (1H, m). CLCN size/10 mm); : 0 (contains TFA 1) volume (contains

ESI = «Aida = 1.04, min; [Ja ©,5 11:0 increments up to 749 11:01 volume/volume in .223.2 M +H) : Step E: Preparation-1 Hydroxymethyl-1a-2,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pentalene-- 4- \o carboxylic acid amide 0 0

OEt NH,

HO N dioxane HO N

H H

Z "4

-901? - NH; added; ZX A) ammonium hydroxide in (Je 5060 (HO) to ester solution (0.1 g; 77.1 mmol) in 0 (Ja As ) dioxane and the mixture was placed in a 52.20 mL Brix flask and stirred. on the gain device plate for YY hours at room temperature. The mixture was concentrated in vacuo to a total volume of 100 ml in which the light yellow precipitate was evident. 0 The mixture was filtered and the solid was washed with HO and further drying of the solid resulted in obtaining the title compound as a white solid. The compound was then used in the immediate following reaction without further purification. 'H NMR (400 MHz, 0180-20: 8 7.29 (1H, bs), 7.12 (1H, s), 4.62 (1H, bs), 3.39 (1H, dd, J=11.4, 6.0 Hz), 3.28 (1H, dd, J = 16.4, 5.3 Hz), 2.82 (1H, dd, J = 16.4, 5.3 Hz), (1H, d, J = 17.8), 2.03 (2H, m), 1.75 (1H , 5), 0.76 (1H, m).1 2.73: 018 Alltech® Prevail (© Alltech® Prevail) 2.73 MS/HPLC; (pa 4.7 7 80 and 15 11.011 [ana] vol (containing TFA 7V vol/v) at 11:0 (containing 174 7 vol/v) stepping up to 799 011:01 vol/v In [Je ¥,0 (HO min; f = 1.54 min = ESI * M + H) 194.0.Vo Step (f): Prepare: (+)-ex0- 2-Benzyl-1-hydroxymethyl-1a-2,5, 5a-tetrahydro-1H-2,3-diaza-cyc-lopropa[a]pentalene-4-carboxylic acid amide

—- YY. - 0 0

NH, Wal | L BnBr, NaCH, 1 l ’ —_— /

HO N dioxane HO “OO

H

H

ml; benzyl bromide 4c sie mmol On wl, the reaction mixture was slowly stirred for 1 hr at room temperature. The mixture was acidified 0 to approximately Y pH by adding HCL (aqueous; +N) and concentrated to dryness in vacuum. The resulting residue was dissolved in 110/82 and washed with NaHCO; (aqueous; saturated” 00 (Je 0 ( HO (Je)) and the residue was purified on a t+ column silica gel EtOAc in <hexane gradually EtOAc Ive ia in (hexane to get . benzyl ic sana processor output: 'H NMR (400 MHz, CDCly): 8 7.38 (3H, m), 7.26 (2H, m), 6.64 (1H, bs) ), 5.30 (1H, d, 0-00

J = 15.0 Hz), 5.23 (1H, d, J = 15.0 Hz), 3.55 (1H, m), 3.19 (1H, m), 2.96 (1H, dd, J = 16.6, 6.2 Hz), 2.88 (1H, d, J = 16.6 Hz), 2.07 (1H, m), 1.76 (1H, m), 1.05 (1H, bs), 0.90 (1H, m). CH3CN 70g vol/mm) £1 X00 (5 Se 0) Alltech® Prevail 018 age: MS/HPLC fran TFA 71 vol/v) in 11:0 (contains TFA 71 volume (contains 10 = 1817 min) last minute [Ja 0 volume/volume in WBL CH;CN 744 increments up to .284.2 M + H)

Step (g): Prepare: (+)-ex0-2-Benzyl-1-chloromethyl-1a-2,5,5a-tetrahydro-1H-2,3-diaza-cycl-opropala]pentalene-4- carbonitrile 0 N

NH, 77

H soc H | A N

HO N DMF cl N 1 of 0 (a) and Asie (; ml) under an atmosphere of 11 to 0 °C SY DMF a flask filled with mmol was cooled. And after flipping for © minutes; 01.7 ce +, YY) thionyl chloride was dripped by adding ml). DMF (4 g) was slowly warmed in 1 (Use 7.5 mL) amide dropwise; a suspension of 01 mL (saturated aqueous NaHCO; 1 h) was added to the mixture. to room temperature for minutes and concentrated until close to Ye and then stirred the mixture for (Ja 1 5 (H,O followed by ml). Yo) and 11:0 (Jo 71) were separated (EtOAc dehydration in vacuum. The rest was diluted with 0 ml). The layers were washed (01 ml) aqueous EtOAc (using shall extraction) and the layers were ve) then brine ( Je "0 saturated; ik) NaHCO; co-organic acid was dried at 14850, filtered and concentrated to obtain the title compound as brown oil. It was carried out directly without further purification. Sal. The compound was used in the reaction" HNMR (400 MHz). , CDCl): 6 7.38 (3H, m), 7.31 (2H, m), 5.30 (1H, d, J = 14.8), 5.26 Vo (IH, d, J =14.8 Hz), 3.47 (1H, dd, J = 11.4, 6.6 Hz), 3.22 (1H, dd, J = 11 4, 8.1 Hz),

YYaq

- YYY - 2.89 (111). Rather, J has 16.5, 64 Hz), 2.79 (1H, d, J = 16.5 Hz), 2.20 (1H, m), 1.92 (1H, m), 1.09 (1H, m). CH3CN 705 mm/size (4.1 X 0 + µm) Alltech® Prevail C18 Column: MS/HPLC (TRA 71 size/size) in 11: 0 (contains TEA 71 vol (contains -- 8581 = AE YY - min; , a [de ¥,0 (HHO) vol/vol in CH3CN 799 scales up to 0.284.4 (M) + H) Step H: Prepare: (#)-ex0-2-Benzyl-1-phenoxymethyl-1a-2,5,5a-tetrahydro-1H-2,3-diaza-cyc-lopropafa]pentalene -4-carbonitrile 7 7 50h PhOH, K,CO3 CL rh 0 N DMF, A 0 N nD n=O

Ve dissolved 0.07 can +, Tee (nitrile mmol) and +,V£1) phenol g; 1.0 mmol) KoCOs g; ¥ mmol) in (de 1) DMF and the reaction vessel was sealed and heated in a microwave reactor to 171 °C for 0 min. After cooling to ambient temperature; The reaction mixture was raised in ethyl acetate, washed once with ele and once more with brine 1, dried at 14850, and concentrated in vacuum. The resulting residue was purified by reverse phase of [16M1]: YY44

- YY - size/CH3CN 70 mm) E; and 4.1 X 90 “5 Sua © Alltech® Prevail 018 Column MS/HPLC: TFA 71 volume/volume) in 11:0 (contains TFA 711 volume/volume) on

ESI = HM min [de M «H,0] gradually up to 744 tv/v in 342.3 (M+11) .: Step (i): Prepare oo (+)-ex0- 2-Benzyl-1-phenoxymethyl-4-(2H-tetrazol-5-yl)1a,2,5,5a-tetrahy-dro-1H-2,3- diaza-cyclopropala]pentalene

H

N is a solution to N / | B N NaNgz, ZnBr H

DTH mem with 0 N DMF, A 0 N

H — ) H a ) then dissolved Y 0 ) nitrile and 0 g ; 0 AA mmol) 5’ p > v, 6 ) ZnBr; solution, 1 mmol) YEO) NaN3y 0, + g; 5.71 mmol) in DMF (© ml). The reaction vessel was sealed and heated in a microwave Jolie to 190°C for 1 minute. After cooling to ambient temperature; The reaction mixture was acidified by adding HCl (aqueous YO standard) and reverse-phase purified by HPLC on a 01 018 column (Phenomex® Luna μ X YOu 17 mm) 75 CH3CN (vol/v) ( containing \\ TFA vol/yo) in 110 (containing 7) TFA vol/yo vol) gradually up to m [Ja 01 HO min; ) = 710 nmol to obtain the title compound as a white solid after freeze-drying.

7-75 - :MS/HPLC on an Alltech® Prevail C18 column (© Microwave © 517 mm) 705 011:01 volume/volume (contains TFA /1 volume/volume) in H0 (contains on TFA 21 vol/v) incrementally up to 749 011:01 vol/v in [da 3.5 (HO min” Ba - VV) min - “zn M +H) 384.9. #0 step (j): -Phenoxymethyl-4-(2H-tetrazol-3 -yl)-1a,2,5,5a-tetrahydro- 1H-2- ,3-diaza-0-1"" p-() cyclopropafa]pentalene NOON NON a sa H N\ - H KOt-BW/THF CL Bl l © N DMSO, Air 0 N 0 LO x Then air bubbles come out of through a volatile solution of the protected compound (YOu 6 g 0 Vv q mm 0 mol) and 120 130 (£ mL) of a 1 M solution in (THF; mmol) in 101 150 (£ sal (Je) 2 hours at room temperature 0 and the remaining THE was extracted in vacuo and the reaction mixture was diluted with (Jo Y+) EtOAc and 1120 Yo (mL). The layers were separated, the organic layer was washed with brine, dried at 50p11, concentrated and purified using reversed phase tHPLC on a Phenomenex® Luna C18 micro 6 198 (ae 707 X 10 CHCN 1) 01 column (vol/v). ) (containing TFA IN vol/v) in 11.0 (containing) 7 TFA vol/v) gradually up to YVE = A (438) [Je 01 H,0 JAY nmol] to obtain the title compound as White solid & after freeze drying .yyaa

— Y Y > — 'H NMR (400 MHz, DMSO-d): & 7.28 (2H, m), 6.94 (3H, m), 4.06 (1 H, dd, 1 10.5, 6.1 Hz), 3.83 (1H,dd , T= 10.4, 7.9 Hz), 2.98 (1H, d, J = 16.3,6.1 Hz), 2.88 (1H, d, J = 16.6 Hz), 2.40 (1H, m), 2.34 (1H, m), 1.21 (1H, m). vol/CH;CN lo (pe 4.1 X 80 μm 5) (Alltech® Prevail 018 age: MS/HPLC [volume]: TFA 11 vol/v) in 11:0 (contains on TFA (1 vol) contains 2 min A = 1.8 min = zw [Je 3.58 11:0 vol in [pas CHCN 79549] gradually up to .295.4 (M +H) (oY -4) Example: Preparation 1-abtaa:2<0-1-1/100-() a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropala- Jpentalene - 01 4-carboxylic acid : Step 0(: Preparation of (£)-exo0-2-Benzyl-1 -hydroxymethyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyc-lopropala ]pentalene-4-carboxylic acid ethyl ester 0 0 0 4 BnBr, NaOH H | \ 0

HO GO dioxane HO N

H H + )

H

\o

-71?? mL) and diluted [0] DMF g was added; 75 mmol) in V,0 ester (mmol) has been dissolved. 0111 g; V,V¥) benzyl bromide followed by (Use 1.59 mM; 1A t) h was done at room temperature. And then dilute the mixture using Ve stirring the reaction mixture for a period of . And washing it with water, then a saline solution, drying it at 14850, and concentrating it to dryness in chicks.‎ 06

Ivo gradually until hexane in EtOAc /06( silica gel) left on a column aan and 0 was finished as a white solid. benzyl to obtain the treated product with hexane in EtOAc 'H NMR (400 MHz, CDCl): 8 7.38 3H, m), 7.30 (2H, m), 5.42 (1H, d, J = 1 49 Hz), 529 (1H, d, J= 14.9 Hz), 4.36 (2H, q, J=7.1Hz),3.14 (1H, m), 2.91 (1H, d, J= 16.7, 6.3 Hz), 2.82 (1H, d, J = 16.7 Hz), 2.03 (1H, m), 1.67 (1H, m), 1.37 GH, t, J=17.1Hz), v/v 10.85 (1H, m). HPLC/MS: Alltech® Prevail C18 column (5p, 50 x 6 mm), 5 01 viv TFA) gradient to 99 / v/v TFA) in HO (containing 1 / .CH3CN (containing 1

CH;CN in H,0, 3.5 mL/min, #; = 1 min, ESI" = 313.2 (M + H). Step (b): Preparation of: z-methoxymethyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyc-71 1 2*0-2-3072-() lopropa[a]pentalene-4-carboxylic acid ethyl ester \o 0 0

OEt OEt m NaH, Mel xh

HO N DMF So N

LO NA

YVV - - NaH (VAT dispersion of G?Vs mmol) at 0 °C below Ny was added to an alcohol solution (8 g; 11 mmol) in (Je©) DMF and the mixture was stirred for 0 minutes and 0.179 (0 Mel g; VY mmol) was added. The reaction mixture was stirred at ambient temperature for Ye hours and quenched with water. The mixture was extracted with (XY) EtOAc (01 0 ml) and the organic co-layers were washed with water (0 ml), dried over MgSO, and concentrated in vacuo. The remainder was purified on a silica gel column; With EtOAc 'hexane eluting' (by q) to obtain the title compound. MS/HPLC: 018 age Alltech® Prevail (© micro 06 7 1 gma £0 011.0 v/v) contains 178.71 vol/v) in 11:0 (contains 1 TFA [vol] volume) 0 scale up to 799 011:01 [volume pas in [Je ¥,0 (HO min.; = 1,16 ESI" = (Aida M + H) 327.4 Step (c): Prepare: (+)-exo-1-Methoxymethyl-1a,3,5,Sa-tetrahydro-1H-2, 3 -diaza-cyclopropala- Jpentalene- 4-carboxylic acid 0 9 OEt OH xr KOt-B THF xT ~o0 N DMSO, Air ~o > Then air bubbles escape through a volatile solution of TY ca vue Ve ester mmol) Y,Y) KOt-Bus ml of a 1 M solution of YoY (THF mmol) in (Ja Y,0) DMSO for

in vacuum and then acidify the THF mixture for an hour at room temperature. The remainder was extracted from the | column molar HPLC) and reverse-phase purification of Y (aqueous HCl reaction by adding (vol/vol) CHCN 105 (ama 70.7 X YOu 01 µM (Phenomex”® Luna C18 vol) gradually [a> TFA 7 (containing H,O vol/vol) in TFA 7) (containing nanomoles for the title compound as solid 1 = A (Ad) ml/Ye. w / q¢ to ° white after freeze-drying. Lira NMR (400 MHz, DMSO-de): 6 13 0 (1H, bs), 3.31 (1H, dd, J= 16.7, 6.4 Hz) , 3.24 (3H, s), 3.22 (1H, dd, J = 10.5, 7.2 Hz), 2.84 (1H, dd, J = 16.9, 6.2 Hz), 2.69 (1H, d,J= 14.8 Hz), 2.09 ( 1H, m), 2.04 (1H, m), 0.84 (1H, m). Size/CH3CN 105 mm (5.1 X 90 µm) Alltech® Prevail 018 with tMS/HPLC shaft 0 vol/vol) TFA A vol/vol) in 10 (contains 1 vol TFA (contains 817 = min = 0.76 t, min; [Je ¥,0 (HO) Volume/volume in CHCN 799 scaled up to .208.9 (M + H): Example (57-9): Preparation of (1aR,5aR-(+)-4-(2H-Tetrazol-5 -yl) -1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclo- yo propa[a]pentalene - “NH 0 a =N 1 1 1. DMF, K-OtBu, 2.2 eq + 2 Na e (1 7 m 7 no 2. 2N HCI, 3 eq NH

N=N H,NNH,, 1.15 eq S.N

H H

1eq 1eq

Procedure: Ketone was then dissolved in DMF and then Tetrazole was added to the solution. The resulting suspension was cooled to zero degrees Asie and a solution of Potassium-t-Butoxide at 7 was slowly added to the mixture and the temperature was kept below 10°C. The mixture was stirred at 0 °C for an hour. HCI titer was then slowly added; followed by the addition of 0 ( hydrazine Ang ) kan hydrazine hydrates 0 and the reaction mixture was allowed to warm to room temperature overnight. Work: DMF was removed, the residue was split with water, and extracted (V times) with 506. The organic layer was dried at 14,880 µm, filtered, and concentrated in vacuum. The crude product was purified on a 7101(atwit + 1 + ela Vo (TFA Z+,) 0 12 wavelength = YO nm) column (run for 10 minutes). Separation of the isomers on SFC (Yu X YY AS) mm) (TFA 20.1 + MeOH 10) and re-purification on an inverted sh column (TFA 1.1 + CH;CN ZY0) no water + L (TFA wavelength = 7766 nm) (01 min run) to remove yellow color 0 The white solid was dissolved in hot water and allowed to crystallize to provide pure white/colourless crystals. vo Example (94 -9): Preparation: (+)-endo-1-methyl-1a,2,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropalajpentalen- e-4- carboxylic acid and exo-1- methyl-1 a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentale-4-car-boxylic acid

— Step 0: Preparation of (R)-5-(chloromethyl)tetrahydrofuran-2-ol O° DIBAL-H HO Xe —_— “a In Vo min 1( diisobutylaluminum) was added hydride molar IY) Je 11 ; 1 “DCM mmol) to a solution of £4,Y an 1.19) (R)-5-(chloromethylihydrofuran-2(3H)-one ° mM (Joe) See Movassaghi, M.; Jacobsen , E.

N.

J.

Am.

Chem.

Soc. 2002, 124, 245 for 0 for preparation) (in 0 DCM (saturated aqueous ml) and the mixture was stirred for 1 hour while heating to room temperature. The organic phase was removed and the aqueous phase was extracted using EtOAc (twice). Drying of the organic co-layers on 148807 and filtration a 3S to yield (R)-5-(chloromethyl)tetrahydrofuran-2-ol (1 5 g; FAY mVe mole by cu product) (clear FAN (1 1),Y0) 'H NMR (400 Miz, CDCl): Major epimer: 5 5.62 (1H, m), 4.48 (1H, dq, /=7.6, 5.6 Hz) ), 3.67 (1H, dd, J=10.8,5.6 Hz), 3.61 (1H, dd, J=11.2,6.0 Hz), 2.65 (1H, m), 2.24 (1H, dq, J= 12.4, 8.0 Hz), 2.10-1.72 (3H, m). Minor epimer: § 5.30 (1H, m), 4.29 (1H, m), 3.53 (2H, m), 2.65 (1H, m), 2.10-1.72 (4H, m). 1 step (b) ) : preparation of cis/trans-(R)-2-(pent-3-enyl)oxirane [PhsPEt]* Br 9 GAP LIHMDS, THF * 0 PN Me” >

mmol) to 00 Je Yo) THF Molar 1 lithiumbis(trimethylsilyl)amide added

Vo) 1115 mmol) in YO (No 8 g; ethyl triphenylphosphonium bromide suspended from: at 0 °C. The solution was reduced for half an hour during which (Je mol) at 0 °C was added EPR ARETE ( (R)-5-(chloromethyl)tetrahydrofuran-2-ol and then allow the resulting solution to warm to room temperature 0 mL) Vo THF e as a solution in ¢ (twice) Et, O and extracted with HO and stirred overnight. The mixture was quenched using (71) silica gel, filtered and concentrated. The mixture was purified by MgSO4 chromatography and dried on: to obtain (pentane in EO fo gradually up to pentane in 0 = cis:trans) olefin isomers binder oil; As unseparated mixture « (R)-2-(pent-3-enyl)oxirane .() X,Y. Tra NMR (400 MHz, CDCl): §5.55-5.26 (2H, m), 2.93 (1H, m), 2.76 (1H, m), 2.49 (from cis isomer, 0.711 , dd, J= 6.0, 2.8 Hz), 2.48 (from trans isomer, 0.3H, dd, J=6.0, 2.8 Hz), 2.21 (from cis isomer, 1 4H, q, J = 7.6 Hz), 2.14 (from trans isomer, 0.6H, m) , 1.67-1.56 (SH, m). Step 1: Preparation iz) 0 S,2S,5R,6S)-6-methylbicyclo[3 .1.0]hexan-2-ol and (1S,2S,5R,6R)-6- methylbicyclo[3.1 .0]hexan-2-ol

- M 7 Me 0 H H Yeh Ha LITMP Me 2 + b Meith the — + a Me” SS H oH HOH Treatment was carried out with a group of cyclopropane Jala compound molecules ( R)-2-(pent-3-enyl)oxirane A ) the sum of AVE mmol) as previously described in Example (1-4); by step (a) to obtain: $,2S ,5R,68)-6-methylbicyclo[3 .1.0]hexan-2-ol and (1S,2S,5R,6R)-6-6 ° 0 methylbicyclo[3.1.0]hexan-2-ol As a mixture not separated after silica gel chromatography. 'H NMR (400 MHz, CDCl3): 84.15 (1H, d,J= 4.8 Hz), 2.08 (1H, m), 1.75-1.25 (5H, m), 0.90 (SH, m). (S,28,5R,6S)-6-methylbicyclo[3.1O]hexan-2-ol 00 1(NMR (400 MHz, CDCl): 84.21 (1H,d,J= 4.8 Hz), 1.88 (1H) , m), 1.75-1.25 (4H, { ' m), 1.15 (1H, m), 1.07 (1H, m), 0.96 3H, d, J=6.0 Hz), 0.41 (1H, m). Step (d): Prepare .(1S,5R)-6-methylbicyclo[3.1.0]hexan-2-one b cat.

TPAP, NMO [E]Lepsis Me Me 4A MS, DCM <2 2< NH oH H YY44

¥YY - - oxidation was performed for the compound: 2S,5R,68)-6-methylbicyclo[3.1 .0Thexan-2-ol/(1S.2S,5R,6R)-6-methylbicy- 18( clof3.1.0]hexan-2-ol qo A) mg; and mmol) as previously described in example (0-8) by step (b) to obtain S,5R)-6-methylbicyclo[3.1.0]hexan-2-one 1). The spectral data was similar to that of (#)-(18,5R)-6-methylbicyclo{3.1 .0]hexan-2-one (as described above). Step (e): Prepare: (1R,1aR,5aS)-1-methyl-1a,2,5,5a-tetrahydro- 1H-2,3-diaza-cyclopropa[a]pent-alene-4- carboxylic acid ethyl ester and (1 S,1aR,5aS)-1-methyl-1 a,2,5,5a-tetrahydro-1H-2,3- diaza-cyclopropa[a]pent-alene-4-carboxylic acid ethyl ester Vo 0 o H E OEt M Ww / " OEt H 1 EO e yy H 0 0 + E —_ ) | Me Vv b KOt-Bu/THF H 08 7 Hin H,NNHy HCI, 2 0 ) N "m Me O H Preparation of the inner derivative — methyl pyrazole and the outer derivative — pure isomer methyl pyrazole was carried out as above Described in example (0-9 1 in step (2) (for the racemic variables) 0 and separation of the isomers was performed using HPLC with inverted sh: with a Phenomenex® Luna C18 column 01) ne microh 001 X You mm) and 75 CHSON (size/size) (contains 7 Joan TFA)

TE - - volume) in HO (containing) 1 vol/vol TFA gradually up to HO 7506 10 mL/min; and Yot = .3 nm to obtain methyl pyrazole inner followed by methyl pyrazole outer 0 Step F: Prepare: (1R,1aR,5aS)-1-methyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza- cyclopropala]pent-alene-4- ° carboxylic acid 0 0 H H LiOH/H,0, dioxane J { OH 084 { Met" N 7 Me" HN HN Hydrolysis of ester, as previously shown in the example (q) to obtain the corresponding acid (MeOH), 0.524 (67.6 + [0]), and the spectral data was similar to the tracer material. 0 Step (g): Prepare (18,1aR,5aS)-methyl-1a,2,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropa[a]pental-ene-4- carboxylic acid 0 0 H H J 1 08 LIOH/H,0, dioxane 1 \ OH Me N ' N Me N 7 N H H H H The ester hydrolysis was carried out as previously explained in Example (4-7) to obtain the corresponding acid vo. The spectral data was similar to the sasmatic material.

- YYo - preparation: (c0-1) eg (-)-endo-1-methyl-1a,2,5,5 a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pentalen - e-4- carboxylic acid and exo-1 -methyl-1a,2,5,5a-tetrahydro- 1H-2,3-diaza- cyclopropa[a]pentalene-4-c- arboxylic acid 0 : 0

H, . H, 1 1 OH 1 1 OH

Me 3 AM Me™ 3 NY

H H H H) and then prepare the previous compounds as pure isoforms by the synthetic method similar to the previously mentioned method as a starter (see: (S)-5-(chloromethyl)dihydrofuran-2(3H)-one as the starting lactone and it was 0 for preparation) Movassaghi, M.; Jacobsen, E.N.J.Am. Chem. Soc. 2002, 124, 245 [a]*'p — 93.0 ( 0.552, MeOH): endogenous - methyl Rotation data for compound ve: Example (1-01): preparation of endogenous acid 1-ethyl-1a,2 ,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropafa]pentalene-4-c- arboxylic acid and exo-1-ethyl-1a,2,5,5a-tetrahydro-1H-2,3 -diaza- cyclopropa[a]pentalene-4-ca-rboxylic acid

Yyaq

7 71 - Step 0 (: Preparation: (R)-4-(hex-3-ynyl)-2,2-dimethyl-1 J3-dioxolane Me Co Me Me Me but 0 ok Me Li —==— AAP DMPU, THF rand Me 2-butyne gas was added to a beaker cooled to = 8 Lm under Ny via a syringe needle until approximately ¾ ml of liquid had condensed in the beaker. Then VY + THF (ml) followed by YO cde 1 (DMPU mmol) 0 was added and the flask was purified with 112 and n-Butyllithium (*,7 M 5 > “Ja”) was added. YAY (£18 mmol) via a syringe over 10 minutes and stirred for an additional 0 minutes during which: YA) cpa (0) (R)-4-(2-iodoethyl)-2,2-dimethyl-1 , was added. 3-dioxolane mmol) as a solution in A (Je Y'+) THF Preparation procedure for the pure isoforms: (R)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane yo From: (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol commercially available using the method described by: [Taber.

D.

F.; Xu, M.; Hartnett, J.

C.

J Am.

Chem.

Soc. The reaction mixture was slowly warmed to room temperature and stirred for a total time of ? hours. The mixture was quenched with saturated NHAC and extracted with BO (twice). The organic 1c layers were washed with THO, then brine, dried at 14850, filtered, and concentrated. The material was purified by chromatography (EtOAc / ©) silica gel at 5 increments until EtOAc 711 in hexanes) to obtain:

- Ala - as a clear oil. (R)-4-(hex-3 -ynyl)-2,2-dimethyl-1,3-dioxolane 'H NMR (400 MHz, CDCl3): 84.19 (1H, m ), 4.08 (1H, dd, J = 8.0, 6.0 Hz), 3.58 (1H, dd, J= 7.6, 6.8 Hz), 2.26 (2H, m), 2.15 2H, qt, 7 4 Hz), 1.81 (1H , m), 1.68 (1H, m), 1.40 (3H, s), 1.36 3H, s), 1.11 GH, t,J=7.6 Hz). (R,Z)-4-(hex-3-enyl)-2,2-dimethyl-1,3-dioxolane Step B: Preparation 0

Me 9 for Me Me 0 00/5850 for Me —_— 0

A quinoline PLY

Me =

Me 76 palladium was added to V, (£) BaSO4 g) and quinoline (freshly distilled from a waste of 171 ml Zn 0.9 mmol). The flasks were then sterilized with Hy and stirred under 11.0 °C for 2 h. The reaction mixture was filtered through celite, washed sequentially with 1 1101 0 N (twice) and then brine. The organic layers were dried on 148507, filtered, and concentrated to alcohol (R,Z)-4-(hex-3-eny})-2,2-dimethyl-1 3-dioxolane which was used without further purification. This material contained approximately IY of the trans olefin isomer that was carried through the synthesis method as a mixture (data not shown due to the smallness of the isomer) finally yielding the corresponding endogenous acid-ethyl pyrazole derivative after separation using HPLC. Inverted phase (cf. Catch) Vo

- YYA- YRA NMR (400 MHz, 0: 5 5.40 (1H, m), 5.31 (1H, m), 4.06 (2H, m), 3.52 (1H, t, J - 4.8 Hz), 2.09 (4H) , m), 1.71 (1H, m), 1.54 (1H, m), 1.41 3H, 5), 1.35 3H, 5), 0.96 GH, t, J = Hz). (R,Z)-oct-5-ene-1,2-diol Step C: Preparation

Me o—kMe AcOH OH

Me m 0 mmol) in YY, T pa 0, 0) (R,Z)-4-(hex-3-enyl)-2,2-dimethyl-1,3-dioxolane was reduced hour. The mixture was concentrated in vacuo and purified 01 for (Ja 0 +) aqueous ACOH 0 in EtOAc 7/970 at 58 degrees until EtOAc /46 (silica gel) by clear chromatography. cu XS ( R,Z)-oct-5-ene-1 2-diol) for hexanes' H NMR (400 MHz, CDCl3): 85 45 (1H, m), 5.36 (1H, m), 3.75 (1H , m), 3.67 (1H, dd, 01

J=10.8,2.8 Hz), 3.45 (111, 0l J= 11.2, 7.6 Hz), 2.16 (2H, m), 2.04 (2H, m), 1.50 (2H, m), 0.96 (3H, t , J = 7.6 Hz). (R,Z)-2-(hex-3-enyl)oxirane Step (d): Preparation

OH Tristem, NaH 0 ce NOH —_— > M ce

Me 8 g V0) dispersed in mineral oil » 1.05 g; 1107 mmol (774) NaH was added

mmol THF (in OMA aa AO ) (R,Z)-oct-5-ene-1,2-diol as a dispersant) to a solution of

- Yre - ml) at zero degrees Celsius. The mixture was warmed to ambient temperature and stirred for (YF): min. The reaction mixture was cooled to 0 °C and 0 mmol was added. A mixture of 108 g; (YY) triisopropylbenzenesulfonyl chloride reaction was warmed to room temperature, stirred for 1 hour, quenched with 11.0, extracted with 10880, and the organic layers were washed with brine and dried over ERO using © pentane at 0 /7 (silica gel A and chromatography) and its filtration and concentration. It led -(R,Z)-2-(hex-3-enyl)oxirane to obtain pentane in 0 IA gradually until an isotropic increase to 784 (increase ZA) determination That a slight formality occurred at this formalism step). to ensure optical purity; The morphologically rich product was also separated using the separation in step e). Jacobsen's (HKR) hydrolysis kinetics of 0' H NMR (400 MHz, CDCl3): 65.41 (1H, m), 5.35 (1H, m) , 2.93 (1H, m), 2.75 (1H, dd, l 52, 4.4 Hz), 2.49 (1H, dd, J = 5.2, 2.8 Hz), 2.20 (2H, q, J = 6.8 Hz), 2.06 (2H, quin, 7.6 Hz), 1.59 (2H, m), 0.97 BH, t, J = 7.6 Hz). (R,Z)-2-(hex-3-enyljoxirane) Step E: Prepare ee ~~ cat. (R.R)-Co-Salen ee ~~]

Me —= —_— <LAAAAAAA_ Me b 849/6 ge 20, (0.18 equiv.) 598% ee

AcOH/THF \o (1+) ACOH 5 mmol) +,Y£A (aaa 101) (RR) - Co - Salen Catalyst added sequentially to a beaker containing (Use mM ITY came 11 ( FRO mmol) 0001 mg;

— (R,Z)-2-(hex-3-enyl)oxirane isotropically rich (4 g 0 mmol) 5 THF (m (Ja) at 0 °C. Then heating The mixture was brought to room temperature and stirred for 1 h. Aan chromatography EO 77 (silica gel in goth pentane) to EO 701 in pentane (Aan) yielded R,Z)-2-(hex-3-enyl)oxirane is conformationally pure.© step (j): (18,28,5R,68)-6-ethylbicyclo[3,1 Olhexan-2-ol H. LITMP 0 EE Me = Me Hon entry made for the Jala cyclopropanation group (R,Z)-2-(hex-3-enyl)oxirane )¥ g; 77 ,8 mmol) as previously described in Example (1-9); step (a) to obtain: S,2S,5R,68)-6-¢thylbicyclo[3.1 .0]hexan-2-ol 1) As a clear oil. 'H NMR (400 MHz, CDCl): 84.18 (1H, m), 2.08 (1H, m), 1.79-1.51 (4H, m), 1.40 01 (2H, m), 1.20 (2H, m), 096 (3H, t, J = 7.6 Hz), 0.74 (1H, m). Step (g): Preparation of .(18,5R,68)-6-ethylbicyclo[3.1.0]hexan-2 -one H H b cat.

TPAP, NMO i.5 / — 2 Me 4 4A MS, DCM Mew 4 OH 0 Oxidation was performed to (aa ),V0) (15,28,5R.65)-6-ethylbicyclo[3.1 .0Jhexan-2-0] 15.1 mmol) as previously described in Example (1-49); step (b) to obtain:

Clear oil. The spectral data were similar for (1S,5R,68)-6-ethyl-bicyclo[3.1.0}hexan-2-one .(#)~(18,5R,68)-6-ethylbicyclo[3.1.0] hexan-2-one of the compound: Step (h): preparation of (1R,1aR,5aS)-1-ethyl-1a,2,5, Sa-tetrahydro-1H-2,3-diaza-cyclopropala] penta-lene-4-carboxylic acid ° 0

OEt

H 1 Swg 1 0 m pn °° J / 1 0 H ve” KOt-BuTHF AN N

H 0 M Ho a (2) H,NNH, HCI, 0 e H 3) LIOH/H,0, dioxane Corresponding to the morphologically pure ketone method of ethyl pyrazole - preparation of the racemic internal derivative was carried out In example (08-1) with the two steps (e) ethyl pyrazole identical to the inner compound method and the spectral data were the same. 0 and (f): Step (i): Preparation of 0 (1S,1aR, 5aS)-1-ethyl-1a,2,5,5a-tetrahydro-1 H-2,3-diaza-cyclopropala]penta-lene-4-carboxylic acid 0

H

Oh

\

LN

Me H N

A conformationally pure exogenous ethyl pyrazole derivative was isolated by reversed-phase HPLC as trace impurities from the previous synthesis method. Example (897-49): Preparation: (£)-endo-1 -methylsulfanylmethyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cycl-opropa[a]pentalene-4 -carboxylic acid °‏ Step 0(: Preparation: .(+)-endo-spiro[bicyclo[3.1 .O]hexane-2,2'-[1,3]dioxolane]-ylmethyl methanesulfonate H H Jin MsCl, EtsN yim HO Rk 0 MsO 5 0 for “” + BN (71© 71 μl 5.11 mM (Use) was added to a solution of: pre Yo.) (+)-endo- spiro[bicyclo[3.1 .OJhexane-2,2'-[1 ,3]dioxolane}-6-ylmethanol 0 7 mmol) in (JsYY) DCM under Np and the flask was cooled to 0°C and Add dropwise (YY A) methanesulfonyl chloride μl 410 mmol). And after stirring for © minutes; Then the flask was warmed to room temperature and stirred for 1 hour (the reaction was nearly completed by 0 (TLC), the DCM was evaporated, the mixture was quenched with HO, the mixture was extracted with EtOAc (twice) and the mixture was dried Abstracts shared on 101650, filtered and concentrated to obtain: YYaa

vey - - (+)-(1R,5R,6S)-spiro[bicyclol3. 1.0]hexane-2,2'-[1 ,3]dioxolane]-6-ylmethyl methanesulfonate Hz), 4.34 (1H, dd, J= 11.2, 6.3, 11.2) HNMR solution (400 MHz, CDCl3): 84.63 (1H, dd, _ Hz), 4.01-3.85 (4H, m), 3.04 (3H, 5), 2.11 (2H, m), 1.89 (1H, m), 1.78 (1H, m) ), 1.70 9.3 (1H, m), 1.63 (1H, m), 1.35 (1H, m) ° The material was used in the following reaction immediately without further purification. Step (b): Preparation: (+)- endo-6-(methylthiomethyl)spiro [bicyclo[3.1.0]hexane-2,2'-[1 ,3]diox- olane] H H NaSMe nm / 1 / MsO 0 MeS 0 b to 0 then added (VV) sodium thiomethoxide mg; Y 5 mmol) to the crude solution: .0]hexane-2,2'-[1,3]dioxolane] -6-ylmethyl methanesulfonate 1]]10 20100-5-(h)YO) Combined 010 mmol) in DMF (© ml). The solution became completely viscous in ise form, then it was stirred at room temperature overnight. The mixture was partitioned between H,0 5 EtOAc, the layers were separated, and the aqueous phase was re-extracted with 106. The organic 1 co-layers were dried over MgSO, filtered, and concentrated. Reduction with a silica chromatograph (¥/ EtOAc in hexanes gradually up to 717 EtOAc in hexanes) resulted in obtaining:

(+)-endo-6-(methylthiomethyl)spiro-[bicycle [3,1.0lhexane-2,2"-[1,-3] dioxolane] clear oil. "H NMR (400 MHz, CDCl3) : 3 .99-3.87 (4H, m), 2.87 (1H, dd, J= 13.5, 5.4 Hz), 2.54 (1H, dd, J= 13.4, 8.8 Hz), 2.19 (3H, s), 2.14-1.96 (2H, m), 1.80 (1H, m), 1.68-1.53 (3H, m), 1.18 (1H, qd, J = 8.6, 5.4 Hz). ° (+)-endo-6-methylthiomethyl)-bicyclo[3.1-Olhexan-2-one . Step C: Preparation

H H im 2 cat. TsOHJn

MeS Hg 0 Acetone/H, 0 MeS . L” μmol) to EV, mg; 4,+Y) p-toluenesulfonic acid monohydrate was added: a solution of ()-endo-6-(methylthiomethyl)spiro [bicyclo[3.1. 0}hexane-2,2"-[1,3]diox- olane]} 10 mL), stirring at 054°C (with a ratio of HO/acetone mg; 949 mmol) at 0) and extraction Using .acetone, concentration in vacuum to remove 0 at room temperature for 2 hours (2 times), washing the organic layers with brine, drying on 148807, and filtration 206 (+)-endo-6-methylsulfanylmethyl-bicyclo[3.1.OJhexan-2]. -one for 38 all .as clear oil \o' H NMR (400 MHz, CDCL3): 82.63 (1H, dd, J=1 3.6, 6.5 Hz), 2.53 (1H, dd, /= 13.6 8.6 Hz), 2.32 (2H, m), 2.24 (1H, m), 2.17 3H, 5), 1 99 (3H, m), 1.75 (1H, m).

YY44

- Yio - : Step (d): Preparation of (+)-endo-1 -(methylthiomethyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclop-ropa[a]pentalene -4-carboxylic acid ethyl ester 0

OE

H 1) co 1 0 m m ' e 1 1 OEt

MeSKOt-BU/THF ww N

H / N 0 2) 42040121401, 0 MeS H H 11 mg OF ) - (+)-endo-6-(methylthiomethyl)bicyclo[3.1 OJhexan-2-oneisxd .then © : mmol) to 1 -methylsulfanylmethyl-1a,2,5,5 a-tetrahydro-1H-2,3 -diaza-cyclopropa[-a]pentalene-4- carboxylic acid ethyl ester Corresponding as previously described in Example (1-9); In step (c). (1H, d, J= 17.7 Hz), 2.50 (1H, m), 2.32 (1H, m), 2.15 (2H, m), 2.08 (3H, s), 1.57 (1H, m), 1.37 GH, 1727 .1 Hz). HPLC/MS: Alltech® Prevail C18 column (5p, v/v TFA) / viv TFA) in HO (containing 1 / viv CH3CN (containing 1 7/50 x 4.6 mm), 5 v/v CH;CN in Hy0, 3.5 mL/min, g 2.29 min, ESI" = 253.3 (M + H). 7. gradient to 99

- Yeu 7- : Step (e): Preparation of (+)-endo-1-(methylthiomethyl)- 1a,2,5,5a-tetrahydro-1H-2,3 -diaza-cyclop-ropa[a]pentalene -4-carboxylic acid 0 0

OEt OH Na 010/020, 686

H by 3 H "m Ww N Ww N

H | H

SMe SMe : Then hydrolysis procedure ° endo-1-(methylthiomethyl)-1a,2,5,5 a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]- pentalene-4-carboxylic acid ethyl ester : mmol) as previously described in Example (9 —¥) to obtain “Yo mg; ve ) endo-1-(methylthiomethyl)-1a,2,5,Sa-tetrahydro-1H-2,3 -diaza-cyclopropa[a]-pentalene- 4-carboxylic acid 1 0 As a white solid after freeze-drying 'H NMR (400 MHz, de-DMSO): 8 13.6-12.1 (1H, bs), 2.82 (1H , dd, J = 17.4, 6.8 Hz), 2.57 (1H, d, J= 17.4 Hz), 2.40 (1H, m), 2.23 (1H, m), 2.08 (1H, dd, J= 13.4, 7.1 Hz) , 1.99 (4H, m), 1.48 (1H, m). CH;CN £05 mm (mm) Alltech® Prevail 018 (© Alltech® Prevail 018) 05 mm (MS/HPLC: 00 µm) TFA 71 µm (volume/volume) in 11:0 (contains TFA 71 volume (contains

- F -:

EST = «Aad y,09 = dad [Je s HO gradually up to 99 hV/V in .225.3 (M+H): Preparation: (0A-1) Example (-exo-) 1 _ethoxymethyl-12,2,5 Sa-tetrahydro-1 H-2,3 _diaza-cyclopropalal- pentalene-4- carboxylic acid and (+)-endo-ethoxymethyl- 1a,2,5,5a-tetrahydro- 1H-2 ,3-diaza- ° cyclopropalalp- entalene-4-carboxylic acid cis and trans (4)-2-(5-ethoxy-pent-3-enyl)-oxirane mand : 0 step 0 2 mol% Zhan cat. 0

INF + Hur La Ai #0 Free FC Et

YAY in CG ) CG 1-2-(but-3-enyl)oxirane and then perform a double exchange chemical reaction of the compound mmol) as previously described in the example 1176 pa 0 ) ethyl ally' mmol) thick 0 as an unseparated mixture (4)-2-(5-ethoxypent-3-enyloxirane) to obtain au (Y- 4) silica gel after chromatography (1:01 (cis trans)). NMR (400 MHz, CDCly): trans isomer: $5.73 (1H, m), 5 63 (1H, m), 3.91 (2H, m) 3.48 (2H,q,J=17.0 Hz), 2.93 (1H, m) , 2.75 (1H, m), 2.48 (1H, dd, J= 5.0, 2.7 Hz), 2.22 (2H, m), 1 63 (2H, m), 1 21 GH, no 7.0 Hz). cis isomer: 5 5.62 (2H, m), 4.04 (2H, : m), 3.48 2H, q, J=1.0 Hz), 2.93 (1H, m), 2.75 (1H, m), 2.49 (1H, m) , 2.22 (2H, vn), 1.63 (2H, m), 1.22 (3H,t,J=17.0 Hz).

YEA - - Step (b): Preparation: (+)-exo0-6-(ethoxymethyl)bicyclo[3 .1.0}hexan-2-ol and (+)-endo-6-(ethoxymethyl)bicyclo [3.1 .0]hexan-2-ol LiTMP H 0 INF OE! —— / EtO by "oo" and then the procedure of introducing a cyclopropane group into the molecules of the compound: (+)-2-(5-ethoxypent-3-enyl)oxirane (6 g; 1,7) mmol) as previously described in Example (1-9) in step (1) to obtain: (+)-ex0-6-(ethoxymethyl)-bicycle[3.1.0]hexan-2-o0l/( +)-endo-6-(ethox- ymethyl)bicyclo[3.1.0O]hexan-2-ol ys (ratio 1:1) = rel as clear oil.'H NMR (400 MHz, CDCls) : 84.29 (1H, m), 3 47 (2H, dd, J= 7.1 Hz), 3.24 (2H, m), 1.94 (1H, m), 1.75 (1H, dd, J= 12.6, 8.1 Hz ), 1.56 (1H, m), 1.40-1.28 (4H, m), 1 20 (3H, t,J=7.1 Hz), 0.78 (1H, m).(£)-ex0-6-(ethoxymethyl) )bicyclof3.1.0Jhexan-2-one : step (c) cat. TPAP, NMO g _——— ie 9. 4A MS, DCM ed 9

HoH H © vo : The compound has been oxidized

- 9;?(+)-endo-6-(ethoxymethyl)bicyclo[3 1.0]hexan-2-ol/(%)-exo0-6-(ethoxy- methyl)bicyclo[3.1. 0]hexan-2-ol: by step (b) to obtain (0-9) as previously described in the example as a clear oil. (2)-6-(ethoxymethyl)bicyclo[3.1.0Jhexan-2] -one 'H NMR (400 MHz, CDCl;): 6 (3H, m), (1H, dd, Gl 10.4, 6.7 Hz), 2.19-2.01 (SH, °m), 1.70 (1H, dd, J=5.2,2.6 Hz), 1.59 (1H, m), 1.20 GH, t, J=17.0Hz). Step (d): prepare (+)-exo-1-ethoxymethyl-1a,2,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]- pentalene-4- carboxylic acid and (+ )-endo-ethoxymethyl- 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropala]p-entalene-4-carboxylic acid 01 0 0 H

OE OH

1 1) smj : I \ 0 EtO HN

EtO KOt-Bu/THF 1 + 0 "6 2( 42080421401, 0 (OH 3) LIOH/H,0, dioxane / wn / N N

EtO H H: Preparation of the compound was carried out as previously described (+)-exo-ethoxymethyl pyrazole/()-endo-ethoxymethyl pyrazole acid, which was developed by HPLC in example (1-4m) in step (2) The separation of the isomers was performed by

_ 7 and c —

CH;CN mm) and 75 ov X YOu Orchim 01 (Phenomenex “Luna C18 inverted): with a column of volume/TFA 7 (containing H,O volume/volume) in TFA 7 ( ) vol/vol) (containing methyl nm to obtain Yo¢ =) min [01 Ja and HO Jo vol) gradually until outer as white solids after drying with intrinsic methyl pyrazole followed by pyrazole . Lyophilized 0 (+)-exo-1-ethoxymethyl-1 a,2,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]p- entalene-4- carboxylic acid 'H NMR (400 MHz, CDCl): 3 50-12.03 (1H, bs), 3.42 2H, 7,0 Hz), 3.35 (1H, dd, J=10.5,6.2),3.23 (1H, dd, J=10.5,7.3 Hz) ), 2.84 (1H, dd, J = 16.9, 6.2 Hz), 2.69 (1H, d, J= 17.0 Hz), 2.09 (1H, m), 2.03 (1H, m), 1.11 GH, t, J = 7.0 Hz), 0.83 (1H, | 0 m). CH;CN volume/ 70g (ae 4.1 X 00 µm 0) Alltech® Prevail 018 column: MS/HPLC (volume/volume) TFA 1) (contains HO) (contains over 71 178 volume/volume) in a minute = 0.95f, (aida gradually up to 799 11.01 volume/volume in 0,¥ 110 ml blu. - 223.2 01+11(0 (+)- endo-1-ethoxymethyl-1 a,2,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropafa)-pentalene-4-carboxylic acid

_ Y o \ — 'H NMR (400 MHz, CDCl3): §3.30-3.15 (2H, m), 3.01 (1H, dd, /= 10.7, 6.8 Hz), 2.91 (1H, dd, J = 10.7, 7.6 Hz), 2.80 (1H, dd, J=17.3, 6.8 Hz), 2.57 (1H, d,J=17.3 Hz), 2.35 (1H, m), 2.24 (1H, m), 1.45 1=(1 H, m), 1.10 (14, m), 1.00 3H, 17 0 Hz). [axa CH3CN 705 mm (4.1 X 900 μm) Alltech® Prevail C18 0) column: MS/HPLC size/size (TRA 1) size/size (in 11:0) containing TRA 77 (containing p20 = 1251 (488) min; ,1 = Ba [Ja M “H,0 v/v in CH;CN 744) gradually up to .223.2 M+ H) : Ex. 1

H

H, (CN to I okt

H a 0 (2) The heading compounds were prepared in a manner similar to the method mentioned in the example (9- ¥” in step

MS m/z : 3 A[M+H]", 255.4 [M+Na]'; 'H NMR (400 MHz, CDCl3): 6 4.37-4.31 (m, 2H), 2.98(dd, 1H) , J;= 17.4 Hz, J» = 6.4 Hz), 2.88 (d, 1H, J = 17.4 Hz), 2.37-2.34 (m, 1H), 2.24-2.18 (m, 1H), 1.37 (t,3H, J=7.2 Hz), 0.74). 0.02- -0.12 (m, 1H).

— X 3 Y —_ : Example )= 1) preparation of (+)-endo-1-cyclopropyl-12,3,5,5 a-tetrahydro-1H-2,3 -diaza-cyclopropala)- pentalene-4 - carboxylic acid

H

H, NN

N\A on

HS0. )- q ) Then prepare the title compound in a manner similar to the method mentioned in an example

MS m/z (ES*): 205.3 IM+H]"; 'H NMR (400 MHz, CDCl3): 8 3.06(dd, 1H, J; = 1 8.9 Hz,

J, =5.9 Hz), 2.99 (d, 1H, J = 18.7 Hz), 2.43(t, 1H, J = 8.2 Hz), 2.05(q, 1H, J = 6.1 Hz), 0.85(q, 1H, J = 8.3 Hz), 0.55-0.50 (m, 1H), 0.41-0.36 (m, 1H), 0.29-0.21(m, 2H), 0.08- 0.00 (m, 1H). Ex. -diaza- cyclopropala]pentalene : step (a): prepare (+)-endo-1-cyclopropyl-12,3,5,5 a-tetrahydro-1H-2,3-diaza-cyclopropala]- pentalene-4 - carboxylic acid amide \o

_x Qo y —

H nH, NN 7 li + NH,

H oS 0 . (2) By step (0-8) Jie of the method mentioned in Allee, the title compound was prepared using a method

MS m/z (EST): 204.5 [M+H]", 226.4 [M+Na]"; “H NMR (400 MHz, CD;0OD): 5 2.99(dd, 1H, J;= 16.7 Hz, J,=5.9 Hz), 2.93 (d, 1H, J = 16.6 Hz), 2.37-2.29 (m, 2H), 0.80 (q, 1H,

J = 8.2 Hz, 0.54-0.48 (m, 1H), 0.33-0.25 (m, 2H), 0.22-0.18 (m, 1H), 0.01- -0.05 (m, 1H). Step B: Prepare (+)-endo-1-cyclopropyl-1a,3,5, 5a-tetrahydro-1H-2,3 -diaza-cyclopropafa]-pentalene-4-carbonitrile:

N

H, 4h

SCN

H8

H ya Then prepare the title compound in a manner similar to the method mentioned in the example (-); Step (and).

MS m/z 125 : 186.1 1.2 [2M+H]"; 11 NMR (400 MHz, 686 2.96 (dd, 1H, J; = 16.5 Hz, J, =6.2 Hz), 2.86 (d, 1H, J = 16.4 Hz), 2.41 2.35 (m, 2H), 0.87 (q, 1H, J = 8.2 Hz), 0.57-0.52 (m, 1H), 0.34-0.27 (m, 2H), 0.22-0.18 ( m, 1H), -0.02- -0.11 (m, 1H) Vo

—_— Y o $ — : Step (c): Prepare )+(-6000-1 -cyclopropyl-4-(2H-tetrazol-5-y1)- 1a,3,5,5a-tetrahydro-1H- 2,- 3-diaza-cyclopropa[a]pentalene a 7 H > NG

H.S.N

H migrate to step (g). 0 The title compound was prepared in a manner similar to the method mentioned in Example (4-?) 0

MS m/z 25: 3 11,2 [M+Na]'; ‘H NMR (400 MHz, CD3;0D): 6 2.99 (dd, 2H, J; = 16.7 Hz, J, = 6.0 Hz), 2.92 (d, 1H, J = 16.7 Hz), 2.36-2.29 (m, 2H), 0.80 (q, 1H, J = 8.3 Hz), 0.53-0.47 (m, 1H), 0.32-0.24 (m, 2H), 0.21-0.17(m, 1H), 0.01- -0.07(m, 1H ). Preparation (MY) ex. 0 (+)-exo-1-vinyl-12,3,5,5 a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pentale-ne-4- carboxylic acid ethyl ester

H

for N-n

ON OEt = R

H 0 . (2) By step 1 0-9) and then prepare the title compound in a manner similar to the method mentioned in the example

_ 7 00 —

MS m/z (ES”): 219.3 [M+H]”, 241.1 [M+Na]"; 'H NMR (400 MHz, CDCl3): 8 5.53-5.44 (m, 1H), 5.04 (dd, 1H, J, = 17.1Hz, J, = 1.0 Hz) , 4.94(dd, 1H, J; = 10.34 Hz, J,=1.4

Hz), 4.33 (q, 2H, J =7.2Hz),3 02 (dd, 1H,J,=173 Hz, J» = 6.1 Hz), 2.90 (d, 111, 1 = 17.3 Hz), 2.34-2.30 (m, 1H), 2.21-2.1 7 (m, 1H), 1.35 ) 3H, J = 7.2 Hz), 1.33- 1.29 (m, 1H). : ° : Example (27-5): preparation of (+)-exo-1-vinyl-1a,3,5,5 a-tetrahydro-1 H-2,3-diaza-cyclopropa[a]pentale-ne -4- carboxylic acid

H

H,, N~N

WON OH

= J

HY 0 Then prepare the title compound in a manner similar to the method mentioned in Example (9-?). 0

MS m/z (ES”): 191.3 [M+H]; 'H NMR (400 MHz, DMSO-de): 6 5.57-5.48 (m, 1H), 5.13(dd, 1H, J, = 17.1 Hz, J, = 1.6 Hz), 4.97(dd, 1H, J1= 10.3 Hz, J2= 1.7 Hz), 2.98 (dd, 1H, J, = 18.2 Hz, J, = 6.3 Hz), 2.80(d, 1H, 12 18.2112, 2.36 (dd, 1H, J; =6.1 Hz, I, = 2.6 Hz), 2.07-2.03 (m, 1H), 1.37 (dt, 1H, J, = 8.8 Hz, J; = 3.1 Hz).

- Ha —:14-9 (example ()-ex0-4-(2H-tetrazol-5-yl)-1 -vinyl-1a,3,5,5a-tetrahydro-1H-2, 3 -diaza- - cyclopropa[a]pentalene : step 0( : preparation (+)-exo-1-vinyl-1a,3,5,5 a-tetrahydro-1H-2,3 -diaza-cyclopropala]pentale - ne-4- ° carboxylic acid amide

H

H, NN

WON NH; = 3

HY 0 . (2) By step (0-8), then prepare the title compound in a manner similar to the method mentioned in the example.

MS m/z 65: 3 [M+H]", 379.2 [2M+H]"; “TH NMR (400 MHz, DMSO-de): 6 5.58- 5.49(m, 1H), 5.09 (dd, 1H, J; = 17.1 Hz, J, = 1.6 Hz), 4.94 (dd, 1H, J; = 10.3 Hz, J, = 01 1.6 Hz), 2.94 (dd, 1H, J; = 17.1 Hz, J2=6.1 Hz), 2.78 (d, 1H, J = 17.1 Hz), 2.29 (dd, 1H,

J, =5.8 Hz, J, =2.1 Hz), 2.25-2.21 (m, 1H), 1.26-1.23 (m, 1H). Step B: Preparation of (+)-exo-1-vinyl-1a,3,5,5a-tetrahydro- 1H-2,3-diaza-cyclopropala]pentale-ne-4-carbonitrile Vohtaf

_ Y o l —

H n, NN

He “4 \ = \ Cn

He The title compound was prepared in a manner similar to that in Example (1-4); Step (and).

MS m/z (EST): 172.3 [M+H]", 343.1 [2M+H]"; ‘” H NMR (400 MHz, CDCls): 8 5.52-5.43 (m, 1H), 5.09 (dd, 1H, J, = 17.0 Hz, J = 0.6 Hz), 5.00 (dd, 1H, J; = 10.3 Hz , J, = 1.2

Hz) . Step C: Prepare 1-(211-161178201-5-71)-2<0-4-(C+)-vinyl-1a,3,5,5a-tetrahydro-1H-2, 3 -diaza-cyclopropa[a]pentalene

H

1 H, Barah" 1

ON N. = 8 | N

H pH 0.1 The title compound was prepared in a manner similar to the method mentioned in Example (7-9); With step (g).

MS m/z (EST): 215.3 1171 429.4 [2M+H]"; Hz), 4.99 (d, 1H, J = 10.4 Hz), 3.14-3.08 (m, 1H), 3.02 (d, 1H, J = 16.5 Hz), 2.38 (s, 1H), 2.07-2.04 (m, 1H ), 1 42-139 (m, 1H).

YYAa4

_ Y o A _ : Preparation: 169-9( Jha (+)-1-spirocyclopropyl-1a,3,5, Sa-tetrahydro-1H-2,3 -diaza-cyclopropa[a]-pentalene-4 - carboxylic acid ethyl ester

H

H, (CN

Ao oo 0 to 0, then prepare the title compound using the Alas method for the method mentioned in Example (7-49); in step (d). MS m/z (ES): 219.4 [M+H]", 241.2 [M+Nal'; 'H NMR (400 MHz, CDCl;): 8 4.37 - 4.31(m, 2H), 2.97 (dd , 1H, J, = 17.0 Hz, J, = 6.1 Hz), 2.70 (d, 1H, J = 17.0 Hz), 2.58 (d, 1H, J = 5.5 Hz), 2.52 (t, 1H, J = 5.8 Hz), 1.37 (t, 3H, J = 7.1 Hz), 1.07-1.02 (m, 1H), 0.98-0.93(m, 1H), 0.53-0.46 (m, 2H). 17-4: ( Jee ve (+)-1-spirocyclopropyl-1a,3,5.5 a-tetrahydro-1H-2,3 _diaza-cyclopropa[a}- pentalene-4- carboxylic acid

H

H, MN 27 0 (7-8). The title compound was prepared in a manner similar to that in the example.

— ¥ 0 4 —_

MS m/z (ES): 191.3 [M+H]", 213.2 [M+Na]'; '"H NMR (400 MHz, CD3;0D): 6 3.03 (dd, 1H, J; = 18.1 Hz, J = 6.1 Hz), 2.78 (d, 1H, J = 17.8 Hz), 2.63 (d, 1H, J = 5.7 Hz), 2.34 (t, 1H, J = 5.7 Hz), 1.12-1.03 (m, 2H) , 0.68-0.63 ) m, 1H), 0.54-0.49 (m, 1H). Example (17-49): Preparation ))-1 -spirocyclopropyl-4-(2H-tetrazol-5 -yl)-1a,3,5,5a-tetrahydro-1H-2,- 3-diaza- ° cyclopropala]pentalene : step (a): prepare (+)-1-spirocyclopropyl-1a,3,5 ,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]- pentalene-4- carboxylic acid amide

H

H,

H0ve. (2) Then prepare the title compound in a manner similar to the method mentioned in Example (4-0); by step

MS m/z (ES): 190.2 [M+H]", 379.3 [2M+H]"; ‘”H NMR (400 MHz, DMSO-d): 6 2.90 (dd, 1H, J; = 16.2 Hz, J,=5.4Hz),2.66 (d, 111, 121 6.4 Hz), 2.54 (2H, overlapped with

DMSO), 1.07-1.03(m, 1H), 0.99-0.95 (m, 1H), 0.55-0.50 (m, 1H), 0.39-0.34 (m, 1H). Step B: Preparation 0

- .1l = (£)-1-spirocyclopropyl-1a,3,5,5 a-tetrahydro-1H-2,3-diaza-cyclopropala]- pentalene-4- carbonitrile

H

HNN

7 \ : CN

H

. (5) In step ((Y-1) the title compound was prepared in a manner similar to the method mentioned in the example

MS m/z [5]: 172.3 [M+H]", 343.4 [2M+H]"; “H NMR (400 MHz, CDCl): § 2.93 (dt, ° 1H, J, = 16.4 Hz, J, = 3.0 Hz), 2.68 (d, 1H, J = 16.3 Hz), 2.61 (d, 2H, J =3.0 Hz), 1.12- 1.08 (m, 1H), 1.02-0.98 (m, 1H), 0.57-0.53 (m, 1H), 0.51 -0.46 (m, 1H). : (C): Preparation 3 shall (+)-1-spirocyclopropyl-4-(2H-tetrazol-5-yl)-1a,3,5 ,Sa-tetrahydro-1H-2,- 3-diaza-cyclopropa[a]pentalene 01

H

.N

N, 3 | LN

H is suitable for the method mentioned in Example (7-9); In step (g), the title compound was prepared by alee method

MS m/z (EST): 215.2 [M+H]", 429.2 [2M+H]"; ‘H NMR (400 MHz, MeOD): 8 3.06 (dd, 1H, J, = 16.1 Hz, J, = 6.1 Hz), 2.85 (d, 1H, J = 16.1 Hz), 2.68 (t, 1H, J = 5.8 Hz), 2.64 (d, 1H, J = 5.4 Hz), 1.11 (quintet, 1H, J = 4.4 Hz), 1.03 (gq, 1H, J=4.0 Hz), 0.61 (q, 1H, \o

J=4.6 Hz), 0.49 (q, 1H, J = 4.3 Hz).

Example (148-9): preparation of (+)-endo-1-propenyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropala]pen- talene-4- carboxylic acid ethyl ester

H

H, NN

AHA on

NON

. (2) In step 0 (Y-14) the title compound was prepared in a manner similar to that in the example

MS m/z (ES): 233.4 [11111] , 255.3 [M+Na]"; 1H-2,3diaza-cyclopropaa]pent-alene-4-carboxylic acid

H

H, MN

AL YA or

H He 0 1 . (*- a ) Then prepare the address compound in a manner similar to the method mentioned in the example

MS m/z 650: 205.2 [M+H]";

- YY -

Preparation: 70:-( Jha (+)-endo-1-propenyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-d- iaza-cyclopropala]pentalene

Step A: Prepare: ()-endo-1-propenyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[ajpen-talene-4- ° carboxylic acid amide H H, NN TAL NH, HS 0 The title compound was prepared in a manner similar to that in Example (7-4) 0 in step (e). MS m/z (ES): 204.1 [M+H]. -01090-( ) carbonitrile 1 Hy 1 SN CN H The title compound was prepared in a manner similar to the method mentioned in Example (4-7) » shally 5 (1). m 0 m m /z 257: 186.1 [11+11] , 371.1 [2M+H]";

- Yr - : (c): preparation 8 shall )(-6000-1 -10 -111-2,3-0-like pt 8-11 5, 8,3,5 1 -(211-1173201- 5-71)-4- the iaza- cyclopropa[a]pentalene

H

H, 10 7

A N

SS 1 No M "N~N in a manner similar to method 1) and then prepare the title compound as a mixture of isoforms (with the ratio of Ara: mentioned in Example (7-9); in step (g).

MS m/z 012570: 229.4 [M+H]", 457.3 [2M+H]"; Major isomer: 'H NMR (400 MHz,

MeOD: 6 5.59-5.51 (m, 1H), 4.69-4.62 (m, 1H), 3.02 (dd, 1H, J, = 6.5 Hz, J, = 4.0 Hz), 2.78 (d, 1H, J = 16.5 Hz), 2.64-2.55 (m, 2H), 2.15 (q, 1H, J = 8.0 Hz), 1.76 (dd, 3H, J, = 6.8 Hz, J, =1.6 Hz). Minor isomer; 'H NMR (400 MHz, MeOD): § 5.79-5.71 (m, 1H), Ve 4.75-4.69 (m, 1H), 3.06 (dd, 1H, J, = 6.5 Hz, J, =4.0 Hz), 2.83 (d, 1H, I = 16.5 Hz), 2.58-2.49 (m, 2H), 2.00 (q, 1H, J = 8.0 Hz), 1.55 (dd, 3H, J; = 6.5 Hz, J, =1.5 Hz) . (4-71): Example 1-methoxymethyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-- 4- carboxylic acid vo release

- Yt - spiro[bicyclo[3.1.0Jhexane-2,2"-[1,3]dioxolane]-6-ylmethanol : Step (): Preparation

H H

H NaBH, mt Qo Job MN 0 o Ho JS MM (mH HI) and add it dropwise to (Ja 7 ( MeOH mmol) in Y, YA cane 4+) NaBH4 was dissolved and then stirred mixture. (Ja A) MeOH (mg a mmol) dissolved in Ean) aldehyde NaOH solution for 701 minutes and then quenching it using 10 C reaction at ambient temperature for a period of 4 C drying and concentrating it in vacuum. 3 J ether was purified and then extracted to a mixture of Ba 3 using mg of You to obtain (silica / hexane) the residue by column chromatography (+ £0 p0a2/d) the title compound. 400 MHz, :(oak 5 4.07-3.88 (5H, m), 3.64 (1H, ddd, J = 12.5,104,2.2

Hz), 2.79 (1H, dd, J = 11.0, 2.2 Hz), 2.18-2.05 (2H, m), 1.82-1.60 (4H, m), 1.40-1.30 \ (1H, m). 6-endo-(methoxymethyl)spiro[bicyclo[3.1.0]Thexane-2,2'-[1,3]dioxolane]: ( <2) step H H

Mel, NaH / wn 0 Tove / aww 0

HO H o MeO H oJ) (97-49); In step (b). Jha The title compound was prepared in a manner similar to that in '" H NMR (400 MHz, CDCl;): § 4.00-3.82 (4H, m), 3.77 (1H, dd, J=10.5, 5.4),3.44 (1H, 0 dd, J =10.5, 8.5 Hz), 3.40 (3H, s), 2.16-2.04 (1H, m), 2.04-1.96 (1H, m) 1.87-1.79 (1H, m) , 1.72-1.65 (1H, m), 1.64-1.54 (2H, m), 1.28-1.15 (1H, m).

6-endo-methoxymethyl-bicyclo[3.1.0thexan-2-one Step C: Prepare

H

TsOHH / weoO — > wm

MeO H oJ Acetone/H,0 ed H 0 . ( 10-4 ) The title compound was prepared in a manner similar to that in Example 'H NMR (400 MHz, CDCl;): E 3.55 (1H, dd, J = 10.8, 6.4 Hz), 3.45 (1H, dd , ] = 10.8, 8.5 Hz), 3.37 (3H, s), 2.36-2.23 (3H, m), 2.05-1.98 (3H, m), 1.82-1.73 (1H, m). ° : step (9) preparation

I-endo-methoxymethyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]penta-lene-4-carboxylic acid ethyl ester 0

OEt 1) SWG 9

H0H081

KOt-Bu, EtOH 1 / wih eee / LK / N

MeOHO2)HoNNHpHCIMeO0

H,0 (2) in step 0) The title compound was prepared in a manner similar to the method mentioned in Example (1-9H 0

Jana CH3CN 70 and Alltech® Prevail C18 (AE 5.1 X © 0 micro” ©) Column MS/HPLC (volume/volume) TFA 71 volume/volume) in 11:0 (contains Contains TFA 71 volume (contains

ESI" = min; VANE =, min; [de 0 «H,0 volume/volume in CH;CN 744 scales up to .236.9 (M+H)

0 Step E: 1-endo-methoxymethyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]penta-lene-4- carboxylic acid 0 0

H 08 LiOH/H,0 H OH 2 Fiona 20

MeO H H MeO H H M 1 M aqueous lithium hydroxide 1 “Jo V (mmol) was added to an ester solution (45 0 g; FA mmol) in dioxane . The solution was reduced overnight at ambient temperature and acidified by the addition of 1 N HCl. The mixture was concentrated and purified by HPLC with inverted sh: 018 01 (Phenomenex® Luna micro; can YV,Y x You 70 (vol/v) 011.07 (contains TFA 71 vol by vol) at 11:0 (containing TFA 71 vol/v) 0 stepwise up to 795 [da 10 (HO) min; .3 = 704 nm to obtain the title compound as a solid after lyophilization. MS: /HPLC with Alltech® Prevail C18 shaft (0 µm; 4,50 mm); and 75 011:01 vol/v (containing 71 TFA vol/v) by 11.0 (containing 71 TFA vol/v) by CHRON 799 Ja vol/v by 11:0; 0,¥ ml/min;

ESI" - 209.1 (M + H) « dads 1,11 =,

:)0 7-9 ) Ex. 1-endo-methoxymethyl-4-(1H-tetrazol-5-yl)-1a,2,5,5a-tetrahydro-1H-2,3-dia-za-cyclopropala ]pentalene

Ng 0 N 8 N

H OEt H NH \ > po / oN jo AY

MeO 10 m MeO HN (—=) by Steps 1 Y—-14) b Prepare the title compound in a manner similar to that in Example 105 mM) 4,1” 50 µm (©) Alltech® Prevail C18 with column: MS/HPLC, (f) and (g). (containing 7 M 717 HO volume/volume) in TFA 71 volume/volume (containing 11.07 077 - mL/min n,# (HO volume/volume in CHRON 795 volume/volume) gradually up to

ESI" - 233.0 (M + H) « assy : Example (77-95): preparation of ys 1-endo-phenoxymethyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropala]penta - lene-4- carboxylic acid : Step 00: Preparation of 6-endo-(phenoxymethyl)spiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolane]

H

Or wd Lo D{BAD, PyPh,P pM Q / — o H o

HO 1 for THF \o

- YA - mmol) 0.5 mg; 75) phenol mmol) 1 mg; 10) Alcohol dissolved

THF mmol) in 1.9 ;? mg; DBAD (©) 5 mmol) 0.8 and 0 (¥40) mg; 1 110 N and then add 0. And stir it at ambient temperature overnight (Je 2) times). The organic layers (¥) ether were washed out of the reaction mixture and extracted and concentrated. The value was purified on the combined MgSO4 using brine; and dried at 0 to obtain the title compound. (silica [hexane EtOAc 7758 - +) Column chromatography 'H NMR (400 MHz, CDCl3): 6 7.31-7.25 (2H, m), 6.99-6.92 (3H, m). m), 4.41 (1H, dd, J = 10.6, 5.2 Hz), 4.03-3.89 (5H, m), 2.18-2.08 (1H, m), 2.08-1.99 (1H, m), 1.92-1.84 (1H, m), 1.81-1.75 (1H, m), 1.70-1.63 (1H, m), 1.63-1.56 (1H, m), 1.44-1.35 (1H, m). 6-endo-phenoxymethyl-bicyclo[3.1.0]hexan-2-one : Step (b) 0

H H

TsOH

Wi 27 f — >» wh 2 / / ye H oJ) Acetone/H,0 . H 0 (11-4). The title compound was prepared in a manner similar to that in the example 'H NMR ( 400 MHz, CDCl): § 7.32-7.25 (2H, m), 7.00-6.94 (1H, m), 6.92-6.88 (2H, m), 4.19 (1H, dd, J=10.6, 6.1 Hz), 3.96 ( 1H, dd, J = 10.6, 8.9 Hz), 2.38-2.32 (3H, m), 2.13-1.94 (4H, m).Vo

YYaa

- -714? Step (c): 1-endo-phenoxymethyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]penta-lene-4- carboxylic acid ethyl ester 0 | o

H 1) The color of Sadi

WA KOr-Bu, 00 M {A

Ore "9 HNN HCl Ore HoH

H,0. (3) The title compound was prepared in a manner similar to the method mentioned in Example (1-4e); by step 0 'H NMR (400 MHz, lute: 8 7.27-7.21 (2H, m), 6.91 (1H, t, J = 7.3 Hz), 6.83-6.79 (2H, m), 4.39-4.25 (2H, m), 3.88-3.82 (1H, m), 3.48 (1H, dd, J = 10.4, 8.3 Hz), 3.02 (1H , dd, J=17.8, 6.8 Hz), 2.84 (1H, d, 17.8 Hz), 2.61-2.56 (1H, m), 2.50-2.43 (1H, m), 1.85-1.76 (1H, m), 1.35 3H , t, J = 7.1 Hz). and 4.1 X 04 "5 Sa 0 column (Alltech® Prevail C18: MS/HPLC 0 volume/volume) (TFA 71 volume/volume) at 11:0 (contains TFA 71 volume/volume) contains min; ,= 7,076 min; [Je ¥,0 (HO in pas volume/CH3CON 799 increments up to

ESI" - 299.1 (M + H) Step D: Prepare 1-endo-phenoxymethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa|a]pentalene-4-V carboxylic acid

— and 7 Y — 0 0 H OEt H OH i \ome WT, (but J : N Dioxane O° H N a — 177 «Ja +, YY) Lithium hydroxide added mmol) to a solution of ester (V0) + , + g; 654 mmol) in dioxane . The solution was stirred at 1 C for ¥ hours and made acidic by adding 1 N HCI. Lal was concentrated and purified by reversed-phase HPLC: Luna M 018 01 (Phenomex® micro X You 1.7 M5/(vol/v) CH3CN (containing 1) TFA volume by volume) in 11:0 (containing 71 TFA vol/v) gradually until [da Ya «H,0O 7 40 min A = 10 nm to obtain the compound as a white solid after Freeze drying. MS/HPLC: Column 018 X 50 (53S 0) Alltech® Prevail 7 mm); and 75 CH3CN v/v (containing TFA 71 v/v) in HzO (containing 0 m v/v) gradually up to 4 CH;CN v/v in (HO m ml/min; M + H) dada 0.10 - © 271.0 - 281 Example (7,9-4): Preparation: 1-endo-phenoxymethyl-4-(1H-tetrazol-5-yl)-1a, 3,5,5a-tetrahydro-1H-2,3-dia- za- cyclopropala]pentalene Ng N 5 N 0 H 08 H NH pM / N six _ MM / N © 0 Vo

- 1 No - The title compound was prepared in a manner similar to that in Example 0 (Y-4) with steps (=—( and (f) du(g).: MS/HPLC in Alltech® Prevail C18 column) © Micro 0 (a £.1 X 765 1107 vol/pas (contains 71 TFA vol/vol) at 11:0 (contains (7 TFA µana >) progressively up to 744 of volume/volume in “H; -1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a-]pentalene-4-carboxylic acid Step 0: Prepare 2-(5-methylsulfanyl-pent-3-enyl) )oxirane AA 5 zh 1 0 2N"Me an cat > La ~~ 5 + 7 Me 0 DCM \©,0V) Epoxide stirred ©T,V m V,+ + +) Allyl methyl sulfide 5 (Js—g; 10” mmol) at Yo for YE 1 h with Zhan catalyst 1 (molecular weight = ALY 177 can 5 MilliMol; Zannan Pharma »»). The solvent was removed under reduced pressure. The remainder was purified by column chromatography (+ = 701 pg2:0/d-pg/silica) to obtain the title compound as oil. (2H, m), 3.07 (2H, d, J = 7.2 Hz), 2.96-2.91 5.60-5.43 h (gives NMR (400 MHz, 1H, m), 2.78-2.74 (1H) , m), 2.49 (1H, dd, J = 5.0, 2.7 Hz), 2.28-2.19 (2H, m), 2.02 (3H, : s), 1.70-1.57 (2H, m).

= YVY - . (+)-exo0-6-methylsulfanylmethyl-bicyclo[3.1.0Thexan-2-0l (b); preparation 3 shall

Li i

N H

0

La ~~ Ve 2 Laa Ss St 73010116, Me—S H OH The title compound was prepared in a manner similar to that in Example (9-01) in step (b). 6 4.28 (1H, l = 5.0 Hz), 2.41 (2H, d, J = 7.0 Hz), 2.14 (3H, s), 2.00-1.89 (1H, m), 1.75 (1H, dd, 12.7, 8.1 Hz), 1.58 (1H, dd, J = 14.6, 8.6 Hz), 1.40-1.28° (4H, m), 0.72-0.66 (1H, m)..(%)-6-ex0-methylsulfanylmethyl-bicyclo[3.1 .0Thexan-2-one (C): Prepare 5 shall 0, modified H AN 0 H — ENMM TPAP mm MeS 8 OH 4A MS, CH,Cl, 055 0 0 for the above method In Example (9-21), step (c). 1H, dd, J = 13.5, Vo 7.7 Hz), 2.18 (3H, s), 2.16-2.03 (4H, m), 2.00 (1H, dd, J=9.1,5.1 Hz), 1.78 1H, dd, J = 5.3,2.5 Hz), 1.56-1.51 (1H, m).

Yyvaq

Step D: Preparation: (*+)-1-exo-methylsulfanylmethyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclo-propala]pentalene-4-carboxylic acid ethyl ester 0 0 sug (H ) 3 H OEt KO#-Bu, EtOH / 2 PO «lalambbbmmttssssssssssssssssssssssssssssssssssss»N MeS H O 2) H;NNH HC MeS H | Mut M Then prepare the title compound by a method Similar to the method mentioned in Example (4-51) (0) in step (2). MS/HPLC: Alltech® Prevail C18 and 70 CH3CN size/ column (ae 4.1 X 80 “5 Sua ©) volume (containing) 7 TFA vol/vol) in HO (containing 7 TFA vol/vol) gradually up to 799 [pas CHRON vol in (HO 0.¥ mL/min; =f 7.75 min; ESI" - 253.1 1 + 1 0 Step E: Prepare: (£)-endo-1-methylsulfanylmethyl-1a,2,5,5a-tetrahydro-1H -2,3-diaza-cycl- opropa[a]pentalene-4-carboxylic acid 0 0 H OBt | iOH/H,0 H OH rrr N Dioxane / N / Mes 8 Mes H HN

Y $7 — — 1 molar Sle lithium hydroxide EVA «ily Kaa £YA (µmol) was added to an ester solution (£0 for 109 550 mol) in dioxane . The solution was stirred at ambient temperature overnight and acidified by the addition of 1 N HCl. The mixture was concentrated and purified by reversed-phase HPLC: 0) Phenomenex® Luna C18 μjo aa YY, ¥ X You ° (vol/v) CH;CN (containing 7 TFA vol. volume) at 11:0 (containing 7 TFA vol/(p>) gradually up to [de 01 HO min}= YVE nm to obtain the title compound as a white solid after freezing. (1H, dd, J = 16.9, 5.9 Hz), 2.82 (1H, d, 16.8 Hz), 2.94 µH NMR (400 MHz, CD;0D): (2H, d, J = 7.0 Hz), 2.14 (3H, s), 2.16-2.08 (2H, m), 0.92-0.86 (1H, m).MS/HPLC: 2.53 0 column ¢ (ae 4.1 X © «5 Sue ©) Alltech® Prevail C18 and 70 CH;CN vol/vol (contains 71 TFA vol/vol) in 11.0 (contains 7 TFA vol/vol) gradually up to 799 CHRON vol/vol in ( HO 7.5 mL/min; 5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-1,1- '-cyclopentan]- \o 4-carboxylic acid

_ Y < 7 mg — (%)-Spiro-[bicyclo[3.1.0]hexane-6-1'"-cyclopentan]-2-0l: Step (1): Preparation. OH (1) The title compound was prepared in a manner similar to the method mentioned in Example (01-9) with steps: . and (b). “HNMR (CDCl): 6 4.11 (d, 1H, J=4.8), 2.05 -1.98 (m, 1H), 1.69-1.46(m, 8H),1.40-1.26 ° (m, SH).: Step (b): Prepare ()-Spiro-[bicyclo[3.1.0]hexane- 6-1'-cyclopentan]-2-one

WN

Re0. (ii) by step 0 (0-9°) and then prepare the title compound in a manner similar to that in Example 0 'H NMR (CDCl): 5 2.23-2.11 (m, 2H), 2.02-1.90 (m, 3H) ), 1.77-1.73(m, 3H), 1.70-1.50 (m, SH), 1.48-1.24 (m, 1H). Step (c): (x)-Spirof1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropala]pentalene-1,1- '-cyclopentan]- 4-carboxylic acid ethyl ester Vo yy M Sama no

HN—N (9) by step 0 (51-4) and then prepare the title compound in a manner similar to that in the example

MS: m/z (ES): 247 [M+H]", 201 [M-OEt]" : Step (d): Preparation of (+)-Spiro[1a,3,5,5a-tetrahydro-1H -2,3-diaza-cyclopropala]pentalene-1,1- - 0 cyclopentan]carboxylic acid 111 0 (Dn 7 “oH Yahya . (Y- 1) According to the method mentioned in the Alles example, the title compound was prepared in a manner

MS: m/z (ES): 219 [M+H]", 201 [M-OH]". HNMR (CD;OD): § 2.94 (dd, 1H, 1,=17.1,J,=2.1), 2.72 (d, 1H, J=17.1, 2.17 (s, 2H), 1.78-1.53 (m, 6H) ), 1.34-1.24 (m, 1 1H), 0.94-0.84 (m, 1H).: (Yv- 1) Example (+)-5-(Spiro-[1a,3,5,5a-tetrahydro -1H-2,3-diaza-cyclopropala]pentalene- -1,1'- cyclopentan]-4-yl)-1H-tetrazole

Ong is / N Hesse H Vo

- YVV - (44-4). The title compound was prepared in a manner similar to the method mentioned in the example

MS: m/z 55: 243 [M+H]", 215 [M-N,+H]". 'H NMR (CD;0D): 8 2.88 (dd, 1H, 1212.3, J,=6.1), 2.72 (d, 1H, J=16.6), 2.18-2.07 (m, 2H), 1.63-1.40 (m, 6H), 1.28-1.13 (m, 1H), 0.83-0.71 (m, 1H). : Preparation (VASA) Example 0 (.+-.)-Spiro[1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-1,1- '-' cyclohexan]-4-carboxylic acid Step 0 Preparation: (.+-.)-Spiro-[bicyclo[3.1.0]Jhexane-6-1'-cyclohexan]-2-ol 00 OH \ was prepared Title compound in a manner similar to the method mentioned in Example (7-9); Steps (1) and (b). 'H NMR (CDCl3): § 4.14 (br 5, 1H), 2.05-2.00 (m, 1H), 2.0-1.1(m, 15H). Step (b): Preparation of (+-.)-Spiro-[bicyclo[3.1.0]hexane-6-1'-cyclohexan]-2-one a OQ \o 0

- YVA - . ©) Then prepare the title compound in a manner similar to the method mentioned in Example (-7); By step 'H NMR (CDCls): § 2.39-2.28 (m, 1H), 2.28-2.14 (m, 1H), 2.10-1.99 (m, 2H), 1.97-1.82 (m, 2H), 1.64 (d, 1H, J=5.2), 1.60-1.44 (m, 7H), 1.33-1.25 (m, 2H). Step (©): Preparation of (.+-.)-Spiro[1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-1,1- '- ° cyclohexan }-4-carboxylic acid ethyl ester 0 2 Ah Ha No °

N=N

H

. (2) The title compound was prepared in a manner similar to the method mentioned in Example (7-4? 1 by step).

MS: m/z 65: 283 [M+Na]', 261 [M+H]", 215 [M-OEt]*.'" H NMR (CDCl): 80 (brs, 1H, NH), -4.41 4.27 (m, 2H), 2.89 (dd, 1H, J,=17.5, J,=6.9), 2.64 (d, 1H, J=17.5), 01 2.08 (d, 1H, J=6.1), 1.98 (t , 1H, J=6.3), 1.62-1.42 (m, 4H), 1.40-1.25 (m, 7H, including 1.36 (t, 3H, J=7.1), 1.10-0.90 (m, 2H). Step (d) Preparation: (.+-.)-Spiro[1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-1,1- '-cyclohexan]-4- carboxylic acid Vo

- No - 0 for “Oo yum N

H

(9-7) The title compound was prepared in a manner similar to the method mentioned in the example

MS: m/z: 255 [M+Na], 233 [M+H]*. ‘” H NMR (CDCl): 8 2.70 (dd, 1H, J,=18.5,

J»=7.0), 2.46-2.40 (m, 2H), 1.90 (d, 1H, J=6.2), 1.60 (t, 1H, J=6.5), 1.40-1.15 (m, 7H), 1.10-0.88 ( m, 2H). ° : Example (49-795): Preparation (.+-.)-5-(Spiro-[1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropaa]pentalene- -1, 1'-cyclohexan]-4-yl)-1H-tetrazole

NN

E the N

WN

N's dream

H

(8-9) The title compound was prepared in a manner similar to that in Example 0

MS: m/z (ES*): 279 [M+Na]", 257 [M+H]", 229 [M-N,+H]". '"H NMR (CD;0D): § 3.20-2.90 ( m, 1H), 2.75 (dd, 1H, J;=16.5, J,=1.0), 2.15-2.08 (m, 2H), 1.67-1.40 (m, 6H), 1.40-1.24 (m, 2H), 1.21 -1.12 (m, 1H), 1.07-0.98 (m, 1H).

Sa Y A _ Example (Ae) Preparation: (.+-.)-exo-1-allyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropala]pentale- ne -4- carboxylic acid Step (A): Preparation: cyclobutyldiphenylsulfonium trifluoromethanesulfonate ° and 0850 °C A solution (1.9 can), + (cyclobutanol mmol) in YO ml of DCM was cooled to . l m and addition of dry pyridine (V,¥0) ml; 16.1 mmol) followed by 1.9 “Ja 7.77) mM trifluoromethanesulfonic anhydride (Use) in 1 ml of DCM and the solution was allowed to warm to room temperature within an hour Then pentane (ml) was added and the resulting mixture was shaken and filtered. The filtrate was concentrated under reduced pressure in a bath at room temperature. All volatile solvents were removed. The remaining oil was cooled to -10°C and (017) diphenylsulfane added ml; Resulting by vacuum filtration J pa all on cyclobutyldiphenylsulfonium trifluoromethanesulfonate £, AT an VAY (770 mmol)

-YAY-

MS: m/z 65 :L 241 [C16H7S]". , 6H), 5.90-5.78 (m, 1H), 5.15 (ddd, 2H, J,=14.9, J,=10.3, J;=1.4), 4.48 (t, 2H, J=14.2), 2.45 (dd, 2H, J,=13.8, J,=7.1).(+-.)-ex0-6-allyl-bicyclo[3.1.0Jhexan-2-one Step B: Prepare

H

H 0 ee body V,AY +) cyclobutyldiphenylsulfonium trifluoromethanesulfonate The t-butyl lithium solution was cooled and dripped with VA = up to THF ml Yo in (Use m 75 cyclopent-min; 71 mmol added). After 094 (Ja [,00] ) pentane molar V and stirring the solution at -8 m for (Ja ¥) THF mmol) in 7.75 «Ja ,190 (190) saturated 2-cnone and heating it to a temperature room temperature, NaHCO, 2 hours, and the reaction mixture was quenched by adding 1, extracting the solvent under reduced pressure, and purifying it with a DCM column chromatography. mL 1.1 aa 6.1 VA) as colorless oil (.+-)-ex0-6-allyl-bicyclo[3.1.0]hexan-2-one .(.+-.)-endo- 6-allyl-bicyclo[3.1.0]hexan-2-one 75 0 m contains approximately 5,6 "Js' H NMR (CDCl3): § 5.95-5.75 (m, 1H), 5.20-5.00 (m , 2H), 2.38-2.20 (m, 1H), 2.20-1.90 10 (m, 5H), 1.65-1.50 (m, 2H), 1.40-1.32 (m, 2H).

YY44

YAY - - Step (c): Prepare: (+-.)-exo-1-allyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentale-ne -4- carboxylic acid ethyl ester ‎H 0 ‎~~ ‎H was referred to in step (D). (Y=) The title compound was prepared in a manner similar to the method mentioned in the example

MS: m/z (ES): 255 [Wanta] , 233 [M+H]", 187 141-080 . 'H NMR :(O00) 6 5.91- 5.81 (m, 1H), 5.02 ( dd, 1H, J,=17.2, J,=1.6), 4.92 (dd, 111, 110.3, J=1.6), 4.34 (q, 2H,

J=7.1),2.97 (dd, 1H, J;=17.1, 1,=6.3), 2.86 (d, 1H, J=17.1), 2.22-2.14 (m, 2H), 2.11-2.00 (m, 2H) , 1.36 (1, 3H, J=7.1), 0.80 (septet, 1H, J=3.4). Step (d): Prepare 0 (-+-.)-exo-1-allyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentale-ne- 4- carboxylic acid H 0 AH ABH Ho -NH The title compound was prepared in a manner similar to the method mentioned in Example (9-©).

-YAY-

MS: m/z (ES"): 227 [M+Na]", 205 [M+H]", 187 [M-OH]". 'H NMR (CD;CN): § 6.00- 5.88 (m, 1H), 5.13 (dq, 1H, J1=17.2, J,=1.7), 5.03 (dq, 1H, J;=10.3, J,=2.1 ), 2.92 (dd,

IH, 1216.8, 1225.8( 2.78 (d, 1H, J=17.0), 2.3-2.0 (m, 4H), 0.71 (septet, 1H, J=3.4).: Example of a stallion: preparation (.+-. )-exo-1-allyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza- - °cyclopropaja]pentalene

H

H for N, 9. || R H \- NH (86-9) and then prepare the title compound in a manner similar to the method mentioned in an example

MS: m/z L: 251 [M+Na]", 229 [M+H]", 201 [M-N,+H]". '" H NMR (CD;CN): 6 5.98-5.84 ( m, 1H, CH=CH), 5.12 (ddd, 1H, 117.2, ,=3.6, J;=1.7,CH=CHH), 5.01 (d, 0 111.000, 1H, 1210.2, J,=3.3, J5=1.4 , CH=CHH), 2.98 (ddd 1H, J,=16.3, J,=4.8, H1 2.88 (d.1H, J=16.3), 2.14-2.04 (m, 2H), 0.80 (septet, 1H , J=3.4).: Example (K-7 TM): Preparation cyclopropa[a]pental-ene-4-carboxylic acid : \o

Step 0: Preparation of (.+-.)-endo-1-allyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pental-ene-4- carboxylic acid

H 0 /111 I~ 0 0 Balhi was prepared by step D 0” ( 7-9 ) and then the title compound was prepared in a manner similar to the method mentioned in the example. (<=) by step (Ar —4 ) using the mixture of stereoisomers mentioned in an example

MS: m/z (ES"): 255 [M+Na]', 233 [M+H]", 187 [M-OEt]". 'H NMR (CDCl): § 5.84- 5.74 (m, 1H) , 5.00 (dd, 1H, J,=17.2, J,=1.7), 4.95 (dd, 1H, J;=10.2, J,=1.5), 4.39-4.31 (m, 2H), 2.95 (dd, 111, J;=17.5, J,=6.9), 2.70 (d, 1H, J=17.5), 2.44 (1, 1H, J=7.6), 2.31 (dd, 1H, J;=14.5, J,=6.5.) , 1.79-1.66 (m, 2H), 1.42-1.33 (m, 4H, including 1.37 (t, 3H, 01)

J=7.1)). Step B: Prepare (.+-.)-endo-1-allyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pental-ene-4- carboxylic acid

H 0 ym J 1

H N -NH Yo . (*- q ) Then prepare the title compound in a manner similar to the method mentioned in an example

—_ Y A M —

MS: m/z (ES). 227 [M+Na]", 205 [M+H]', 187 [M-OH]". HNMR (CD;CN): 6 5.68- 5.56 (m, 1H), 4.81 (dq, 1H, J;=15.5, J;=1.7), 5.03 (dq, 1H, 1110.2, J,=1.4), 2.68 (dd,

IH, 1)=17.4,1,=6.8), 2.43 (d, 1H, J=17.3), 2.17-2.12 (m, 1H), 2.10-2.03 (m, 1H), 1.61- 1.50 (m, 1H) , 1.45-1.36 (m, 1H), 1.13 (pentet, 1H, J=7.8). Preparation (AT) eg oo (.+-.)-endo-1-allyl-4-(2H-tetrazol-5 -y1)-1a,3,5,5a-tetrahydro-1H-2, 3-diaz-a-cyclopropalajpentalene

H

H A N

N

_ 11 JN

H the NH The title compound was prepared in a manner similar to the method mentioned in Example (2-49); by using a mixture of step (b) “(A” 1) JE dimers mentioned in 0

MS: m/z (ES): 251 [M+Na]*, 229 [M+H]", 201 [M-N,+H]". 'H NMR (CD;CN): § 5.77-5.68 (m, 1H), 4.92-4.80 (m, 2H), 2.88 (dd, 1H, J,=16.7, J,=6.8), 2.64 (d, 1H ,

J=16.7), 2.37-2.30 (m, 1H), 2.30-2.23 (m, 1H), 1.75-1.67 (m, 1H), 1.55-1.476 (m, 1H), 1.29 (pentet, 1H, J=7.9 ). Example: (4-4+): Synthesis 0 (-+-.)-exo0-4-methyl-3b,4,4a,5 tetrahydro-1 H-cyclopropa[3,4]cyclopenta[ 1 ,2- c|pyrazole- 3-carboxylic acid

YY4a4

Step A: Prepare (+-.)-exo-d-methyl-3b,4,4a,5-tetrahydro- 1H-cyclopropa[3,4]cyclopentaf1,2- -c]pyrazole- 3- carboxylic acid ethyl ester 0 J L 0 H « NH

N

By step (2) of oY -9) then prepare the title compound in a manner similar to the method mentioned in the example: from 1:1 mixture in the ratio of 6-exo-methylbicyclo[3.1.0]hexan-3-one and 6-endo-methylbicyclo[3.1.0]Thexan-3-one See P. S. Mariano, E. Bay, D.G. Watson, 1. Rose, and C. Bracken, J.Org. Chem. 1980, 45, 1753; J. Nishimura, N. Kawabata, J. Furukawa, Tetrahedron. 1969, 25, 2647 va

MS: m/z (ES™): 229 [M+Na] 7, 207 [M+H] * 161 [M-OEt] 0 NMR (CDCl): 6 4.39 (t, 2H, J=7.2 ), 2.96 (dd, 1H, J}=16.9, 1=6.6), 2.82 (d, 1H, J=16.8), 2.03-2.01 (m, 1H), 1.89-1.85 (m, 1H), 1.40 (t , 3H, J=7.2), 1.14 (d, 3H, J=6.1), 0.69-0.64 (m, 1H). Step (b): Preparation of (+-.)-exo-4-methyl-3b,4,4a,5-tetrahydro-1 H-cyclopropa[3,4]cyclopenta[1,2- -c]pyrazole- 0 3-carboxylic acid

- YAY - 0

H « _NH

N

The title compound was isolated during the reaction mentioned in Example (84-4); In step (a).

MS: m/z (ES): 179 [M+H]*, 161 [M-OH]". 'H NMR (CD;CN): 8 2.90 (dd, 1H,

J,=16.5, 176.6), 2.74 (d, 1H, J=16.0), 2.02-1.99 (m, 1H), 1.88-1 78 (m, 1H), 1.13 (d, 3H, J=6.1), 0.62 -0.55 (m, 1H). °:85-49( Ex. (.+-.)-endo-4-methyl-3b.4,4a,5-tetrahydro-1 H-cyclopropa[3,4]cyclopenta[1,- 2- ¢]pyrazole-3-carboxylic acid : Step A: Prepare (+-.)-endo-4-methyl-3b,4,4a,5tetrahydro-1 H-cyclopropa[3,4]cyclopenta[1, 2 -c]pyrazole-00 3-carboxylic acid ethyl ester .0 2 Jd

H « NH

N

(2) The title compound was prepared in a manner similar to that mentioned in Example (?-? ( ¢) by step using the mixture of the enantiomers mentioned in Example (84-4); by step (a).

MS: m/z (ES): 229 [M+Na]*, 207 [M+H]", 161 [M-OEt]". tide

What - : Step (b): Prepare (+-.)-endo-4-methyl-3b,4,4a,5tetrahydro-1H-cyclopropa|3,4]cyclopentafl,2--¢]pyrazole -3-carboxylic acid. 0 ” Alu OH

H « NH

N

(1) the title compound was isolated during the reaction in Example (58-49); by step 0

MS: m/z (ES): 179 [M+H], 161 [M-OH] 7.” HNMR (CD;CN): 3 2.83 (dd, 1H, 1,216.8, 1,=6.9), 2.55 (d , 1H, J=16.9), 2.29 (t, 1H, J=6.9), 2.10 (dd, 1H, 1114.4, J,=6.6), 1.37-1.31 (m, 1H), 0.61 (d, 3H, J= 6.4).: Example (below): preparation of (+-.)-endo-1-cyclopropylmethyl-1a,3,5,5a-tetrahydro-1 H-2,3-diaza-cyclopr- \ opa[a] pentalene-4-carboxylic acid

N~2.01

HO

H 0 4-(2-Todo-ethyl)-2,2-dimethyl-[1,3]dioxolane : Step A: Preparation of PhsP, Im, Wa “Lo 0 —— SS © "Aon THF/CH,CN A

- 9m - dissolved (VY) Triphenylphosphine mM “dso (48 g) YVY) imidazoles mmol; 11 g) in acetonitrile /THF (at a ratio of 0 (Ja Yor 0") and the mixture was cooled under an ice bath and iodine (177 mmol; ;; g) was added in four parts with vigorous stirring during Yo min. The resulting slurry was heated to 17 °C and then cooled to 0 °C.

Yo (Js Mm 101) (4-)-2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol Add oo min. The mixture was stirred at room temp overnight. Chromatography as a clear oil. 4-(2-iodo-ethyl)-2,2-dimethyl-[1,3]dioxolane yielded silica gel 'H NMR (400 MHz, O00'). 6 4.18-4.12 (m, 1H), 4.06 (dd, 1H, drag 8.0112, J, 6.1 01

Hz), 3.55 (dd, 111, J, = 8.0 Hz, J,= 6.5 Hz), 3.28-3.17 (m, 2H), 2.11 -1.98 (m, 2H), 1.38 (s, 3H), 1.33 ( s, 3H). Step B: Prepare [4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-but-1-ynyl}-trimethyl-silane except 1 ml Bulli ml for 1 | DMPU 4 cl 0,¥ molar (YA) mmol was slowly added; Buli (Jo 1 in hexane at -a VA) to a solution of TMS-acetylene (mmol; 1,/g) in THF Jor anhydrous DMPUy (no ¥ fill 777 mM mol) and then 4-(2-lodo-ethyl)-2,2-dimethyl-[ 1,3]dioxolane was added

— .qla - to the mixture. It was stirred at -a VA for 11 minutes and slowly warmed to room temperature. The reaction mixture was quenched with saturated 111.01, extracted by EtOAc, the organic co-layer was washed with H,O, then brine, dried with MgSO4, and concentrated. Chromatography of JY) silica gel around hexane [EtOAc 701] yielded: 4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-but-1 -ynyl}- trimethyl-silane 0 as clear oil.' H NMR (400 MHz, CDCl): 8 4.19-4.12 (m, 1 H), 4.07 (dd, 1H, J, = 8.0 Hz, J,=6.0 Hz) , 3.57 (dd, 1H, J, = 8.0 Hz, J,= 6.9 Hz), 2.39-2.26 (m, 2H), 1.86-1.79 (m, 1H), 1 76- (m, 1H), 1.39 (s, 3H), 1.34 (s, 3H), 0.13 (s, 9H). )-but-1-ynyl]-trimethyl-silane MOL K,CO3 MLA MLA B O — | ~~ OA TT MeOH = == 1 K,CO added; ) 9 ¢ mmol ml" 1 g) to a solution of: 4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-but-1-ynyl]-trimethyl-silane ) 23 mM; JE silica gel chromatography around hexane [EtOAc NY] yielded: 4-But-3-ynyl-2,2-dimethyl-[1,3]dioxolane as a clear oil.

- Yay - 'H NMR (400 MHz, 086 4.215 (m, 1 H), 4.05 (dd, 1H, J,=80Hz J,=6.0

Hz), 3.55 (dd, 1H, J;= 8.0 Hz, J, = 6.9 Hz), 2.31-2.26 (m, 2H), 1.94 (t, 1H, J = 2.6 Hz), 1.84-1.75 (m, 1H ), 1.73-1.68 (m, 1H), 1.38 (s, 3H), 1.33 (s, 3H). 4-(5-Cyclopropyl-pent-3-ynyl)-2,2-dimethyl-[1 ,3]dioxolane : Step 8: Preparation of MN8 __A 0 L pb L Br DMPU — 1 1 YA-mL) at 0 mmol (0.0 mmol) hexane in Buli to which a 0.¥ M solution of

Ev g) in 0 mmol 1) 4-But-3-ynyl-2,2-dimethyl-[1,3]dioxolane to a solution of 10 mmol; 7 g). It was stirred at -8°C for (0140 yt) anhydrous and anhydrous THF (ml saturated NH4Cl) min and slowly warmed to room temperature. And then the reaction mixture was quenched using, and the common organic layer was washed using 0:11 and EtOAc solution and extracted by 0 to about (silica gel) chromatography and its concentration was MgSO, saline and dried by: to Obtaining (hexane [EtOAc 0 as a clear oil. 4(5-Cyclopropyl-pent-3-ynyl)-2,2-dimethyl-[1,3]dioxolane 'H NMR (400 MHz, CDCl3)): 4.22-5.15 (m, 1H), 4.07 (dd, 1H, J; - 8.0 Hz, J, = 0

Hz), 3.57 (dd, 1H, J; = 7.9 Hz, J, = 7.1 Hz), 2.29-2.23 (m, 2H), 2.20-2.16 (m, 2H), 1.83- Vo 1.77 (m, 1H), 1.72-1.65 (m, 1H), 1.40 (s, 3H), 1.35 (s, 3H), 0.91-0.86 (m, 1H), 0.46- 0.41(m, 2H), 0.21-0.17 (m, 2H).

yay - - shal 5 (e): Preparation: 4-(5-Cyclopropyl-pent-3-enyl)-2,2-dimethyl-[1,3]dioxolane Y) quinoline added 1 + mmol; YEA mg) to a solution of : 4-(5-Cyclopropyl-pent-3-ynyl)-2,2-dimethyl-[1,3]dioxolane . (17, ml 460 g) in hexane (© ml); followed by the addition of Pdfo to 504 (YAS Ba, + mmol). M was stirred at room temperature under an atmosphere of Hy for a period of time; hours. TLC has shown that the reaction is complete. And its filtration through celite and its concentration. It was diluted with hexane, washed with petrella, then brine, and dried on MgSO. The chromatography of Y) silica gel to about LY (hexane [EtOAc) resulted in obtaining: 4-(5-Cyclopropyl-pent -3-enyl)-2,2-dimethyl-[1,3]dioxolane as a clear oil.'H NMR (400 MHz, CDCl3): § 5.52-5.45 (m, 1H), 5.40-5.34 (m,1H) ), 4.11-4.04 (m, 1H), 01 Hz, J,= 6.0 Hz), 3.51 (t, 1H, J = 7.5 Hz), 2.17-2.04 (m, 2H), 7 8.0 free ( dd, 1H, J 4.02 (t,2H, J = 7.0 Hz), 1.74-1.66 (m, 1H), 1.58-1.49 (m, 1H), 1.41 (s, 3H), 1.35 (s, 3H) , (m, 1H), 0.43-0.39 (m, 2H), 0.08-0.04 (m, 2H). 0.73-0.68 shal 5 (f): preparation of 7-Cyclopropyl-hept-5-ene -1,2-diol 80%H 9 mOA SRA iad Ho A ~< \o — +,Y+) .4-(5-Cyclopropyl-pent-3-enyl)- has been stirred 2,2-dimethyl-[1,3]dioxolane g 16 mmol) in 788 (Je©) ACOH overnight at room temperature. focus and refine it

- Yar - to collect (hexanes) in EtOAc 79580 about Ve) silica gel chromatography: as a clear oil. 7-Cyclopropyl-hept-5-ene-1,2-diol 'H NMR (400 MHz, CDCl3): 8 5.52-5.47 (m, 1H), 5.41-5.35 (m, 1H), 3.77-3.71 (m, 1H), 3.66 (d, 1H, J = 11.2 Hz), 3.46 (dd, 1 J;=11.2 Hz, J,=7.7 Hz), 2.19-2.10 (m, 2H), 1.97 (t, 2H, J = 7.1 Hz), 1.53-1.46 (m, 2H), 0.74-0.68 (m, 1H ), 0.44-0.39 (m, 2H), 0.08-0.04° (m, 2H). 2.-(4Cyclopropyl-but-2-enyl)-oxirane Step (0): Preparation of “0 << mT, = I~

THF — : mmol) to a solution of YVAE vol 1 (220 sodiuim hydride 7-Cyclopropyl-hept-5-ene-1,2-diol Ve)© 8 g added; 9,748 mmol) in (Je Vo) THF at zero degrees Celsius. The mixture was slowly warmed to room temperature and stirred for one hour. Vey (TrisIm VY mmol) was added once at 0°C followed by stirring at room temperature for 1.5 hours. The mixture was quenched with water, extracted with EO, and the organic layers were washed with brine, dried on 1/850 hexanes in EtOAc ZV silica gel, filtered, and concentrated. Chromatography 1 2-(4-Cyclopropyl-but-2-enyl)- resulted in obtaining the hexanes in EtOAc 714 gradually to a clear oil.

- Yat - 'H NMR (400 MHz, CDCl3): § 5.54-5.48 (m, 1H), 5.44-5.37 (m, 1H), 2.94-2.91 (m, 1H), 2.75 (dd, 1H, J;= 4.9 Hz, J, = 4.1 Hz), 2.48 (dd, 1H, J, = 5.0 Hz, J,=2.7 Hz), 2.19 (q, 2H, J=7.3 Hz), 1.98 (t, 2H, J = 7.0 Hz), 1.62-1.56 (m, 2H), 0.75-0.66 (m, 1H), 0.44- 0.39 (m, 2H), 0.09-0.05(m, 2H). 6-Cyclopropylmethyl-bicyclo[3.1.0]hexan-2-0l Step h: Preparation © ne om Le b —_—

MTBE Ras n-Butyllithium 7.5 M (da, ©) hexanes, mmol) at VA - 5 was added to a solution of Y,V «Ja 17 4 (tetramethylpiperidine mmol) in MTBE (0 mL). The solution was slowly warmed to approximately 0°C and added via tube to 0 solution of 0.894 (ax +, YAA) 2-(4-cyclopropyl-but-2-enyl)-oxirane) in MTBE (Y) ml) within 10 minutes at 0°C. The mixture was allowed to warm to room temperature, stirred overnight, and washed with 1 N HCI (twice) and then saline. The organic layers were dried at 14850, filtered and concentrated to obtain: 6-cyclopropylmethyl-bicyclo[3.1.0]hexan-2-ol as a clear oil. H NMR (400 MHz, CDCl3): 64.19 (d, 1H, J = 5.5 Hz), 2.15-2.06 (m, 1H), 1.75 (dd, \o 1H, J, = 11.0 Hz, J, = 9.7 Hz), 1.69-1.52(m, 4H), 1.42 (dd, 1H, J; = 8.1 Hz, J; = 6.2 Hz),

- Yao - 0.98-0.87 (m, 2H), 0.75-0.68 (m, 1H), 0.46-0.41 (m, 2H), 0.03 (dd, 2H, J; =9.1 Hz, J, = 4.7 Hz). 6-Cyclopropylmethyl-bicyclo[3.1.0]hexan-2-one Step (i): preparation

HoH Hoo s TPAP, NMO - 8. ———— = 4A MS 8

H H

NMO (N-Methyl morpholine N-oxide) mg) and Y++) 4A Addition of Ll ae Molecular Sieves to a Solution (Use 0775 mM cama YO,6 6A) TPAP Label (Usa mg; 7.90 mM YT4) as a clear oil. 2.16 (dd, 1H, J, = 13.4 Hz, 11-4

Hz), 1.97-1.86 (m, 3H), 1.61-1.53 (m, 1H), 1.38-1.28 (m, 2H), 0.82-0.73 (m, 1H), 0.49- 0.44 (m, 2H), -0.09 0.05 (m, 2H). \ : Step (j): Preparation of (.+-.)-endo-1-cycloproylmethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopro-pa[a]pentalene-4 -carboxylic acid ethyl ester

N~

Hy, NH = OEt

H b H 0 . (2) In step 0 (-9) the title compound was prepared in a manner similar to that in Example 1

- yan -

MS m/z (ES”): 247.3 [M+H]”, 269.1 [M+Na]"; For NMR (400 MHz, CDCl3): 8 4.38-4.29 (m, 2H), 2.93 (dd, 1H, J; = 17.4 Hz, J, = 6.8 Hz), 2.65 (d, 1H,J = 17.4 Hz ), 2.40 (t, 1H, 126.9 Hz), 2.23 (dd, 1H, J; = 14.0 Hz, J, = 6.7 Hz), 1.40-1.35 (m, 1H), 1.37 (t, 3H, J = 7.1 Hz ), 1.03-0.96 (m, 1H), 0.78-0.64 (m, 2H), 0.39- 0.32 (m, 2H), -0.02- -0.12 (m, 2H). Step (k): Preparation of 0 (.+-.)-endo-1-cyclopropylmethyl-1a,3,5 ,5a-tetrahydro-111-2,3-diaza-cyclopr-opa[a]pentalene-4 -carboxylic acid 8 == OH

H WS 0 Then prepare the title compound in a manner similar to the method mentioned in Example (4-). MS m/z (ES): 21 9.3 [M+H]"; 'H NMR (400 MHz, CD;0D): § 2.95 (dd, 1H, J, = 18.5 01 Hz, J, = 6.9 Hz), 2.69 (d, 1H, J = 18.5 Hz), 2.40 (1, 1H, J = 6.9 Hz), 2.17 (dd, 1H, J, = Hz, J, = 6.7 Hz), 1.47-1.42 (m, 1H), 1.15-1.08 (m, 1H), 0.86-0.79 (m, 1H), 0.76- 14.0 (m, 1H), 0.44- 0.36 (m, 2H), 0.02- -0.11 (m , 2H). The inventions that were disclosed and that fall within the scope of responsibility of the skilled person in this field within the previous discovery and within the elements of protection that follow later.

- 19 -

Although a variety of expression vectors are available to those skilled in this field for use in endogenous and non-endogenous GPCRs, it is highly preferred for the vector used to be PCMV. This vector was deposited with an American type culture group (ATCC) in 11 Oct University Blvd., Manassas, VA 20110-2209 USA) 1448 10801) under the terms of the 6 Budapest Treaty on the International Recognition of Deposition of Microorganisms for the Purpose of Patent Procedure. The DNA was tested by the ATCC and determined to be viable. The ATCC has identified No

The following PMV filing: ATCC No. 707781

Claims (2)

- Y4A- Claimant (la) A compound selected from compounds of the formula - 1 1 Ry Ry Rj X XT H 85 Rk for (Ia) JF salts or hydrates or solutes thereof are pharmaceutically acceptable ¢ where: © * is N and 2 is “CRy” or X is “CRy” and 7 is ON Res Ry 1 are selected separately from the pool of 11 acyl Cres and alkyl Cis alkoxy Cis alkenyl C65 acyloxy Cis 7 and from alkylamine and alkylcarboxamide Cj. A and from alkynyl Cpe alkylthiocarboxamide and E alkylsulfinyl Cie alkylsulfinyl Cie alkylsulfonamide q and alkylthio and 0 bitter alkylureyl Cy. alkylthioureyl and amino and from alkylamido and Alkoxy - Cis — carbo alkylthioamido Cj. alkylsulfinyl from amino carboxy s carboxamide s 1 and cyano dialkylamino C45 cycloalkyl lin and VV bitter dialkylthiocarboxamide Ci. dialkylcarboxamide and halogen and haloalkyl Cs haloalkylsulfinyl Ciss haloalkyl Ci. haloalkoxy Cj VY¢ heterocyclic and heterocyclic group haloalkyl thio Cis sulfingl 0 ¢ thiol and sulfonamide s nitro hydroxyls 01 Ry VY Will are selected separately from the group consisting of acyl Cros H and acyloxy C14 YA and alkoxy Ciss alkenyl and of alkyl zyme alkylamine and Cis alkynyl Cy alkylthiocarboxamide or alkylcarboxamide Cys 14 alkylsulfinyl Cis alkylsulfinyl Ci. alkylsulfonamide 0 alkylthio ware f - Yas - amino s alkylamido Cis amino alkylureyl and alkylthioureyl Cis 71 arylthio 5 arylsulfonyl s arylsulfinyl and alkylthioamido Cis alkylsulfinyl bitter VY cyano s carboxy s carboxamide s alkoxy — Cis — carbo carbamimidoyly YY and dialkylamino Cs. cycloalkyloxy and cycloalkyl joule 4 dialkylamido — Cs dialkylthiocarboxamide C,¢s dialkylcarboxamide Cys Y© haloalkyl Cis haloalkoxy Css halogens dialkylthioamido Y1 haloalkyl thio Cis haloalkyl sulfinyl bitter© haloalkylsulfinyl Cs Y V is an inhomogeneous toroid oxy, heterocyclic group YA heterocyclic group, sulfonyl heterocyclic group, sulfonyl heterocyclic group ?, heteroaryl group, heteroaryl 5 heterocyclic group carbonyl Ye Exist Cus ¢ thiol 3 sulfonic acid s sulfonamide s nitro s hydroxyls carbonyl Y) mentioned substitution groups are chosen by alkyl Cig optional substitution in the YY Cis alkoxy group between acyloxy Cres acyl from the group consisting of M FV amino s alkylthio Razer alkylsulfinyl and alkylsulfinyl in alkylamino 4 cycloalkyl C373 cyano carboxys carboxamide alkoxy — Cig — carboy Yo Cis haloalkoxy and from dialkylamino Cp cycloalkyloxy C375 1 hydroxyl s haloalkyl thio from haloalkyl sulfinyl and haloalkylsulfin yl YV or ¢ phenyl and phenoxy s nitros YA Cis form with the carbon atom to which each is attached a group of R35 R, 4; cycloalkyl 0 acyl Cis and 18 and with each being selected separately from the group of 11 and 1 alkylamine wren alkyl Cis alkoxy Ces alkenyl weed acyloxy Cigs!;? Smooth alkylsulfonamide ¢¢ and alkylsulfinyl ir from alkylsulfinyl and from alkylthio and 45 er alkylthioureyl and m alkylureyl and alkoxy Ci. — carbo amino dialkylamino Cj cycloalkyl C375 cyanos carboxys carboxamides ¢7 and dialkylcarboxamide Cj 6 and halogens dialkylthiocarboxamide and haloalkyl Cs haloalkylsulfinyl C;¢s haloalkyl Cis haloalkoxy Ci; ¢A haloalkyl thio Cig sulfinyl £9 and heterocyclic group heterocyclic thiol s sulfonamide s nitro s hydroxyls 0 ¢ f)0 be the carbo group — ter alkoxy or tetrazol-5-yl 0 carboxy. 1?- compound according to claim (1); where: R39 R, Y are each selected separately from the group consisting of 11 acyl Cres and alkyl Cis alkoxy Cis alkenyl Cis acyloxy Cis Y Win alkylamino and ¢ of alkylthiocarboxamide Cj alkylcarboxamide min Cis alkynyl alkylsulfonamide ° alkylthio cis alkylsulfinyl zomer Cis alkylsulfinyl and 1 of alkylthioureyl rum amino alkylureyl and amino y alkylamido l of arylsulfinyl 5 alkylthioamido Cs alkylsulfinyl A, carbo y carbamimidoyl arylthio - bitter - alkoxy cycloalkyloxy C375 cycloalkyl C375 cyanos carboxys carboxamide 1 0 min dialkylamino rmen dialkylcarboxamide rin dialkylthiocarboxamide 11 m - dialkylamido tumor haloalkoxy C;.ss halogens dialkylthioamido haloalkyl Cjgs 01 and of haloalkylsulfinyl m cis haloalkyl sulfinyl haloalkyl thio VY heterocyclic group heterocyclic and oxycyclic group 4 heterocyclic heterocyclic and a heterocyclic sulfonyl group — 7 0 1 — heteroaryl s heterocyclic carbonyl group and VO phenoxy 5 cycloalkyl - oxy Caz nitro 5 hydroxyl s heteroaryl carbonyl 11 group; Where there is an optional substitution in the 5 sulfonic thiol, the sulfonamide base, and the aforementioned compound 1, with substitution groups chosen from the group in which the alkyl group of VA is an alkylamine between the alkoxy acyloxy Cres acyl Cre to be of 14, amino y alkylthio and alkylsulfinyl Cis alkylsulfinyl AC cycloalkyl C375 cyanos carboxy s carboxamide s alkoxy — Cig — carbo 71 and haloalkoxy Cis dialkylamino Ci. cycloalkyloxy, YY haloalkyl thio Cis haloalkyl sulfinyl and M haloalkylsulfinyl Cis YY ¢ phenyl 5 phenoxy nitros hydroxyls Y ¢ provided that they are 81 and 84 in the same. oY)? - Composite to claim (1) or 1 direction. (CRT and 7 being N be X where oF) Compounded to either claim - + 1 .carboxy or alkoxy - Ci - carbo R75 Y (CRT, 7 be oN, be X, where oF) compounded under any of the claims - * 1. carboxy, 17 be 1 (CRT, 2 be N be X where oF) compounded according to any of the claims - 1 1 tetrazol-5-yl . be R7 5 Y Yvaa LAS - 1 7 - compound according to any of the claims (1-7); where X is (CRT and 87 is alkoxy 01-6 - carbo or carboxy ¢ or 7 is N A) - composite under any of the oF claims) where X is R75 “CRT is carboxy Y ” and 7 is N 1 4 - composite under any of the oF claims) where X is R75 «CRT is tetrazol-5-yl ; and 7 is N 0 1 - compound according to any of the claims ( = 4)" where 11 is H or halogen 11 1 - compound according to any of the claims (1-1); where 81 is H 11 1 - compound according to any of the claims (1-11); where 84 is halogen 3 H 1” 1 - compound according to any of the claims (1-11); where 84 is 11. VE) - lis compound of any of the claims (1-4); where both RI and 84 Y are H V0) = compound according to either Claims (1-41), where RS is halogen § H YYa4q — SARS H is RS compounded according to any of the claims (1-4?1); where - 11 1 'halogen sl H is R6 compounded according to any of the claims (1-17); where - 17 1 H is compound according to any of the claims (1-17); where 86 is - VA) R63 RS where each of (VE) is compounded according to any of the claims - 11 1 He is a Y statement 71 1 - Compound according to any of the claims (1-4); where RI, 84 7, 65, and 86 Hes ke Ry is compounded according to any of the claims (1-17); where both - 1 71 ; Where there are alkyl halogens, 0 H, and 8 separately from the group consisting of - " mentioned with substitution groups, then an optional substitution alkyl is selected in the group of Mr 7 and alkylamino Ces alkoxy Ciss acyloxy Cis from the group that Consists of ¢ and amino alkylthio Cis alkylsulfinyl Ces alkylsulfinyl m ° cycloalkyloxy Cs; 1 Cis dialkylamino haloalkoxy med and haloalkyl thio bitter haloalkyl sulfinyl C ss haloalkylsulfinyl no of .phenyl and phenoxy and hydroxyl Ro A Cis or H being Ry where (Ye) is a compound according to any of the claims - YY) Cis is an optional substituent in Cua; alkyl halogens are 11 and Rs ¢alkyl Yt — - and the mentioned alkyl with substituent groups to be selected from the group consisting of: ¢ m-alkylamino cis alkoxy cis acyloxy mer alkylsulfinyl r alkylsulfinyl 0 m amino alkylthio and cycloalkyloxy ryon dialkylamino Cis haloalkyl sulfinyl C4 haloalkylsulfinyl Ciss haloalkoxy Cis 1 No phenoxy s hydroxyls haloalkyl thio and phenyl . YY - compound lh of any of the claims (1-70); where Ry is H, Crs is Rj talkyl Y is H, or alkenyl cities, or Cis, or of cycloalkyl, halogen, or phenyl ¥; Cus there is an optional substitution in said alkyl Cr with 3 substituent groups chosen from the group consisting of alkoxy Cis alkylthio phenoxy hydroxyls ° and phenyl ¢ or 1 b with carbon atom _Al JS is attached to it to form a cyclopropyl group L or cyclopentyl or cyclohexyl . VE 1 - Compound according to any of the claims (YoY) where Ry is 1! or © talkkyl Y and ya H is an alkynyl, an alkyl, a halogen, or ©. phenyl; where 3 is an optional substitution in said alkyl Cr with substituent groups chosen from the ¢ group consisting of phenyl 5 phenoxy s hydroxyls alkoxy Cis . Yoo 1 - compound according to any of the claims (1-17); where 82 is -11 or (CHI) and 83 is H or CH3 or benzyl Oras - (CH; be 11- or Ry of any of the claims (1-17); where lh is a compound - YT) and 8 be 11 or 0 methyl, ethyl, n-propyl, isopropyl, isobutyl , n-butyl, n-pentyl, vinyl, v hydroxymethyl, methoxymethyl, benzyl, phenyl or phenoxymethyl : (CH; R = H being Ry for any of the claims (1-17); where Wh is a compound - YY) with 11 or 0" methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, v hydroxymethyl, methoxymethyl, benzyl, phenyl, phenoxymethyl, ¢ methylsulfanylmethyl, ethoxymethyl, cyclopropyl, 1-but-2-enyl, or allyl 8 or 1 of which has a JS group that forms with the carbon atom _ that Ryy Ry is bonded to ,. cyclohexyl or cyclopentyl 0 cyclopropyl A compounded according to any of the claims (1-7); where: -YA) or —~COEt or carboxyl be Ry and 7 be B8©; where oN is X Y ; or tetrazol-5-yl v and 7 « tetrazolyl § “CO,Et ar carboxyl Ry where “CR; X ¢ IN of which ° is 11; JS and what Rss Res R is 1 5¢CH; Or H be © 7 be 11 or R, A z 75 methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, 1 hydroxymethyl, methoxymethyl, benzyl, phenyl or phenoxymethyl. 01 YE) - compound according to any of claims (1-7), where: X ¥ is oN, 2 is “CRy, and b is tetrazol-5-yl § 0 carboxyl ; Res Rss Res 18. YF are 11 each; 4 85 is H or none; and © can be 11 (methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-pentyl, vinyl, 1 hydroxymethyl, methoxymethyl, benzyl, phenyl or phenoxymethyl v Ye) - compound according to for any of the claims (1-7); where: k is (N, 7 is “CRy, and b is carboxyl); or X 13 is “CR; and b is carboxyl or tetrazolyl + and 7 be {IN Ry € b Rss and some JS of which is tH © w8 be s¢CH; JH 1 d88 be benzyl of CH; J H ¢ 1 © - Compound of claim (1); chosen from any one of the following compounds: =N, 2 L NH 7 7 ~~ “OH > N < Q~” OH A\NS NH : Hm : 0 NH Haft : NH Lm NH 0 ' 0 0 XQ OH XU N ~~" OH \ \ \ N= NH : Dream NH : N= NH : - Y.VY -— 0 0 ¢ ~y~ OH ~~ “OH N and “1 N =" NH NH 0 ~~ 7 ~ / \ N\ n- NH : NE : 0 yum NH " ~~ 7 A ~NH : \ ~NH : 0 NE L NH 7 TTT OH TTT N N \ \ —0 \ \ n- NH : YM : N 0“ 2 >. 7 N H L , N H 9 Ab Tman \ \ Yam : Tull : 0 0 a 0 H ~~ Hoss 1 0 \ 8 A NH ; N= NH : 0 0 <> Sam OQ \ \ 11 Lm : NEL "1 0 N="% NH AA OQ Ct 1 \ \ VY L NH \ ; Hazm NH : yum sy 1 a \ \ VY N- NH : ham : 0 0 ~~ s nah bhass 1 lanum : nal m : YY44 - YA - _N =N N=" 2l NH { H- 0 NH Yo > 7 ~ 7 <=" 1 ka N \ \ N - N H 5 N 7 N H " 0 \ 0 N\ \ N=" \ 1 \ <n VY \ \ Yam: Bala ; 0 -0 0 A aS <r <Q A \ N - N H N 5 N - N H 5 = 0 —0 N NH HO =~. 7 PN =~ N = 0 3 \ N\ N Pd N H s N and N H ; =N, HO 1 NH HO % I love Y 0 They are N sea a N L NH N-~ NH; and of them are pharmaceutically acceptable. hydrates, salts and solutes and 71 compound according to claim (1); Chosen from any one of the following compounds: - FY 0 for “ 0 0 Y Maha Njah \ ~NH \ N ; meat: ; 0 N=" =, 3 on >< N \ \ H NH : Ns NH : Rho N 0 N 7 NH $ ~ 7 > or <>] in N \ N\ 0 0 8 8 m NH m NH : = N, = l \ NH 8 NH 4 yama N J =~ N 8 ~NH for no” 0 m ; n and 0 N=" = NH 7 > OH > N \ \ wo NH : wo NH : =N, 3 wo NH A \ N\ NH dream : wo NH - N N “F == 2 = NH 1 TO oH N \ \ Ni NH : Live NH : 0 ~~ “OH 1 0 No “ 00 of which are pharmaceutically acceptable hydrates, salts, solutes and 11 of claimant (1); selected from any of the following compounds, salts and compound Gk - FY and pharmaceutically acceptable solutes thereof: hydrates Y 3b,4,4a,5-Tetrahydro-2H-cyclopropa[3,4 [cyclopenta[ | ,2-c]pyrazole-3- ¥ carboxylic acid; : 1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-© carboxylic acid; and 1 4-(2H-Tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza- v cyclopropala]pentalene A 1! where the stereochemical configuration is FY compound according to claim-TE (a® 5a) or af and bY for each of the two carbon atoms defined as stereochemistry Y .1 for 1; Selected from any of the following compounds and salts and (1) Cb according to the claim - ©© 1. Pharmacologically acceptable Lie and soluble Y hydrates 1-Benzyl-1a,3,5,5a-tetrahydro-1H-2 ,3-diaza-cyclopropa[a]pentalene-4- ¥ carboxylic acid;¢ 1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza- ° cyclopropa[a]pentalene-4 -carboxylic acid; 1 1,1-Dimethyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3- v diaza-cyclopropa[a]pentalene; and A 1-Benzyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza- 1 cyclopropala]pentalene Ye; chosen from any of the following compounds and salts ) 1) Compound according to claim -©“ 1. Of these, pharmaceutically acceptable lish hydrates 5 7 1-Methyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene- 4- 1 carboxylic acid; ¢ I-Isobuty!-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4- 8 carboxylic acid; ,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pentalene-4-carboxylic v acid, A YY4q - YAY - 1-Pentyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropala]pentalene-4- 1 carboxylic acid; 0 1-Propyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[aJpentalene-4-1 carboxylic acid; VY 1-Methoxymethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-l carboxylic acid; Vi 1-Ethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid; 1 1-Benzyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropala]pentalene-4- VY carboxylic acid; YA 1-Benzyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4- 4 carboxylic acid ethyl ester; ve 1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4- 7 carboxylic acid ethyl ester; vy 1-Phenyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4- YY carboxylic acid ethyl ester; ve 1-Phenyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4- ve carboxylic acid; 71 1-Ethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic vv acid ethyl ester, YA 1-Methyl-1a,3,5,5a- tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-v4 carboxylic acid ethyl ester; ve 1-Pentyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4- 9 - 11 - carboxylic acid ethyl ester; YY 1-Isopropyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4- vY carboxylic acid; vi 1-Vinyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic vo acid ethyl ester; v1 1-Vinyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid 99; FA 1-Ethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a] pentalene-4-carboxylic va acid ethyl ester; 3 1-Methoxymethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4- carboxylic acid ethyl ester; 3 1-Hydroxymethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropala]pentalene-4-tv carboxylic acid ethyl ester; and ¢ 1-Hydroxymethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza- ¢o cyclopropala]pentalene-4-carboxylic acid. 1; Selected from any of the following compounds and salts of (1) compound according to claim - TY). Pharmaceutically acceptable solubles thereof are hydrates and Y 1-Methylsulfanylmethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza- ¥ cyclopropala]pentalene-4-carboxylic acid, ¢ 1-Ethoxymethyl-1a, 3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4- 8 carboxylic acid; 1 1-Cyclopropyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4- 7 - 11 - carboxylic acid; A 1-Spirocyclopropyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene- 1 4-carboxylic acid; i. (E)-1-Propenyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-1 carboxylic acid; 'Y(£)-1-Propenyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-b carboxylic acid; 1-Phenoxymethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4- 10 carboxylic acid; 1 Spiro[12,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-1,1°- VY cyclopentan]-4-carboxylic acid; 1A Spiro[1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-1,1°- 4 cyclohexan]-4-carboxylic acid; y 1-Allyl-1a,3,5,5a-tetrahydro-1H-2,3 -diaza-cyclopropa[a]pentalene-4-carboxylic 7 acid; and VY 4-Methyl-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3- vy carboxylic acid; Yi 1-Cyclopropylmethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza- Yo cyclopropala]pentalene-4-carboxylic acid. va; Selected from any of the following compounds and salts (1) compound according to claim - ©* 1 and solubles thereof are pharmaceutically acceptable hydrates and - YE 1-Methyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza- ¥ cyclopropa[a]pentalene; 4 1-Ethyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-°cyclopropala]pentalene; 1 1-Propyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-l cyclopropala]pentalene; A 1-Isobutyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3- 1 diaza-cyclopropa[a]pentalene; Ve 1-Phenyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-1 cyclopropala]pentalene; YY 1-Benzyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-0 cyclopropala]pentalene; Ve 1-Pentyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza- Vo cyclopropa[a]pentalene; 1 1-Butyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza- VY cyclopropafa]pentalene; YA 1-Isopropyl-4-(2H-tetrazol-3-yl)-1a,3,5,5a-tetrahydro-1H-2,3- 4 diaza-cyclopropa[a]pentalene; ve 1-Phenoxymethyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H- 7 2,3-diaza-cyclopropala]pentalene; vy 4-(2H-Tetrazol-5-yl)-1-vinyl-1a,3,5,5a-tetrahydro- 1H-2,3-diaza- YY cyclopropala]pentalene; Yi 1-Methoxymethyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H- Yo SPA - 2,3-diaza-cyclopropala]pentalene; and 7 [4-(2H-Tetrazol-5-yl)-1a,3,5,5a-tetrahydro- 1 H-2,3-diaza- 7 cyclopropa[a]pentalen-1-yl]- methanol. YA TE) - compound according to claim ( 1 ); Selected from any of the following compounds and salts - and id 535 hydrates of them are pharmaceutically acceptable. 1-Cyclopropyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3- 1 diaza-cyclopropa[a]pentalene; ¢ 1-Spirocyclopropyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-°2,3-diaza-cyclopropa[a]pentalene; 1 (E)-1-Propenyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3- v diaza-cyclopropaa]pentalene; A(Z)-1-Propenyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3- 1 diaza-cyclopropala]pentalene; Ve 5-(Spiro-[1a,3,5,5a-tetrahydro-1H-2,3-diaza-1 cyclopropa[a]pentalene-1,1°-cyclopentan]-4-yl)-1H-tetrazole; VY 5-(Spiro-[1a,3,5,5a-tetrahydro-1H-2,3-diaza- for cyclopropala]pentalene-1,1’-cyclohexan]-4-yl)-1H-tetrazole; and Ve 1-Allyl-4-(2H-tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza- 1e cyclopropa[a]pentalene. 1 vt - - 1 £0 Compound under any of the claims (705-719); where the stereochemistry ¥ configuration of carbon atom defined as a) is 1 and the stereochemical configuration ¥ of carbon atom k 80 is 5. 1 1; - a compound according to any of the elements protection (0"-40); where the chemical configuration Y is stereochemistry of the priority group associated with the carbon atom identified as 1 7 inner. £Y 1 - compound according to any of the claims (1"- 40); wherein the chemical configuration Y is stereochemistry of the priority group associated with the carbon atom specified as dalla) ov 1 £7 - compound according to claim (1); selected from any of the following compounds and salts hydrates s Y and solutes thereof are acceptable for Sayd Lania: 0 ates > \ v yum (£8 - compound according to claim (1) selected from any of the following compounds and salts of hydrates Y and solutes thereof are pharmaceutically acceptable. No NH . Arim \_-OH = \ HS H 0 YYaq 1 - - 1 ©; - a compound of claim (1); selected from any of the following compounds and salts of "| and 8p0:81l and pharmaceutically acceptable solutes thereof. With the flag NH 1 | - = N = N\n- NH )£ 7- Compound according to claim (1); selected from any of the following compounds and the salts of hydrates s and solutes thereof are pharmaceutically acceptable H H -N, IN r Sn ~ N \ = non-H 1 7 - lik compound of protectant (1); selected from any of the following compounds and i 535 hydrates 7 salts of which are pharmaceutically acceptable. 0 oH' yama N\ n- NH EA) - compound according to claim (1); chosen from any of the following compounds and the salts of Y hydrates and solutes thereof are acceptable fish H 0 v A110 I ~ OH \ = H \- NH YY44 - A - 491 - a compound according to claim (1)”; selected from any of the following compounds and ld 55 hydrates Y salts thereof are pharmaceutically acceptable. 0 SS OH \ NH Y M 10 1 - Compound of claim (1); chosen from any of the following compounds and pharmaceutically acceptable s Y hydrates and solutes thereof: H 0 nm I OH Ho NN v H 51 1 - A compound according to claim (1); selected from any of the following compounds and the salts of hydrates and solutes thereof which are pharmaceutically acceptable. 0 ' OH b <— \ OY) - compound according to claim (1); ie: H 0 Oe Y \ titt = OH H \ ~NH -am - OF) - compound lh of claimant (1); chosen from which of the following compounds and salts of ? | ll sd hydrates, of which are pharmaceutically acceptable: 0 OH "~~ v in 1 0 ;e - compound of claim (1); selected from any of the following compounds and pharmaceutically acceptable salts of s Y hydrates and solutes thereof. 0 H \ Oh me!" / N HR 00) - compound according to claim (1); selected from any of the following compounds and salts of Y hydrates and solutes thereof acceptable as Ly. 0 y > Oh N \ Compound according to claim (1) chosen from any of the following compounds and salts - H 1 1. Lay and solvents thereof are acceptable hydrates Y H 0 J H \ ~NH Y Compound of claim (1); Chosen from any of the following compounds and salts - OV: Lay and solutes thereof are acceptable Sid hydrates Y YY44 YY. - - =N, NH i N ~~ \ NH ham 1 8e - compound according to claim (1); selected from any of the following compounds and the salts of hydrates and solutes thereof pharmaceutically acceptable . R N N H = H —N ON 4 ) 04 - A pharmaceutical composition comprising a compound according to any of the claims (0A) “- in combination with a pharmaceutically acceptable carrier. 60 1 - A pharmaceutical composition according to a claim Protect (59); also includes an agent selected from the group consisting of a-glucosidase, an aldose reductase inhibitor biguanides¥, an HMG-CoA reductase inhibitor, a fibrate s squalene synthesis inhibitor, and an enhancer of LDL catabolism angiotensin converting enzyme inhibitor, insulin 5-thiazolidinedione secretion enhancer, DP receptor antagonist \ (= use of a compound according to any of the protective elements (A=)°) and DP receptor antagonist 1 for the manufacture of a drug For use in the treatment of a metabolic disorder 1710 - - 1 17 - Use of a compound according to any of the Claims (1-58) and an antagonist of the DP receptor for the manufacture of a drug for use in the treatment of a disorder related to metabolism ¢ Cus the antagonist of the DP receptor is selected Mentioned from the group consisting of: 4 Composition (c) compound (b) of compound () MeO,S = and CL 2. Cn com “Ay CoH ~ TL : TL 0 ~~ al : “ICH 0 > 0° Ze CH cl ' compound ) ( compound (e) compound (3( N 2 COM )| 0 MeO,S Pa F cl v l m l nakri T rs “s_COH N 5 27 N 5 OL ° m ws Oa 27 wa m - compound (z) compound (h) Compound (g) SMe cl 50/6 cl SO,Me 5 the s— Xx xX 1 m 8 [ l ] [ l ] COH NTN coH | | |s word NN COH - Compound (J) Compound (k) Compound (j) SO,Me 0 0 1 m (5-4 se poe for "a NTS | Er | | for ON CO,H | 1 | NO NTN COH CO,H OY Compound (x) Compound N) Compound (3) SO,Me cl 0 806 5-5 S 806 cl oS 5 F 8 Tx | - +77 - Compound (R) Compound (F) of Compound (P) 04 502/6 0 0 50/6 RLB 50/6 0 | sot Vo Seo Be Nin L rahm COH NN CoH NTN COH (3) Compound (u) Component (0) Compound 1 SO,Me = cl SO;Me = =) SO,Me so PN s— (_)c VY NON COM She “a NTN CoH 4 SO,M = b He F \ con A Pa \ o N ND cop 7 a 0 he CH, cl i. Y. of compound (1) compound (z) compound (x) 0 0 Sat' 3 ] coH F 9 cl I BD meznene. BRT NT > 0 CH NN 0 _ Compound (A) Compound (A) Compound (AB) TT 1, 0 0 0, ML A NH H CD + ok "within TL 0 ° CHj ( = 1) Compound (Az) Compound (or) Compound YE Aio F N F .. & sab” Snni NH ae) pd C= 0 0 and CHs Compound (A) Compound (A) Compound (A) YR F. Nr, ACOH i NN F C COM Yv M J CoM q — )—CF Ao ~~ ee CHiO:S RIM ? YA, salt, soluble, or pharmaceutically acceptable Ala hydrate. AT) - use of a compound under any of Claims (58-1); for the manufacture of a drug for use in the treatment of dyslipidemia. TE = use according to any of Claims (17-71); where said individual Ls is object Y 1 5# - use lida of claim (715); Where the said mammal is a human being. 111 = compound pursuant to any of the claims (28-1); For use in a method of healing the body of a human or animal Y. 1 7+ - use of a compound pursuant to any of Claims (28-1); To produce a drug for use “in the treatment of a metabolic disorder. TA) = use of a compound pursuant to any of claims (1-28); to produce a drug for use 0 7 in the treatment of a metabolic disorder chosen from the group that -YY¢- 7 consists of Dual dyslipidemia, atherosclerosis ¢, coronary heart disease, insulin resistance, obesity 0, impaired glucose tolerance, and atherosclerotic disease 1, high blood pressure, hypertension, stroke V, syndrome X, heart disease, and type 1 diabetes [1]. 141 - use of the lids compound for any of the claims (1-/2); To produce a drug for use in the treatment of atherosclerosis + 71 1 - Use of a compound under any of the claims ¢(0A=1) to produce a drug for use In raising .1101 in the individual. 711 - A method for producing a pharmaceutical composition involving mixing the compound according to any of the elements ¥ Protection (58-1) 0 and a pharmaceutically acceptable carrier.