CN102656147A - Spiro indole-cyclopropane indolinones useful as AMPK modulators - Google Patents

Abstract

A compound of formula (I) as well as pharmaceutically acceptable salt thereof, wherein R1 to R4 have the significance given in claim 1, can be used as a modulator of AMPK.

Description

Spiroindole-cyclopropaneindolinones useful as AMPK modulators

The present invention relates to compounds which are activators of AMP-activated protein kinase (AMPK) and which can be used in the treatment or prevention of diseases associated with AMPK modulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or 2 type diabetes.

The present invention relates especially to compounds of formula (I)

in

R ^and R are ^{independently} selected from hydrogen, alkyl, pyridyl, phenyl, halophenyl, alkoxyphenyl, alkylsulfonylphenyl, cyanophenyl and trifluoromethylphenyl;

Or R ¹ and R ² form cycloalkyl or tetrahydropyranyl together with the carbon atoms they are bound to;

唑烷基、氧代-吡咯烷基、氧代-咪唑烷基、吗啉基烷基氨基羰基、烷基氨基烷基哌嗪基羰基、环烷基-1H-吡唑基氨基羰基和环烷基磺酰基氨基羰基； ^R3 is hydrogen, pyridyl, piperidinyl, carboxypyridyl, tetrahydropyranyl, alkylamino, morpholinyl, morpholinylalkylamino, alkylmorpholinylalkylamino, alkylsulfonyl Piperidinyl, alkylpiperazinyl, alkylaminoalkylpiperazinyl, pyridylpiperazinyl, alkylaminopyrrolidinyl, 1H-imidazolyl, carboxyalkyl-1H-imidazolyl, carboxy-1H- imidazolyl, cycloalkylsulfonylaminocarbonylpyridyl or substituted phenyl, wherein the substituted phenyl is phenyl substituted by one or two substituents independently selected from the following groups: alkyl, halogen, Hydroxyalkylamino, Carboxyl, Alkylsulfonyl, Alkylaminocarbonyl, Alkylsulfonylaminocarbonyl, Piperidinylcarbonyl, Piperazinylcarbonyl, Morpholinylcarbonyl, Pyridylpiperazinylcarbonyl, Alkylpiperazine Alkylcarbonyl, alkylsulfonylpiperazinylcarbonyl, alkylpyrrolidinylaminocarbonyl, alkyl-1H-pyrazolylaminocarbonyl, oxo-

Oxazolidinyl, oxo-pyrrolidinyl, oxo-imidazolidinyl, morpholinylalkylaminocarbonyl, alkylaminoalkylpiperazinylcarbonyl, cycloalkyl-1H-pyrazolylaminocarbonyl and cycloalkane Sulfonylaminocarbonyl;

^R is hydrogen, halogen, carboxy, cyano, trifluoromethyl or alkylsulfonyl; and

n is 0, 1, 2 or 3;

or their pharmaceutically acceptable salts or esters.

The invention also relates to processes for the preparation of these novel compounds and medicaments containing them. The compounds of the present invention have an activating effect on AMP (adenosine monophosphate)-activated protein kinase, which leads to decreased blood glucose. The present invention therefore also relates to the use of these compounds for the treatment or prevention of diseases 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 disease are diseases characterized by severe disturbances in glucose or lipid metabolism that seriously affect the health and quality of life of the individual patient. The increasing prevalence of these diseases makes finding new drug targets for the treatment of these syndromes an urgent task.

AMP-activated protein kinase acts as an energy sensor and regulator of the cell. It is activated by an increase in the cellular AMP:ATP ratio triggered by metabolic stress, hormones and nutritional signals. Once activated, AMPK switches on ATP-producing catabolic pathways and switches off ATP-consuming anabolic pathways through acute regulation of key enzyme activities in metabolism and chronic regulation of key transcription factor expression (Hardie, DG. Nature reviews) 8 (2007b), 774-785; Woods, A et al., Molecular and cellular biology 20 (2000), 6704-6711). Evidence of increased AMPK regulation of glucose and lipid metabolism makes it a potential drug target for the treatment of diabetes and metabolic syndrome (Carling, D. Trends Biochem Sci (Biochemical Science Trends) 29 (2004), 18- 24; Hardie, DG. Annual review of pharmacology and toxicology (Annual Review of Pharmacology and Toxicology) 47 (2007a), 185-210; Kahn, BB et al., Cell metabolism (2005), 15-25; Long, YC et al., The Journal of clinical investigation 116 (2006), 1776-1783).

At the physiological level, this concept has been supported by two adipokines, leptin and adiponectin, which have excellent effects on glucose and lipid metabolism (Friedman, JM and Halaas, JL. Nature (Nature) 395 (1998), 763-770; Muoio, DM et al., Diabetes (1997), 1360-1363; Yamauchi, T et al., Nature medicine (Nature - Medicine) 7 (2001), 941-946 ). Recent studies imply that leptin and adiponectin exert their antidiabetic effects by activating AMPK. Leptin stimulates muscle fatty acid oxidation by directly activating AMPK and via the hypothalamic adrenergic pathway (Minokoshi, Y et al., Nature 415 (2002), 339-343). Adiponectin stimulates glucose uptake and fatty acid oxidation in vitro by activating AMPK. In addition, it exerts its hypoglycemic effect by reducing the expression of PEPCK and G6Pase, and administration of dominant negative α1 adenovirus reverses this effect in vivo (Yamauchi, T et al., Nature medicine (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 discovery that two main classes of existing antidiabetic drugs, the thiazolidinediones (rosiglitazone ( rosiglitazone), troglitazone and pioglitazone) and biguanides (metformin and phenformin) activate AMPK in cultured cells as well as in vivo. It is traditionally believed that rosiglitazone is a PPARγ agonist and exerts its antidiabetic effect through the differentiation of adipocytes (Semple, RK, etc., The Journal of clinical investigation (Clinical Research Journal) 116 (2006), 581-589 ). Recent findings suggest that AMPK may be involved in the antidiabetic effects of rosiglitazone (Brunmair, B et al, The Journal of biological chemistry (Biochemical Journal) 277 (2002), 25226-25232; Kadowaki, T et al, The Journal of clinical investigation (Journal of Clinical Investigation) 116 (2006), 1784-1792). In the case of metformin, an existing antidiabetic drug with an unexplained mechanism of action, recent studies demonstrated its ability to activate AMPK in vitro and in vivo by inhibiting complex I (El-Mir, MY et al., The Journal of biological chemistry (biochemical journal) 275 (2000), 223-228; Owen, MR et al., The Biochemical journal (biochemical journal) 348Pt 3 (2000), 607-614; Zhou, G et al., The Journal of clinical investigation (clinical Research Journal) 108 (2001), 1167-1174), and can completely prevent the hypoglycemic effect by knocking out its upstream kinase LKB1, demonstrating the key role of AMPK in mediating the antidiabetic effects of metformin (Shaw, RJ et al. , Science (New York) N.Y. 310 (2005), 1642-1646).

Recently, Cool and colleagues have identified a small direct AMPK activator, A-769662, which exerts antidiabetic effects in vivo (Cool, B et al., Cell metabolism 3 (2006), 403-416). The Jia Li lab has identified a small AMPK activator, PT1, which activates inactive forms of AMPK α2 ₃₉₈ and α1 ₃₉₄ with micromolar activity and exerts certain cellular effects (Pang, T et al., The Journal of biological chemistry ( Journal of Biochemistry) 283 (2008), 16051-16060).

The compounds of the present invention have been found to be potent AMPK activators. Therefore, the compounds of the present invention can be used for the treatment or prevention of diseases associated with the regulation of AMPK, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes and cancer.

As used herein, the term "alkyl", alone or in combination, means a saturated, straight or branched chain alkane containing 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon atoms radicals, such as methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, tert-butyl, etc. Preferred "alkyl" groups are methyl, ethyl, isopropyl, tert-butyl.

The term "alkoxy", alone or in combination, denotes the group alkyl-O-, wherein "alkyl" is defined above; for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, 2-butoxy, tert-butoxy, etc. 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, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl, etc. Preferred cycloalkyl groups are cyclopropyl and cyclopentyl, with cyclopropyl being especially 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 ( _-NH2- ), secondary (-NH-) or tertiary (-N-) amino group.

The term "hydroxyl", 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 exist 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 compounds of formula (I) and are prepared from suitable nontoxic organic or inorganic acids or organic or inorganic bases. form. Acid addition salts include, for example, those derived from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric and nitric acids, and from organic acids such as p-toluenesulfonic, salicylic, methanesulfonic, acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. Base addition salts include those derived from ammonium, potassium, sodium and quaternary ammonium hydroxides such as, for example, tetramethylammonium hydroxide. The chemical modification of pharmaceutical compounds into salts is a technique known to medicinal chemists for obtaining improved physical and chemical stability, hygroscopicity, flow and solubility of compounds. It is described, for example, in Bastin R.J. et al., Organic Process Research & Development (Organic Process Research & Development) 2000, 4, 427-435; or Ansel, H. et al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems (pharmaceutical dosage forms and drug delivery systems), It is described in 6th Edition (1995), pages 196 and 1456-1457. Preferred are the sodium salts of compounds of formula (I).

"Pharmaceutically acceptable ester" means that a compound of general formula (I) can be derivatized at a functional group to provide a derivative that can be converted back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically unstable ester derivatives such as methoxymethyl ester, methylthiomethyl ester and pivaloyloxymethyl ester. Furthermore, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, capable of producing the parent compound of general formula (I) in vivo, fall within the scope of the present invention. Preferred are the methyl and ethyl esters of compounds of formula (I).

Especially preferred are compounds of formula (I), wherein

R ^and R are ^{independently} selected from hydrogen, alkyl, pyridyl, phenyl, halophenyl, alkoxyphenyl, alkylsulfonylphenyl, cyanophenyl and trifluoromethylphenyl;

Or R ¹ and R ² , together with the carbon atoms to which they are bound, form cycloalkyl or tetrahydropyranyl;

唑烷基、氧代-吡咯烷基和氧代-咪唑烷基；R ³ is pyridyl, carboxypyridyl, tetrahydropyranyl, dialkylamino, morpholinyl, alkylsulfonylpiperidinyl, alkylpiperazinyl, dialkylaminoalkylpiperazinyl, dialkylaminoalkylpiperazinyl, Alkylaminopyrrolidinyl, carboxyalkyl-1H-imidazolyl, carboxy-1H-imidazolyl or substituted phenyl, wherein the substituted phenyl is substituted by one or two substituents independently selected from the following groups Phenyl: alkyl, halogen, carboxyl, alkylsulfonyl, alkylaminocarbonyl, alkylsulfonylaminocarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, pyridylpiperazinylcarbonyl, Alkylpiperazinylcarbonyl, alkylsulfonylpiperazinylcarbonyl, alkylpyrrolidinylaminocarbonyl, alkyl-1H-pyrazolylaminocarbonyl, oxo-

Oxazolidinyl, oxo-pyrrolidinyl and oxo-imidazolidinyl;

^R is hydrogen, halogen, cyano, trifluoromethyl or alkylsulfonyl; and

n is 0, 1, 2 or 3;

or their pharmaceutically acceptable salts or esters.

Preference is given to compounds according to formula (I), wherein one of R ^{and R} is selected from hydrogen and alkyl and the other is selected from pyridyl, halophenyl, alkylsulfonylphenyl, cyanophenyl and Trifluoromethylphenyl, or R ¹ and R ² together with the carbon atoms they are bound to form cycloalkyl or tetrahydropyranyl;

Further preferred are compounds of formula (I), wherein one of R ^{and R} is selected from hydrogen and isopropyl and the other is selected from pyridyl, fluorophenyl, chlorophenyl, cyanophenyl, methyl Sulfonylphenyl and trifluoromethylphenyl.

唑烷基、氧代-吡咯烷基和氧代-咪唑烷基。Preference is given to compounds according to formula (I), wherein ^R is pyridyl, carboxypyridyl, tetrahydropyranyl, dialkylamino, morpholinyl, alkylsulfonylpiperidinyl, alkylpiperazinyl , dialkylaminoalkylpiperazinyl, dialkylaminopyrrolidinyl, carboxyalkyl-1H-imidazolyl, carboxy-1H-imidazolyl or substituted phenyl, wherein the substituted phenyl is independently selected Phenyl substituted with one or two substituents from the following groups: alkyl, halogen, carboxyl, alkylsulfonyl, alkylaminocarbonyl, alkylsulfonylaminocarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, Morpholinylcarbonyl, pyridylpiperazinylcarbonyl, alkylpiperazinylcarbonyl, alkylsulfonylpiperazinylcarbonyl, alkylpyrrolidinylaminocarbonyl, alkyl-1H-pyrazolylaminocarbonyl, oxygen generation-

Oxazolidinyl, oxo-pyrrolidinyl and oxo-imidazolidinyl.

唑烷基取代的苯基。Also preferred are compounds of formula (I), wherein R ³ is carboxypyridyl, carboxyalkyl-1H-imidazolyl, carboxyphenyl or is replaced by carboxy and oxo-

Azolidinyl-substituted phenyl groups.

Also preferred are compounds of formula (I), wherein R ⁴ is hydrogen, halogen, cyano, trifluoromethyl or alkylsulfonyl.

Also preferred are compounds of formula (I), wherein R ⁴ is hydrogen, halogen, carboxy, cyano, trifluoromethyl or alkylsulfonyl.

Especially preferred are compounds of formula (I), wherein R ⁴ is hydrogen or halogen.

Especially preferred are compounds of formula (I), wherein R ⁴ is hydrogen, halogen or carboxy.

Further preferred are compounds of formula (I), wherein R ⁴ is hydrogen, fluoro or chloro.

Preference is given to 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′-indoline]-1′-yl)methyl)benzene formic acid;

(1S, 2R)-3-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1R,2R)-3-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1S, 2S)-3-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1S, 2R)-3-((2-(3-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1R, 2S)-3-((2-(3-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

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

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

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

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

(1S, 2R)-2-Chloro-5-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid;

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

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

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

(1S, 2R)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1R, 2S)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1S, 2S)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1R, 2R)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1S, 2R)-3-((2-(3-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1R, 2S)-3-((2-(3-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1S, 2S)-3-((2-(3-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1R, 2R)-3-((2-(3-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1S, 2S)-3-((2′-oxo-2-(2-(trifluoromethyl)phenyl)-spiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid;

(1R,2R)-3-((2′-oxo-2-(2-(trifluoromethyl)phenyl)-spiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(1S, 2R)-3-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1R, 2S)-3-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

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

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

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

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

(1S, 2S)-3-((2-(4-cyanophenyl)-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid;

(1R,2R)-3-((2-(4-cyanophenyl)-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid;

(1S,2R)-3-((2-(4-cyanophenyl)-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid;

(1R,2S)-3-((2-(4-cyanophenyl)-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid;

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

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

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

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

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

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

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

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

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

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

(1S, 2S)-3-((2-(3-fluorophenyl)-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid;

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

(1S,2S)-3-((2-(3-Chlorophenyl)-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(1S,2R)-2-(4-Chlorophenyl)-1′-(3-(piperidine-1-carbonyl)benzyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone;

(1R,2S)-2-(4-Chlorophenyl)-1′-(3-(piperidine-1-carbonyl)benzyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone;

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

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

(1S,2R)-2-(4-Chlorophenyl)-1′-(3-(piperazine-1-carbonyl)benzyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone;

(1R,2S)-2-(4-Chlorophenyl)-1′-(3-(piperazine-1-carbonyl)benzyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone;

(1R,2S)-2-(4-Chlorophenyl)-1′-(3-(morpholine-4-carbonyl)benzyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone;

(1S,2R)-2-(4-Chlorophenyl)-1′-(3-(morpholine-4-carbonyl)benzyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone;

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

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

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

(1R,2S)-2-(4-Chlorophenyl)-1′-(3-(4-isopropylpiperazine-1-carbonyl)benzyl)spiro[cyclopropane-1,3′-dihydro Indole]-2'-one;

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

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

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

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

(1S,2R)-6-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid;

(1R,2S)-6-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid;

(1S, 2R)-6-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid;

(1R,2S)-6-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid;

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

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

(1S,2R)-2-(4-Chlorophenyl)-1′-(2-(diethylamino)ethyl)spiro[cyclopropane-1,3′-indoline]-2′- ketone;

(1R,2S)-2-(4-Chlorophenyl)-1′-(2-(diethylamino)ethyl)spiro[cyclopropane-1,3′-indoline]-2′- ketone;

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

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

(1S,2R)-2-(4-Chlorophenyl)-1′-((1-(methylsulfonyl)piperidin-4-yl)methyl)spiro[cyclopropane-1,3′-di Indoline]-2'-one;

(1R,2S)-2-(4-Chlorophenyl)-1′-((1-(methylsulfonyl)piperidin-4-yl)methyl)spiro[cyclopropane-1,3′-di Indoline]-2'-one;

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

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

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

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

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

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

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

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

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

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

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

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

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

(1R,2S)-2-(4-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-1H -imidazol-1-yl)acetic acid;

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

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

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

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

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

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

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

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

(1S, 2S)-2-(4-Chlorophenyl)-1′-(3-(morpholine-4-carbonyl)phenyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone;

(1R,2R)-2-(4-chlorophenyl)-1′-(3-(morpholine-4-carbonyl)phenyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone;

(1S,2S)-2-(4-Chlorophenyl)-1′-(3-(4-methylpiperazine-1-carbonyl)phenyl)spiro[cyclopropane-1,3′-indoline Indole]-2'-one;

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

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

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

(1R,2S)-2-(4-Chlorophenyl)-1′-(3-(morpholine-4-carbonyl)phenyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone;

(1S,2R)-2-(4-Chlorophenyl)-1′-(3-(morpholine-4-carbonyl)phenyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone;

(1S,2R)-2-(4-Chlorophenyl)-1′-(3-(4-methylpiperazine-1-carbonyl)phenyl)spiro[cyclopropane-1,3′-indoline Indole]-2'-one;

(1R,2S)-2-(4-Chlorophenyl)-1′-(3-(4-methylpiperazine-1-carbonyl)phenyl)spiro[cyclopropane-1,3′-indoline Indole]-2'-one;

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

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

(1R, 2R)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-N-(methyl (sulfonyl) benzamide;

(1S, 2S)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-N-(methyl (sulfonyl) benzamide;

唑烷-3-基)苯甲酸；(1S, 2S)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2 -oxo

oxazolidin-3-yl) benzoic acid;

唑烷-3-基)苯甲酸；(1R, 2R)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2 -oxo

oxazolidin-3-yl) benzoic acid;

(1S, 2S)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(methyl sulfonyl) benzoic acid;

(1R, 2R)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(methyl sulfonyl) benzoic acid;

(1S, 2S)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2 -oxopyrrolidin-1-yl)benzoic acid;

(1R, 2R)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2 -oxopyrrolidin-1-yl)benzoic acid;

唑烷-3-基)苯甲酸；(1R,2R)-3-(2-(4-Chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline] -1′-yl)-5-(2-oxo

oxazolidin-3-yl) benzoic acid;

唑烷-3-基)苯甲酸；(1S,2S)-3-(2-(4-Chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline] -1′-yl)-5-(2-oxo

oxazolidin-3-yl) benzoic acid;

(1R,2S)-3-(2-(4-Chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline] -1′-yl)-5-(2-oxo oxazolidin-3-yl) benzoic acid;

唑烷-3-基)苯甲酸；(1S,2R)-3-(2-(4-Chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline] -1′-yl)-5-(2-oxo

oxazolidin-3-yl) benzoic acid;

唑烷-3-基)苯甲酸；(1R, 2R)-3-(2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl )-5-(2-oxo

oxazolidin-3-yl) benzoic acid;

唑烷-3-基)苯甲酸；(1S, 2S)-3-(2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl )-5-(2-oxo

oxazolidin-3-yl) benzoic acid;

唑烷-3-基)苯甲酸；(1S, 2S)-3-(2-(4-cyanophenyl)-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base)-5-(2-oxo

oxazolidin-3-yl) benzoic acid;

唑烷-3-基)苯甲酸；(1R,2R)-3-(2-(4-cyanophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'- base)-5-(2-oxo

oxazolidin-3-yl) benzoic acid;

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

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

唑烷-3-基)苯甲酸；(R)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-5-( 2-oxo

oxazolidin-3-yl) benzoic acid;

唑烷-3-基)苯甲酸；(S)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-5-( 2-oxo

oxazolidin-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;

唑烷-3-基)-5-(2-氧代-2″，3″，5″，6″-四氢二螺[吲哚-3，1′-环丙烷-2′，4″-吡喃]-1(2H)-基)苯甲酸；(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;

唑烷-3-基)-5-(2-氧代-2″，3″，5″，6″-四氢二螺[吲哚-3，1′-环丙烷-2′，4″-吡喃]-1(2H)-基)苯甲酸；(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′-indoline]-1′-yl) Methyl)benzoic acid;

(1R, 2R)-2-Chloro-5-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid;

(1R, 2S)-4-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1S, 2R)-4-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

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

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

(1R, 2S)-4-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1R, 2S)-4-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

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

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

(1R,2S)-3-((2-(3-Chloro-4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid;

(1S,2R)-3-((2-(3-Chloro-4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(1R, 2S)-6-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) -N-(cyclopropylsulfonyl)pyridinamide;

(1S, 2R)-6-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) -N-(cyclopropylsulfonyl)pyridinamide;

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

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

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

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

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

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

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

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

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

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

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

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

(1S,2R)-2-(4-Chlorophenyl)-1′-(2-(piperidin-1-yl)ethyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone;

(1R,2S)-2-(4-Chlorophenyl)-1′-(2-(piperidin-1-yl)ethyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone;

(1S,2R)-2-(4-Chlorophenyl)-1′-(2-(3-morpholinopropylamino)ethyl)spiro[cyclopropane-1,3′-indoline] -2'-one;

(1R,2S)-2-(4-Chlorophenyl)-1′-(2-(3-morpholinopropylamino)ethyl)spiro[cyclopropane-1,3′-indoline] -2'-one;

(1S,2R)-2-(4-Chlorophenyl)-1′-(2-(3-morpholinopropylamino)ethyl)spiro[cyclopropane-1,3′-indoline] -2'-one;

(1R,2S)-2-(4-Chlorophenyl)-1′-(2-(3-morpholinopropylamino)ethyl)spiro[cyclopropane-1,3′-indoline] -2'-one;

(1S,2R)-2-(4-Chlorophenyl)-1′-(2-(2-morpholinoethylamino)ethyl)spiro[cyclopropane-1,3′-indoline] -2'-one;

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

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

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

(1S, 2R)-2-(4-Chlorophenyl)-1′-(2-(2-(2,6-Dimethylmorpholino)ethylamino)ethyl)spiro[cyclopropane-1 , 3'-indoline]-2'-one;

(1R, 2S)-2-(4-Chlorophenyl)-1′-(2-(2-(2,6-Dimethylmorpholino)ethylamino)ethyl)spiro[cyclopropane-1 , 3'-indoline]-2'-one;

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

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

(1S, 2R)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-N-(form (sulfonyl) benzamide;

(1R, 2S)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-N-(form (sulfonyl) benzamide;

唑烷-3-基)苯甲酸；(1S, 2S)-3-(2-(4-Chlorophenyl)-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) -5-(2-oxo

oxazolidin-3-yl) benzoic acid;

唑烷-3-基)苯甲酸；(1R,2R)-3-(2-(4-Chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl) -5-(2-oxo

oxazolidin-3-yl) benzoic acid;

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

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

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

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

唑烷-3-基)苯甲酸酯；(R)-methyl-3-(2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-5-(2- Oxo

(oxazolidin-3-yl) benzoate;

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

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

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

唑烷-3-基)-5-(2-氧代-2″，3″，5″，6″-四氢二螺[吲哚-3，1′-环丙烷-2′，4″-吡喃]-1(2H)-基)苯甲酸酯；(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;

唑烷-3-基)-5-(2-氧代-2″，3″，5″，6″-四氢二螺[吲哚-3，1′-环丙烷-2′，4″-吡喃]-1(2H)-基)苯甲酸酯；(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' - formic acid;

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

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

(1S, 2S)-1'-(2-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5' - formic 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 the group consisting of:

(2S,1R)-3-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1S, 2R)-3-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1S, 2R)-3-((2-(3-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1R, 2S)-3-((2-(3-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

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

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

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

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

(1S, 2R)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1R, 2S)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1S, 2S)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1R, 2R)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1S, 2R)-3-((2-(3-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1R, 2S)-3-((2-(3-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1S, 2S)-3-((2′-oxo-2-(2-(trifluoromethyl)phenyl)-spiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid;

(1R,2R)-3-((2′-oxo-2-(2-(trifluoromethyl)phenyl)-spiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid;

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

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

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

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

(1S, 2R)-3-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1R, 2S)-3-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

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

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

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

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

(1S,2R)-6-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid;

(1R,2S)-6-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid;

(1S, 2R)-6-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid;

(1R,2S)-6-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid;

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

(1R,2S)-2-(4-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-1H -imidazol-1-yl)acetic acid;

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

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

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

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

唑烷-3-基)苯甲酸；(1S, 2S)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2 -oxo

oxazolidin-3-yl) benzoic acid;

(1R, 2R)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2 -oxo oxazolidin-3-yl) benzoic acid;

(1S,2S)-2-Chloro-5-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid;

(1R, 2R)-2-Chloro-5-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid;

(1R, 2S)-4-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1S, 2R)-4-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

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

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

(1R, 2S)-4-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

(1R, 2S)-4-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid;

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

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

(1R,2S)-3-((2-(3-Chloro-4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid;

(1S,2R)-3-((2-(3-Chloro-4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid;

(1R, 2S)-6-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) -N-(cyclopropylsulfonyl)pyridinamide;

(1S, 2R)-6-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) -N-(cyclopropylsulfonyl)pyridinamide;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

唑烷基、氧代-咪唑烷基。R⁶和R⁷独立地选自氢、烷基、环烷基、烷基磺酰基、环烷基磺酰基、氨基烷基和氨基环烷基。除非另外说明，R¹、R²、R³、R⁴和n如上所限定。The compounds of the invention may be prepared by any conventional means. Suitable methods for the synthesis of these compounds are provided in the schemes below. In the following schemes, R ⁵ is hydrogen, halogen, oxo-

Oxazolidinyl, oxo-imidazolidinyl. ^R6 and ^R7 are independently selected from hydrogen, alkyl, cycloalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminoalkyl and aminocycloalkyl. Unless otherwise stated, R ¹ , R ² , R ³ , R ⁴ and n are as defined above.

plan 1

Compounds of formula Ia and Ib can be prepared according to Scheme 1 . Intermediates IIIIII are prepared by condensation reactions between II and various aldehydes or ketones. Cyclopropanation of III provides intermediate IV. Alkylation between IV and bromide V affords ester VI. Esters VII can be obtained by introducing ^R5 into intermediate VI under copper salt catalyst. Hydrolysis of methyl ester VII yields the corresponding acid Ia. Amides Ib can be prepared by a coupling reaction between acids Ia and amines VIII.

Condensation reactions between II and different aldehydes are carried out overnight in refluxing toluene or refluxing alcohol when bases such as piperidine or pyrrolidine are used as catalysts.

Cyclopropanation of III is carried out in organic solvents such as DMSO at 50° for several hours by treatment of trimethylsulfoxide iodide with sodium hydride to generate sulfur ylides in situ.

烷、N，N-二甲基甲酰胺、二甲亚砜或N-甲基吡咯烷酮中，在100℃至180℃的温度，在微波照射下进行15至60分钟。备选地，该反应可以在加热的温度诸如80℃进行更长的反应时间而不进行微波照射。(Ley，S.V.等，Angew.Chem.Iht.Ed.(应用化学国际版)42(2003)5400)。In the third step outlined in _Scheme 1, _when n = 1, _IV and bromide V _are Alkylation of provides the methyl ester VI; when n = 0, it can be found in copper sources bound to ligands such as 2,2'-bipyridine, proline, N,N'-dimethylglycine or ethylene glycol In the presence of copper(I) iodide (CuI), in a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride or 1, Coupling of IV with aryl bromide VI was performed in the presence of 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-bis

alkanes, N,N-dimethylformamide, dimethylsulfoxide or N-methylpyrrolidone at a temperature of 100°C to 180°C under microwave irradiation for 15 to 60 minutes. Alternatively, the reaction can be carried out at a heated temperature such as 80°C for a longer reaction time without microwave irradiation. (Ley, SV et al., Angew. Chem. Iht. Ed. (International Edition of Applied Chemistry) 42 (2003) 5400).

烷、N，N-二甲基甲酰胺、二甲亚砜或N-甲基吡咯烷酮中在100℃至180℃的温度在微波照射下进行15至60分钟。备选地，该反应可以在加热的温度诸如80℃进行更长的反应时间而不进行微波照射。(Ley，S.V.等，Angew.Chem.Int.Ed.(应用化学国际版)42(2003)5400)。In the fourth step, copper (I) iodide (CuI) 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] In the presence of undec-7-ene (DBU), R ⁵ is 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-

alkanes, N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone at a temperature of 100°C to 180°C under microwave irradiation for 15 to 60 minutes. Alternatively, the reaction can be carried out at a heated temperature such as 80°C for a longer reaction time without microwave irradiation. (Ley, SV et al., Angew. Chem. Int. Ed. (International Edition of Applied Chemistry) 42 (2003) 5400).

烷或四氢呋喃中在室温进行若干小时以产生Ia的立体异构体。Hydrolysis of methyl ester VII can 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-di

Alkanes or tetrahydrofuran at room temperature for several hours to produce the stereoisomer of Ia.

六氟磷酸盐(PyBop)、o-(7-氮杂苯并三唑-1-基)-N，N，N’，N’-四甲基脲六氟磷酸盐(HATU)、o-(1H-苯并三唑-1-基)-N，N，N’，N’-四甲基脲六氟磷酸盐(HBTU)或1-乙基-3-(3’-二甲基氨基)碳二亚胺盐酸盐(EDCI)的存在下，在羟基苯并三唑(HOBt)或N，N-二甲基氨基吡啶(DMAP)的存在或不存在下，在碱诸如三乙胺或N，N-二异丙基乙胺的存在下进行。该反应可以在溶剂诸如二氯甲烷或N，N-二甲基甲酰胺中在室温进行若个小时(Montalbetti，C.A.G.N.等，Tetrahedron(四面体)61(2005)10827)。Conversion of acids 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 the presence of coupling reagents such as dicyclohexylcarbodiimide (DCC), benzotriazol-1-yl-oxy-tri-pyrrolidinyl

Hexafluorophosphate (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) In the presence of carbodiimide hydrochloride (EDCI), in the presence or absence of hydroxybenzotriazole (HOBt) or N,N-dimethylaminopyridine (DMAP), in the presence or absence of a base such as triethylamine or in the presence of N,N-diisopropylethylamine. The reaction can be performed in a solvent such as dichloromethane or N,N-dimethylformamide for several hours at room temperature (Montalbetti, CAGN et al., Tetrahedron 61 (2005) 10827).

Scenario 2

Compounds of formula Ic and Id can be prepared according to Scheme 2. Diazo compounds XXXIII can be obtained by treating isatin IX with p-toluenesulfonylhydrazide under basic conditions. Cyclopropanation of alkenes XI with diazo compounds XXXIII over a Rh catalyst provides intermediates XII. Alkylation or arylation of XII with bromide V affords methyl ester XIII. Introduction of ^R5 into XIII by using a copper salt as a catalyst leads to intermediate XIV.

烷或四氢呋喃中在室温进行若干小时。Hydrolysis of this methyl ester yields the corresponding acid Ic. The hydrolysis can 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-bis

Alkanes or tetrahydrofuran at room temperature for several hours.

六氟磷酸盐(PyBop)、o-(7-氮杂苯并三唑-1-基)-N，N，N’，N’-四甲基脲六氟磷酸盐(HATU)、o-(1H-苯并三唑-1-基)-N，N，N’，N’-四甲基脲六氟磷酸盐(HBTU)或1-乙基-3-(3’-二甲基氨基)碳二亚胺盐酸盐(EDCI)的存在下，在羟基苯并三唑(HOBt)或N，N-二甲基氨基吡啶(DMAP)的存在或不存在下，在碱诸如三乙胺或N，N-二异丙基乙胺的存在下进行。该反应可以在溶剂诸如二氯甲烷或N，N-二甲基甲酰胺中在室温进行若干小时(Montalbetti，C.A.G.N.等，Tetrahedron(四面体)61(2005)10827)。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 out in the presence of coupling reagents such as dicyclohexylcarbodiimide (DCC), benzotriazol-1-yl-oxy-tri-pyrrolidinyl

Hexafluorophosphate (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) In the presence of carbodiimide hydrochloride (EDCI), in the presence or absence of hydroxybenzotriazole (HOBt) or N,N-dimethylaminopyridine (DMAP), in the presence or absence of a base such as triethylamine or in the presence of N,N-diisopropylethylamine. This reaction can be carried out at room temperature for several hours in a solvent such as dichloromethane or N,N-dimethylformamide (Montalbetti, CAGN et al., Tetrahedron 61 (2005) 10827).

Option 3

Compounds of formula Ie can be prepared according to Scheme 3. Alkylation of IV with alkyl halides XIV using a base such as NaH, _K2CO3 or _Cs2CO3 in an organic solvent such as THF or _DMF at room _temperature for several hours affords compounds of formula le.

Option 4

Compounds of formula If can be prepared according to Scheme 4. Alkylation of _IV with bromide XVI using a base such as NaH, _K2CO3 or _Cs2CO3 in an organic solvent such as THF or _DMF at room temperature for several hours affords bromide XVII. If can be obtained by treatment of XVII with amine VIII under basic conditions such as NaH, _K2CO3 or _Cs2CO3 in _an organic solvent such as THF or _DMF at room temperature.

Option 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 give aldehyde XX. Amines Ig can be prepared by reductive amination between XX and various amines VIII.

In the first step shown in Scheme 5, the alkylation _between IV and iodide XVIII can be carried out by using a base such as NaH, _K2CO3 or _Cs2CO3 in an organic solvent such as THF, _DMF at room temperature several hours.

In the second step shown in Scheme 5, 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 with different amines VIII can be carried out at room temperature in organic solvents such as DCM, THF by using reducing agents such as _NaBH4 or NaHB(OAc) ₃ to provide formula Ig.

Option 6

Compounds of formula Ih and Ii can be prepared according to Scheme 6. Ih and Ii can be obtained by alkylation of _IV with XXI using a base such as NaH, _K2CO3 or _Cs2CO3 in an organic solvent such as THF or DMF at room _temperature for several hours.

Option 7

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, provides Ij. Subsequent alkylation with XXIII provides formula XXIV. Finally, hydrolysis of the methyl ester XXIV yields the corresponding acid Ik.

In the first step shown in Scheme 7, the coupling reaction can be performed on a copper source such as In the presence of copper(I) iodide (CuI), in 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 - in the presence of 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-bis alkanes, N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone at a temperature of 100°C to 180°C under microwave irradiation for 15 to 60 minutes. Alternatively, the reaction can be carried out at elevated temperature such as 80° C. for a longer reaction time without using microwaves (Ley, SV et al., Angew. Chem. Int. Ed. (International Edition of Applied Chemistry) 42 (2003) 5400 ). Deprotection can be carried out using TFA in an organic solvent such as DCM or THF at room temperature to afford stereoisomer Ij.

Alkylation _of Ij with bromide XXIII can be carried out by using a base such as NaH, _K2CO3 or _Cs2CO3 in an organic solvent such as THF or _DMF at room temperature for several hours.

烷或四氢呋喃中在室温进行若干小时。Finally, hydrolysis of the methyl ester yields compound Ik. Hydrolysis can 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-bis

Alkanes or tetrahydrofuran at room temperature for several hours.

Option 8

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

In the first step shown in Scheme 8, the condensation between IV and ethylene dibromide can _be performed in an organic solvent (THF or DMF) by _using a base such as NaH, _K2CO3 or _Cs2CO3 at room temperature 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, _K2CO3 or _Cs2CO3 at room temperature for several hours .

烷或四氢呋喃中在室温进行若干小时。Finally, hydrolysis of the methyl ester XXVIIXXXVIII can yield compound IL. The reaction can 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-bis

Alkanes or tetrahydrofuran at room temperature for several hours.

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

a) Compounds of formula (A)

Reaction in the presence of R ⁶ R ⁷ NH and a coupling agent;

b) Compounds of formula (B)

Reaction in the presence of Y-CH ₂ -R and a base;

c) Compounds of formula (C)

Reaction in the presence of R ⁶ R ⁷ NH and a base;

d) Compounds of formula (D)

Reaction in the presence of R ⁶ R ⁷ NH and a reducing agent;

e) Compounds of formula (E)

In the presence of a compound of formula (E1)

and the reaction in the presence of a base;

f) Compounds of formula (F)

reaction in the presence of a base;

g) compounds of formula (G)

reaction in the presence of a base;

唑烷基或氧代-咪唑烷基；其中R⁶和R⁷独立地选自氢、烷基、环烷基、烷基磺酰基、环烷基磺酰基、氨基烷基和氨基环烷基；其中X是碳或氮；其中Y是Br、I或OTs；其中Q是Br或I；并且其中R是烷基。wherein R ¹ , R ² , R ³ , R ⁴ and n are as defined in any one of claims 1 to 8; wherein R ⁵ is hydrogen, halogen, oxo-

Oxazolidinyl or oxo-imidazolidinyl; wherein R ^{and R} are independently selected from 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.

六氟磷酸盐(PyBop)、o-(7-氮杂苯并三唑-1-基)-N，N，N’，N’-四甲基脲六氟磷酸盐(HATU)、o-(1H-苯并三唑-1-基)-N，N，N’，N’-四甲基脲六氟磷酸盐(HBTU)或1-乙基-3-(3’-二甲基氨基)碳二亚胺盐酸盐(EDCI)。步骤(a)可以在羟基苯并三唑(HOBt)或N，N-二甲基氨基吡啶(DMAP)存在或不存在下，在碱诸如三乙胺或N，N-二异丙基乙胺的存在下进行。步骤(a)的反应可以在溶剂诸如二氯甲烷或N，N-二甲基甲酰胺中进行。该反应可以在室温进行若干小时。In step (a), the coupling agent is, for example, dicyclohexylcarbodiimide (DCC), benzotriazol-1-yl-oxy-tris-pyrrolidinyl

Hexafluorophosphate (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) can be in the presence or absence of hydroxybenzotriazole (HOBt) or N,N-dimethylaminopyridine (DMAP), in the presence or absence of a base such as triethylamine or N,N-diisopropylethylamine in the presence of. The reaction of step (a) can be performed in a solvent such as dichloromethane or N,N-dimethylformamide. The reaction can be performed at room temperature for several hours.

In step (b), the base may be, for example, NaH, K ₂ CO ₃ or Cs ₂ CO ₃ . Step (b) can be performed in an organic solvent such as THF or DMF. The reaction can be performed at room temperature for several hours.

In step (c), the base may be, for example, NaH, K ₂ CO ₃ or Cs ₂ CO ₃ . Step (c) can be performed in an organic solvent such as THF or DMF. The reaction can be performed at room temperature.

The reaction of step (d) can be carried out in an organic solvent such as DCM or THF. The reducing agent of step (d) can be eg NaBH ₄ or NaHB(OAc) ₃ . The reaction can be performed at room temperature.

In step (e), the base may be, for example, NaH, K ₂ CO ₃ or Cs ₂ CO ₃ . The solvent may be an organic solvent such as THF or DMF. The reaction can be performed at room temperature for several hours.

烷或四氢呋喃。该反应可以在室温进行若干小时。In step (f), the base may be an inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide. The solvent of step (f) can be e.g. methanol, 1,4-bis

alkanes or tetrahydrofuran. The reaction can be performed at room temperature for several hours.

烷或四氢呋喃。该反应可以在室温进行若干小时。In step (g), the base may be an inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide. The solvent of step (g) can be e.g. methanol, 1,4-bis

alkanes or tetrahydrofuran. The reaction can be performed at room temperature for several hours.

The invention also relates to compounds of the 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.

One of the objects of the present invention is the use of the compound of formula (I) for the preparation of a medicament for the treatment or prevention of diseases associated with AMPK regulation.

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

The drug can be administered orally (for example in the form of a pharmaceutical preparation), for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions . However, rectal administration, for example in the form of suppositories, or parenteral administration, for example in the form of injections with an effective amount of a compound as described above, may also be possible.

The aforementioned pharmaceutical compositions can be obtained by processing the compounds according to the invention together with pharmaceutically inert, inorganic or organic carriers. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts may be used as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine 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 carrier is generally required in the case of soft gelatine capsules. Carriers suitable for preparing solutions and syrups are, for example, water, polyols, glycerin, 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.

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

Dosage depends on various factors such as mode of administration, species, age and/or individual's health condition. The daily dose to be administered is about 5-400 mg/kg, preferably about 10-100 mg/kg, and it may be taken in a single dose or divided into several doses.

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

Furthermore, the present invention also relates to a method for treating or preventing diseases associated with AMPK modulation, said method comprising administering an effective amount of a compound of formula (I).

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

In addition, the present invention also relates to a compound of formula (I) for preparing a medicament for treating cancers related to AMPK regulation, and provides a method for treating cancers related to AMPK regulation.

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

Example

Materials and Instruments

粒度：40-60μM；ii)CAS注册号：硅胶：63231-67-4，粒度：47-60微米硅胶；iii)来自Qingdao Haiyang ChemicalCo.，Ltd的ZCX，孔：200-300或300-400。Intermediates and final compounds were purified by flash chromatography using one of the following: i) Biotage SP1 system and Quad 12/25 Cartridge module. ii) ISCO combi-flash chromatograph. Silica gel brand and pore size: i) KP-SIL

Particle size: 40-60 μM; ii) CAS registration number: silica gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400.

Intermediate and final compounds were analyzed by preparative HPLC on a reverse phase column using either an X Bridge ^™ Perp C ₁₈ (5 μm, OBD ^™ 30×100 mm) column or a SunFire ^™ Perp C ₁₈ (5 m, OBD ^™ 30×100 mm) column. purification.

LC/MS spectra were acquired using a MicroMass Plateform LC (Waters™ alliance 2795-ZQ2000). Standard LC/MS conditions are as follows (running time 6min):

Acidic conditions: A: 0.1% formic acid dissolved in H ₂ O; B: 0.1% formic acid dissolved in acetonitrile;

Alkaline conditions: A: 0.01% NH ₃ .H ₂ O dissolved in H ₂ O; B: Acetonitrile;

Neutral conditions: A: H ₂ O; B: acetonitrile.

Mass Spectrometry (MS): Usually only ions indicating the parent mass are reported, and unless otherwise stated, the mass ions cited are positive mass ions -(M+H) ⁺ .

Microwave-assisted reactions were performed in a Biotage Initiator Sixty.

NMR spectra were acquired using a Bruke Avance 400 MHz.

All reactions involving air-sensitive reagents were performed under an argon atmosphere. Reagents were used (directly) without further purification when obtained from suppliers unless otherwise stated.

Example 1

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

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

Oxindole (0.13 g, 1 mmol), 4-chlorobenzaldehyde (0.17 g, 1.2 mmol) were mixed in ethanol; then pyrrolidine (0.17 ml, 2 mmol) was added. The mixture was refluxed for 3 hours. The formed precipitate was collected by filtration and washed twice with ethanol to yield the title compound (0.24 g, 92%) as a yellow powder. LC _/ MS m/e calcd for _C15H10ClNO 255, found (M+H) ⁺ : 256.1.

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

A solution of dimethylsulfoxamethylenesulfoxonium was prepared from 60% NaH dispersion in mineral oil (88 mg, 2.2 mmol), trimethylsulfoxide iodide (484 mg, 2.2 mmol) and DMSO (10 mL) under argon. . After 20 min, a solution of (Z)-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one (510 mg, 2 mmol) in THF (5 mL) was added over 20 min Add dropwise. After stirring for 1 hour at room temperature and another hour at 50° C., the solution was poured into ice-cold water (20 mL) and extracted with diethyl 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 yield the title compound as a white solid (333 mg, 62%). LC _/ MS m/e calcd for _C16H12ClNO 269, found (M+H) ⁺ : 270.5. ¹ H NMR (400MHz, DMSO-d ₆ ) 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′- Indoline]-1'-yl)methyl)benzoate

(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 14h. Completion of the reaction was monitored by HPLC. 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 (586 mg, 67%) as a white powder. LC _/ MS m/e calcd for _C25H20ClNO3 : 417, found (M+H) ₊ ^: 418.1. ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline]-1′ -yl)methyl)benzoic acid

(1R, 2S) and (1S, 2R)-methyl-3-(((2-(4-chlorophenyl)-2′-oxospiro[cyclo-propane-1,3′-indoline Indol]-1'-yl)methyl)benzoate (48 mg) was dissolved in 1 mL of methanol; then 0.1 mL of water was added, followed by lithium hydroxide (10 mg). The mixture was stirred at room temperature for 14 hours. Removed under reduced pressure Solvent. The residue was dissolved in 2 mL DMF and purified by preparative HPLC to give the title compound (10 mg) as a white powder. LC/MS m/e calculated for C ₂₄ H ₁₈ ClNO ₃ : 403, found (M+ H) ⁺ : 404.1. ¹ H NMR (400MHz, DMSO-d ₆ ) 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 = 7.71 Hz, 1H) 7.60 (d, J = 7.58 Hz, 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'-indoline]-1'- base) methyl) benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro The title compound was prepared analogously to Example 1 starting from [cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd for _C24H18ClNO3 : 403.1, found (M+H) ⁺ : _404.2 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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 = 7.58 Hz, 1H) 13.05 (br.s., 1H).

Example 3

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

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro The title compound was prepared analogously to Example 1 starting from [cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd for _C24H18ClNO3 : 403.1, found (M+H) ⁺ : _404.1 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline]- 1'-yl)methyl)benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-2-(4-(methylsulfonyl) as prepared in Scheme 1 )phenyl)spiro[cyclopropane-1,3'-indoline]-2'-one, the title compound was prepared analogously to Example 1. LC/MS m/e calcd _{for C25H21NO5S} : 447, found ( _M +H) ⁺ : 448.2. ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline]-1′ -yl)methyl)benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1S,2R) and (1R,2S)-2-(4-cyanophenyl) prepared as in Scheme 1 The title compound was prepared analogously to Example 1, starting from spiro[cyclopropane-1,3'-indoline]-2'-one. LC/MS m/e calcd. _{for C25H18N2O3} : 394, found (M+H) ⁺ : _{395.1 .} ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline] -1'-yl)methyl)benzoic acid

(1S,2R) and (1R,2S)-2-(4-chlorophenyl)spiro[ The title compound was prepared analogously to Example 1 starting from cyclopropane-1,3'-indolin]-2'-one. LC _/ MS m/e calcd _{for C24H17Cl2NO3} : 437, found (M+H) ⁺ : _438.3 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline ]-1'-yl)methyl)benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-2-(4-(methylsulfonyl) as prepared in Scheme 1 )phenyl)spiro[cyclopropane-1,3'-indoline]-2'-one, the title compound was prepared analogously to Example 1. LC/MS m/e calcd _{for C25H21NO5S} : 447, found (M+H) ⁺ : 448.2 _. ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline]-1′- base) methyl) benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-2-(2-fluorophenyl)spiro The title compound was prepared analogously to Example 1 starting from [cyclopropane-1,3'-indoline]-2'-one. LC/MS m/e calcd for _C24H18FNO3 : 387, found ( _M +H) ₊ ^: 388.2. ¹ H NMR (400MHz, MeOD-d ₄ ) 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) ( m, 1H) 7.46 (t, J = 7.71 Hz, 1H) 7.50-7.57 (m, 2H) 7.96 (d, J = 7.83 Hz, 1H) 8.05 (s, 1H).

Example 9

(1S, 2S) and (1R, 2R)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-2-(2-fluorophenyl)spiro The title compound was prepared analogously to Example 1 starting from [cyclopropane-1,3'-indoline]-2'-one. LC/MS m/e calcd for _C24H18FNO3 : 387, found ( _M +H) ₊ ^: 388.1. ¹ H NMR (400MHz, MeOD-d ₄ ) 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′-indoline]-1′- base) methyl) benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-2-(3-fluorophenyl)spiro The title compound was prepared analogously to Example 1 starting from [cyclopropane-1,3'-indoline]-2'-one. LC/MS m/e calcd for _C24H18FNO3 : 387, found ( _M +H) ₊ ^: 388.1. ¹ H NMR (400MHz, DMSO-d ₆ ) 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 = 7.71 Hz, 1H) 7.60 (d, J = 7.83 Hz, 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′-indoline]-1′- base) methyl) benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-2-(3-fluorophenyl)spiro The title compound was prepared analogously to Example 1 starting from [cyclopropane-1,3'-indoline]-2'-one. LC/MS m/e calcd for _C24H18FNO3 : 387, found ( _M +H) ₊ ^: 388.2. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 2.27 (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′-indoline Indol]-1'-yl)methyl)benzoic acid

From methyl-(2-(trifluoromethyl)phenyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-2-(3- The title compound was prepared analogously to Example 1 starting from fluorophenyl)spiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C25H18F3NO3} : 437 _, found (M+H) ⁺ : 438.1. ¹ H NMR (400MHz, DMSO-d ₆ ) 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 ( br.s., 1H).

Example 13

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

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-5′-chloro-2-(4- The title compound was prepared analogously to Example 1 starting from chlorophenyl)spiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C24H17Cl2NO3} : 437, found (M+H) ⁺ : _438.2 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline ]-1'-yl)methyl)benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-5′-chloro-2-(4- The title compound was prepared analogously to Example 1 starting from chlorophenyl)spiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C24H17Cl2NO3} : 437, found (M+H) ⁺ : _438.1 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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 = 7.07 Hz, 1H).

Example 15

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

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-5′-bromo-2-(4- The title compound was prepared analogously to Example 1 starting from chlorophenyl)spiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd for _{C24H17BrClNO3} : 481, found (M+H) ⁺ : _482.1 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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 ( m, 2H).

Example 16

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

From methyl-(3-bromomethyl)-benzoate (commercially available) and racemic (1S, 2R) and (1R, 2S)-5′-bromo-2- The title compound was prepared analogously to Example 1 starting from (4-chlorophenyl)spiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd for _{C24H17BrClNO3} : 481, found (M+H) ⁺ : _482.1 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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 = 7.07 Hz, 1H).

Example 17

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

From methyl-(3-bromomethyl)-benzoate (commercially available), (1S,2S) and (1R,2R)-2-(4-cyanophenyl) prepared as in Scheme 1 The title compound was prepared analogously to Example 1, starting from spiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C25H18N2O3} : 394, found (M+H) ⁺ : _394.2 . ¹ H NMR (400MHz, CDCl ₃ ) 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′-indoline]-1 '-yl)methyl)benzoic acid

(1R,2S) and (1S,2R)-2-(3-methoxyphenyl) prepared as in Scheme 1 from methyl-(3-bromomethyl)-benzoate (commercially available) ) spiro[cyclopropane-1,3'-indoline]-2'-one, the title compound was prepared analogously to Example 1. LC/MS m/e calcd _{for C25H21NO4} : 399, found (M+H) ₊ ^: 400.1. ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline]-1 '-yl)methyl)benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-2-(3-methoxyphenyl) prepared as in Scheme 1 ) spiro[cyclopropane-1,3'-indoline]-2'-one, the title compound was prepared analogously to Example 1. LC/MS m/e calcd _{for C25H21NO4} : 399, found (M+H) ⁺ : _400.2 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline]-1 '-yl)methyl)benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-2-(4-methoxyphenyl) prepared as in Scheme 1 ) spiro[cyclopropane-1,3'-indoline]-2'-one, the title compound was prepared analogously to Example 1. LC/MS m/e calcd _{for C25H21NO4} : 399, found (M+H) ⁺ : _400.1 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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 = 7.07 Hz, 1H) 13.02 (br.s., 1H).

Example 21

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

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-2-(4-methoxyphenyl) prepared as in Scheme 1 ) spiro[cyclopropane-1,3'-indoline]-2'-one, the title compound was prepared analogously to Example 1. LC/MS m/e calcd _{for C25H21NO4} : 399, found (M+H) ₊ ^: 400.1. ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline ]-1'-yl)methyl)benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1S,2R) and (1R,2S)-2-(4-chlorophenyl)- as prepared in Scheme 1 The title compound was prepared analogously to Example 1 starting from 5'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd for _C24H17ClFNO3 : 421, found (M+H) ⁺ : 422.1 _. ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline ]-1'-yl)methyl)benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1S,2S) and (1R,2R)-2-(4-chlorophenyl)- as prepared in Scheme 1 The title compound was prepared analogously to Example 1 starting from 5'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd for _C24H17ClFNO3 : 421, found (M+H) ⁺ : 422.1 _. ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline]-1′ -yl)methyl)benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available) and racemic (1S,2R)-2-(4-fluorophenyl)spiro[cyclopropane] prepared as in Scheme 1 -1,3'-indolin]-2'-one, the title compound was prepared analogously to Example 1. LC/MS m/e calcd _{for C24H18FNO3} : 421, found (M+H) ₊ ^: 422.1. ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline]-1′- base) methyl) benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1S,2R) and (1R,2S)-2-(pyridin-3-yl)spiro The title compound was prepared analogously to Example 1 starting from [cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C23H18N2O3} : 370, found (M+H) ⁺ : 371.1 _. ¹ H NMR (400MHz, DMSO-d ₆ ) 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 = 7.33 Hz, 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′-indoline]-1′ -yl)methyl)benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1S,2S) and (1R,2R)-2-(4-fluorophenyl)spiro The title compound was prepared analogously to Example 1 starting from [cyclopropane-1,3'-indoline]-2'-one. LC/MS m/e calcd for _C24H18FNO3 : 421, found ( _M +H) ₊ ^: 422.1. ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline Indol]-1'-yl)methyl)benzoic acid

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

A 2.0M 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 nitrogen _. (0.35 g, 1 mmol) in a stirred solution in 150 ml dry THF. After the addition, stirring was continued for 10 min at the same temperature. The reaction was quenched by pouring the mixture into dilute hydrochloric acid and extracted with several portions of diethyl ether. The combined ether extracts were washed with aqueous NaHCO ₃ , water and dried over Na ₂ SO ₄ . Removal of the organic solvent under vacuum yielded the product as a colorless oil. And this crude product was used in the next step without further purification.

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

的溶液中加入叔丁锂(14.7ml，1.5M溶于己烷)并且溶液变成褐色。0℃搅拌1小时后，将来自上一步的20mL THF中的未经纯化的1-(4-碘-苯基)-2-甲基-丙烷-1-酮逐滴加入并且在室温将溶液搅拌14小时。冷却至约20℃后，加入52mL水并且用二氯甲烷(3x 50mL)对溶液进行萃取。将有机层在MgSO₄上干燥并将溶剂除去以产生白色固体状的粗的标题化合物。将产物用于下个步骤而不进行进一步的纯化。At 0°C, to 7.07 g (20 mmol) of methyltriphenyl bromide in 50 mL of anhydrous THF

To a solution of tert-butyllithium (14.7ml, 1.5M in hexane) was added and the solution turned brown. After stirring at 0 °C for 1 h, unpurified 1-(4-iodo-phenyl)-2-methyl-propan-1-one from the previous step in 20 mL THF was added dropwise and the solution was stirred at room temperature 14 hours. After cooling to about 20°C, 52 mL of water was added and the solution was extracted with dichloromethane (3 x 50 mL). The organic layer was dried over _MgSO4 and the solvent was 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 (64.3 mmol) was suspended in MeOH (300 mL). The suspension was heated to reflux, at which point a deep red solution was obtained. To the hot solution was added tosylhydrazide (64.8 mmol) in one portion. A yellow product started to precipitate out of the hot mixture. The reaction was cooled to room temperature and the light colored tosylhydrazone was filtered off. The product was used in the next step without further purification.

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

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

3-Diazo-5-fluoroindolin-2-one (0.177 g, 1 mmol) and Rh(OAc) _dimer (2.2 mg) were placed in a Schlenk tube under an argon atmosphere, and then It was dissolved in anhydrous benzene (3 mL). The mixture was heated to 80°C for 10 minutes. 1-Iodo-4-(3-methylbut-1-en-2-yl)benzene (0.544 g) was dissolved in anhydrous THF (2 mL) 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 yield the title compound (0.446 g, 53%) as a white powder. LC/MS m/e calcd for _C19H17FINO : 421, found (M+H) ⁺ : _422.1 .

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

(1S, 2S) and (1R, 2R)-5′-fluoro-2-(4-iodophenyl)-2-isopropylspiro[cyclopropane-1,3′-indoline]-2 '-Kone (0.88g, 2.1mmol), methyl-(3-bromomethyl)-benzoate (725mg, 3.15mmol) and _Cs2CO3 ( _1.37g , 4.2mmol) were mixed in anhydrous DMF and stirred at room temperature for 14 hours. 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 product (1.10 g, 92%) as a white solid. LC _{/MS m/e calcd for C28H25FINO :} 569, found (M+H) ⁺ : 570.1

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

(1S, 2S) and (1R, 2R)-methyl-3-((-5'-fluoro-2-(4-iodophenyl)-2-isopropyl-2 '-Oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)benzoate (1.35g, 2.4mmol), NaCN (240mg, 4.9mmol), CuI ( A solution of 50 mg, 0.3 mmol) and Pd(PPh ₃ ) ₄ (140 mg, 0.12 mmol) was stirred at 65°C for 2 hours. The mixture was cooled to room temperature and extracted with ethyl acetate and washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo. Purification by flash column chromatography eluting with hexane/ethyl acetate (8:1 to 4:1) afforded a pale yellow oil (500 mg, 45.5% yield). LC/MS m/e calcd _{for C29H25FN2O3 :} 469, found ( _M +H) ₊ ^: 469.2

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

To (1S, 2S) and (1R, 2R)-methyl-3-((2-(4-cyanophenyl)-5'-fluoro-2-isopropyl) in tetrahydrofuran (10 mL) at room temperature -2′-Oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoate (500 mg, 1.1 mmol) was added to a solution of 30% aqueous sodium hydroxide ( 3 mL) and the mixture was stirred at that temperature for 16 hours. The mixture was neutralized with 2N aqueous hydrochloric acid, diluted with ethyl acetate (50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by waters automated fast system (column: Xterra 30mm x 100mm, sample manager 2767, pump 2525, detector: zQ mass and UV 2487, solvent system: acetonitrile and 0.1% trifluoroacetic acid in water) yielded the title compound as a white solid (270 mg, _{59.5%): LC/MS m/e calcd. for C28H23FN2O3 :} 454, found (M+H) ₊ ^: _455.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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=15.92 Hz, 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′-indoline Indol]-1'-yl)methyl)benzoic acid

Prepared as in Scheme 2 from methyl-(3-bromomethyl)-benzoate (commercially available), (1S,2S) and (1R,2R)-4-(2-methyl-2' The title compound was prepared analogously to Example 27 starting from -oxospiro[cyclopropane-1,3'-indolin-2-yl)benzonitrile. LC _/ MS m/e calcd _{for C26H20FN2O3 :} 408, found (M+H) ₊ ^: 409.1. ¹ H NMR (400MHz, MeOD-d ₄ ) 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′-indoline Indol]-1'-yl)methyl)benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available) and racemic (1S,2R) and (1R,2S)-4-(2-methyl Starting from -2'-oxospiro[cyclopropane-1,3'-indolin]-2-yl)benzonitrile, the title compound was prepared analogously to Example 27. LC _/ MS m/e calcd _{for C26H20FN2O3 :} 408, found (M+H) ₊ ^: 409.1. ¹ H NMR (400MHz, MeOD-d ₄ ) 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).

Example 30 and Example 31

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

(1S,2S) and (1R,2R)-3-((2-(4-chloro Stereoisomerism of phenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)benzoic acid (Example 32) to obtain the title compound.

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

LC/MS m/e calcd _{for C27H24ClNO3} : 445, found (M+H) ⁺ : _446.7 . ¹ H 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 = 4.80 Hz, 1H) 0.94 (d, J = 7.07 Hz, 3H) 0.82 (d, J = 6.82 Hz, 3H). [α] _D ²⁵ =+114 (c=5 mg/mL, CH ₂ Cl ₂ ).

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

LC/MS m/e calcd for _C27H24ClNO3 : 445, found (M+H) ₊ ^: _446.5 . ¹ H 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 = 4.80 Hz, 1H) 0.94 (d, J = 7.07 Hz, 3H) 0.82 (d, J = 6.82 Hz, 3H). [α] _D ²⁵ = -126.00 (c = 5.2 mg/mL, CH ₂ Cl ₂ ).

Example 32

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

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-2-(4-chlorophenyl)- as prepared in Scheme 2 The title compound was prepared analogously to Example 27 starting from 2-isopropylspiro[cyclopropane-1,3'-indoline]-2'-one. LC/MS m/e calcd for _C27H24ClNO3 : 445, found (M+H) ₊ ^: _446.5 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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 = 4.80 Hz, 1H) 2.15 (d, J = 4.80 Hz, 1H) 0.94 (d, J = 7.07 Hz, 3H) 0.82 (d, J = 6.82 Hz, 3H).

Example 33 and Example 34

(+)-3-((2-(4-chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[(trans)-cyclopropane-1,3′-di Indoline]-1'-yl)methyl)benzoic acid and (-)-3-((2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxo spiro[(trans)-cyclopropane-1,3'-indoline]-1'-yl)methyl)benzoic acid

(1S,2S) and (1R,2R)-3-((2-(4-chloro Phenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)benzoic acid (Example 35 ) to obtain the title compound.

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

LC _/ MS m/e calcd for _C27H23ClFNO3 : 463, found (M+H) ⁺ : _464.2 . ¹ HNMR (400MHz, MeOD) 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). White powder. MS (ESI) (M+H) ⁺ 463.5; [α] _D ²⁵ = 109.52 (c = 5 mg/mL, CH ₂ Cl ₂ ). (-)-3-((2-(4-chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[[(trans)-cyclopropane-1,3′- Indoline]-1'-yl)methyl)benzoic acid

LC _/ MS m/e calcd for _C27H23ClFNO3 : 463, found (M+H)+: 464.1. _1H NMR (400MHz, MeOD) δppm 8.01 (s, 1H) 7.98 (d, J = 7.83Hz, 1H) 7.δ4 (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). White powder. MS (ESI) (M+H) + 463.8; [α] D25 = -133.26 (c = 5 mg/mL, CH2Cl2).

Example 35

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

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-2-(4-chlorophenyl)- as prepared in Scheme 2 The title compound was prepared analogously to Example 27 starting from 5'-fluoro-2-isopropylspiro[cyclopropane-1,3'-indolin]-2'-one. LC _/ MS m/e calcd for _C27H23ClFNO3 : 463, found (M+H) ⁺ : _464.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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 '-indoline]-1'-yl)methyl)benzoic acid

Racemic (1S,2S) and (1R,2R)-2-(4-fluorobenzene) prepared as in Scheme 2 from methyl-(3-bromomethyl)-benzoate (commercially available) The title compound was prepared analogously to Example 27, starting from 3'-5'-fluoro-2-isopropylspiro[cyclopropane-1,3'-indolin]-2'-one. LC _/ MS m/e calcd _{for C27H23F2NO3} : 447, found (M+H) ⁺ : 448.1 _. ¹ H NMR (400MHz, MeOD-d ₄ ) 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 = 4.80 Hz, 1H) 2.16-2.21 (m, 1H) 0.93 (d, J = 6.82 Hz, 3H) 0.83 (d, J = 6.82 Hz, 3H).

Example 37

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

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-2-(3-fluorophenyl)- as prepared in Scheme 2 The title compound was prepared analogously to Example 27 starting from 2-isopropylspiro[cyclopropane-1,3'-indoline]-2'-one. LC/MS m/e calcd for _C27H24FNO3 : 429, found (M+H) ₊ ^: _430.1 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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′-indoline Indol]-1'-yl)methyl)benzoic acid

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-2-(3-chlorophenyl)- as prepared in Scheme 2 The title compound was prepared analogously to Example 27 starting from 2-isopropylspiro[cyclopropane-1,3'-indoline]-2'-one. LC/MS m/e calcd for _C27H24ClNO3 : 445, found (M+H) ₊ ^: _446.1 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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, 2.91 Hz, 3H).

Example 39

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

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-2-(4-fluorophenyl)- as prepared in Scheme 2 The title compound was prepared analogously to Example 27 starting from 2-isopropylspiro[cyclopropane-1,3'-indoline]-2'-one. LC/MS m/e calcd for _C27H24FNO3 : 429, found (M+H) ₊ ^: _430.1 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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 = 7.07 Hz, 3H) 0.83 (d, J = 6.82 Hz, 3H).

Example 40 and Example 41

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

(1S,2S) and (1R,2R)-3-((2-(4-chloro Stereoisomerism of phenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)benzoic acid (Example 27) to obtain the title compound.

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

LC _/ MS m/e calcd _{for C28H23FN2O3 :} 454 _, found (M+H) ⁺ : 455.6. ¹ H 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). White powder. MS (ESI) (M+H) ⁺ ; [α] _D ²⁵ = 166.88 (c = 5 mg/mL, CH ₂ Cl ₂ ).

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

LC _/ MS m/e calcd _{for C28H23FN2O3} : 454, found (M+H) ₊ ^: 455.5. ¹ H 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 = 5 mg/mL, _CH2Cl2 ).

Example 42

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

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)- as prepared in Scheme 2 The title compound was prepared analogously to Example 27 starting from 2-methylspiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd for _C25H20ClNO3 : 417, found (M+H) ₊ ^: 418.1. ¹ H NMR (400MHz, MeOD-d ₄ ) 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′-indoline]-1 '-yl)methyl)benzoic acid and (-)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[(trans)-cyclopropane-1, 3'-indoline]-1'-yl)methyl)benzoic acid

(1R,2S) and (1S,2R)-3-((2-(4-chloro Stereoisomers of phenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)benzoic acid (Example 42) to obtain the title compound.

(+)-3-((2-(4-Chlorophenyl)-2-methyl-2′-oxospiro[[(trans)-cyclopropane-1,3′-indoline]- 1'-yl)methyl)benzoic acid

LC _/ MS m/e calcd for _C25H20ClNO3 : 417, found (M+H) ₊ ^: 418.6. ¹ HNMR (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=4 mg/mL, MeOH).

(-)-3-((2-(4-Chlorophenyl)-2-methyl-2′-oxospiro[[(trans)-cyclopropane-1,3′-indoline]- 1'-yl)methyl)benzoic acid

LC _/ MS m/e calcd for _C25H20ClNO3 : 417, found (M+H) ₊ ^: 418.5. ¹ H NMR (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 = 4 mg/mL, MeOH).

Example 45

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

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-2-(4-chlorophenyl)- as prepared in Scheme 2 The title compound was prepared analogously to Example 27 starting from 2-methylspiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd for _C25H20ClNO3 : 417, found (M+H) ₊ ^: 418.1. ¹ H NMR (400MHz, MeOD-d ₄ ) 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′-indoline]-1 '-yl)methyl)benzoic acid and (-)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[(cis)-cyclopropane-1, 3'-indoline]-1'-yl)methyl)benzoic acid

(1R,2R) and (1S,2S)-3-((2-(4-chloro Stereoisomers of phenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)benzoic acid (Example 45) to obtain the title compound.

(+)-3-((2-(4-Chlorophenyl)-2-methyl-2′-oxospiro[[(cis)-cyclopropane-1,3′-indoline]- 1'-yl)methyl)benzoic acid

LC _/ MS m/e calcd for _C25H20ClNO3 : 417, found (M+H) ₊ ^: 418.5. ¹ H 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=4 mg/mL, MeOH).

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

LC _/ MS m/e calcd for _C25H20ClNO3 : 417, found (M+H) ₊ ^: 418.4. ¹ H 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 = 7.71 Hz, 1H) 7.55 (d, 1H) 7.90 (s, 1H) 7.96 (d, J = 7.58 Hz, 1H). [α] _D ²⁵ = -260.784 (c = 4 mg/mL, MeOH).

Example 48

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

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-4-(5′-fluoro-2- The title compound was prepared analogously to Example 27 starting from methyl-2'-oxospiro[cyclopropane-1,3'-indolin-2-yl)benzonitrile. LC _/ MS m/e calcd _{for C26H19FN2O3 :} 426, found (M+H) ₊ ^: 427.1. ¹ H NMR (400MHz, MeOD-d ₄ ) 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′-di Indoline]-1'-yl)methyl)benzoic acid and (-)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxo spiro[(trans)-cyclopropane-1,3'-indoline]-1'-yl)methyl)benzoic acid

(1R,2S) and (1S,2R)-3-((2-(4-cyano phenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)benzoic acid (Example 48 ) to obtain the title compound.

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

LC _/ MS m/e calcd _{for C26H19FN2O3 :} 426, found (M+H) ₊ ^: 427.5. ¹ H 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 = 7.58 Hz, 1H) 7.92 (s, 1H). [α] _D ²⁵ =203.431 (c=4 mg/mL, MeOH).

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

LC _/ MS m/e calcd _{for C26H19FN2O3 :} 426, found (M+H) ₊ ^: 427.6. ¹ H NMR (400MHz, MeOD) δppm 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 = 7.58 Hz, 1H) 7.92 (s, 1H). White powder. MS (ESI) (M+H) ⁺ 427.6; [α] _D ²⁵ =-- 209.00 (c = 4 mg/mL, MeOH).

Example 51

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

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-4-(2-isopropyl-2) prepared as in Scheme 2 The title compound was prepared analogously to Example 27 starting from '-oxospiro[cyclopropane-1,3'-indolin-2-yl)benzonitrile. LC _/ MS m/e calcd for _C28H24N2O3 : 436, found (M+H) ⁺ : _{437.1 .} ¹ H NMR (400MHz, MeOD-d ₄ ) 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′-indoline] -1′-yl)methyl)benzoic acid and (-)-3-((2-(4-cyanophenyl)-2-isopropyl-2′-oxospiro[(trans)-cyclo Propane-1,3'-indolin]-1'-yl)methyl)benzoic acid

(1S,2S) and (1R,2R)-3-((2-(4-cyano phenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)benzoic acid (Example 51 ) to obtain the title compound.

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

LC/MS m/e calcd _{for C28H24N2O3} : 436, found ( _M +H) ⁺ : _437.7 . ¹ H 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 = 7.83 Hz, 1H) 7.99 (s, 1H). [α] _D ²⁵ =180.88 (c=4 mg/mL, MeOH).

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

LC _/ MS m/e calcd _{for C28H24N2O3} : 436, found (M+H) ⁺ : _437.5 . ¹ H 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 = 7.83 Hz, 1H) 7.99 (s, 1H). [α] _D ²⁵ = -182.52 (c = 4 mg/mL, MeOH).

Example 54

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

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2R) and (1S,2S)-4-(5′-fluoro-2- The title compound was prepared analogously to Example 27 starting from methyl-2'-oxospiro[cyclopropane-1,3'-indolin-2-yl)benzonitrile. LC _/ MS m/e calcd _{for C26H19FN2O3 :} 426, found (M+H) ₊ ^: 427.1. ¹ H NMR (400MHz, MeOD-d ₄ ) 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′-di Indoline]-1'-yl)methyl)benzoic acid and (-)-3-((2-(4-cyanophenyl)-5'-fluoro-2-methyl-2'-oxo spiro[(cis)-cyclopropane-1,3'-indoline]-1'-yl)methyl)benzoic acid

(1R,2R) and (1S,2S)-3-((2-(4-cyano phenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)benzoic acid (Example 54 ) to obtain the title compound.

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

LC _/ MS m/e calcd _{for C26H19FN2O3 :} 426, found (M+H) ₊ ^: 426.8. ¹ H 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 = 7.71 Hz, 3H) 7.53 (br.s., 1H) 7.67 (d, J = 8.59 Hz, 2H) 7.85 (s, 1H) 7.95 (d, J = 7.58 Hz, 1H). [α] _D ²⁵ =313.53 (c=4 mg/mL, MeOH).

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

LC _/ MS m/e calcd _{for C26H19FN2O3 :} 426, found (M+H) ₊ ^: 426.5. ¹ H 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] _D25 = ^-286.00 (c=4 mg/mL 00, MeOH).

Example 57

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

From methyl-(3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)- as prepared in Scheme 2 The title compound was prepared analogously to Example 27 starting from 5'-fluoro-2-methylspiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd for _C25H19ClFNO3 : 435, found (M+H) ⁺ : _436.5 . ¹ H 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).

Example 58 and Example 59

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

(1R,2S) and (1R,2S)-3-((2-(4-chloro Phenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)benzoic acid (Example 57) stereoisomer to obtain the title compound.

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

LC _/ MS m/e calcd for _C25H19ClFNO3 : 435, found (M+H) ⁺ : _436.5 . ¹ HNMR (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=7.83 Hz, 1H) 7.89-7.99 (m, 2H). [α] _D ²⁵ =191.09 (c=4 mg/mL, MeOH). (-)-3-((2-(4-chlorophenyl)-5′-fluoro-2-methyl-2′-oxospiro[[(trans)-cyclopropane-1,3′-di Indoline]-1'-yl)methyl)benzoic acid

LC _/ MS m/e calcd _{for C25H19ClFNO3} : 435, found (M+H) ⁺ : 436.7. ¹ HNMR (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 = 4 mg/mL, MeOH).

Example 60

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

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)methanol base) benzoic acid (prepared according to Scheme 1) (60 mg, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) (44 mg, 0.225 mmol 1.5 mmol), anhydrous 1-hydroxybenzotriazole (HOBt) (31 mg, 0.225 mmol) and piperidine (15 mg, 0.18 mmol) were dissolved 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 by preparative HPLC , 3'-indoline]-2'-one as a white solid (42 mg, 60%). LC _/ MS m/e calcd _{for C29H27ClN2O2} : 470, found (M+H) ⁺ : _471.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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'-indoline]-1'- Base) methyl) -N- isopropyl benzamide

From isopropylamine, (3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-3-((2-(4-chloro The title compound was prepared analogously to Example 60 starting from phenyl)-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)methyl)benzoic acid. LC _/ MS m/e calcd _{for C27H25ClN2O2} : 444, found (M+H) ⁺ : _445.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) δppm 1.23 (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′-di Indoline]-2′-one

From piperazine, (3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-3-((2-(4-chloro The title compound was prepared analogously to Example 60 starting from phenyl)-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)methyl)benzoic acid. LC _/ MS m/e calcd _{for C28H26ClN3O2} : 471, found (M+H) ⁺ : _472.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) δppm 2.17-2.30 (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′-di Indoline]-2′-one

From morpholine, (3-bromomethyl)-benzoate (commercially available) and (1R,2S) and (1S,2R)-3-((2-(4-chloro The title compound was prepared analogously to Example 60 starting from phenyl)-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)methyl)benzoic acid. LC _/ MS m/e calcd _{for C28H25ClN2O3} : 472, found (M+H) ⁺ : _473.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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'-indoline]-2'-one

Prepared as in Scheme 1 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′-indolindol]-1′-yl)methyl)benzoic acid started with Example 60 The title compound was prepared analogously. LC _/ MS m/e calcd. _{for C33H29ClN4O2} : 548, found (M+H) ⁺ : _549.1 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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′-indoline]-2′-one

From 1-isopropylpiperazine, (3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-3-((2 Starting from -(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)benzoic acid, the title was prepared analogously to Example 60 compound. LC _/ MS m/e calcd _{for C31H32ClN3O2} : 513, found (M+H) ⁺ : _514.2 . ¹ H NMR (400MHz, CDCl ₃ ) 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 = 7.33 Hz, 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'-indoline]-1'-yl)methyl)- N-(2-((S)-1-methylpyrrolidinyl-2-yl)ethyl)benzamide and 3-(((1R,2S)-2-(4-chlorophenyl)-2 '-Oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)-N-(2-((S)-1-methylpyrrolidin-2-yl) Ethyl) benzamide

Prepared from (2S)-2-(3-aminopropyl)-N-methylpyrrolidine, (3-bromomethyl)-benzoate (commercially available), (1R,2S ) and (1S, 2R)-3-((2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl ) benzoic acid, the title compound was prepared analogously to Example 60. LC/MS m/e calcd for C ₃₁ H ₃₂ ClN ₃ O ₂ : 513, found (M+H) ⁺ : 514.2. 1H NMR (400 MHz, MeOD-d ₄ ) δ ppm 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'-indoline]-1'- Base) 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]-1′-yl)methyl)benzoic acid started , The title compound was prepared similarly to Example 60. LC _/ MS m/e calcd _{for C28H23ClN4O2} : 482, found (M+H) ⁺ : 483.2 _. ¹ H NMR (400MHz, MeOD-d ₄ ) 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'-indoline]-1'- base) methyl) picolinic acid

From 6-bromomethyl-pyridine-2-carboxylic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclo The title compound was prepared analogously to Example 1 starting from propane-1,3'-indolin]-2'-one. LC _/ MS n/e calcd _{for C23H17ClN2O3} : 404, found (M+H) ⁺ : _405.2 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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 = 1.01 Hz, 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′-indoline]-1′- base) methyl) picolinic acid

From 6-bromomethyl-pyridine-2-carboxylic acid methyl ester (commercially available) and (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclo The title compound was prepared analogously to Example 1 starting from propane-1,3'-indolin]-2'-one. LC _/ MS m/e calcd. _{for C23H17FN2O3} : 388, found (M+H) ⁺ : _389.1 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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 '-indoline]-2'-one

Under an argon atmosphere at 0°C, racemic (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indoline]-2′-one and (1R ,2S)-2-(4-Chlorophenyl)spiro[cyclopropane-1,3′-indoline]-2′-one (270 mg, 1.0 mmol, 1.0 equiv) was added to 5 mL of sodium hydride in DMF (60%, 60mg, 1.5mmol) in a stirred solution. After stirring for 1 hour, 4-bromomethyl-pyran (215 mg, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours. The crude product was purified by HPLC to yield the title compound (258 mg, 70%) as a white solid. LC _/ MS m/e calcd _{for C22H22ClNO2} : 367, found (M+H) ⁺ : 368.2. ¹ H NMR (400MHz, MeOD-d ₄ ) 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 _: Calcd. for _C22H22ClNO2 367, found (ESI ⁺ ) [(M+H) ⁺ ] ₃₆₈ .

Example 71

(1S, 2R) and (1R, 2S)-2-(4-chlorophenyl)-1′-(2-(diethylamino)ethyl)spiro[cyclopropane-1,3′-indoline Indole]-2′-one

From 2-chloro-N,N-diethylethaneamine hydrochloride (commercially available), (1S,2R) and (1R,2S)-2-(4-chlorophenyl ) spiro[cyclopropane-1,3'-indoline]-2'-one, the title compound was prepared analogously to Example 70. LC _/ MS m/e calcd _{for C22H25ClN2O} : 368, found (M+H) ⁺ : 369.1. ¹ H NMR (400MHz, MeOD-d ₄ ) 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′-indoline]- 2′-keto

From 4-(2-chloroethyl)morpholine hydrochloride (commercially available), (1S,2R) and (1R,2S)-2-(4-chlorophenyl)spiro[ The title compound was prepared analogously to Example 70 starting from cyclopropane-1,3'-indolin]-2'-one. LC _/ MS m/e calcd _{for C22H23ClN2O2} : 382, found (M+H) ⁺ : _383.1 . ¹ HNMR (400MHz, MeOD-d ₄ ) 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'-indoline]-2'-one

From 4-chloromethyl-1-methanesulfonyl-piperidine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[ The title compound was prepared analogously to Example 70 starting from cyclopropane-1,3'-indolin]-2'-one. LC _/ MS m/e calcd _{for C23H25ClN2O3S} : 444, found (M+H) ⁺ : _445.1 . ¹ HNMR (400MHz, DMSO-d ₆ ) 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) ( m, 2H).

Example 74

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

(1R, 2S) and (1S, 2R)-2-(4-chlorophenyl)-1′-(2,2-dimethoxyethyl)spiro[cyclopropane-1,3′-indoline Indole]-2′-one

(1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indoline]-2′- To a solution of the ketone (135 mg, 1 mmol) was added KHMS (0.5 M in THF, 1.1 mL) dropwise. The mixture was stirred for half an hour before bromoacetaldehyde dimethyl acetal (95 mg, 0.55 mmol) was added. The mixture was heated to 50°C and stirred at this temperature for 2 hours. The mixture was poured into water, extracted with ethyl acetate (3 x 15 mL), dried and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with hexane-EtOAc (6:1 then 4:1) gave the desired product (268 mg, 75%) as a colorless oil. LC _/ MS m/e calcd _{for C20H20ClNO3} : 3570, found (M+H) ⁺ : 358.7.

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

(1R,2S) and (1S,2R)-2-(4-chlorophenyl)-1′-(2,2-dimethoxyethyl)spiro[cyclopropane- A suspension of 1,3'-indoline]-2'-one (1 g) was cooled to 0°C and treated with a mixture of DCM and TFA (1:1, 6 mL) for 2 hours. The reaction mixture was poured into saturated aqueous NaHCO ₃ and extracted with DCM (3 x 6 mL). _The combined organic layers were washed with brine and dried over _Na2SO4 . The solvent was evaporated under reduced pressure. The crude product was used directly in the next step without further purification. LC/MS m/e calcd _{for C18H14ClNO2} : 311, found (M+H) ₊ ^: 312.3.

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

(1R,2S) and (1S,2R)-2-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-dihydro A mixture of indol]-1'-yl)acetaldehyde (0.1 mmol), (1-isopropyl)piperazine (0.15 mmol) and acetic acid (catalytic amount) was stirred at room temperature for 20 minutes. The mixture was cooled to 0 °C and NaBH(OAc) ₃ (2 mmol) was added carefully. 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 the title product (35 mg) as a colorless oil. LC _/ MS m/e calcd _{for C25H30ClN3O} : 423, found (M+H) ⁺ : 424.1. ¹ HNMR (400MHz, MeOD-d ₄ ) 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 = 3.54 Hz, 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'-indoline]-2'-one

Prepared as in Scheme 1 from 1-(2-dimethylamino-ethyl)-piperazine, bromoacetaldehyde dimethyl acetal (commercially available), (1R,2S) and (1S,2R) -2-(4-Chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one The title compound was prepared analogously to Example 74, starting from. LC _/ MS m/e calcd _{for C26H33ClN4O} : 452, found (M+H) ⁺ : 453.1. ¹ HNMR (400MHz, MeOD-d ₄ ) 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'-indoline]-2'-one and (1R,2S)-2-(4-chlorophenyl)-1'-(2-((S)-3-(dimethylamino )pyrrolidin-1-yl)ethyl)spiro[cyclopropane-1,3'-indoline]-2'-one

Prepared from (3S)-(-)-3-(dimethylamino)pyrrolidine, bromoacetaldehyde dimethyl acetal (commercially available), (1R,2S) and (1S, The title compound was prepared analogously to Example 74 starting from 2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one. LC _/ MS m/e calcd for _C24H28ClN3O : 409, found (M+H) ⁺ : _410.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) δppm 1.32 (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 ( ( 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'-indoline]-2'-one and (1R,2S)-2-(4-chlorophenyl)-1'-(2-((R)-3-(dimethylamino )pyrrolidin-1-yl)ethyl)spiro[cyclopropane-1,3'-indoline]-2'-one

Prepared from (3R)-(+)-3-(dimethylamino)pyrrolidine, bromoacetaldehyde dimethyl acetal (commercially available), (1R,2S) and (1S, The title compound was prepared analogously to Example 74 starting from 2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one. LC/MS m/e calcd for C ₂₉ H ₂₇ ClN ₂ O ₂ : 470, found (M+H) ⁺ : 471.2. 1H NMR (400 MHz, MeOD-d ₄ ) δ ppm 1.32 (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'-indoline]- 2′-keto

(1R, 2S) and (1S, 2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indoline]-2'-one (135mg, 0.5mmol), 4 -Bromomethyl-pyridine (98 mg, 0.6 mmol) and Cs ₂ CO ₃ (245 mg, 0.75 mmol) were 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 2 mL DMF. Purification by preparative HPLC yielded the title compound (140 mg, 76%) as a yellowish solid. LC _/ MS m/e calcd _{for C22H17ClN2O} : 360, found (M+H) ⁺ : 361.2. ¹ HNMR (400MHz, MeOD-d ₄ ) 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 _: Calcd. for _C22H17ClN2O 360, found (ESI ⁺ ) _[ (M+H) ⁺ ] 361.1.

Example 79

(1S, 2R) and (2R, 1S)-2-(4-chlorophenyl)-1'-(pyridin-3-ylmethyl)spiro[cyclopropane-1,3'-indoline]- 2′-keto

From 3-bromomethyl-pyridine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′ prepared as in Scheme 1 Starting with -indoline]-2'-one, the title compound was prepared analogously to Example 78. LC _/ MS m/e calcd _{for C29H27ClN2O2} : 470, found (M+H) ⁺ : _471.2 . ¹ HNMR (400MHz, MeOD-d ₄ ) 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′-indoline]-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′ -Indoline]-2'-one

4-Iodo-1-trityl-1H-imidazole (210 mg, 0.48 mmol) was added to racemic (1S,2R)-2-(4-chlorobenzene) in acetonitrile (2 mL) under nitrogen atmosphere base) spiro[cyclopropane-1,3'-indoline]-2'-one (107mg, 0.4mmol) in suspension. A steady stream of nitrogen was bubbled through the suspension while heating the suspension to 40°C for 15 minutes. Potassium carbonate (110 mg, 0.8 mmol), copper(I) iodide (12 mg, 15 mol%), and N,N-dimethylethylenediamine (0.12 mmol, 30 mol%) were added and the reaction mixture was heated to 80°C and hold for 21 hours. The mixture was cooled to room temperature, filtered and concentrated to give the title product. Purification of the residue by flash column chromatography (gradient elution, 5-10% ethyl acetate in petroleum ether) gave racemic trans-2-(4-chlorophenyl)-1'-(1H-imidazole -4-trityl)spiro[cyclopropane-1,3'-indoline]-2'-one (157 mg, 68%). LC _/ MS m/e calcd _{for C38H28ClN3O} : 577, found (M+H) ⁺ : 578.2. MS _{: Calcd} . for _C38H28ClN3O 578, found (ESI ⁺ ) [(M+H) ⁺ ] 579.3.

(1S, 2R) and (1R, 2S)-2-(4-chlorophenyl)-1′-(1H-imidazol-4-yl)spiro[cyclopropane-1,3′-indoline]- 2′-keto

To the racemic (1S,2R) and (1R,2S)-2-(4-chlorophenyl)-1'-(1-triphenyl) in DCM (2mL) and water (0.5mL) at 0°C To a solution of methyl-1H-imidazol-4-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (115 mg, 0.2 mmol) was added TFA (0.1 mL) dropwise. The mixture was stirred at room temperature for 14 hours. The mixture was poured into saturated aqueous NaHCO ₃ , extracted with DCM (3 x 10 mL), dried and concentrated to give the title product. The residue was dissolved in 2 mL DMF. Purification by preparative HPLC yielded the title compound (60 mg, 89%) as a white powder. LC _/ MS m/e calcd for _C19H14ClN3O : 335, found (M+H) ⁺ : _336.1 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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: _Calcd . for _C19H14ClN3O 335, found (ESI ⁺ ) [(M+H) ⁺ _] 336.3.

Synthesis of (1S,2R) and (1R,2S)-2-(4-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]- 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, 50% KOH (0.5 mL). The reaction mixture was stirred at room temperature for 14 hours. The mixture was then concentrated and acidified to pH~4 under reduced pressure. The residue was dissolved in 2 mL DMF. Purification by preparative HPLC yielded the title compound (113 mg, 68%) as a white powder. LC _/ MS m/e calcd _{for C21H16ClN3O3} : 393, found (M+H) ⁺ : _394.2 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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 _{: Calcd} . for _{C21H16ClN3O3 393} , found (ESI ⁺ ) [(M+H) ⁺ ] 394.3.

Example 81

(1S, 2R) and (1R, 2S)-1-(2-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-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′-indoline]-2 '-ketone

(1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indoline]-2′- To a solution of the ketone (173mg, 0.64mmol) was added KHMDS (0.5M, 1.4mL) dropwise. The mixture was stirred for half an hour after which ethylene dibromide (300 mg, 1.6 mmol) was added. The mixture was warmed to 50 °C and stirred at this temperature for 14 hours. The mixture was poured into water, extracted with ethyl acetate (3 x 15 mL), 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 (98 mg, 41%) as a white solid. LC/MS m/e calcd for _C18H15BrClNO : ₃₇₅ , found (M+H) ⁺ : 376.

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

To a solution of methyl-imidazole-4-carboxylate (100 mg, 0.2 mmol) in 1 mL of anhydrous DMF was added NaH (60% dispersion) (8.8 mg, 0.22 mmol) at room temperature. The reaction mixture was stirred at this temperature for 1 hour. To the mixture was added racemic (1R,2S) and (1S,2R)-1′-(2-bromoethyl)-2-(4-chlorophenyl)spiro[cyclopropane-1 , a solution of 3'-indoline]-2'-one (75.2 mg, 0.2 mmol). The reaction was stirred at room temperature for 14 hours then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with saturated anhydrous NaHCO ₃ . The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined and washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give the title compound (30 mg, 35%) as _a white solid. LC _/ MS m/e calcd _{for C23H20ClN3O3} : 421, found (M+H) ⁺ : _422.3 .

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

To methyl-1-(2-((1S,2R)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1, 3'-indoline]-1'-yl)ethyl)-1H-imidazole-4-carboxylate and methyl-1-(2-((1R,2S)-2-(4-chlorobenzene Base)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)-1H-imidazole-4-carboxylate (0.07mmol) _LiOH.H2O (18 mg, 0.4 mmol) was added. The mixture was stirred at room temperature for 3 hours until the starting material was consumed. The mixture was concentrated and acidified to pH~3 under reduced pressure. The residue was dissolved in 2 mL DMF. Purification by preparative HPLC yielded the title compound (26 mg, 88%) as a white powder. LC _/ MS m/e calcd _{for C22H18ClN3O3} : 407, found (M+H) ⁺ : _408.8 . ¹ H 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′-indoline]-1 '-yl)ethyl)-1H-imidazole-4-carboxylic acid

(1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro The title compound was prepared analogously to Example 81 starting from [cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C22H18ClN3O3} : 407, found (M+H) ⁺ : _408.8 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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'-indoline]-1'-yl )benzoic acid

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

CuI (9.6 mg, 0.05 mmol, 5.0 mol%), racemic (1R, 2S) and (1S, 2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-dihydro Indole]-2'-one (270 mg, 1.0 mmol) and _K2CO3 (276 mg, 2.0 mmol) were _charged into a Schlenk tube, evacuated and backfilled with argon. N,N'-Dimethylethylenediamine (11 μL, 0.10 mmol, 10 mol%), ethyl 3-iodobenzoate (278.8 mg, 1.01 mmol) and acetonitrile (1.5 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 80°C for 23 hours. Completion of the reaction was monitored by HPLC. 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 yield the title compound (290 mg, 72%) as a yellow powder. LC/MS m/e calcd for _C24H18ClNO3 : 403, found (M+H) ₊ ^: _404.1 .

Synthesis of (1S,2R) and (1R,2S)-3-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base) benzoic acid

To methyl-3-((1S,2R)-2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1 in 1 mL of methanol '-yl)benzoate and methyl-3-((1R,2S)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline ]-1'-yl)benzoate (50 mg) was added 0.1 mL of water, followed by lithium hydroxide (10 mg). The mixture was stirred at room temperature for 14 hours. Completion of the reaction was monitored by HPLC. The solvent was removed under reduced pressure. The residue was dissolved in 2 mL DMF. Purification by preparative HPLC yielded the title compound (11 mg) as a white powder. LC/MS m/e calcd _{for C23H16ClNO3} , 389, found (M+H) ⁺ : _390.1 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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'-indoline]-1'- base) benzoic acid

From methyl-ethyl-3-iodobenzoate (commercially available), (1R,2R) and (1S,2S)-2-(4-chlorophenyl)spiro[ The title compound was prepared analogously to Example 81 starting from cyclopropane-1,3'-indolin]-2'-one. LC/MS m/e calcd _{for C23H16ClNO3} , 389, found (M+H) ⁺ : _390.1 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-di Indoline]-2′-one

(1S,2S) and (1R,2R)-3-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-dihydro Indol]-1'-yl)benzoic acid (117mg, 0.3mmol), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroboron A mixture of TBTU (145 mg, 0.45 mmol), N,N-diisopropylethylamine (DIPEA) (154 μL, 0.9 mmol) and morpholine (79 μL, 0.9 mmol) was stirred at room temperature for 14 hours. Purification by preparative HPLC yielded the desired product (83 mg, 60%) as a white solid. LC _/ MS m/e calcd _{for C27H23ClN2O3} : 458, found (M+H) ⁺ : _459.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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′-Indoline]-2′-one

Prepared as in Scheme 1 from 1-methylpiperazine, methyl-3-iodobenzoate (commercially available), (1R,2R) and (1S,2S)-2-(4-chlorobenzene yl)spiro[cyclopropane-1,3'-indolin]-2'-one, the title compound was prepared analogously to Example 85. LC _/ MS m/e calcd _{for C28H26ClN3O2} : 471, found (M+H) ⁺ : _472.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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[ring propane-1,3'-indoline]-2'-one

From 1-methylsulfonyl-piperazine, methyl-3-iodobenzoate (commercially available), (1R,2R) and (1S,2S)-2-(4- The title compound was prepared analogously to Example 85 starting from chlorophenyl)spiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C28H26ClN3O4S} : 535, found (M+H) ⁺ : _536.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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′-di Indoline]-2′-one

From morpholine, methyl-3-iodobenzoate (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[ The title compound was prepared analogously to Example 85 starting from cyclopropane-1,3'-indolin]-2'-one. LC _/ MS m/e calcd _{for C27H23ClN2O3} : 458, found (M+H) ⁺ : _459.1 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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′-Indoline]-2′-one

From 1-methylpiperazine, methyl-3-iodobenzoate (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorobenzene) as prepared in Scheme 1 yl)spiro[cyclopropane-1,3'-indolin]-2'-one, the title compound was prepared analogously to Example 85. LC _/ MS m/e calcd _{for C28H26ClN3O2} : 471, found (M+H) ⁺ : _472.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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=7.71 Hz, 2H) 7.67 (t, J=7.83 Hz, 1H).

Example 90

(1R, 2S) and (1S, 2R)-2-(4-chlorophenyl)-1′-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)phenyl)spiro[ring propane-1,3'-indoline]-2'-one

From 1-methylsulfonyl-piperazine, methyl-3-iodobenzoate (commercially available), (1S, 2R) and (1R, 2S)-2-(4- The title compound was prepared analogously to Example 85 starting from chlorophenyl)spiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C28H26ClN3O4S} : 535, found (M+H) ⁺ : _536.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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'-indoline]-1'-yl )-N-(Methylsulfonyl)benzamide

From methanesulfonamide, methyl-3-iodobenzoate (commercially available), (1R,2R) and (1S,2S)-2-(4-chlorophenyl)spiro The title compound was prepared analogously to Example 85 starting from [cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C24H19ClN2O4S} : 466, found ( _M +H) ⁺ : 467.2. ¹ H NMR (400MHz, DMSO-d ₆ ) 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 ( ( m, 2H) 12.24 (br.s., 1H).

Example 92

唑烷-3-基)苯甲酸(1S, 2S) and (1R, 2R)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl )-5-(2-oxo

Azolidin-3-yl)benzoic acid

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

To a suspension of 3-bromo-5-iodo-benzoic acid (6.5 g, 20 mmol) in 25 mL of methanol was added _δOCl2 (1.14 mL, 40 mmol) dropwise at 0°C. 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 5.12 g (75%). LC/MS m/e calcd for _C8H6BrIO2 : 341, found (M+H) ₊ ^: 342.2 _. Synthesis of (1S,2S) and (1R,2R)-methyl-3-bromo-5-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-dihydro Indole]-1'-yl)benzoate

Packed with CuI (214mg, 1.124mmol, 20mmol%), (1S, 2S) and (1R, 2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indoline] - The Schlenk tube of 2'-ketone (1.50 g, 5.62 mmol) and _K2CO3 (2.30 g, 16.86 mmol) was evacuated and backfilled _with argon. N,N'-Dimethylethylenediamine (242 μL, 2.25 mmol, 40 mol%), methyl 3-bromo-5-iodo-benzoate (2.30 g, 6.75 mmol, 1.2 eq) and acetonitrile were added under argon (5 mL). The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 90°C for 3 hours. Completion of the reaction was monitored by HPLC. 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 (1.3 g, 48%) as a white powder. LC/MS m/e calcd for _{C24H17BrClNO3} : 482, found ( _M +H) ⁺ : ₄₈₃ .

Synthesis of racemic methyl-(1R,2R) and (1S,2S)-3-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline Indol]-1'-yl)-5-(2-oxo oxazolidin-3-yl) benzoate

唑烷-2-酮(27mg，0.3mmol)、CuI(10mg，20mmol％)、二甲基氨基-乙酸(11mg，40mmol％)和K₂CO₃(68mg，0.5mmol)的混合物在150℃搅拌1.5小时。滤出沉淀并浓缩滤液从而产生所需的粗产物(43mg，35％)，将其用于下一步而不进行进一步的纯化。(1S,2S) and (1R,2R)-3-bromo-5-(2-(4-chlorophenyl)-2′-oxospiro[cyclo Propane-1,3'-indoline]-1'-yl)benzoate (120mg, 0.25mmol),

A mixture of oxazolidin-2-one (27 mg, 0.3 mmol), CuI (10 _mg , 20 mmol%), dimethylamino-acetic acid (11 mg, 40 mmol%) and _K2CO3 (68 mg, 0.5 mmol) was stirred at 150 °C 1.5 hours. The precipitate was filtered off and the filtrate was concentrated to give the desired crude product (43 mg, 35%) which was used in the next step without further purification.

Synthesis of (1S,2S) and (1R,2R)-3-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base)-5-(2-oxo Azolidin-3-yl)benzoic acid

唑烷-3-基)苯甲酸酯(43mg，0.088mmol)的溶液中加入氢氧化锂(18mg，0.44mmol)。将反应混合物在室温搅拌直到TLC指示没有进一步的反应。在减压下除去甲醇。在使用浓HCl(3.0N)终止反应后，用乙酸乙酯萃取混合物三次。在无水Na₂SO₄上干燥有机层并且浓缩从而产生粗产物。通过制备型HPLC的纯化产生所需的白色固体状的产物(29mg，70％)。C₂₆H₁₉ClN₂O₅的LC/MSm/e计算值：474，实测(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)。To (1S, 2S) and (1R, 2R)-3-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane] in MeOH (2 mL) and H ₂ O (0.2 mL) -1,3'-indoline]-1'-yl)-5-(2-oxo

To a solution of oxazolidin-3-yl)benzoate (43 mg, 0.088 mmol) was added lithium hydroxide (18 mg, 0.44 mmol). The reaction mixture was stirred at room temperature until TLC indicated no further reaction. Methanol was removed under reduced pressure. After quenching the reaction with concentrated HCl (3.0 N), the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous _Na2SO4 and concentrated to _give crude product. Purification by preparative HPLC yielded the desired product (29 mg, 70%) as a white solid. LC _/ MS m/e calcd _{for C26H19ClN2O5} : 474, found (M+H) ⁺ : _475.1 . ¹ H NMR (400MHz, MeOD-d4) δppm 2.22-2.33 (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'-indoline]-1'-yl )-5-(methylsulfonyl)benzoic acid

Prepared as in Scheme 1 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]-2'-one, the title compound was prepared analogously to Example 92. LC _/ MS m/e calcd for _C24H18ClNO5S : 467, found (M+H) ₊ ^: 468.1. ¹ H NMR (400MHz, MeOD-d ₄ ) 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'-indoline]-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[ The title compound was prepared analogously to Example 92 starting from cyclopropane-1,3'-indolin]-2'-one. LC/MS m/e calcd for C ₂₇ H ₂₁ ClN ₂ O ₄ : 472, found (M+H) ⁺ : 4731.2 ^{1 H} NMR (400 MHz, MeOD-d ₄ ) 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

唑烷-3-基)苯甲酸(1R, 2R) and (1S, 2S)-3-(2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-Indoline]-1'-yl)-5-(2-oxo

Azolidin-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'-indoline]-1'-yl)benzoate

(1R,2R) and (1S,2S)-2-(4-chlorophenyl)-5′-fluoro-2-isopropylspiro[cyclopropane-1,3 '-Indoline]-2'-one (0.33g, 1mmol) and 3-bromo-5-iodo-benzoic acid methyl ester (0.409g, 1.2mmol), CuI (20mg), K ₂ CO ₃ (0.276 g, 2 mmol) into a Schlenk tube and dissolved in anhydrous acetonitrile. N,N'-Dimethyl-1,2-ethanediamine (21 μL) was added to the mixture. The mixture was stirred at 80°C for 14 hours. The solvent was removed under vacuum and the residue was purified by flash column chromatography to give the title compound (0.444 g, 82%) as a white powder. LC _{/MS m/e calcd. for C27H22BrClFNO3 :} 541, found (M+H) ⁺ : ₅₄₂ .

唑烷-3-基)苯甲酸酯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-oxo

oxazolidin-3-yl) benzoate

3-Bromo-5-((1S,2S)-2-(4-chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[cyclopropane-1 , 3'-indoline]-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 (0.105 _g , 1.2 mmol), CuI (20 mg) and _K2CO3 (0.276 g, 2 mmol) were charged in a Schlenk tube and dissolved in anhydrous acetonitrile. N,N'-Dimethyl-1,2-ethanediamine (21 μL, 20% equiv) was added to the mixture. The mixture was stirred at 80°C for 14 hours. The solvent was removed in vacuo and the residue was purified by flash column chromatography to give the title compound (0.40 g, 73%) as a white powder. LC/MS m/e calcd. _{for C30H26ClFN2O5} : 548, found (M ₊ H) ⁺ : _549.5 .

唑烷-3-基)苯甲酸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-oxo

Azolidin-3-yl)benzoic acid

(1R,2R) and (1S,2S)-3-bromo-5-(2-(4-chlorophenyl)-5′-fluoro-2-iso Add LiOH.H ₂ O (18mg , 0.4mmol). The mixture was stirred at room temperature for 3 hours until the starting material was consumed. The mixture was concentrated and acidified to pH~3 under reduced pressure. The precipitate was collected by filtration and dissolved in 2 mL of DMF. Purification by preparative HPLC yielded the title compound (15 mg) as a white solid. LC/MS m/e calcd for _{C29H24ClFN2O5} 534, found (M ₊ H) ₊ ^: _545.7 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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, 2.02 Hz, 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-oxo Azolidin-3-yl)benzoic acid

唑烷酮(市售)、在实施例92中制备的溴-5-碘-苯甲酸甲酯、如在方案2中制备的(1S，2R)和(1R，2S)-2-(4-氯苯基)-5′-氟-2-异丙基螺[环丙烷-1，3′-二氢吲哚]-2′-酮开始，与实施例95类似地制备标题化合物。C₂₉H₂₄ClFN₂O₅的LC/MS m/e计算值：534，实测(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)。by 2-

Oxazolidinone (commercially available), bromo-5-iodo-benzoic acid methyl ester prepared in Example 92, (1S,2R) and (1R,2S)-2-(4- The title compound was prepared analogously to Example 95 starting from chlorophenyl)-5'-fluoro-2-isopropylspiro[cyclopropane-1,3'-indoline]-2'-one. LC/MS m/e calcd _{for C29H24ClFN2O5} : 534, found (M ₊ H) ⁺ : _535.1 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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 = 9.35 Hz, 1H) 7.64 (br.s., 1H) 7.79 (br.s., 1H) 8.11 (br.s., 1H).

Example 97

唑烷-3-基)苯甲酸(1R,2R) and (1S,2S)-3-(2-(4-chlorophenyl)-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline ]-1′-yl)-5-(2-oxo

Azolidin-3-yl)benzoic acid

唑烷酮(市售)、如在实施例92中制备的溴-5-碘-苯甲酸甲酯、如在方案2中制备的(1R，2R)和(1S，2S)-2-(4-氯苯基)-2-异丙基螺[环丙烷-1，3′-二氢吲哚]-2′-酮开始，与实施例95类似地制备标题化合物。C₂₉H₂₅ClN₂O₅的LC/MS m/e计算值：516，实测(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)。by 2-

Oxazolidinone (commercially available), bromo-5-iodo-benzoic acid methyl ester as prepared in Example 92, (1R,2R) and (1S,2S)-2-(4 The title compound was prepared analogously to Example 95 starting from -chlorophenyl)-2-isopropylspiro[cyclopropane-1,3'-indolin]-2'-one. LC _/ MS m/e calcd _{for C29H25ClN2O5} : 516, found (M+H) ⁺ : _516.1 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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

唑烷-3-基)苯甲酸(1S, 2S) and (1R, 2R)-3-(2-(4-cyanophenyl)-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline Indol]-1'-yl)-5-(2-oxo

Azolidin-3-yl)benzoic acid

唑烷酮(市售)、如在实施例92中制备的溴-5-碘-苯甲酸甲酯、如在方案2中制备的(1R，2R)和(1S，2S)-4-(2-异丙基-2′-氧代螺[环丙烷-1，3′-二氢吲哚]-2-基)苄腈开始，与实施例95类似地制备标题化合物。C₃₀H₂₅lN₃O₅的LC/MS m/e计算值：507，实测(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)。by 2-

Oxazolidinone (commercially available), bromo-5-iodo-benzoic acid methyl ester as prepared in Example 92, (1R,2R) and (1S,2S)-4-(2 The title compound was prepared analogously to Example 95 starting from -isopropyl-2'-oxospiro[cyclopropane-1,3'-indolin]-2-yl)benzonitrile. LC/MS m/e calcd _{for C30H25lN3O5} : 507, found ( _M +H) ⁺ : 508.2 _. ¹ H NMR (400MHz, DMSO-d ₆ ) 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'-indoline]-1'-yl )-5-(2-oxoimidazolidin-1-yl)benzoic acid

From ethylene urea (commercially available), bromo-5-iodo-benzoic acid methyl ester as prepared in Example 92, (1R,2R) and (1S,2S)-2- The title compound was prepared analogously to Example 92 starting from (4-chlorophenyl)spiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C26H20ClN3O4} : 473, found (M+H) ⁺ : _474.2 . ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 2.14 (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′-indoline]-1′-yl ) methyl) benzoic acid

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

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

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

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

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

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

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

(R) and (S)-3-((5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-dihydro A mixture of indol]-1'-yl)methyl)benzoate (850 mg, 2.4 mmol) and 30% sodium hydroxide in water (5 mL) was stirred at 25°C for 16 hours. The mixture was neutralized with 2N aqueous hydrochloric acid, diluted with ethyl acetate (50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by waters automated fast 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 a white solid The title compound (410 mg, 50%): LC/MS m/e calcd (M+H) ⁺ for C ₂₀ H ₁₈ FNO ₃ : 340.37, found: 340.2; LC/MS m/e for C ₂₀ H ₁₈ FNO ₃ e Calculated: 339, found (M+H) ⁺ : 340.1. ¹ H NMR (400MHz, DMSO-d ₆ ) 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, 2.53 Hz, 1H) 7.44-7.57 (m, 2H) 7.80-7.93 (m, 2H) 12.99 (s, 1H).

Example 101

唑烷-3-基)苯甲酸(R) and (S)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl) -5-(2-oxo

Azolidin-3-yl)benzoic acid

唑烷-3-基)苯甲酸酯将在乙腈(15mL)中的3-溴-5-碘-苯甲酸甲酯(682mg，2mmol)、唑烷-2-酮(191mg，2.2mmol)、CuI(76mg，0.4mmol)、碳酸钾(545mg，4mmol)和N，N’-二甲基-乙烷-1，2-二胺(86uL，0.8mmol)的悬浮液在90℃搅拌16小时。滤出沉淀并用乙酸乙酯洗涤。在真空中浓缩滤液从而产生3-溴-5-(2-氧代-

唑烷-3-基)-苯甲酸甲酯(480mg，80％)，其不经进一步的纯化而被用于下一步。Synthesis of methyl-3-bromo-5-(2-oxo

oxazolidin-3-yl)benzoate 3-bromo-5-iodo-benzoic acid methyl ester (682 mg, 2 mmol) in acetonitrile (15 mL), Oxazolidin-2-one (191mg, 2.2mmol), CuI (76mg, 0.4mmol), potassium carbonate (545mg, 4mmol) and N, N'-dimethyl-ethane-1,2-diamine (86uL, 0.8 mmol) was stirred at 90°C for 16 hours. The precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo to yield 3-bromo-5-(2-oxo-

Oxazolidin-3-yl)-benzoic acid methyl ester (480 mg, 80%), which was used in the next step without further purification.

唑烷-3-基)苯甲酸酯Synthesis of (R) and (S)-methyl-3-(5′-fluoro-2,2-dimethyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1 '-yl)-5-(2-oxo

oxazolidin-3-yl) benzoate

唑烷-3-基)苯甲酸酯(682mg，2mmol)、CuI(76mg，0.4mmol)、碳酸钾(545mg，4mmol)和N，N’-二甲基-乙烷-1，2-二胺(86uL，0.8mmol)的悬浮液在90℃搅拌16小时。滤出沉淀并用乙酸乙酯洗涤。在真空中浓缩滤液从而产生白色粉末状标题化合物(480mg，80％)，其不经进一步的纯化而被用于下一步。(R) and (S)-5'-fluoro-2,2-dimethylspiro[cyclopropane-1,3'-indoline]-2'-one (2 mmol ) (as prepared in Example 100), methyl-3-bromo-5-(2-oxo

Azolidin-3-yl)benzoate (682mg, 2mmol), CuI (76mg, 0.4mmol), potassium carbonate (545mg, 4mmol) and N,N'-dimethyl-ethane-1,2-di A suspension of the amine (86uL, 0.8mmol) was stirred at 90°C for 16 hours. The precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo to yield the title compound (480 mg, 80%) as a white powder, which was used in the next step without further purification.

唑烷-3-基)苯甲酸Synthesis of (R) and (S)-3-(5′-fluoro-2,2-dimethyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl )-5-(2-oxo

Azolidin-3-yl)benzoic acid

(R) and (S)-methyl-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'- Indoline]-1′-yl)-5-(2-oxo A mixture of oxazolidin-3-yl)benzoate (850 mg, 2.4 mmol) and 30% sodium hydroxide in water (5 mL) was stirred at 25°C for 16 hours. The mixture was neutralized with 2N aqueous hydrochloric acid, diluted with ethyl acetate (50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by waters automated fast 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 a white solid The title compound (410 mg, 50%): LC/MS m/e calcd. for C ₂₀ H ₁₈ FNO ₃ : 340, found (M+H) ⁺ : 340.; ¹ H NMR (400 MHz, MeOD) δ ppm 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 analogously to Example 100 according to Scheme 2 starting from methyl-(3-bromomethyl)-benzoate, 4-methylene-tetrahydro-pyran and isatin (commercially available) . LC/MS m/e calcd _{for C22H21NO4} : 363, found (M+H) ₊ ^: 364.2. ¹ H NMR (400MHz, DMSO-d ₆ ) 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

唑烷-3-基)-5-(2-氧代-2″，3″，5″，6″-四氢二螺[吲哚-3，1′-环丙烷-2′，4″-吡喃]-1(2H)-基)苯甲酸(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

唑烷-3-基)苯甲酸酯、4-亚甲基-四氢-吡喃、靛红(市售)开始，与实施例101类似地制备标题化合物。C₂₄H₂₂N₂O₆的LC/MS m/e计算值：434，实测(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)。According to Scheme 2, from methyl-3-bromo-5-(2-oxo

The title compound was prepared analogously to Example 101 starting from oxazolidin-3-yl)benzoate, 4-methylene-tetrahydro-pyran, isatin (commercially available). LC _/ MS m/e calcd _{for C24H22N2O6} : 434, found (M+H) ⁺ : _434.2 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline] -1'-yl)methyl)benzoic acid

From methyl-2-chloro-(3-bromomethyl)-benzoate (commercially available), (1S,2S) and (1R,2R)-2-(4-chloro The title compound was prepared analogously to Example 1 starting from phenyl)spiro[cyclopropane-1,3'-indoline]-2'-one. LC/MS m/e calcd for C ₂₄ H ₁₇ ClFNO ₃ : 421, found (M+H) ⁺ : 422.2. 1H NMR (400 MHz, DMSO-d ₆ ) 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′-indoline]-1′- base) methyl) benzoic acid

(1R,2S) and (1S,2R)-2-(pyridin-3-yl)spiro[cyclopropane-1 prepared as in Scheme 1 from 4-bromomethyl-benzoic acid methyl ester (commercially available) , 3'-indolin]-2'-one, the title compound was prepared analogously to Example 1. LC _/ MS m/e calcd _{for C23H18ClN2O3} : 370, found (M+H) ⁺ : _371.2 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline]-1′ -yl)methyl)benzoic acid

From 4-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-4-(2′-oxospiro[cyclopropane-1, The title compound was prepared analogously to Example 1 starting from 3'-indolin]-2-yl)benzonitrile. LC _/ MS m/e calcd _{for C25H18ClN2O3} : 394, found (M+H) ⁺ : _395.2 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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'-indoline]-1'- base) methyl) benzoic acid

(1R,2S) and (1S,2R)-2-(4-fluorophenyl)spiro[cyclopropane-1 , 3'-indolin]-2'-one, the title compound was prepared analogously to Example 1. LC/MS m/e calcd for _C24H18FlNO3 : 387, found (M+H) ⁺ : _{388.1 .} ¹ H NMR (400MHz, DMSO-d ₆ ) 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'- Indoline]-1'-yl)methyl)benzoic acid

From methyl-2-chloro-(3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-2-(4-chloro The title compound was prepared analogously to Example 1 starting from phenyl)-5'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one. LC/MS m/e calcd _{for C24H16Cl2FNO3} : 455, found (M ₊ H) ⁺ : 456.2 _. ¹ HNMR (400MHz, DMSO-d ₆ ) 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′-indoline] -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[ The title compound was prepared analogously to Example 1 starting from cyclopropane-1,3'-indolin]-2'-one. LC _/ MS m/e calcd for _C24H17ClFNO3 : 421, found (M+H) ⁺ : _422.2 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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'-indoline]-1'- Base) methyl) -N-methylbenzamide

From 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1 , 3'-indolin]-2'-one, the title compound was prepared analogously to Example 60. LC _/ MS m/e calcd _{for C25H21ClN2O2} : 416, found (M+H) ⁺ : _417.1 . ¹ H NMR (400MHz, MeOH-d ₄ ) 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=7.58 Hz, 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: _Calcd ^. for _{C25H21N2O2 ,} 381, found (ESI ⁺ ) [(M+H) ₊ ] 382.

Example 111

(1S, 2R) and (1R, 2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'- Base) 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]-2'-one, the title compound was prepared analogously to Example 60. LC _/ MS m/e calcd _{for C29H27ClN2O2} : 470, found (M+H) ⁺ : _471.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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'-indoline]-1'- Base) methyl) -N-(3-morpholinopropyl) benzamide

From 33-morpholinopropan-1-amine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R, 2S) and (1S, 2R)-2-(4 The title compound was prepared analogously to Example 60 starting from -chlorophenyl)spiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C31H32ClN3O3} : 529, found (M+H) ⁺ : _530.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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 = 7.33 Hz, 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 = 7.71 Hz, 1H) 7.53-7.61 (m, 1H) 7.78 (d, J = 8.08 Hz, 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'-indoline]-2'-one

From N,N-dimethyl-2-(piperazin-1-yl)ethylamine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) as prepared in Scheme 1 and The title compound was prepared analogously to Example 60 starting from (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one. LC _/ MS m/e calcd _{for C32H35ClN4O2} : 542, found (M+H) ⁺ : 543.1 _. ¹ H NMR (400MHz, CDCl ₃ ) 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'-indoline]-1'- Base) methyl) -N-(2-morpholinoethyl) benzamide

From 2-morpholinoethylamine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorobenzene) as prepared in Scheme 1 yl)spiro[cyclopropane-1,3'-indoline]-2'-one, the title compound was prepared analogously to Example 60. LC _/ MS m/e calcd _{for C30H30ClN3O3} : 515, found (M+H) ⁺ : _516.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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[ring propane-1,3'-indoline]-2'-one

From 1-(methylsulfonyl)piperazine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(4 The title compound was prepared analogously to Example 60 starting from -chlorophenyl)spiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C29H28ClN3O4S} : 549, found (M+H) ₊ ^: 550.2. ¹ H NMR (400MHz, MeOD-d ₄ ) 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'-indoline]-1'- Base) methyl) -N-(3-cyclopropyl-1H-pyrazol-5-yl) benzamide

Prepared as in Scheme 1 from 3-cyclopropyl-1H-pyrazol-5-amine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R, 2S) and (1S, 2R)- The title compound was prepared analogously to Example 60 starting from 2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one. LC _/ MS m/e calcd _{for C30H25ClN4O2} : 508, found (M+H) ⁺ : _509.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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'-indoline]-1'- Base) methyl) -N-(5-cyclopropyl-1H-pyrazol-3-yl) benzamide

Prepared as in Scheme 1 from 5-cyclopropyl-1H-pyrazol-3-amine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R, 2S) and (1S, 2R)- The title compound was prepared analogously to Example 60 starting from 2-(4-chlorophenyl)spiro[cyclopropane-1,3'-indolin]-2'-one. LC _{/MS m/e calcd for C30H25ClN4O2 : 508} , found (M+H) ⁺ : _509.2 . ¹ H NMR (400MHz, MeOD-d ₄ ) 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 = 7.83 Hz, 1H) 7.94 (s, 1H).

Example 118

(1R, 2S) and (1S, 2R)-6-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′ -yl)methyl)-N-(cyclopropylsulfonyl)pyridineamide

(1R,2S) and (1S,2R)-4-(2′-oxospiro[ The title compound was prepared analogously to Example 60 starting from cyclopropane-1,3'-indolin]-2-yl)benzonitrile. LC _/ MS m/e _{calcd for C27H22N4O4S} : 498, found (M+H) ⁺ : 499.2. ¹ HNMR (400MHz, DMSO-d ₆ ) 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′-indoline]-1′ -yl)methyl)-N-(cyclopropylsulfonyl)benzamide

(1R,2S) and (1S,2R)-4-(2′-oxospiro[ The title compound was prepared analogously to Example 60 starting from cyclopropane-1,3'-indolin]-2-yl)benzonitrile. LC/MS m/e calcd for C ₂₈ H ₂₃ ClN ₃ O ₄ S: 497, found (M+H) ⁺ : 498.2, 1H NMR (400MHz, DMSO-d ₆ ) 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'-indoline]-1'- base)methyl)-N-(methylsulfonyl)benzamide

(1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro The title compound was prepared analogously to Example 60 starting from [cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C25H21ClN2O4S} : 480, found (M+H) ⁺ : _481.2 . ¹ HNMR (400MHz, DMSO-d ₆ ) 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′-indoline]-1′- base)methyl)-N-(methylsulfonyl)benzamide

(1R,2S) and (1S,2R)-2-(4-fluorophenyl)spiro The title compound was prepared analogously to Example 60 starting from [cyclopropane-1,3'-indoline]-2'-one. _{LC /} MS m/e calcd _{for C25H21FN2O4S :} 470, found (M+H) ⁺ : 471.2. ¹ HNMR (400MHz, DMSO-d ₆ ) 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′ -Indoline]-1'-yl)methyl)benzamide

From 3-bromomethyl-benzoic acid methyl ester, cyclopropanesulfonamide (commercially available), (1R,2S) and (1S,2R)-2-(4-fluorophenyl)spiro The title compound was prepared analogously to Example 60 starting from [cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C27H23FN2O4S :} 490, found (M+H ₎ ⁺ : 491.2. ¹ HNMR (400MHz, DMSO-d ₆ ) 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′ -Indoline]-1'-yl)methyl)benzamide

(1R,2S) and (1S,2R)-2-(4-fluorophenyl)spiro The title compound was prepared analogously to Example 60 starting from [cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C27H23FN2O4S :} 490, found (M+H ₎ ⁺ : 491.2. ¹ H NMR (400MHz, DMSO-d ₆ ) 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′-indoline] -2'-one

From 4-(chloromethyl)piperidine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1, as prepared in Scheme 1, The title compound was prepared analogously to Example 70 starting from 3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C22H23ClN2O} : 366, found (M+H) ⁺ : 367.2. ¹ HNMR (400MHz, MeOD-d ₄ ) 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 = 7.58 Hz, 1H) 7.11 (d, J = 7.83 Hz, 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′-di Indoline]-2′-one

From 1-(2-chloroethyl)piperidine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane- The title compound was prepared analogously to Example 70 starting from 1,3'-indolin]-2'-one. LC _/ MS m/e calcd _{for C23H25ClN2O} : 380, found (M+H) ⁺ : 371.2. ¹ HNMR (400MHz, MeOD-d ₄ ) 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) ( m, 2H).

Example 126

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

From 1-(3-chloropropyl)piperidine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane- The title compound was prepared analogously to Example 70 starting from 1,3'-indolin]-2'-one. LC _/ MS m/e calcd for _C24H27ClN2O : 394, found (M+H) ⁺ : _395.2 . ¹ HNMR (400MHz, MeOD-d ₄ ) 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

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

From ethylene dibromide, 3-morpholinopropan-1-amine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro The title compound was prepared analogously to Example 81 starting from [cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C25H30ClN3O2} : 439, found (M+H) ⁺ : 440.1 _. ¹ HNMR (400MHz, MeOD-d ₄ ) 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′ -Indoline]-2'-one

(1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane] prepared as in Scheme 1 from ethylene dibromide, 2-morpholinoethylamine (commercially available) -1,3'-indolin]-2'-one, the title compound was prepared analogously to Example 81. LC _/ MS m/e calcd _{for C24H28ClN3O2} : 425, found (M+H) ⁺ : 426.2 _. ¹ HNMR (400MHz, MeOD-d ₄ ) 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'-indoline]-2'-one

From ethylene dibromide, 1-(pyridin-4-yl)piperazine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl) as prepared in Scheme 1 The title compound was prepared analogously to Example 81 starting from spiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd for _C27H27ClN4O : 458, found (M+H) ⁺ : _459.2 . ¹ HNMR (400MHz, MeOD-d ₄ ) 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'-indoline]-2'-one

From 2-(2,6-dimethylmorpholino)ethylamine, ethylene dibromide (commercially available), (1R,2S) and (1S,2R)-2-(4 The title compound was prepared analogously to Example 81 starting from -chlorophenyl)spiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C26H32ClN3O2} : 453, found (M+H) ⁺ : 454.1 _. ¹ HNMR (400MHz, MeOD-d ₄ ) 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

(1S, 2R) and (1R, 2S)-2-(4-chlorophenyl)-1′-(1H-imidazol-4-yl)spiro[cyclopropane-1,3′-indoline]- 2′-keto

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

4-Iodo-1-trityl-1H-imidazole (210 mg, 0.48 mmol) was added to (1R, 2S) and (1S, 2R)-2-(4 -Chlorophenyl)spiro[cyclopropane-1,3'-indoline]-2'-one (107mg, 0.4mmol) in suspension. A steady stream of nitrogen was bubbled through the suspension while heating the suspension to 40°C for 15 minutes. Potassium carbonate (110 mg, 0.8 mmol), copper(I) iodide (12 mg, 15 mol%) and N,N-dimethylethylenediamine (0.12 mmol, 30 mol%) were added and the reaction mixture was heated to 80°C for 21 hours. The mixture was cooled to room temperature, filtered and concentrated to give the title product. The residue was purified by flash column chromatography (gradient elution, 5-10% ethyl acetate in petroleum ether) to give racemic trans-2-(4-chlorophenyl)-1'-(1H-imidazole -4-trityl)spiro[cyclopropane-1,3'-indoline]-2'-one (157 mg, 68%). LC _/ MS m/e calcd _{for C38H28ClN3O} : 577, found (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'-one

(1S, 2R) and (1R, 2S)-2-(4-chlorophenyl)-1′-(1-trityl-1H-imidazol-4-yl)spiro[cyclopropane-1,3 '-Indoline]-2'-one (115 mg, 0.2 mmol) was dissolved in DCM (2 mL) and water (0.5 mL). TFA (0.1 mL) was added dropwise at 0°C. The mixture was stirred at room temperature for 14 hours. The mixture was poured into saturated NaHCO ₃ , extracted with DCM (3 x 10 mL), dried and concentrated to give the title product. The residue was dissolved in 2 mL DMF. Purification by preparative HPLC gave the title compound (60 mg, 89%) as a white powder. ¹ H NMR (400MHz, DMSO-d ₆ ) 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). LC _/ MS m/e calcd _{for C19H14ClN3O} 335, found (M+H) ⁺ : 336.3.

Example 132

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

From methanesulfonamide, methyl-3-iodobenzoate (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl) as prepared in Scheme 1 The title compound was prepared analogously to Example 85 starting from spiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C24H19ClN2O4S} : 466, found ( _M +H) ⁺ : 467.2. ¹ H NMR (400MHz, DMSO-d ₆ ) 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

唑烷-3-基)苯甲酸(1S, 2S) and (1R, 2R)-3-(2-(4-chlorophenyl)-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline] -1′-yl)-5-(2-oxo

Azolidin-3-yl)benzoic acid

唑烷-2-酮(市售)、在实施例92中制备的3-溴-5-碘代苯甲酸甲酯、如在方案2中制备的(1R，2R)和(1S，2S)-2-(4-氯苯基)-2-甲基螺[环丙烷-1，3′-二氢吲哚]-2′-酮开始，与实施例95类似地制备标题化合物。C₂₇H₂₁ClN₂O₅的LC/MS m/e计算值：488，实测(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)。Depend on

Oxazolidin-2-one (commercially available), methyl 3-bromo-5-iodobenzoate prepared in Example 92, (1R,2R) and (1S,2S) as prepared in Scheme 2- The title compound was prepared analogously to Example 95 starting from 2-(4-chlorophenyl)-2-methylspiro[cyclopropane-1,3'-indolin]-2'-one. LC _/ MS m/e calcd _{for C27H21ClN2O5} : 488, found (M+H) ⁺ : _489.1 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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 = 2.02 Hz, 1H) 8.12 (s, 1H).

Example 134

唑烷-3-基)苯甲酸(1S, 2S) and (1R, 2R)-3-(2-(4-chlorophenyl)-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline ]-1′-yl)-5-(2-oxo

Azolidin-3-yl)benzoic acid

唑烷-2-酮、3-溴-5-碘代苯甲酸甲酯(如在实施例92中制备的)、如在方案2中制备的(1R，2R)和(1S，2S)-2-(4-氯苯基)-2-异丙基螺[环丙烷-1，3′-二氢吲哚]-2′-酮开始，与实施例95类似地制备标题化合物。C₂₉H₂₅ClN₂O₅的LC/MS m/e计算值：516，实测(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)。Depend on

Oxazolidin-2-one, methyl 3-bromo-5-iodobenzoate (as prepared in Example 92), (1R,2R) and (1S,2S)-2 as prepared in Scheme 2 The title compound was prepared analogously to Example 95 starting from -(4-chlorophenyl)-2-isopropylspiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C29H25ClN2O5} : 516, found (M+H) ⁺ : _517.2 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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

唑烷-3-基)苯甲酸(1S, 2S) and (1R, 2R)-3-(2-(4-chlorophenyl)-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline ]-1′-yl)-5-(2-oxo

Azolidin-3-yl)benzoic acid

唑烷-2-酮、3-溴-5-碘代苯甲酸甲酯(如在实施例92中制备的)、如在方案2中制备的(1S，2S)和(1R，2R)-2-(4-氯苯基)-2-异丙基螺[环丙烷-1，3′-二氢吲哚]-2′-酮开始，与实施例95类似地制备标题化合物。C₂₉H₂₅ClN₂O₅的LC/MS m/e计算值：516，实测(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)。Depend on

Oxazolidin-2-one, methyl 3-bromo-5-iodobenzoate (as prepared in Example 92), (1S,2S) and (1R,2R)-2 as prepared in Scheme 2 The title compound was prepared analogously to Example 95 starting from -(4-chlorophenyl)-2-isopropylspiro[cyclopropane-1,3'-indoline]-2'-one. LC _/ MS m/e calcd _{for C29H25ClN2O5} : 516, found (M+H) ⁺ : _517.2 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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

唑烷-3-基)苯甲酸酯(R) and (S)-methyl-3-(2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-5 -(2-oxo

oxazolidin-3-yl) benzoate

唑烷-3-基)苯甲酸甲酯(682mg，2mmol)(如在实施例100中制备的)、CuI(76mg，0.4mmol)、碳酸钾(545mg，4mmol)和N，N’-二甲基-乙烷-1，2-二胺(86uL，0.8mmol)的悬浮液在90℃搅拌16小时。滤出沉淀并用乙酸乙酯洗涤。在真空中浓缩滤液从而产生白色粉末状标题化合物(480mg，80％)。C₂₃H₂₁FN₂O₅的LC/MS m/e计算值：424，实测(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)。(R) and (S)-5'-fluoro-2,2-dimethylspiro[cyclopropane-1,3'-indoline]-2'-one (2 mmol ) (as prepared in Example 100), 3-bromo-5-(2-oxo

Azolidin-3-yl)methylbenzoate (682mg, 2mmol) (as prepared in Example 100), CuI (76mg, 0.4mmol), potassium carbonate (545mg, 4mmol) and N,N'-dimethyl A suspension of oxy-ethane-1,2-diamine (86uL, 0.8mmol) was stirred at 90°C for 16 hours. The precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo to yield the title compound (480 mg, 80%) as a white powder. LC _/ MS m/e calcd _{for C23H21FN2O5 :} 424, found (M+H) ⁺ : _425.2 . ¹ H NMR (400MHz, DMSO-d ₆ ) 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'-indoline]-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 as prepared in Scheme 2 The title compound was prepared analogously to Example 95 starting from '-fluoro-2,2-dimethylspiro[cyclopropane-1,3'-indolin]-2'-one. LC/MS m/e calcd _{for C21H21FN2O4 :} 384 _, found (M ₊ H) ⁺ : 385.1. ¹ H NMR (400MHz, MeOD-d ₄ ) 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

唑烷-3-基)-5-(2-氧代-2″，3″，5″，6″-四氢二螺[吲哚-3，1′-环丙烷-2′，4″-吡喃]-1(2H)-基)苯甲酸酯(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 The title compound was prepared analogously to Example 101 starting from oxazolidin-3-yl)benzoate, 4-methylenetetrahydro-2H-pyran, isatin (commercially available). LC _/ MS m/e calcd _{for C25H24ClN2O6} : 448, found (M+H) ⁺ : _449.2 . ¹ HNMR (400MHz, DMSO-d ₆ ) 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′-dihydro Indole]-5′-carboxylic acid

Synthesis of (Z)-methyl-3-(4-fluorobenzylidene)-2-oxoindoline-5-carboxylate

To a solution of methyl-2-oxindole-5-carboxylate (4.764 g) in EtOH (100 mL) was added 4-fluoro-benzaldehyde (4.72 mL) in one portion, followed by the addition of piperidine ( 790 μL). The mixture was refluxed for 3 hours and a 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′- Formate

A solution of dimethylsulfoxamethylenesulfoxonium was prepared from 60% NaH dispersion in mineral oil (88 mg, 2.2 mmol), trimethylsulfoxide iodide (2.2 mmol) and DMSO (10 mL) under argon. After 20 min, a solution of (Z)-methyl-3-(4-fluorobenzylidene)-2-oxoindoline-5-carboxylate (594 mg, 2 mmol) in THF (5 mL) Added dropwise over 20 minutes. After stirring at room temperature for 1 hour and at 50° C. for another hour, the solution was poured into ice-cold water (20 mL) and extracted with diethyl 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 yield the title compound as a white solid (317 mg, 51% yield). LC/MS m/e calcd _{for C18H14FNO3} : 311, found (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[cyclo] in methanol (1 mL), water (0.1 mL) at room temperature Lithium hydroxide (10 mg) was added to a solution of propane-1,3'-indoline]-5'-carboxylate (80 mg). The mixture was stirred at room temperature for 14 hours. Completion of the reaction was monitored by HPLC. The solvent was removed under reduced pressure. The residue was dissolved in 2 mL DMF. Purification by preparative HPLC yielded the title compound (30 mg) as a white solid. LC _{/MS m/e calcd. for C17H12FNO3 :} 297, found (MH) ⁺ : ₂₉₆ . ¹ HNMR (400MHz, DMSO-d ₆ ) 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, 1.52 Hz, 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'-formate

(1S, 2R) and (1R, 2S)-methyl-2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′- Formate (500 mg, 1.61 mmol), 1-bromomethyl-2-fluoro-benzene (456 mg, 2.14 mmol) and Cs ₂ CO ₃ (785 mg, 4.2 mmol) were mixed in anhydrous DMF and stirred at room temperature for 8 hours . Completion of the reaction was monitored by HPLC. 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 (405 mg, 60%) as a white solid. LC _/ MS m/e calcd _{for C25H19F2NO3 420} , found (M+H) ₊ ^: 420.5. Synthesis of (1R,2S) and (1S,2R)-1′-(3-fluorobenzyl)-2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-bis Indoline]-5′-carboxylic acid

(1R,2S) and (1S,2R)-methyl-1'-(3-fluorobenzyl)-2-( Lithium hydroxide (50 mg) was added to a solution of 4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylate (50 mg). The mixture was heated to 60°C and stirred at 60°C for 3 hours. Completion of the reaction was monitored by HPLC. The solvent was removed under reduced pressure. Purification by preparative HPLC yielded the title compound (10 mg) as a white powder. LC/MS m/e calcd _{for C24H17F2lNO3 :} 405, found (M ₊ H) ⁺ : 406.2 _. ¹ H 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: _{Calcd. for C24H17F2NO3 406 ,} found (ESI ⁺ ) [(M+H) ⁺ ] _406.4 .

Example 140

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

Prepared analogously to Example 139 starting from methyl-2-oxoindoline-5-carboxylate, 1-(bromomethyl)-3-fluorobenzene, 4-fluorobenzaldehyde (commercially available) title compound. LC/MS m/e calcd _{for C24H17F2lNO3 :} 405, found (M ₊ H) ⁺ : 406.2 _. ¹ HNMR (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, 4.80 Hz, 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 analogously to Example 139 starting from methyl-2-oxoindoline-5-carboxylate, 4-fluorobenzaldehyde (commercially available). LC/MS m/e calcd for _C17H12FNO3 : 297, found (M+H) ₊ ^: _298.2 . ¹ HNMR (400MHz, DMSO-d ₆ ) 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 analogously to Example 139 starting from methyl-2-oxoindoline-5-carboxylate, 4-formylbenzonitrile (commercially available). LC _/ MS m/e calcd for _C18H12N2O3 : 304, found ( _M +H) ⁺ : 305.2 _. ¹ HNMR (400MHz, DMSO-d ₆ ) 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 analogously to Example 139 starting from methyl-2-oxoindoline-5-carboxylate, 4-formylbenzonitrile. LC _/ MS m/e calcd for _C18H12N2O3 : 304, found ( _M +H) ⁺ : 305.2 _. ¹ HNMR (400MHz, DMSO-d ₆ ) 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, 3.41 Hz, 3H) 7.85 (dd, J=8.21, 1.64 Hz, 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

(1R,2S) and (1S,2R)-methyl-2-(4-fluorophenyl)-2'-oxospiro[cyclo] in methanol (1 mL) and water (0.1 mL) at room temperature To a solution of propane-1,3'-indoline]-5'-carboxylate (80 mg) (prepared as in Example 139) was added lithium hydroxide (10 mg). The mixture was stirred at room temperature for 14 hours. Completion of the reaction was monitored by HPLC. The solvent was removed under reduced pressure. Purification by preparative HPLC yielded the title compound (30 mg) as a white solid. LC/MS m/e calcd for _C17H12FNO3 : 297, found ( _M +H) ₊ ^: 298.2. LC/MS m/e calculated for C ₁₇ H ₁₂ FNO ₃ : 297.08, found (MH) ⁺ : 296.1; ¹ HNMR (400MHz, DMSO-d ₆ ) 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 analyzing AMPK and ACC phosphorylation

This method uses Western blot analysis to assess the endogenous expression and phosphorylation of AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase (ACC) in L6 cell lines. This was used to determine the potency 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 ^3x106 /plate in 10ml on 10cm dishes and they reached 70-80% subconfluency within 24 hours. Cells were subjected to overnight serum starvation prior to treatment with AMPK modulators. Compound concentrations typically range from 0 to 100 [mu]M and cells are treated for 1-4 hours. Once the incubation is complete, the medium is aspirated and the cell layer is gently washed with 2 ml of ice-cold PBS. Add 500 ul of lysis buffer comprising 150 mM NaCl, 5 mM EDTA, 2 mM EGTA, 25 mM NaF, 2 mM Na ₃ VO ₄ , 1 mg/ml Pefabloc, 1% Triton X-100 and Roche Complete Protease Inhibitor Tablet (Roche Complete Protease Inhibitor Tablet) and It was incubated on ice for 10 min. Cell lysates were collected and centrifuged at 12,000 rpm for 10 min at 4°C. The supernatant was retained and its protein concentration was determined using the Quick Start Bradford Protein Quantification Kit (Bio-Rad). 40 μg was loaded for 7.5% SDS-PAGE analysis and then blotted to PVDF membrane following standard procedures. The membrane was treated with blocking buffer (5% skim milk) for 1 h at room temperature with stirring. Phospho-AMPKα (Thr172) (40H9) rabbit mAb (Cell Signaling) and phospho-acetyl CoA carboxylase (Ser79) antibody (Cell Signaling) were used as primary antibodies, and phospho-AMPK and Phospho-ACC levels. The blot was stripped and reprobed using Acetyl CoA Carboxylase (C83B10) Rabbit mAb (Cell Signaling), AMPK (23A3) Rabbit mAb (Cell Signaling), and β-Actin Antibody (Cell Signaling) to determine ACC, AMPK, and β, respectively Global protein levels of actin. Individual protein bands in the blot were visualized and quantified by scanning analysis using the ECL Plus Western Blot Detection Kit (Amersham). _EC50 values (defined as the concentration of activator that produces half the maximum level of protein phosphorylation) and Emax (defined as the maximum phosphorylation at infinite activator concentration) were determined semiquantitatively and recorded.

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

Example 146

Scintillation Proximity Assay

Enzyme preparation

As previously described (Pang, 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) Constructed, expressed and purified recombinant human AMPKα1β1γ1, α2β1γ1 or AMPKα subunit truncations α1(1-335), α1(1-394) and α2(1-394) or purchased from Invitrogen (San Diego , CA, U.S.A.). The rat liver AMPK heterotrimer enzyme was obtained from Upstate (Billerica, MA, U.S.A.).

scintillation proximity assay

200 nM recombinant AMPK proteins (α1β1γ1, α2β1γ1, α1(1-335), α1(1-394) or α2(1-394)) were fully phosphorylated as previously described before the scintillation proximity assay (SPA) (Pang et al., 2008). In a 96-well plate, in a final volume of 50 μl (containing 20 mM Tris-HCl pH 7.5, 5 mM MgCl ₂ , 1 mM DTT, 2 μM biotin-SAMS, 2 μM ATP, 0.2 μCi/well [γ- ³³ p]ATP and different amounts activator) for SPA reaction. Reactions were initiated by adding 50 nM recombinant AMPK protein to the reaction solution and incubated at 30°C for 2 hrs. Afterwards, the reaction was allowed to react by adding 40 μl of a stop solution containing 80 μg streptavidin-coated SPA beads/well, 50 mM EDTA, 0.1% Triton X-100 in PBS (pH 7.5) and incubating for 1 hr termination. Finally, 160 µl of a suspension solution containing 2.4 MCsCl, 50 mM 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 30 min, the SPA signal was measured using a Wallac MicroBeta plate counter (PerkinElmer) for calculation of the amount of product formed. The amount of product formed over 2 hours was plotted against the concentration of activator to determine the effective concentration of activator required for 50% maximal enzyme activity ( _EC50 ).

Compounds as described above have _EC50 values between 0.5 uM and 50 uM. Preferred compounds have _EC50 values between 0.5 uM and 10 uM. Especially preferred compounds have _EC50 values between 0.5 uM and 1 uM. These results have been obtained using the scintillation proximity assay described above (uM means micromolar).

The _EC50 values obtained for the specific compounds of formula (I) are listed in the table below.

Example _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 compound of formula (I) can be used in a manner known per se as active ingredient for the preparation of tablets having the following composition:

Example B

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

Claims (17)

1. Compounds of formula (I)

in R ^and R are ^{independently} selected from hydrogen, alkyl, pyridyl, phenyl, halophenyl, alkoxyphenyl, alkylsulfonylphenyl, cyanophenyl and trifluoromethylphenyl; Or R ¹ and R ² form cycloalkyl or tetrahydropyranyl together with the carbon atoms they are bound to; ^R3 is hydrogen, pyridyl, piperidinyl, carboxypyridyl, tetrahydropyranyl, alkylamino, morpholinyl, morpholinylalkylamino, alkylmorpholinylalkylamino, alkylsulfonyl Piperidinyl, alkylpiperazinyl, alkylaminoalkylpiperazinyl, pyridylpiperazinyl, alkylaminopyrrolidinyl, 1H-imidazolyl, carboxyalkyl-1H-imidazolyl, carboxy-1H- imidazolyl, cycloalkylsulfonylaminocarbonylpyridyl, or substituted phenyl, wherein substituted phenyl is phenyl substituted with one or two substituents independently selected from the following groups: alkyl, halogen, hydroxy Alkylamino, Carboxyl, Alkylsulfonyl, Alkylaminocarbonyl, Alkylsulfonylaminocarbonyl, Piperidinylcarbonyl, Piperazinylcarbonyl, Morpholinylcarbonyl, Pyridylpiperazinylcarbonyl, Alkylpiperazinyl Carbonyl, alkylsulfonylpiperazinylcarbonyl, alkylpyrrolidinylaminocarbonyl, alkyl-1H-pyrazolylaminocarbonyl, oxo-

Oxazolidinyl, oxo-pyrrolidinyl, oxo-imidazolidinyl, morpholinylalkylaminocarbonyl, alkylaminoalkylpiperazinylcarbonyl, cycloalkyl-1H-pyrazolylaminocarbonyl and cycloalkane Sulfonylaminocarbonyl; ^R is hydrogen, halogen, carboxy, cyano, trifluoromethyl or alkylsulfonyl; and n is 0, 1, 2 or 3; or a pharmaceutically acceptable salt or ester thereof. 2. The compound according to claim 1, wherein one of R ^{and R} is selected from hydrogen and alkyl and the other is selected from pyridyl, halophenyl, alkylsulfonylphenyl, cyanophenyl and Trifluoromethylphenyl. 3. The compound according to any one of claims 1 or ² , wherein one of R and R is selected ^from hydrogen and isopropyl and the other is selected from pyridyl, fluorophenyl, chlorophenyl, cyano phenyl, methylsulfonylphenyl and trifluoromethylphenyl. 4. The compound according to any ^one of claims 1-3, wherein R is pyridyl, carboxypyridyl, tetrahydropyranyl, dialkylamino, morpholinyl, alkylsulfonylpiperidinyl , alkylpiperazinyl, dialkylaminoalkylpiperazinyl, dialkylaminopyrrolidinyl, carboxyalkyl-1H-imidazolyl, carboxy-1H-imidazolyl or substituted phenyl, wherein substituted benzene The radical is phenyl substituted by one or two substituents independently selected from the following groups: alkyl, halogen, carboxyl, alkylsulfonyl, alkylaminocarbonyl, alkylsulfonylaminocarbonyl, piperidinylcarbonyl , piperazinylcarbonyl, morpholinylcarbonyl, pyridylpiperazinylcarbonyl, alkylpiperazinylcarbonyl, alkylsulfonylpiperazinylcarbonyl, alkylpyrrolidinylaminocarbonyl, alkyl-1H-pyrrolidinyl Azolylaminocarbonyl, oxo-

Oxazolidinyl, oxo-pyrrolidinyl and oxo-imidazolidinyl. 5. The compound according to any one of claims 1-4, wherein R ³ is carboxypyridyl, carboxyalkyl-1H-imidazolyl, carboxyphenyl or carboxyl and oxo-

Azolidinyl-substituted phenyl groups. 6. The compound according to any one of claims 1-5, wherein ^R4 is hydrogen, halogen or carboxy. 7. The compound according to any one of claims 1-6, wherein R ⁴ is hydrogen, fluoro, chloro or carboxyl. 8. The compound according to any one of claims 1-7, wherein n is 0 or 1 . 9. The compound according to any one of claims 1-8, selected from the group consisting of (1R,2S)-3-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2R)-3-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1R,2R)-3-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2S)-3-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2R)-3-((2-(3-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1R, 2S)-3-((2-(3-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1R, 2R)-((2-(4-(methylsulfonyl)phenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methanol base) benzoic acid; (1S, 2S)-((2-(4-(methylsulfonyl)phenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methanol base) benzoic acid; (1S, 2R)-3-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) benzoic acid; (1R, 2S)-3-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) benzoic acid; (1S, 2R)-2-Chloro-5-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid; (1R,2S)-2-chloro-5-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl) Methyl)benzoic acid; (1S, 2R)-3-((2-(4-(methylsulfonyl)phenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1R, 2S)-3-((2-(4-(methylsulfonyl)phenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1S, 2R)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1R, 2S)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2S)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1R, 2R)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2R)-3-((2-(3-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1R, 2S)-3-((2-(3-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2S)-3-((2-(3-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1R, 2R)-3-((2-(3-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2S)-3-((2′-oxo-2-(2-(trifluoromethyl)phenyl)-spiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid; (1R,2R)-3-((2′-oxo-2-(2-(trifluoromethyl)phenyl)-spiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid; (1S, 2R)-((5'-chloro-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl base) benzoic acid; (1R, 2S)-((5'-chloro-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl base) benzoic acid; (1R, 2R)-3-((5'-chloro-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1S, 2S)-3-((5'-chloro-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1R, 2R)-3-((5'-bromo-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1S, 2S)-3-((5'-bromo-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1S, 2R)-3-((5'-bromo-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1R, 2S)-3-((5'-bromo-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1S, 2S)-3-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) benzoic acid; (1R, 2R)-3-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) benzoic acid; (1S, 2R)-3-((2-(3-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl )benzoic acid; (1R, 2S)-3-((2-(3-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl )benzoic acid; (1S, 2S)-3-((2-(3-methoxyphenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl )benzoic acid; (1R, 2R)-3-((2-(3-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl )benzoic acid; (1S, 2S)-3-((2-(4-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl )benzoic acid; (1R, 2R)-3-((2-(4-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl )benzoic acid; (1S, 2R)-3-((2-(4-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl )benzoic acid; (1R, 2S)-3-((2-(4-methoxyphenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl )benzoic acid; (1S, 2R)-3-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1R, 2S)-3-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1S, 2S)-3-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1R, 2R)-3-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1S, 2R)-3-((-2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) benzoic acid; (1R, 2S)-3-((-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl) benzoic acid; (1S, 2R)-3-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1R, 2S)-3-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2S)-3-((-2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) benzoic acid; (1R, 2R)-3-((-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl) benzoic acid; (1S, 2S)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'- base) methyl) benzoic acid; (1R,2R)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'- base) methyl) benzoic acid; (1S, 2S)-3-((2-(4-cyanophenyl)-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid; (1R,2R)-3-((2-(4-cyanophenyl)-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid; (1S,2R)-3-((2-(4-cyanophenyl)-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid; (1R,2S)-3-((2-(4-cyanophenyl)-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid; (+)-3-((2-(4-Chlorophenyl)-2-isopropyl-2′-oxospiro[(trans)-cyclopropane-1,3′-indoline]- 1'-yl)methyl)benzoic acid; (-)-3-((2-(4-chlorophenyl)-2-isopropyl-2′-oxospiro[(trans)-cyclopropane-1,3′-indoline]- 1'-yl)methyl)benzoic acid; (1S, 2S)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'- base) methyl) benzoic acid; (1R,2R)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'- base) methyl) benzoic acid; (+)-3-((2-(4-chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[(trans)-cyclopropane-1,3′-di Indoline]-1'-yl)methyl)benzoic acid; (-)-3-((2-(4-chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[(trans)-cyclopropane-1,3′-di Indoline]-1'-yl)methyl)benzoic acid; (1S,2S)-3-((2-(4-chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline ]-1'-yl)methyl)benzoic acid; (1R,2R)-3-((2-(4-Chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline ]-1'-yl)methyl)benzoic acid; (1S,2S)-3-((5′-fluoro-2-(4-fluorophenyl)-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline ]-1'-yl)methyl)benzoic acid; (1R,2R)-3-((5′-fluoro-2-(4-fluorophenyl)-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline ]-1'-yl)methyl)benzoic acid; (1S, 2S)-3-((2-(3-fluorophenyl)-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid; (1R,2R)-3-((2-(3-fluorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'- base) methyl) benzoic acid; (1S,2S)-3-((2-(3-Chlorophenyl)-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid; (1R,2R)-3-((2-(3-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'- base) methyl) benzoic acid; (1S, 2S)-3-((2-(4-fluorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'- base) methyl) benzoic acid; (1R,2R)-3-((2-(4-fluorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'- base) methyl) benzoic acid; (+)-3-((2-(4-Chlorophenyl)-2-isopropyl-2′-oxospiro[(trans)-cyclopropane-1,3′-indoline]- 1'-yl)methyl)benzoic acid; (-)-3-((2-(4-chlorophenyl)-2-isopropyl-2′-oxospiro[(trans)-cyclopropane-1,3′-indoline]- 1'-yl)methyl)benzoic acid; (1R, 2S)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1S, 2R)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (+)-3-((2-(4-chlorophenyl)-2-methyl-2′-oxospiro[(trans)-cyclopropane-1,3′-indoline]-1 '-yl)methyl)benzoic acid; (-)-3-((2-(4-chlorophenyl)-2-methyl-2′-oxospiro[(trans)-cyclopropane-1,3′-indoline]-1 '-yl)methyl)benzoic acid; (1R, 2R)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1S, 2S)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (+)-3-((2-(4-chlorophenyl)-2-methyl-2′-oxospiro[(cis)-cyclopropane-1,3′-indoline]-1 '-yl)methyl)benzoic acid; (-)-3-((2-(4-chlorophenyl)-2-methyl-2′-oxospiro[(cis)-cyclopropane-1,3′-indoline]-1 '-yl)methyl)benzoic acid; (1R,2S)-3-((2-(4-cyanophenyl)-5′-fluoro-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline ]-1'-yl)methyl)benzoic acid; (1S,2R)-3-((2-(4-cyanophenyl)-5′-fluoro-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline ]-1'-yl)methyl)benzoic acid; (-)-3-((2-(4-cyanophenyl)-5′-fluoro-2-methyl-2′-oxospiro[(trans)-cyclopropane-1,3′-di Indoline]-1'-yl)methyl)benzoic acid; (+)-3-((2-(4-cyanophenyl)-5′-fluoro-2-methyl-2′-oxospiro[(trans)-cyclopropane-1,3′-di Indoline]-1'-yl)methyl)benzoic acid; (1S,2S)-3-((2-(4-cyanophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1' -yl)methyl)benzoic acid; (1R,2R)-3-((2-(4-cyanophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1' -yl)methyl)benzoic acid; (-)-3-((2-(4-cyanophenyl)-2-isopropyl-2′-oxospiro[(trans)-cyclopropane-1,3′-indoline] -1'-yl)methyl)benzoic acid; (+)-3-((2-(4-cyanophenyl)-2-isopropyl-2′-oxospiro[(trans)-cyclopropane-1,3′-indoline] -1'-yl)methyl)benzoic acid; (1R,2R)-3-((2-(4-cyanophenyl)-5′-fluoro-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline ]-1'-yl)methyl)benzoic acid; (1S,2S)-3-((2-(4-cyanophenyl)-5′-fluoro-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline ]-1'-yl)methyl)benzoic acid; (-)-3-((2-(4-cyanophenyl)-5′-fluoro-2-methyl-2′-oxospiro[(cis)-cyclopropane-1,3′-di Indoline]-1'-yl)methyl)benzoic acid; (+)-3-((2-(4-cyanophenyl)-5′-fluoro-2-methyl-2′-oxospiro[(cis)-cyclopropane-1,3′-di Indoline]-1'-yl)methyl)benzoic acid; (1R,2S)-3-((2-(4-chlorophenyl)-5'-fluoro-2-methyl-2'-oxospiro[cyclopropane-1,3'-indoline] -1'-yl)methyl)benzoic acid; (1S,2R)-3-((2-(4-Chlorophenyl)-5′-fluoro-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline] -1'-yl)methyl)benzoic acid; (-)-3-((2-(4-chlorophenyl)-5′-fluoro-2-methyl-2′-oxospiro[(trans)-cyclopropane-1,3′-dihydro Indole]-1'-yl)methyl)benzoic acid; (+)-3-((2-(4-chlorophenyl)-5′-fluoro-2-methyl-2′-oxospiro[(trans)-cyclopropane-1,3′-dihydro Indole]-1'-yl)methyl)benzoic acid; (1S,2R)-2-(4-Chlorophenyl)-1′-(3-(piperidine-1-carbonyl)benzyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone; (1R,2S)-2-(4-Chlorophenyl)-1′-(3-(piperidine-1-carbonyl)benzyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone; (1R, 2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-isopropylbenzamide; (1S, 2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-isopropylbenzamide; (1S,2R)-2-(4-Chlorophenyl)-1′-(3-(piperazine-1-carbonyl)benzyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone; (1R,2S)-2-(4-Chlorophenyl)-1′-(3-(piperazine-1-carbonyl)benzyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone; (1R,2S)-2-(4-Chlorophenyl)-1′-(3-(morpholine-4-carbonyl)benzyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone; (1S,2R)-2-(4-Chlorophenyl)-1′-(3-(morpholine-4-carbonyl)benzyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone; (1R,2S)-2-(4-chlorophenyl)-1'-(3-(4-(pyridin-4-yl)piperazine-1-carbonyl)benzyl)spiro[cyclopropane-1,3 '-indoline]-2'-one; (1S, 2R)-2-(4-chlorophenyl)-1'-(3-(4-(pyridin-4-yl)piperazine-1-carbonyl)benzyl)spiro[cyclopropane-1,3 '-indoline]-2'-one; (1S,2R)-2-(4-chlorophenyl)-1'-(3-(4-isopropylpiperazine-1-carbonyl)benzyl)spiro[cyclopropane-1,3'-dihydro Indole]-2'-one; (1R,2S)-2-(4-Chlorophenyl)-1′-(3-(4-isopropylpiperazine-1-carbonyl)benzyl)spiro[cyclopropane-1,3′-dihydro Indole]-2'-one; 3-(((1S,2R)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(2-((S)-1-methylpyrrolidin-2-yl)ethyl)benzamide 3-(((1R,2S)-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(2-((S)-1-methylpyrrolidin-2-yl)ethyl)benzamide; (1R, 2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(3-methyl-1H-pyrazol-5-yl)benzamide; (1S, 2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(3-methyl-1H-pyrazol-5-yl)benzamide; (1S,2R)-6-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid; (1R,2S)-6-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid; (1S, 2R)-6-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid; (1R,2S)-6-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid; (1S,2R)-2-(4-Chlorophenyl)-1′-((tetrahydro-2H-pyran-4-yl)methyl)spiro[cyclopropane-1,3′-indoline ]-2'-one; (1R,2S)-2-(4-Chlorophenyl)-1′-((tetrahydro-2H-pyran-4-yl)methyl)spiro[cyclopropane-1,3′-indoline ]-2'-one; (1S,2R)-2-(4-Chlorophenyl)-1′-(2-(diethylamino)ethyl)spiro[cyclopropane-1,3′-indoline]-2′- ketone; (1R,2S)-2-(4-Chlorophenyl)-1′-(2-(diethylamino)ethyl)spiro[cyclopropane-1,3′-indoline]-2′- ketone; (1S,2R)-2-(4-chlorophenyl)-1'-(2-morpholinoethyl)spiro[cyclopropane-1,3'-indoline]-2'-one; (1R,2S)-2-(4-chlorophenyl)-1'-(2-morpholinoethyl)spiro[cyclopropane-1,3'-indoline]-2'-one; (1S,2R)-2-(4-Chlorophenyl)-1′-((1-(methylsulfonyl)piperidin-4-yl)methyl)spiro[cyclopropane-1,3′-di Indoline]-2'-one; (1R,2S)-2-(4-Chlorophenyl)-1′-((1-(methylsulfonyl)piperidin-4-yl)methyl)spiro[cyclopropane-1,3′-di Indoline]-2'-one; (1S,2R)-2-(4-chlorophenyl)-1'-(2-(4-isopropylpiperazin-1-yl)ethyl)spiro[cyclopropane-1,3'-dihydro Indole]-2'-one; (1R,2S)-2-(4-chlorophenyl)-1'-(2-(4-isopropylpiperazin-1-yl)ethyl)spiro[cyclopropane-1,3'-dihydro Indole]-2'-one; (1S, 2R)-2-(4-chlorophenyl)-1'-(2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)ethyl)spiro[ring Propan-1,3'-indoline]-2'-one; (1R, 2S)-2-(4-chlorophenyl)-1'-(2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)ethyl)spiro[ring Propan-1,3'-indoline]-2'-one; (1S, 2R)-2-(4-chlorophenyl)-1'-(2-((S)-3-(dimethylamino)pyrrolidin-1-yl)ethyl)spiro[cyclopropane- 1,3'-indoline]-2'-one; (1R, 2S)-2-(4-chlorophenyl)-1′-(2-((S)-3-(dimethylamino)pyrrolidin-1-yl)ethyl)spiro[cyclopropane- 1,3'-indoline]-2'-one; (1S, 2R)-2-(4-chlorophenyl)-1'-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)ethyl)spiro[cyclopropane- 1,3'-indoline]-2'-one; (1R, 2S)-2-(4-chlorophenyl)-1'-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)ethyl)spiro[cyclopropane- 1,3'-indoline]-2'-one; (1R,2S)-2-(4-chlorophenyl)-1'-(pyridin-4-ylmethyl)spiro[cyclopropane-1,3'-indoline]-2'-one; (1S,2R)-2-(4-chlorophenyl)-1'-(pyridin-4-ylmethyl)spiro[cyclopropane-1,3'-indoline]-2'-one; (1S,2R)-2-(4-Chlorophenyl)-1'-(pyridin-3-ylmethyl)spiro[cyclopropane-1,3'-indoline]-2'-one; (2R,1S)-2-(4-chlorophenyl)-1'-(pyridin-3-ylmethyl)spiro[cyclopropane-1,3'-indoline]-2'-one; (1S,2R)-2-(4-(2-(4-Chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1H -imidazol-1-yl)acetic acid; (1R,2S)-2-(4-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-1H -imidazol-1-yl)acetic acid; (1S, 2R)-1-(2-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl )-1H-imidazole-4-carboxylic acid; (1R, 2S)-1-(2-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl )-1H-imidazole-4-carboxylic acid; (1S, 2S)-1-(2-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl )-1H-imidazole-4-carboxylic acid; (1R, 2R)-1-(2-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl )-1H-imidazole-4-carboxylic acid; (1S,2R)-3-(2-(4-Chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)benzoic acid; (1R,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)benzoic acid; (1S,2S)-3-(-2-(4-Chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)benzoic acid; (1R,2R)-3-(-2-(4-Chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)benzoic acid; (1S, 2S)-2-(4-Chlorophenyl)-1′-(3-(morpholine-4-carbonyl)phenyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone; (1R,2R)-2-(4-chlorophenyl)-1′-(3-(morpholine-4-carbonyl)phenyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone; (1S,2S)-2-(4-Chlorophenyl)-1′-(3-(4-methylpiperazine-1-carbonyl)phenyl)spiro[cyclopropane-1,3′-indoline Indole]-2'-one; (1R,2R)-2-(4-chlorophenyl)-1′-(3-(4-methylpiperazine-1-carbonyl)phenyl)spiro[cyclopropane-1,3′-indoline Indole]-2'-one; (1S, 2S)-2-(4-chlorophenyl)-1'-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)phenyl)spiro[cyclopropane-1,3' -indoline]-2'-one; (1R,2R)-2-(4-chlorophenyl)-1'-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)phenyl)spiro[cyclopropane-1,3' -indoline]-2'-one; (1R,2S)-2-(4-Chlorophenyl)-1′-(3-(morpholine-4-carbonyl)phenyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone; (1S,2R)-2-(4-Chlorophenyl)-1′-(3-(morpholine-4-carbonyl)phenyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone; (1S,2R)-2-(4-Chlorophenyl)-1′-(3-(4-methylpiperazine-1-carbonyl)phenyl)spiro[cyclopropane-1,3′-indoline Indole]-2'-one; (1R,2S)-2-(4-Chlorophenyl)-1′-(3-(4-methylpiperazine-1-carbonyl)phenyl)spiro[cyclopropane-1,3′-indoline Indole]-2'-one; (1R,2S)-2-(4-chlorophenyl)-1'-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)phenyl)spiro[cyclopropane-1,3' -indoline]-2'-one; (1S,2R)-2-(4-chlorophenyl)-1'-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)phenyl)spiro[cyclopropane-1,3' -indoline]-2'-one; (1R, 2R)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-N-(methyl (sulfonyl) benzamide; (1S, 2S)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-N-(methyl (sulfonyl) benzamide; (1S, 2S)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2 -oxo

oxazolidin-3-yl) benzoic acid; (1R, 2R)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2 -oxo

oxazolidin-3-yl) benzoic acid; (1S, 2S)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(methyl sulfonyl) benzoic acid; (1R, 2R)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(methyl sulfonyl) benzoic acid; (1S, 2S)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2 -oxopyrrolidin-1-yl)benzoic acid; (1R, 2R)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-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-oxo

oxazolidin-3-yl) benzoic acid; (1S,2S)-3-(2-(4-Chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline] -1′-yl)-5-(2-oxo

oxazolidin-3-yl) benzoic acid; (1R,2S)-3-(2-(4-Chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline] -1′-yl)-5-(2-oxo

oxazolidin-3-yl) benzoic acid; (1S,2R)-3-(2-(4-Chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline] -1′-yl)-5-(2-oxo

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

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

oxazolidin-3-yl) benzoic acid; (1S, 2S)-3-(2-(4-cyanophenyl)-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′- base)-5-(2-oxo

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

oxazolidin-3-yl) benzoic acid; (1S, 2S)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-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'-indoline]-1'-yl)methyl) benzoic acid; (S)-3-((5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl) benzoic acid; (R)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-5-( 2-oxo oxazolidin-3-yl) benzoic acid; (S)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-5-( 2-oxo

oxazolidin-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′-indoline]-1′-yl) Methyl)benzoic acid; (1R, 2R)-2-Chloro-5-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid; (1R, 2S)-4-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2R)-4-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2R)-4-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) benzoic acid; (1R, 2S)-4-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) benzoic acid; (1R, 2S)-4-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1R, 2S)-4-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2R)-2-chloro-5-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]- 1'-yl)methyl)benzoic acid; (1R, 2S)-2-chloro-5-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]- 1'-yl)methyl)benzoic acid; (1R,2S)-3-((2-(3-Chloro-4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid; (1S,2R)-3-((2-(3-Chloro-4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid; (1R, 2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-Methylbenzamide; (1S, 2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-Methylbenzamide; (1S, 2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N,N-Dimethylbenzamide; (1R, 2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N,N-Dimethylbenzamide; (1R, 2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(3-morpholinopropyl)benzamide; (1S, 2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(3-morpholinopropyl)benzamide; (1R, 2S)-2-(4-chlorophenyl)-1'-(3-(4-(2-(dimethylamino)ethyl)piperazine-1-carbonyl)benzyl)spiro[ring Propan-1,3'-indoline]-2'-one; (1S, 2R)-2-(4-chlorophenyl)-1'-(3-(4-(2-(dimethylamino)ethyl)piperazine-1-carbonyl)benzyl)spiro[ring Propan-1,3'-indoline]-2'-one; (1R, 2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(2-morpholinoethyl)benzamide; (1S, 2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(2-morpholinoethyl)benzamide; (1R,2S)-2-(4-chlorophenyl)-1'-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)benzyl)spiro[cyclopropane-1,3' -indoline]-2'-one; (1S, 2R)-2-(4-chlorophenyl)-1'-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)benzyl)spiro[cyclopropane-1,3' -indoline]-2'-one; (1S, 2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(3-cyclopropyl-1H-pyrazol-5-yl)benzamide; (1R, 2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(3-cyclopropyl-1H-pyrazol-5-yl)benzamide; (1R, 2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(5-cyclopropyl-1H-pyrazol-3-yl)benzamide; (1R, 2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(5-cyclopropyl-1H-pyrazol-3-yl)benzamide; (1R, 2S)-6-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) -N-(cyclopropylsulfonyl)pyridinamide; (1S, 2R)-6-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) -N-(cyclopropylsulfonyl)pyridinamide; (1S, 2R)-4-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) -N-(cyclopropylsulfonyl)benzamide; (1R, 2S)-4-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) -N-(cyclopropylsulfonyl)benzamide; (1R, 2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(methylsulfonyl)benzamide; (1S, 2R)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(methylsulfonyl)benzamide; (1R, 2S)-3-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(methylsulfonyl)benzamide; (1S, 2R)-3-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(methylsulfonyl)benzamide; (1S,2R)-N-(cyclopropylsulfonyl)-3-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline] -1'-yl)methyl)benzamide; (1R,2S)-N-(cyclopropylsulfonyl)-3-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline] -1'-yl)methyl)benzamide; (1S,2R)-N-(cyclopropylsulfonyl)-4-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline] -1'-yl)methyl)benzamide; (1R,2S)-N-(cyclopropylsulfonyl)-4-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline] -1'-yl)methyl)benzamide; (1S,2R)-2-(4-Chlorophenyl)-1'-(piperidin-4-ylmethyl)spiro[cyclopropane-1,3'-indoline]-2'-one; (1R,2S)-2-(4-chlorophenyl)-1'-(piperidin-4-ylmethyl)spiro[cyclopropane-1,3'-indoline]-2'-one; (1S,2R)-2-(4-Chlorophenyl)-1′-(2-(piperidin-1-yl)ethyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone; (1R,2S)-2-(4-Chlorophenyl)-1′-(2-(piperidin-1-yl)ethyl)spiro[cyclopropane-1,3′-indoline]-2 '-ketone; (1S,2R)-2-(4-Chlorophenyl)-1′-(2-(3-morpholinopropylamino)ethyl)spiro[cyclopropane-1,3′-indoline] -2'-one; (1R,2S)-2-(4-Chlorophenyl)-1′-(2-(3-morpholinopropylamino)ethyl)spiro[cyclopropane-1,3′-indoline] -2'-one; (1S,2R)-2-(4-Chlorophenyl)-1′-(2-(3-morpholinopropylamino)ethyl)spiro[cyclopropane-1,3′-indoline] -2'-one; (1R,2S)-2-(4-Chlorophenyl)-1′-(2-(3-morpholinopropylamino)ethyl)spiro[cyclopropane-1,3′-indoline] -2'-one; (1S,2R)-2-(4-Chlorophenyl)-1′-(2-(2-morpholinoethylamino)ethyl)spiro[cyclopropane-1,3′-indoline] -2'-one; (1R,2S)-2-(4-chlorophenyl)-1′-(2-(2-morpholinoethylamino)ethyl)spiro[cyclopropane-1,3′-indoline] -2'-one; (1S, 2R)-2-(4-chlorophenyl)-1'-(2-(4-(pyridin-4-yl)piperazin-1-yl)ethyl)spiro[cyclopropane-1,3 '-indoline]-2'-one; (1R, 2S)-2-(4-chlorophenyl)-1'-(2-(4-(pyridin-4-yl)piperazin-1-yl)ethyl)spiro[cyclopropane-1,3 '-indoline]-2'-one; (1S, 2R)-2-(4-Chlorophenyl)-1′-(2-(2-(2,6-Dimethylmorpholino)ethylamino)ethyl)spiro[cyclopropane-1 , 3'-indoline]-2'-one; (1R, 2S)-2-(4-chlorophenyl)-1'-(2-(2-(2,6-dimethylmorpholino)ethylamino)ethyl)spiro[cyclopropane-1 , 3'-indoline]-2'-one; (1S,2R)-2-(4-chlorophenyl)-1'-(1H-imidazol-4-yl)spiro[cyclopropane-1,3'-indoline]-2'-one; (1R,2S)-2-(4-chlorophenyl)-1'-(1H-imidazol-4-yl)spiro[cyclopropane-1,3'-indoline]-2'-one; (1S, 2R)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-N-(form (sulfonyl) benzamide; (1R, 2S)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-N-(form (sulfonyl) benzamide; (1S, 2S)-3-(2-(4-Chlorophenyl)-2-methyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) -5-(2-oxo

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

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

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

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

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

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

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

(oxazolidin-3-yl) benzoate; (R)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-5-( 2-hydroxyethylamino)benzoic acid; (S)-3-(5'-fluoro-2,2-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-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' - formic acid; (1R,2S)-1'-(3-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5' - formic acid; (1R,2R)-1'-(2-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5' - formic acid; (1S, 2S)-1'-(2-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5' - formic 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. 10. The compound according to any one of claims 1-9, selected from the group consisting of (2S,1R)-3-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2R)-3-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2R)-3-((2-(3-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1R, 2S)-3-((2-(3-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2R)-3-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) benzoic acid; (1R, 2S)-3-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) benzoic acid; (1S, 2R)-3-((2-(4-(methylsulfonyl)phenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1R, 2S)-3-((2-(4-(methylsulfonyl)phenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1S, 2R)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1R, 2S)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2S)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1R, 2R)-3-((2-(2-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2R)-3-((2-(3-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1R, 2S)-3-((2-(3-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2S)-3-((2′-oxo-2-(2-(trifluoromethyl)phenyl)-spiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid; (1R,2R)-3-((2′-oxo-2-(2-(trifluoromethyl)phenyl)-spiro[cyclopropane-1,3′-indoline]-1′- base) methyl) benzoic acid; (1S, 2R)-((5'-chloro-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl base) benzoic acid; (1R, 2S)-((5'-chloro-2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl base) benzoic acid; (1S, 2S)-3-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1R, 2R)-3-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl ) methyl) benzoic acid; (1S, 2R)-3-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1R, 2S)-3-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (+)-3-((2-(4-Chlorophenyl)-2-isopropyl-2′-oxospiro[(trans)-cyclopropane-1,3′-indoline]- 1'-yl)methyl)benzoic acid; (-)-3-((2-(4-chlorophenyl)-2-isopropyl-2′-oxospiro[(trans)-cyclopropane-1,3′-indoline]- 1'-yl)methyl)benzoic acid; (1S, 2S)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'- base) methyl) benzoic acid; (1R,2R)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-1'- base) methyl) benzoic acid; (1S,2R)-6-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid; (1R,2S)-6-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid; (1S, 2R)-6-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid; (1R,2S)-6-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)pyridine formic acid; (1S,2R)-2-(4-(2-(4-Chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1H -imidazol-1-yl)acetic acid; (1R,2S)-2-(4-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-1H -imidazol-1-yl)acetic acid; (1S,2R)-3-(2-(4-Chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)benzoic acid; (1R,2S)-3-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)benzoic acid; (1S,2S)-3-(-2-(4-Chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)benzoic acid; (1R,2R)-3-(-2-(4-Chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)benzoic acid; (1S, 2S)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2 -oxo

oxazolidin-3-yl) benzoic acid; (1R, 2R)-3-(2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2 -oxo

oxazolidin-3-yl) benzoic acid; (1S,2S)-2-Chloro-5-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid; (1R, 2R)-2-Chloro-5-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid; (1R, 2S)-4-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2R)-4-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2R)-4-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) benzoic acid; (1R, 2S)-4-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) benzoic acid; (1R, 2S)-4-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1R, 2S)-4-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzene formic acid; (1S, 2R)-2-chloro-5-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]- 1'-yl)methyl)benzoic acid; (1R, 2S)-2-chloro-5-((2-(4-chlorophenyl)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]- 1'-yl)methyl)benzoic acid; (1R,2S)-3-((2-(3-Chloro-4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid; (1S,2R)-3-((2-(3-Chloro-4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl) Methyl)benzoic acid; (1R, 2S)-6-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) -N-(cyclopropylsulfonyl)pyridinamide; (1S, 2R)-6-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) -N-(cyclopropylsulfonyl)pyridinamide; (1S, 2R)-4-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) -N-(cyclopropylsulfonyl)benzamide; (1R, 2S)-4-((2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) -N-(cyclopropylsulfonyl)benzamide; (1R, 2S)-3-((2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(methylsulfonyl)benzamide; (1S,2R)-3-((2-(4-Chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) -N-(methylsulfonyl)benzamide; (1R, 2S)-3-((2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)methyl)- N-(methylsulfonyl)benzamide; (1 S, 2R)-3-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl) -N-(methylsulfonyl)benzamide; (1S,2R)-N-(cyclopropylsulfonyl)-3-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline] -1'-yl)methyl)benzamide; (1R,2S)-N-(cyclopropylsulfonyl)-3-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline] -1'-yl)methyl)benzamide; (1S,2R)-N-(cyclopropylsulfonyl)-4-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline] -1'-yl)methyl)benzamide; (1R,2S)-N-(cyclopropylsulfonyl)-4-((2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline] -1'-yl)methyl)benzamide; (1S,2R)-1'-(3-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5' - formic acid; (1R,2S)-1'-(3-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5' - formic acid; (1R,2R)-1'-(2-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5' - formic acid; (1S, 2S)-1'-(2-fluorobenzyl)-2-(4-fluorophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5' - formic 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; and (1R,2R) and (1S,2S)-2-(4-cyanophenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylic acid. 11. A method for preparing a compound of formula (I) according to any one of claims 1-10, said method comprising one of the following steps: a) Compounds of formula (A)

Reaction in the presence of R ⁶ R ⁷ NH and a coupling agent; b) Compounds of formula (B) Reaction in the presence of Y-CH ₂ -R and a base; c) Compounds of formula (C)

Reaction in the presence of R ⁶ R ⁷ NH and a base; d) Compounds of formula (D)

Reaction in the presence of R ⁶ R ⁷ NH and a reducing agent; e) compounds of formula (E)

In the presence of a compound of formula (E1)

and the reaction in the presence of a base; f) Compounds of formula (F)

reaction in the presence of a base; g) compounds of formula (G)

reaction in the presence of a base; wherein R ¹ , R ² , R ³ , R ⁴ and n are as defined in any one of claims 1 to 8; wherein R ⁵ is hydrogen, halogen, oxo-

Oxazolidinyl or oxo-imidazolidinyl; wherein R ^{and R} are independently selected from 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. 12. Compounds according to any one of claims 1-10 for use as therapeutically active substances. 13. A pharmaceutical composition comprising a compound according to any one of claims 1-10 and a therapeutically inert carrier. 14. Use of the compound according to any one of claims 1-10 for preparing a medicament for treating or preventing obesity, hyperglycemia, dyslipidemia, type 1 or type 2 diabetes. 15. A compound according to any one of claims 1-10 prepared according to the process of claim 11. 16. A method for treating or preventing obesity, hyperglycemia, dyslipidemia, type 1 or type 2 diabetes, said method comprising administering an effective amount of any one of claims 1-10 defined compounds. 17. The invention as hereinbefore described.