HK1169991A

HK1169991A - Spiro indole-cyclopropane indolinones useful as ampk modulators

Info

Publication number: HK1169991A
Application number: HK12110829.2A
Authority: HK
Inventors: 陈力; 冯立春; 贺耘; 黄孟伟; 昀宏英
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2009-12-11
Filing date: 2010-12-08
Publication date: 2013-02-15

Description

spiroindole-cyclopropaneindolinones useful as AMPK modulators

The present invention relates to compounds that are activators of AMP-activated protein kinase (AMPK) and may be useful for treating or preventing diseases associated with AMPK modulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes.

The invention relates in particular to compounds of the formula (I)

Wherein

R¹And R²Independently selected from the group consisting of hydrogen, alkyl, pyridyl, phenyl, halophenyl, alkoxyphenyl, alkylsulfonylphenyl, cyanophenyl and trifluoromethylphenyl;

or R¹And R²Together with the carbon atom to which they are bound form a cycloalkyl or tetrahydropyranyl group;

R³is hydrogen, pyridyl, piperidyl, carboxypyridyl, tetrahydropyranA group, alkylamino, morpholinyl, morpholinylalkylamino, alkylmorpholinylalkylamino, alkylsulfonylpiperidinyl, alkylpiperazinyl, alkylaminoalkylpiperazinyl, pyridylpiperazinyl, alkylaminopyrrolyl, 1H-imidazolyl, carboxyalkyl-1H-imidazolyl, carboxy-1H-imidazolyl, cycloalkylsulfonylaminocarbonylpyridinyl or substituted phenyl, wherein substituted phenyl is phenyl substituted with one or two substituents independently selected from the group consisting of: alkyl, halogen, hydroxyalkylamino, carboxyl, alkylsulfonyl, alkylaminocarbonyl, alkylsulfonylaminocarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, pyridylpiperazinylcarbonyl, alkylpiperazinylcarbonyl, alkylsulfonylpiperazinylcarbonyl, alkylpyrrolidinylalkylaminocarbonyl, alkyl-1H-pyrazolylaminocarbonyl, oxo-Oxazolidinyl, oxo-pyrrolidinyl, oxo-imidazolidinyl, morpholinylalkylaminocarbonyl, alkylaminoalkylpiperazinocarbonyl, cycloalkyl-1H-pyrazolyl aminocarbonyl, and cycloalkylsulfonyl aminocarbonyl;

R⁴is hydrogen, halogen, carboxy, cyano, trifluoromethyl or alkylsulfonyl; and is

n is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt or ester thereof.

The invention also relates to processes for the preparation of these novel compounds and medicaments comprising them. The compound of the present invention has an activating effect on AMP (adenosine monophosphate) -activated protein kinase, which results in lowered blood glucose. The invention therefore also relates to the use of these compounds in the treatment or prevention of diseases which are associated with the modulation of AMPK, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes.

Obesity and type 2 diabetes, hypertension, cancer and cardiovascular diseases are diseases characterized by severe disturbances of glucose or lipid metabolism, which severely affect the health and quality of life of individual patients. The increasing prevalence of these diseases has made the search for new drug targets for the treatment of these syndromes an urgent task.

AMP-activated protein kinase acts as an energy receptor and regulator for cells. It is activated by an increase in cellular AMP: ATP ratio triggered by metabolic stress, hormonal and nutritional signals. Once activated, AMPK switches on the catabolic pathway for ATP production and closes the anabolic pathway for ATP consumption through acute regulation of key enzymatic activities in metabolism and chronic regulation of key transcription factor expression (Hardie, dg. nature reviews 8(2007b), 774-. Evidence of increased modulation of glucose and lipid metabolism by AMPK makes it a potential drug target for The treatment of diabetes and metabolic syndrome (Carling, D.trends biochem Sci (trends in Biochemical sciences) 29(2004), 18-24; Hardie, DG.Annualreview of pharmacology and toxicology Ann. Tokyo 47(2007a), 185 & 210; Kahn, BB et al, Cell metabolism 1(2005), 15-25; Long, YC et al, The Journal of clinical involvement (J. Clin. Res. 116 (2006)), 1776 & 1783).

At the physiological level, this concept has been supported by two adipokines (adipokines), leptin and adiponectin, which have excellent effects on glucose and lipid metabolism (Friedman, JM and Halaas, JL. Nature 395(1998), 763-770; Muoio, DM et al, Diabetes 46(1997), 1360-1363; Yamauchi, T et al, Nature medicine 7(2001), 941-946). Recent studies suggest that leptin and adiponectin exert their anti-diabetic effects by activating AMPK. Leptin stimulates muscle fatty acid oxidation by direct activation of AMPK and via the hypothalamic adrenergic pathway (Minokoshi, Y et al, Nature 415(2002), 339-. Adiponectin stimulates glucose uptake and fatty acid oxidation in vitro by activating AMPK. Furthermore, it exerts its hypoglycemic effect by reducing PEPCK and G6Pase expression, whereas administration of dominant negative α 1 adenovirus reverses this effect in vivo (Yamauchi, T et al, Nature medicine 8(2002), 1288-1295).

At the pharmacological level, the concept of AMPK as a potential target for the treatment of metabolic syndrome has been further supported by the following findings: two major types of existing antidiabetic drugs, the thiazolidinediones (rosiglitazone, troglitazone and pioglitazone) and biguanides (metformin and phenformin) activate AMPK in cultured cells and in vivo. Rosiglitazone has traditionally been considered to be a PPAR γ agonist and exerts its antidiabetic effect by differentiation of adipocytes (sample, RK et al, The Journal of clinical investigation 116(2006), 581-. Recent findings indicate that AMPK may be involved in The anti-diabetic effect of rosiglitazone (Brunamair, B et al, The Journal of biological chemistry 277(2002), 25226-. In The case of metformin, an existing antidiabetic agent whose mechanism of action is unexplained, recent studies have demonstrated that it is capable of activating AMPK in vitro and in vivo by inhibiting complex I (El-Mir, MY et al, The Journal of biochemical chemistry 275(2000), 223- & 228; Owen, MR et al, The biochemical Journal of 348Pt 3(2000), 607- & 614; Zhou, G et al, The Journal of clinical investigation 108(2001), 1167- & 1174), and that it is possible to completely prevent The hypoglycemic effect by knocking out its upstream kinase LKB1, demonstrating The key role of AMPK in mediating The antidiabetic effect of metformin (Shaw, RJ et al, Science (New York) N.Y.310(2005), 2 1646).

Recently, Cool and colleagues have identified a small direct AMPK activator, a-769662, which exerts an anti-diabetic effect in vivo (Cool, B et al, Cell metabolism 3(2006), 403-. The Jia Li laboratory has identified a small AMPK activator, PT1, which activates inactivity at micromolar activitySexual form of AMPK alpha 2₃₉₈And alpha 1₃₉₄And exert a certain cellular action (Pang, T, et al, The Journal of biological chemistry 283(2008), 16051-.

It has been found that the compounds of the present invention are effective AMPK activators. Accordingly, the compounds of the present invention may be useful for the treatment or prevention of diseases associated with AMPK modulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes, and cancer.

The term "alkyl", alone or in combination, as used herein, denotes a saturated, straight-chain or branched alkyl group containing from 1 to 8, preferably from 1 to 6, more preferably from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, tert-butyl and the like. Preferred "alkyl" groups are methyl, ethyl, isopropyl, tert-butyl.

The term "alkoxy", alone or in combination, denotes the group alkyl-O-, wherein "alkyl" is as defined above; such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, 2-butoxy, t-butoxy and the like. Preferred alkoxy groups are methoxy and ethoxy and more preferably methoxy.

The term "cycloalkyl", alone or in combination, refers to a saturated carbocyclic ring containing 3 to 7 carbon atoms, preferably 3 to 6 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Preferred cycloalkyl groups are cyclopropyl and cyclopentyl, with cyclopropyl being particularly preferred.

The term "halogen" or "halo", alone or in combination, refers to fluorine, chlorine, bromine or iodine. Halogen is preferably fluorine, chlorine or bromine.

The term "halophenyl" refers to a phenyl group substituted with a halogen.

The term "carboxy", alone or in combination, refers to the group-COOH.

The term "carbonyl", alone or in combination, refers to the group-C (O) -.

The term "amino", alone or in combination, refers to a primary (-NH)₂-), secondary (-NH-) or tertiary amino (-N-).

The term "hydroxy", alone or in combination, refers to the group-OH.

The term "sulfonyl", alone or in combination, refers to the group-S (O)₂-。

The compounds according to the invention may be present in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts which retain the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid addition salts include, for example, those derived from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric and nitric acids, and those derived from organic acids such as p-toluenesulfonic, salicylic, methanesulfonic, oxalic, succinic, citric, malic, lactic, fumaric, and the like. Base addition salts include those derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides, such as, for example, tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound into a salt is a technique known to pharmaceutical chemists to achieve improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is described in, for example, Bastin R.J., et al, organic Process Research & Development 2000, 4, 427-; or Ansel, H, et al, In: pharmaceutical Dosage Forms and Drug delivery systems, 6 th edition (1995), pages 196 and 1456-. Preferred are the sodium salts of the compounds of formula (I).

"pharmaceutically acceptable ester" refers to a derivative which can be derivatised with a compound of formula (I) at a functional group to provide a compound which can be converted back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl, methylthiomethyl and pivaloyloxymethyl esters. Furthermore, any physiologically acceptable equivalent of a compound of formula (I) that is similar to a metabolically labile ester, capable of producing the parent compound of formula (I) in vivo, falls within the scope of the present invention. Preferred are the methyl and ethyl esters of the compounds of formula (I).

Particularly preferred are compounds of formula (I), wherein

R³is pyridyl, carboxypyridyl, tetrahydropyranyl, dialkylamino, morpholinyl, alkylsulfonylpiperidinyl, alkylpiperazinyl, dialkylaminoalkylpiperazinyl, dialkylaminopyrrolidinyl, carboxyalkyl-1H-imidazolyl, carboxy-1H-imidazolyl or substituted phenyl, wherein substituted phenyl is phenyl substituted with one or two substituents independently selected from: alkyl, halogen, carboxyl, alkylsulfonyl, alkylaminocarbonyl, alkylsulfonylaminocarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, pyridylpiperazinylcarbonyl, alkylpiperazinylcarbonyl, alkylsulfonylpiperazinylcarbonyl, alkylpyrrolidinylalkylaminocarbonyl, alkyl-1H-pyrazolylaminocarbonyl, oxo-Oxazolidinyl, oxo-pyrrolidinyl, and oxo-imidazolidinyl;

R⁴is hydrogen, halogen, cyano, trifluoromethyl or alkylsulfonyl; and is

n is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt or ester thereof.

Preferred are compounds according to formula (I), wherein R¹And R²One of which is selected from hydrogen and alkyl and the other is selected from pyridyl, halophenyl, alkylsulfonicAcylphenyl, cyanophenyl and trifluoromethylphenyl, or R¹And R²Together with the carbon atom to which they are bound form a cycloalkyl or tetrahydropyranyl group;

further preferred are compounds of formula (I) wherein R is¹And R²One of which is selected from hydrogen and isopropyl and the other is selected from pyridyl, fluorophenyl, chlorophenyl, cyanophenyl, methylsulfonylphenyl and trifluoromethylphenyl.

Preferred are compounds according to formula (I), wherein R³Is pyridyl, carboxypyridyl, tetrahydropyranyl, dialkylamino, morpholinyl, alkylsulfonylpiperidinyl, alkylpiperazinyl, dialkylaminoalkylpiperazinyl, dialkylaminopyrrolidinyl, carboxyalkyl-1H-imidazolyl, carboxy-1H-imidazolyl or substituted phenyl, wherein substituted phenyl is phenyl substituted with one or two substituents independently selected from: alkyl, halogen, carboxyl, alkylsulfonyl, alkylaminocarbonyl, alkylsulfonylaminocarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, pyridylpiperazinylcarbonyl, alkylpiperazinylcarbonyl, alkylsulfonylpiperazinylcarbonyl, alkylpyrrolidinylalkylaminocarbonyl, alkyl-1H-pyrazolylaminocarbonyl, oxo-Oxazolidinyl, oxo-pyrrolidinyl, and oxo-imidazolidinyl.

Also preferred are compounds of formula (I) wherein R³Is carboxypyridyl, carboxyalkyl-1H-imidazolyl, carboxyphenyl or substituted by carboxy and oxoAn oxazolidinyl substituted phenyl.

Also preferred are compounds of formula (I) wherein R⁴Is hydrogen, halogen, cyano, trifluoromethyl or alkylsulfonyl.

Also preferred are compounds of formula (I) wherein R⁴Is hydrogen,Halogen, carboxy, cyano, trifluoromethyl or alkylsulfonyl.

Especially preferred are compounds of formula (I) wherein R⁴Is hydrogen or halogen.

Especially preferred are compounds of formula (I) wherein R⁴Is hydrogen, halogen or carboxyl.

Further preferred are compounds of formula (I) wherein R is⁴Is hydrogen, fluorine or chlorine.

Preferred are compounds of formula (I) wherein n is 0 or 1.

Especially preferred are compounds of formula (I) selected from:

(1R, 2S) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((2- (3-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((2- (3-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) - ((2- (4- (methylsulfonyl) phenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2S) - ((2- (4- (methylsulfonyl) phenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -2-chloro-5- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -2-chloro-5- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((2- (4- (methylsulfonyl) phenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((2- (4- (methylsulfonyl) phenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((2- (2-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((2- (2-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (2-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (2-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((2- (3-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((2- (3-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (3-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (3-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2 ' -oxo-2- (2- (trifluoromethyl) phenyl) -spiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2 ' -oxo-2- (2- (trifluoromethyl) phenyl) -spiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) - ((5 '-chloro-2- (4-chlorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1R, 2S) - ((5 '-chloro-2- (4-chlorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((5 '-chloro-2- (4-chlorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((5 '-chloro-2- (4-chlorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((5 '-bromo-2- (4-chlorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((5 '-bromo-2- (4-chlorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((5 '-bromo-2- (4-chlorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((5 '-bromo-2- (4-chlorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((2- (3-methoxyphenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((2- (3-methoxyphenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (3-methoxyphenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (3-methoxyphenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (4-methoxyphenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (4-methoxyphenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((2- (4-methoxyphenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((2- (4-methoxyphenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((-2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((-2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((2 ' -oxo-2- (pyridin-3-yl) spiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((2 ' -oxo-2- (pyridin-3-yl) spiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((-2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((-2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (4-chlorophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (4-chlorophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (4-cyanophenyl) -2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (4-cyanophenyl) -2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((2- (4-cyanophenyl) -2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((2- (4-cyanophenyl) -2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(+) -3- ((2- (4-chlorophenyl) -2-isopropyl-2 ' -oxospiro [ (trans) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(-) -3- ((2- (4-chlorophenyl) -2-isopropyl-2 ' -oxospiro [ (trans) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(+) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-isopropyl-2' -oxospiro [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(-) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-isopropyl-2' -oxospiro [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-isopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-isopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((5 '-fluoro-2- (4-fluorophenyl) -2-isopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((5 '-fluoro-2- (4-fluorophenyl) -2-isopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (3-fluorophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (3-fluorophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (3-chlorophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (3-chlorophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (4-fluorophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (4-fluorophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(+) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ (trans) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(-) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ (trans) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(+) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ (cis) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(-) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ (cis) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(-) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(+) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (4-cyanophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (4-cyanophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(-) -3- ((2- (4-cyanophenyl) -2-isopropyl-2 ' -oxospiro [ (trans) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(+) -3- ((2- (4-cyanophenyl) -2-isopropyl-2 ' -oxospiro [ (trans) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1S, 2S) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(-) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ (cis) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(+) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ (cis) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(-) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(+) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (piperidine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (3- (piperidine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N-isopropylbenzamide;

(1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N-isopropylbenzamide;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (piperazine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (3- (piperazine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (3- (morpholine-4-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (morpholine-4-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (3- (4- (pyridin-4-yl) piperazine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (4- (pyridin-4-yl) piperazine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (4-isopropylpiperazine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (3- (4-isopropylpiperazine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

3- (((1S, 2R) -2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (2- ((S) -1-methylpyrrolidinyl-2-yl) ethyl) benzamide

3- (((1R, 2S) -2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (2- ((S) -1-methylpyrrolidin-2-yl) ethyl) benzamide;

(1R, 2S) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (3-methyl-1H-pyrazol-5-yl) benzamide;

(1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (3-methyl-1H-pyrazol-5-yl) benzamide;

(1S, 2R) -6- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) picolinic acid;

(1R, 2S) -6- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) picolinic acid;

(1S, 2R) -6- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) picolinic acid;

(1R, 2S) -6- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) picolinic acid;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - ((tetrahydro-2H-pyran-4-yl) methyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - ((tetrahydro-2H-pyran-4-yl) methyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (2- (diethylamino) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (diethylamino) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (2-morpholinoethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (2-morpholinoethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - ((1- (methylsulfonyl) piperidin-4-yl) methyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - ((1- (methylsulfonyl) piperidin-4-yl) methyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (2- (4-isopropylpiperazin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (4-isopropylpiperazin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (2- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (2- ((S) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- ((S) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (pyridin-4-ylmethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (pyridin-4-ylmethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (pyridin-3-ylmethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(2R, 1S) -2- (4-chlorophenyl) -1 ' - (pyridin-3-ylmethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -1H-imidazol-1-yl) acetic acid;

(1R, 2S) -2- (4- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -1H-imidazol-1-yl) acetic acid;

(1S, 2R) -1- (2- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) ethyl) -1H-imidazole-4-carboxylic acid;

(1R, 2S) -1- (2- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) ethyl) -1H-imidazole-4-carboxylic acid;

(1S, 2S) -1- (2- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) ethyl) -1H-imidazole-4-carboxylic acid;

(1R, 2R) -1- (2- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) ethyl) -1H-imidazole-4-carboxylic acid;

(1S, 2R) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) benzoic acid;

(1R, 2S) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) benzoic acid;

(1S, 2S) -3- (-2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) benzoic acid;

(1R, 2R) -3- (-2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) benzoic acid;

(1S, 2S) -2- (4-chlorophenyl) -1 ' - (3- (morpholine-4-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2R) -2- (4-chlorophenyl) -1 ' - (3- (morpholine-4-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2S) -2- (4-chlorophenyl) -1 ' - (3- (4-methylpiperazine-1-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2R) -2- (4-chlorophenyl) -1 ' - (3- (4-methylpiperazine-1-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2S) -2- (4-chlorophenyl) -1 ' - (3- (4- (methylsulfonyl) piperazine-1-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2R) -2- (4-chlorophenyl) -1 ' - (3- (4- (methylsulfonyl) piperazine-1-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (3- (morpholine-4-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (morpholine-4-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (4-methylpiperazine-1-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (3- (4-methylpiperazine-1-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (3- (4- (methylsulfonyl) piperazine-1-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (4- (methylsulfonyl) piperazine-1-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2R) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -N- (methylsulfonyl) benzamide;

(1S, 2S) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -N- (methylsulfonyl) benzamide;

(1S, 2S) -3- (2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid;

(1R, 2R) -3- (2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid;

(1S, 2S) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -5- (methylsulfonyl) benzoic acid;

(1R, 2R) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -5- (methylsulfonyl) benzoic acid;

(1S, 2S) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -5- (2-oxopyrrolidin-1-yl) benzoic acid;

(1R, 2R) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -5- (2-oxopyrrolidin-1-yl) benzoic acid;

(1R, 2R) -3- (2- (4-chlorophenyl) -5 ' -fluoro-2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid;

(1S, 2S) -3- (2- (4-chlorophenyl) -5 ' -fluoro-2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid;

(1R, 2S) -3- (2- (4-chlorophenyl) -5 ' -fluoro-2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid;

(1S, 2R) -3- (2- (4-chlorophenyl) -5 ' -fluoro-2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid;

(1R, 2R) -3- (2- (4-chlorophenyl) -2-isopropyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid;

(1S, 2S) -3- (2- (4-chlorophenyl) -2-isopropyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid;

(1S, 2S) -3- (2- (4-cyanophenyl) -2-isopropyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid;

(1R, 2R) -3- (2- (4-cyanophenyl) -2-isopropyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid;

(1S, 2S) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -5- (2-oxoimidazolidin-1-yl) benzoic acid;

(1R, 2R) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -1 ' -yl) -5- (2-oxoimidazolidin-1-yl) benzoic acid;

(R) -3- ((5 '-fluoro-2, 2-dimethyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(S) -3- ((5 '-fluoro-2, 2-dimethyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(R) -3- (5 ' -fluoro-2, 2-dimethyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid;

(S) -3- (5 ' -fluoro-2, 2-dimethyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid;

(R) -3- [ (2-oxo-2 ", 3", 5 ", 6" -tetrahydrodispiro [ indole-3, 1 '-cyclopropane-2', 4 "-pyran ] -1(2H) -yl) methyl ] benzoic acid;

(S) -3- [ (2-oxo-2 ", 3", 5 ", 6" -tetrahydrodispiro [ indole-3, 1 '-cyclopropane-2', 4 "-pyran ] -1(2H) -yl) methyl ] benzoic acid;

(R) -3- (2-oxo-1, 3-)Oxazolidin-3-yl) -5- (2-oxo-2 ', 3 ', 5 ', 6 ' -tetrahydrodispiro [ indole-3, 1 ' -cyclopropane-2 ', 4 ' -pyran]-1(2H) -yl) benzoic acid;

(S) -3- (2-oxo-1, 3-)Oxazolidin-3-yl) -5- (2-oxo-2 ', 3 ', 5 ', 6 ' -tetrahydrodispiro [ indole-3, 1 ' -cyclopropane-2 ', 4 ' -pyran]-1(2H) -yl) benzoic acid;

(1S, 2S) -2-chloro-5- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2R) -2-chloro-5- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -4- ((2 ' -oxo-2- (pyridin-3-yl) spiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -4- ((2 ' -oxo-2- (pyridin-3-yl) spiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -4- ((2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -4- ((2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -4- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -2-chloro-5- ((2- (4-chlorophenyl) -5 '-fluoro-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1R, 2S) -2-chloro-5- ((2- (4-chlorophenyl) -5 '-fluoro-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((2- (3-chloro-4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -3- ((2- (3-chloro-4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1R, 2S) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N-methylbenzamide;

(1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N-methylbenzamide;

(1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N, N-dimethylbenzamide;

(1R, 2S) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N, N-dimethylbenzamide;

(1R, 2S) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (3-morpholinopropyl) benzamide;

(1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (3-morpholinopropyl) benzamide;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (3- (4- (2- (dimethylamino) ethyl) piperazine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (4- (2- (dimethylamino) ethyl) piperazine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (2-morpholinoethyl) benzamide;

(1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (2-morpholinoethyl) benzamide;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (3- (4- (methylsulfonyl) piperazine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (4- (methylsulfonyl) piperazine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (3-cyclopropyl-1H-pyrazol-5-yl) benzamide;

(1R, 2S) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (3-cyclopropyl-1H-pyrazol-5-yl) benzamide;

(1R, 2S) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (5-cyclopropyl-1H-pyrazol-3-yl) benzamide;

(1R, 2S) -6- ((2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (cyclopropylsulfonyl) picolinamide;

(1S, 2R) -6- ((2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (cyclopropylsulfonyl) picolinamide;

(1S, 2R) -4- ((2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (cyclopropylsulfonyl) benzamide;

(1R, 2S) -4- ((2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (cyclopropylsulfonyl) benzamide;

(1R, 2S) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (methylsulfonyl) benzamide;

(1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (methylsulfonyl) benzamide;

(1R, 2S) -3- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (methylsulfonyl) benzamide;

(1S, 2R) -3- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (methylsulfonyl) benzamide;

(1S, 2R) -N- (cyclopropylsulfonyl) -3- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzamide;

(1R, 2S) -N- (cyclopropylsulfonyl) -3- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzamide;

(1S, 2R) -N- (cyclopropylsulfonyl) -4- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzamide;

(1R, 2S) -N- (cyclopropylsulfonyl) -4- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzamide;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (piperidin-4-ylmethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (piperidin-4-ylmethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (2- (piperidin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (piperidin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (2- (3-morpholinopropylamino) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (3-morpholinopropylamino) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (2- (2-morpholinoethylamino) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (2-morpholinoethylamino) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (2- (4- (pyridin-4-yl) piperazin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (4- (pyridin-4-yl) piperazin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (2- (2- (2, 6-dimethylmorpholino) ethylamino) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (2- (2, 6-dimethylmorpholino) ethylamino) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -2- (4-chlorophenyl) -1 ' - (1H-imidazol-4-yl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1R, 2S) -2- (4-chlorophenyl) -1 ' - (1H-imidazol-4-yl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one;

(1S, 2R) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -N- (methylsulfonyl) benzamide;

(1R, 2S) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -N- (methylsulfonyl) benzamide;

(1S, 2S) -3- (2- (4-chlorophenyl) -2-methyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid;

(1R, 2R) -3- (2- (4-chlorophenyl) -2-methyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid;

(1R, 2R) -3- (2- (4-chlorophenyl) -2-isopropyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidine-3-Yl) benzoic acid;

(R) -methyl-3- (2, 2-dimethyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoate;

(S) -methyl-3- (2, 2-dimethyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoate;

(R) -3- (5 '-fluoro-2, 2-dimethyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) -5- (2-hydroxyethylamino) benzoic acid;

(S) -3- (5 '-fluoro-2, 2-dimethyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) -5- (2-hydroxyethylamino) benzoic acid;

(R) -methyl-3- (2-oxo-1, 3-Oxazolidin-3-yl) -5- (2-oxo-2 ', 3 ', 5 ', 6 ' -tetrahydrodispiro [ indole-3, 1 ' -cyclopropane-2 ', 4 ' -pyran]-1(2H) -yl) benzoate;

(S) -methyl-3- (2-oxo-1, 3-Oxazolidin-3-yl) -5- (2-oxo-2 ', 3 ', 5 ', 6 ' -tetrahydrodispiro [ indole-3, 1 ' -cyclopropane-2 ', 4 ' -pyran]-1(2H) -yl) benzoate;

(1S, 2R) -1 '- (3-fluorobenzyl) -2- (4-fluorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indoline ] -5' -carboxylic acid;

(1R, 2S) -1 '- (3-fluorobenzyl) -2- (4-fluorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indoline ] -5' -carboxylic acid;

(1R, 2R) -1 '- (2-fluorobenzyl) -2- (4-fluorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indoline ] -5' -carboxylic acid;

(1S, 2S) -1 '- (2-fluorobenzyl) -2- (4-fluorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indoline ] -5' -carboxylic acid;

(1R, 2R) -2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylic acid;

(1S, 2S) -2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylic acid;

(1R, 2S) -2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylic acid;

(1S, 2R) -2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylic acid;

(1R, 2R) -2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylic acid;

(1S, 2S) -2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylic acid;

(1S, 2R) -2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylic acid; and

(1R, 2S) -2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylic acid.

Also particularly preferred are compounds of formula (I) selected from:

(2S, 1R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid;

(1S, 2R) -2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylic acid; and

(1R, 2R) and (1S, 2S) -2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylic acid.

The compounds of the present invention may be prepared by any conventional means. Suitable methods for synthesizing these compounds are provided in the schemes below. In the scheme below, R⁵Is hydrogen, halogen, oxo-Oxazolidinyl, oxo-imidazolidinyl. R⁶And R⁷Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminoalkyl and aminocycloalkyl. Unless otherwise indicated, R¹、R²、R³、R⁴And n is as defined above.

Scheme 1

Compounds of formula Ia and Ib can be prepared according to scheme 1. Intermediate IIIIII is prepared by condensation reaction between II and different aldehydes or ketones. Cyclopropanation of III provides intermediate IV. Alkylation between IV and bromide V provides ester VI. Can be prepared by reacting R under a copper salt catalyst⁵Is introduced into intermediate VI to obtain ester VII. Hydrolysis of the methyl ester VII produces the corresponding acid Ia. The amide Ib may be prepared by a coupling reaction between the acid Ia and the amine VIII.

When a base such as piperidine or pyrrolidine is used as a catalyst, the condensation reaction between II and the different aldehydes is carried out overnight in refluxing toluene or refluxing alcohol.

Cyclopropanation of III at 50 ° in an organic solvent such as DMSO was performed for several hours by treating trimethyl sulfoxide iodide with sodium hydride to generate a thioylide in situ.

In the third step outlined in scheme 1, when n ═ 1, the reaction is carried out by using a base such as NaH, K in an organic solvent such as THF, DMF at room temperature₂CO₃Or Cs₂CO₃Alkylation of IV and bromide V provided methyl ester VI for several hours; when N ═ 0, it is possible to use a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride or 1, 8-diazabicyclo [5.4.0 ] in the presence of a copper source such as copper (I) iodide (CuI) bound to a ligand such as 2, 2 '-bipyridine, proline, N' -dimethylglycine or ethylene glycol]The coupling of IV to aryl bromide VI is carried out in the presence of undec-7-ene (DBU). The reaction can be carried out in a suitable solvent such as acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1, 4-bisIn an alkane, N-dimethylformamide, dimethylsulfoxide or N-methylpyrrolidone at a temperature of 100 ℃ to 180 ℃ for 15 to 60 minutes under microwave irradiation. Alternatively, the reaction may be carried out at a heated temperature such as 80 ℃ for a longer reaction time without microwave irradiation. (Ley, s.v. et al, angelw.chem.iht.ed. (applied chemistry international edition) 42(2003) 5400).

In the fourth step, the copper source such as copper (I) iodide (CuI) in the presence of a binding ligand such as 2, 2 '-bipyridine, proline, N' -dimethylglycine or ethylene glycol may be combined in the presence of a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride or 1, 8-diazabicyclo [5.4.0 ]]Reacting R in the presence of undec-7-ene (DBU)⁵Is introduced into the methyl ester VI. The reaction can be carried out in a suitable solvent such as acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1, 4-In an alkane, N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone at a temperature of from 100 ℃ to 180 ℃ for from 15 to 60 minutes under microwave irradiation. Alternatively, the reaction may be carried out at a heated temperature such as 80 ℃ for a longer reaction time without microwave irradiation. (Ley, S.V. et al, Angew. chem. int. Ed. (applied chemistry International edition) 42(2003) 5400).

Hydrolysis of the methyl ester VII may be carried out in the presence of a water-soluble inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1, 4-bisIn an alkane or tetrahydrofuran at room temperature for several hours to yield the stereoisomer of Ia.

The conversion of the acid Ia with the appropriate amine VIII to the corresponding amide Ib can be readily accomplished using known methods. The reaction is usually carried out in a coupling agent such as Dicyclohexylcarbodiimide (DCC), benzotriazol-1-yl-oxy-tris-pyrrolidinylHexafluorophosphate (PyBop), o- (7-azabenzotriazol-1-yl) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), o- (1H-benzotriazol-1-yl) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HBTU) or 1-ethyl-3- (3 ' -dimethylamino) carbodiimide hydrochloride (EDCI), in the presence or absence of hydroxybenzotriazole (HOBt) or N, N-Dimethylaminopyridine (DMAP), in the presence of a base such as triethylamine or N, N-diisopropylethylamine. The reaction can be carried out in a solvent such as dichloromethane or N, N-dimethylformamide at room temperature for several hours (Montalbetti, c.a.g.n., et al, Tetrahedron 61(2005) 10827).

Scheme 2

Compounds of formula Ic and Id can be prepared according to scheme 2. The diazo compound XXXIII can be obtained by treating isatin IX with p-toluenesulfonyl hydrazide under basic conditions. Cyclopropanation of alkene XI with diazo XXXIII via Rh catalyst provides intermediate XII. Alkylation or arylation of XII with bromide V provides methyl ester XIII. By using copper salts as catalysts⁵Introduction into XIII yields intermediate XIV.

Hydrolysis of the methyl ester gives the corresponding acid Ic. The hydrolysis may be carried out in the presence of a water-soluble inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1, 4-bisIn an alkane or tetrahydrofuran at room temperature for several hours.

The conversion of the acid Ic with the appropriate amine VIII to the corresponding amide Id can be readily accomplished using methods known to those skilled in the art. The reaction is usually carried outIn coupling agents such as Dicyclohexylcarbodiimide (DCC), benzotriazol-1-yl-oxy-tri-pyrrolidinylHexafluorophosphate (PyBop), o- (7-azabenzotriazol-1-yl) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), o- (1H-benzotriazol-1-yl) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HBTU) or 1-ethyl-3- (3 ' -dimethylamino) carbodiimide hydrochloride (EDCI), in the presence or absence of hydroxybenzotriazole (HOBt) or N, N-Dimethylaminopyridine (DMAP), in the presence of a base such as triethylamine or N, N-diisopropylethylamine. The reaction can be carried out in a solvent such as dichloromethane or N, N-dimethylformamide at room temperature for several hours (Montalbetti, c.a.g.n., et al, Tetrahedron 61(2005) 10827).

Scheme 3

The compounds of formula Ie may be prepared according to scheme 3. By using bases such as NaH, K₂CO₃Or Cs₂CO₃Alkylation of IV with alkyl halide XIV in an organic solvent such as THF or DMF at room temperature for several hours provides the compound of formula Ie.

Scheme 4

The compounds of formula If may be prepared according to scheme 4. By using bases such as NaH, K₂CO₃Or Cs₂CO₃Alkylation of IV with bromide XVI in an organic solvent such as THF or DMF at room temperature for several hours provides bromide XVII. Can be prepared by reacting under alkaline conditions (such as NaH, K)₂CO₃Or Cs₂CO₃) XVII is then treated with amine VIII in an organic solvent such as THF or DMF at room temperature to obtain If.

Scheme 5

Compounds of formula Ig can be prepared according to scheme 5.

Alkylation between IV and XVIII provides intermediate XIX, which can be treated with TFA to produce aldehyde XX. The amine Ig can be prepared by reductive amination between XX and a different amine VIII.

In the first step shown in scheme 5, alkylation between IV and iodide XVIII can be achieved by using a base such as NaH, K₂CO₃Or Cs₂CO₃In an organic solvent such as THF, DMF at room temperature for several hours.

In the second step shown in scheme 5, the deprotection of XIX using TFA can be performed in a solvent such as DCM or THF at room temperature for several hours.

Reductive amination of XX using different amines VIII can be carried out at room temperature in organic solvents such as DCM, THF by using reducing agents such as NaBH₄Or NaHB (OAc)₃To provide formula Ig.

Scheme 6

The compounds of formula Ih and Ii may be prepared according to scheme 6. Can be prepared by using bases such as NaH, K₂CO₃Or Cs₂CO₃Alkylation of IV with XXI in an organic solvent such as THF or DMF at room temperature for several hours to give Ih and Ii.

Scheme 7

The compounds of formula Ij and Ik can be prepared according to scheme 7. Coupling between IV and iodoimidazole XXII, followed by deprotection in the presence of TFA, affords Ij. Subsequent alkylation with XXIII affords formula XXIV. Finally, hydrolysis of methyl ester XXIV gives the corresponding acid Ik.

In the first step shown in scheme 7, the coupling reaction can be carried out in the presence of a copper source such as copper (I) iodide (CuI) in combination with a ligand such as 2, 2 '-bipyridine, proline, N' -dimethylglycine or ethylene glycol, in the presence of a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride or 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (DBU). The reaction can be carried out in a suitable solvent such as acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1, 4-bisIn an alkane, N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone at a temperature of from 100 ℃ to 180 ℃ for from 15 to 60 minutes under microwave irradiation. Alternatively, the reaction may be carried out at elevated temperatures such as 80 ℃ for longer reaction times without the use of microwaves (Ley, s.v. et al, angelw.chem.int.ed. (applied chemistry international edition) 42(2003) 5400). Deprotection can be performed at room temperature using TFA in an organic solvent such as DCM or THF to provide the stereoisomer Ij.

Alkylation of Ij with bromide XXIII can be achieved by the use of bases such as NaH, K₂CO₃Or Cs₂CO₃In an organic solvent such as THF or DMF at room temperature for several hours.

Finally, hydrolysis of the methyl ester yields compound Ik. The hydrolysis may be carried out in the presence of a water-soluble inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1, 4-bisIn an alkane or tetrahydrofuran at room temperature for several hours.

Scheme 8

Compounds of formula IL may be prepared according to scheme 8. Alkylation between IV and ethylene dibromide XXV affords bromide XXVI. Nucleophilic substitution reaction between ester XXVII and bromide XXVI yields methyl ester XXVIII. Hydrolysis of the methyl ester produces the corresponding acid IL.

In the first step shown in scheme 8, the condensation between IV and ethylene dibromide can be carried out in an organic solvent (THF or DMF) by using a base such as NaH, K₂CO₃Or Cs₂CO₃At room temperature for several hours.

In the second step shown in scheme 8, the substitution reaction between imidazoles XXVII and XXVI can be carried out in an organic solvent such as THF or DMF by using a base such as NaH, K₂CO₃Or Cs₂CO₃At room temperature for several hours.

Finally, hydrolysis of methyl ester xxvixxxviii can yield compound IL. The reaction may be carried out in the presence of a water-soluble inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1, 4-bisIn an alkane or tetrahydrofuran at room temperature for several hours.

The present invention also relates to a process for the preparation of a compound of formula (I), said process comprising one of the following steps:

a) a compound of formula (A)

At R⁶R⁷Reaction in the presence of NH and a coupling agent;

b) a compound of formula (B)

In Y-CH₂-R and a base;

c) a compound of formula (C)

At R⁶R⁷Reaction in the presence of NH and a base;

d) a compound of formula (D)

At R⁶R⁷Reaction in the presence of NH and a reducing agent;

e) a compound of formula (E)

In the presence of a compound of formula (E1)

And in the presence of a base;

f) a compound of formula (F)

Reaction in the presence of a base;

g) a compound of formula (G)

Reaction in the presence of a base;

wherein R is¹、R²、R³、R⁴And n is as defined in any one of claims 1 to 8; wherein R is⁵Is hydrogen, halogen, oxo-Oxazolidinyl or oxo-imidazolidinyl; wherein R is⁶And R⁷Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminoalkyl and aminocycloalkyl; wherein X is carbon or nitrogen; wherein Y is Br, I or OTs; wherein Q is Br or I; and wherein R is alkyl.

In step (a), the coupling agent is, for example, Dicyclohexylcarbodiimide (DCC), benzotriazol-1-yl-oxy-tri-pyrrolidinylHexafluorophosphate (PyBop), o- (7-azabenzotriazol-1-yl) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), o- (1H-benzotriazol-1-yl) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HBTU) or 1-ethyl-3- (3 ' -dimethylamino) carbodiimide hydrochloride (EDCI). Step (a) may be carried out on hydroxybenzotriazole (HOBt) or N,in the presence or absence of N-Dimethylaminopyridine (DMAP), in the presence of a base such as triethylamine or N, N-diisopropylethylamine. The reaction of step (a) may be carried out in a solvent such as dichloromethane or N, N-dimethylformamide. The reaction can be carried out at room temperature for several hours.

In step (b), the base may be, for example, NaH, K₂CO₃Or Cs₂CO₃. Step (b) may be carried out in an organic solvent such as THF or DMF. The reaction can be carried out at room temperature for several hours.

In step (c), the base may be, for example, NaH, K₂CO₃Or Cs₂CO₃. Step (c) may be carried out in an organic solvent such as THF or DMF. The reaction may be carried out at room temperature.

The reaction of step (d) may be carried out in an organic solvent such as DCM or THF. The reducing agent of step (d) may be, for example, NaBH₄Or NaHB (OAc)₃. The reaction may be carried out at room temperature.

In step (e), the base may be, for example, NaH, K₂CO₃Or Cs₂CO₃. The solvent may be an organic solvent such as THF or DMF. The reaction can be carried out at room temperature for several hours.

In step (f), the base may be an inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide. The solvent of step (f) may be, for example, methanol, 1, 4-bisAn alkane or tetrahydrofuran. The reaction can be carried out at room temperature for several hours.

In step (g), the base may be an inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide. The solvent of step (g) may be, for example, methanol, 1, 4-bisAn alkane or tetrahydrofuran. The reaction can be carried out at room temperature for several hours.

The invention also relates to compounds of formula (I) for use as therapeutically active substances.

The invention also relates to pharmaceutical compositions comprising a compound of formula (I) and a therapeutically inert carrier.

The use of compounds of the formula (I) for the preparation of medicaments which can be used for the treatment or prevention of diseases which are associated with AMPK modulation is one of the objects of the present invention.

The invention relates in particular to the use of compounds of formula (I) for the preparation of medicaments for the treatment or prophylaxis of obesity, hyperglycemia, dyslipidemia, type 1 or type 2 diabetes, especially type 2 diabetes.

The medicaments can be administered orally (for example in the form of pharmaceutical preparations), for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, it can also be administered rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions with an effective amount of a compound as described above.

The above pharmaceutical compositions may be obtained by processing the compounds according to the invention together with pharmaceutically inert inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance, however, no carriers are generally required in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical compositions may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may still contain other therapeutically valuable substances.

The dosage depends on various factors such as mode of administration, species, age, and/or the health of the individual. The dose to be administered daily is about 5-400mg/kg, preferably about 10-100mg/kg, and it may be administered in a single dose or dispersed over several administrations.

The compounds of formula (I) prepared according to the above process are also objects of the present invention.

Furthermore, the present invention relates to a method for the treatment or prevention of diseases which are associated with the modulation of AMPK, which method comprises administering an effective amount of a compound of formula (I).

The invention further relates to a method for the treatment or prophylaxis of obesity, hyperglycemia, dyslipidemia, type 1 or type 2 diabetes, especially type 2 diabetes, comprising administering an effective amount of a compound of formula (I).

In addition, the present invention relates to compounds of formula (I) useful for the preparation of medicaments useful for the treatment of cancers associated with AMPK modulation, and provides methods for the treatment of cancers associated with AMPK modulation.

The invention will be illustrated by the following non-limiting examples. Unless otherwise explicitly stated, all reactions, reaction conditions, abbreviations and symbols have meanings well known to those skilled in the art of organic chemistry.

Examples

Materials and instruments

Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) biotage SP1 system and Quad 12/25Cartridge module. ii) ISCO combi-flash chromatograph. Silica gel brand and pore size: i) KP-SILGranularity: 40-60 mu M; ii) CAS, registration number: silica gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang chemical Co., Ltd, well: 200-300 or 300-400.

Use of X Bridge on reverse phase column by preparative HPLC^TM Perp C₁₈(5μm，OBD^TM30 x 100mm) column or SunAire^TM Perp C₁₈(5m，OBD^TM30 x 100mm) column to purify the intermediate and final compounds.

The LC/MS spectra were obtained using MicroMass platform LC (Waters. Indiane 2795-ZQ 2000). Standard LC/MS conditions were as follows (run time 6 min):

acid conditions: a: dissolved in H₂0.1% formic acid to O; b: 0.1% formic acid in acetonitrile;

alkaline conditions: a: dissolved in H₂0.01% NH of O₃.H₂O; b: acetonitrile;

neutral conditions are as follows: a: h₂O; b: and (3) acetonitrile.

Mass Spectrum (MS): typically only ions indicative of parent mass are reported, and unless otherwise indicated, the mass ions referred to are positive mass ions- (M + H)⁺。

The microwave-assisted reaction was carried out in a Biotage Initiator six.

NMR spectra were obtained using Bruke Avance 400 MHz.

All reactions involving air sensitive reagents were carried out under argon atmosphere. Unless otherwise indicated, reagents were (directly) used without further purification when obtained from the supplier.

Example 1

(1R, 2S) and (1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

Synthesis of (Z) -3- (4-chloro-benzylidene) -1, 3-dihydro-indol-2-one

Mixing oxindole (0.13g, 1mmol) and 4-chlorobenzaldehyde (0.17g, 1.2mmol) in ethanol; pyrrolidine (0.17ml, 2mmol) was then added. The mixture was refluxed for 3 hours. The precipitate formed was collected by filtration and washed twice with ethanol to give the title compound as a yellow powder (0.24g, 92%). C₁₅H₁₀LC/MS M/e calculation of ClNO 255, found (M + H)⁺：256.1。

Synthesis of (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3 '-indolin ] -2' -one

A solution of dimethylmethylenesulfoxonium was prepared from 60% NaH mineral oil dispersion (88mg, 2.2mmol), trimethylsulfoxonium iodide (484mg, 2.2mmol), and DMSO (10mL) under argon. After 20min, a solution of (Z) -3- (4-chloro-benzylidene) -1, 3-dihydro-indol-2-one (510mg, 2mmol) in THF (5mL) was added dropwise over 20 min. After stirring at room temperature for 1 hour and at 50 ℃ for another 1 hour, the solution was poured into ice-cold water (20mL) and extracted with ether (3 × 20 mL). The combined ether extracts were washed with brine, dried and evaporated to an oil which was purified by flash column chromatography (gradient elution, 15-25% ethyl acetate in petroleum ether) to give the title compound as a white solid (333mg, 62%). C₁₆H₁₂LC/MS M/e calculation of ClNO 269, found (M + H)⁺：270.5。¹H NMR(400MHz，DMSO-d₆)δppm 1.95(dd，J＝8.97，4.67Hz，1H)2.21(dd，J＝7.83，4.80Hz，1H)3.04(t，J＝8.46Hz，1H)6.08(d，J＝7.58Hz，1H)6.59-6.71(m，1H)6.87(d，J＝7.58Hz，1H)7.01-7.10(m，1H)7.27-7.33(m，2H)7.33-7.40(m，2H)10.59(s，1H)。

Synthesis of racemic (1R, 2S) and (1S, 2R) -methyl-3- (((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclo-propane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoate

Reacting (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline]-2' -one (2.1mmol), methyl- (3-bromomethyl) -benzoate (725mg, 3.15mmol) and Cs₂CO₃(1.369g, 4.2mmol) were mixed in anhydrous DMF and stirred at room temperature for 14 h. The reaction was monitored by HPLC for completion. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (gradient elution, 15-25% ethyl acetate in petroleum ether) to yield the title compound (586mg, 67%) as a white powder. C₂₅H₂₀ClNO₃Calculated LC/MS m/e of: 417, actual measurement (M + H)⁺：418.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.12(dd，J＝9.09，4.80Hz，1H)2.38(dd，J＝8.08，5.05Hz，1H)3.22(t，J＝8.59Hz，1H)3.85(s，3H)5.11(s，2H)6.16(d，J＝7.33Hz，1H)6.72(t，J＝7.58Hz，1H)6.94(d，J＝7.83Hz，1H)7.07(t，J＝7.71Hz，1H)7.30-7.41(m，4H)7.52(t，J＝7.71Hz，1H)7.59-7.66(m，1H)7.88(d，J＝7.58Hz，1H)7.92(s，1H)。

Synthesis of (1R, 2S) and (1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

Mixing (1R, 2S) and (1S, 2R) -methyl-3- (((2- (4-chlorophenyl) -2 '-oxospiro [ cyclo-propane-1, 3' -indoline)]-1' -yl) methyl) benzoate (48mg) dissolved in 1mL of methanol; then 0.1mL of water was added followed by hydrogenLithium oxide (10 mg). The mixture was stirred at room temperature for 14 hours. The solvent was removed under reduced pressure. The residue was dissolved in 2mL DMF and purified by preparative HPLC to give the title compound (10mg) as a white powder. C₂₄H₁₈ClNO₃Calculated LC/MS m/e of: 403, actual measurement (M + H)⁺：404.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.12(dd，J＝9.09，4.80Hz，1H)2.40(dd，J＝7.96，4.93Hz，1H)3.19-3.24(m，1H)5.10(s，2H)6.17(d，J＝7.33Hz，1H)6.72(t，J＝7.58Hz，1H)6.95(d，J＝7.83Hz，1H)7.08(t，J＝7.83Hz，1H)7.30-7.41(m，4H)7.50(t，J＝7.71Hz，1H)7.60(d，J＝7.58Hz，1H)7.82-7.89(m，2H)13.04(s，1H)。

Example 2

(1R, 2R) and (1S, 2S) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₈ClNO₃Calculated LC/MS m/e of: 403.1, actual measurement (M + H)⁺：404.2。¹H NMR(400MHz，DMSO-d₆)δppm 2.26(dd，J＝8.97，4.67Hz，1H)2.34(dd，J＝8.34，4.80Hz，1H)3.34(t，J＝8.72Hz，1H)4.84-5.01(m，2H)6.95(d，J＝7.58Hz，1H)7.04(t，J＝7.45Hz，1H)7.14-7.23(m，2H)7.29-7.37(m，4H)7.41-7.52(m，2H)7.76(s，1H)7.83(d，J＝7.58Hz，1H)13.05(br.s.，1H)。

Example 3

(1S, 2R) and (1R, 2S) -3- ((2- (3-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₈ClNO₃Calculated LC/MS m/e of: 403.1, actual measurement (M + H)⁺：404.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.10(dd，J＝9.22，4.93Hz，1H)2.45(dd，J＝7.96，4.93Hz，1H)3.19-3.25(m，1H)5.10(s，2H)6.17(d，J＝7.33Hz，1H)6.71(t，J＝7.58Hz，1H)6.95(d，J＝7.83Hz，1H)7.08(t，J＝7.71Hz，1H)7.27(s，1H)7.30-7.37(m，2H)7.42(s，1H)7.50(t，J＝7.58Hz，1H)7.60(d，J＝7.83Hz，1H)7.80-7.99(m，2H)。

Example 4

(1R, 2R) and (1S, 2S) - ((2- (4- (methylsulfonyl) phenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2R) and (1S, 2S) -2- (4- (methylsulfonyl) phenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₅H₂₁NO₅LC/MS m/e calculated for S: 447, measured (M + H)⁺：448.2。¹H NMR(400MHz，DMSO-d₆)δppm 2.34(dd，J＝8.84，4.80Hz，1H)2.42(dd，J＝8.34，4.80Hz，1H)3.47(t，J＝8.72Hz，1H)4.86-5.02(m，2H)6.97(d，J＝7.83Hz，1H)7.06(t，J＝7.58Hz，1H)7.17-7.27(m，2H)7.43-7.52(m，2H)7.60(d，J＝8.34Hz，2H)7.75(s，1H)7.80-7.88(m，3H)。

Example 5

(1S, 2R) and (1R, 2S) -3- ((2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1S, 2R) and (1R, 2S) -2- (4-cyanophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₅H₁₈N₂O₃Calculated LC/MS m/e of: 394, measured (M + H)⁺：395.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.16(dd，J＝8.84，5.05Hz，1H)2.45-2.50(m，1H)3.26-3.33(m，1H)5.10(s，1H)6.18(d，J＝7.58Hz，1H)6.71(t，J＝7.58Hz，1H)6.95(d，J＝7.83Hz，1H)7.08(t，J＝7.83Hz，1H)7.47-7.57(m，3H)7.60(d，J＝7.83Hz，1H)7.79(d，J＝8.08Hz，2H)7.83-7.89(m，2H)13.04(br.s.，1H)。

Example 6

(1S, 2R) and (1R, 2S) -2-chloro-5- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From 5-bromomethyl-2-chloro-benzoic acid methyl ester (commercially available), (1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₇Cl₂NO₃Calculated LC/MS m/e of: 437, actual measurement (M + H)⁺：438.3。¹H NMR(400MHz，DMSO-d₆)δppm 2.07-2.15(m，1H)2.39(dd，J＝7.83，5.05Hz，1H)3.20(t，J＝8.72Hz，1H)5.06(s，2H)6.16(d，J＝7.58Hz，1H)6.73(t，J＝7.58Hz，1H)6.97(d，J＝7.83Hz，1H)7.09(t，J＝7.83Hz，1H)7.28-7.40(m，4H)7.43-7.57(m，2H)7.73(s，1H)。

Example 7

(1S, 2R) and (1R, 2S) -3- ((2- (4- (methylsulfonyl) phenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -2- (4- (methylsulfonyl) phenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₅H₂₁NO₅LC/MS m/e calculated for S: 447, measured (M + H)⁺：448.2。¹H NMR(400MHz，DMSO-d₆)δppm 2.18(dd，J＝9.09，5.05Hz，1H)2.51-2.55(m，1H)3.20(s，3H)3.32(t，J＝8.59Hz，1H)5.06-5.17(m，2H)6.22(d，J＝7.33Hz，1H)6.71(t，J＝7.45Hz，1H)6.95(d，J＝7.58Hz，1H)7.08(t，J＝7.83Hz，1H)7.51(t，J＝7.83Hz，1H)7.62(d，J＝8.59Hz，3H)7.84-7.90(m，4H)13.06(br.s.，1H)。

Example 8

(1S, 2R) and (1R, 2S) -3- ((2- (2-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -2- (2-fluorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₈FNO₃Calculated LC/MS m/e of: 387, measured (M + H)⁺：388.2。¹H NMR(400MHz，MeOD-d₄)δppm 2.22-2.34(m，2H)3.21(t，J＝8.59Hz，1H)5.06-5.28(m，2H)6.02(d，J＝7.58Hz，1H)6.62-6.71(m，1H)6.88(d，J＝7.83Hz，1H)6.91-6.99(m，1H)7.01-7.16(m，1H)7.25(t，J＝7.07Hz，1H)7.29-7.37(m，1H)7.46(t，J＝7.71Hz，1H)7.50-7.57(m，2H)7.96(d，J＝7.83Hz，1H)8.05(s，1H)。

Example 9

(1S, 2S) and (1R, 2R) -3- ((2- (2-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2R) and (1S, 2S) -2- (2-fluorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₈FNO₃Calculated LC/MS m/e of: 387, measured (M + H)⁺：388.1。¹H NMR(400MHz，MeOD-d₄)δppm 2.29(dd，J＝8.97，4.67Hz，1H)2.35(dd，J＝8.34，4.80Hz，1H)3.22(t，J＝8.72Hz，1H)4.89-5.12(m，2H)6.92(d，J＝7.83Hz，1H)6.99-7.25(m，5H)7.23-7.34(m，1H)7.38-7.51(m，3H)7.88-8.02(m，2H)。

Example 10

(1S, 2R) and (1R, 2S) -3- ((2- (3-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -2- (3-fluorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₈FNO₃Calculated LC/MS m/e of: 387, measured (M + H)⁺：388.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.07-2.15(m，1H)2.45(dd，J＝8.08，5.05Hz，1H)3.24(t，J＝8.46Hz，1H)5.10(s，2H)6.20(d，J＝7.58Hz，1H)6.95(d，J＝7.83Hz，1H)7.04-7.18(m，3H)7.22(d，J＝10.11Hz，1H)7.31-7.40(m，1H)7.50(t，J＝7.71Hz，1H)7.60(d，J＝7.83Hz，1H)7.81-7.91(m，2H)13.05(s，1H)。

Example 11

(1S, 2S) and (1R, 2R) -3- ((2- (3-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2R) and (1S, 2S) -2- (3-fluorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₈FNO₃Calculated LC/MS m/e of: 387, measured (M + H)⁺：388.2。¹H NMR(400MHz，DMSO-d₆)δppm2.27(dd，J＝8.84，4.80Hz，1H)2.38(dd，J＝8.34，4.80Hz，1H)3.36-3.41(m，1H)4.88-4.99(m，2H)6.96(d，J＝7.83Hz，1H)7.04(t，J＝7.83Hz，2H)7.12-7.24(m，4H)7.277.34(m，1H)7.41-7.48(m，2H)7.78(s，1H)7.82(d，J＝6.57Hz，1H)。

Example 12

(1S, 2S) and (1R, 2R) -3- ((2 ' -oxo-2- (2- (trifluoromethyl) phenyl) -spiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (2- (trifluoromethyl) phenyl) -benzoate (commercially available), (1R, 2R) as prepared in scheme 1 and (1S, 2S) -2- (3-fluorophenyl) spiro [ cyclopropane-1, 3' -indoline]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₅H₁₈F₃NO₃Calculated LC/MS m/e of: 437, actual measurement (M + H)⁺：438.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.16(dd，J＝9.09，5.05Hz，1H)2.57(dd，J＝7.58，5.56Hz，1H)3.27(t，J＝8.21Hz，1H)4.91-5.26(m，2H)6.07(d，J＝7.33Hz，1H)6.63(t，J＝7.20Hz，1H)6.93(d，J＝7.83Hz，1H)7.05(t，J＝7.33Hz，1H)7.44-7.55(m，2H)7.60(t，J＝7.96Hz，2H)7.76(t，J＝7.58Hz，1H)7.87(t，J＝8.84Hz，2H)7.96(s，1H)12.99(br.s.，1H)。

Example 13

(1S, 2R) and (1R, 2S) - ((5 '-chloro-2- (4-chlorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -5 '-chloro-2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₇Cl₂NO₃Calculated LC/MS m/e of: 437, actual measurement (M + H)⁺：438.2。¹H NMR(400MHz，DMSO-d₆)δppm 2.16(dd，J＝9.09，5.05Hz，1H)2.56(dd，J＝8.08，5.05Hz，1H)3.26(t，J＝8.59Hz，1H)5.10(s，2H)6.19(d，J＝2.02Hz，1H)6.96(d，J＝8.34Hz，1H)7.14(dd，J＝8.34，2.02Hz，1H)7.39(q，J＝8.42Hz，4H)7.50(t，J＝7.58Hz，1H)7.54-7.61(m，1H)7.81-7.89(m，2H)13.07(s，1H)。

Example 14

(1R, 2R) and (1S, 2S) -3- ((5 '-chloro-2- (4-chlorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2R) and (1S, 2S) -5 '-chloro-2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₇Cl₂NO₃Calculated LC/MS m/e of: 437, actual measurement (M + H)⁺：438.1。¹H NMR(400MHz，MeOD-d₄)δppm 2.32(dd，J＝9.09，5.05Hz，1H)2.44(dd，J＝8.59，5.05Hz，1H)3.37(t，J＝8.97Hz，1H)4.82-5.10(m，4H)6.87(d，J＝8.08Hz，1H)7.19(d，J＝2.02Hz，1H)7.21(s，1H)7.31(s，4H)7.39-7.49(m，2H)7.85(s，1H)7.93(d，J＝7.07Hz，1H)。

Example 15

(1R, 2R) and (1S, 2S) -3- ((5 '-bromo-2- (4-chlorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2R) and (1S, 2S) -5 '-bromo-2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₇BrClNO₃Calculated LC/MS m/e of: 481, actually measured (M + H)⁺：482.1。¹H NMR(400MHz，MeOD-d₄)δppm 2.25-2.37(m，2H)3.34-3.40(m，1H)5.05-5.21(m，2H)6.19(d，J＝1.77Hz，1H)6.83(d，J＝8.34Hz，1H)7.20-7.30(m，3H)7.32-7.40(m，2H)7.50(t，J＝7.71Hz，1H)7.60(d，J＝7.83Hz，1H)7.90-8.01(m，2H)。

Example 16

(1S, 2R) and (1R, 2S) -3- ((5 '-bromo-2- (4-chlorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available) and racemic (1S, 2R) and (1R, 2S) -5 '-bromo-2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₇BrClNO₃Calculated LC/MS m/e of: 481, actually measured (M + H)⁺：482.1。¹H NMR(400MHz，MeOD-d₄)δppm 2.33(dd，J＝8.97，4.93Hz，1H)2.44(dd，J＝8.84，5.05Hz，1H)3.38(t，J＝8.84Hz，1H)4.85(s，1H)5.05(d，J＝16.17Hz，1H)6.81-6.86(m，1H)7.31(s，4H)7.33-7.38(m，2H)7.41-7.49(m，2H)7.85(s，1H)7.94(d，J＝7.07Hz，1H)。

Example 17

(1S, 2S) and (1R, 2R) -3- ((2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1S, 2S) and (1R, 2R) -2- (4-cyanophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₅H₁₈N₂O₃Calculated LC/MS m/e of: 394, measured (M + H)⁺：394.2。¹H NMR(400MHz，CDCl₃)δppm 2.23(dd，J＝8.84，5.05Hz，1H)2.52(dd，J＝8.59，5.31Hz，1H)3.23(t，J＝8.72Hz，1H)4.95(d，J＝61.89Hz，2H)6.82(d，J＝7.83Hz，1H)7.00-7.05(m，1H)7.10(t，J＝7.45Hz，1H)7.19-7.26(m，1H)7.43(s，2H)7.49(d，J＝8.08Hz，2H)7.65(d，J＝8.08Hz，2H)7.96(s，1H)8.02(d，J＝7.33Hz，1H)。

Example 18

(1S, 2R) and (1R, 2S) -3- ((2- (3-methoxyphenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -2- (3-methoxyphenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₅H₂₁NO₄Calculated LC/MS m/e of: 399, actually measured (M + H)⁺：400.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.09(q，J＝4.46Hz，1H)2.41(dd，J＝8.08，4.80Hz，1H)3.20(t，J＝8.84Hz，1H)3.72(s，3H)5.10(s，2H)6.22(d，J＝7.33Hz，1H)6.70(t，J＝7.58Hz，1H)6.81-6.89(m，3H)6.94(d，J＝7.83Hz，1H)7.06(t，J＝7.71Hz，1H)7.22(t，J＝8.08Hz，1H)7.50(t，J＝7.58Hz，1H)7.60(d，J＝7.58Hz，1H)7.85(d，J＝7.83Hz，1H)7.89(s，1H)13.04(br.s.，1H)。

Example 19

(1S, 2S) and (1R, 2R) -3- ((2- (3-methoxyphenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2R) and (1S, 2S) -2- (3-methoxyphenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₅H₂₁NO₄Calculated LC/MS m/e of: 399, actually measured (M + H)⁺：400.2。¹H NMR(400MHz，DMSO-d₆)δppm 2.24(dd，J＝9.09，4.55Hz，1H)2.34(dd，J＝8.59，4.55Hz，1H)3.31(t，J＝8.72Hz，1H)3.72(s，3H)4.88-5.02(m，2H)6.76-6.82(m，1H)6.85-6.90(m，2H)6.95(d，J＝7.58Hz，1H)7.04(t，J＝7.45Hz，1H)7.19(t，J＝7.96Hz，3H)7.39-7.49(m，2H)7.77-7.88(m，2H)13.02(br.s.，1H)。

Example 20

(1S, 2S) and (1R, 2R) -3- ((2- (4-methoxyphenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2R) and (1S, 2S) -2- (4-methoxyphenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting from the 2' -ketone, analogously to example 1The title compound was prepared. C₂₅H₂₁NO₄Calculated LC/MS m/e of: 399, actually measured (M + H)⁺：400.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.23(dd，J＝8.84，4.55Hz，1H)2.30(dd，J＝8.46，4.67Hz，1H)3.26(t，J＝8.72Hz，1H)3.73(s，3H)4.85-5.02(m，2H)6.84(d，J＝8.59Hz，1H)6.93(d，J＝7.58Hz，1H)7.03(t，J＝7.58Hz，1H)7.14-7.27(m，4H)7.42-7.52(m，2H)7.77(s，1H)7.82(d，J＝7.07Hz，1H)13.02(br.s.，1H)。

Example 21

(1S, 2R) and (1R, 2S) -3- ((2- (4-methoxyphenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -2- (4-methoxyphenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₅H₂₁NO₄Calculated LC/MS m/e of: 399, actually measured (M + H)⁺：400.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.05-2.14(m，1H)2.33(dd，J＝7.96，4.67Hz，1H)3.17(t，J＝8.46Hz，1H)3.73(s，3H)5.10(d，J＝2.27Hz，2H)6.15(d，J＝7.33Hz，1H)6.69(t，J＝7.20Hz，1H)6.87(d，J＝8.59Hz，1H)6.93(d，J＝7.58Hz，1H)7.05(t，J＝7.33Hz，1H)7.22(d，J＝8.59Hz，2H)7.50(t，J＝7.58Hz，1H)7.60(d，J＝7.83Hz，1H)7.84-7.90(m，2H)13.05(br.s.，1H)。

Example 22

(1S, 2R) and (1R, 2S) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -5 '-fluorospiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₇ClFNO₃Calculated LC/MS m/e of: 421, actual measurement (M + H)⁺：422.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.17(dd，J＝9.09，4.80Hz，1H)2.45-2.50(m，1H)3.26(t，J＝8.59Hz，1H)5.03-5.17(m，2H)5.98-6.05(m，1H)6.88-6.97(m，2H)7.38(q，J＝8.59Hz，4H)7.47-7.54(m，1H)7.55-7.63(m，1H)7.81-7.91(m，2H)13.05(s，1H)。

Example 23

(1S, 2S) and (1R, 2R) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1S, 2S) and (1R, 2R) -2- (4-chlorophenyl) -5 '-fluorospiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₇ClFNO₃Calculated LC/MS m/e of: 421, actual measurement (M + H)⁺：422.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.28-2.42(m，2H)3.41(t，J＝8.84Hz，1H)4.82-5.02(m，2H)6.86-6.96(m，1H)6.98-7.07(m，1H)7.19(dd，J＝8.59，2.53Hz，1H)7.34(s，4H)7.41-7.53(m，2H)7.74(s，1H)7.83(d，J＝6.82Hz，1H)13.04(br.s.，1H)。

Example 24

(1S, 2R) and (1R, 2S) -3- ((-2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available) and racemic (1S, 2R) -2- (4-fluorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₈FNO₃Calculated LC/MS m/e of: 421, actual measurement (M + H)⁺：422.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.12(dd，J＝9.09，4.80Hz，1H)2.38(dd，J＝7.83，5.05Hz，1H)3.21(t，J＝8.59Hz，1H)5.10(s，2H)6.12(d，J＝7.58Hz，1H)6.70(t，J＝7.58Hz，1H)6.94(d，J＝7.83Hz，1H)7.07(t，J＝7.71Hz，1H)7.14(t，J＝8.72Hz，2H)7.35(dd，J＝8.34，5.56Hz，2H)7.50(t，J＝7.58Hz，1H)7.60(d，J＝7.58Hz，1H)7.81-7.90(m，2H)13.03(br.s.，1H)。

Example 25

(1S, 2R) and (1R, 2S) -3- ((2 ' -oxo-2- (pyridin-3-yl) spiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1S, 2R) and (1R, 2S) -2- (pyridin-3-yl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₃H₁₈N₂O₃Calculated LC/MS m/e of: 370, actual measurement (M + H)⁺：371.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.18(dd，J＝8.59，5.05Hz，1H)3.27(t，J＝8.59Hz，2H)5.11(s，2H)6.14(d，J＝7.33Hz，1H)6.71(t，J＝7.45Hz，1H)6.97(d，J＝7.58Hz，1H)7.05-7.15(m，1H)7.46-7.57(m，2H)7.61(d，J＝7.33Hz，1H)7.90(br.s.，1H)7.86(d，J＝7.33Hz，2H)8.57(br.s.，1H)8.66(br.s.，1H)。

Example 26

(1S, 2S) and (1R, 2R) -3- ((-2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1S, 2S) and (1R, 2R) -2- (4-fluorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₈FNO₃Calculated LC/MS m/e of: 421, actual measurement (M + H)⁺：422.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.26(dd，J＝8.97，4.67Hz，1H)2.33(dd，J＝8.34，4.80Hz，1H)3.14-3.29(m，1H)4.83-5.02(m，2H)6.95(d，J＝7.58Hz，1H)7.04(t，J＝7.33Hz，1H)7.10(t，J＝8.72Hz，2H)7.15-7.23(m，2H)7.35(dd，J＝8.21，5.68Hz，2H)7.40-7.53(m，2H)7.76(s，1H)7.82(d，J＝7.33Hz，1H)。

Example 27

(1S, 2S) and (1R, 2R) -3- ((2- (4-chlorophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

Synthesis of 1- (4-iodo-phenyl) -2-methyl-propan-1-one

A2.0M solution of isopropylmagnesium chloride (10ml, 20mmol) was added dropwise (30min) to freshly distilled 4-iodobenzoyl chloride (5.32g, 20mmol) and Fe (acac) at room temperature under nitrogen₃(0.35g, 1mmol) in 150ml of anhydrous THF. After the addition, stirring was continued at the same temperature for 10 min. The reaction was quenched by pouring the mixture into dilute hydrochloric acid and extracted with several portions of diethyl ether. With NaHCO₃The combined ether extracts were washed with aqueous, water and washed with Na₂SO₄And drying. Removal of the organic solvent under vacuum gave the product as a colorless oil. And the crude product was used in the next step without further purification.

Synthesis of 1-iodo-4- (2-methyl-1-methylene-propyl) -benzene

7.07g (20mmol) of methyltriphenylphosphonium bromide in 50mL of anhydrous THF at 0 deg.CTo the solution of (2) was added tert-butyllithium (14.7ml, 1.5M in hexane) and the solution turned brown. After stirring for 1 hour at 0 ℃, unpurified 1- (4-iodo-phenyl) -2-methyl-propan-1-one in 20mL THF from the previous step was added dropwise and the solution was stirred at room temperature for 14 hours. After cooling to about 20 ℃, 52mL of water was added and the solution was extracted with dichloromethane (3 × 50 mL). The organic layer was washed with MgSO 2₄Dried and the solvent removed to give the crude title compound as a white solid. The product was used in the next step without further purification.

Synthesis of 3-diazo-5-fluoroindolin-2-one

5-Fluoroisatin (64.3mmol) was suspended in MeOH (300 mL). The suspension was heated to reflux, at which time a dark red solution was obtained. To this hot solution was added tosylhydrazide (64.8mmol) in one portion. A yellow product began to precipitate out of the hot mixture. The reaction was allowed to cool to room temperature and the light colored tosylhydrazone was filtered off. The product was used in the next step without further purification.

Tosylhydrazone (38.1mmol) was treated with 375mL of aqueous NaOH (76.1 mmol). The reaction mixture was stirred in a water bath at 50 ℃ for 15 hours and then allowed to cool to room temperature. The reaction mixture was neutralized by adding dry ice, whereupon the diazo compound precipitated (5.94g, 88%).

Synthesis of (1S, 2S) and (1R, 2R) -5 ' -fluoro-2- (4-iodophenyl) -2-isopropylspiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

3-diazo-5-fluoroindolin-2-one (0.177g, 1mmol) and Rh (OAc)₂The dimer (2.2mg) was put into a Schlenk tube under an argon atmosphere, which was then dissolved in anhydrous benzene (3 mL). The mixture was heated to 80 ℃ for 10 minutes. 1-iodo-4- (3-methylbut-1-en-2-yl) benzene (0.544g) was dissolved in anhydrous THF (2mL) and added to the mixture in one portion. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (petroleum ether: AcOEt ═ 5: 1) to give the title compound (0.446g, 53%) as a white powder. C₁₉H₁₇LC/MS m/e Calculations for FINO: 421, actual measurement (M + H)⁺：422.1。

Synthesis of (1S, 2S) and (1R, 2R) -methyl-3- ((-5 '-fluoro-2- (4-iodophenyl) -2-isopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoate

Mixing (1S, 2S) and (1R, 2R) -5 '-fluoro-2- (4-iodophenyl) -2-isopropylspiro [ cyclopropane-1, 3' -indoline]-2' -one (0.88g, 2.1mmol), methyl- (3-bromomethyl) -benzoate (725mg, 3.15mmol) and Cs₂CO₃(1.37g, 4.2mmol) was mixed in anhydrous DMF and stirred at room temperature for 14 h. The solvent was removed under reduced pressure. By flash column chromatography (ladder)Elution, 15-25% ethyl acetate in petroleum ether) to yield the title product as a white solid (1.10g, 92%). C₂₈H₂₅LC/MS m/e Calculations for FINO: 569, actual measurement (M + H)⁺：570.1

Synthesis of (1S, 2S) and (1R, 2R) -methyl-3- ((2- (4-cyanophenyl) -5 '-fluoro-2-isopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoate

(1S, 2S) and (1R, 2R) -methyl-3- ((-5 ' -fluoro-2- (4-iodophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline) in tetrahydrofuran (9.0mL)]-1' -yl) methyl) benzoate (1.35g, 2.4mmol), NaCN (240mg, 4.9mmol), CuI (50mg, 0.3mmol) and Pd (PPh)₃)₄(140mg, 0.12mmol) of the solution was stirred at 65 ℃ for 2 hours. The mixture was cooled to room temperature and extracted with ethyl acetate and washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by flash column chromatography eluting with hexane/ethyl acetate (8: 1 to 4: 1) afforded a pale yellow oil (500mg, 45.5% yield). C₂₉H₂₅FN₂O₃Calculated LC/MS m/e of: 469, actually measured (M + H)⁺：469.2

Synthesis of (1S, 2S) and (1R, 2R) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-isopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

(1S, 2S) and (1R, 2R) -methyl-3- ((2- (4-cyanophenyl) -5 ' -fluoro-2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline) in tetrahydrofuran (10mL) at room temperature]-1' -yl) methylYl) benzoate (500mg, 1.1mmol) was added 30% aqueous sodium hydroxide (3mL) and the mixture was stirred at that temperature for 16 h. The mixture was neutralized with 2N aqueous hydrochloric acid, diluted with ethyl acetate (50mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by a waters automated rapid system (column: Xterra 30mm x 100mm, sample manager 2767, pump 2525, detector: zQ mass and UV 2487, solvent system: acetonitrile and 0.1% aqueous trifluoroacetic acid) yielded the title compound as a white solid (270mg, 59.5%): c₂₈H₂₃FN₂O₃Calculated LC/MSm/e of (1): 454, actual measurement (M + H)⁺：455.2。¹H NMR(400MHz，MeOD-d₄)δppm7.97(s，1H)，7.94(d，J＝7.83Hz，1H)，7.85(dd，J＝7.96，1.64Hz，1H)，7.67(dd，J＝7.96，1.39Hz，1H)，7.61(d，J＝7.58Hz，1H)，7.48(q，J＝7.83Hz，2H)，6.74-6.86(m，3H)，5.28(d，J＝15.92Hz，1H)，5.17(dd，J＝8.72，2.40Hz，1H)，4.97(d，J＝16.17Hz，1H)，3.04(dt，J＝13.64，6.82Hz，1H)，2.23-2.28(m，1H)，2.20-2.23(m，1H)，0.92(d，J＝7.07Hz，3H)，0.81(d，J＝6.82Hz，3H)。

Example 28

(1S, 2S) and (1R, 2R) -3- ((2- (4-cyanophenyl) -2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1S, 2S) and (1R, 2R) -4- (2-methyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline) as prepared in scheme 2]The title compound was prepared in analogy to example 27 starting from-2-yl) benzonitrile. C₂₆H₂₀FN₂O₃Calculated LC/MS m/e of: 408, measured (M + H)⁺：409.1。¹H NMR(400MHz，MeOD-d₄)δppm 7.96(d，J＝7.58Hz，1H)7.87(s，1H)7.67(d，J＝8.08Hz，2H)7.53-7.57(m，1H)7.48(t，J＝7.71Hz，3H)7.32(d，J＝7.58Hz，1H)7.26(t，J＝7.71Hz，1H)7.11(t，J＝7.58Hz，1H)6.97(d，J＝7.83Hz，1H)5.12(d，J＝15.92Hz，1H)4.75(d，J＝15.92Hz，1H)2.49(d，J＝5.05Hz，1H)2.10(d，J＝5.05Hz，1H)1.72(s，3H)。

Example 29

(1S, 2R) and (1R, 2S) -3- ((2- (4-cyanophenyl) -2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available) and racemic (1S, 2R) and (1R, 2S) -4- (2-methyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline as prepared in scheme 2]The title compound was prepared in analogy to example 27 starting from-2-yl) benzonitrile. C₂₆H₂₀FN₂O₃Calculated LC/MS m/e of: 408, measured (M + H)⁺：409.1。¹H NMR(400MHz，MeOD-d₄)δppm 7.91-7.97(m，2H)7.57(br.s.，4H)7.47(t，J＝7.33Hz，2H)7.04(t，J＝7.83Hz，1H)6.86(d，J＝8.08Hz，1H)6.61(t，J＝7.71Hz，1H)5.61(d，J＝7.58Hz，1H)5.18-5.26(m，1H)5.01-5.10(m，1H)2.37(d，J＝5.05Hz，1H)2.19(d，J＝5.05Hz，1H)1.88(s，3H)。

Examples 30 and 31

(-) -3- ((2- (4-chlorophenyl) -2-isopropyl-2 '-oxospiro [ (trans) -cyclopropane-1, 3' -indolin ] -1 '-yl) methyl) benzoic acid and (+) -3- ((2- (4-chlorophenyl) -2-isopropyl-2' -oxospiro [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

The title compound was obtained by separation of stereoisomers of (1S, 2S) and (1R, 2R) -3- ((2- (4-chlorophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid (example 32) by chiral preparative hplc (chiralpak ad) (elution with a mixture of n-heptane/5% isopropanol).

(+) -3- ((2- (4-chlorophenyl) -2-isopropyl-2 ' -oxospiro [ (trans) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

C₂₇H₂₄ClNO₃Calculated LC/MS m/e of: 445, actual measurement (M + H)⁺：446.7。¹H NMR(400MHz，MeOD)δppm 8.01(s，1H)7.96(d，J＝7.58Hz，1H)7.64(d，J＝7.83Hz，1H)7.46-7.52(m，3H)7.05-7.12(m，1H)7.10(d，J＝8.08Hz，1H)6.89(d，J＝7.83Hz，1H)6.64(t，J＝7.58Hz，1H)6.53(d，J＝8.34Hz，1H)5.50-5.53(m，2H)5.31(d，J＝15.92Hz，1H)5.00(d，J＝16.17Hz，1H)3.01(dt，J＝13.83，6.85Hz，1H)2.20(d，J＝4.80Hz，1H)2.15(d，J＝4.80Hz，1H)0.94(d，J＝7.07Hz，3H)0.82(d，J＝6.82Hz，3H)。[α]_D ²⁵＝+114(c＝5mg/mL，CH₂Cl₂)。

(-) -3- ((2- (4-chlorophenyl) -2-isopropyl-2 ' -oxospiro [ [ (trans) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

C₂₇H₂₄ClNO₃Calculated LC/MS m/e of: 445, actual measurement (M + H)⁺：446.5。¹H NMR(400MHz，MeOD)δppm 8.01(s，1H)7.96(d，J＝7.58Hz，1H)7.64(d，J＝7.83Hz，1H)7.46-7.52(m，3H)7.05-7.12(m，1H)7.10(d，J＝8.08Hz，1H)6.89(d，J＝7.83Hz，1H)6.64(t，J＝7.58Hz，1H)6.53(d，J＝8.34Hz，1H)5.50-5.53(m，2H)5.31(d，J＝15.92Hz，1H)5.00(d，J＝16.17Hz，1H)3.01(dt，J＝13.83，6.85Hz，1H)2.20(d，J＝4.80Hz，1H)2.15(d，J＝4.80Hz，1H)0.94(d，J＝7.07Hz，3H)0.82(d，J＝6.82Hz，3H)。[α]_D ²⁵＝-126.00(c＝5.2mg/mL，CH₂Cl₂)。

Example 32

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2R) and (1S, 2S) -2- (4-chlorophenyl) -2-isopropylspiro [ cyclopropane-1, 3' -indoline as prepared in scheme 2]Starting with the 2' -ketone, the title compound was prepared in analogy to example 27. C₂₇H₂₄ClNO₃Calculated LC/MS m/e of: 445, actual measurement (M + H)⁺：446.5。¹H NMR(400MHz，MeOD-d₄)δppm 8.01(s，1H)7.96(d，J＝7.58Hz，1H)7.64(d，J＝7.83Hz，1H)7.46-7.52(m，3H)7.05-7.12(m，1H)7.10(d，J＝8.08Hz，1H)6.89(d，J＝7.83Hz，1H)6.64(t，J＝7.58Hz，1H)6.53(d，J＝8.34Hz，1H)5.50-5.53(m，2H)5.31(d，J＝15.92Hz，1H)5.00(d，J＝16.17Hz，1H)3.01(dt，J＝13.83，6.85Hz，1H)2.20(d，J＝4.80Hz，1H)2.15(d，J＝4.80Hz，1H)0.94(d，J＝7.07Hz，3H)0.82(d，J＝6.82Hz，3H)。

Example 33 and example 34

(+) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-isopropyl-2' -oxospiro [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid and (-) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-isopropyl-2' -oxospiro [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

The title compound was obtained by separation of stereoisomers of (1S, 2S) and (1R, 2R) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-isopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid (example 35) by chiral preparative hplc (chiralpak ad) (elution with a mixture of n-heptane/5% isopropanol).

(+) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-isopropyl-2' -oxospiro [ [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

C₂₇H₂₃ClFNO₃Calculated LC/MS m/e of: 463, actual measurement (M + H)⁺：464.2。¹HNMR (400MHz, MeOD) δ ppm 8.01(s, 1H)7.98(d, J ═ 7.83Hz, 1H)7.64(d, J ═ 7.58Hz, 1H)7.47-7.54(m, 1H)7.51(t, J ═ 7.07Hz, 2H)7.18(dd, J ═ 8.34, 1.52Hz, 1H)6.85(d, J ═ 4.55Hz, 1H)6.79-6.88(m, 1H)6.59(d, J ═ 8.08Hz, 1H)5.31(d, J ═ 16.17Hz, 1H)5.25(dd, J ═ 8.97, 2.15Hz, 1H)5.00(d, J ═ 16.17, 1H)3.02 (J ═ 3.82, J ═ 4.82 Hz, 1H) 3.85 (d, J ═ 4.82H), 1H) 6.7.7.7 (d, 1H) 6.7H, 1H)6.7 (m, 1H)6.59(d, 1H). White powder. MS (ESI) (M + H)⁺463.5；[α]_D ²⁵＝109.52(c＝5mg/mL，CH₂Cl₂). (-) -3- ((2- (4-chlorophenyl) -5 ' -fluoro-2-isopropyl-2 ' -oxospiro [ [ (trans) -cyclopropane-1, 3 ' -indoline)]-1' -yl) methyl) benzoic acid

C₂₇H₂₃ClFNO₃Calculated LC/MS m/e of: 463, found (M + H) +: 464.1. 1HNMR (400MHz, MeOD) δ ppm 8.01(s, 1H)7.98(d, J ═ 7.83Hz, 1H)7 δ 4(d, J ═ 7.58Hz, 1H)7.47-7.54(m, 1H)7.51(t, J ═ 7.07Hz, 2H)7.18(dd, J ═ 8.34, 1.52Hz, 1H)6.85(d, J ═ 4.55Hz, 1H)6.79-6.88(m, 1H)6.59(d, J ═ 8.08Hz, 1H)5.31(d, J ═ 16.17Hz, 1H)5.25(dd, J ═ 8.97, 2.15, 1H)5.00(d, J ═ 16.17, 1H) 3.01 (s, 1H)7.98(d, J ═ 4.82H), 1H) (d, J ═ 6.85H, 1H)6.7 (d, 1H) 6.7.7.7 Hz, 1H) 5.7 (d, 1H) 5.7H, 1H)5.0 (d, 1H, 3.82H, 1H)6.7 (d, 1H) 6.7H, 1H) 6.7. White powder. Ms (esi) (M + H) + 463.8; [ alpha ] to]D25＝-133.26(c＝5mg/mL，CH2Cl2)。

Example 35

(1S, 2S) and (1R, 2R) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-isopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2R) and (1S, 2S) -2- (4-chlorophenyl) -5 '-fluoro-2-isopropylspiro [ cyclopropane-1, 3' -indoline as prepared in scheme 2]Starting with the 2' -ketone, the title compound was prepared in analogy to example 27. C₂₇H₂₃ClFNO₃Calculated LC/MS m/e of: 463, actual measurement (M + H)⁺：464.2。¹H NMR(400MHz，MeOD-d₄)δppm 8.01(s，1H)7.98(d，J＝7.83Hz，1H)7.64(d，J＝7.58Hz，1H)7.47-7.54(m，1H)7.51(t，J＝7.07Hz，2H)7.18(dd，J＝8.34，1.52Hz，1H)6.85(d，J＝4.55Hz，1H)6.79-6.88(m，1H)6.59(d，J＝8.08Hz，1H)5.31(d，J＝16.17Hz，1H)5.25(dd，J＝8.97，2.15Hz，1H)5.00(d，J＝16.17Hz，1H)3.02(dt，J＝13.64，6.82Hz，1H)2.25(d，J＝4.80Hz，1H)2.18-2.23(m，1H)0.95(d，J＝6.82Hz，3H)0.85(d，J＝6.57Hz，3H)。

Example 36

(1S, 2S) and (1R, 2R) -3- ((5 '-fluoro-2- (4-fluorophenyl) -2-isopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), rac (1S, 2S) as prepared in scheme 2, and (1R, 2R) -2- (4-fluorophenyl) -5' -fluoro-2-isopropylspiro [ cyclopropane-1,3' -indoline]Starting with the 2' -ketone, the title compound was prepared in analogy to example 27. C₂₇H₂₃F₂NO₃Calculated LC/MS m/e of: 447, measured (M + H)⁺：448.1。¹H NMR(400MHz，MeOD-d₄)δppm 7.99(s，1H)7.95(d，J＝7.83Hz，1H)7.61(d，J＝7.83Hz，1H)7.49(d，J＝7.58Hz，1H)7.46-7.54(m，1H)7.22(td，J＝8.65，2.65Hz，1H)6.77-6.92(m，3H)6.60(ddd，J＝8.27，5.62，2.27Hz，1H)5.29(d，J＝15.92Hz，1H)5.20(dd，J＝8.84，2.27Hz，1H)4.98(d，J＝15.92Hz，1H)2.99(dt，J＝13.64，6.82Hz，1H)2.23(d，J＝4.80Hz，1H)2.16-2.21(m，1H)0.93(d，J＝6.82Hz，3H)0.83(d，J＝6.82Hz，3H)。

Example 37

(1S, 2S) and (1R, 2R) -3- ((2- (3-fluorophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2R) and (1S, 2S) -2- (3-fluorophenyl) -2-isopropylspiro [ cyclopropane-1, 3' -indoline as prepared in scheme 2]Starting with the 2' -ketone, the title compound was prepared in analogy to example 27. C₂₇H₂₄FNO₃Calculated LC/MS m/e of: 429, actual measurement (M + H)⁺：430.1。¹H NMR(400MHz，MeOD-d₄)δppm 8.02(s，1H)7.95(d，J＝7.33Hz，1H)7.61(d，J＝7.58Hz，1H)7.48(t，J＝7.58Hz，1H)7.31(d，J＝7.83Hz，1H)7.06(dd，J＝10.86，7.58Hz，2H)7.11(d，J＝6.32Hz，1H)6.89(t，J＝8.08Hz，1H)6.56-6.68(m，1H)6.38(d，J＝7.58Hz，1H)5.50(t，J＝8.21Hz，1H)5.28(dd，J＝15.92，10.36Hz，1H)5.01(d，J＝16.42Hz，2H)5.07(s，1H)3.01(d，J＝6.82Hz，1H)2.19(d，J＝5.56Hz，1H)2.12-2.26(m，1H)0.95(dd，J＝6.82，3.28Hz，3H)0.85(dd，J＝6.82，3.79Hz，3H)。

Example 38

(1S, 2S) and (1R, 2R) -3- ((2- (3-chlorophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2R) and (1S, 2S) -2- (3-chlorophenyl) -2-isopropylspiro [ cyclopropane-1, 3' -indoline as prepared in scheme 2]Starting with the 2' -ketone, the title compound was prepared in analogy to example 27. C₂₇H₂₄ClNO₃Calculated LC/MS m/e of: 445, actual measurement (M + H)⁺：446.1。¹H NMR(400MHz，MeOD-d₄)δppm 8.02(d，J＝9.85Hz，1H)7.96(d，J＝7.58Hz，1H)7.62(d，J＝7.58Hz，1H)7.40-7.52(m，3H)7.32(d，J＝7.58Hz，1H)7.03-7.12(m，J＝7.01，7.01，7.01，7.01Hz，2H)6.89(dd，J＝11.75，7.96Hz，1H)6.62(dt，J＝10.61，7.71Hz，1H)6.46-6.51(m，1H)5.48(dd，J＝16.67，7.58Hz，1H)5.27(t，J＝16.42Hz，1H)4.95-5.08(m，1H)3.01(dt，J＝13.64，6.82Hz，1H)2.19(d，J＝4.55Hz，1H)2.15(t，J＝5.18Hz，1H)0.94(d，J＝6.82Hz，3H)0.83(dd，J＝6.69，2.91Hz，3H)。

Example 39

(1S, 2S) and (1R, 2R) -3- ((2- (4-fluorophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2R) and (1S, 2S) -2- (4-fluorophenyl) -2-isopropyl, as prepared in scheme 2Spiro [ cyclopropane-1, 3' -indoline]Starting with the 2' -ketone, the title compound was prepared in analogy to example 27. C₂₇H₂₄FNO₃Calculated LC/MS m/e of: 429, actual measurement (M + H)⁺：430.1。¹H NMR(400MHz，MeOD-d₄)δppm 8.02(s，1H)7.96(d，J＝7.83Hz，1H)7.62(d，J＝7.83Hz，1H)7.49(q，J＝7.49Hz，2H)7.19(td，J＝8.72，2.53Hz，1H)7.07(t，J＝7.71Hz，1H)6.89(d，J＝7.83Hz，1H)6.83(td，J＝8.72，2.78Hz，1H)6.63(t，J＝7.58Hz，1H)6.57(ddd，J＝8.21，5.68，2.02Hz，1H)5.49(d，J＝7.58Hz，1H)5.30(d，J＝16.17Hz，1H)5.01(d，J＝16.17Hz，1H)3.00(dt，J＝13.64，6.82Hz，1H)2.20(d，J＝4.55Hz，1H)2.15(d，J＝4.55Hz，1H)0.94(d，J＝7.07Hz，3H)0.83(d，J＝6.82Hz，3H)。

Examples 40 and 41

The title compound was obtained by separation of stereoisomers of (1S, 2S) and (1R, 2R) -3- ((2- (4-chlorophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid (example 27) by chiral preparative hplc (chiralpak ad) (elution with a mixture of n-heptane/5% isopropanol).

(+) -3- ((2- (4-chlorophenyl) -2-isopropyl-2 ' -oxospiro [ [ (trans) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

C₂₈H₂₃FN₂O₃Calculated LC/MS m/e of: 454, actual measurement (M + H)⁺：455.6。¹H NMR (400MHz, MeOD) δ ppm 7.97(s, 1H)7.94(d, J ═ 7.83Hz, 1H)7.85(dd, J ═ 7.96, 1.64Hz, 1H)7.67(dd, J ═ 7.96, 1.39Hz, 1H)7.61(d, J ═ 7.58Hz, 1H)7.48(q, J ═ 7.83Hz, 2H)6.74-6.86(m, 3H)5.28(d, J ═ 15.92Hz, 1H)5.17(dd, J ═ 8.72, 2.40Hz, 1H)4.97(d, J ═ 16.17Hz, 1H)3.04(dt, J ═ 13.64, 6.82, 1H)2.23, 2.81, 2H) 3.81 (d, J ═ 3H) 3.07 (d, J ═ 13.64, 6.82, 1H), 2.81, 2H) 3.81, 3H (d, 3H) 3.07 (d, J ═ 7.7.7.7.7H). White powder. MS (ESI) (M + H)⁺；[α]_D ²⁵＝166.88(c＝5mg/mL，CH₂Cl₂)。

C₂₈H₂₃FN₂O₃Calculated LC/MS m/e of: 454, actual measurement (M + H)⁺：455.5。¹H NMR(400MHz，MeOD)δppm 7.97(s，1H)7.94(d，J＝7.83Hz，1H)7.85(dd，J＝7.96，1.64Hz，1H)7.67(dd，J＝7.96，1.39Hz，1H)7.61(d，J＝7.58Hz，1H)7.48(q，J＝7.83Hz，2H)6.74-6.86(m，3H)5.28(d，J＝15.92Hz，1H)5.17(dd，J＝8.72，2.40Hz，1H)4.97(d，J＝16.17Hz，1H)3.04(dt，J＝13.64，6.82Hz，1H)2.23-2.28(m，1H)2.20-2.23(m，1H)0.92(d，J＝7.07Hz，3H)0.81(d，J＝6.82Hz，3H)。[α]_D ²⁵＝-151.37(c＝5mg/mL，CH2Cl₂)。

Example 42

(1R, 2S) and (1S, 2R) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) -2-methylspiro [ cyclopropane-1, 3' -dihydro ] as prepared in scheme 2Indoles]Starting with the 2' -ketone, the title compound was prepared in analogy to example 27. C₂₅H₂₀ClNO₃Calculated LC/MS m/e of: 417, actual measurement (M + H)⁺：418.1。¹H NMR(400MHz，MeOD-d₄)δppm：1.86(s，3H)2.15(d，J＝5.05Hz，1H)2.31(d，J＝5.05Hz，1H)5.07(d，1H)5.22(d，1H)5.67(d，J＝7.58Hz，1H)6.62(t，J＝7.58Hz，1H)6.85(d，J＝7.83Hz，1H)7.04(t，J＝7.83Hz，1H)7.29(s，2H)7.48(t，J＝7.96Hz，1H)7.60(d，J＝7.83Hz，1H)7.93-7.98(m，2H)。

Example 43 and example 44

(+) -3- ((2- (4-chlorophenyl) -2-methyl-2 '-oxospiro [ (trans) -cyclopropane-1, 3' -indolin ] -1 '-yl) methyl) benzoic acid and (-) -3- ((2- (4-chlorophenyl) -2-methyl-2' -oxospiro [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

The title compound was obtained by separation of stereoisomers of (1R, 2S) and (1S, 2R) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid (example 42) by chiral preparative hplc (chiralpak ad) (elution with a mixture of n-heptane/5% isopropanol).

(+) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ [ (trans) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

C₂₅H₂₀ClNO₃Calculated LC/MS m/e of: 417, actual measurement (M + H)⁺：418.6。¹HNMR(400MHz，MeOD)δppm 1.86(s，3H)2.15(d，J＝4.80Hz，1H)2.31(d，J＝5.05Hz，1H)5.07(d，1H)5.23(d，1H)5.67(d，J＝7.33Hz，1H)6.62(t，J＝7.58Hz，1H)6.85(d，J＝7.83Hz，1H)7.04(t，J＝7.71Hz，1H)7.30(br.s.，3H)7.48(t，J＝7.83Hz，1H)7.60(d，J＝7.58Hz，1H)7.90-8.01(m，2H)。[α]_D ²⁵＝168.00(c＝4mg/mL，MeOH)。

(-) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ [ (trans) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

C₂₅H₂₀ClNO₃Calculated LC/MS m/e of: 417, actual measurement (M + H)⁺：418.5。¹HNMR(400MHz，MeOD)δppm 1.83(s，3H)2.12(d，J＝4.80Hz，1H)2.28(d，J＝4.80Hz，1H)5.04(d，1H)5.19(d，1H)5.64(d，J＝7.58Hz，1H)6.59(t，J＝7.71Hz，1H)6.82(d，J＝7.83Hz，1H)7.01(t，J＝7.71Hz，1H)7.27(br.s.，2H)7.45(t，J＝7.96Hz，1H)7.57(d，J＝7.58Hz，1H)7.89-7.96(m，2H)。[α]_D ²⁵＝-158.42(c＝4mg/mL，MeOH)。

Example 45

(1R, 2R) and (1S, 2S) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2R) and (1S, 2S) -2- (4-chlorophenyl) -2-methylspiro [ cyclopropane-1, 3' -indoline as prepared in scheme 2]Starting with the 2' -ketone, the title compound was prepared in analogy to example 27. C₂₅H₂₀ClNO₃Calculated LC/MS m/e of: 417, actual measurement (M + H)⁺：418.1。¹H NMR(400MHz，MeOD-d₄)δppm 1.69(s，3H)2.05(d，J＝4.80Hz，1H)2.45(d，J＝4.80Hz，1H)4.75(d，J＝15.92Hz，1H)5.12(d，J＝16.17Hz，1H)6.94(d，J＝7.83Hz，1H)7.09(t，J＝7.58Hz，1H)7.24(d，J＝7.58Hz，2H)7.21(s，1H)7.27-7.31(m，3H)7.46(t，J＝7.58Hz，1H)7.51-7.56(m，1H)7.89(s，1H)7.95(d，J＝7.58Hz，1H)。

Example 46 and example 47

(+) -3- ((2- (4-chlorophenyl) -2-methyl-2 '-oxospiro [ (cis) -cyclopropane-1, 3' -indolin ] -1 '-yl) methyl) benzoic acid and (-) -3- ((2- (4-chlorophenyl) -2-methyl-2' -oxospiro [ (cis) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

The title compound was obtained by separation of stereoisomers of (1R, 2R) and (1S, 2S) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid (example 45) by chiral preparative hplc (chiralpak ad) (elution with a mixture of n-heptane/5% isopropanol).

(+) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ [ (cis) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

C₂₅H₂₀ClNO₃Calculated LC/MS m/e of: 417, actual measurement (M + H)⁺：418.5。¹H NMR(400MHz，MeOD)δppm 1.70(s，3H)2.06(d，J＝5.05Hz，1H)2.46(d，J＝5.05Hz，1H)4.77(d，J＝15.92Hz，1H)5.13(d，J＝16.17Hz，1H)6.96(d，J＝7.83Hz，1H)7.10(t，J＝7.58Hz，1H)7.25(t，J＝7.58Hz，3H)7.28-7.33(m，3H)7.48(t，J＝7.58Hz，1H)7.56(d，1H)7.90(s，1H)7.96(d，J＝7.58Hz，1H)。[α]_D ²⁵＝257.43(c＝4mg/mL，MeOH)。

(-) -3- ((2- (4-chlorophenyl) -2-methyl-2 ' -oxospiro [ [ (cis) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

C₂₅H₂₀ClNO₃Calculated LC/MS m/e of: 417, actual measurement (M + H)⁺：418.4。¹H NMR(400MHz，MeOD)δppm 1.70(s，3H)2.06(d，J＝5.05Hz，1H)2.46(d，J＝5.05Hz，1H)4.77(d，J＝16.17Hz，1H)5.13(d，J＝15.92Hz，1H)6.95(d，J＝7.83Hz，1H)7.10(t，J＝7.58Hz，1H)7.24(t，J＝7.45Hz，3H)7.28-7.32(m，3H)7.48(t，J＝7.71Hz，1H)7.55(d，1H)7.90(s，1H)7.96(d，J＝7.58Hz，1H)。[α]_D ²⁵＝-260.784(c＝4mg/mL，MeOH)。

Example 48

(1R, 2S) and (1S, 2R) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -4- (5 ' -fluoro-2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline) as prepared in scheme 2]The title compound was prepared in analogy to example 27 starting from-2-yl) benzonitrile. C₂₆H₁₉FN₂O₃Calculated LC/MS m/e of: 426, actual measurement (M + H)⁺：427.1。¹H NMR(400MHz，MeOD-d₄)δppm 1.87(s，3H)2.21(d，J＝5.31Hz，1H)2.40(d，J＝5.31Hz，1H)5.04(d，1H)5.21(d，1H)5.36(dd，J＝8.84，2.27Hz，1H)6.73-6.87(m，1H)6.80(d，J＝4.55Hz，1H)7.48(t，J＝7.71Hz，1H)7.59(s，2H)7.69(br.s.，2H)7.94(d，J＝7.58Hz，1H)7.91(s，1H)。

Example 49 and example 50

(+) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid and (-) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

The title compound was obtained by separation of stereoisomers of (1R, 2S) and (1S, 2R) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid (example 48) by chiral preparative hplc (chiralpak ad) (elution with a mixture of n-heptane/5% isopropanol).

(+) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

C₂₆H₁₉FN₂O₃Calculated LC/MS m/e of: 426, actual measurement (M + H)⁺：427.5。¹H NMR(400MHz，MeOD)δppm 1.87(s，3H)2.21(d，J＝5.31Hz，1H)2.41(d，J＝5.31Hz，1H)5.04(d，1H)5.21(d，1H)5.36(dd，J＝8.84，2.27Hz，1H)6.73-6.87(m，1H)6.80(d，J＝4.80Hz，1H)7.48(t，J＝7.71Hz，2H)7.60(d，J＝7.83Hz，2H)7.69(br.s.，2H)7.94(d，J＝7.58Hz，1H)7.92(s，1H)。[α]_D ²⁵＝203.431(c＝4mg/mL，MeOH)。

(-) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

C₂₆H₁₉FN₂O₃Calculated LC/MS m/e of: 426, actual measurement (M + H)⁺：427.6。¹H NMR (400MHz, MeOD) δ ppm 1.88(s, 3H)2.22(d, J ═ 5.31Hz, 1H)2.41(d, J ═ 5.31Hz, 1H)5.05(d, 1H)5.21(d, 1H)5.36(dd, J ═ 8.84, 2.27Hz, 1H)6.80(d, J ═ 4.55Hz, 1H)6.74-6.85(m, 1H)7.48(t, J ═ 7.71Hz, 1H)7.60(d, J ═ 7.58Hz, 2H)7.71(br.s., 2H)7.95(d, J ═ 7.58Hz, 1H)7.92(s, 1H). White powder. MS (ESI) (M + H)⁺427.6；[α]_D ²⁵＝--209.00(c＝4mg/mL，MeOH)。

Example 51

(1S, 2S) and (1R, 2R) -3- ((2- (4-cyanophenyl) -2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2R) and (1S, 2S) -4- (2-isopropyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline) as prepared in scheme 2]The title compound was prepared in analogy to example 27 starting from-2-yl) benzonitrile. C₂₈H₂₄N₂O₃Calculated LC/MS m/e of: 436, actual measurement (M + H)⁺：437.1。¹H NMR(400MHz，MeOD-d₄)δppm 0.81(d，J＝6.82Hz，3H)0.92(d，J＝6.82Hz，3H)2.18(d，1H)2.22(d，1H)2.98-3.09(m，1H)4.98(d，J＝16.17Hz，1H)5.30(d，J＝15.92Hz，1H)5.43(d，J＝7.58Hz，1H)6.61(t，J＝7.58Hz，1H)6.71(dd，J＝8.08，1.52Hz，1H)6.88(d，J＝7.83Hz，1H)7.06(t，J＝7.71Hz，1H)7.48(t，J＝7.71Hz，1H)7.44(dd，J＝8.08，1.77Hz，1H)7.68(dd，J＝7.83，1.52Hz，1H)7.63(d，J＝7.83Hz，1H)7.83(dd，J＝7.96，1.64Hz，1H)7.94(d，J＝7.83Hz，1H)7.99(s，1H)。

Example 52 and example 53

(+) -3- ((2- (4-cyanophenyl) -2-isopropyl-2 '-oxospiro [ (trans) -cyclopropane-1, 3' -indolin ] -1 '-yl) methyl) benzoic acid and (-) -3- ((2- (4-cyanophenyl) -2-isopropyl-2' -oxospiro [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

The title compound was obtained by separation of stereoisomers of (1S, 2S) and (1R, 2R) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid (example 51) by chiral preparative hplc (chiralpak ad) (elution with a mixture of n-heptane/5% isopropanol).

(+) -3- ((2- (4-cyanophenyl) -2-isopropyl-2 ' -oxospiro [ [ (trans) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

C₂₈H₂₄N₂O₃Calculated LC/MS m/e of: 436, actual measurement (M + H)⁺：437.7。¹H NMR(400MHz，MeOD)δppm 0.80(d，J＝6.82Hz，3H)0.92(d，J＝6.82Hz，3H)2.17(d，1H)2.22(d，1H)2.97-3.10(m，J＝6.88，6.88，6.88，6.88Hz，1H)4.98(d，J＝16.17Hz，1H)5.30(d，J＝15.92Hz，1H)5.43(d，J＝7.58Hz，1H)6.61(t，J＝7.58Hz，1H)6.71(dd，J＝8.08，1.52Hz，1H)6.88(d，J＝7.83Hz，1H)7.06(t，J＝7.71Hz，1H)7.48(t，J＝7.71Hz，1H)7.44(dd，J＝8.08，1.77Hz，1H)7.67(dd，J＝7.96，1.64Hz，1H)7.63(d，J＝7.83Hz，1H)7.83(dd，J＝7.96，1.64Hz，1H)7.94(d，J＝7.83Hz，1H)7.99(s，1H)。[α]_D ²⁵＝180.88(c＝4mg/mL，MeOH)。

(-) -3- ((2- (4-cyanophenyl) -2-isopropyl-2 ' -oxospiro [ [ (trans) -cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

C₂₈H₂₄N₂O₃Calculated LC/MS m/e of: 436, actual measurement (M + H)⁺：437.5。¹H NMR(400MHz，MeOD)δppm 0.81(d，J＝6.82Hz，3H)0.93(d，J＝6.82Hz，3H)2.18(dd，1H)2.21-2.25(m，1H)3.03(d，J＝6.82Hz，1H)4.98(d，J＝15.92Hz，1H)5.30(d，J＝16.17Hz，1H)5.44(d，J＝7.58Hz，1H)6.62(t，J＝7.58Hz，1H)6.72(dd，J＝8.08，1.52Hz，1H)6.89(d，J＝7.83Hz，1H)7.07(t，J＝7.71Hz，1H)7.48(t，J＝7.71Hz，1H)7.45(dd，J＝8.08，1.52Hz，1H)7.68(d，J＝7.83Hz，1H)7.65(dd，J＝18.57，7.71Hz，1H)7.84(dd，J＝7.96，1.64Hz，1H)7.95(d，J＝7.83Hz，1H)7.99(s，1H)。[α]_D ²⁵＝-182.52(c＝4mg/mL，MeOH)。

Example 54

(1R, 2R) and (1S, 2S) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2R) and (1S, 2S) -4- (5 ' -fluoro-2-methyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline) as prepared in scheme 2]The title compound was prepared in analogy to example 27 starting from-2-yl) benzonitrile. C₂₆H₁₉FN₂O₃Calculated LC/MS m/e of: 426, actual measurement (M + H)⁺：427.1。¹H NMR(400MHz，MeOD-d₄)δppm 1.71(s，3H)2.14(d，J＝5.05Hz，1H)2.50(d，J＝5.31Hz，1H)4.73(d，J＝15.92Hz，1H)5.10(d，J＝15.92Hz，1H)6.92(d，J＝4.29Hz，1H)6.98(dd，J＝9.09，2.53Hz，1H)7.16(dd，J＝8.84，2.53Hz，1H)7.47(t，J＝7.71Hz，2H)7.46(br.s.，1H)7.51-7.56(m，1H)7.67(d，J＝8.59Hz，2H)7.85(s，1H)7.95(d，J＝7.83Hz，1H)。

Example 55 and example 56

(+) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ (cis) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid and (-) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ (cis) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

The title compound was obtained by separation of stereoisomers of (1R, 2R) and (1S, 2S) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid (example 54) by chiral preparative hplc (chiralpak ad) (elution with a mixture of n-heptane/5% isopropanol).

(+) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ [ (cis) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

C₂₆H₁₉FN₂O₃Calculated LC/MS m/e of: 426, actual measurement (M + H)⁺：426.8。¹H NMR(400MHz，MeOD)δppm 1.71(s，3H)2.14(d，J＝5.05Hz，1H)2.50(d，J＝5.05Hz，1H)4.73(d，J＝15.92Hz，1H)5.10(d，J＝15.66Hz，1H)6.93(d，J＝4.29Hz，1H)6.98(dd，J＝9.09，2.53Hz，1H)7.16(dd，J＝8.72，2.40Hz，1H)7.47(t，J＝7.71Hz，3H)7.53(br.s.，1H)7.67(d，J＝8.59Hz，2H)7.85(s，1H)7.95(d，J＝7.58Hz，1H)。[α]_D ²⁵＝313.53(c＝4mg/mL，MeOH)。

(-) -3- ((2- (4-cyanophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ [ (cis) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

C₂₆H₁₉FN₂O₃Calculated LC/MS m/e of: 426, actual measurement (M + H)⁺：426.5。¹H NMR(400MHz，MeOD)δppm 1.71(s，3H)2.14(d，J＝5.31Hz，1H)2.50(d，J＝5.05Hz，1H)4.73(d，J＝15.92Hz，1H)5.10(d，J＝15.92Hz，1H)6.92(d，J＝4.55Hz，1H)6.98(dd，J＝9.09，2.53Hz，1H)7.16(dd，J＝8.72，2.40Hz，1H)7.47(t，J＝7.58Hz，3H)7.52-7.59(m，1H)7.67(d，J＝8.59Hz，2H)7.84(s，1H)7.95(d，J＝7.83Hz，1H[α]_D ²⁵＝-286.00(c＝4mg/mL 00，MeOH)。

Example 57

(1R, 2S) and (1R, 2S) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

From methyl- (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) -5 '-fluoro-2-methylspiro [ cyclopropane-1, 3' -indoline as prepared in scheme 2]Starting with the 2' -ketone, the title compound was prepared in analogy to example 27. C₂₅H₁₉ClFNO₃Calculated LC/MS m/e of: 435, actual measurement (M + H)⁺：436.5。¹H NMR(400MHz，MeOD)δppm 1.88(s，3H)2.20(d，J＝5.05Hz，1H)2.37(d，J＝5.05Hz，1H)5.02-5.10(m，1H)5.18-5.25(m，1H)5.41(dd，J＝8.84，2.27Hz，1H)6.72-6.86(m，1H)6.80(d，J＝5.05Hz，1H)7.30(br.s.，2H)7.50(t，J＝7.71Hz，1H)7.61(d，J＝7.58Hz，1H)7.96(d，J＝8.08Hz，1H)7.94(br.s.，1H)。

Examples 58 and 59

(+) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid and (-) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

The title compound was obtained by separation of stereoisomers of (1R, 2S) and (1R, 2S) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid (example 57) by chiral preparative hplc (chiralpak ad) (elution with a mixture of n-heptane/5% isopropanol).

(+) -3- ((2- (4-chlorophenyl) -5 '-fluoro-2-methyl-2' -oxospiro [ [ (trans) -cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

C₂₅H₁₉ClFNO₃Calculated LC/MS m/e of: 435, actual measurement (M + H)⁺：436.5。¹HNMR(400MHz，MeOD)δppm 1.87(s，3H)2.19(d，J＝5.05Hz，1H)2.36(d，J＝5.05Hz，1H)5.01-5.10(m，1H)5.17-5.26(m，1H)5.41(dd，J＝8.97，2.15Hz，1H)6.67-6.86(m，3H)7.34(br.s.，2H)7.49(t，J＝7.58Hz，2H)7.60(d，J＝7.83Hz，1H)7.89-7.99(m，2H)。[α]_D ²⁵191.09(c 4mg/mL, MeOH). (-) -3- ((2- (4-chlorophenyl) -5 ' -fluoro-2-methyl-2 ' -oxospiro [ [ (trans) -cyclopropane-1, 3 ' -indoline)]-1' -yl) methyl) benzoic acid

C₂₅H₁₉ClFNO₃Calculated LC/MS m/e of: 435, actual measurement (M + H)⁺：436.7。¹HNMR(400MHz，MeOD)δppm 1.88(s，3H)2.20(d，J＝5.05Hz，1H)2.37(d，J＝5.05Hz，1H)5.06(d，1H)5.22(d，1H)5.41(dd，J＝8.84，2.27Hz，1H)6.75-6.85(m，1H)6.81(d，J＝4.80Hz，1H)7.32(br.s.，2H)7.50(t，J＝7.71Hz，2H)7.61(d，J＝7.83Hz，1H)7.93-7.99(m，2H)。[α]_D ²⁵＝-186.14(c＝4mg/mL，MeOH)。

Example 60

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (3- (piperidine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

Reacting 3- (((1S, 2R) -2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1 ' -yl) methyl) benzoic acid and 3- (((1R, 2S) -2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-1' -yl) methyl) benzoic acid (prepared according to scheme 1) (60mg, 0.15mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl) (44mg, 0.225mmol, 1.5mmol), anhydrous 1-hydroxybenzotriazole (HOBt) (31mg, 0.225mmol) and piperidine(15mg, 0.18mmol) in DMF. The mixture was stirred at room temperature for 14 hours. Purification of (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) -1 '- (3- (piperidine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3' -indoline by preparative HPLC]-2' -one as a white solid (42mg, 60%). C₂₉H₂₇ClN₂O₂Calculated LC/MS m/e of: 470, actually measured (M + H)⁺：471.2。¹H NMR(400MHz，MeOD-d₄)δppm 1.41(br.s.，2H)1.67(br.s.，4H)2.19-2.30(m，2H)3.28(br.s，2H)3.30(s，1H)3.69(br.s.，2H)5.14(s，2H)6.11(d，J＝7.33Hz，1H)6.74(t，J＝7.20Hz，1H)6.91(d，J＝7.83Hz，1H)7.03-7.15(m，1H)7.20-7.28(m，2H)7.28-7.38(m，4H)7.43-7.57(m，2H)。

Example 61

(1R, 2S) and (1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N-isopropylbenzamide

From isopropylamine, (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -3- ((2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline) as prepared in scheme 1]Starting with-1' -yl) methyl) benzoic acid, the title compound was prepared in analogy to example 60. C₂₇H₂₅ClN₂O₂Calculated LC/MSm/e of (1): 444, measured (M + H)⁺：445.2。¹H NMR(400MHz，MeOD-d₄)δppm1.23(d，J＝6.82Hz，6H)2.21(d，J＝8.59Hz，2H)3.21-3.28(m，1H)4.07-4.25(m，1H)5.10(s，2H)6.05(d，J＝7.58Hz，1H)6.69(t，J＝7.58Hz，1H)6.88(d，J＝7.83Hz，1H)7.05(t，J＝7.83Hz，1H)7.16-7.25(m，2H)7.25-7.34(m，2H)7.37-7.52(m，2H)7.69(d，J＝7.58Hz，1H)7.78(s，1H)。

Example 62

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (3- (piperazine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From piperazine, (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -3- ((2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline) as prepared in scheme 1]Starting with-1' -yl) methyl) benzoic acid, the title compound was prepared in analogy to example 60. C₂₈H₂₆ClN₃O₂Calculated LC/MS m/e of: 471, actual measurement (M + H)⁺：472.2。¹H NMR(400MHz，MeOD-d₄)δppm2.17-2.30(m，2H)3.51(br.s.，8H)3.21-3.35(m，1H)5.04-5.23(m，2H)6.10(d，J＝7.58Hz，1H)6.74(t，J＝7.45Hz，1H)6.95(d，J＝7.83Hz，1H)7.05-7.16(m，1H)7.23(d，J＝8.34Hz，2H)7.29-7.38(m，2H)7.40-7.49(m，2H)7.49-7.58(m，2H)。

Example 63

(1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (morpholine-4-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From morpholine, (3-bromomethyl) -benzoate (commercially available) and (1R, 2S) and (1S, 2R) -3- ((2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline) as prepared in scheme 1]Starting with-1' -yl) methyl) benzoic acid, the title compound was prepared in analogy to example 60. C₂₈H₂₅ClN₂O₃Calculated LC/MS m/e of: 472, actual measurement (M + H)⁺：473.2。¹H NMR(400MHz，MeOD-d₄)δppm 2.15-2.27(m，2H)3.18-3.36(m，1H)3.47(br.s.，4H)3.70(br.s.，4H)5.11(s，2H)6.08(d，J＝7.58Hz，1H)6.71(t，J＝7.58Hz，1H)6.88(d，J＝8.08Hz，1H)7.01-7.12(m，1H)7.17-7.26(m，2H)7.25-7.40(m，4H)7.43-7.56(m，2H)。

Example 64

(1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (4- (pyridin-4-yl) piperazine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 1- (pyridin-4-yl) piperazine, (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -3- ((2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline) as prepared in scheme 1]Starting with-1' -yl) methyl) benzoic acid, the title compound was prepared in analogy to example 60. C₃₃H₂₉ClN₄O₂Calculated LC/MS m/e of: 548, measured (M + H)⁺：549.1。¹H NMR(400MHz，MeOD-d₄)δppm 2.20-2.29(m，2H)3.26-3.31(m，1H)3.58(br.s.，4H)3.88(br.s.，4H)5.08-5.25(m，2H)6.14(d，J＝7.58Hz，1H)6.77(t，J＝7.58Hz，1H)6.92(d，J＝7.83Hz，1H)7.12(t，J＝7.20Hz，3H)7.21-7.32(m，4H)7.41(s，1H)7.45(d，J＝7.33Hz，1H)7.50-7.61(m，2H)8.19(d，J＝7.58Hz，2H)。

Example 65

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (3- (4-isopropylpiperazine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 1-isopropylpiperazine, (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -3- ((2- (4-chloro) as prepared in scheme 1Phenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline]Starting with-1' -yl) methyl) benzoic acid, the title compound was prepared in analogy to example 60. C₃₁H₃₂ClN₃O₂Calculated LC/MS m/e of: 513, actual measurement (M + H)⁺：514.2。¹H NMR(400MHz，CDCl₃)δppm 1.37(d，J＝6.32Hz，6H)2.04(dd，J＝7.71，4.67Hz，1H)2.28(dd，J＝9.22，4.67Hz，1H)2.86(br.s.，2H)3.35(t，J＝8.46Hz，1H)3.61(br.s.，6H)4.96(d，J＝15.92Hz，1H)5.18(d，J＝16.17Hz，1H)6.02(d，J＝7.33Hz，1H)6.71-6.82(m，2H)7.06-7.19(m，3H)7.31(s，1H)7.33-7.39(m，1H)7.39-7.51(m，3H)。

Example 66

3- (((1S, 2R) -2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indolin ] -1 '-yl) methyl) -N- (2- ((S) -1-methylpyrrolidinyl-2-yl) ethyl) benzamide and 3- (((1R, 2S) -2- (4-chlorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) -N- (2- ((S) -1-methylpyrrolidin-2-yl) ethyl) benzamide

From (2S) -2- (3-aminopropyl) -N-methylpyrrolidine, (3-bromomethyl) -benzoate (commercially available), (1R, 2S) as prepared in scheme 1 and (1S, 2R) -3- ((2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline)]Starting with-1' -yl) methyl) benzoic acid, the title compound was prepared in analogy to example 60. C₃₁H₃₂ClN₃O₂Calculated LC/MS m/e of: 513, actual measurement (M + H)⁺：514.2。1H NMR(400MHz，MeOD-d₄)δppm 1.76-1.94(m，2H)2.00-2.20(m，2H)2.24(d，J＝8.59Hz，2H)2.26-2.37(m，1H)2.42-2.58(m，1H)2.94(s，3H)3.10-3.22(m，1H)3.25-3.31(m，1H)3.35-3.43(m，1H)3.52(t，J＝6.69Hz，2H)3.63-3.75(m，1H)5.13(s，2H)6.09(d，J＝7.58Hz，1H)6.73(t，J＝7.58Hz，1H)6.91(d，J＝7.83Hz，1H)7.09(t，J＝7.71Hz，1H)7.21-7.28(m，2H)7.28-7.37(m，2H)7.45-7.52(m，1H)7.52-7.60(m，1H)7.76(d，J＝7.58Hz，1H)7.85(s，1H)。

Example 67

(1R, 2S) and (1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (3-methyl-1H-pyrazol-5-yl) benzamide

From 3-methyl-1H-pyrazol-5-amine, (3-bromomethyl) -benzoate (commercially available), racemic (1R, 2S) and (1S, 2R) -3- ((2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline) as prepared in scheme 1]Starting with-1' -yl) methyl) benzoic acid, the title compound was prepared in analogy to example 60. C₂₈H₂₃ClN₄O₂Calculated LC/MS m/e of: 482, measured (M + H)⁺：483.2。¹H NMR(400MHz，MeOD-d₄)δppm 2.23(d，J＝8.59Hz，2H)2.55(s，3H)3.26-3.32(m，1H)5.08-5.23(m，2H)5.85(d，J＝1.01Hz，1H)6.08(d，J＝7.07Hz，1H)6.73(t，J＝7.58Hz，1H)6.94(d，J＝7.83Hz，1H)7.07-7.14(m，1H)7.19(d，J＝8.08Hz，2H)7.30(d，J＝8.59Hz，2H)7.48(t，J＝7.71Hz，1H)7.58(d，J＝8.34Hz，1H)7.80(d，J＝7.83Hz，1H)7.85(s，1H)。

Example 68

(1S, 2R) and (1R, 2S) -6- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) picolinic acid

Prepared from 6-bromomethyl-pyridine-2-carboxylic acid methyl ester (commercially available) as in scheme 1Prepared (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₃H₁₇ClN₂O₃Calculated LC/MS n/e: 404, actual measurement (M + H)⁺：405.2。¹H NMR(400MHz，DMSO-d₆)δppm 2.12(dd，J＝9.09，4.80Hz，1H)2.39(dd，J＝8.08，4.80Hz，1H)3.22(t，J＝8.59Hz，1H)5.14(s，2H)6.15(d，J＝7.33Hz，1H)6.73(t，J＝7.45Hz，1H)6.88(d，J＝7.58Hz，1H)7.00-7.10(m，1H)7.26(d，J＝1.01Hz，1H)7.38(s，4H)7.84-7.98(m，2H)。

Example 69

(1S, 2R) and (1R, 2S) -6- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) picolinic acid

From 6-bromomethyl-pyridine-2-carboxylic acid methyl ester (commercially available) and (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₃H₁₇FN₂O₃Calculated LC/MS m/e of: 388, actual measurement (M + H)⁺：389.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.06-2.18(m，1H)2.32-2.39(m，1H)3.13-3.31(m，1H)5.12(s，2H)6.13(d，1H)6.68(t，1H)6.88(d，1H)6.98-7.08(m，1H)7.10-7.18(m，2H)7.23(d，1H)7.33-7.47(m，2H)7.79-7.93(m，2H)。

Example 70

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - ((tetrahydro-2H-pyran-4-yl) methyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

Racemic (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline at 0 ℃ under argon atmosphere]-2 '-one and (1R, 2S) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline]-2' -Ketone (270mg, 1.0mmol, 1.0 equiv.) was added to a stirred solution of sodium hydride (60%, 60mg, 1.5mmol) in 5mL DMF. After stirring for 1 hour, 4-bromomethyl-pyran (215mg, 1.2mmol) was added. The reaction mixture was stirred at room temperature for 14 hours. The crude product was purified by HPLC to give the title compound as a white solid (258mg, 70%). C₂₂H₂₂ClNO₂Calculated LC/MS m/e of: 367, actually measured (M + H)⁺：368.2。¹H NMR(400MHz，MeOD-d₄)δppm 1.39-1.55(m，2H)1.65(dd，J＝13.14，1.77Hz，2H)2.11-2.25(m，3H)3.22(t，J＝8.46Hz，1H)3.37-3.47(m，2H)3.79(d，J＝7.33Hz，2H)3.94-4.04(m，2H)6.09(d，J＝7.58Hz，1H)6.76(t，J＝7.58Hz，1H)7.11(d，J＝7.83Hz，1H)7.17-7.25(m，3H)7.33(d，J＝8.34Hz，2H)。MS：C₂₂H₂₂ClNO₂367, measured (ESI)⁺)[(M+H)⁺]368。

Example 71

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (diethylamino) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 2-chloro-N, N-diethylethanamine hydrochloride (commercially available), (1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 70. C₂₂H₂₅ClN₂LC/MS m/e calculated for O: 368, actual measurement (M + H)⁺：369.1。¹H NMR(400MHz，MeOD-d₄)δppm 1.41(t，J＝7.20Hz，6H)2.21-2.31(m，2H)3.32(t，J＝8.59Hz，1H)3.39-3.55(m，4H)3.60(t，J＝6.44Hz，2H)4.23-4.42(m，2H)6.16(d，J＝7.58Hz，1H)6.85(t，J＝7.45Hz，1H)7.19(d，J＝7.83Hz，1H)7.24-7.32(m，3H)7.33-7.40(m，2H)。

Example 72

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (2-morpholinoethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 4- (2-chloroethyl) morpholine hydrochloride (commercially available), (1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 70. C₂₂H₂₃ClN₂O₂Calculated LC/MS m/e of: 382, actual measurement (M + H)⁺：383.1。¹HNMR(400MHz，MeOD-d₄)δppm 2.21-2.29(m，2H)3.30(t，J＝8.72Hz，1H)3.54-3.69(m，2H)3.97(br.s.，8H)4.21-4.32(m，1H)4.36-4.48(m，1H)6.15(d，J＝7.33Hz，1H)6.83(t，J＝7.20Hz，1H)7.14-7.21(m，1H)7.22-7.30(m，3H)7.31-7.39(m，2H)。

Example 73

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - ((1- (methylsulfonyl) piperidin-4-yl) methyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 4-chloromethyl-1-methanesulfonyl-piperidine (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]-2′-The title compound was prepared in analogy to example 70 starting from ketone. C₂₃H₂₅ClN₂O₃LC/MS m/e calculated for S: 444, measured (M + H)⁺：445.1。¹HNMR(400MHz，DMSO-d₆)δppm 1.23-1.41(m，2H)1.66-1.78(m，2H)1.84-1.98(m，1H)2.02(dd，J＝9.09，4.80Hz，1H)2.30(dd，J＝7.71，4.67Hz，1H)2.67(t，J＝11.75Hz，2H)2.83(s，3H)3.11(t，J＝8.46Hz，1H)3.56(d，J＝12.13Hz，2H)3.71(d，J＝7.33Hz，2H)6.12(d，J＝7.33Hz，1H)6.66-6.80(m，1H)7.10-7.20(m，2H)7.25-7.34(m，2H)7.34-7.43(m，2H)。

Example 74

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (4-isopropylpiperazin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

(1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) -1 ' - (2, 2-dimethoxyethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

(1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline in DMF (1mL) at room temperature]To a solution of-2' -ketone (135mg, 1mmol) was added KHM S (0.5M in THF, 1.1mL) dropwise. The mixture was stirred for half an hour before adding bromoacetaldehyde dimethylacetal (95mg, 0.55 mmol). The mixture was heated to 50 ℃ and stirred at this temperature for 2 hours. The mixture was poured into water, extracted with ethyl acetate (3 × 15mL), dried and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with hexane-EtOAc (6: 1 then 4: 1) yielded the desired product as a colorless oil (268mg, 75%). C₂₀H₂₀ClNO₃Calculated LC/MS m/e of: 3570, actual measurement (M + H)⁺：358.7。

(1R, 2S) and (1S, 2R) -2- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) acetaldehyde

(1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) -1 '- (2, 2-dimethoxyethyl) spiro [ cyclopropane-1, 3' -indoline in water (1mL)]The suspension of the-2' -ketone (1g) was cooled to 0 ℃ and treated with a mixture of DCM and TFA (1: 1, 6mL) for 2 h. The reaction mixture was poured into saturated NaHCO₃Aqueous solution and extracted with DCM (3 × 6 mL). The combined organic layers were washed with brine and washed over Na₂SO₄And drying. The solvent was evaporated under reduced pressure. The crude product was used directly in the next step without further purification. C₁₈H₁₄ClNO₂Calculated LC/MS m/e of: 311, actual measurement (M + H)⁺：312.3。

(1R, 2S) and (1S, 2R) -2- (2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline) in DCM (2ml)]A mixture of (E) -1' -yl) acetaldehyde (0.1mmol), (1-isopropyl) piperazine (0.15mmol) and acetic acid (catalytic amount) was stirred at room temperature for 20 minutes. The mixture was cooled to 0 ℃ and NaBH (OAc) was carefully added₃(2 mmol). The mixture was warmed to room temperature and stirred at room temperature for 14 hours. The mixture was concentrated under reduced pressure and dissolved in DMF. Purification by preparative HPLC gave a colorless oilThe title product (35 mg). C₂₅H₃₀ClN₃LC/MS m/e calculated for O: 423, actual measurement (M + H)⁺：424.1。¹HNMR(400MHz，MeOD-d₄)δppm 1.37(d，J＝6.57Hz，6H)2.18(dd，J＝8.46，5.94Hz，2H)2.46-2.64(m，1H)2.85(d，J＝3.54Hz，2H)3.22(s，2H)3.50(d，J＝6.57Hz，2H)3.90-4.27(m，2H)6.09(d，J＝7.58Hz，1H)6.76(s，1H)7.10(d，J＝7.83Hz，1H)7.16-7.25(m，3H)7.33(d，J＝8.59Hz，2H)。

Example 75

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 1- (2-dimethylamino-ethyl) -piperazine, (1R, 2S) as prepared in scheme 1, bromoacetaldehyde dimethyl acetal (commercially available), and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline]The title compound was prepared analogously to example 74, starting with the 2' -ketone. C₂₆H₃₃ClN₄LC/MS m/e calculated for O: 452, measured (M + H)⁺：453.1。¹HNMR(400MHz，MeOD-d₄)δppm 2.15-2.33(m，3H)2.86(t，J＝5.81Hz，3H)2.96(s，6H)3.27(t，J＝8.59Hz，3H)3.45-3.76(m，3H)4.32(d，J＝48.76Hz，3H)6.12(d，J＝7.58Hz，1H)6.81(t，J＝7.20Hz，1H)7.11-7.19(m，1H)7.20-7.28(m，3H)7.30-7.41(m，2H)。

Example 76

(1S, 2R) -2- (4-chlorophenyl) -1 '- (2- ((S) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) spiro [ cyclopropane-1, 3' -indolin ] -2 '-one and (1R, 2S) -2- (4-chlorophenyl) -1' - (2- ((S) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) spiro [ cyclopropane-1, 3 '-indolin ] -2' -one

From (3S) - (-) -3- (dimethylamino) pyrrolidine, bromoacetaldehyde dimethylacetal (commercially available), (1R, 2S) as prepared in scheme 1 and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline]The title compound was prepared analogously to example 74, starting with the 2' -ketone. C₂₄H₂₈ClN₃LC/MS m/e calculated for O: 409, actual measurement (M + H)⁺：410.2。¹H NMR(400MHz，MeOD-d₄)δppm1.32(s，2H)2.09-2.40(m，5H)2.50-2.76(m，1H)2.96(d，J＝6.82Hz，6H)3.15-3.32(m，3H)3.43-3.55(m，1H)3.66(br.s.，3H)3.75-3.93(m，1H)4.00-4.42(m，5H)6.09(d，J＝7.58Hz，1H)6.79(t，J＝7.58Hz，1H)7.13(d，J＝7.58Hz，1H)7.18-7.26(m，3H)7.28-7.40(m，2H)。

Example 77

(1S, 2R) -2- (4-chlorophenyl) -1 '- (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) spiro [ cyclopropane-1, 3' -indolin ] -2 '-one and (1R, 2S) -2- (4-chlorophenyl) -1' - (2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) spiro [ cyclopropane-1, 3 '-indolin ] -2' -one

From (3R) - (+) -3- (dimethylamino) pyrrolidine, bromoacetaldehyde dimethylacetal (commercially available), (1R, 2S) as prepared in scheme 1 and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline]The title compound was prepared analogously to example 74, starting with the 2' -ketone. C₂₉H₂₇ClN₂O₂Calculated LC/MS m/e of: 470, actually measured (M + H)⁺：471.2。1H NMR(400MHz，MeOD-d₄)δppm1.32(s，1H)2.04-2.39(m，4H)2.47-2.69(m，1H)2.95(d，J＝6.82Hz，6H)3.23(s，3H)3.58(br.s.，4H)3.72-3.93(m，1H)3.98-4.50(m，4H)6.09(d，J＝7.33Hz，1H)6.79(t，J＝7.58Hz，1H)7.13(d，J＝7.83Hz，1H)7.17-7.25(m，3H)7.28-7.39(m，2H)。

Example 78

(1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) -1 ' - (pyridin-4-ylmethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

Reacting (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline]-2' -one (135mg, 0.5mmol), 4-bromomethyl-pyridine (98mg, 0.6mmol) and Cs₂CO₃(245mg, 0.75mmol) was dissolved in DMF (2 mL). The mixture was stirred at room temperature for 14 hours. The mixture was poured into water, extracted with ethyl acetate, dried and concentrated under reduced pressure. The residue was dissolved in 2ml of dmdm. Purification by preparative HPLC gave the title compound as a yellowish solid (140mg, 76%). C₂₂H₁₇ClN₂LC/MS m/e calculated for O: 360, measured (M + H)⁺：361.2。¹HNMR(400MHz，MeOD-d₄)δppm 2.22-2.37(m，2H)3.32-3.40(m，1H)5.39(s，2H)6.15(d，J＝7.58Hz，1H)6.74-6.85(m，1H)6.92(d，J＝7.83Hz，1H)7.10-7.19(m，1H)7.24-7.42(m，4H)7.93(d，J＝6.32Hz，2H)8.80(d，J＝6.06Hz，2H)。MS：C₂₂H₁₇ClN₂Calculated O360, actual measurement (ESI)⁺)[(M+H)⁺]361.1。

Example 79

(1S, 2R) and (2R, 1S) -2- (4-chlorophenyl) -1 ' - (pyridin-3-ylmethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 3-bromomethyl-pyridine (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]The title compound was prepared analogously to example 78, starting with the 2' -ketone. C₂₉H₂₇ClN₂O₂Calculated LC/MS m/e of: 470, actually measured (M + H)⁺：471.2。¹HNMR(400MHz，MeOD-d₄)δppm 2.25(dd，J＝8.59，1.77Hz，2H)3.31(br.s.，1H)5.28(d，J＝3.03Hz，2H)6.12(d，J＝7.58Hz，1H)6.71-6.85(m，1H)7.03(d，J＝8.08Hz，1H)7.12-7.19(m，1H)7.21-7.29(m，2H)7.30-7.39(m，2H)7.86-7.99(m，1H)8.40(d，J＝8.59Hz，1H)8.74(d，J＝5.31Hz，1H)8.84(s，1H)。

Example 80

(1S, 2R) and (1R, 2S) -2- (4- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -1H-imidazol-1-yl) acetic acid

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (1-trityl-1H-imidazol-4-yl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

4-iodo-1-trityl-1H-imidazole (210mg, 0.48mmol) was added to racemic (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline in acetonitrile (2mL) under nitrogen atmosphere]-2' -Ketone (107mg, 0.4mmol) in suspension. A steady stream of nitrogen was bubbled through the suspension while heating the suspension to 40 ℃ for 15 minutes. Potassium carbonate (110mg, 0.8mmol), copper (I) iodide (12mg, 15 mol%) and N, N-dimethylethylenediamine (0.12 mol%) were addedmmol, 30 mol%) and the reaction mixture was heated to 80 ℃ and held for 21 hours under nitrogen. The mixture was cooled to room temperature, filtered and concentrated to yield the title product. The residue was purified by flash column chromatography (gradient elution, 5-10% ethyl acetate in petroleum ether) to yield racemic trans-2- (4-chlorophenyl) -1 '- (1H-imidazole-4-trityl) spiro [ cyclopropane-1, 3' -indoline]-2' -one (157mg, 68%). C₃₈H₂₈ClN₃LC/MS m/e calculated for O: 577, actual measurement (M + H)⁺：578.2。MS：C₃₈H₂₈ClN₃Calculated O578, found (ESI)⁺)[(M+H)⁺]579.3。

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (1H-imidazol-4-yl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

Racemic (1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 '- (1-trityl-1H-imidazol-4-yl) spiro [ cyclopropane-1, 3' -indoline ] in DCM (2mL) and water (0.5mL) at 0 deg.C]To a solution of (115mg, 0.2mmol) of (E) -2' -ketone was added TFA (0.1mL) dropwise. The mixture was stirred at room temperature for 14 hours. The mixture was poured into saturated NaHCO₃Aqueous, extracted with DCM (3 × 10mL), dried and concentrated to give the title product. The residue was dissolved in 2mL of DMF. Purification by preparative HPLC gave the title compound as a white powder (60mg, 89%). C₁₉H₁₄ClN₃LC/MS m/e calculated for O: 335, actual measurement (M + H)⁺：336.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.13(dd，J＝9.09，5.05Hz，1H)2.42(dd，J＝8.08，4.80Hz，1H)3.23(t，J＝8.72Hz，1H)6.20(d，J＝7.58Hz，1H)6.81(t，J＝7.20Hz，1H)7.16(t，J＝7.83Hz，1H)7.30-7.45(m，5H)7.66(s，1H)8.27(s，1H)。MS：C₁₉H₁₄ClN₃Calculated O335, found (ESI)⁺)[(M+H)⁺]336.3。

Synthesis of (1S, 2R) and (1R, 2S) -2- (4- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -1H-imidazol-1-yl) acetic acid

To racemic (1S, 2R) and (1S, 2R) -2- (4-chlorophenyl) -1 '- (1H-imidazol-4-yl) spiro [ cyclopropane-1, 3' -indoline in 2mL DCM]To a mixture of-2' -ketone (0.4mmol, 134mg), methyl-bromoacetate (61.2mg, 0.4mmol) and 5mg of TEBA (0.008mmol) was added 50% KOH (0.5 mL). The reaction mixture was stirred at room temperature for 14 hours. The mixture was then concentrated under reduced pressure and acidified to pH-4. The residue was dissolved in 2mL of DMF. Purification by preparative HPLC gave the title compound as a white powder (113mg, 68%). C₂₁H₁₆ClN₃O₃Calculated LC/MS m/e of: 393, actual measurement (M + H)⁺：394.2。¹H NMR(400MHz，DMSO-d₆)8ppm 2.05-2.16(m，1H)2.39(dd，J＝7.96，4.93Hz，1H)3.20(t，J＝8.72Hz，1H)4.97(s，2H)6.18(d，J＝7.07Hz，1H)6.79(t，J＝7.20Hz，1H)7.06-7.22(m，1H)7.38(s，4H)7.54(d，J＝1.01Hz，1H)7.69(d，J＝7.83Hz，1H)7.74(d，J＝1.26Hz，1H)。MS：C₂₁H₁₆ClN₃O₃Calculated 393, found (ESI)⁺)[(M+H)⁺]394.3。

Example 81

(1S, 2R) and (1R, 2S) -1- (2- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) ethyl) -1H-imidazole-4-carboxylic acid

Synthesis of (1S, 2R) and (1R, 2S) -1 ' - (2-bromoethyl) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

(1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline in DMF (2mL) at room temperature]To a solution of-2' -one (173mg, 0.64M mol) was added KHMDS (0.5M, 1.4mL) dropwise. The mixture was stirred for half an hour before ethylene dibromide (300mg, 1.6mmol) was added. The mixture was warmed to 50 ℃ and stirred at this temperature for 14 hours. The mixture was poured into water, extracted with ethyl acetate (3 × 15mL), dried and concentrated under reduced pressure. The residue was purified by flash column chromatography (gradient elution, 5-10% ethyl acetate in petroleum ether) to yield the title compound as a white solid (98mg, 41%). C₁₈H₁₅LC/MS m/e Calculations for BrClNO: 375, actual measurement (M + H)⁺：376。

Synthesis of (1S, 2R) and (1R, 2S) -methyl-1- (2- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) ethyl) -1H-imidazole-4-carboxylate

To a solution of methyl-imidazole-4-carboxylate (100mg, 0.2mmol) in 1mL of anhydrous DMF at room temperature was added NaH (60% dispersion) (8.8mg, 0.22 mmol). The reaction mixture was stirred at this temperature for 1 hour. To the mixture were added racemic (1R, 2S) and (1S, 2R) -1 '- (2-bromoethyl) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline in 1mL DMF]-2' -ketone (75.2mg, 0.2 mmol). The reaction was stirred at room temperature for 14 hours and then concentrated under reduced pressure. The residue was dissolved in EtOAc and taken up with saturated anhydrous NaHCO₃And (6) washing. The layers were separated and the aqueous layer was extracted with EtOAc. Combining the organic layers and using saltWashing with water, and dissolving in anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to yield the title compound as a white solid (30mg, 35%). C₂₃H₂₀ClN₃O₃Calculated LC/MS m/e of: 421, actual measurement (M + H)⁺：422.3。

Synthesis of (1S, 2R) and (1R, 2S) -1- (2- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) ethyl) -1H-imidazole-4-carboxylic acid

To methyl-1- (2- ((1S, 2R) -2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline) in methanol (2mL) and water (1mL)]-1 ' -yl) ethyl) -1H-imidazole-4-carboxylate and methyl-1- (2- ((1R, 2S) -2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-1' -yl) ethyl) -1H-imidazole-4-carboxylate (0.07mmol) solution LiOH₂O (18mg, 0.4 mmol). The mixture was stirred at room temperature for 3 hours until the starting material was consumed. The mixture was concentrated under reduced pressure and acidified to pH-3. The residue was dissolved in 2mL of DMF. Purification by preparative HPLC gave the title compound as a white powder (26mg, 88%). C₂₂H₁₈ClN₃O₃Calculated LC/MS m/e of: 407, actual measurement (M + H)⁺：408.8。¹H NMR(400MHz，MeOD)δppm 2.10(dd，J＝28.17，8.46Hz，2H)3.10(s，1H)4.31(s，2H)4.86(s，2H)6.05(d，J＝7.33Hz，1H)6.75(s，1H)6.90-7.45(m，6H)7.86(s，1H)8.27(s，1H)。

Example 82

(1S, 2S) and (1R, 2R) -1- (2- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) ethyl) -1H-imidazole-4-carboxylic acid

From methyl-imidazole-4-carboxylate, ethylene dibromide (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 81. C₂₂H₁₈ClN₃O₃Calculated LC/MS m/e of: 407, actual measurement (M + H)⁺：408.8。¹H NMR(400MHz，MeOD-d₄)δppm 2.25(dd，J＝8.59，1.77Hz，2H)3.31(br.s.，1H)5.28(d，J＝3.03Hz，2H)6.12(d，J＝7.58Hz，1H)6.71-6.85(m，1H)7.03(d，J＝8.08Hz，1H)7.12-7.19(m，1H)7.21-7.29(m，2H)7.30-7.39(m，2H)7.86-7.99(m，1H)8.40(d，J＝8.59Hz，1H)8.74(d，J＝5.31Hz，1H)8.84(s，1H)。

Example 83

(1S, 2R) and (1R, 2S) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) benzoic acid

Synthesis of (1S, 2R) and (1R, 2S) -methyl-3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) benzoate

CuI (9.6mg, 0.05mmol, 5.0 mol%), racemic (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline]-2' -Ketone (270mg, 1.0mmol) and K₂CO₃(276mg, 2.0mmol) was charged into a Schlenk tube, evacuated and backfilled with argon. N, N' -dimethylethylenediamine (11. mu.L, 0.10mmol, 10 mol%) and 3-iodo were added under argonEthyl benzoate (278.8mg, 1.01mmol) and acetonitrile (1.5 mL). The Schlenk tube was sealed with a Teflon (Teflon) valve and the reaction mixture was stirred at 80 ℃ for 23 hours. The reaction was monitored by HPLC for completion. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (gradient elution, 5-10% ethyl acetate in petroleum ether) to give the title compound as a yellow powder (290mg, 72%). C₂₄H₁₈ClNO₃Calculated LC/MS m/e of: 403, actual measurement (M + H)⁺：404.1。

Synthesis of (1S, 2R) and (1R, 2S) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) benzoic acid

To methyl-3- ((1S, 2R) -2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline in 1mL of methanol]-1 ' -yl) benzoate and methyl-3- ((1R, 2S) -2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]To a solution of the-1' -yl) benzoate (50mg) was added 0.1mL of water, followed by lithium hydroxide (10 mg). The mixture was stirred at room temperature for 14 hours. The reaction was monitored by HPLC for completion. The solvent was removed under reduced pressure. The residue was dissolved in 2mL of DMF. Purification by preparative HPLC gave the title compound (11mg) as a white powder. C₂₃H₁₆ClNO₃LC/MS M/e calculated 389, found (M + H)⁺：390.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.14(dd，J＝9.09，5.05Hz，1H)2.41(dd，J＝8.08，5.05Hz，1H)3.25(t，J＝8.59Hz，1H)6.19(d，J＝7.33Hz，1H)6.77-6.86(m，2H)7.12(t，J＝7.71Hz，1H)7.36-7.46(m，4H)7.72(t，J＝7.83Hz，1H)7.76-7.85(m，1H)8.01-8.09(m，2H)。

Example 84

(1S, 2S) and (1R, 2R) -3- (-2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) benzoic acid

From methyl-ethyl-3-iodobenzoate (commercially available), (1R, 2R) and (1S, 2S) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 81. C₂₃H₁₆ClNO₃LC/MS M/e calculated 389, found (M + H)⁺：390.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.31-2.42(m，2H)3.42(t，J＝8.72Hz，1H)6.88(d，J＝7.58Hz，1H)7.15(t，J＝7.20Hz，1H)7.22-7.28(m，1H)7.28-7.36(m，3H)7.36-7.41(m，2H)7.60-7.70(m，2H)7.86(s，1H)7.93-8.00(m，1H)13.24(br.s，1H)。

Example 85

(1S, 2S) and (1R, 2R) -2- (4-chlorophenyl) -1 ' - (3- (morpholine-4-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

(1S, 2S) and (1R, 2R) -3- (2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline in DMF (2mL)]A mixture of-1 ' -yl) benzoic acid (117mg, 0.3mmol), O- (1H-benzotriazol-1-yl) -N, N, N ', N ' -tetramethyluronium tetrafluoroborate (TBTU) (145mg, 0.45mmol), N, N-Diisopropylethylamine (DIPEA) (154. mu.L, 0.9mmol), and morpholine (79. mu.L, 0.9mmol) was stirred at room temperature for 14 hours. Purification by preparative HPLC gave the desired product as a white solid (83mg, 60%). C₂₇H₂₃ClN₂O₃Calculated LC/MS m/e of: 458, actual measurement (M + H)⁺：459.2。¹H NMR(400MHz，MeOD-d₄)δppm 2.23-2.31(m，2H)3.28-3.32(m，1H)3.77(br.s.，8H)6.16(d，J＝7.58Hz，1H)6.81(t，J＝7.58Hz，1H)6.93(d，J＝7.83Hz，1H)7.11-7.19(m，1H)7.26-7.33(m，2H)7.33-7.38(m，2H)7.56(d，J＝7.58Hz，1H)7.60-7.67(m，2H)7.68-7.76(m，1H)。

Example 86

(1S, 2S) and (1R, 2R) -2- (4-chlorophenyl) -1 ' - (3- (4-methylpiperazine-1-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 1-methylpiperazine, methyl-3-iodobenzoate (commercially available), (1R, 2R) and (1S, 2S) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 85. C₂₈H₂₆ClN₃O₂Calculated LC/MS m/e of: 471, actual measurement (M + H)⁺：472.2。¹H NMR(400MHz，MeOD-d₄)δppm 2.22-2.35(m，2H)2.98(s，3H)3.35-3.39(m，1H)6.17(d，J＝7.58Hz，1H)6.83(t，J＝7.58Hz，1H)6.96(d，J＝8.08Hz，1H)7.13-7.21(m，1H)7.27-7.33(m，2H)7.34-7.40(m，2H)7.60-7.65(m，1H)7.68-7.80(m，3H)。

Example 87

(1S, 2S) and (1R, 2R) -2- (4-chlorophenyl) -1 ' - (3- (4- (methylsulfonyl) piperazine-1-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 1-methanesulfonyl-piperazine, methyl-3-iodobenzoate (commercially available), (1R, 2R) and (1S, 2S) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting from the-2' -ketone, analogously to example 85The title compound was prepared. C₂₈H₂₆ClN₃O₄LC/MS m/e calculated for S: 535, actual measurement (M + H)⁺：536.2。¹H NMR(400MHz，MeOD-d₄)δppm 2.22-2.36(m，2H)2.90(s，3H)3.35-3.39(m，1H)3.58-4.01(m，8H)6.16(d，J＝7.58Hz，1H)6.82(t，J＝7.58Hz，1H)6.95(d，J＝7.58Hz，1H)7.16(t，J＝7.83Hz，1H)7.27-7.40(m，4H)7.58(d，J＝7.33Hz，1H)7.62-7.79(m，3H)。

Example 88

(1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (morpholine-4-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From morpholine, methyl-3-iodobenzoate (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 85. C₂₇H₂₃ClN₂O₃Calculated LC/MS m/e of: 458, actual measurement (M + H)⁺：459.1。¹H NMR(400MHz，MeOD-d₄)δppm 2.34(dd，J＝8.97，4.93Hz，1H)2.44(dd，J＝8.59，5.05Hz，1H)3.35-3.39(m，1H)3.67(br.s.，8H)6.96(d，J＝7.83Hz，1H)7.17-7.26(m，2H)7.26-7.36(m，5H)7.41(s，1H)7.46-7.52(m，2H)7.64(t，J＝7.83Hz，1H)。

Example 89

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (3- (4-methylpiperazine-1-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 1-methylpiperazine, methyl-3-iodobenzoate (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 85. C₂₈H₂₆ClN₃O₂Calculated LC/MS m/e of: 471, actual measurement (M + H)⁺：472.2。¹H NMR(400MHz，MeOD-d₄)δppm 2.34(dd，J＝9.09，5.05Hz，1H)2.43(dd，J＝8.59，5.05Hz，1H)2.93(s，3H)3.17(br.s.，4H)3.40(t，J＝8.84Hz，1H)3.62(br.s.，4H)6.97(d，J＝7.83Hz，1H)7.16-7.25(m，2H)7.26-7.38(m，5H)7.49(s，1H)7.55(t，J＝7.71Hz，2H)7.67(t，J＝7.83Hz，1H)。

Example 90

(1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (4- (methylsulfonyl) piperazine-1-carbonyl) phenyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 1-methanesulfonyl-piperazine, methyl-3-iodobenzoate (commercially available), (1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 85. C₂₈H₂₆ClN₃O₄LC/MS m/e calculated for S: 535, actual measurement (M + H)⁺：536.2。¹H NMR(400MHz，MeOD-d₄)δppm 2.32(dd，J＝8.97，4.93Hz，1H)2.43(dd，J＝8.72，4.93Hz，1H)2.86(s，3H)3.20(br.s.，4H)3.38(t，J＝8.84Hz，1H)3.71(br.s.，4H)6.96(d，J＝7.83Hz，1H)7.14-7.24(m，2H)7.24-7.36(m，5H)7.46(s，1H)7.47-7.53(m，2H)7.64(t，J＝7.83Hz，1H)。

Example 91

(1R, 2R) and (1S, 2S) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -N- (methylsulfonyl) benzamide

From methanesulfonamide, methyl-3-iodobenzoate (commercially available), (1R, 2R) and (1S, 2S) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 85. C₂₄H₁₉ClN₂O₄LC/MS m/e calculated for S: 466, found (M + H)⁺：467.2。¹H NMR(400MHz，DMSO-d₆)δppm 2.31-2.41(m，2H)3.37(s，3H)3.43(t，J＝8.72Hz，1H)6.90(d，J＝7.83Hz，1H)7.16(t，J＝7.33Hz，1H)7.25(dd，J＝7.83，1.01Hz，1H)7.27-7.35(m，3H)7.35-7.43(m，2H)7.62-7.70(m，2H)7.94-7.99(m，2H)12.24(br.s.，1H)。

Example 92

(1S, 2S) and (1R, 2R) -3- (2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid

Synthesis of 3-bromo-5-iodo-benzoic acid methyl ester

To a suspension of 3-bromo-5-iodo-benzoic acid (6.5g, 20mmol) in 25mL of methanol at 0 deg.C was added δ OCl dropwise₂(1.14mL, 40 mmol). The mixture was then warmed to room temperature and stirred at room temperature for 2 days. The precipitate formed was collected by filtration to give the desired product as a white solid 5.12g (75%). C₈H₆BrIO₂Calculated LC/MS m/e of: 341, measured (M + H)⁺: 342.2. synthesis of (1S, 2S) and (1R, 2R) -methyl-3-bromo-5- (2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) benzoic acid esters

The solution containing CuI (214mg, 1.124mmol, 20 mmol%), (1S, 2S) and (1R, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline]-2' -Ketone (1.50g, 5.62mmol) and K₂CO₃A Schlenk tube (2.30g, 16.86mmol) was evacuated and back-filled with argon. N, N' -dimethylethylenediamine (242. mu.L, 2.25mmol, 40 mol%), 3-bromo-5-iodo-benzoic acid methyl ester (2.30g, 6.75mmol, 1.2 equiv.) and acetonitrile (5mL) were added under argon. The Schlenk tube was sealed with a teflon valve and the reaction mixture was stirred at 90 ℃ for 3 hours. The reaction was monitored by HPLC for completion. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (gradient elution, 5-15% ethyl acetate in petroleum ether) to yield the title compound as a white powder (1.3g, 48%). C₂₄H₁₇BrClNO₃Calculated LC/MS m/e of: 482, measured (M + H)⁺：483。

Synthesis of racemic methyl- (1R, 2R) and (1S, 2S) -3- (2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid esters

(1S, 2S) and (1R, 2R) -3-bromo-5- (2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline) in DMSO (5.0mL) were combined under microwave irradiation]-1' -yl) benzoic acidEsters (120mg, 0.25mmol),Oxazolidin-2-one (27mg, 0.3mmol), CuI (10mg, 20 mmol%), dimethylamino-acetic acid (11mg, 40 mmol%) and K₂CO₃(68mg, 0.5mmol) of the mixture was stirred at 150 ℃ for 1.5 hours. The precipitate was filtered off and the filtrate was concentrated to give the desired crude product (43mg, 35%) which was used for the next step without further purification.

Synthesis of (1S, 2S) and (1R, 2R) -3- (2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid

To a reaction vessel in MeOH (2mL) and H₂(1S, 2S) and (1R, 2R) -3- (2- (4-chlorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline in O (0.2mL)]-1' -yl) -5- (2-oxoTo a solution of oxazolidin-3-yl) benzoate (43mg, 0.088mmol) was added lithium hydroxide (18mg, 0.44 mmol). The reaction mixture was stirred at room temperature until TLC indicated no further reaction. Methanol was removed under reduced pressure. After the reaction was quenched with concentrated HCl (3.0N), the mixture was extracted three times with ethyl acetate. In the absence of anhydrous Na₂SO₄The organic layer was dried and concentrated to give the crude product. Purification by preparative HPLC gave the desired product as a white solid (29mg, 70%). C₂₆H₁₉ClN₂O₅Calculated LC/MSm/e of (1): 474 measured (M + H)⁺：475.1。¹H NMR(400MHz，MeOD-d4)δppm2.22-2.33(m，2H)3.35-3.39(m，1H)4.22(t，J＝8.08Hz，2H)4.56(t，J＝7.96Hz，2H)6.15(d，J＝7.07Hz，1H)6.81(t，J＝7.20Hz，1H)6.96(d，J＝7.83Hz，1H)7.15(t，J＝7.33Hz，1H)7.33(q，J＝8.51Hz，4H)7.91(s，1H)8.11(t，J＝2.02Hz，1H)8.26(s，1H)。

Example 93

(1S, 2S) and (1R, 2R) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -5- (methylsulfonyl) benzoic acid

From methanesulfinic acid sodium salt, 3-bromo-5-iodo-benzoic acid (commercially available), (1R, 2R) and (1S, 2S) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 92. C₂₄H₁₈ClNO₅LC/MS m/e calculated for S: 467, actual measurement (M + H)⁺：468.1。¹H NMR(400MHz，MeOD-d₄)δppm 2.27-2.36(m，2H)3.28(s，3H)3.38(t，J＝8.59Hz，1H)6.18(d，J＝7.58Hz，1H)6.85(t，J＝7.20Hz，1H)7.00(d，J＝7.83Hz，1H)7.14-7.23(m，1H)7.28-7.40(m，4H)8.38(t，J＝1.89Hz，1H)8.49(s，1H)8.62(s，1H)。

Example 94

(1S, 2S) and (1R, 2R) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -5- (2-oxopyrrolidin-1-yl) benzoic acid

From 2-pyrrolidone, 3-bromo-5-iodo-benzoic acid (commercially available), (1R, 2R) and (1S, 2S) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]The title compound was prepared in analogy to example 92 starting from the 2' -ketoneA compound (I) is provided. C₂₇H₂₁ClN₂O₄Calculated LC/MS m/e of: 472, actual measurement (M + H)⁺：4731.2¹HNMR(400MHz，MeOD-d₄)δppm 2.18-2.35(m，4H)2.67(t，J＝8.08Hz，2H)3.35-3.39(m，1H)4.05(t，J＝7.07Hz，2H)6.16(d，J＝7.07Hz，1H)6.82(t，J＝7.45Hz，1H)6.97(d，J＝7.33Hz，1H)7.12-7.20(m，1H)7.34(q，J＝8.67Hz，4H)7.95(s，1H)8.20(t，J＝1.89Hz，1H)8.33(s，1H)。

Example 95

(1R, 2R) and (1S, 2S) -3- (2- (4-chlorophenyl) -5 ' -fluoro-2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid

Synthesis of (1S, 2S) and (1R, 2R) -methyl-3-bromo-5- (2- (4-chlorophenyl) -5 '-fluoro-2-isopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) benzoate

(1R, 2R) and (1S, 2S) -2- (4-chlorophenyl) -5 '-fluoro-2-isopropylspiro [ cyclopropane-1, 3' -indoline prepared according to scheme 2 were reacted under argon atmosphere]-2' -one (0.33g, 1mmol) and methyl 3-bromo-5-iodo-benzoate (0.409g, 1.2mmol), CuI (20mg), K₂CO₃(0.276g, 2mmol) was charged into a Schlenk tube and dissolved in anhydrous acetonitrile. N, N' -dimethyl-1, 2-ethanediamine (21. mu.L) was added to the mixture. The mixture was stirred at 80 ℃ for 14 hours. The solvent was removed under vacuum and the residue was purified by flash column chromatography to yield a white powderThe title compound (0.444g, 82%) was obtained as a powder. C₂₇H₂₂BrClFNO₃Calculated LC/MS m/e of: 541, actual measurement (M + H)⁺：542。

Synthesis of (1R, 2R) and (1S, 2S) -methyl-3- (2- (4-chlorophenyl) -5 ' -fluoro-2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid esters

Reacting 3-bromo-5- ((1S, 2S) -2- (4-chlorophenyl) -5 ' -fluoro-2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline under argon atmosphere]-1 '-yl) benzoate, 3-bromo-5- ((1R, 2R) -2- (4-chlorophenyl) -5' -fluoro-2-isopropyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) benzoate (0.545g, 1mmol), 2-Oxazolidinone (0.105g, 1.2mmol), CuI (20mg) and K₂CO₃(0.276g, 2mmol) was charged into a Schlenk tube and dissolved in anhydrous acetonitrile. N, N' -dimethyl-1, 2-ethanediamine (21. mu.L, 20% equiv.) was added to the mixture. The mixture was stirred at 80 ℃ for 14 hours. The solvent was removed in vacuo and the residue was purified by flash column chromatography to give the title compound (0.40g, 73%) as a white powder. C₃₀H₂₆ClFN₂O₅Calculated LC/MS m/e of: 548, measured (M + H)⁺：549.5。

Synthesis of (1R, 2R) and (1S, 2S) -3- (2- (4-chlorophenyl) -5 ' -fluoro-2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid

To (1R, 2R) and (1S, 2S) -3-bromo-5- (2- (4-chlorophenyl) -5 ' -fluoro-2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline in methanol (2mL) and water (1mL)]To a solution of (e) -1' -yl) benzoate (27.4mg) was added LiOH₂O (18mg, 0.4 mmol). The mixture was stirred at room temperature for 3 hours until the starting material was consumed. The mixture was concentrated under reduced pressure and acidified to pH-3. The precipitate was collected by filtration and dissolved in 2mL DMF. Purification by preparative HPLC gave the title compound as a white solid (15 mg). C₂₉H₂₄ClFN₂O₅LC/MS M/e calculated 534, found (M + H)⁺：545.7。¹H NMR(400MHz，MeOD-d₄)δppm 0.89(dd，J＝20.34，6.69Hz，6H)2.21-2.28(m，2H)2.89-3.01(m，1H)4.22(t，J＝8.08Hz，2H)4.55(t，J＝8.08Hz，2H)5.28(dd，J＝8.84，2.27Hz，1H)6.65(dd，J＝8.34，1.77Hz，1H)6.80-6.89(m，2H)7.19(dd，J＝8.34，2.02Hz，1H)7.45-7.54(m，2H)7.86(s，1H)8.09(s，1H)8.22(s，1H)。

Example 96

(1R, 2S) and (1S, 2R) -3- (2- (4-chlorophenyl) -5 ' -fluoro-2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid

From 2-Oxazolidinone (commercially available), bromo-5-iodo-benzoic acid methyl ester prepared in example 92, (1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -5 '-fluoro-2-isopropylspiro [ cyclopropane-1, 3' -indoline, as prepared in scheme 2]Starting with the-2' -ketone, the title compound was prepared in analogy to example 95. C₂₉H₂₄ClFN₂O₅Calculated LC/MS m/e of: 534, actual measurement (M + H)⁺：535.1。¹H NMR(400MHz，DMSO-d₆)δppm 0.55-0.61(m，3H)0.87(s，3H)2.11-2.18(m，1H)2.28-2.39(m，2H)4.07-4.19(m，2H)4.42-4.52(m，2H)6.84-6.98(m，1H)7.07-7.15(m，1H)7.23(d，J＝8.34Hz，1H)7.32-7.42(m，1H)7.52(d，J＝9.35Hz，1H)7.64(br.s.，1H)7.79(br.s.，1H)8.11(br.s.，1H)。

Example 97

(1R, 2R) and (1S, 2S) -3- (2- (4-chlorophenyl) -2-isopropyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid

From 2-Oxazolidinone (commercially available), bromo-5-iodo-benzoic acid methyl ester as prepared in example 92, (1R, 2R) and (1S, 2S) -2- (4-chlorophenyl) -2-isopropylspiro [ cyclopropane-1, 3' -indoline as prepared in scheme 2]Starting with the-2' -ketone, the title compound was prepared in analogy to example 95. C₂₉H₂₅ClN₂O₅Calculated LC/MS m/e of: 516, actual measurement (M + H)⁺：516.1。¹H NMR(400MHz，DMSO-d₆)δppm 0.77(d，3H)0.85(d，3H)2.10-2.16(m，1H)2.18-2.25(m，1H)2.81-2.97(m，1H)4.17(t，2H)4.50(t，2H)5.49(d，1H)6.64(d，1H)6.71(t，1H)6.86(d，1H)7.10(t，1H)7.22(d，1H)7.45-7.62(m，2H)7.77(s，1H)7.98(s，1H)8.20(s，1H)。

Example 98

(1S, 2S) and (1R, 2R) -3- (2- (4-cyanophenyl) -2-isopropyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid

From 2-Oxazolidinone (commercially available), bromo-5-iodo-benzoic acid methyl ester as prepared in example 92, (1R, 2R) and (1S, 2S) -4- (2-isopropyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline as prepared in scheme 2]The title compound was prepared in analogy to example 95 starting from-2-yl) benzonitrile. C₃₀H₂₅lN₃O₅Calculated LC/MS m/e of: 507, actual measurement (M + H)⁺：508.2。¹H NMR(400MHz，DMSO-d₆)δppm 0.78(d，3H)0.86(d，3H)2.14-2.21(m，1H)2.23-2.33(m，1H)2.85-3.02(m，1H)4.10-4.24(m，2H)4.50(t，2H)5.43(d，1H)6.68(t，1H)6.79-6.89(m，2H)7.11(t，1H)7.61(d，2H)7.70(d，2H)7.80(s，1H)7.94-8.02(m，2H)8.22(s，1H)13.45(s，1H)。

Example 99

(1S, 2S) and (1R, 2R) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -5- (2-oxoimidazolidin-1-yl) benzoic acid

From ethylene urea (commercially available), methyl bromo-5-iodo-benzoate as prepared in example 92, (1R, 2R) and (1S, 2S) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 92. C₂₆H₂₀ClN₃O₄Calculated LC/MSm/e of (1): 473, actual measurement (M + H)⁺：474.2。¹H NMR(400MHz，DMSO-d₆)δppm2.14(dd，J＝9.22，4.93Hz，1H)2.41(dd，J＝7.96，4.67Hz，1H)3.22-3.28(m，1H)3.43-3.49(m，1H)3.92-3.98(m，1H)6.19(d，J＝7.58Hz，1H)6.80(t，J＝7.71Hz，1H)6.85(d，J＝7.83Hz，1H)7.12(t，J＝8.34Hz，1H)7.22(s，1H)7.42(q，J＝8.59Hz，3H)7.64(s，1H)7.99(t，J＝2.02Hz，1H)8.13(s，1H)。

Example 100

(R) and (S) -3- ((5 '-fluoro-2, 2-dimethyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

Synthesis of 5-fluoro-3- (prop-2-ylidene) indolin-2-one

A mixture of 5-fluoro-1, 3-dihydro-indol-2-one (2.84g, 20mmol), acetone (2.2mL, 30mmol) and piperidine (0.8mL, 8mmol) in methanol (100mL) was heated to reflux for 16 h. The reaction mixture was then allowed to cool to room temperature. The solid was collected by filtration, washed with methanol (20mL) and dried in vacuo to give 5-fluoro-3-isopropylidene-1, 3-dihydro-indol-2-one (2.6g, 68%) as a powder.

Synthesis of (R) and (S) -5 ' -fluoro-2, 2-dimethylspiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

A solution of NaH (60%) (0.6g, 15mmol) and trimethyl sulfoxide iodide (3.3g, 15mmol) in dimethyl sulfoxide (30mL) was stirred at 25 deg.C for 30 minutes. A solution of 5-fluoro-3-isopropylidene-1, 3-dihydro-indol-2-one (2.6g, 13.6mmol) in anhydrous tetrahydrofuran (30mL) was then added dropwise over 20 minutes. After stirring at 25 ℃ for 1 hour and at 50 ℃ for 1 hour, the reaction solution was poured into ice-cold water and extracted with ether (3 × 100mL), washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ether to yield the title compound as a white solid (2.39g, 85%).

Synthesis of methyl- (R) and (S) -3- ((5 '-fluoro-2, 2-dimethyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoate

3-bromomethyl-benzoic acid methyl ester (610mg, 2.68mmol) was added to a suspension of cesium carbonate (1.2g, 3.66mmol) and (R) and (S) -5 ' -fluoro-2, 2-dimethylspiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one (500mg, 2.44mmol) in DMF (10 mL). The reaction mixture was stirred at 25 ℃ for 1 hour. Then extracted with ethyl acetate (3 × 25mL), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a white powder (850mg, 98%).

Synthesis of 3- ((5 '-fluoro-2, 2-dimethyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

(R) and (S) -3- ((5 ' -fluoro-2, 2-dimethyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline) in tetrahydrofuran (10mL)]A mixture of-1' -yl) methyl) benzoate (850mg, 2.4mmol) and 30% sodium hydroxide in water (5mL) was stirred at 25 ℃ for 16 h. The mixture was neutralized with 2N aqueous hydrochloric acid, diluted with ethyl acetate (50mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by a waters automated rapid system (column: Xterra 30mm x 100mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% trifluoro-acetic acid in water) yielded the title compound as a white solid (410mg, 50%): c₂₀H₁₈FNO₃LC/MS M/e calculation (M + H)⁺: 340.37, actually measuring: 340.2 of the total weight of the mixture; c₂₀H₁₈FNO₃Calculated LC/MS m/e of: 339, actual measurement (M + H)⁺：340.1。¹H NMR(400MHz，DMSO-d₆)δppm 1.37(s，3H)1.48(s，3H)1.76(d，J＝4.29Hz，1H)1.88(d，J＝4.29Hz，1H)5.04(dd，2H)6.91-7.08(m，2H)7.17(dd，J＝9.35，2.53Hz，1H)7.44-7.57(m，2H)7.80-7.93(m，2H)12.99(s，1H)。

Example 101

(R) and (S) -3- (5 ' -fluoro-2, 2-dimethyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid

Synthesis of methyl-3-bromo-5- (2-oxo)Oxazolidin-3-yl) benzoate 3-bromo-5-iodo-benzoic acid methyl ester (682mg, 2mmol) in acetonitrile (15mL),A suspension of oxazolidin-2-one (191mg, 2.2mmol), CuI (76mg, 0.4mmol), potassium carbonate (545mg, 4mmol) and N, N' -dimethyl-ethane-1, 2-diamine (86uL, 0.8mmol) was stirred at 90 ℃ for 16 h. The precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo to give 3-bromo-5- (2-oxo-Oxazolidin-3-yl) -benzoic acid methyl ester (480mg, 80%) which was used in the next step without further purification.

Synthesis of (R) and (S) -methyl-3- (5' -fluoro-2,2-dimethyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid esters

(R) and (S) -5 '-fluoro-2, 2-dimethylspiro [ cyclopropane-1, 3' -indoline in acetonitrile (15mL)]-2' -one (2mmol) (as prepared in example 100), methyl-3-bromo-5- (2-oxo)A suspension of oxazolidin-3-yl) benzoate (682mg, 2mmol), CuI (76mg, 0.4mmol), potassium carbonate (545mg, 4mmol) and N, N' -dimethyl-ethane-1, 2-diamine (86uL, 0.8mmol) was stirred at 90 ℃ for 16 h. The precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo to give the title compound (480mg, 80%) as a white powder, which was used in the next step without further purification.

Synthesis of (R) and (S) -3- (5 ' -fluoro-2, 2-dimethyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid

(R) and (S) -methyl-3- (5 ' -fluoro-2, 2-dimethyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline) in tetrahydrofuran (10mL)]-1' -yl) -5- (2-oxoOxazolidinesA mixture of-3-yl) benzoate (850mg, 2.4mmol) and 30% sodium hydroxide in water (5mL) was stirred at 25 ℃ for 16 h. The mixture was neutralized with 2N aqueous hydrochloric acid, diluted with ethyl acetate (50mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by a waters automated rapid system (column: Xterra 30mm x 100mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% trifluoro-acetic acid in water) yielded the title compound as a white solid (410mg, 50%): c₂₀H₁₈FNO₃Calculated LC/MS m/e of: 340, actual measurement (M + H)⁺：340.；¹H NMR(400MHz，MeOD)δppm 1.50(s，3H)1.57(s，3H)1.86(d，J＝4.29Hz，1H)1.93(d，J＝4.55Hz，1H)4.22(t，J＝7.96Hz，2H)4.56(t，J＝7.96 Hz，2H)6.86-6.94(m，1H)6.94-7.02(m，1H)7.06(d，J＝8.59Hz，1H)7.84(s，1H)8.03(br.s.，1H)8.25(br.s.，1H)。

Example 102

(R) and (S) -3- [ (2-oxo-2 ', 3 ', 5 ', 6 ' -tetrahydrodispiro [ indole-3, 1 ' -cyclopropane-2 ', 4 ' -pyran ] -1(2H) -yl) methyl ] benzoic acid

The title compound was prepared according to scheme 2 in analogy to example 100 starting from methyl- (3-bromomethyl) -benzoate, 4-methylene-tetrahydro-pyran and isatin (commercially available). C₂₂H₂₁NO₄Calculated LC/MSm/e of (1): 363, actual measurement (M + H)⁺：364.2。¹H NMR(400MHz，DMSO-d₆)δppm 1.66-1.76(m，1H)1.76-1.81(m，1H)1.88-2.04(m，3H)2.09-2.16(m，1H)3.21-3.29(m，1H)3.42-3.46(m，1H)3.54-3.66(m，2H)4.99(d，1H)5.12(d，1H)6.95-7.04(m，2H)7.19(t，2H)7.48(t，J＝7.58Hz，1H)7.57(d，1H)7.84(d，J＝7.83Hz，1H)7.87(s，1H)12.98(d，J＝2.27Hz，1H)。

Example 103

(R) and (S) -3- (2-oxo-1, 3-)Oxazolidin-3-yl) -5- (2-oxo-2 ', 3 ', 5 ', 6 ' -tetrahydrodispiro [ indole-3, 1 ' -cyclopropane-2 ', 4 ' -pyran]-1(2H) -yl) benzoic acid

According to scheme 2, from methyl-3-bromo-5- (2-oxo), as prepared in example 101The title compound was prepared in analogy to example 101 starting from oxazolidin-3-yl) benzoate, 4-methylene-tetrahydro-pyran, isatin (commercially available). C₂₄H₂₂N₂O₆Calculated LC/MS m/e of: 434, actual measurement (M + H)⁺：434.2。¹H NMR(400MHz，DMSO-d₆)δppm 1.72-1.80(m，1H)1.83(d，J＝4.29Hz，1H)1.91-2.01(m，3H)2.06-2.16(m，1H)3.36-3.44(m，1H)3.50-3.56(m，1H)3.58-3.65(m，2H)4.13-4.21(m，2H)4.48(t，J＝7.96Hz，2H)6.90(d，J＝8.08Hz，1H)7.07(t，1H)7.23(t，1H)7.29(d，J＝7.58Hz，1H)7.71(s，1H)7.92(s，1H)8.19(s，1H)13.40(s，1H)。

Example 104

(1S, 2S) and (1R, 2R) -2-chloro-5- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

Prepared from methyl-2-chloro- (3-bromomethyl) -benzoate (commercially available) as in scheme 1Prepared (1S, 2S) and (1R, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₇ClFNO₃Calculated LC/MS m/e of: 421, actual measurement (M + H)⁺：422.2。1H NMR(400MHz，DMSO-d₆)δppm 2.22-2.29(m，1H)2.32(dd，J＝8.34，4.80Hz，1H)3.29-3.32(m，1H)4.81-4.98(m，2H)6.96-7.00(m，1H)7.02-7.14(m，3H)7.17-7.23(m，2H)7.32(dd，J＝8.46，5.68Hz，2H)7.37(dd，J＝8.34，2.27Hz，1H)7.50(d，J＝8.34Hz，1H)7.56(d，J＝2.02Hz，1H)13.46(br.s.，1H)。

Example 105

(1R, 2S) and (1S, 2R) -4- ((2 ' -oxo-2- (pyridin-3-yl) spiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From 4-bromomethyl-benzoic acid methyl ester (commercially available), (1R, 2S) and (1S, 2R) -2- (pyridin-3-yl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₃H₁₈ClN₂O₃Calculated LC/MS m/e of: 370, actual measurement (M + H)⁺：371.2。¹H NMR(400MHz，DMSO-d₆)δppm 2.14-2.23(m，1H)3.30(t，1H)5.10(s，2H)6.14(d，1H)6.70(t，1H)6.93(d，1H)7.10(t，1H)7.45(d，2H)7.57-7.65(m，1H)7.93(d，2H)8.06(d，1H)8.61(d，1H)8.71(s，1H)。

Example 106

(1S, 2R) and (1R, 2S) -4- ((2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From 4-bromomethyl-benzoic acid methyl ester (commercially available), (1R, 2S) and (1S, 2R) -4- (2 '-oxospiro [ cyclopropane-1, 3' -indoline) as prepared in scheme 1]-2-yl) benzonitrile the title compound was prepared in analogy to example 1. C₂₅H₁₈ClN₂O₃Calculated LC/MS m/e of: 394, measured (M + H)⁺：395.2。¹H NMR(400MHz，DMSO-d₆)δppm 2.11-2.20(m，1H)2.43-2.50(m，1H)5.10(s，2H)6.16(d，1H)6.70(t，1H)6.92(d，1H)7.08(t，1H)7.43(d，2H)7.55(d，2H)7.80(d，2H)7.93(d，2H)。

Example 107

(1R, 2S) and (1R, 2S) -4- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From 4-bromomethyl-benzoic acid methyl ester (commercially available), (1R, 2S) and (1S, 2R) -2- (4-fluorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₈FlNO₃Calculated LC/MS m/e of: 387, measured (M + H)⁺：388.1。¹H NMR(400MHz，DMSO-d₆)δppm 2.05-2.14(m，1H)2.30-2.40(m，1H)3.21(t，2H)5.09(s，2H)6.10(d，1H)6.70(t，1H)6.92(d，1H)7.07(t，1H)7.11-7.20(m，2H)7.31-7.38(m，2H)7.44(d，2H)7.93(d，2H)。

Example 108

(1S, 2R) and (1R, 2S) -2-chloro-5- ((2- (4-chlorophenyl) -5 '-fluoro-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) methyl) benzoic acid

From methyl-2-chloro- (3-bromomethyl) -benzoate (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) -5 '-fluorospiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₆Cl₂FNO₃Calculated LC/MS m/e of: 455, actual measurement (M + H)⁺：456.2。¹HNMR(400MHz，DMSO-d₆)δppm 2.15(dd，J＝9.09，4.80Hz，1H)2.46-2.50(m，1H)3.25(t，J＝8.59Hz，1H)5.05(s，2H)6.00(dd，J＝8.97，1.89Hz，1H)6.91-6.98(m，2H)7.33-7.42(m，4H)7.44-7.49(m，1H)7.52-7.57(m，1H)7.73(d，J＝2.02Hz，1H)13.47(br.s.，1H)。

Example 109

(1R, 2S) and (1S, 2R) -3- ((2- (3-chloro-4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzoic acid

From 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R, 2S) and (1S, 2R) -2- (3-chloro-4-fluorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 1. C₂₄H₁₇ClFNO₃Calculated LC/MS m/e of: 421, actual measurement (M + H)⁺：422.2。¹H NMR(400MHz，DMSO-d₆)δppm 2.04-2.15(m，1H)2.40-2.49(m，1H)3.21(t，1H)5.09(s，2H)6.18(d，1H)6.75(t，1H)6.96(d，1H)7.06-7.14(m，1H)7.29-7.39(m，2H)7.46-7.53(m，1H)7.56-7.65(m，2H)7.82-7.93(m，2H)13.03(s，1H)。

Example 110

(1R, 2S) and (1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N-methylbenzamide

From 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 60. C₂₅H₂₁ClN₂O₂Calculated LC/MS m/e of: 416, actual measurement (M + H)⁺：417.1。¹H NMR(400MHz，MeOH-d₄)δppm 2.24(d，J＝8.84Hz，2H)2.93(s，3H)3.27-3.39(m，1H)5.13(s，2H)6.09(d，J＝7.58Hz，1H)6.73(t，J＝7.71Hz，1H)6.91(d，J＝7.83Hz，1H)7.03-7.13(m，1H)7.21-7.28(m，2H)7.29-7.38(m，2H)7.41-7.50(m，1H)7.50-7.56(m，1H)7.72(d，J＝7.58Hz，1H)7.82(s，1H)。MS：C₂₅H₂₁N₂O₂Calculated value 381, found (ESI)⁺)[(M+H)⁺]382。

Example 111

(1S, 2R) and (1R, 2S) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N, N-dimethylbenzamide

From 3-bromomethyl-benzoic acid methyl ester, dimethylamine, methylamine (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 60. C₂₉H₂₇ClN₂O₂Calculated LC/MS m/e of: 470, actually measured (M + H)⁺：471.2。¹H NMR(400MHz，MeOD-d₄)δppm 2.15-2.24(m，2H)2.90(s，3H)3.06(s，3H)3.21-3.35(m，1H)5.09(s，2H)6.05(d，J＝7.58Hz，1H)6.69(t，J＝7.58Hz，1H)6.89(d，J＝8.08Hz，1H)7.01-7.10(m，1H)7.19(d，J＝8.59Hz，2H)7.25-7.38(m，4H)7.40-7.49(m，2H)。

Example 112

(1R, 2S) and (1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (3-morpholinopropyl) benzamide

From 33-morpholinopropan-1-amine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R, 2S) as prepared in scheme 1 and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline]Starting with the 2' -ketone, the title compound was prepared in analogy to example 60. C₃₁H₃₂ClN₃O₃Calculated LC/MS m/e of: 529, measured (M + H)⁺：530.2。¹H NMR(400MHz，MeOD-d₄)δppm 2.02-2.15(m，2H)2.24(d，J＝8.59Hz，2H)3.15(br.s.，2H)3.23(d，J＝8.08Hz，2H)3.25-3.31(m，1H)3.47-3.57(m，4H)3.79(t，J＝12.38Hz，2H)4.06(br.s.，2H)5.14(s，2H)6.09(d，J＝7.33Hz，1H)6.73(t，J＝7.58Hz，1H)6.91(d，J＝8.08Hz，1H)7.09(t，J＝7.71Hz，1H)7.20-7.28(m，2H)7.28-7.37(m，2H)7.49(t，J＝7.71Hz，1H)7.53-7.61(m，1H)7.78(d，J＝8.08Hz，1H)7.87(s，1H)。

Example 113

(1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (4- (2- (dimethylamino) ethyl) piperazine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From N, N-dimethyl-2- (piperazin-1-yl) ethylamine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 60. C₃₂H₃₅ClN₄O₂Calculated LC/MS m/e of: 542, actual measurement (M + H)⁺：543.1。¹H NMR(400MHz，CDCl₃)δppm 2.04(dd，J＝7.96，4.67Hz，1H)2.28(dd，J＝8.97，4.67Hz，1H)2.93(s，6H)3.18(br.s.，4H)3.34(t，J＝8.59Hz，1H)3.62(br.s.，4H)3.87(br.s.，4H)4.95(d，J＝15.92Hz，1H)5.16(d，J＝15.92Hz，1H)6.02(d，J＝7.58Hz，2H)6.70-6.84(m，2H)7.06-7.19(m，3H)7.31(s，1H)7.35(d，J＝5.31Hz，1H)7.43(d，J＝6.06Hz，3H)。

Example 114

(1R, 2S) and (1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (2-morpholinoethyl) benzamide

From 2-morpholinoethylamine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 60. C₃₀H₃₀ClN₃O₃Calculated LC/MS m/e of: 515, actual measurement (M + H)⁺：516.2。¹H NMR(400MHz，MeOD-d₄)δppm 2.24(d，J＝8.59Hz，2H)3.20(br.s.，2H)3.29(s，1H)3.42(t，J＝5.81Hz，2H)3.69(br.s.，4H)3.80(t，J＝5.81Hz，2H)4.08(br.s.，2H)5.14(d，J＝1.52Hz，2H)6.09(d，J＝7.33Hz，1H)6.73(t，J＝7.58Hz，1H)6.91(d，J＝8.08Hz，1H)7.04-7.13(m，1H)7.22-7.28(m，2H)7.29-7.36(m，2H)7.50(t，J＝7.71Hz，1H)7.55-7.62(m，1H)7.80(d，J＝7.58Hz，1H)7.90(s，1H)。

Example 115

(1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) -1 ' - (3- (4- (methylsulfonyl) piperazine-1-carbonyl) benzyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 1- (methylsulfonyl) piperazine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 60. C₂₉H₂₈ClN₃O₄LC/MS m/e calculated for S: 549, measured (M + H)⁺：550.2。¹H NMR(400MHz，MeOD-d₄)δppm 8.19-8.05(m，2H)7.49(s，3H)7.25(br.s.，4H)7.09-7.05(m，1H)6.88(br.s.，2H)6.50(br.s.，2H)5.29-5.12(m，2H)4.23(d，J＝7.58Hz，1H)3.64-3.56(m，1H)3.41(d，J＝7.58Hz，1H)3.29-3.19(m，1H)3.11(d，J＝8.08Hz，2H)3.07-2.99(m，2H)2.98-2.91(m，2H)2.88-2.75(m，2H)。

Example 116

(1S, 2R) and (1R, 2S) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (3-cyclopropyl-1H-pyrazol-5-yl) benzamide

From 3-cyclopropyl-1H-pyrazol-5-amine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R, 2S) as prepared in scheme 1, and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline]Starting with the 2' -ketone, the title compound was prepared in analogy to example 60. C₃₀H₂₅ClN₄O₂Calculated LC/MS m/e of: 508, measured (M + H)⁺：509.2。¹H NMR(400MHz，MeOD-d₄)δppm 0.66-0.77(m，2H)1.02(dd，J＝8.34，1.77Hz，2H)2.24(d，J＝8.59Hz，2H)2.47-2.57(m，1H)3.26-3.32(m，1H)5.07-5.25(m，2H)5.65(s，1H)6.09(d，J＝7.58Hz，1H)6.73(t，J＝7.58Hz，1H)6.96(d，J＝7.83Hz，1H)7.07-7.14(m，1H)7.20(d，J＝8.34Hz，2H)7.31(d，J＝8.34Hz，2H)7.49(t，J＝7.83Hz，1H)7.55-7.63(m，1H)7.80(d，J＝7.83Hz，1H)7.83(s，1H)。

Example 117

(1S, 2R) and (1R, 2S) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (5-cyclopropyl-1H-pyrazol-3-yl) benzamide

From 5-cyclopropyl-1H-pyrazol-3-amine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 60. C₃₀H₂₅ClN₄O₂Calculated LC/MS m/e of: 508, measured (M + H)⁺：509.2。¹H NMR(400MHz，MeOD-d₄)δppm 0.54-0.77(m，2H)0.79-0.95(m，2H)1.62-1.77(m，1H)2.05(s，1H)2.18-2.30(m，2H)3.23-3.31(m，1H)5.07-5.26(m，2H)6.09(d，J＝6.82Hz，1H)6.72(t，J＝7.58Hz，1H)6.95(d，J＝7.83Hz，1H)7.05-7.14(m，1H)7.14-7.20(m，2H)7.30(d，J＝8.34Hz，2H)7.51(t，J＝7.71Hz，1H)7.62(d，J＝7.83Hz，1H)7.89(d，J＝7.83Hz，1H)7.94(s，1H)。

Example 118

(1R, 2S) and (1S, 2R) -6- ((2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (cyclopropylsulfonyl) picolinamide

From methyl-6- (bromomethyl) picolinate, cyclopropanesulfonamide, and (1R, 2S) and (1S, 2R) -4- (2 '-oxospiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]The title compound was prepared in analogy to example 60 starting from-2-yl) benzonitrile. C₂₇H₂₂N₄O₄LC/MS m/e calculated for S: 498, found (M + H)⁺：499.2。¹HNMR(400MHz，DMSO-d₆)δppm 1.02-1.15(m，2H)1.14-1.24(m，2H)2.08-2.20(m，1H)2.43-2.48(m，1H)2.99-3.15(m，1H)3.27-3.34(m，1H)5.19(s，2H)6.14(d，1H)6.72(t，1H)6.99(d，1H)7.09(t，1H)7.47(d，1H)7.59(d，2H)7.79(d，2H)7.92-8.06(m，2H)。

Example 119

(1S, 2R) and (1R, 2S) -4- ((2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (cyclopropylsulfonyl) benzamide

From 4-bromomethyl-benzoic acid methyl ester, cyclopropanesulfonamide (commercially available), (1R, 2S) and (1S, 2R) -4- (2 '-oxospiro [ cyclopropane-1, 3' -indoline) as prepared in scheme 1]The title compound was prepared in analogy to example 60 starting from-2-yl) benzonitrile. C₂₈H₂₃ClN₃O₄LC/MS m/e calculated for S: 497, actual measurement (M + H)⁺：498.2，1H NMR(400MHz，DMSO-d₆)δppm 0.69-0.79(m，2H)0.83-0.92(m，2H)2.11-2.18(m，1H)2.44-2.49(m，1H)2.91-3.00(m，1H)3.12-3.20(m，1H)3.27-3.32(m，1H)5.04(s，2H)6.15(d，1H)6.68(t，1H)6.91(d，1H)7.02-7.09(m，2H)7.28-7.37(m，2H)7.50-7.59(m，2H)7.77-7.82(m，2H)7.87-7.94(m，2H)。

Example 120

(1R, 2S) and (1S, 2R) -3- ((2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (methylsulfonyl) benzamide

From 3-bromomethyl-benzoic acid methyl ester, methylsulfonamide (commercially available), as prepared in scheme 1, (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline]Starting with the 2' -ketone, the title compound was prepared in analogy to example 60. C₂₅H₂₁ClN₂O₄LC/MS m/e calculated for S: 480, actual measurement (M + H)⁺：481.2。¹HNMR(400MHz，DMSO-d₆)δppm 2.08-2.18(m，1H)2.35-2.42(m，1H)2.92(s，3H)3.13-3.25(m，2H)4.95-5.13(m，2H)6.15(d，1H)6.70(t，1H)6.87(d，1H)7.02-7.10(m，2H)7.30-7.44(m，6H)7.81-7.89(m，2H)。

Example 121

(1R, 2S) and (1S, 2R) -3- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (methylsulfonyl) benzamide

From 3-bromomethyl-benzoic acid methyl ester, methylsulfonamide (commercially available), as prepared in scheme 1, (1R, 2S) and (1S, 2R) -2- (4-fluorophenyl) spiro [ cyclopropane-1, 3' -indoline]Starting with the 2' -ketone, preparation is carried out analogously to example 60The title compound was prepared. C₂₅H₂₁FN₂O₄LC/MS m/e calculated for S: 470, actually measured (M + H)⁺：471.2。¹HNMR(400MHz，DMSO-d₆)δppm 2.10-2.18(m，1H)2.33-2.42(m，1H)3.18-3.27(m，1H)3.38(s，3H)5.10(s，2H)6.12(d，1H)6.71(t，1H)6.89-6.97(m，1H)7.03-7.09(m，1H)7.11-7.18(m，2H)7.31-7.41(m，2H)7.48-7.55(m，1H)7.56-7.63(m，1H)7.82-7.93(m，2H)。

Example 122

(1S, 2R) and (1R, 2S) -N- (cyclopropylsulfonyl) -3- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzamide

From 3-bromomethyl-benzoic acid methyl ester, cyclopropanesulfonamide (commercially available), (1R, 2S) and (1S, 2R) -2- (4-fluorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 60. C₂₇H₂₃FN₂O₄LC/MS m/e calculated for S: 490, actual measurement (M + H)⁺：491.2。¹HNMR(400MHz，DMSO-d₆)δppm 0.84-0.94(m，2H)0.94-1.04(m，2H)2.08-2.18(m，1H)2.32-2.40(m，1H)2.98-3.09(m，1H)3.21(t，1H)5.06(s，2H)6.09(d，1H)6.68(t，1H)6.89(d，1H)7.00-7.18(m，4H)7.33-7.50(m，4H)7.80-7.92(m，2H)。

Example 123

(1S, 2R) and (1R, 2S) -N- (cyclopropylsulfonyl) -4- ((2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) benzamide

From 4-bromomethyl-benzoic acid methyl ester, cyclopropanesulfonamide (commercially available), (1R, 2S) and (1S, 2R) -2- (4-fluorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 60. C₂₇H₂₃FN₂O₄LC/MS m/e calculated for S: 490, actual measurement (M + H)⁺：491.2。¹H NMR(400MHz，DMSO-d₆)δppm 0.70-0.81(m，2H)0.84-0.91(m，2H)2.06-2.17(m，1H)2.31-2.40(m，1H)2.91-3.02(m，1H)3.14-3.24(m，2H)5.04(s，2H)6.09(d，1H)6.68(t，1H)6.89(d，1H)7.05(t，2H)7.11-7.19(m，3H)7.89(d，2H)。

Example 124

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (piperidin-4-ylmethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 4- (chloromethyl) piperidine (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 70. C₂₂H₂₃ClN₂LC/MS m/e calculated for O: 366, actually measured (M + H)⁺：367.2。¹HNMR(400MHz，MeOD-d₄)δppm 1.51-1.67(m，2H)1.96(br.s.，2H)2.12-2.21(m，2H)2.21-2.35(m，1H)2.93-3.07(m，2H)3.22(t，J＝8.59Hz，1H)3.38-3.50(m，2H)3.84(d，J＝7.33Hz，2H)6.09(d，J＝7.58Hz，1H)6.77(t，J＝7.58Hz，1H)7.11(d，J＝7.83Hz，1H)7.16-7.26(m，3H)7.29-7.35(m，2H)。

Example 125

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (piperidin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 1- (2-chloroethyl) piperidine (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 70. C₂₃H₂₅ClN₂LC/MS m/e calculated for O: 380, actual measurement (M + H)⁺：371.2。¹HNMR(400MHz，MeOD-d₄)δppm 1.62(br.s.，1H)1.89(br.s.，3H)2.05(br.s.，2H)2.21-2.30(m，2H)3.09(br.s.，2H)3.30(t，J＝8.59Hz，1H)3.48-3.62(m，2H)3.76(br.s.，1H)3.93(br.s.，1H)4.22-4.32(m，1H)4.34-4.46(m，1H)6.15(d，J＝7.58Hz，1H)6.84(t，J＝7.58Hz，1H)7.15-7.21(m，1H)7.23-7.31(m，3H)7.33-7.40(m，2H)。

Example 126

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (3-morpholinopropylamino) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 1- (3-chloropropyl) piperidine (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 70. C₂₄H₂₇ClN₂LC/MS m/e calculated for O: 394, measured (M + H)⁺：395.2。¹HNMR(400MHz，MeOD-d₄)δppm 1.46-1.62(m，1H)1.69-1.91(m，3H)1.98(d，J＝14.91Hz，2H)2.15-2.27(m，4H)2.97(t，J＝12.76Hz，2H)3.17-3.29(m，3H)3.57(d，J＝12.13Hz，2H)3.92-4.07(m，2H)6.11(d，J＝7.58Hz，1H)6.79(t，J＝7.58Hz，1H)7.12(d，J＝7.83Hz，1H)7.18-7.26(m，3H)7.28-7.37(m，2H)。

Example 127

From ethylene dibromide, 3-morpholinopropan-1-amine (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 81. C₂₅H₃₀ClN₃O₂Calculated LC/MS m/e of: 439, measured (M + H)⁺：440.1。¹HNMR(400MHz，MeOD-d₄)δppm 2.07-2.32(m，6H)3.26(s，8H)3.47(t，J＝5.94Hz，3H)4.24(d，J＝28.55Hz，3H)6.12(d，J＝7.07Hz，1H)6.81(t，J＝7.07Hz，1H)7.14(d，J＝7.58Hz，1H)7.19-7.29(m，3H)7.30-7.39(m，2H)。

Example 128

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (2-morpholinoethylamino) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From ethylene dibromide, 2-morpholinoethylamine (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 81. C₂₄H₂₈ClN₃O₂Calculated LC/MS m/e of: 425, actual measurement (M + H)⁺：426.2。¹HNMR(400MHz，MeOD-d₄)δppm 2.09-2.34(m，3H)3.02(br.s.，4H)3.17(t，J＝6.19Hz，2H)3.27(t，J＝8.72Hz，1H)3.44-3.61(m，4H)3.87(t，J＝4.67Hz，4H)4.12-4.45(m，2H)6.11(d，J＝7.83Hz，1H)6.80(t，J＝7.58Hz，1H)7.10-7.18(m，1H)7.20-7.27(m，3H)7.29-7.40(m，2H)。

Example 129

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (4- (pyridin-4-yl) piperazin-1-yl) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From ethylene dibromide, 1- (pyridin-4-yl) piperazine (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 81. C₂₇H₂₇ClN₄LC/MS m/e calculated for O: 458, actual measurement (M + H)⁺：459.2。¹HNMR(400MHz，MeOD-d₄)δppm 1.32(s，2H)2.02-2.40(m，3H)3.26(s，1H)3.47(d，J＝9.09Hz，8H)4.02(br.s.，4H)4.25(s，2H)6.11(d，J＝7.33Hz，1H)6.80(s，1H)7.12-7.18(m，1H)7.19-7.27(m，3H)7.32(t，J＝8.97Hz，4H)8.27(d，J＝7.83Hz，2H)。

Example 130

(1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (2- (2- (2, 6-dimethylmorpholino) ethylamino) ethyl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

From 2- (2, 6-dimethylmorpholino) ethylamine, ethylene dibromide (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ 2 ], as prepared in scheme 1Cyclopropane-1, 3' -indolines]Starting with the 2' -ketone, the title compound was prepared in analogy to example 81. C₂₆H₃₂ClN₃O₂Calculated LC/MS m/e of: 453, actual measurement (M + H)⁺：454.1。¹HNMR(400MHz，MeOD-d₄)δppm 1.22(dd，J＝6.32，2.27Hz，2H)1.26-1.37(m，6H)2.15-2.32(m，3H)2.43-2.67(m，1H)2.88(br.s.，3H)3.26(d，J＝8.59Hz，2H)3.40-3.62(m，4H)3.70-3.96(m，1H)4.13(br.s.，4H)6.05-6.21(m，1H)6.81(t，J＝7.58Hz，1H)7.06-7.18(m，1H)7.24(d，J＝8.34Hz，3H)7.29-7.38(m，2H)。

Example 131

Synthesis of (1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 ' - (1-trityl-1H-imidazol-4-yl) spiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one

4-iodo-1-trityl-1H-imidazole (210mg, 0.48mmol) was added to (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline in acetonitrile (2mL) under nitrogen atmosphere]-2' -Ketone (107mg, 0.4mmol) in suspension. A steady stream of nitrogen was bubbled through the suspension while heating the suspension to 40 ℃ for 15 minutes. Potassium carbonate (110mg, 0.8mmol), copper (I) iodide (12mg, 15 mol%) and N, N-dimethylethylenediamine (0.12mmol, 30 mol%) were added and the reaction mixture was heated to 80 ℃ under nitrogen for 21 hours. The mixture was cooled to room temperature, filtered and concentrated to give the title product. By flash column chromatography (gradient)Eluting, 5-10% ethyl acetate in petroleum ether) to yield racemic trans-2- (4-chlorophenyl) -1 '- (1H-imidazole-4-trityl) spiro [ cyclopropane-1, 3' -indoline]-2' -one (157mg, 68%). C₃₈H₂₈ClN₃LC/MS m/e calculated for O: 577, actual measurement (M + H)⁺: 578.3. synthesis of (1S, 2R) and (1R, 2S) -2- (4-chlorophenyl) -1 '- (1H-imidazol-4-yl) spiro [ cyclopropane-1, 3' -indoline]-2' -ketones

Mixing (1S, 2R) and (1R, 2S) -2- (4-chlorphenyl) -1 '- (1-trityl-1H-imidazole-4-yl) spiro [ cyclopropane-1, 3' -indoline]-2' -Ketone (115mg, 0.2mmol) was dissolved in DCM (2mL) and water (0.5 mL). TFA (0.1mL) was added dropwise at 0 ℃. The mixture was stirred at room temperature for 14 hours. The mixture was poured into saturated NaHCO₃Was extracted with DCM (3 × 10mL), dried and concentrated to give the title product. The residue was dissolved in 2mL of DMF. Purification by preparative HPLC gave the title compound as a white powder (60mg, 89%).¹H NMR(400MHz，DMSO-d₆)δppm 2.13(dd，J＝9.09，5.05Hz，1H)2.42(dd，J＝8.08，4.80Hz，1H)3.23(t，J＝8.72Hz，1H)6.20(d，J＝7.58Hz，1H)6.81(t，J＝7.20Hz，1H)7.16(t，J＝7.83Hz，1H)7.30-7.45(m，5H)7.66(s，1H)8.27(s，1H)。C₁₉H₁₄ClN₃LC/MS M/e calculation of O335, found (M + H)⁺：336.3。

Example 132

(1S, 2R) and (1R, 2S) -3- (2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) -N- (methylsulfonyl) benzamide

From methylsulfonamide, methyl-3-iodobenzoate (commercially available), (1R, 2S) and (1S, 2R) -2- (4-chlorophenyl) spiro [ cyclopropane-1, 3' -indoline as prepared in scheme 1]Starting with the 2' -ketone, the title compound was prepared in analogy to example 85. C₂₄H₁₉ClN₂O₄LC/MS m/e calculated for S: 466, found (M + H)⁺：467.2。¹H NMR(400MHz，DMSO-d₆)δppm 2.15(dd，J＝9.09，4.80Hz，1H)2.44(dd，J＝8.08，4.80Hz，1H)3.25(t，J＝8.59Hz，1H)3.41(s，3H)6.21(d，J＝7.58Hz，1H)6.79-6.88(m，2H)7.10-7.17(m，1H)7.37-7.45(m，4H)7.75(t，J＝7.83Hz，1H)7.80-7.85(m，1H)8.04(d，J＝7.83Hz，1H)8.11-8.16(m，1H)12.29(br.s.，1H)。

Example 133

(1S, 2S) and (1R, 2R) -3- (2- (4-chlorophenyl) -2-methyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid

ByOxazolidin-2-one (commercially available), methyl 3-bromo-5-iodobenzoate prepared in example 92, (1R, 2R) and (1S, 2S) -2- (4-chlorophenyl) -2-methylspiro [ cyclopropane-1, 3' -indoline as prepared in scheme 2]Starting with the-2' -ketone, the title compound was prepared in analogy to example 95. C₂₇H₂₁ClN₂O₅Calculated LC/MS m/e of: 488, measured (M + H)⁺：489.1。¹H NMR(400MHz，DMSO-d₆)δppm 1.66(s，3H)2.18(d，J＝4.80Hz，1H)2.38(d，J＝5.05Hz，1H)4.12(t，J＝8.08Hz，2H)4.47(t，J＝7.96Hz，2H)6.95(d，J＝8.08Hz，1H)7.15(t，J＝7.45Hz，1H)7.25-7.34(m，5H)7.45(d，J＝7.33Hz，1H)7.59-7.62(m，1H)7.85(t，J＝2.02Hz，1H)8.12(s，1H)。

Example 134

(1S, 2S) and (1R, 2R) -3- (2- (4-chlorophenyl) -2-isopropyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid

ByOxazolidin-2-one, methyl 3-bromo-5-iodobenzoate (as prepared in example 92), (1R, 2R) and (1S, 2S) -2- (4-chlorophenyl) -2-isopropylspiro [ cyclopropane-1, 3' -indoline) as prepared in scheme 2]Starting with the-2' -ketone, the title compound was prepared in analogy to example 95. C₂₉H₂₅ClN₂O₅Calculated LC/MS m/e of: 516, actual measurement (M + H)⁺：517.2。¹H NMR(400MHz，DMSO-d₆)δppm 0.77(d，3H)0.89(d，3H)2.16(d，1H)2.28(d，1H)2.95-3.02(m，1H)4.17-4.25(m，2H)4.40-4.58(m，2H)5.43(d，1H)6.65-6.76(m，1H)6.78-6.91(m，2H)7.11(t，1H)7.61(d，1H)7.69(d，1H)7.79(s，1H)7.92-8.03(m，2H)8.21(s，1H)13.44(s，1H)。

Example 135

ByOxazolidin-2-one, methyl 3-bromo-5-iodobenzoate (as prepared in example 92), (1S, 2S) and (1R, 2R) -2- (4-chlorophenyl) -2-isopropylspiro [ cyclopropane-1, 3' -indoline) as prepared in scheme 2]Starting with the-2' -ketone, the title compound was prepared in analogy to example 95. C₂₉H₂₅ClN₂O₅Calculated LC/MS m/e of: 516, actual measurement (M + H)⁺：517.2。¹H NMR(400MHz，DMSO-d₆)δppm 0.77(d，3H)0.89(d，3H)2.16(d，1H)2.28(d，1H)2.85-3.02(m，1H)4.07-4.25(m，2H)4.41-4.59(m，2H)5.43(d，1H)6.62-6.75(m，1H)6.78-6.91(m，2H)7.11(t，1H)7.61(d，1H)7.69(d，1H)7.79(s，1H)7.92-8.03(m，2H)8.21(s，1H)13.44(s，1H)。

Example 136

(R) and (S) -methyl-3- (2, 2-dimethyl-2 '-oxospiro [ cyclopropane-1, 3' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid esters

(R) and (S) -5 '-fluoro-2, 2-dimethylspiro [ cyclopropane-1, 3' -indoline in acetonitrile (15mL)]-2' -one (2mmol) (as prepared in example 100), 3-bromo-5- (2-oxo)Oxazolidin-3-yl) benzathinesA suspension of methyl acid ester (682mg, 2mmol) (prepared as in example 100), CuI (76mg, 0.4mmol), potassium carbonate (545mg, 4mmol) and N, N' -dimethyl-ethane-1, 2-diamine (86uL, 0.8mmol) was stirred at 90 ℃ for 16 h. The precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo to give the title compound (480mg, 80%) as a white powder. C₂₃H₂₁FN₂O₅Calculated LC/MS m/e of: 424, actual measurement (M + H)⁺：425.2。¹H NMR(400MHz，DMSO-d₆)δppm 1.42(s，3H)1.48(s，3H)1.79(d，J＝4.29Hz，1H)1.95(d，J＝4.55Hz，1H)3.90(s，3H)4.17(t，2H)4.48(t，J＝7.96Hz，2H)6.87(dd，J＝8.72，4.42Hz，1H)7.04(t，J＝9.09Hz，1H)7.27(dd，J＝8.84，2.53Hz，1H)7.73(s，1H)7.91(s，1H)8.24(s，1H)。

Example 137

(R) and (S) -3- (5 '-fluoro-2, 2-dimethyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -1' -yl) -5- (2-hydroxyethylamino) benzoic acid

From 2-aminoethanol (commercially available), methyl-3-bromo-5-iodobenzoate, as prepared in example 92, (R) and (S) -5 '-fluoro-2, 2-dimethylspiro [ cyclopropane-1, 3' -indoline, as prepared in scheme 2]Starting with the-2' -ketone, the title compound was prepared in analogy to example 95. C₂₁H₂₁FN₂O₄Calculated LC/MS m/e of: 384, actually measured (M + H)⁺：385.1。¹H NMR(400MHz，MeOD-d₄)δppm 1.48(s，3H)1.56(s，3H)1.83(d，J＝4.55Hz，1H)1.90(d，J＝4.55Hz，1H)3.30-3.37(m，2H)3.76(t，J＝5.68Hz，2H)6.84(dd，J＝8.59，4.55Hz，1H)6.91-6.99(m，2H)7.03(dd，J＝8.84，2.27Hz，1H)7.33(s，1H)7.47(s，1H)。

Example 138

(R) and (S) -methyl-3- (2-oxo-1, 3-Oxazolidin-3-yl) -5- (2-oxo-2 ', 3 ', 5 ', 6 ' -tetrahydrodispiro [ indole-3, 1 ' -cyclopropane-2 ', 4 ' -pyran]-1(2H) -yl) benzoate

According to scheme 2, from methyl-3-bromo-5- (2-oxo), as prepared in example 101The title compound was prepared in analogy to example 101 starting from oxazolidin-3-yl) benzoate, 4-methylenetetrahydro-2H-pyran, isatin (commercially available). C₂₅H₂₄ClN₂O₆Calculated LC/MS m/e of: 448, measured (M + H)⁺：449.2。¹HNMR(400MHz，DMSO-d₆)δppm 1.72-1.81(m，1H)1.83(d，J＝4.55Hz，1H)1.92-1.99(m，3H)2.07-2.15(m，1H)3.38-3.47(m，1H)3.51-3.57(m，1H)3.57-3.66(m，2H)3.90(s，3H)4.16(t，J＝7.83Hz，2H)4.49(t，J＝7.83Hz，2H)6.90(d，J＝7.83Hz，1H)7.08(t，J＝7.58Hz，1H)7.23(t，J＝7.71Hz，1H)7.29(d，J＝7.58Hz，1H)7.74(s，1H)7.93(s，1H)8.24(s，1H)。

Example 139

(1S, 2R) and (1R, 2S) -1 '- (3-fluorobenzyl) -2- (4-fluorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indoline ] -5' -carboxylic acid

Synthesis of (Z) -methyl-3- (4-fluorobenzylidene) -2-oxoindoline-5-carboxylic acid ester

To a solution of methyl-2-oxindole-5-carboxylate (4.764g) in EtOH (100mL) was added 4-fluoro-benzaldehyde (4.72mL) in one portion, followed by piperidine (790 μ L). The mixture was refluxed for 3 hours and the yellow precipitate was collected by filtration. The yellow product was used in the next step without further purification.

Synthesis of (1S, 2R) and (1R, 2S) -methyl-2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylate

A solution of dimethylmethyleneoxysulfonium was prepared under argon from 60% NaH mineral oil dispersion (88mg, 2.2mmol), trimethylsulfoxonium iodide (2.2mmol), and DMSO (10 mL). After 20min, a solution of (Z) -methyl-3- (4-fluorobenzylidene) -2-oxoindoline-5-carboxylate (594mg, 2mmol) in THF (5mL) was added dropwise over 20 min. After stirring at room temperature for 1 hour and at 50 ℃ for another 1 hour, the solution was poured into ice-cold water (20mL) and extracted with ether (3 × 20 mL). The combined ether extracts were washed with brine, dried and evaporated to an oil, which was isolated by flash column chromatography (gradient elution, 15-25% ethyl acetate in petroleum ether) to give the title compound as a white solid (317mg, 51% yield). C₁₈H₁₄FNO₃Calculated LC/MS m/e of: 311, actual measurement (M + H)⁺：312.6。

Synthesis of (1R, 2S) and (1S, 2R) -2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylic acid

To (1S, 2R) and (1R, 2S) -methyl-2- (4-fluorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -bis ] in methanol (1mL), water (0.1mL) at room temperatureHydroindoles]Lithium hydroxide (10mg) was added to a solution of the-5' -carboxylic acid ester (80 mg). The mixture was stirred at room temperature for 14 hours. The reaction was monitored by HPLC for completion. The solvent was removed under reduced pressure. The residue was dissolved in 2mL of DMF. Purification by preparative HPLC gave the title compound (30mg) as a white solid. C₁₇H₁₂FNO₃LC/MS M/e calculated 297, found (M-H)⁺：296。¹HNMR(400MHz，DMSO-d₆)δppm 1.99(dd，J＝9.09，4.80Hz，1H)2.35(dd，J＝8.08，4.80Hz，1H)，3.11(t，J＝8.46Hz，1H)6.65(d，J＝1.52Hz，1H)6.94(d，J＝8.08Hz，1H)7.14(t，J＝8.84Hz，2H)7.34(dd，J＝8.34，5.56Hz，2H)7.72(dd，J＝8.08，1.52Hz，1H)10.97(s，1H)12.36(br.s.，1H)。

Synthesis of (1R, 2S) and (1S, 2R) -methyl-1 '- (3-fluorobenzyl) -2- (4-fluorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indoline ] -5' -carboxylate

Mixing (1S, 2R) and (1R, 2S) -methyl-2- (4-fluorophenyl) -2 '-oxo spiro [ cyclopropane-1, 3' -indoline]-5' -Carboxylic acid ester (500mg, 1.61mmol), 1-bromomethyl-2-fluoro-benzene (456mg, 2.14mmol) and Cs₂CO₃(785mg, 4.2mmol) was mixed in anhydrous DMF and stirred at room temperature for 8 h. The reaction was monitored by HPLC for completion. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (gradient elution, 15-25% ethyl acetate in petroleum ether) to give the title compound as a white solid (405mg, 60%). C₂₅H₁₉F₂NO₃LC/MS M/e calculated 420, found (M + H)⁺: 420.5. synthesis of (1R, 2S) and (1S, 2R) -1 ' - (3-fluorobenzyl) -2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-5' -carboxylic acid

To (1R, 2S) and (1S, 2R) -methyl-1 ' - (3-fluorobenzyl) -2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline in methanol (5mL), THF (5mL) and water (1mL) at room temperature]Lithium hydroxide (50mg) was added to a solution of the-5' -carboxylic acid ester (50 mg). The mixture was heated to 60 ℃ and stirred at 60 ℃ for 3 hours. The reaction was monitored by HPLC for completion. The solvent was removed under reduced pressure. Purification by preparative HPLC gave the title compound (10mg) as a white powder. C₂₄H₁₇F₂lNO₃Calculated LC/MS m/e of: 405, actual measurement (M + H)⁺：406.2。¹H NMR(400MHz，MeOD)δppm 7.83(dd，J＝8.34，1.52Hz，1H)7.24-7.38(m，5H)7.15(d，J＝2.02Hz，1H)7.18(d，J＝7.83Hz，2H)7.06(t，J＝8.72Hz，2H)6.99(d，J＝8.08Hz，1H)6.75(d，J＝1.52Hz，1H)5.17(s，2H)2.24-2.35(m，2H)；MS：C₂₄H₁₇F₂NO₃Calculated value 406, actual measurements (ESI)⁺)[(M+H)⁺]406.4。

Example 140

(1R, 2R) and (1S, 2S) -1 '- (2-fluorobenzyl) -2- (4-fluorophenyl) -2' -oxospiro [ cyclopropane-1, 3 '-indoline ] -5' -carboxylic acid

The title compound was prepared in analogy to example 139, starting from methyl-2-oxoindoline-5-carboxylate, 1- (bromomethyl) -3-fluorobenzene, 4-fluorobenzaldehyde (commercially available). C₂₄H₁₇F₂lNO₃Calculated LC/MS m/e of: 405, actual measurement (M + H)⁺：406.2。¹HNMR(400MHz，MeOD)δppm 7.96(dd，J＝8.34，1.52Hz，1H)7.80(d，J＝1.52Hz，1H)7.32(dd，J＝8.46，5.43Hz，3H)7.08-7.15(m，3H)7.02(t，J＝8.97Hz，3H)5.01(d，J＝16.93Hz，2H)4.93-5.09(m，1H)2.45(dd，J＝8.59，5.05Hz，1H)2.36(dd，J＝9.09，4.80Hz，1H)。

Example 141

(1R, 2R) and (1S, 2S) -2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylic acid

The title compound was prepared in analogy to example 139, starting from methyl-2-oxoindoline-5-carboxylate, 4-fluorobenzaldehyde (commercially available). C₁₇H₁₂FNO₃Calculated LC/MS m/e of: 297, actual measurement (M + H)⁺：298.2。¹HNMR(400MHz，DMSO-d₆)δppm 2.19-2.31(m，2H)3.31(s，1H)6.95(d，J＝8.08Hz，1H)7.08(t，J＝8.84Hz，2H)7.33(dd，J＝8.59，5.56Hz，2H)7.69(d，J＝1.52Hz，1H)7.83(dd，J＝8.21，1.64Hz，1H)10.72(s，1H)。

Example 142

(1R, 2S) and (1S, 2R) -2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylic acid

The title compound was prepared in analogy to example 139, starting from methyl-2-oxoindoline-5-carboxylate, 4-formylbenzonitrile (commercially available). C₁₈H₁₂N₂O₃Calculated LC/MS m/e of: 304, actual measurement (M + H)⁺：305.2。¹HNMR(400MHz，DMSO-d₆)δppm 2.02(dd，J＝8.84，5.05Hz，1H)2.49(s，1H)3.19(t，J＝8.59Hz，1H)6.67(d，J＝1.26Hz，1H)6.94(d，J＝8.08Hz，1H)7.55(d，＝8.08Hz，2H)7.72(dd，J＝8.21，.64Hz，1H)7.79(d，J＝8.34Hz，2H)11.01(br.s.，1H)12.40(br.s.，1H)。

Example 143

(1R, 2R) and (1S, 2S) -2- (4-cyanophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylic acid

The title compound was prepared in analogy to example 139, starting from methyl-2-oxoindoline-5-carboxylate, 4-formylbenzonitrile. C₁₈H₁₂N₂O₃Calculated LC/MS m/e of: 304, actual measurement (M + H)⁺：305.2。¹HNMR(400MHz，DMSO-d₆)δppm 2.29-2.37(m，2H)3.45(t，J＝8.72Hz，1H)6.96(d，J＝8.08Hz，1H)7.52(d，J＝8.34Hz，2H)7.73(dd，J＝4.93，3.41Hz，3H)7.85(dd，J＝8.21，1.64Hz，1H)10.77(br.s.，1H)。

Example 144

(1S, 2R) and (1R, 2S) -2- (4-fluorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline ] -5 ' -carboxylic acid

To (1R, 2S) and (1S, 2R) -methyl-2- (4-fluorophenyl) -2 '-oxospiro [ cyclopropane-1, 3' -indoline in methanol (1mL) and water (0.1mL) at room temperature]To a solution of the-5' -carboxylic acid ester (80mg) (as prepared in example 139) was added lithium hydroxide (10 mg). The mixture was stirred at room temperature for 14 hours. The reaction was monitored by HPLC for completion. The solvent was removed under reduced pressure. Purification by preparative HPLC gave the title compound as a white solid (30 mg). C₁₇H₁₂FNO₃Calculated LC/MS m/e of: 297, actual measurement (M + H)⁺：298.2。C₁₇H₁₂FNO₃Calculated LC/MS m/e of: 297.08, actual measurement (M-H)⁺：296.1；¹HNMR(400MHz，DMSO-d₆)δppm 1.99(dd，J＝9.09，4.80Hz，1H)2.35(dd，J＝8.08，4.80Hz，1H)，3.11(t，J＝8.46Hz，1H)6.65(d，J＝1.52Hz，1H)6.94(d，J＝8.08Hz，1H)7.14(t，J＝8.84Hz，2H)7.34(dd，J＝8.34，5.56Hz，2H)7.72(dd，J＝8.08，1.52Hz，1H)10.97(s，1H)12.36(br.s.，1H)。

Example 145

Evaluation of AMPK modulators by analysis of AMPK and ACC phosphorylation

This method uses western blot analysis to assess endogenous expression and phosphorylation of AMP-activated protein kinase (AMPK) and Acetyl CoA Carboxylase (ACC) in the L6 cell line. It is used to determine the efficacy and efficacy of small molecule AMPK modulators.

L6 cells (ATCC) were cultured and maintained in DMEM (high glucose, Gibco, BRL) containing 10% fetal bovine serum (FBS, Hyclone). In the assay, cells were plated at 3 × 10⁶The plates were in 10ml on 10cm dishes and they reached 70-80% sub-confluence within 24 hours. Cells were subjected to overnight serum starvation prior to treatment with AMPK modulators. The compound concentration is usually in the range of 0 to 100. mu.M and the cells are treated for 1-4 hours. Once incubation was complete, the medium was aspirated and the cell layer was gently washed with 2ml ice-cold PBS. 500ul of a solution containing 150mM NaCl, 5mM EDTA, 2mM EGTA, 25mM NaF, 2mM Na was added₃VO₄1mg/ml Pefabloc, 1% Triton X-100 and Roche Complete Protease Inhibitor Tablet and incubating it on ice for 10 min. After collection of the cell lysate, it was centrifuged at 12,000rpm for 10min at 4 ℃. The supernatant was retained and its protein concentration was determined using the Quick Start Bradford protein quantitation kit (Bio-Rad). Loading 40 μ g was used for 7.5% SDS-PAGE analysis before blotting onto PVDF membranes following standard procedures. The membrane was treated with blocking buffer (5% skim milk) at room temperature with stirring for 1 h. phospho-AMPK alpha (Thr172) (40H9) rabbit mAb (Cell Signaling) and phospho-acetyl CoA carboxylase (Ser79) antibody (Cell Signaling) were used as aanti-AMPK and phospho-ACC levels were determined by incubating the blot overnight at 4 ℃. Blots were stripped and re-probed using acetyl CoA carboxylase (C83B10) rabbit mab (Cell Signaling), AMPK (23A3) rabbit mab (Cell Signaling), and beta actin antibody (Cell Signaling) to determine overall protein levels for ACC, AMPK, and beta actin, respectively. Individual protein bands in the blot were visualized using ECL Plus western blot detection kit (Amersham) and quantified by scanning analysis. Semi-quantitatively determining EC₅₀Values (defined as the concentration of activator that produces half of the highest level of protein phosphorylation) and Emax (defined as the maximum phosphorylation at infinite activator concentration) were recorded.

All compounds of formula (I) were active in the AMPK and ACC phosphorylation assays described above.

Example 146

Scintillation Proximity Assay (science Proximity Assay)

Preparation of enzymes

Recombinant human AMPK α 1 β 1 γ 1, α 2 β 1 γ 1 or AMPK α subunit truncate α 1(1-335), α 1(1-394) and α 2(1-394) or from Invitrogen (San Diego, CA, u.s.a.). rat liver AMPK heterologous enzyme was obtained from Upstate (Billerica, MA, u.s.a.) (ping, t., Zhang, z.s., Gu, m., Qiu, b.y., Yu, l.f., Cao, p.r., Shao, w., Su, m.b., Li, j.y., Nan, f.j., and Li, J. (2008)) construction, expression and purification.

Scintillation proximity assay

Prior to Scintillation Proximity Assay (SPA), 200nM recombinant AMPK protein (. alpha.1beta1gamma1,. alpha.2beta1gamma1,. alpha.1 (1-335),. alpha.1 (1-394), or. alpha.2 (1-394)) was fully phosphorylated as described previously (Pang et al, 2008). In 96-well plates, 50. mu.l final volume (containing 20mM Tris-HCl pH 7.5, 5mM MgCl)₂1mM DTT, 2. mu.M biotin-SAMS, 2. mu.M ATP, 0.2. mu. Ci/well [ gamma-³³p]ATP and varying amounts of activator) were subjected to the SPA reaction. By adding 50nM recombinant AM to the reaction solutionThe PK protein allowed the reaction to start and incubate for 2hr at 30 ℃. Thereafter, the reaction was terminated by adding 40. mu.l of a termination solution containing 80. mu.g of streptavidin-coated SPA beads (beads) in PBS (pH 7.5), 50mM EDTA, 0.1% Triton X-100 and incubating for 1 hr. Finally, 160. mu.l of a suspension solution containing 2.4MCsCl, 50mM EDTA and 0.1% Triton X-100 in PBS (pH 7.5) was added to the reaction solution to completely suspend the SPA microbeads. After 30min, the SPA signal was measured using a Wallac MicroBeta plate counter (PerkinElmer) for calculating the amount of product formed. The amount of product formed in 2 hours was plotted against the activator concentration to determine the effective concentration of activator (EC) required for 50% of maximum enzyme activity₅₀)。

EC of the Compounds described above₅₀Values were between 0.5uM and 50 uM. Preferred compounds have an EC between 0.5uM and 10uM₅₀The value is obtained. Particularly preferred compounds have an EC between 0.5uM and 1uM₅₀The value is obtained. These results have been obtained by using the scintillation proximity assay described above (uM stands for micromolar).

EC of the particular compound of formula (I) obtained₅₀Values are listed in the table below.

Examples	EC₅₀(uM)
		Example 1	2.57
Example 2	0.96
		Example 3	2.98
Example 4	2.2
		Example 5	5.3
Example 6	7.1
		Example 7	10.85
Example 8	2.77
		Example 9	1.19
Example 10	2.02
		Example 11	2.04
Example 12	2.36
		Example 13	3.23
Example 14	2.03
		Example 15	2.48
Example 16	2.72
		Example 17	1.63
Example 18	1.66
		Example 19	1.42
Example 20	0.90
		Example 21	2.03
Example 22	11.16
		Example 23	1.66

Example 24	5.75
		Example 26	1.79
Example 60	3.5
		Example 61	8.67
Example 62	6.57
		Example 63	1.54
Example 64	1.6
		Example 65	1.71
Example 66	1.07
		Example 67	2.29
Example 68	2.8
		Example 70	1.54
Example 71	3.2
		Example 72	4.1
Example 73	1.65
		Example 74	8.8
Example 75	5.91
		Example 76	1.09
Example 77	2.17
		Example 78	4.2
Example 79	2.6
		Example 80	1.25
Example 81	2.22
		Example 82	4.03

Example 83	2.59
		Example 84	2.98
Example 85	0.95
		Example 86	1.73
Example 87	6.73
		Example 88	2.56
Example 89	1.40
		Example 90	1.47
Example 91	1.55
		Example 92	0.87
Example 93	0.91
		Example 94	1.50
Example 110	1.37
		Example 111	1.29
Example 112	1.27
		Example 113	1.84
Example 114	6.48
		Example 115	5.14
Example 116	4.33
		Example 117	0.99
Example 124	5.4
		Example 125	1.75
Example 126	1.7
		Example 127	4.5

Example 128	2.04
		Example 129	1.68
Example 130	1.10
		Example 131	3.27
Example 132	1.55

Example A

The compounds of formula (I) can be used in a manner known per se as active ingredients for the preparation of tablets having the following composition:

example B

The compounds of formula (I) can be used in a manner known per se as active ingredients for the preparation of capsules having the following composition:

Claims

1. A compound of formula (I)

Wherein

R³is hydrogen, pyridyl, piperidinyl, carboxypyridinyl, tetrahydropyranyl, alkylamino, morpholinyl, morpholinylalkylamino, alkylmorpholinylalkylamino, alkylsulfonylpiperidinyl, alkylpiperazinyl, alkylaminoalkylpiperazinyl, pyridylpiperazinyl, alkylaminopyrrolidinyl, 1H-imidazolyl, carboxyalkyl-1H-imidazolyl, carboxy-1H-imidazolyl, cycloalkylsulfonylaminocarbonylpyridinyl or substituted phenyl, wherein substituted phenyl is phenyl substituted with one or two substituents independently selected from: alkyl, halogen, hydroxyalkylamino, carboxyl, alkylsulfonyl, alkylaminocarbonyl, alkylsulfonylaminocarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, pyridylpiperazinylcarbonyl, alkylpiperazinylcarbonyl, alkylsulfonylpiperazinylcarbonyl, alkylpyrrolidinylalkylaminocarbonyl, alkyl-1H-pyrazolylaminocarbonyl, oxo-Oxazolidinyl, oxo-pyrrolidinyl, oxo-imidazolidinyl, morpholinylalkylaminocarbonyl, alkylaminoalkylpiperazinocarbonyl, cycloalkyl-1H-pyrazolyl aminocarbonyl, and cycloalkylsulfonyl aminocarbonyl;

n is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt or ester thereof.

2. The compound of claim 1, wherein R¹And R²One of which is selected from hydrogen and alkyl and the other is selected from pyridyl, halophenyl, alkylsulfonylphenyl, cyanophenyl and trifluoromethylphenyl.

3. The compound of any one of claims 1 or 2, wherein R¹And R²One of them is selectedFrom hydrogen and isopropyl and the other is selected from pyridyl, fluorophenyl, chlorophenyl, cyanophenyl, methylsulfonylphenyl and trifluoromethylphenyl.

4. The compound of any one of claims 1-3, wherein R³Is pyridyl, carboxypyridyl, tetrahydropyranyl, dialkylamino, morpholinyl, alkylsulfonylpiperidinyl, alkylpiperazinyl, dialkylaminoalkylpiperazinyl, dialkylaminopyrrolidinyl, carboxyalkyl-1H-imidazolyl, carboxy-1H-imidazolyl or substituted phenyl, wherein substituted phenyl is phenyl substituted with one or two substituents independently selected from: alkyl, halogen, carboxyl, alkylsulfonyl, alkylaminocarbonyl, alkylsulfonylaminocarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, pyridylpiperazinylcarbonyl, alkylpiperazinylcarbonyl, alkylsulfonylpiperazinylcarbonyl, alkylpyrrolidinylalkylaminocarbonyl, alkyl-1H-pyrazolylaminocarbonyl, oxo-Oxazolidinyl, oxo-pyrrolidinyl, and oxo-imidazolidinyl.

5. The compound of any one of claims 1-4, wherein R³Is carboxypyridyl, carboxyalkyl-1H-imidazolyl, carboxyphenyl or substituted by carboxy and oxoAn oxazolidinyl substituted phenyl.

6. The compound of any one of claims 1-5, wherein R⁴Is hydrogen, halogen or carboxyl.

7. According to any one of claims 1-6The compound of (1), wherein R⁴Is hydrogen, fluorine, chlorine or carboxyl.

8. The compound of any one of claims 1-7, wherein n is 0 or 1.

9. The compound according to any one of claims 1 to 8, selected from

3- (((1S, 2R) -2- (4-chlorophenyl) -2 ' -oxospiro [ cyclopropane-1, 3 ' -indolin ] -1 ' -yl) methyl) -N- (2- ((S) -1-methylpyrrolidin-2-yl) ethyl) benzamide

(1R, 2S) -3- (2- (4-chloro)Phenyl) -5 ' -fluoro-2-isopropyl-2 ' -oxospiro [ cyclopropane-1, 3 ' -indoline]-1' -yl) -5- (2-oxoOxazolidin-3-yl) benzoic acid;

10. The compound according to any one of claims 1 to 9, selected from

11. A process for the preparation of a compound of formula (I) according to any one of claims 1-10, comprising one of the following steps:

a) a compound of formula (A)

At R⁶R⁷Reaction in the presence of NH and a coupling agent;

b) a compound of formula (B)

In Y-CH₂-R and a base;

c) a compound of formula (C)

At R⁶R⁷Reaction in the presence of NH and a base;

d) a compound of formula (D)

At R⁶R⁷Reaction in the presence of NH and a reducing agent;

e) a compound of formula (E)

In the presence of a compound of formula (E1)

And in the presence of a base;

f) a compound of formula (F)

Reaction in the presence of a base;

g) a compound of formula (G)

Reaction in the presence of a base;

12. A compound according to any one of claims 1-10 for use as therapeutically active substance.

13. A pharmaceutical composition comprising a compound according to any one of claims 1-10 and a therapeutically inert carrier.

14. The use of a compound according to any one of claims 1-10 for the preparation of a medicament for the treatment or prophylaxis of obesity, hyperglycemia, dyslipidemia, type 1 or type 2 diabetes.

15. A compound according to any one of claims 1 to 10, when manufactured according to a process of claim 11.

16. A method for the treatment or prophylaxis of obesity, hyperglycemia, dyslipidemia, type 1 or type 2 diabetes, which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 10.

17. The invention as hereinbefore described.