EA044347B1 - SUBSTITUTED PYRROLIDINE III AMIDES - Google Patents

Description

The invention relates to compounds of general formula (I)

which act as glucocorticoid receptor modulators and can be used in the treatment and/or prevention of disorders that are at least partially mediated by the glucocorticoid receptor.

Glucocorticoids (GC) exert potent anti-inflammatory, immune suppressive, and disease-modifying therapeutic effects mediated by the glucocorticoid receptor (GR). They have been widely used to treat inflammatory and immune diseases for decades and still represent the most effective therapy for these conditions. However, chronic GC treatment of inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, acute respiratory distress syndrome, cystic fibrosis, osteoarthritis, polymyalgia rheumatica, and giant cell arteritis is hampered by the side effects associated with GC. These unwanted side effects include insulin resistance, diabetes, hypertension, glaucoma, depression, osteoporosis, adrenal suppression, and muscle wasting, with osteoporosis and diabetes being the most serious of these from a physician's perspective (Hapgood JP. et al., Pharmacol Ther. 2016 Sep ; 165: 93-113; Buttgereit F. el al, Clin Exp Rheumatol. 2015 Jul-Aug;33(4 Suppl 92):S29-33; Hartmann K. et al, Physiol Rev. 2016 Apr;96(2): 409-47).

One example of an oral glucocorticoid is prednisone, which is often prescribed to treat several inflammatory diseases (De Bosscher K et al., Trends Pharmacol Sci. 2016 Jan;37(1):4-16; Buttgereit F. et al., JAMA. 2016 ;315(22):2442-2458). Because GCs cause adrenal suppression, prednisolone withdrawal symptoms can be severe if the drug is stopped abruptly when all signs of the disease have disappeared. Thus, gradual reduction of GC to physiological doses is often part of treatment protocols to reduce the risk of relapse and other withdrawal symptoms (Liu D. et al., Allergy Asthma Clin Immunol. 2013 Aug 15;9(1):30). Consequently, there is a high medical need for new, potent anti-inflammatory drugs with fewer side effects.

Recent research has focused on developing partial agonists or selective glucocorticoid receptor modulators that activate anti-inflammatory pathways but avoid targeting pathways that lead to GC-related side effects. Most of these effects have been demonstrated to be mediated by various GR-dependent genomic mechanisms called transactivation and transrepression. The anti-inflammatory effects of GC are mainly due to the transrepression of inflammatory genes, while certain side effects are predominantly mediated by the transactivation of several genes. Depending on the nature of the ligand, GR can be selectively modulated into a specific conformation that promotes transrepression versus transactivation, resulting in improved therapeutic effect (De Bosscher K et al., Trends Pharmacol Sci. 2016 Jan;37(1):4-16 ). The concept of such dissociating ligands was already defined about two decades ago, and several compounds have been identified and evaluated in preclinical and clinical trials, but none have yet been approved for clinical use.

Compounds which act as glucocorticoid receptor modulators are also known, for example from WO 2007/122165, WO 2008/076048 and WO 2008/043789, WO 2009/035067, WO 2009/142571, WO 2016/046260 and WO 2017/ 034006.

The purpose of the invention was to provide new compounds that are glucocorticoid receptor modulators and that preferably have advantages over prior art compounds.

The new compounds should be particularly suitable for use in the treatment and/or prevention of disorders or diseases that are at least partially mediated by the glucocorticoid receptor.

This purpose was achieved by the subject matter of the patent claim.

Surprisingly, the compounds of the invention have been found to be potent glucocorticoid receptor modulators.

The invention relates to a compound of general formula (I)

- 1 044347

(I) where

R1 represents phenyl; -C _1-6 -alkylene-phenyl; 5 or 6 membered heteroaryl; -C _1-6 -alkylene-(5 or 6-membered heteroaryl); or -C _1-10 -alkyl;

R1' represents H; -C _1-10 -alkyl; or -C _3-10 -cycloalkyl;

R2 represents -C(=O)-C _1-10 -alkyl; -C(=O)-C _3-10 -cycloalkyl; -C(=O)-C _1-6 -alkylene-C _3-10 cycloalkyl; -C(=O)-(3 to 7 membered heterocycloalkyl); -C(=O)-C _1-6 -alkylene-(3 to 7 membered heterocycloalkyl); -C(=O)-phenyl; -C(=O)-C _1-6 -alkylene-phenyl; -C(=O)-(5 or 6-membered heteroaryl); -C(=O)-C _1-6 alkylene-(5 or 6 membered heteroaryl); -S(=O) _1-2 -C _1-10 -alkyl; -S(=O) _1-2 -C _3-10 -cycloalkyl; -S(=O) _1-2 -C _1-6 alkylene-C _3-10 -cycloalkyl; -S(=O) _1-2 -(3 to 7 membered heterocycloalkyl); -S(=O) _1-2 -C _1-6 -alkylene-(3 to 7 membered heterocycloalkyl); -S(=O) _1-2 -phenyl; -S(=O) _1-2 -C _1-6 -alkylene-phenyl; -S(=O) _1-2 -(5 or 6 membered heteroaryl); or -S(=O) _1-2 -C _1-6 -alkylene-(5 or 6 membered heteroaryl);

R3 and _R3 ' independently represent H; F; Cl; -C _1-10 -alkyl; -C _3-6 -cycloalkyl; -CH ₂ -C _3-6 cycloalkyl; 3 to 7 membered heterocycloalkyl; -CH ₂ -(3 to 7 membered heterocycloalkyl); -CH ₂ -phenyl; or -CH ₂ -(5 or 6 membered heteroaryl);

or R3 and _R3 ' together with the carbon atom to which they are bonded form C _3-10 -cycloalkyl; or 3 to 7 membered heterocycloalkyl;

R4 is phenyl; -C _1-6 -alkylene-phenyl; -5 or 6-membered heteroaryl;

or -C _1-6 -alkylene-(5 or 6 membered heteroaryl);

A, X, Y and Z independently represent N or CH;

where at least one of R1', R3 and _R3 ' is not H;

where -C _1-10 -alkyl and -C _1-6 -alkylene- are in each case, independently of each other, linear or branched, saturated or unsaturated; where -C _1-10 -alkyl, -C _1-6 -alkylene-, -C _3-10 -cycloalkyl and 3 to 7 membered heterocycloalkyl are in each case independently of each other unsubstituted or mono- or polysubstituted with one or more substituents , selected from -F; -Cl; -Br; -I; -CN; -C _1-6 -alkyl; -CF ₃ ; -CF2H; -CFH2; -CF ₂ Cl; _-CFCl2 ; -C(=O)-C _1-6 -alkyl; -C(=O)-OH; -C(=O)-OC _1-6 alkyl; -C(=O)-NH ₂ ; -C(=O)-NH(C _1-6 -alkyl); -C(=O)-N(C _1-6 -alkyl) ₂ ; -HE; =O; -OCF ₃ ; -OCF2H; -OCFH2; -OCF ₂ Cl; -OCFCl ₂ ; -O-C _1-6 -alkyl; -O-C(=O)-C _1-6 -alkyl; -O-C(=O)-O-C _1-6 -alkyl; -O-(CO)-NH(C _1-6 alkyl); -О-С(=О)-N(C _1-6 -alkyl) ₂ ; -OS(=O) ₂ -NH ₂ ; -O-S(=O) ₂ -NH(C _1-6 -alkyl); -O-S(=O) ₂ -N(C _1-6 -alkyl) ₂ ; -NH2; -NH(C _1-6 -alkyl); -N(C _1-6 -alkyl) ₂ ; -NH-C(=O)-C _1-6 -alkyl; -NH-C(=O)-OC _1-6 -alkyl; -NH-C(=O)NH2; -NH-C(=O)-NH(C _1-6 -alkyl); -NH-C(=O)-N(C _1-6 -alkyl) ₂ ; -N(C _1-6 -alkyl)-C(=O)-C _1-6 -alkyl; -N(C _1-6 alkyl)-C(=O)-O-C _1-6 alkyl; -N(C _1-6 -alkyl)-C(=O)-NH ₂ ; -N(C _1-6 -alkyl)-C(=O)-NH(C _1-6 -alkyl); -N(C _1-6 alkyl)-C(=O)-N(C _1-6 -alkyl) ₂ ; -NH-S(=O)2OH; NH-S(=O) ₂ -C _1-6 -alkyl; -NH-S(=O) ₂ -O-C _1-6 -alkyl; -NHS(=O) ₂ -NH ₂ ; -NH-S(=O) ₂ -NH(C _1-6 -alkyl); -NH-S(=O) ₂ N(C _1-6 -alkyl) ₂ ; -N(C _1-6 -alkyl)-S(=O) ₂ -OH; -N(C _1-6 alkyl)-S(=O) ₂ -C _1-6 alkyl; -N(C _1-6 -alkyl)-S(=O) ₂ -O-C _1-6 -alkyl; -N(C _1-6 -alkyl)-S(=O) ₂ -NH ₂ ; -N(C ₁ . ₆ alkyl)-S(=O) ₂ -NH(C _1-6 alkyl); -N(C _1-6 -alkyl)-S(=O) ₂ -N(C _1-6 -alkyl) ₂ ; -SCF ₃ ; -SCF2H; -SCFH2; -SC _1-6 alkyl; -S(=O)-C1-6-alkyl; -S(=O)2-C1-6-alkyl; -S(=O>2-OH;-S(=O)2-O-C1-6-alkyl;-S(=O)2-NH2; -S(=O)2NH(C _1-6 -alkyl ); -S(=O) ₂ -N(C _1-6 -alkyl) ₂ ; -C _3-6 -cycloalkyl; 3 to 6-membered heterocycloalkyl; phenyl; 5 or 6-membered heteroaryl; -O-C _3-6 -cycloalkyl; -O-(3 to 6-membered heterocycloalkyl); -O-phenyl; -O-(5 or 6-membered heteroaryl); -C(=O)-C _3-6 -cycloalkyl; -C(=O)-(3 to 6-membered heterocycloalkyl); -C(=O)-phenyl; -C(=O)-(5 or 6-membered heteroaryl); -S(=O) ₂ - (C _3-6 -cycloalkyl); -S(=O) ₂ -(ot 3 to 6-membered heterocycloalkyl); -S(=O) ₂ -phenyl or -S(=O) ₂ -(ot 5 or 6 -membered heteroaryl);

wherein the phenyl and the 5- or 6-membered heteroaryl are in each case independently of each other unsubstituted or mono- or polysubstituted with one or more substituents selected from -F; -Cl; -Br; -I; -CN; -C _1-6 -alkyl; -CF ₃ ; -CF2H; -CFH2; -CF ₂ Cl; _-CFCl2 ; -C _1-4 -alkylene-CF ₃ ; -C _1-4 -alkyleneCF2H; -C1-4-alkylene-CFH2; -C(=O)-C1-6-alkyl; -C(=O)-OH; -C(=O)-OC1-6-alkyl; -C(=O)-NH(OH); -C(=O)-NH2; -C(=O)-NH(C1-6-alkyl); -C(=O)-N(C1-6-alkyl)2; -HE; =O; -OCF3; -OCF2H; -OCFH2; -OCF2Cl; -OCFCl ₂ ; -OC _1-6 -alkyl; -O-C _3-6 -cycloalkyl; -0-(3 to 6 membered heterocycloalkyl); -NH2; -NH(C _1-6 alkyl); -N(C _1-6 -alkyl) ₂ ; -NH-C(=O)-C _1-6 -alkyl; -N(C _1-6 -alkyl)-C(=O)-C _1-6 -alkyl; -NH-C(=O)-NH ₂ ; -NHC(=O)-NH(C _1-6 -alkyl); -NH-C(=O)-N(C _1-6 -alkyl) ₂ ; -N(C _1-6 -alkyl)-C(=O)-NH(C _1-6 -alkyl); -N(C _1-6 -alkyl)C(=O)-N(C1-6-alkyl)2; -NH-S(=O)2-C1-6-alkyl; -SCF3; -S-C1-6-alkyl; -S(=O)-C1-6-alkyl; -S(=O) ₂ -C1.6alkyl; -S(=O) ₂ -NH ₂ ; -S(=O) ₂ -NH(C _1-6 -alkyl); -S(=O) ₂ -N(C _1-6 -alkyl) ₂ ; -C _3-6 -cycloalkyl; -C _1-4 -alkylene- 2 044347

C ₃ - ₆ -cycloalkyl; 3 to 6 membered heterocycloalkyl; -C1-4-alkylene-(3 to 6-membered heterocycloalkyl); phenyl or 5 or 6 membered heteroaryl;

in the form of the free compound or a physiologically acceptable salt thereof;

provided that the following connections are excluded:

N-[(2R, 3 S)-4,4-Dimethyl-1-[1-(1 -methyl-6-oxo-1 H-pyridin-3-yl)-1H-indazol-5 -yl]-5 -oxo-2-phenylpyrrolidin-3-yl]-cyclopropanecarboxylic acid amide;

N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo -2-phenylpyrrolidin-3-yl]-cyclopropanecarboxylic acid amide;

N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo -2-phenylpyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic acid amide;

N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo -2-phenylpyrrolidin-3-yl]-5-methyl-[1,2,4]oxodiazole-3-carboxylic acid amide;

N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo -2-phenylpyrrolidin-3-yl]-4-methyl-thiazol-5-carboxylic acid amide;

N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo -2-phenylpyrrolidin-3-yl]-thiazol-4-carboxylic acid amide; And

N-[(2S,3R)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo -2-phenylpyrrolidin-3-yl]-5-methyl-thiazol-4-carboxylic acid amide.

In a preferred embodiment, the compound of the invention is present in the form of a free compound. For purposes of description, a free compound preferably means that the compound of the invention is not present in salt form. Methods for determining whether a chemical is present as a free compound or as a salt are known to those skilled in the art, such as ¹⁴ N or ¹⁵ N solid state NMR, X-ray diffraction, X-ray powder diffraction, infrared (IR), Raman light scattering, X-ray photoemission spectroscopy (XPS). The recorded 1H-NMR in solution can also be used to account for protonation.

In another preferred embodiment of the invention, the compound of the invention is present in the form of a physiologically acceptable salt. For purposes of this description, the term physiologically acceptable salt preferably refers to the salt obtained from a compound of the invention and a physiologically acceptable acid or base.

In accordance with the invention, the compound of the invention may be present in any possible form, including solvates, cocrystals and polymorphs. For purposes of this description, the term solvate preferably refers to the adduct of (i) a compound of the invention and/or a physiologically acceptable salt thereof with (ii) various molecular equivalents of one or more solvents.

In addition, the compound of the invention may be present in the form of a racemate, enantiomers, diastereomers, tautomers, or any mixtures thereof.

The invention also includes isotopic isomers of a compound of the invention wherein at least one atom of the compound is replaced by an isotope of the corresponding atom that is different from the predominantly naturally occurring isotope, as well as any mixtures of isotopic isomers of such a compound. Preferred isotopes are ² H (deuterium), ³ H (tritium), ¹³ C and ¹⁴ C. Isotopic isomers of the compound of the invention can generally be prepared by conventional methods known to one skilled in the art.

According to the invention, the terms -C1_ ₁₀ -alkyl, -C ₁ . ₈ -alkyl, -C ₁ . ₆ -alkyl and _-C1-4 -alkyl preferably mean acyclic saturated or unsaturated aliphatic (i.e. non-aromatic) hydrocarbon radicals which may be linear (i.e. straight-chain) or branched and which may be unsubstituted, mono- or polysubstituted (e.g. di- or trisubstituted) and which contain from 1 to 10 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), from 1 to 8 (i.e. 1, 2, 3, 4, 5, 6, 7 or 8), 1 to 6 (i.e. 1, 2, 3, 4, 5 or 6) and 1 to 4 (i.e. 1, 2, 3 or 4) carbon atoms, respectively. In a preferred embodiment, -C1_ ₁₀ -alkyl, -C ₁ . ₈ -alkyl, -C ₁ . ₆ -alkyl and _-C1-4 -alkyl are substituted.

Preferably -C1_ ₁₀ -alkyl groups are selected from methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (-CH ₂ CH=CH ₂ , -CH=CH-CH ₃ , -C(=CH ₂ )-CH ₃ ), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1- inyl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3hexyl, 2-methylpentyl, 4-methylpentyl, 4-methylpent-2-yl, 2-methylpent-2-yl, 3,3-dimethylbutyl, 3, 3-dimethylbut-2-yl, 3-methylpentyl, 3-methylpent-2-yl and 3-methylpent-3-yl; more preferably methyl, ethyl, n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (-CH2CH=CH2, -CH=CH-CH3, -C(=CH2)-CH3), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2- pentynyl, 2methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1-ynyl, 2,2dimethylpropyl, n-hexyl, n-heptyl, n-octyl, n- nonyl and n-decyl. Particularly preferred

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-C1- ₁₀ -alkyl groups are selected from C1_ ₄ -alkyl groups.

Preferably -C1- ₈ -alkyl groups are selected from methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (-CH ₂ CH=CH ₂ , -CH=CH- CH ₃ , -C(=CH ₂ )-CH ₃ ), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2pentyl , 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1 -inyl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3hexyl, 2-methylpentyl, 4-methylpentyl, 4-methylpent-2-yl, 2-methylpent-2-yl, 3,3-dimethylbutyl, 3 ,3dimethylbut-2-yl, 3-methylpentyl, 3-methylpent-2-yl and 3-methylpent-3-yl; more preferably methyl, ethyl, n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (-CH2CH=CH2, -CH=CH-CH3, C(=CH2)-CH3), n-butyl, 1 -butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl , 2methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1-ynyl, 2,2dimethylpropyl, n-hexyl, n-heptyl and n-octyl. Particularly preferred are -C ₁ . _{The 8-} alkyl groups are selected from C1_ ₄ -alkyl groups.

Preferably -C ₁ . _6- alkyl groups selected from methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2methylbutyl , 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2-dimethylpropyl, n-hexyl, 2hexyl, 3-hexyl, 2-methylpentyl, 4-methylpentyl, 4-methylpent-2 -yl, 2-methylpent-2-yl, 3,3-dimethylbutyl, 3,3-dimethylbut-2-yl, 3-methylpentyl, 3-methylpent-2-yl and 3-methylpent-3-yl; more preferably methyl, ethyl, n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (-CH2-CH=CH2, -CH=CH-CH3, -C(=CH2)-CH3), n- butyl, 1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1pentynyl, 2-pentynyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 3methylbut-1-ynyl, 2,2-dimethylpropyl, n-hexyl. Particularly preferred are -C ₁ . _{The 6} -alkyl groups are selected from C1_ ₄ -alkyl groups.

Preferably -C1_ ₄ -alkyl groups are selected from methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (-CH ₂ CH=CH ₂ , -CH=CH-CH ₃ , -C(=CH ₂ )-CH ₃ ), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl and 3-methylbut-1ynyl. More preferably, the -C1_ ₄ -alkyl groups are selected from methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

Further, according to the invention, the terms -C ₁ . ₆ -alkylene-; -C1_ ₄ -alkylene- and -C ₁ . ₂ -alkylene- refers to linear or branched, preferably linear and preferably saturated aliphatic radicals, which are preferably selected from the group consisting of methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2- or -C(CH3 )2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-) and hexylene (-CH2CH2CH2CH2CH2CH2-); more preferably methylene (-CH2-) and ethylene (-CH2CH2-) and most preferably methylene (-CH2-).

Preferably -C ₁ . ₆ -αalkylene- is selected from -C ₁ - ₄ -alkylene-, more preferably from -C ₁ . ₂ -alkylene-.

Moreover, according to the invention, the terms -C ₃ _ ₁₀ -cycloalkyl and -C ₃ _ ₆ -cycloalkyl preferably mean cyclic aliphatic hydrocarbons containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 3, 4, 5 or 6 carbon atoms, respectively, and the hydrocarbons in each case may be saturated or unsaturated (but not aromatic), unsubstituted or mono- or polysubstituted.

Preferably -C ₃ - ₁₀ -cycloalkyl and -C ₃ - ₆ -cycloalkyl are saturated. -C ₃ _ ₁₀ -cycloalkyl and -C ₃ _ ₆ -cycloalkyl can be linked to the corresponding higher general structure through any desired and possible ring member of the cycloalkyl group. _{-C3_10} - _cycloalkyl and _{-C3_6 -} cycloalkyl groups can also be fused with additional saturated, (partially) unsaturated, (hetero)cyclic, aromatic or heteroaromatic ring systems, i.e. cycloalkyl, heterocyclyl, aryl or heteroaryl residues, which in each case, in turn, can be unsubstituted, mono- or polysubstituted. In addition, -C ₃ _ ₁₀ -cycloalkyl and -C ₃ _ ₆ -cycloalkyl may be single or multiple bridged, such as for example in the case of adamantyl, bicyclo[2.2.1]heptyl or bicyclo[2.2.2]octyl . However, it is _preferable that -C _{3_10} -cycloalkyl and -C _{3_6} -cycloalkyl do not condense with other ring _systems or form a bridge. More preferably, -C _{3_10} -cycloalkyl and -C _{3_6} -cycloalkyl do not condense _, bridge, or saturate with other ring systems _. Preferred -C ₃ . _{The 10} -cycloalkyl groups are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]heptyl and bicyclo[ 2.2.2]octyl. Particularly preferred -C ₃ - ₁₀ -cycloalkyl groups are selected from -C ₃ - ₆ -cycloalkyl groups.

Preferred -C ₃ - ₆ -cycloalkyl groups are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl. Particularly preferred -C ₃ _ ₆ -cycloalkyl groups are selected from the group consisting of cyclopropyl, cyclobutyl,

- 4 044347 cyclopentyl and cyclohexyl, most preferably cyclopropyl.

According to the invention, the terms 3-7 membered heterocycloalkyl and 3-6 membered heterocycloalkyl preferably mean heterocycloaliphatic saturated or unsaturated (but not aromatic) residues containing from 3 to 7, i.e. 3, 4, 5, 6 or 7 ring members and 3 to 6, i.e. 3, 4, 5 or 6 ring members, respectively, where in each case at least one, optionally also two or three carbon atoms are replaced by a heteroatom or a heteroatom group, each independently selected from the group consisting of O, S, S(=O), S(=O) ₂ , N, NH and N(C ₁ .4-alkyl), such as N( CH ₃ ), where the carbon atoms of the ring can be unsubstituted, mono- or polysubstituted. Preferably, the 3-7 membered heterocycloalkyl and the 3-6 membered heterocycloalkyl contain only one heteroatom or heteroatom group on the ring.

Preferably, the 3-7 membered heterocycloalkyl and the 3-6 membered heterocycloalkyl are saturated. 3-7 membered heterocycloalkyl and 3-6 membered heterocycloalkyl groups can also be fused with additional saturated or (partially) unsaturated cycloalkyl or heterocyclyl, aromatic or heteroaromatic ring systems. However, more preferably, the 3-7 membered heterocycloalkyl and the 3-6 membered heterocycloalkyl do not condense with other ring systems. Even more preferably, the 3-7 membered heterocycloalkyl and the 3-6 membered heterocycloalkyl do not condense with other ring systems and are saturated. The 3-7 membered heterocycloalkyl and 3-6 membered heterocycloalkyl group may be linked to the higher general structure through any desired and possible ring member of the heterocycloaliphatic moiety unless otherwise indicated. In a preferred embodiment of the invention, the 3-7 membered heterocycloalkyl and the 3-6 membered heterocycloalkyl are linked to the higher general structure via a carbon atom.

Preferred 3-7 membered heterocycloalkyl groups are selected from the group consisting of tetrahydrofuranyl, azepanyl, dioxepanyl, oxazepanyl, diazepanyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydropyridinyl, thiomorpholinyl, tetrahydropyranyl, oxetanyl, oxiranyl, morpholinyl, pyrrolidinyl, 4- methylpiperazinyl, morpholinonyl, azetidinyl, aziridinyl , dithiolanyl, dihydropyrrolyl, dioxanil, dioxolanil, dihydropyridinyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyranyl; tetrahydropyrrolyl, dihydroquinolinyl, dihydroisoquinolinyl, dihydroindolinyl, dihydroisoindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and tetrahydroindolinyl. Particularly preferred 3-7 membered heterocycloalkyl groups are selected from 3-6 membered heterocycloalkyl groups.

Preferred 3-6 membered heterocycloalkyl groups are selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, oxiranyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydropyridinyl, thiomorpholinyl, morpholinyl, pyrrolidinyl, 4-methylpiperazinyl, morpholinonyl, azetidinyl, aziri dinyl, dithiolanil, dihydropyrrolyl, dioxanil, dioxolanil , dihydropyridinyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyranyl, tetrahydropyrrolyl, dihydroindolinyl, dihydroisoindolyl and tetrahydroindolinyl. More preferred 3-6 membered heterocycloalkyl groups are selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, oxetanyl and oxiranyl; most preferably tetrahydrofuranyl.

In accordance with the invention, the term 5-6-membered heteroaryl preferably means a 5- or 6-membered cyclic aromatic residue containing at least 1, optionally also 2, 3, 4 or 5 heteroatoms, each of the heteroatoms being selected independently of each other other from the group S, N and O and the heteroaryl moiety may be unsubstituted or mono- or polysubstituted unless otherwise indicated. In the case of substitution in heteroaryl, the substituents may be the same or different and located in any desired and possible position of the heteroaryl. Linking to a higher general structure can be accomplished through any desired and possible ring member of a heteroaryl moiety unless otherwise indicated. Preferably, the 5-6 membered heteroaryl is linked to the higher overall structure via a heterocycle carbon atom. Heteroaryl may also be part of a bi- or polycyclic system containing up to 14 ring members, where the ring system may be formed with additional saturated or (partially) unsaturated cycloalkyl or heterocycloalkyl, aromatic or heteroaromatic ring systems, which in turn may be unsubstituted or mono- or polysubstituted unless otherwise indicated. In a preferred embodiment of the invention, the 5-6 membered heteroaryl is part of a bi- or polycyclic, preferably bicyclic, system. In another preferred embodiment of the invention, the 5-6 membered heteroaryl is not part of a bi- or polycyclic system.

Preferably, the 5-6 membered heteroaryl is selected from the group consisting of pyridyl (i.e. 2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, pyridone (pyridinone), pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, isothiazolyl, furanyl, thienyl (thiophenyl), triazolyl, thiadiazolyl, 4,5,6,7-tetrahydro-2H-indazolyl, 2,4,5,6

- 5 044347 tetrahydrocyclopenta [c] pyrazolyl, benzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzoxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, imidazothiazolyl , indazolyl, indolizinyl, indolyl, isoquinolinyl, naphthyridinyl, oxazolyl , phenazinyl, phenothiazinyl, phthalazinyl, purinyl, phenazinyl, tetrazolyl and triazinyl. A particularly preferred 5-6 membered heteroaryl is selected from the group consisting of pyridyl (ie 2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl, oxazolyl, isoxazolyl, pyrazolyl and oxadiazolyl. Since pyridones can be considered as pyridines that are substituted with =O, for purposes of description, the definition of pyridines that may optionally be substituted with =O includes pyridones.

The compounds of the invention are defined by substituents, for example R1, _R2 and R3 (1st generation substituents), which may not necessarily themselves be substituted (2nd generation substituents). Depending on the definition, these substituent substituents may not necessarily be re-substituted (3rd generation substituents). If, for example, R1 = phenyl (1st generation substituent), then phenyl on its part can be substituted, for example, by -C ₁ - ₆ -alkyl (2nd generation substituent). This gives the functional group R1=phenyl- _{C1_6 -} alkyl. Then -C _{1_6 -alkyl} can be re-substituted, for example, -F (3rd generation substituent). In general, the functional group is R1 = phenyl-C ₁ _ ₆ -alkyl, where -Cl. ₆ -alkyl is substituted by -F.

However, in a preferred embodiment, the 3rd generation substituents cannot be re-substituted, i.e. then there will be no 4th generation deputies.

More preferably, the 2nd generation substituents cannot be re-substituted, i.e. there are no 3rd generation substitutes.

If a residue occurs multiple times in a molecule, then this residue can have correspondingly different meanings for different substituents: if, for example, both R3 and R ₃ ' denote -C ₁ _ ₁₀ -alkyl, then -C ₁ _ ₁₀ -alkyl can, for example, denote ethyl for R3 and may be methyl for R3'.

In connection with the terms -C ₁ _ ₁₀ -alkyl, -C ₁ - ₆ -alkyl, -C ₁ . ₄ -alkyl, -C ₃ . ₁₀ -cycloalkyl, -C ₃ _ ₆ -cycloalkyl, 3-7 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, -C ₁ . ₆ -alkylene-, -C ₁ _ ₄ -alkylene- and -C ₁ . ₂ -alkylene-, the term substituted refers in the sense of the invention in relation to the corresponding radicals or groups to a single substitution (mono-substitution) or multiple substitution (poly-substitution), for example disubstitution or tri-substitution; more preferably to mono-substitution or dis-substitution; of one or more hydrogen atoms, each independently of each other, with at least one substituent. In case of multiple substitution, i.e. in the case of polysubstituted residues, such as di- or trisubstituted residues, these residues can be polysubstituted either on different or on the same atoms, for example, trisubstituted on the same carbon atom, as in the case of -CF ₃ , -CH2CF3 or disubstituted, as in the case of 1,1-difluorocyclohexyl, or at various points, as in the case of -CH(OH)-CH=CH-CHC1 ₂ or 1-chloro-3-fluorocyclohexyl. Multiple substitution can be carried out using the same or different substituents.

With regard to the terms phenyl, heteroaryl and 5-6 membered heteroaryl, the term substituted refers in the sense of this invention to a single substitution (mono-substitution) or multiple substitution (poly-substitution), for example disubstitution or tri-substitution of one or more hydrogen atoms, each independently of the other, at least one deputy. Multiple substitution can be carried out using the same or different substituents.

According to the invention, it is preferable -C ₁ _ ₁₀ -alkyl-, -C ₁ _ ₆ -alkyl, -C ₁ _ ₄ -alkyl, -C ₃ _ ₁₀ -cycloalkyl, -C ₃ - ₆ -cycloalkyl, 3-7 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, -C ₁ - ₆ -alkylene-, -C ₁ - ₄ -alkylene- and -C ₁ - ₂ -alkylene- are in each case independently unsubstituted or mono- or polysubstituted by one or more substituents selected from -F; -Cl; -Br; -I; -CN; -C1-6-alkyl; -CF3; -CF2H; -CFH2; -CF2Cl; -CFCb; -C(=O)-C1-6-alkyl; -C(=O)-OH; -Q^-OC^alkyl; -C(=O)-NH2; -C(=O)-NH(C1.6-alkyl); -C(=O)-N(C1.6-alkyl)2; -HE; =O; -OCF3; -OCF2H; -OCFH2; -OCF2Cl; -OCFCl ₂ ; -OC ₁ . ₆ -alkyl; -O-C(=O)-C ₁ - ₆ -alkyl; -O-C(=O)-OC ₁ . ₆ -alkyl; -O-(CO)-NH(C ₁ - ₆ alkyl); -О-С(=О)-N(C ₁ . ₆ -alkyl) ₂ ; -OS(=O) ₂ -NH ₂ ; -OS(=O) ₂ -NH(C ₁ . ₆ -alkyl); -OS(=O) ₂ -N(C ₁ . ₆ -alkyl) ₂ ; -NH2; -NH(C ₁ . ₆ -alkyl); -N(C ₁ . ₆ -alkyl) ₂ ; -NH-C(=O)-C ₁ . ₆ -alkyl; -NH-C(=O)-OC ₁ . ₆ -alkyl; -NH-C(=O)NH2; -NH-C(=O)-NH(C ₁ . ₆ -alkyl); -NH-C(=O)-N(c ₁ . ₆ -alkyl) ₂ ; -N(C ₁ . ₆ -alkyl)-C(=O)-C ₁ . ₆ -alkyl; -N(C _W alkyl)-C(=O)-O-C ₁ _ ₆ -alkyl; -N(C ₁ . ₆ -alkyl)-C(=O)-NH ₂ ; -N(C ₁ . ₆ -alkyl)-C(=O)-NH(C ₁ . ₆ -alkyl); -N(C ₁ - ₆ alkyl)-C(=o)-N(C ₁ . ₆ -alkyl) ₂ ; -NH-S(=O)2OH; -NH-S(=O) ₂ -C ₁ . ₆ -alkyl; -NH-S(=O) ₂ -O-C ₁ . ₆ -alkyl; -NHS(=O) ₂ -NH ₂ ; -NH-S(=O) ₂ -NH(C ₁ . ₆ -alkyl); -NH-S(=O) ₂ N(C ₁ . ₆ -alkyl) ₂ ; -N(C ₁ . ₆ -alkyl)-S(=O) ₂ -OH; -N(C ₁ - ₆ alkyl)-S(=O) ₂ -C ₁ . ₆ -alkyl; -N(C ₁ . ₆ -alkyl)-S(=O) ₂ -O-C ₁ . ₆ -alkyl; -N(C ₁ . ₆ -alkyl)-S(=O) ₂ -NH ₂ ; -N(C ₁ . ₆ -alkyl)S(=O) ₂ -NH(C ₁ . ₆ -alkyl); -N(C ₁ . ₆ -alkyl)-S(=O) ₂ -N(C ₁ . ₆ -alkyl) ₂ ; -SCF ₃ ; -SCF2H; -SCFH2; -SC ₁ . ₆ -alkyl; -S(=O)-C ₁ . ₆ -alkyl; -S(=O) ₂ -C ₁ . ₆ -alkyl; -S(=O) ₂ -OH; -S(=O) ₂ -O-C ₁ . ₆ -alkyl; -S(=O) ₂ -NH ₂ ; -S(=O) ₂ NH(C ₁ . ₆ -alkyl); -S(=O) ₂ -N(C ₁ . ₆ -alkyl) ₂ ; -C ₃ - ₆ -cycloalkyl; 3-6 membered heterocycloalkyl; phenyl; 5 or 6 membered heteroaryl; -O-C ₃ - ₆ -cycloalkyl; -O-(3-6 membered heterocycloalkyl); -O-phenyl; -O-(5 or 6 membered heteroaryl); -C(=O)-C ₃ - ₆ -cycloalkyl; C(=O)-(3-6-membered heterocycloalkyl); -C(=O)-phenyl; -C(=O)-(5 or 6 membered heteroaryl); -S(=O) ₂ -(C ₃ . ₆ -cycloalkyl); -S(=O) ₂ -(3-6 membered heterocycloalkyl); -S(=O) ₂ -phenyl and -S(=O) ₂ -(5 or 6 membered heteroaryl).

- 6 044347

Preferred substituents -C _1-10 -alkyl, -C _1- b-alkyl, -C1- ₄ -alkyl, -C ₃ - ₁₀ -cycloalkyl, -C ₃ - ₆ -cycloalkyl, 3-7 membered heterocycloalkyl, 3-6 -membered heterocycloalkyl, -C ₁ . ₆ -alkylene- and -C _1-4 -alkylene- are selected from the group consisting of -F; -Cl; -Br; -I; -CN; -C ₁ . ₆ -alkylα; -CF ₃ ; -CF2H; -CFH2; -C(=O)-NH2; -C(=O)-NH(C ₁ . ₆ -alkyl); -C(=O)-N( _{C1.6 -} alkyl) ₂ ; -OH; -OCF ₃ ; -OCF2H; -OCFH2; -O-C ₁ . ₆ -alkyl; -NH2; -NH(C ₁ . ₆ -alkyl); -N(C ₁ . ₆ -alkyl) ₂ ; -SCF ₃ ; -SCF2H; -SCFH2; -SC ₁ . ₆ -alkyl; -S(=O)-C ₁ . ₆ -alkyl; -S(=O) ₂ -Cl. ₆ -alkyl; -C ₃ _ ₆ -cycloalkyl; 3-6 membered heterocycloalkyl; phenyl and 5 or 6 membered heteroaryl; and especially preferably -F, -CN, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ ; -CF2H; -CFH2; -C(=O)-NH2; -C(=O)-NH(CH3); -C(=O)-N(CH3)2; -OH, -NH2, -OCH3, -SCH3, -S(=O)2(CH3), -S(=O)(CH3), -N(CH3)2, cyclopropyl and oxetanyl. According to this embodiment of the invention, -C1_ ₁₀ -alkyl, -C ₁ . ₆ -alkyl, _-C1-4 -alkyl, _-C3-10 -cycloalkyl _{, -C3-6} -cycloalkyl, _3-7 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, preferably each independently unsubstituted, mono- or trisubstituted, more preferably unsubstituted or monosubstituted or disubstituted with a substituent selected from the group consisting of -F; -Cl; -Br; -I; -CN; -C ₁ . ₆ -alkyl; -CF ₃ ; -CF2H; -CFH2; -C(=O)-NH ₂ ; -C(=O)-NH(C1.6-alkyl); -C(=O)-N(C1. ₆ -alkyl) ₂ ; -OH; -OCF3; -OCF2H; -OCFH2; -O-C1. ₆ -alkylα; -NH2; -NH(C ₁ . ₆ -alkyl); -N(C ₁ . ₆ -alkyl) ₂ ; -SCF ₃ ; -SCF2H; -SCFH2; -SC ₁ . ₆ -alkyl; -S(=O)-C ₁ . ₆ -alkyl; -S(=O) ₂ -C1. ₆ alkyl; -C ₃ _ ₆ -cycloalkyl; 3-6 membered heterocycloalkyl; phenyl and 5 or 6 membered heteroaryl; more preferably -F; -Cl; -Br; -CN; -C ₁ . ₆ -alkyl; -CF ₃ ; -CF2H; -CFH2; -HE; -OCF ₃ ; -OCF2H; and -OCFH2; and especially preferably -F; -Cl; -Br. Preferably -C ₁ . ₆ -alkylene groups and -C1. _{The 4} -alkylene groups are unsubstituted.

According to the invention, preferably the phenyl and the 5- or 6-membered heteroaryl are in each case, independently of each other, unsubstituted or mono- or polysubstituted; preferably unsubstituted, mono- or tri-substituted, even more preferably unsubstituted or mono- or disubstituted; with one or more substituents selected from -F; -Cl; -Br; -I; -CN; -C ₁ . ₆ -alkyl; -CF ₃ ; -CF2H; -CFH2; -CF ₂ Cl; _-CFCl2 ; -C ₁ . _4- alkylene-CF ₃ ; C ₁ . _4- alkylene-CF ₂ H; -C1_ ₄ alkylene-CFH;.; -C(=O)-C1.6-alkyl; -C(=O)-OH; -C(=O)-OC1.6-alkyl; -C(=O)-NH(OH); -C(=O)-NH2; -C(=O)NH( _{C1.6 -} alkyl); -C(=O)-N( _{C1.6 -} alkyl) ₂ ; =O; -HE; -OCF ₃ ; -OCF2H; -OCFH2; -OCF ₂ Cl; -OCFCl ₂ ; -O-C1-6alkyl; -O-C _{3_6 -} cycloalkyl; -O-(3 to 6 membered heterocycloalkyl); -NH2; -NH(C ₁ . ₆ -alkyl); -N(C1_ ₆ alkyl) ₂ ; -NH-C(=O)-C ₁ . ₆ -alkyl; -N(C ₁ . ₆ -alkyl)-C(=O)-C ₁ . ₆ -alkyl; -NH-C(=O)-NH ₂ ; -NH-C(=o)-Nh(c ₁ _ ₆ alkyl); -NH-C(=O)-N(C ₁ . ₆ -alkyl) ₂ ; -N(C ₁ . ₆ -alkyl)-C(=O)-NH(C ₁ . ₆ -alkyl); -N _{( C1.6} -alkyl)-C(=O)-N( _C1.6alkyl ) _{2 ;} -NH-S(=O) ₂ -C ₁ . ₆ -alkyl; -SCF ₃ ; -SC ₁ . ₆ -alkyl; -S(=O)-C ₁ . ₆ -αalkyl; -S(=O) ₂ -C ₁ . ₆ -alkyl; -S(=O) ₂ NH2; -S(=O) ₂ -NH(C ₁ . ₆ -alkyl); -S(=O) ₂ -N(C ₁ . ₆ -alkyl) ₂ ; -C ₃ _ ₆ -cycloalkyl; -C1. _4- alkylene-C ₃ . ₆ -cycloalkyl; 3 to 6 membered heterocycloalkyl; -C1- ₄ -alkylene-(3 to 6-membered heterocycloalkyl); phenyl or 5 or 6 membered heteroaryl.

Preferred phenyl and 5- or 6-membered heteroaryl substituents are selected from the group consisting of -F; -Cl; -Br; -I; -CN; -C ₁ . ₆ -alkyl; -CF ₃ ; -CF2H; -CFH2; -C ₁ . _4- alkylene-CF ₃ ; -C ₁ . ₄ -alkylene--CF ₂ H; -C ₁ . ₄ -αalculene-CFH ₂ ; -HE; -OCF ₃ ; -OCF2H; -OCFH2; -OC ₁ . ₆ -alkyl; -O-C ₃ - ₆ -cycloalkyl and -C ₃ _ ₆ -cycloalkyl; and more preferably -F; -Cl; -Br; -CN; -CH3; -CH2CH3; -CF3; -CF2H; -CFH2; -CH2-CF3; =O; -OH; -OCF3; -OCF2H; -OCFH2; -O-CH ₃ ; -O-cyclopropyl and cyclopropyl; even more preferably -F; -Cl; -Br; -CH ₃ ; -CH ₂ CH ₃ ; -CF ₃ ; -CF2H; -CFH2; =O; -HE; -OCF ₃ ; and -O-CH ₃ ; and especially preferably -F; -Cl; -Br; -CH ₃ ; =O; and -O-CH ₃ . According to this embodiment, the phenyl and 5- or 6-membered heteroaryl are preferably each independently unsubstituted, mono- or tri-substituted, more preferably unsubstituted or mono-substituted or disubstituted with a substituent selected from the group consisting of -F; -Cl; -Br; -I; -CN; -C ₁ . ₆ -alkyl; -CF ₃ ; -CF2H; -CFH2; -C ₁ . _4- alkylene-CF ₃ ; -C ₁ . _4- alkylene-CF ₂ H; -C ₁ . _4- alkylene-CFH ₂ ; =O; -HE; -OCF ₃ ; -OCF2H; -OCFH2; -OC ₁ . ₆ -alkyl; -O-C ₃ - ₆ cycloalkyl and -C ₃ _ ₆ -cycloalkyl. A particularly preferred substituted 5- or 6-membered heteroaryl is N-methyl-2-oxopyridyl.

In a preferred embodiment, the compound according to the invention has stereochemistry in accordance with the general formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX).

- 7 044347

In a preferred embodiment, the compound of the invention has stereochemistry according to the general formula (II), (III), (VI) or (VII), such that the -R1 and -NH-R2 residues on the pyrrolidone ring are oriented trans. Preferably, the compound according to the invention has stereochemistry in accordance with the general formula (II) or (VI). Preferably, the compound according to the invention has stereochemistry in accordance with the general formula (III) or (VII). Stereochemistry according to general formula (II) or (VI) is particularly preferred.

In another preferred embodiment, the compound of the invention has a stereochemistry according to general formula (IV), (V), (VIII) or (IX), such that the -R1 and -NH-R2 residues on the pyrrolidone ring are cis oriented. Preferably, the compound of the invention has stereochemistry according to general formula (IV) or (VIII). Preferably, the compound of the invention has stereochemistry according to general formula (V) or (IX).

In a particularly preferred embodiment, the compound according to the invention has a stereochemistry in accordance with the general formula (II) or (VI), more preferably (II).

In the compound of the invention, any of the general formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) R1 represents phenyl; -C _1-6 -alkylene-phenyl; 5 or 6 membered heteroaryl; -C _1-6 -alkylene-(5 or 6 membered heteroaryl); or -C _1-10 -alkyl.

Preferably, R1 is phenyl or ethyl; more preferably phenyl.

In a particularly preferred embodiment, R1 is phenyl, unsubstituted or mono- or disubstituted with substituents independently selected from the group consisting of -F, -Cl, -Br, -OCH ₃ ; -CH ₃ , -CF ₃ , -CN, and cyclopropyl; more preferably -F, -OSH ₃ ; and -CH ₃ .

In the compound of the invention, any of the general formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) R1' represents H; -C _1-10 -alkyl; or -C _3-10 -cycloalkyl.

In a preferred embodiment, R1' is H; methyl, ethyl, n-propyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; more preferably H, methyl, ethyl, cyclopropyl or cyclobutyl; even more preferably H, methyl or cyclopropyl.

In a particularly preferred embodiment, R1' is H.

In the compound of the invention, any of the general formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) R2 is -C( =O)-C _1-10 -alkyl; -C(=O)-C _3-10 -cycloalkyl; -C(=O)-C _1-6 -alkyleneC _3-10 -cycloalkyl; -C(=O)-(3-7 membered heterocycloalkyl); -C(=O)-C _1-6 -alkylene-(3-7 membered heterocyclic- 8 044347 loalkyl); -C(=O)-phenyl; -C(=O)-C _1- b-alkylene-phenyl; -C(=O)-(5 or 6-membered heteroaryl); -C(=O)-C1. ₆ alkylene (5 or 6 membered heteroaryl); -S(=O) ₁ . ₂ -C1-10-alkyl; -S(=O) ₁ . ₂ -C ₃ . ₁₀ -cycloalkyl; -S(=O) ₁ _ ₂ -C ₁ _ ₆ alkylene-C ₃ _ ₁₀ -cycloalkyl; -S(=O) ₁ . ₂ -(3-7 membered heterocycloalkyl); -S(=O) _1-2 -C _1-6 -alkylene-(3-7 membered heterocycloalkyl); -S(=O) _1-2 -phenyl; -S(=O) _1-2 -C _1-6 -alkylene-phenyl; -S(=O) _1-2 -(5 or 6 membered heteroaryl); or -S(=O) _1-2 -C _1-6 -alkylene-(5 or 6 membered heteroaryl).

In a preferred embodiment, R2 is -C(=O)-C ₁ . ₁₀ -αlkul; -C(=O)-C _3-10 -cycloalkyl; -C(=O)-C _1-6 -alkylene-C _3-10 -cycloalkyl; -C(=O)-(3-7-membered heterocycloalkyl); -C(=O)-(5 or 6-membered heteroaryl); -S(=O) ₂ -C1-10-αalkyl; -S(=O) ₂ -C _3-10 -cycloalkyl; -S(=O) ₂ -C ₁ . ₆ -alkyleneC _3-10 -cycloalkyl; -S(=O) ₂ -(3-7 membered heterocycloalkyl); or -S(=O) ₂ -(5 or 6 membered heteroaryl).

In particularly preferred embodiments, R2 is (i) -C(=O)-Ci _-10 -alkyl, unsubstituted or mono- or disubstituted with substituents independently selected from the group consisting of -F, -Cl and -Br ;

(ii) -C(=O)-cyclopropyl, unsubstituted or mono- or disubstituted with substituents independently selected from the group consisting of -F, -Cl -Br, -CH ₃ , -CF ₃ , -CN, -OSN ₃ ;

(iii) -C(=O)-2-tetrahydrofuranyl, unsubstituted;

(iv) -C(=O)-(5-6 membered heteroaryl), where said 5-6 membered heteroaryl is selected from the group consisting of thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1-oxa-2,4-diazolyl , 1,2,5oxadiazolyl and isothiazolyl, where in each case said 5-6-membered heteroaryl is unsubstituted or mono- or disubstituted with substituents independently selected from the group consisting of F, -Cl -Br, -CH ₃ , -CF ₃ , -CN, =O, and -OSH ₃ ;

(v) -S(=O) ₂ -C _1-10 -alkyl, unsubstituted; (vi) -S(=O) ₂ -cyclopropyl, unsubstituted; (vii) -S(=O) ₂ -CH ₂ cyclopropyl, unsubstituted; (viii) -S(=O) ₂ -2-tetrahydrofuranyl; or (ix) -S(=O) ₂ -(5-6 membered heteroaryl), wherein said 5-6 membered heteroaryl is selected from the group consisting of thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1-oxa-2,4 -diazolyl, 1,2,5oxadiazolyl and isothiazolyl, where in each case said 5-6 membered heteroaryl is unsubstituted or mono- or disubstituted with substituents independently selected from the group consisting of -F, -Cl -Br, -CH ₃ , -CF ₃ , -CN, =O, and -OSH ₃ .

In the compound of the invention, any of the general formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) R ₃ and R ₃ ' independently represents H; F; Cl; -C _1-10 -alkyl; -C _3-6 -cycloalkyl; -CH ₂ -C _3-6 -cycloalkyl; 3-7 membered heterocycloalkyl; -CH ₂ -(3-7 membered heterocycloalkyl); -CH ₂ -phenyl; or -CH2- (5 or 6 membered heteroaryl); or R ₃ and R ₃ together with the carbon atom to which they are bonded form a C ₃ - ₁₀ -cycloalkyl, or 3-7 membered heterocycloalkyl.

In a preferred embodiment, R ₃ and R 3 are both -C1_ ₁₀ -alkyl. In a particularly preferred embodiment, R ₃ and R 3 are both -CH ₃ .

In another preferred embodiment, R ₃ and R 3 independently represent H; F; -CH ₃ ; cyclopropyl; -CH2-cyclopropyl; or -CH2-phenyl. In yet another preferred embodiment, _R3 and _R3 ' are both F.

In another preferred embodiment, at least one of R ₃ and R ₃ is not H. In yet another preferred embodiment, one of R ₃ and R ₃ is H.

In yet another preferred embodiment, R ₃ and R ₃ together with the carbon atom to which they are bonded form cyclopropyl.

In the compound of the invention, any of the general formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) R ₄ represents phenyl; -C ₁ . _6- alkylene-phenyl; 5 or 6 membered heteroaryl; or -C ₁ . ₆ -alkylene-(5 or 6-membered heteroaryl).

Preferably, R4 is phenyl or 5- or 6-membered heteroaryl.

In particularly preferred embodiments, R4 is phenyl, unsubstituted or mono- or disubstituted with substituents independently selected from the group consisting of -F, -Cl-Br, -CH ₃ , -CF ₃ , -CN, and - OSN ₃ ; or

A 5- or 6-membered heteroaryl selected from the group consisting of pyridyl, pyrazolyl and pyrimidinyl, wherein in each case said 5-6 membered heteroaryl is unsubstituted or mono- or disubstituted with substituents independently selected from the group consisting of =O, -F, -Cl -Br, _-CH3 , -CF3, -CN, and -OCH3.

In a particularly preferred embodiment, R ₄ is not Nmethylpyridinone.

In the compound of the invention, any of the general formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) A, X, Y and Z independently of each other represent N or CH. Preferably, A is N.

In a preferred embodiment, X is CH.

In a preferred embodiment, Y is CH.

In a preferred embodiment, Z represents CH.

In a preferred embodiment of the invention (i) A is N, X is CH, Y is CH; and Z represents

- 9 044347 is CH; or (ii) A is N, X is N, Y is CH; and Z represents CH; or (iii) A is N, X is CH, Y is N; and Z represents CH; or (iv) A is N, X is CH, Y is CH; and Z is N; or (v) A is N, X is N, Y is N; and Z represents CH; or (vi) A is N, X is N, Y is CH; and Z is N; or (vii) A is N, X is CH, Y is N; and Z is N; or (viii) A is N, X is N, Y is N; and Z is N; or (ix) A is CH, X is CH, Y is CH; and Z represents CH; or (x) A is CH, X is N, Y is CH; and Z represents CH; or (xi) A is CH, X is CH, Y is N; and Z represents CH; or (xii) A is CH, X is CH, Y is CH; and Z is N; or (xiii) A is CH, X is N, Y is N; and Z represents CH; or (xiv) A is CH, X is N, Y is CH; and Z is N; or (xv) A is CH, X is CH, Y is N; and Z is N; or (xvi) A is CH, X is N, Y is N; and Z represents N.

In a particularly preferred embodiment of the invention according to any of the general formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX),

R1 is phenyl, unsubstituted or mono- or disubstituted with substituents independently selected from the group consisting of -F, -Cl-Br, -CH ₃ , and -OCH ₃ ; and/or

R1' is H, CH ₃ or cyclopropyl and/or

R2 represents -C(=O)-C ₁ . ₆ -alkyl; -C(=O)-cyclopropyl; or -C(=O)-(5-6 membered heteroaryl), unsubstituted or mono- or disubstituted with substituents independently selected from the group consisting of -F, -Cl -Br; and -CH ₃ ; and/or

R4 is fluorophenyl or N-methyl-2-oxopyridyl.

In a preferred embodiment, a compound of the invention is selected from the group consisting of

- 10 044347

N-[(2R,3S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4,4-Dimethyl-5-oxo-2-phenylpyrrolidin-3-yl]-cyclopropanecarboxylic acid amide

N-[(2S,3R)-l-[l-(4-φτopφenyl)-lH-indazol-5-yl]-4,4-Dimethyl-5-oκco-2-φenylpyrrolidin-3-yl]-cyclopropanecarboxylic acid amide

H-[rac-(6K.78)-5-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-oxo-6-phenyl-5azaspiro[2,4]heptan-7-yl ]-cyclopropanecarboxylic acid amide

2,2-Difluoro-M-[(2S,3R)-1 - [1-(4-fluorophenyl)-1H-indazol-5-yl]-4,4-Dimethyl-5-oxo

2-phenyl-pyrrolidin-3-yl]-propionamide

H-[rac-(6^78)-5-[1-(4-Fluorophenyl)-1H-indol-5-yl]-4-oxo-6-phenyl-5azaspiro[2,4]heptan-7-yl ]-cyclopropanecarboxylic acid amide

N-[(2R,3 S)-4,4-Dimethyl-1 -[ 1 -(1-methyl-6-oxo-1H-pyridin-3-yl)-1 H-indazol-5-yl] -

-oxo-2-phenyl-pyrrolide in-3-yl]-5-methyl-thiazol-2-carboxylic acid amide

N-[(2R,3 S)-4,4-Dimethyl-1 -[ 1 -(1-methyl-6-oxo-1H-pyridin-3-yl)-1 H-indazol-5-yl] -

-oxo-2-phenyl-pyrrolide in-3-yl]-5-methyl-isoxazole-3-carboxylic acid amide

N-[(2S,3R)-4,4-Dimethyl-l-[l-(l-methyl-6-oκco-lH-pyridin-3-yl)-lH-indazol-5-yl]5-oxo- 2-phenyl-pyrrolidin-3-yl]-2,2-difluoropropionamide

N-[(2R,3 S)-4,4-Dimethyl-1 -[ 1 -(1-methyl-6-oxo-1H-pyridin-3-yl)-1 H-indazol-5-yl] 5 -oxo-2-phenyl-pyrrolidin-3-yl]-2,2-difluoropropionamide

- 11 044347

2,2-D iforo-M-[(2d, 3 S)-1 - [1 -(4-fluorophenyl)-1 N-indazol-5 -yl]-4,4-Dimethyl-5-oxo2-phenyl- pyrrolidin-3-yl]-propionamide

N-[(2R,3 8)-4,4-Dimethyl-1 -[1 -(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]5-oxo -2-phenyl-pyrrolide in-3-yl]-1-methyl-1 H-pyrazole-3-carboxylic acid amide

N-[(2R,3 8)-4,4-Dimethyl-1 -[1 -(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]5-oxo -2-phenyl-pyrrolid in-3-yl]-oxazole-5-carboxylic acid amide

N-[(2R,3 S)-4,4-Dimethyl-1 -[ 1 -(1 -methyl-6-oxo-1 H-pyridin-3-yl)-1 H-indazol-5-yl]-

-oxo-2-phenyl-pyrrolid in-3-yl]-5-methyl-[1,2,4]oxodiazol-3-carboxylic acid amide

N-[(2R,3 S)-4,4-Dimethyl-1 -[ 1 -(1 -methyl-6-oxo-1 H-pyridin-3-yl)-1 H-indazol-5-yl]5 -oxo-2-phenyl-pyrrolide in-3-yl]-thiazol-5-carboxylic acid amide

N-[(2R,3 S)-4,4-Dimethyl-1 -[ 1 -(1 -methyl-6-oxo-1 H-pyridin-3-yl)-1 H-indazol-5-yl]-

-oxo-2-phenyl-pyrrolide in-3-yl]-4-methyl-thiazol-5-carboxylic acid amide

N-[(2R,3 S)-4,4-Dimethyl-1 -[ 1 -(1 -methyl-6-oxo-1 H-pyridin-3-yl)-1 H-indazol-5-yl]-

-oxo-2-phenyl-pyrrolide in-3-yl]-thiazol-4-carboxylic acid amide

N-[(2R,3 S)-4,4-Dimethyl-1 -[ 1 -(1 -methyl-6-oxo-1 H-pyridin-3-yl)-1 H-indazol-5-yl]-

-oxo-2-phenyl-pyrrolide in-3-yl]-5-methyl-thiazol-4-carboxylic acid amide

N-[(2S,3R)-4,4-Dimethyl-l-[l-(l-methyl-6-oκco-lH-pyridin-3-yl)-lH-indazol-5-yl]5-oxo- 2-phenyl-pyrrolide in-3-yl]-oxazole-5-carboxylic acid amide

N-[(2S,3R)-4,4-flHMeT№i-l-[l-(l-MeT№i-6-OKCO-lH-nHpHflHH-3-№i)-lH-HHfla3Ofl-5-№i] 5-oxo-2-phenyl-pyrrolide in-3-yl]-5-methyl-isoxazole-3-carboxylic acid amide

N-[(2S,3R)-4,4-Dimethyl-l-[l-(l-methyl-6-oκco-lH-pyridin-3-yl)-lH-indazol-5-yl]5-oxo- 2-phenyl-pyrrolide in-3-yl]-thiazol-5-carboxylic acid amide

N-[(2S,3R)-4,4-Dimethyl-l-[l-(l-methyl-6-oκco-lH-pyridin-3-yl)-lH-indazol-5-yl]-

-oxo-2-phenyl-pyrrolide in-3-yl]-5-methyl-thiazol-2-carboxylic acid amide

N-[pac-(6R,7S)-5-[l-(l-Meτyl-6-oκco-lH-πpyridin-3-yl)-lH-indazol-5-yl]-4-oκco-6 phenyl- 5-azaspiro[2,4]heptan-7-yl]-cyclopropanecarboxylic acid amide

H-[rac-(6Al78)-5-[1-(4-Fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-4-oxo-6phenyl-5-azaspiro[2,4 ]heptan-7-yl]-cyclopropanecarboxylic acid amide

H-[rac-(6Al78)-5-[1-(4-Fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl]-4-oxo-6phenyl-5-azaspiro[2,4 ]heptan-7-yl]-cyclopropanecarboxylic acid amide

- 12 044347

18G-[rac-(6K.78)-5-[1-(4-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-4-oxo-6 phenyl-5-azaspiro [2,4]heptan-7-yl]-cyclopropanecarboxylic acid amide

34a H-((2K,38)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolidin-3-yl)methanesulfonamide

34b H-((28,3K)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolidin-3-yl)methanesulfonamide

35a N-((2R,38)-1-(1 -(4-fluorophenyl)-1 H-indazol-5-yl)-4,4-Dimethyl-5-oxo-2phenylpyrrolidin-3-yl)cyclopropanesulfonamide

35b M-((28,ZI)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-Dimethyl-5-oxo-2phenylpyrrolidin-3-yl)cyclopropanesulfonamide

36a N-((2R,38)-1-(1 -(4-fluorophenyl)-1 H-indazol-5-yl)-4,4-Dimethyl-5-oxo-2phenylpyrrolid in-3 -yl)oxazol- 5-carboxamide

36b H-((28,3K)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-Dimethyl-5-oxo-2phenylpyrrolidin-3 -yl)oxazol-5 - carboxamide

N-((2R,38)-1-(1 -(4-fluorophenyl)-1 H-indazol-5-yl)-4,4-Dimethyl-5-oxo-2phenylpyrrolid in-3 -yl)-1 - methyl-1H-pyrazole-3-carboxamide

38a M-((28,3Zh)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolidin-3-yl)-4-methylthiazole -5-carboxamide

38b H-((2K,38)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolidin-3-yl)-4-methylthiazole -5-carboxamide

39a H-((2K,38)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolidin-3-yl)-5-methylthiazole -4-carboxamide

39b H-((28,3K)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolidin-3-yl)-5-methylthiazole -4-carboxamide

40a H-((2K,38)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolid in-3 -yl)-3 - Methylisoxazole-4-carboxamide

40b X-((28,3K)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolid in-3 -yl)-3 - Methylisoxazole-4-carboxamide

41a N-((2R,38)-1-(1 -(4-fluorophenyl)-1 H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolid in-3 -yl)-1 -methyl-1H-pyrazole-4-carboxamide

41b H-((28,3K)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolid in-3 -yl)-1 - methyl-1H-pyrazole-4-carboxamide

42a H-((2K,38)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2- 13 044347 phenylpyrrolidin-3-yl) nicotinamide

42b N-((2S,3R)-l-(l-(4-φτopφenyl)-lH-indazol-5-yl)-4,4-dimethyl-5-oκco-2phenylpyrrolidin-3-yl)nicotinamide

43a ^((2H38)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolidin-3-yl)pyrimidin-2-carboxamide

43b N-((2S,3R)-l-(l-(4-φτopφenyl)-lH-indazol-5-yl)-4,4-dimethyl-5-oκco-2phenylpyrrolidin-3-yl)pyrimidin-2- carboxamide

44a ^((2H38)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolid in-3 -yl)-2-methyloxazol-5 -carboxamide

44b ^((28,3K)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolid in-3 -yl)-2-methyloxazole -5-carboxamide

45a M-((2H38)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolid in-3 -yl)-4-methyloxazol- 5-carboxamide

45b M-((28,33)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolid in-3 -yl)-4- methyloxazol-5-carboxamide ^[rac-(2H38.48)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl ]-cyclopropanecarboxylic acid amide

M-[rac-(2H38.48)-2-(2-)Chlorophenyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl5-oxo-pyrrolidin-3-yl ]-2,2-difluoropropionamide

M-[rac-(2d,38,48)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(3-methoxyphenyl)-4methyl-5-oxo-pyrrolidine-3 -yl]-cyclopropanecarboxylic acid amide

M-[rac-(2d,38,48)-2-(4-Fluorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl5-oxo-pyrrolidine-3 -yl]-cyclopropanecarboxylic acid amide

M-[rac(2d,38,48)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl]-4 -methyl-thiazole-5-carboxylic acid amide

N-[pau-(2R,3S,4S)-l-[l-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl]- methanesulfonic acid amide

N-[pau-(2R,3S,4S)-l-[l-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-n-tolyl-5-oxo pyrrolidine-3 -yl]-methanesulfonic acid amide

N-[pau-(2R,3S,4S)-l-[l-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-n-tolyl-5-oxo pyrrolidine-3 -yl]-cyclopropanecarboxylic acid amide

N-[pau-(2R,3S,4S)-l-[l-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl]- 1-methyl-1H-pyrazole-3-carboxylic acid amide

- 14 044347

N-[pan-(2R,3S,4S)-l-[l-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl]- pyridine-3-carboxylic acid amide

N-[pap-(2R,3S,4S)-l-[l-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl]- pyrimidine-2-carboxylic acid amide

N-[pan-(2R,3S,4S)-l-[l-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-n-tolyl-5-oxopyrrolidine-3 -yl]-4-methyl-thiazol-5-carboxylic acid amide

N-[pac-(2R,3S,4S)-l-[l-(4-Φτopφenyl)-lH-indazol-5-yl]-4-methyl-2-m-tholyl-5-ocopyrrolidin-3-yl ]-pyridine-3-carboxylic acid amide

N-[pan-(2R,3S,4S)-l-[l-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-n-tolyl-5-oxopyrrolidin-3-yl ]-pyrimidine-2-carboxylic acid amide

N-[pac-(2R,3S,4R)-l-[l-(4-Φτopφenyl)-lH-indazol-5-yl]-4-methyl-2-m-tholyl-5-oκco pyrrolidin-3- yl]-cyclopropanecarboxylic acid amide

N-[pac-(2R,3S,4R)-l-[l-(4-Φτopφenyl)-lH-indazol-5-yl]-4-methyl-2-m-tholyl-5-oκco pyrrolidin-3- yl]-4-methyl-thiazol-5-carboxylic acid amide

N-[pac-(2R,3S,4R)-l-[l-(4-Φτopφenyl)-lH-indazol-5-yl]-4-methyl-2-m-tholyl-5-oκco pyrrolidin-3- yl]-1-methyl-1H-pyrazole-3-carboxylic acid amide

N-[pac-(2R,3S,4R)-l-[l-(4-Φτopφenyl)-lH-indazol-5-yl]-4-methyl-2-m-tholyl-5-oκco pyrrolidin-3- yl]-pyridine-3-carboxylic acid amide

N-[pac-(2R,3S,4R)-l-[l-(4-Φτopφenyl)-lH-indazol-5-yl]-4-methyl-2-m-tholyl-5-oκco pyrrolidin-3- yl]-pyrimidine-2-carboxylic acid amide

N-[pap-(2R,3S,4S)-l-[l-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-t-tolyl-5-oxopyrrolidin-3-yl ]-1-methyl-1H-pyrazole-3-carboxylic acid amide

N-[pac-(2R,3S,4R)-l-[l-(4-Φτopφenyl)-lH-indazol-5-yl]-4-methyl-2-m-tholyl-5-oκco pyrrolidin-3- yl]-methanesulfonic acid amide

2,2-Diφτopo-N-[pac-(2R,3S,4R)-l-[l-(4-φτopphenyl)-lH-indazol-5-yl]-4-methyl-2-tolyl-5-oxo -pyrrolidin-3-yl]-propionamide

N-[pac-(2R,3S,4R)-2-(2-chlorophenyl)-l-[l-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl5-oxo-pyrrolidin-3 -yl]-cyclopropanecarboxylic acid amide

N-[pac-(2R,3S,4R)-2-(2-)Chlorophenyl-l-[l-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-

-oxo-pyrrolidin-3-yl]-2,2-difluoropropionamide

2,2-Difluoro-M-[rac-(2C38.48)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5oxo-2-phenyl-pyrrolidin-3 -yl]-propionamide

2,2-Diφτopo-N-[pac-(2R,3S,4S)-l-[l-(4-φτopφenyl)-lH-indazol-5-yl]-4-methyl-2-m- 15 044347 tolyl -5-oxo-pyrrolidin-3-yl]-propionamide

N-[paii-(2R,3 S,4S)-1 -[ 1 -(4-Fluorophenyl)-1 H-indazol-5-yl]-2-(4-methoxyphenyl)-4methyl-5-oxo-pyrrolidine -3-yl]-4-methyl-thiazol-5-carboxylic acid amide

N-[paii-(2R,3 S,4S)-1 -[ 1 -(4-Fluorophenyl)-1 H-indazol-5-yl]-2-(4-methoxyphenyl)-4methyl-5-oxo-pyrrolidine -3-yl]-1-methyl-1H-pyrazole-3-carboxylic acid amide

N-[paii-(2R,3 S,4S)-1 -[ 1 -(4-Fluorophenyl)-1 H-indazol-5-yl]-2-(4-methoxyphenyl)-4methyl-5-oxo-pyrrolidine -3-yl]-pyridin-3-carboxylic acid amide

N-[paii-(2R,3 S,4S)-1 -[ 1 -(4-Fluorophenyl)-1 H-indazol-5-yl]-2-(4-methoxyphenyl)-4methyl-5-oxo-pyrrolidine -3-yl]-pyrimidin-2-carboxylic acid amide

N-[paii-(2R,3 S,4R)-2-(2-Chlorophenyl)-1 -[1 -(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl5-oxo-pyrrolidin- 3-yl]-methanesulfonic acid amide

N-[paii-(2R,3 S,4R)-2-(2-Chlorophenyl)-1 -[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl5-oxo-pyrrolidin- 3-yl]-pyridine-3-carboxylic acid amide

N-[pap-(2R,3 S,4R)-2-(2-Chlorophenyl)-1 -[1 -(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl5-oxo-pyrrolidin- 3-yl]-pyrimidin-2-carboxylic acid amide

X-[rac-(2^38.48)-4-benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxopyrrolidin-3-yl]- pyridine-3-carboxylic acid amide

X-[rac-(2^38.48)-4-benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxopyrrolidin-3-yl]- pyrimidine-2-carboxylic acid amide

X-[rac-(2^38.48)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxopyrrolidin-3-yl]- methanesulfonic acid amide

X-[rac-(2^38.48)-2-(2-Chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl5-oxo-pyrrolidin-3 -yl]-pyridine-3-carboxylic acid amide

X-[rac-(2^38.48)-2-(2-Chlorophenyl)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl5-oxo-pyrrolidine-3 -yl]-methanesulfonic acid amide

N-[paii-(2R,3 S,4R)-2-(2-Chlopphenyl)-1 -[ 1 -(4-fluorophenyl)-1 H-ind azol-5-yl]-4-methyl-

-oxo-pyrrolidin-3-yl]-1-methyl-1 H-pyrazole-3-carboxylic acid amide

N-((2R,3R,4S)-4-φτopo-l-(l-(4-τopφenyl)-lH-indazol-5-yl)-5-oκco-2phenylpyrrolidin-3-yl)cyclopropanecarboxamide

N-((2R,3R)-4,4-diφτopo-l-(l-(4-τopφenyl)-lH-indazol-5-yl)-5-oκco-2phenylpyrrolidin-3-yl)cyclopropanecarboxamide

2,2-Diφτopo-N-[pac-(2R,3S,4R)-l-[l-(4-φτopφenyl)-lH-indazol-5-yl]-2-(4methoxyphenyl)-4-methyl-5 -oxo-pyrrolidin-3-yl]-propionamide

- 16 044347

2,2-Difluoro-M-[rac-(2H38.48)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(4methoxyphenyl)-4-methyl-5-oxo -pyrrolidin-3-yl]-propionamide

N-[pan-(2R,3S,4S)-l-[l-(4-Fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4methyl-5-oxo-pyrrolidine-3 -yl]-methanesulfonic acid amide

100 2,2-Difluoro-M-[rac-(2SH3 S)-1 - [1 -(4-fluorophenyl)-1 H-ind azol-5 -yl]-2-methyl-5-oxo2-phenyl-pyrrolidine -Z-yl]-propionamide

101 X-[rac-(2d,38)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl]-cyclopropanecarboxylic acid amide

102 2,2-Diφτopo-N-[pac-(2R,3S)-2-methyl-l-[l-(l-methyl-6-oκco-lH-pyridin-3-yl)-lHindazol-5 -yl ]-5-oxo-2-phenyl-pyrrolidin-3-yl]-propionamide

103 N-[pan-(2R,3S)-2-Methyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-

-oxo-2-phenyl-pyrrolide in-3-yl]-cyclopropanecarboxylic acid amide

104 1X-[rac-(2H38.48)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxopyrrolidin-3-yl]-1 -methyl-1H-pyrazole-3-carboxylic acid amide

105 X-[rac-(2d,38,48)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxopyrrolidin-3-yl] -4-methyl-thiazole-5-carboxylic acid amide

106 N-[pac-(2R,3S,4S)-4-Benzyl-2-ethyl-l-[l-(4-φτopphenyl)-lH-indazol-5-yl]-5-ocopyrrolidin-3-yl] -cyclopropanecarboxylic acid amide

107 X-[rac-(2d,38,48)-4-Benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxopyrrolidin-3 -yl] -2,2-difluoropropionamide

108 X-[rac-(28,38,48)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4methyl- 5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide

109 X-[rac-(28,38,48)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4methyl- 5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic acid amide

PO X-[rac-(28,38,48)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4methyl- 5-oxo-pyrrolidin-3-yl]-1-methyl-1 H-pyrazole-3-carboxylic acid amide

111 X-[rac-(28,38,48)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4methyl- 5-oxo-pyrrolidin-3-yl]-pyridin-3-carboxylic acid amide

112 N-[pan-(2R,3S,48)-2-(2-chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5oxo-pyrrolidin- 3-yl]-cyclopropanecarboxylic acid amide

113 X-[rac-(28,38,48)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4methyl- 5-oxo-pyrrolidin-3-yl]-4-methyl-thiazol-5-carboxylic acid amide

114 M-[(28,38,48)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4- 17 044347 methyl 5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide

115 M-[rac-(28,38,48)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1Hpyrazol-3 -yl )-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide

116 M-[rac-(28,38,48)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1Hpyrazol-3 -yl )-5-oxo-pyrrolidin-3-yl]-4-methyl-thiazol-5-carboxylic acid amide

117 M-[rac-(28,38,48)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1Hpyrazol-3 -yl )-5-oxo-pyrrolidin-3-yl]-1-methyl-1 H-pyrazole-3-carboxylic acid amide

118 M-[rac-(28,38,48)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1Hpyrazol-3 -yl )-5-oxo-pyrrolidin-3-yl]-pyridin-3-carboxylic acid amide

119 M-[rac-(28,38,48)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1Hpyrazol-3 -yl )-5-oxo-pyrrolidin-3-yl]-pyrimidine-2-carboxylic acid amide

120 2,2-Difluoro-M-[rac-(28,38,48)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1methyl-1 N-pyrazol-3 -yl)-5-oxo-pyrrolidin-3 -yl]-propionamide

121 ^[rac-(2K,38,48)-4-(Cyclopropyl-methyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5oxo-2-phenyl-pyrrolidine-3 -yl]-cyclopropanecarboxylic acid amide

122 M-[rac-(28,38,48)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1Hpyrazol-3 -yl )-5-oxo-pyrrolidin-3-yl]-methanesulfonic acid amide

123 M-[rac-(28,38,48)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4methyl- 5-oxo-pyrrolidin-3-yl]-2,2-difluoropropionamide

124 N-[pau-(2S,3 8.4K)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4 · methyl-5-oxo-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide

125 N-[pau-(2S,3 8.4K)-2-(5-Chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4 · methyl-5-oxo-pyrrolidin-3-yl]-2,2-difluoropropionamide

126 18G-[rac-(2K,38,48)-4-Ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-2-phenylpyrrolidin-3-yl] -cyclopropanecarboxylic acid amide

127 H-((2K,38)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2phenylpyrrolidin-3-yl)cyclopropanecarboxamide, diastereomer 2

128 18G-[rac-(2K,3K,4K)-4-Fluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2phenyl-pyrrolidin- 3-yl]-cyclopropanecarboxylic acid amide

129 18G-[rac-(2K,3K,48)-4-Fluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2phenyl-pyrrolidin- 3-yl]-cyclopropanecarboxylic acid amide

- 18 044347

130 N-((2R, 3S)-I-(I-(4-fluorophenyl)-1 H-indazol-5-yl)-5-oxo-4-phenethyl-2phenylpyrrolidin-3-yl)cyclopropanecarboxamide, diastereomer 1

131 N-((2R,3S,48)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2phenylpyrrolidine-3- yl)cyclopropanecarboxamide

132 N-((2R,3S,4R)-4-(2,2-diφτopoethyl)-l-(l-(4-φτopφenyl)-lH-indazol-5-yl)-5-oκco-2phenylpyrrolidine-3- yl)cyclopropanecarboxamide

133 N-[pan-(2R,3 S,4S)-1-[1 -(4-fluorophenyl)-1 H-ind azol-5-yl]-2-(4-methoxyphenyl)-4methyl-5-oxo -pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide

134 N-(pan-(2R,3 S,4R)-4-ethyl-1 -(1 -(4-fluorophenyl)- 1H-indazol-5-yl)-4-methyl-5-oxo-2phenylpyrrolidine-3 -yl)cyclopropanecarboxamide

135 N-((7R,88)-6-(1 -(4-fluorophenyl)-1 H-indazol-5-yl)-5-oxo-7-phenyl-6azaspiro[3,4]octan-8-yl )cyclopropanecarboxamide

136 M-(rac (2C38.48)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4methyl-5-oxo-2-phenylpyrrolidine -Z -yl)cyclopropanecarboxamide

137 M-(rac-(2,3,48)-4-benzyl-2-ethyl-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5oxopyrrolidin-3- yl)cyclopropanecarboxamide

138 N-((2R,3S,48)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((3-methyl-1,2,4-oxadiazol-5yl) methyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide

139 M-((2nd,38,48)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((1-methyl-1H-pyrazol-4yl)methyl)-5 -oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide

142 N-(pan-(2R, 3 8)-2-cyclopropyl-1 -(1 -(4-fluorophenyl)-1 H-indazol-5 -yl)-5 -oxo-2phenylpyrrolidin-3-yl)cyclopropanecarboxamide

143 N-(pac-(2R,3R)-2-cycloπpoπyl-l-(l-(4-τopτopphenyl)-lH-indazol-5-yl)-5-oκco-2phenylpyrrolidin-3-yl)cyclopropanecarboxamide

144 N-(pan-(2R, 3 8)-2-cyclopropyl-1 -(1 -(4-fluorophenyl)-1 H-indazol-5 -yl)-5 -oxo-2phenylpyrrolidin-3-yl)-2 ,2-difluoropropanamide

145 M-(rac-(2I,ZI)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2phenylpyrrolidin-3-yl)-2.2 -difluoropropanamide

146 N-(pan-(2R, 3 8)-2-cyclopropyl-1 -(1 -(4-fluorophenyl)-1 H-indazol-5 -yl)-5 -oxo-2phenylpyrrolid in-3 -yl)oxetane -3-carboxamide

147 N-(pac-(2R,ЗR)-2-cycloπpoπyl-l-(l-(4-τopphenyl)-lH-indazol-5-yl)-5-oκco-2phenylpyrrolid in-3 -yl)oxetan-3 -carboxamide

148 N-(pan-(2R,3 S,48)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4methyl-5-oxo -2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide

149 N-(pap-(2R, 3 S,48)-4-(cyclopropylmethyl)-1-(1 -(4-fluorophenyl)-1 H-indazol-5 -yl)-4methyl-5-oxo-2- phenylpyrrolidin-3-yl)cyclopropanecarboxamide

150 N-((2R,3S,4R)-l-(l-(4-φτopφenyl)-lH-indazol-5-yl)-5-oκco-2-φenyl-4-(τthiazol-2ylmethyl)pyrrolidin-3 -yl)cyclopropanecarboxamide

151 No.((2A,35)-2-(5-chlorothiophen-2-yl)-1-(1 -(4-fluorophenyl)-1 H-indazol-5-yl)-2-methyl-5oxopyrrolidin-3- yl)cyclopropanecarboxamide in each case in the form of the free compound or a physiologically acceptable salt thereof.

The compounds of the invention can be synthesized by standard reactions in the field of organic chemistry known to a person skilled in the art, or by the method described here (see reaction schemes below) or by analogy. The reaction conditions in the synthetic methods described herein are known to one skilled in the art and, in some cases, are also illustrated by the examples given in the Examples described herein.

Reaction scheme 1.

The substituted indazole moieties in the compounds of formula (D) and formula (F) are introduced by subjecting the lactams (B) or lactams (E) to a regioselective metal-catalyzed C-N coupling reaction with the corresponding indazole halides (C), preferably with the corresponding indazole iodides. Metal-catalyzed C-N coupling reactions are generally known in the art (Current Organic Synthesis, 2011, 8, 53). Favorable C-N coupling reactions are cross-coupling reactions catalyzed by palladium and copper. (Chem. Rev., 2016, 116, 12564; Chem. Soc. Rev., 2014, 43, 3525; Chem. Sci., 2010, 1, 13). Regioselective C-N couplings with aryl halides are known in the art (Chem. Sci., 2011, 2, 27; J. Am. Chem. Soc, 2001, 123, 7727).

Primary amines (A) and (G) are converted to the corresponding amides and sulfonamides (acylation and formation of sulfonamides) (B) and (D) using commercially available acids (acid activation using, for example, HATU) or acid chlorides under standard reaction conditions amide coupling (March's Advanced Organic Chemistry, 2007, 6th Edition, pages 1427-1474).

The introduction of various orthogonal PG protecting groups (eg BOC, Cbz) to convert (A) to (E), as well as deprotection of compounds of formula (E) to (A) are well described in the literature. (T.W. Green, P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 1999).

Reaction scheme 1.1.

Compounds (A) and (E) can be synthesized according to methods described in the literature.

Route 1. The synthesis of compounds of formula (I) starting from compounds of formula (H) is described in the literature. (Org. Lett 2011, 13, 6406, Org. Lett 2009, 4512, ACS Sustainable Chem. Eng. 2015, 1873). For R3 and R3' =Me, the synthesis of the corresponding acid (H) is described (Journal of Chemical and Engineering Data, 1966, 11, 617), and the synthesis can be carried out similarly to the above references. Removal of PG=PMB is well known in the art (Greene's Protective Groups in Organic Synthesis, 2007, 4th Edition, page 905ff). Reduction of nitro groups is well known in the art (March's Advanced Organic Chemistry, 2007, 6th Edition, page 1815f).

Route 2. The synthesis of compounds of formula (J) is described in the literature (Org. Lett., 2007, 9, 4077). The introduction of R3 and R3' substituents can be achieved by alkylation. C-alkylation of pyrrolidinones (Tetrahedron 1999, 55, 13321) and elimination of sulfonium salts (Tetrahedron Letters 1983, 24, 4331) is good

- 20 044347 are known in the art. Compounds of formula (A) and (E) can be synthesized using the Curtius rearrangement as a key step to convert carboxylic acid (1) to the corresponding primary amine (A) or (E). The Curtius rearrangement is well known in the art (Tetrahedron Letters, 2010, 51, 385).

Route 3. The synthesis of compounds of formula (N) starting from compounds of formula (M) is described in the literature (J. Am. Chem. Soc, 2008, 130, 16146). Amidophosphate cleavage is described in the literature (J. Am. Chem. Soc, 2008, 130, 16146). Compounds of formula (A) and (E) can be synthesized using the Curtius rearrangement as a key step to convert carboxylic acid (1) to the corresponding primary amine (A) or (E). The Curtius rearrangement is well known in the art (Tetrahedron Letters, 2010, 51, 385).

Reaction scheme 2.

'GA

Ch. CT

Hal = G BgL . *

Compounds of formula (D) can be synthesized via regioselective C-N coupling of compound (O). Suitable C-N coupling reactions for NH-containing heterocycles are known in the art (Synthesis, 2011, 829; Chem. Sci., 2011, 2, 27; Beilstein J. Org Chem., 2011, 7, 59; J. Org Chem. , 2004, 69, 5578). The compound of formula (O) is synthesized by deprotecting the compound (N) in an acidic environment.

The compounds of the invention can be prepared by the method described herein or by a similar method.

In a preferred embodiment, the compounds of the invention are glucocorticoid receptor modulators. Within the meaning of the invention, the term selective glucocorticoid receptor modulator (glucocorticoid receptor modulator) preferably means that the corresponding compound exhibits, in an interaction assay with a cellular target, agonistic or antagonistic activity towards the glucocorticoid receptor, an EC50 or IC50 value at the glucocorticoid receptor of a maximum of 15 μM (10 10-6 mol/l) or maximum 10 µM; more preferably no more than 1 μM; even more preferably at most 500 nM (10-9 mol/l); even more preferably at most 300 nM; even more preferably not more than 100 nM; most preferably no more than 10 nM; and in particular not more than 1 nM. In a preferred embodiment, the compound of the invention exhibits, in a cellular target interaction assay for glucocorticoid receptor agonist or antagonist activity, a glucocorticoid receptor EC50 or IC50 value in the range of 1 μM to 15 μM, more preferably 100 nM to 1 μM, most preferably less than 100 nM.

One skilled in the art will know how to test compounds for modulation (agonist or antagonist) of glucocorticoid receptor activity. Preferred target interaction assays for testing compounds for their agonist or antagonist activity (EC50, IC50) at the glucocorticoid receptor are described below.

Cellular assays of glucocorticoid receptors.

Potential selective glucocorticoid receptor modulators of this intervention can be tested for modulation of glucocorticoid receptor activity using cell-based assays. These assays include a Chinese hamster ovary (CHO) cell line that contains glucocorticoid receptor fragments as well as fusion proteins. The glucocorticoid receptor fragments used are capable of binding a ligand (eg, beclomethasone) to identify molecules that compete for binding to glucocorticoid receptor ligands. In more detail, the ligand binding domain of the glucocorticoid receptor is fused to the DNA binding domain (DBD) of the transcription factor GAL4 (GAL4 DBD-GR) and is stably integrated into a CHO cell line containing a GAL4-UAS-luciferase reporter construct. To identify selective glucocorticoid receptor modulators, a reporter cell line is incubated with the molecules using a semi-log 8 compound dilution curve for several hours. After cell lysis, the luminescence produced by luciferase upon addition of substrate is detected and EC50 or IC50 values can be calculated. Engagement of molecules that induce gene expression through glucocortoid receptor binding to DNA results in luciferase gene expression under the control of the GAL4 DBD-GR fusion protein and hence a dose-dependent increase in the luminescence signal. Binding of molecules that suppress beclomethasone-induced luciferase gene expression under the control of the GAL4 DBD-GR fusion protein results in a dose-dependent decrease in the luminescence signal.

In a preferred embodiment, the compound of the invention exhibits a glucocorticoid receptor EC50 or IC50 value of no more than 1 μM (10 ^-6 mol/L) in a cellular target assay for glucocorticoid receptor agonist or antagonist activity; even more preferably at most 500 nM (10 ^-9 mol/l); even more preferably at most 300 nM; even more preferably not more than 100 nM; most preferably no more than 50 nM; and in particular not more than 10 nM or not more than 1 nM.

In a preferred embodiment, the compound of the invention exhibits, in a cellular target interaction assay for glucocorticoid receptor agonist or antagonist activity, a glucocorticoid receptor EC50 or IC50 value in the range of 1 μM to 15 μM, more preferably 100 nM to 1 μM, most preferably less than 100 nM.

In a preferred embodiment, the compound of the invention exhibits a glucocorticoid receptor EC50 or IC50 value in a cellular target assay for glucocorticoid receptor agonist or antagonist activity in the range of 0.1 nM (10 ^-9 mol/L) to 1000 nM; even more preferably from 1 nM to 800 nM; even more preferably from 1 nM to 500 nM; even more preferably from 1 nM to 300 nM; most preferably from 1 nM to 100 nM; and in particular from 1 nM to 80 nM.

Human glucocorticoid receptor (hGR) ligand binding assay.

Potential selective glucocorticoid receptor modulators of this intervention can be tested for their glucocorticoid receptor binding affinity using the binding assay described below.

Preferably, the glucocorticoid receptor extracted from the cytosol of IM9 cells is used for competitive radioligand binding assays to calculate the percentage inhibition of the binding of the radiolabeled 3H-dexamethasone ligand to the human glucocorticoid receptor. Preferably, a fixed concentration of 3H-dexamethasone radioligand and 1 μM of a compound of the present invention (as unlabeled competitors of dexamethasone) are mixed with the extracted glucocorticoid receptor to measure the percentage inhibition of 3H-dexamethasone binding.

In a preferred embodiment, the compound of the invention demonstrates, in an hGR ligand binding assay, an inhibition of 3H-dexamethasone binding at 1 μM of at least 40%, more preferably at least 60%, most preferably at least 85%. In a preferred embodiment, the compound of the invention exhibits, in an hGR ligand binding assay, an inhibition of 3H-dexamethasone binding at 1 μM that is in the range of 40% to 60%, more preferably greater than 60% to 85%, most preferably greater than 85%.

Preferably, the compounds of the invention are useful as selective glucocorticoid receptor modulators.

Therefore, the compounds of the invention are preferably useful for the treatment or prevention of diseases in vivo in which the glucocorticoid receptor is involved.

Thus, the invention further provides a compound of the invention for use in modulating glucocorticoid receptor activity.

Accordingly, another aspect of the invention relates to a compound of the invention for use in the treatment and/or prevention of a disorder that is mediated, at least in part, by the glucocorticoid receptor. Another aspect of the invention relates to a method of treating a disorder mediated at least in part by a glucocorticoid receptor, comprising administering a therapeutically effective amount of a compound of the invention to a subject in need thereof, preferably a human.

A further aspect of the invention relates to the use of a compound of the invention as a medicine.

Another aspect of the invention relates to a pharmaceutical dosage form containing a compound of the invention. Preferably, the pharmaceutical dosage form includes a compound of the invention and one or more pharmaceutical excipients, such as physiologically acceptable carriers, additives and/or excipients; and optionally one or more additional pharmacologically active ingredients. Examples of suitable physiologically acceptable carriers, additives and/or excipients are fillers, solvents, diluents, colorants and/or binders. These substances are known to those skilled in the art (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete,

Editio Cantor Aulendoff).

The pharmaceutical dosage form of the invention is preferably intended for systemic, local or topical administration, preferably for oral administration. Therefore, the pharmaceutical dosage form may be in the form of a liquid, semi-solid or solid, for example, in the form of injections, drops, juices, syrups, sprays, suspensions, tablets, plasters, films, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, optionally compressed into tablets, decanted into capsules or suspended in liquid, and may also be administered as such.

The pharmaceutical dosage form of the invention is preferably prepared using conventional means, devices, methods and processes known in the art. The amount of a compound of the invention that is administered to a patient may vary and is, for example, depending on the weight or age of the patient, as well as the type of administration, indication and severity of the disease. Preferably, 0.001 to 100 mg/kg, more preferably 0.05 to 75 mg/kg, most preferably 0.05 to 50 mg of a compound of the invention is administered per kg of body weight of the patient.

It is believed that the glucocorticoid receptor can modify various diseases or disorders in mammals such as humans. These include, in particular, inflammatory diseases.

Another aspect of the invention relates to a compound of the invention for use in the treatment and/or prevention of pain and/or inflammation; more preferably inflammatory pain.

Another aspect of the invention relates to a method for treating pain and/or inflammation; more preferably inflammatory pain.

The following examples further illustrate the invention but should not be construed as limiting its scope.

The following abbreviations are used in experimental descriptions: AcOH = acetic acid; Cbz = carboxybenzyl; DCM = dichloromethane; DEA = diethylamine; DIPEA = N,N-diisopropylethylamine; DMAP = 4-(dimethylamino)pyridine; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoryl azide; EtOAc = ethyl acetate; EtOAc = ethanol; HATU = 1-[bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate; ; h = hour; MeOH = methanol; min = minute; sat. = saturated; RT = room temperature; Rt = retention time; tert = tertiary; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran.

Synthesis of trans-benzyl-4,4-dimethyl-(5-oxo-2-phenylpyrrolidin-3-yl)carbamate (intermediate A1).

Step 1: Solution of benzaldehyde (95.18 g, 0.898 mol), 4-methylbenzenethiol (111.37 g, 0.898 mol), maleic anhydride (88.04 g, 0.898 mol) and 2,4-dimethoxybenzylamine (150.00 g . 0.4) the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give the crude product, which was triturated with MTBE to give 1(2,4-dimethoxybenzyl)-5-oxo-2-phenyl-3-p-tolylsulfanylpyrrolidine- 3-carboxylic acid (150.0 g, 35%) as an off-white solid.

Step 2: To a suspension of 1-(2,4-dimethoxybenzyl)-5-oxo-2-phenyl-3-p-tolylsulfanylpyrrolidine-3carboxylic acid (500.0 g, 1.05 mol) in acetone (5 L) was added K ₂ CO ₃ (579.0 g, 4.19 mol) followed by methyl iodide (261.0 ml, 4.19 mol). The resulting suspension was stirred at ambient temperature for 16 hours. The reaction mixture was then filtered and the filtrate was concentrated. The residue was dissolved in EtOAc (1.5 L) and washed with water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 1-(2,4-dimethoxybenzyl)-5-oxo-2-phenyl-3-p-tolylsulfanylpyrrolidine-3-carboxylic acid methyl ester (480, 0 g, 94%) as an off-white solid.

- 23 044347

Step 3: To a solution of 1-(2,4-dimethoxybenzyl)-5-oxo-2-phenyl-3-rtolylsulfanylpyrrolidine-3-carboxylic acid methyl ester (50.0 g, 0.101 mol) in DMF (0.5 L ) sodium hydride (50% in mineral oil, 24.4 g, 0.509 mol) was added at 0°C. The resulting reaction mixture was stirred at 0°C for 30 minutes. After 30 min, methyl iodide (31.7 mL, 0.509 mol) was added slowly. The resulting reaction mixture was then stirred for 30 minutes at 0°C. After completion of the reaction (monitored by TLC, mobile phase 30% ethyl acetate-hexane, Rf 0.3), the reaction was quenched with saturated ammonium chloride and extracted with EtOAc (2.0 L). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (silica gel, 100-200 mesh, 10-20% EtOAc/hexane) to give 1-(2,4-dimethoxybenzyl) methyl ester )-4,4-dimethyl-5-oxo-2phenyl-4,5-dihydro-1H-pyrrole-3-carboxylic acid (28.0 g, 70%) as a pale yellow solid.

Step 4: To a solution of 1-(2,4-dimethoxybenzyl)-4,4-dimethyl-5-oxo-2phenyl-4,5-dihydro-1H-pyrrole-3-carboxylic acid methyl ester (26.0 g , 0.117 mol) in methanol (300 ml), 10% palladium on carbon (50% humidity, 13.4 g, 0.063 mol) was added and the resulting mixture was stirred for 16 hours at ambient temperature under hydrogen pressure (balloon pressure). After completion of the reaction (monitored by TLC, mobile phase 30% ethyl acetate-hexane, R _f 0.30), the reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the crude compound, which was triturated in diethyl ether to give 1-(2,4-dimethoxybenzyl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidine-3-carboxylic acid methyl ester (25 .0 g, 96%).

Step 5: A stirred suspension of 1-(2,4-dimethoxybenzyl)-4,4dimethyl-5-oxo-2-phenylpyrrolidine-3-carboxylic acid methyl ester (25.0 g, 0.063 mol) in TFA (250 ml) was heated to 90°C for 16 hours. After completion of the reaction (control with TLC, 50% ethyl etherhexane, Rf-0.3), the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The remains were fortified with saturating food. NaHCO ₃ solution, followed by the addition of EtOAc (1 l) and stirring the resulting mixture for 30 minutes. The resulting solid was filtered and dried under high vacuum to yield 4,4dimethyl-5-oxo-2-phenylpyrrolidine-3-carboxylic acid methyl ester (18.0 g, crude), which was used in the next step.

Step 6: To a suspension of 4,4-dimethyl-5-oxo-2-phenylpyrrolidine-3-carboxylic acid methyl ester (43.0 g, 0.174 mmol) in MeOH (400 ml) was added 2 M NaOH (174 ml) at 0 °C. The resulting suspension was stirred at 100°C for 4 hours. After consumption of the starting material (TLC control, mobile phase 5% MeOH/DCM, Rf 0.2), the reaction mixture was concentrated and the residue was diluted with water and washed with ethyl acetate (2x75 ml). The aqueous layer was then acidified to pH 3 with 6N HCl and extracted with 10% MeOH/DCM (2x75 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give trans-4,4-dimethyl-5-oxo-2-phenylpyrrolidine-3-carboxylic acid (22.0 g, 55.0%) in the form of a brown solid.

Step 7: To a stirred solution of trans-4,4-dimethyl-5-oxo-2-phenylpyrrolidine-3carboxylic acid (22.0 g, 0.095 mol) in benzene-THF (4:1, 125 ml) was added DPPA (25, 0 ml, 0.114 mol) then TEA (13.35 ml, 0.095 mol) at ambient temperature and the mixture was stirred for 2 hours. Benzyl alcohol (14.8 ml, 0.142 mol) was then added and the reaction mixture was heated to 90 °C for 4 hours. After completion of the reaction (control by TLC), the reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with 10% citric acid (100 ml), then saturated NaHCO ₃ solution (2x100 ml), and then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was triturated with diethyl ether (2x80 ml). The resulting solid was filtered and dried under high vacuum to give Intermediate A1 (25.0 g, 78%) as an off-white solid.

Synthesis of N-((trans)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl) cyclopropanecarboxamide (intermediate A2).

Step 1: To a stirred solution of intermediate A1 (5.0 g, 14.775 mmol, 1.0 eq) in methanol:THF (80 ml, 2:1), add Pd/C (10.0 g, 10%, wet) and the reaction mixture was stirred in a hydrogen cylinder for 2 hours at ambient temperature. Once complete (TLC monitor, TLC system, 5% methanol in DCM, Rf-0.2), the reaction mixture was filtered through a pad

- 24 044347 celite, which was then washed 2-3 times with THF. The filtrate was concentrated to give (trans)-4amino-3,3-dimethyl-5-phenylpyrrolidin-2-one as a brown gum (3.0 g, 99%).

Step 2: To a stirred solution of cyclopropanecarboxylic acid (0.253 g, 2.941 mmol, 1.2 eq.) in DMF (10 ml), HATU (1.86 g, 4.90 mmol, 2.0 eq.), DIPEA (2 .0 ml, 12.25 mmol, 5.0 eq.) and (trans)-4-amino3,3-dimethyl-5-phenylpyrrolidin-2-one (0.50 g, 2.45 mmol, 1.0 eq. .) was added at 0°C and the reaction mixture was stirred at ambient temperature for 16 hours. After completion of the reaction (TLC control, TLC system, 5% methanol in DCM, Rf-0.3), the reaction mixture was diluted with EtOAc (50 ml), washed with ice water (3x25 ml), dried over Na ₂ SO ₄ and concentrated to give a residue, which was purified by column chromatography (silica gel 230-400 mesh; 0 to 2% MeOH-DCM) to give intermediate A2 (0.46 g, 70%).

Synthesis of N-((trans)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)-2,2-difluoropropanamide (intermediate A3).

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Step 1: To a stirred solution of 2,2-difluoropropanoic acid (0.647 g, 5.88 mmol, 1.2 eq.) in DMF (15 ml), HATU (3.72 g, 9.80 mmol, 2.0 eq. .), DIPEA (4.0 ml, 24.50 mmol, 5.0 eq.) and (trans)-4-amino3,3-dimethyl-5-phenylpyrrolidin-2-one (1.0 g, 4.90 mmol, 1.0 eq.) was added at 0°C and the reaction mixture was stirred at ambient temperature for 16 hours. After completion of the reaction (TLC control, TLC system, 5% methanol in DCM, Rf-0.3) the reaction mixture was diluted with ethyl acetate (50 ml), washed with ice water (3x25 ml), dried over Na ₂ SO ₄ and concentrated to obtain a residue, which was purified by column chromatography (silica gel 230-400 mesh; 0 to 2% MeOH-DCM) with yielding intermediate A3 (0.93 g, 64%).

Synthesis of 5-(5-((4S,5R)-4-amino-3,3-dimethyl-2-oxo-5-phenyln-pyrrolidin-1-yl)-1H-indazol-1-yl)-1methylpyridin-2(1H )-one (intermediate A4-ent1) and 5-(5-((4R,5S)-4-amino-3,3-dimethyl-2oxo-5-phenylpyrrolidin-1-yl)-1 H-indazol-1 -yl)-1-methylpyridin-2(1H)-one (intermediate A4-ent 2).

Step 1: To a stirred solution of trans-benzyl-4,4-dimethyl-(5-oxo-2-phenylpyrrolidin-3-yl) carbamate (2.0 g, 5.91 mmol) in 1,4-dioxane (80 ml ) 5-(5-iodindazol-1yl)-1-methyl-1H-pyridin-2-one (2.28 g, 6.5 mmol) was added to a sealed tube, followed by potassium phosphate (2.51 g, 11. 83 mmol). The mixture was degassed under argon for 30 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (0.37 ml, 2.36 mmol) and CuI (225 mg, 1.18 mmol) were added and the mixture was heated to 90°C for 16 hours. After completion of the reaction (under LCMS monitoring), the reaction mixture was filtered through a pad of celite, and the celite pad was washed with 1,4-dioxane (100 ml). The filtrate was then concentrated under reduced pressure. The reaction was carried out in parallel in four batches (2.0 g each), and the residues from all batches were purified together by column chromatography (silica gel, 100-200 mesh, 1-2% MeOH/DCM) to give benzyl((trans)-4. 4-dimethyl-1-(1-(1 -methyl-6-oxo-1,6-dihydropyridin-3 -yl)-1 H-indazol-5 -yl)-5 -oxo-2phenylpyrrolidin-3-yl)- carbamate (12.8 g, 48%) as a pale yellow solid.

Step 2. Stirred suspension of benzyl((trans)-4,4-dimethyl-1-(1-(1-methyl-6-oxo-1,6dihydropyridin-3-yl)-1H-indazol-5-yl)-5 -oxo-2-phenylpyrrolidin-3-yl)carbamate (3.0 g, 5.35 mmol) in TFA (30 ml) was heated to 90°C for 3 hours. After completion of the reaction (LCMS monitor, 5% MeOH in DCM), the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residues were then azeotroped with toluene (2x50 ml). The resulting residue was made alkaline with saturated NaHCO ₃ solution and the mixture was extracted with 5% MeOH/DCM (2x150 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude compound. This reaction was carried out in parallel in four batches (3.0 g each) and the combined crude compound was purified by column chromatography (100-200 silica gel, 1.5-2% MeOH/DCM as eluent) to give 5( 5-((trans)-4-amino-3,3-dimethyl-2-oxo-5-phenylpyrrolidin-1 -yl)-1 H-indazol-1 -yl)-1 -methylpyridin2(1H)-one (7 .0 g, 76%) as a gray solid.

Chiral resolution (Chiralpak IC (21.0x250 mm), 5 µm, mobile phase DCM: EtOH 50:50, flow rate 18.0 ml/min) of racemic compound (7.0 g) in normal phase (intermediate A4-ent1 , retention time 5.56 minutes) and (intermediate A4-ent2, retention time 6.41 minutes).

Synthesis of N-[rac-((6R,7S)-4-oxo-6-phenyl-5-azaspiro[2.4]heptan-7-yl)]cyclopropanecarboxamide (intermediate A5).

Step 1: To a stirred solution of (2,4-dimethoxybenzyl)-5-oxo2-phenyl-3-p-tolylsulfanylpyrrolidine-3-carboxylic acid methyl ester (56.0 g, 152.42 mmol) in DMF (560 ml) NaH (18.3 g, 60% dispersion in mineral oil, 457.24 mmol) was slowly added followed by 1,2dibromoethane (17.13 mL, 198.14 mmol) at 0°C. The resulting reaction mixture was stirred at 0°C for 3 hours. After completion of the reaction (monitored by TLC, mobile phase 20% ethyl acetate-hexane, Rf 0.4), the reaction mixture was poured into cold saturated NH ₄ Cl solution. The mixture was then extracted with EtOAc (2x1 L). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (silica gel 100-200 mesh, 10% ethyl acetate hexane as eluent) to give methyl 5-(2,4-dimethoxybenzyl) -4-oxo-6-phenyl-5azaspiro[2,4]hept-6-ene-7-carboxylate (34.0 g, 57%) as an off-white solid.

Step 2: To a stirred solution of methyl 5-(2,4-dimethoxybenzyl)-4-oxo-6-phenyl-5azaspiro[2,4]hept-6-ene-7-carboxylate (7.5 g, 19.08 mmol ) in MeOH (125 ml) was added 10% Pd/C (3.0 g, 50% humidity) and a catalytic amount of AcOH. The reaction mixture was stirred under hydrogen pressure (using a balloon) until starting material consumption (monitored by LCMS) was reached. The reaction was carried out in parallel in two batches, which were combined for processing. The combined reaction mixture was filtered through a pad of celite, which was washed with MeOH (75 ml). The filtrate was then concentrated to give crude 5-(2,4-dimethoxybenzyl)-4-oxo-6-phenyl-5-azaspiro[2,4]heptane-7-carboxylic acid methyl ester (12.0 g), which was used at the next stage without additional purification.

Step 3: Stirred suspension of 5-(2,4-dimethoxybenzyl)-4-oxo6-phenyl-5-azaspiro[2,4]heptane-7-carboxylic acid methyl ester (16.0 g, 40.5 mmol) in TFA (80 ml) was heated to 50°C for 14 hours. After completion of the reaction (under LCMS monitoring), the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residues were azeotroped with toluene, then made alkaline with NaHCO ₃ solution, followed by extraction with ethyl acetate (2x125 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 4oxo-6-phenyl-5-azaspiro[2,4]heptane-7-carboxylic acid methyl ester (9.0 g crude) in in the form of a brown solid.

Step 4: To a suspension of 4-oxo-6-phenyl-5-azaspiro[2,4]heptane-7carboxylic acid methyl ester (9.0 g crude) in MeOH (90 ml) was added 2 M NaOH (60 ml, 3.0 eq.) at 10°C. The resulting suspension was then stirred at 100°C for 4 hours. After completion of the reaction (monitored by TLC, mobile phase 50% EtOAc-hexane, Rf 0.1), the reaction mixture was concentrated. The residue was diluted with water and washed with EtOAc. The alkaline aqueous layer was acidified to pH 2-3 with 6 N HCl and then extracted with 10% MeOH/DCM (3 x 60 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give trans-4-oxo-6-phenyl-5-azaspiro[2,4]heptane-7-carboxylic acid (40 g, 32% via stage 3) as a brown solid.

Step 5. To a stirred solution of trans-4-oxo-6-phenyl-5-azaspiro[2,4]heptane-7-carboxylic acid

- 26 044347 acid (5.0 g, 21.6 mmol) in benzene-THF (4:1, 80 ml) and DPPA (5.6 ml, 25.9 mmol) added TEA (3 ml, 21.6 mmol ) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 2 hours, followed by the addition of benzyl alcohol (3.4 ml, 32.4 mmol) and heating to 90°C for 4 hours. After completion of the reaction (monitored by TLC, mobile phase 5% MeOH in DCM, R _f 0.4), the reaction mixture was diluted with water and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with 10% citric acid solution, then sat. NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting residue was triturated with 10% DCM-hexane and then with MTBE (25 ml). The resulting solid was filtered and dried to yield 6.5 g of crude compound, which was purified by preparative LCMS to yield N-(trans-4-oxo-6-phenyl-5aza-spiro[2,4]hept-7-yl benzyl ester )carbamic acid (1.16 g, 16%) as an off-white solid

Step 6: To a stirred solution of N-(trans-4-oxo-6-phenyl-5aza-spiro[2,4]hept-7-yl)carbamic acid benzyl ester (3.2 g, 9.52 mmol) in MeOH (300 ml) was added with 10% Pd/C (1.7 g, 50% humidity) and the reaction mixture was stirred at ambient temperature under a hydrogen atmosphere using a balloon. After completion of the reaction (TLC monitor, mobile phase 10% MeOH/DCM, R _f 0.2), the reaction mixture was filtered through a pad of celite, which was then washed with MeOH (50 ml x 2 ). The filtrate was concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (5 ml) to give crude trans-7-amino-6-phenyl-5-azaspiro[2,4]heptan4-one (1.6 g), which was used without further purification in the next step.

Step 7: TEA (1 .3 ml, 1.7 eq.) followed by the addition of cyclopropanecarbonyl chloride (0.65 ml, 1.3 eq.) at 0°C. The resulting reaction mixture was then stirred for 1 hour at the same temperature. After completion of the reaction (control with TL C, mobile phase 5% MeOH/DCM), the reaction mixture was concentrated and diluted with water. The resulting mixture was stirred for 30 minutes at ambient temperature, causing precipitation of a white solid. The solid was filtered and washed with diethyl ether (10 ml x 2) and dried to give crude N-(trans-4-oxo-6-phenyl-5-azacniro[2,4]heptan-7-yl)cyclopropanecarboxamide (1,2 G). The reaction was carried out in parallel in two batches. The resulting solid from both batches was mixed and purified by preparative reverse phase LCMS to yield Intermediate A5 (436.9 mg, 13%) as an off-white solid.

Synthesis of benzyl(trans-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)carbamate (intermediate A6).

Step 1: Sodium acetate (17, 07 g, 208.07 mmol, 5 eq) and the mixture was refluxed for 12 hours. Once complete (monitored by TLC), the reaction mixture was evaporated to remove EtOAc and diluted with EtOAc (2x300 ml) and water (300 ml) . The extracted organic layer was washed with brine (300 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh, TLC system: EtOAc/hexane (2:8); R _f = 0.3) to give (E)-1-phenylethan-1-one oxime (4.73 g , 84%).

Step 2: To a stirred solution of (E)-1-phenylethan-1-one oxime (5 g, 36.993 mmol, 1 eq.) in DCM (50 mL), TEA (5.7 mL, 40.692 mmol, 1.2 eq. .), and then chlorodiphenylphosphane (7.3 ml, 40.692 mmol, 1.1 eq.) was added at -40°C. The reaction mixture was then stirred at room temperature for 16 hours. After completion of the reaction (control with TLC, 50% EtOAc in hexane, R _f =0.3), the reaction mixture was quenched with ice and extracted with EtOAc. The organic layer was washed with water (200 ml), brine (200 ml), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography using silica gel 230400 and 30-50% EtOAc in hexanes yielding (E)-P,P-diphenyl-N-(1-phenylethylidene)phosphine amide (10.1 g, 86%) as a brown gum.

Step 3: To a stirred solution of (E)-P,P-diphenyl-N-(1-phenylethylidene)phosphine amide (5 g, 15.657 mmol, 1 eq.) in THF (75 ml) 1,4-diethyl (2E) -but-2-enedioate (6.75 g, 39.143 mmol, 2.5 eq.),

- 27 044347

Cu(OAc) (285 mg, 1.5657 mmol, 0.1 eq.), PPh ₃ (410 mg, 1.5657 mmol, 0.1 eq.) was added at room temperature and the mixture was stirred at room temperature for 20 min. Pinacolborane (5.62 g, 43.839 mmol, 2.8 eq.) was then added at room temperature and the reaction mixture was stirred at room temperature for 48 hours. After completion of the reaction (control with TLC, 50% EtOAc in hexane, Rf = 0.4), the reaction mixture was diluted with EtOAc, washed with water (100 ml) and brine (100 ml), dried over Na ₂ SO ₄ and concentrated to give the crude product, which was purified by column chromatography using silica gel 230-400 and 20-40% EtOAc in hexanes to give the pure desired ethyl 1-(diphenylphosphoryl)-2-methyl-5-oxo-2phenylpyrrolidine-3-carboxylate (4 g. 57%).

Step 4: To a solution of ethyl 1-(diphenylphosphoryl)-2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylate (5 g, 11.174 mmol, 1 eq.) in EtOAc (50 mL), concentrated HCl (6 mL) was added at room temperature. The mixture was stirred at 90°C for 16 hours. After completion of the reaction (control with TLC, 50% EtOAc in hexane, Rf = 0.6), the reaction mixture was evaporated under reduced pressure, neutralized with saturated sodium bicarbonate solution, extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated to give ethyl 2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylate (1.1 g, 40%) as an off-white solid.

Step 5. To a solution of ethyl 2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylate (4 g, 16.1753 mmol, 1 eq.) in THF:H2O (3:1) (80 ml), LiOH- H2O (1.36 g, 32.351 mmol, 2 eq.) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (control with TLC, 5% MeOH in DCM, Rf = 0.1), the organic solvent was evaporated under reduced pressure, dissolved in water, washed with ether and acidified with HCl. A solid precipitated, filtered, washed with water and hexane, and rotary dried to give 2-methyl5-oxo-2-phenylpyrrolidine-3-carboxylic acid (3 g, 85%) as a white solid.

Step 6: TEA (2 mL, 14.368 mmol, 1.05 eq.) and DPPA (4.5 g, 16.4203 mmol, 1.2 eq.), and the reaction mixture was stirred at 90°C for 30 min. Benzyl alcohol (2.8 g, 27.3672 mmol, 2.0 eq.) was then added to the reaction mixture and the mixture was refluxed for 16 hours. Once complete (monitored by TLC, TLC system 5% MeOH in DCM , R _f -0.3) the reaction mixture was concentrated under reduced pressure and diluted with EtOAc (100 ml), washed with water (2x100 ml), dried over English. Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel 230-400 mesh; 0-3% MeOH in DCM) to give benzyl(trans-2-methyl-5-oxo-2phenylpyrrolidine-3 -yl)carbamate (1.8 g, 41%).

Synthesis of (4S,5R)-4-amino-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-5-phenylpyrrolidin-2one (intermediate A7-ent1) and (4R,5S)-4-amino-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3dimethyl-5-phenylpyrrolidin-2-one (intermediate A7-ent 2).

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Step 1: Add a stirred solution of benzyl(trans-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3yl)carbamate (2.0 g, 5.91 mmol) in 1,4-dioxane (100 ml) in a sealed container 1-(4Fluorophenyl)-5-iodo-1H-indazole (2.4 g, 7.10 mmol) was added to the tube, followed by potassium phosphate (2.51 g, 11.83 mmol), and the mixture was degassed using argon for 30 min. Trans-N,N'-dimethylcyclohexane1,2-diamine (0.4 ml, 2.37 mmol) and copper(I) iodide (225 mg, 1.18 mmol) were then added and the mixture was heated to 100-110°C for 16 hours. After completion of the reaction (LCMS control, 5% MeOH in DCM), the reaction mixture was filtered through a pad of celite and the celite pad was washed with 1,4-dioxane (100 ml), then the filtrate was concentrated under reduced pressure. The reaction was carried out in parallel in 10 portions (2 g each). The combined crude material was purified by column chromatography (silica gel, 100-200 mesh, 2-2.5% MeOH/DCM) to give benzyl (trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)- 4,4-dimethyl-5-oxo-2phenylpyrrolidin-3-yl)carbamate (14.5 g, 45%) as a pale yellow solid. Step 2: To a stirred solution of benzyl (trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2phenylpyrrolidin-3-yl)carbamate (4, 0 g, 7.68 mmol) in THF/MeOH (500 ml, 1:1) was added 10% Pd/C (50% humidity, 2.0 g) and the resulting mixture was stirred at ambient temperature under pressure

- 28 044347 by filling the H2 balloon until the reaction is complete (control with TLC, 5% MeOH in DCM). The reaction mixture was then filtered through celite and the celite layer was washed with THF. The filtrate was then concentrated under reduced pressure. The reaction was carried out in parallel in four batches (4 g each), and the combined crude material was purified by column chromatography (silica gel, 100-200 mesh, 1.5-2% MeOH/DCM as eluent) to give trans-4-amino-1- (1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3dimethyl-5-phenylpyrrolidin-2-one (7.1 g, 56%) as an off-white solid.

Chiral separation (Chiralpak IC (21.0x250 mm), 5 µm, mobile phase nhexane/EtOAc/EtOAc/isopropylamine 70/15/15/0.1, flow rate 21.0 ml/min) of racemic compound (7.1 g ) in normal phase were obtained (intermediate A7-ent1, retention time 6.10 min) and (intermediate A7-ent2, retention time 7.30 min).

Synthesis of methyl 2-methyl-3-nitropropanoate.

Step 1: Preparation of 3-nitropropionic acid methyl ester: NaNO ₂ (120.6 g, 1.74 mol) was added to a stirred solution of 3-bromopropionic acid methyl ester (200 g, 1.19 mol) in DMSO (3 L). ) in portions at 0°C. The resulting solution was stirred at room temperature for 24 hours. After completion of the reaction, the mixture was diluted with cold brine (1.5 L) and extracted with MTBE (3x1500 ml). The combined organic layers were washed with cold water (500 mlx2), then brine (500 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure (bath temperature 30 C) to obtain crude 3-nitropropionic acid methyl ester. The crude material was purified by column chromatography (using 100-200 mesh silica gel, 10% EA-hexane as eluent). An oil was obtained which was further distilled under reduced pressure (120°C, 0.1-0.5 mm Hg) to obtain 3-nitropropionic acid methyl ester (45 g, 28%) as a light yellow oil.

Step 2: Methyl 2-methyl-3-nitropropanoate: To a stirred solution of 3-nitropropionic acid methyl ester (25 g, 187.97 mmol) in THF (400 mL) was added LDA (2M in EPA, 188 mL, 376 mmol 2.0 eq.) at -78°C and stirred for 30 minutes at the same temperature. Mel (23.4 ml, 375.93 mmol, 2.0 eq.) was added at -78°C. The reaction mixture was gradually heated to 25°C and stirring was continued for 16 hours. The reaction mixture was quenched with aqueous NH ₄ Cl at 0°C. The layers were separated and the aqueous portion was extracted with ethyl acetate (600 ml x 3). The combined organic layers were washed with brine (300 ml), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (using silica gel 100-200, 5-10% ethyl acetate-hexane as eluent) to give methyl 2-methyl-3-nitropropanoate (10 g, 36%).

Synthesis of intermediate A8 (benzyl(rac-(2R,3S,4S)-4-methyl-5-oxo-2-phenylpyrrolidin-3yl)carbamate).

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Step 1. Synthesis of rac-(3S, 4S, 5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-phenylpyrrolidin-2-one. 4methoxybenzylamine (13.99 g, 102.04 mmol) was added to a stirred solution of benzaldehyde (10.82 g, 102.04 mmol) in toluene (100 mL) at room temperature and stirred for 2 hours at room temperature. To this reaction mixture was added methyl 2-methyl-3-nitropropanoate (10 g, 68.03 mmol), followed by benzoic acid (12.46 g, 102.04 mmol) and stirring was continued for 16 hours at 70°C. After completion of the reaction (under LCMS monitoring), the reaction mixture was diluted with ethyl acetate (400 ml) and washed with water (100 ml x 2) and then saturated. NaHCO ₃ (100 ml x 2). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (using 100-200 mesh silica gel; 25-30% ethyl acetate in hexane as eluent) to give rac-(3S,4S,5R)-1-(4-methoxybenzyl)-3-methyl -4-nitro-5phenylpyrrolidin-2-one (10 g, 43%) as a brownish solid.

Step 2. Synthesis of rac-(3S, 4S, 5R)-3-methyl-4-nitro-5-phenylpyrrolidin-2-one. To a stirred solution of rac-(3S, 4S, 5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-phenylpyrrolidin-2-one (10

- 29 044347 g, 29.41 mmol) in acetonitrile (100 ml), a solution of CAN (48.37 g, 88.24 mmol) in water (100 ml) was added dropwise at 0°C. The reaction mixture was slowly heated to 15°C and stirring was continued for 3-4 hours. Once complete (TLC monitor, 50% ethyl acetate/hexane, Rf 0.2), the reaction mixture was diluted with ethyl acetate (500 ml) and washed with water (100 ml x2), and then with brine (250 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude material was purified by column chromatography (using 100-200 mesh silica gel; 40-50% ethyl acetate in hexane as eluent) to give rac-(3S,4S,5R)-3-methyl-4-nitro-5-phenylpyrrolidine-2 -onα (4.00 g, 62%) as a light yellow solid.

Step 3. Synthesis of rac-(3S,4S,5R)-4-amino-3-methyl-5-phenylpyrrolidin-2-one: To a stirred solution of rac-(3S,4S,5R)-3-methyl-4-nitro -5-phenylpyrrolidin-2-one (4.5 g, 20.45 mmol) in EtOAc-MeOH (2:1, 450 ml) was added 6 M aq. HCl (102.2 ml) at 0°C. Sputtered Zn (80.25 g, 1.227 mol) was added to this reaction mixture in portions at the same temperature. The resulting suspension was stirred at room temperature for 16 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with saturated NaHCO ₃ solution at 0°C, stirred for 1 hour, filtered through celite and washed with EtOAc-MeOH (500 ml, 2:1). The filtrate was concentrated to give rac(3S,4S,5R)-4-amino-3-methyl-5-phenylpyrrolidin-2-one (3.9 g crude, considered 100% yield), which was used without further purification.

Step 4: To a stirred suspension of rac-(3S,4S,5R)-4-amino-3-methyl-5-phenylpyrrolidin-2-one (3.9 g crude, 20.45 mmol) in THF:water (1: 1, 225 ml) sodium bicarbonate (9.95 g, 118.42 mmol) was added at 0°C and stirred for 30 minutes. Benzyl chloroformate (11.8 mL, 35.53 mmol, 50% in toluene) was added to the reaction mixture at 0° C. and stirring was continued for 16 hours at room temperature. After completion (under LCMS control), the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (3x500 ml). The combined organic layers were washed with water (200 ml x2), then brine (200 ml) and dried over Na ₂ SO ₄ . After removal of the solvent, the crude material was purified by column chromatography (using 100-200 mesh silica gel; 2-2.5% MeOH in DCM as eluent) to give intermediate A8 benzyl (rac-(2R,3S,4S)-4methyl-5 -oxo-2-phenylpyrrolidin-3-yl)carbamate (3.5 g, 53% in two stages).

Synthesis of intermediate A10-trans(benzyl(rac(2R,3S,4S)-4-methyl-5-oxo-2-(m-tolyl) pyrrolidin-3-yl) carbamate) and intermediate A10-cis (benzyl( rac(2S,3S,4S)-4-methyl-5oxo-2-(m-tolyl)pyrrolidin-3-yl)carbamate).

Step 1. Synthesis of rac-(4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2-one: To a stirred solution of 3-methyl-benzaldehyde ( 11.02 g, 91.75 mmol) in toluene (90 ml) was added 4-methoxybenzylamine (12.58 g, 91.75 mmol) at room temperature and stirred for 2 hours. To this reaction mixture was added methyl 2-methyl -3-nitropropanoate (9.00 g, 61.27 mmol), then benzoic acid (11.2 g, 91.75 mmol) and stirred for 16 h at 70°C. After completion of the reaction (under LCMS monitoring), the reaction mixture was diluted with ethyl acetate (500 ml) and washed with water (200 ml x 2) and then with saturated NaHCO ₃ (150 ml x 2). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to give rac-(4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-(mtolyl)pyrrolidin-2-one (7, 1 g, 32.7%) as a brown gum.

Step 2. Synthesis of rac-(4S,5R)-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2-one: to a stirred solution of rac-(4S,5R)-1-(4-methokCibenzyl )-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2-one (4 g, 11.28 mmol) in acetonitrile (42 ml) was added a solution of CAN (18.56 g, 33.86 mmol ) in water (42 ml) drop by drop at 0°C. The reaction mixture was slowly heated to 15°C and stirring was continued for 3-4 hours. Once complete (under LCMS monitoring), the reaction mixture was diluted with ethyl acetate (300 ml) and washed with water (100 ml x 2) and then brine (200 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude material was purified by column chromatography (using silica gel 100-200 mesh; 1-1.5% MeOH in DCM) to give rac-(4S,5R)-3-methyl-4-nitro-5-(m-tolyl) pyrrolidin2-one (1.5 g, 56.8%) as an off-white solid.

Step 3. Synthesis of rac-(4S,5R)-4-amino-3-methyl-5-(m-tolyl)pyrrolidin-2-one: to stir

- 30 044347 solution of rac-(4S,5R)-3-methyl-4-nitro-5-(m-tolyl)n-irrolidin-2-one (1.5 g, 6.37 mmol) in EtOAc-MeOH (2: 1, 136 ml) added 6N aq. HCl (34 ml) at 0°C. Zn sputter (25.01 g, 382.55 mmol) was added to this reaction mixture in small portions at the same temperature. The resulting suspension was stirred at room temperature for 16 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with a saturated solution of NaHCO ₃ (to the main reaction) at 0°C, stirred for 1 hour, filtered through celite and washed with EtOAc: MeOH (250 ml, 2:1). The filtrate was concentrated to give rac-(4S,5R)-4-amino-3-methyl-5-(m-tolyl)pyrrolidin-2-one (1.3 g crude, considered 100% yield).

Step 4. Synthesis of intermediate compounds A10-trans and A10-cis. To a stirred suspension of rac-(4S,5R)-4-amino-3-methyl-5-(m-tolyl)pyrrolidin-2-one (1.3 g crude, 6.37 mmol) in THF water (1: 1, 160 ml) sodium bicarbonate (2.67 g, 31.89 mmol) was added at 0°C and stirred for 30 minutes. Benzyl chloroformate (50% in toluene, 3.7 ml) was added to this reaction mixture at 0°C and stirred at room temperature for 16 hours. Once complete (under LCMS monitoring), the reaction mixture was diluted with water (75 ml) and extracted with ethyl acetate ( 3x75 ml). The combined organic layers were washed with water (50 ml x2), then brine (50 ml x 2), dried over Na ₂ SO ₄ and concentrated. The crude material was mixed with another batch of the same size and purified by column chromatography (using 100-200 mesh silica gel; 1-2% MeOH in DCM as eluent) to give intermediate A10-trans(benzyl(rac-(2R,3S, 4S)-4-methyl-5-oxo-2-(mtolyl)pyrrolidin-3-yl)carbamate, 1.39 g, 20.8% in two steps) and the impure fraction contained, which was further purified by preparative HPLC to give intermediate A10-cis(benzyl(rac-(2R,3S,4S)-4-methyl-5-oxo-2-(m-tolyl)pyrrolidin-3-yl)carbamate 690 mg, 10.3% in two stages ).

Synthesis of intermediate A12-trans-benzyl(rac-(2R,3S,4S)-2-(2-chlorophenyl)-4-methyl-5oxopyrrolidin-3-yl)carbamate and intermediate A12-cisbenzyl(rac-(2S, 3S, 4S)-2-(2chlorenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate.

Step 1. Synthesis of rac-(4S,5R)-5-(2-chlorophenyl)-1-(4-methoxybenzyl)-3-methyl-4-nitropyrrolidin-2one. To a stirred solution of 2-chlorobenzaldehyde (11.46 g, 81.56 mmol) in toluene (80 ml) was added 4-methoxybenzylamine (11.2 g, 81.56 mmol) at room temperature and stirred for 2 hours. Methyl 2-methyl-3-nitropropanoate (8 g, 54.37 mmol) was added to the reaction mixture, followed by benzoic acid (9.96 g, 81.56 mmol) and stirred for 16 hours at 70°C. After completion of the reaction (under LCMS monitoring), the reaction mixture was diluted with ethyl acetate (500 ml) and washed with water (150 ml x2), then sat. aq. NaHCO ₃ (150 ml x2). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to give rac-(4S,5R)-5-(2-chlorophenyl)-1-(4-methoxybenzyl)-3-methyl-4nitropyrrolidin-2-one (8.2 g, 40.3%) as a brown solid.

Step 2. Synthesis of rac-(4S,5R)-5-(2-chlorophenyl)-3-methyl-4-nitropyrrolidin-2-one To a stirred solution of rac-(4S,5R)-5-(2-chlorophenyl)- 1-(4-methoxybenzyl)-3-methyl-4-nitropyrrolidin-2-one (8 g, 21.33 mmol) in acetonitrile (80 ml) added an aqueous solution of CAN (35 g, 64 mmol) to water (80 ml ) drop by drop at 0°C. The reaction mixture was slowly heated to 15°C and stirring was continued for 3-4 hours.

Once complete (under LCMS monitoring), the reaction mixture was diluted with ethyl acetate (500 ml) and washed with water (100 ml x2) and then brine (200 ml). The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by column chromatography (using 100-200 mesh silica gel; 25-30% ethyl acetate in hexane as eluent) to give rac-(4S,5R)-5-(2chlorophenyl)-3-methyl-4-nitropyrrolidine-2 -one (2.5 g, 46%) as an off-white solid.

Step 3. rac-(4S,5R)-4-Amino-5-(2-chlorophenyl)-3-methylpyrrolidin-2-one. To a stirred solution of rac-(4S,5R)-5-(2-chlorophenyl)-3-methyl-4-nitropyrrolidin-2-one (2.5 g, 10.684 mol) in EtOAc/MeOH (2:1, 250 ml ) added 6 N aq. HCl (53 ml) at 0°C. Sputtered Zn (41.92 g, 641 mmol) was added to this reaction mixture in portions at the same temperature. The resulting suspension was stirred at room temperature for 16 hours. After completion of the reaction (under LCMS control)

- 31 044347 the mixture was quenched with a saturated solution of NaHCO ₃ (to the main reaction) at 0°C, stirred for an hour, filtered through celite and washed with EtOAc/MeOH (250 ml, 2:1). The filtrate was concentrated to give rac-(4S,5R)-4-amino-5-(2-chlorophenyl)-3-methylpyrrolidin-2-one (2.2 g crude, considered 100% yield). The crude product was used without further purification in the next step.

Step 4. Synthesis of intermediate A12-trans and intermediate A12-cis. To a stirred suspension of rac-(4S,5R)-4-amino-5-(2-chlorophenyl)-3-methylpyrrolidin-2-one (1.9 g crude, 8.48 mmol) in THF water (1:1 , 100 ml) sodium bicarbonate (3.56 g, 86.36 mmol) was added at 0°C and the mixture was stirred for 30 minutes. Benzyl chloroformate (50% in toluene, 4.3 ml) was added to this reaction mixture at 0°C and stirred at room temperature for 16 hours. Once the reaction was considered complete (monitored by LCMS), the reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with water (100 ml x2), then brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The crude product was mixed with another 1.5 g batch and the combined material was purified by column chromatography (using 100-200 mesh silica gel; 1-2% MeOH in DCM as eluent) to give a mixture of isomers of intermediate A12-trans and intermediate compounds A12-cis (3.3 g). Preparative HPLC purification yielded intermediate A12-trans-benzyl (rac-(2R,3S,4S)-2-(2-chlorophenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate (815 mg, 14.9 %, in two stages after pre-purification) and another fraction (1.7 g), which was further purified by preparative HPLC to obtain the intermediate compound A12-cis-benzyl(rac-(2R,3S,4S)-2-(2-chlorophenyl )-4-methyl-5oxopyrrolidin-3-yl)carbamate (810 mg, 14.8%).

Synthesis of intermediate A14 benzyl (rac-(2R,3S,4S)-2-(4-methoxyphenyl)-4-methyl-5oxopyrrolidin-3-yl)carbamate.

Szh-L. G.hN.TT hg th-— : — s:

Stage 4

Ome

Proezhutovm with mdkizhia A14

Step 1. Synthesis of rac-(3S, 4S, 5R)-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-3-methyl-4nitropyrrolidin-2-one. To a stirred solution of 4-methoxybenzaldehyde (13.88 g, 101.95 mmol) in toluene (100 ml) was added 4-methoxybenzylamine (13.98 g, 101.95 mmol) at room temperature and the mixture was stirred for 2 hours. 2-methyl-3-nitropropanoate (10.0 g, 67.96 mmol) was added to this reaction mixture, followed by benzoic acid (12.45 g, 101.95 mmol) and stirred for 16 hours at 70°C. After completion of the reaction (under LCMS monitoring), the mixture was diluted with ethyl acetate (250 ml) and washed with water (100 ml) and then saturated. aq. NaHCO ₃ (100 ml x 2). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated. The crude material was purified by column chromatography (using silica gel 100-200 mesh; eluent 20-25% ethyl acetate/hexanes) rac-(3S,4S,5R)-1-(4methoxybenzyl)-5-(4-methoxyphenyl)-3-methyl -4-nitropyrrolidin-2-one (11.5 g, 45.7%) as a brown solid.

Step 2. Synthesis of rac-(3S, 4S, 5R)-5-(4-methoxyphenyl)-3-methyl-4-nitropyrrolidin-2-one. To a stirred solution of rac-(3S,4S,5R)-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-3-methyl-4nitropyrrolidin-2-one (14.5 g, 39.04 mmol) in In acetonitrile (150 ml), a solution of CAN (64.2 g, 117.12 mmol) in water (150 ml) was added dropwise at 0°C. The reaction mixture was slowly heated to 15°C and stirring was continued for 3-4 hours. After consumption of the starting material (TLC control, 50% ethyl acetate/hexane, Rf 0.2), the reaction mixture was diluted with ethyl acetate (300 ml) and washed with water (100 ml x2) and then brine (150 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude material was purified by column chromatography (using 100-200 mesh silica gel; eluent 20-30% ethyl acetate/hexane) to give rac-(3S,4S,5R)-5-(4-methoxyphenyl)3-methyl-4-nitropyrrolidine- 2-one (3.82 g, 39%) as a light yellow solid.

Step 3. Synthesis of rac-(3S, 4S, 5K)-4-amino-5-(4-methoxyphenyl)-3-methylpyrrolidin-2-one. To a stirred solution of rac-(3S, 4S, 5K)-5-(4-methoxyphenyl)-3-methyl-4-nitropyrrolidin-2-one (3.8 g,

- 32 044347

15.2 mmol) in EtOAc/MeOH (2:1, 380 ml) was added 6 N aq. HCl (76 ml) at 0°C. Sputtered Zn (59.64 g, 912 mmol) was added to this reaction mixture in portions at the same temperature. The resulting suspension was stirred at room temperature for 16 hours. After completion of the reaction (under LCMS control), the reaction mixture was quenched with a saturated solution of NaHCO ₃ at 0°C, stirred for 1 hour, filtered through celite and washed with EtOAc/MeOH (300 ml, 2 :1). The filtrate was concentrated to give rac-(3S,4S,5R)-4-amino-5-(4-methoxyphenyl)-3-methylnurrolidin-2-one (3.52 g crude, considered 100% yield). The crude product was used in the next step without further purification.

Step 4: To a stirred suspension of rac-(3S,4S,5R)-4-amino-5-(4-methoxyphenyl)-3methylpyrrolidin-2-one (3.52 g crude, 15.2 mmol) in THF water ( 1:1, 200 ml) sodium bicarbonate (7.25 g, 86.36 mmol) was added at 0°C and stirred for 30 min. Benzyl chloroformate (50% in toluene, 8.66 ml) was added to this reaction mixture at 0°C and stirring was continued at room temperature for 16 hours. Once complete (under LCMS monitoring), the reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3x150 ml). The combined organic layers were washed with water (150 mlx2), then brine (200 ml), dried over Na ₂ SO ₄ and concentrated. The crude material was purified by column chromatography (using 100-200 mesh silica gel; 1-2% MeOH in DCM as eluant) to intermediate A14 as an off-white solid (2.5 g, 39% in two steps).

Synthesis of intermediate A16 benzyl (rac-(2S,3S,4S)-2-(5-chlorothiophen-2-yl)-4-methyl-5oxopyrrolidin-3-yl)carbamate.

Step 1. Synthesis of rac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-1-(4-methoxybenzyl)-3-methyl-4nitropyrrolidin-2-one. To a stirred solution of 5-chlorothiophene-2-carbaldehyde (10 g, 0.068 mol) in toluene (250 ml) was added 4-methoxybenzylamine (10.26 g, 0.0748 mol) at room temperature and stirred for 2 hours. 2-methyl-3-nitropropanoate (11 g, 0.0748 mol) was added to the reaction mixture, followed by benzoic acid (12.46 g, 0.102 mol) and stirred at 80°C for 16 hours. After completion of the reaction (control with TLC, 30% EA/hexane) the reaction mixture was diluted with ethyl acetate (200 ml) and washed with water (500 ml), and then with sat. aq. NaHCO ₃ (300 ml x3). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting crude material was purified by column chromatography (using 100-200 mesh silica gel; eluent 2530% ethyl acetate/hexane) to give rac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-1- (4-methoxybenzyl)-3methyl-4-nitropyrrolidin-2-one (8 g, 28%) as a brown gum.

Stage-2. Synthesis of rac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-3-methyl-4-nitropyrrolidin-2-one. To a stirred solution of rac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-1-(4-methoxybenzyl)-3-methyl-4nitropyrrolidin-2-one (5 g, 0.013 mol) in CH ₃ CN (50 ml) a solution of CAN (21.38 g, 0.039 mol) in water (50 ml) was added dropwise at 0°C. The reaction mixture was stirred at the same temperature for 2 hours. Once complete (monitored with TLC in 50% EA-hexane, Rf 0.3), the reaction mixture was diluted with ethyl acetate and washed with water and then brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. The resulting crude material was purified by column chromatography (using 100-200 mesh silica gel, 70% EA-hexane as eluent) to give rac-(3S,4S,5S)-5-(5chlorothiophen-2-yl)-3-methyl-4 -nitropyrrolidin-2-one (2.3 g, 82%) as an off-white solid.

Stage-3. Synthesis of rac-(3S,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-3-methylpyrrolidin-2-one. To a stirred solution of rac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-3-methyl-4-nitropyrrolidin-2-one (1.8 g, 6.9 mmol) in EtOAc/ MeOH (360 ml, 2:1) was added 6 N aq. HCl (35 ml) at 0°C. Sputtered Zn (27.07 g, 414 mmol) was added to the mixture in portions at the same temperature. The resulting suspension was stirred at room temperature for 16 hours. After completion (control using LCMS), the reaction mixture was quenched with a saturated solution of NaHCO ₃ at 0°C, stirred for 1 hour, filtered

- 33 044347 through celite and washed with EtOAc/MeOH (500 ml, 2:1). The filtrate was concentrated to give rac(3S,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-3-methyln-pyrrolidin-2-one (1.6 g, crude) as a crude solid. white. The crude product was used in the next step without further purification.

Step 4. Synthesis of intermediate A16. To a stirred suspension of rac-(3S,4S,5S)-4amino-5-(5-chlorothiophen-2-yl)-3-methylpyrrolidin-2-one (3 g, 0.013 mol) in THF/water (60 ml, 1 :1) Add sodium bicarbonate (5.46 g, 0.065 mol) at 0°C and stir for 30 minutes. To this was added benzyl chloroformate (50% solution in toluene, 6.65 g, 0.0195 mol) at the same temperature and stirring was continued at room temperature for 16 hours. Once complete (under LCMS monitoring), the reaction mixture was diluted with water (100 ml ) and extracted with ethyl acetate (3x90 ml). The combined organic layers were washed with water (90 ml) and then brine (90 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude material was purified by column chromatography (using 100-200 mesh silica gel; eluent 2-2.5% MeOH/DCM) to give intermediate A16 benzyl(rac-(2S,3S,4S)-2-(5-chlorothiophene-2 -yl)-4-methyl-5-oxopyrrolidin-3yl)carbamate (3 g, 79% in step 2) as an off-white solid.

Synthesis of intermediate A18 benzyl (rac-(2S,3S,4S)-4-methyl-2-(1-methyl-1H-pyrazol-3yl)-5-oxopyrrolidin-3-yl)carbamate.

Zr. Kalshwei? b Μ N C i

NHCbz

Oww 3 /

AI 8

Stage-1. Preparation of rac-(3S,4S,5S)-1-(4-methoxybenzyl)-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)-4nitropyrrolidin-2-one. To a stirred solution of 1-methyl-1H-pyrazole-3-carbaldehyde (5 g, 45.46 mmol) in toluene (75 ml) was added 4-methoxybenzylamine (6.86 g, 50.01 mmol) at room temperature and stirred over 2 hours. To this reaction mixture was added 2-methyl-3nitropropanoate (8.68 g, 59.09 mmol) followed by benzoic acid (8.33 g, 687.18 mmol) and stirring was continued for 16 hours at 70 °C. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with ethyl acetate (200 ml) and washed with water (200 ml), then sat. aq. NaHCO ₃ (75 ml x2). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (using 100-200 mesh silica gel; 25-30% ethyl acetate/hexane eluent) to give rac-(3S,4S,5S)-1-(4-methoxybenzyl)-3-methyl-5-( 1-Methyl-1Hpyrazol-3-yl)-4-nitropyrrolidin-2-one (4 g, 26%) off-white solid.

Stage-2. Preparation of rac-(3S,4S,5S)-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)-4-nitropyrrolidin-2one. To a stirred solution of rac-(3S, 4S, 5S)-1-(4-methoxybenzyl)-3-methyl-5-(1-methyl-1Hpyrazol-3-yl)-4-nitropyrrolidin-2-one (2 g, 5.814 mmol) in CH ₃ CN (40 ml) a solution of CAN (6.37 g, 11.63 mmol) in water (40 ml) was added dropwise at 0°C. The reaction mixture was stirred at the same temperature for 2 hours. Once complete (monitored with TLC in 50% EA-hexane, Rf 0.3), the reaction mixture was diluted with ethyl acetate and washed with water and then brine. The organic layer was dried over Na2SO4 and concentrated. Two more identical batches were run using the procedure described above. The crude composite batch material was purified by column chromatography (using 100-200 mesh silica gel, 70% EA-hexane as eluent) to give rac(3S,4S,5S)-3-methyl-5-(1-methyl-1H-pyrazol- 3-yl)-4-nitron-pyrrolidin-2-one (2.4 g, 61.4%) as an off-white solid.

Stage-3. Preparation of rac-(3S,4S,5S)-4-amino-3-methyl-5-(1-methyl-1-pyrazol-3-yl)pyrrolidin-2one. To a stirred solution of rac-(3S,4S,5S)-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)-4nitropyrrolidin-2-one (2.5 g, 11.16 mmol) in EtOAc/MeOH (2;1, 200 ml) was added aq. 6 N HCl (56 ml) at 0°C. Sputtered Zn (43.8 g, 669.64 mmol) was added to this reaction mixture in portions at the same temperature. The resulting suspension was stirred at room temperature for 16 hours. Once complete (monitored by TLC in 10% MeOH-DCM, Rf 0.4), the reaction mixture was quenched with saturated aq. NaHCO ₃ solution at 0°C and filtered through celite, washed with EtOAc/MeOH (500 ml, 2:1) and concentrated to give rac-(3S, 4S, 5S)-4-amino-3-methyl-5-(1 -methyl-1H-pyrazol-3yl)pyrrolidin-2-one (2.5 g, crude). The crude product was used in the next step without further purification.

- 34 044347

Step 4. Preparation of intermediate A18. To a stirred suspension of rac(3S,4S,5S)-4-amino-3-methyl-5-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (2.5 g crude, 12.87 mmol) in THF/water (1;1, 250 ml), sodium bicarbonate (5.41 g, 64.43 mmol) was added at 0°C and stirred for 30 min. Benzyl chloroformate (6.4 ml, 19.32 mmol, 50% in toluene) was added to this reaction mixture at 0°C and stirred at room temperature for 16 hours. After completion of the reaction (under LCMS monitoring), the mixture was diluted with water (500 ml ) and extracted with ethyl acetate (3x500 ml). The combined organic layers were washed with water (250 ml x2) and then brine (500 ml). The organic part was dried over Na ₂ SO ₄ and concentrated. The crude material was purified by column chromatography (using 100-200 mesh silica gel; 2-2.5% MeOH/DCM as eluent) to give intermediate A18 benzyl(rac-(2S,3S,4S)-4-methyl-2-( 1-Methyl-1H-pyrazol-3-yl)-5oxopyrrolidin-3-yl)carbamate (1.99 g, 54.3% in two steps) as an off-white solid.

Synthesis of intermediate A20 benzyl (rac-(2R,3S,4S)-4-benzyl-2-ethyl-5-oxopyrrolidin3-yl)carbamate.

Stage 1. Synthesis of methyl 2-benzyl-3-nitropropanoate. To a stirred solution of LDA (2M in THF, 22.5 mL, 45.09 mmol) in THF (30 mL) was added a solution of methyl 3-nitropropanoate (3 g, 22.54 mmol) and DMPU (27.3 mL, 222. 49 mmol) in THF (20 ml) at -78°C and stirring was continued for 30 minutes at the same temperature. A solution of (bromomethyl)benzene (2.69 ml, 22.54 mmol) in THF (15 ml) was added at -78°C and stirred for 2 hours at the same temperature. The mixture was gradually allowed to warm to 25°C and stirred for 16 hours. The reaction mixture was quenched with 1 N HCl (100 ml) at 0°C and extracted with ethyl acetate (100 ml x2). The combined organic layers were washed with water (100 ml), saturated aqueous NaHCO ₃ (100 ml), then brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (using 100-200 silica gel, 1012% ethyl acetate-hexane as eluent) to give methyl 2-benzyl-3-nitropropanoate (3.3 g, 65.65%) as a light yellow oil.

Stage-2. Synthesis of rac-(3S,4S,5R)-3-benzyl-5-ethyl-1-(4-methoxybenzyl)-4-nitropyrrolidin-2-one. To a stirred solution of propionaldehyde (3.61 ml, 50.39 mmol) in toluene (75 ml) was added 4methoxybenzylamine (6.91 g, 50.39 mmol) at 25°C and stirring was continued for 2 hours. To this reaction mixture methyl 2-benzyl-3-nitropropanoate (7.5 g, 33.59 mmol) was added followed by benzoic acid (6.15 g, 50.39 mmol) and stirred for 7-8 hours at 70°C. After completion of the reaction (TLC control, 30% EA/hexane, Rf = 0.4), the reaction mixture was diluted with ethyl acetate (300 ml) and washed with water (300 ml) and then saturated. aq. NaHCO ₃ (200 ml x 2). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (using 100-200 mesh silica gel; 25-30% ethyl acetate/hexane eluent) to give rac(3S,4S,5R)-3-benzyl-5-ethyl-1-(4-methoxybenzyl)- 4-nitropyrrolidin-2-one (3.5 g, 28.3%) as a brown oil.

Stage-3. Synthesis of rac-(3S, 4S, 5R)-3-benzyl-5-ethyl-4-nicropyrrolidin-2-one. To a stirred solution of rac-(3S,4S,5R)-3-benzyl-5-ethyl-1-(4-methoxybenzyl)-4-nitropyrrolidin-2-one (3.6 g, 9.77 mmol) in acetonitrile ( 36 ml) a solution of CAN (16.1 g, 29.31 mmol) in water (36 ml) was added dropwise at 0°C. The reaction mixture was slowly heated to 10-15°C and stirring was continued for 3-4 hours. After completion of the reaction (TLC control, 40% acetone in hexane, Rf 0.3), the mixture was diluted with ethyl acetate (200 ml) and washed with water (200 ml) and then brine (200 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude material was purified by column chromatography (using 100-200 mesh silica gel; 35-40% ethyl acetate/hexanes as eluent) to give rac-(3S,4S,5R)-3benzyl-5-ethyl-4-nitropyrrolidin-2-one ( 1.53 g, 63%) as a light yellow solid.

Stage-4. Synthesis of rac-(3S,4S,5R)-4-amino-3-benzyl-5-ethylpyrrolidin-2-one. To a stirred solution of rac-(3S,4S,5R)-3-benzyl-5-ethyl-4-nitron-pyrrolidin-2-one (2.8 g, 11.27 mmol) in EtOAc/MeOH (252 ml, 2:1 ) added 6M aq. HCl solution (80 ml) at 0°C. To this was added Zn sputter (44.24 g, 676.68 mmol) in portions at the same temperature. The resulting suspension was stirred at room temperature for 16 hours. After completion of the reaction (under LCMS control), the reaction

- 35 044347 the mixture was quenched with saturated NaHCO ₃ solution at 0°C, stirred for 1 hour, filtered through celite and washed with EtOAc/MeOH (300 ml, 2:1). The filtrate was concentrated to give rac-(3S,4S,5R)4-amino-3-benzyl-5-ethylpyrrolidin-2-one (2.43 g crude, considered 100% yield) as an off-white solid, which used in the next step without further purification.

Step 5. Synthesis of intermediate A20. To a stirred suspension of rac-(3S,4S,5R)-4amino-3-benzyl-5-ethylpyrrolidin-2-one (2.43 g crude, 11.18 mmol) in THF/water (300 ml, 1:1) add sodium bicarbonate (4.69 g, 55.91 mmol) at 0°C and stir for 30 minutes. To this was added benzyl chloroformate (5.58 ml, 16.77 mmol, 50% in toluene) at 0°C and stirred at room temperature for 16 hours. After completion of the reaction (under LCMS monitoring), the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (3x300 ml). The combined organic layers were washed with water (300 ml), then brine (300 ml), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (using 100-200 mesh silica gel; eluent 1.52% MeOH/DCM) to give intermediate A20 benzyl(rac-(2R,3S,4S)-4-benzyl-2-ethyl5-oxopyrrolidine- 3-yl)carbamate (2.95 g, 74.9%) as an off-white solid.

Synthesis of intermediate compound A9 rac-(3S, 4S, 5R)-4-amino-1-(1-(4-fluorophenyl)-1H-indazol-5yl)-3-methyl-5-phenylpyrrolidin-2-one.

% /

HN λ

S-M combination

Stage 1

O / _G G\ Civ ' . ' A

IMSCIWhI

Herd!

NH®

Intermediate AS connection

Intermediate connection A8

Step 1. Synthesis of benzyl-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)indazol-5-yl]-4-methyl-5-oxo-2phenylpyrrolidin-3-yl] carbamate. In a microwave vessel, benzyl N-[rac(2R,3S,4S)-4methyl-5-oxo-2-phenylpyrrolidin-3-yl]carbamate (500 mg, 1.54 mmol) was added to 1-(4- fluorophenyl)-5iodindazole (537 mg, 1.70 mmol), K3PO4 (654 mg, 3.08 mmol) and CuI (58.7 mg, 0.308 mmol). The vessel was hermetically sealed and purged with nitrogen. 1,4-Dioxane (15.4 mL) was added to the mixture followed by (1R,2R)-N,N'Dimethyl-1,2-cyclohexanediamine (87.7 mg, 0.617 mmol) sequentially. The mixture was heated to 100°C overnight and then to 110°C for 5 hours. After reaction control (UPLC) showed complete conversion of the starting material, the suspension was allowed to cool to room temperature and ethyl acetate was added followed by the addition of us. NaHCO3 solution. The mixture was stirred for 5 minutes, the layers were separated and the aqueous layer was extracted once with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO ₄ . Flash chromatography (40 g silica gel cartridge, gradient cyclohexane/ethyl acetate eluent) of the crude material gave N-[rac-(2R,3S,4S)-1-[1(4-fluorophenyl)indazol-5-yl]- 4-methyl-5-oxo-2-phenylpyrrolidin-3-yl]carbamate (465 mg, 0.870 mmol, 56%) as a white solid.

Step 2. Solution of N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)indazol-5-yl]-4-methyl-5-oxo-2phenylpyrrolidin-3-yl]carbamate ( 465 mg, 0.870 mmol) in acetonitrile (23 ml) was added to NaI (783 mg, 5.22 mmol) in a sealed tube. Trimethylsilyl chloride (0.442 mL, 3.48 mmol) was added dropwise to this mixture. The reaction mixture was stirred at room temperature overnight and slowly added to ethanol (28 ml) after reaction control indicated completion (UPLC). The resulting solution was loaded into a 5 g SCX cartridge, washed twice with ethanol (15 ml each) and eluted with 2 M ammonia in methanol. Methanol fractions were combined. Evaporation of the solvent gives intermediate A9 (rac-3S,4S,5R)-4-amino-1-[1-(4-fluorophenyl)indazol-5-yl]-3-methyl-5-phenylpyrrolidin-2-one ( 316 mg, 0.789 mmol, 91%) as a white solid.

The intermediates in the following table were synthesized similarly to intermediate 9 described above using different building blocks.

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Intermediate connection no. Structure Retrieved from A11-trans Ok ✓ NH ₂ O JL Intermediate connection A-10- trance AP-cis cm GCH! S Z-Z o Intermediate connection A-10- cis A13-trans O _x > N^\ A_/ m/\L ₍ 4 =/ Y ^NH 2 Cl^/L χχ Intermediate connection Alltrans A13-cis /X o _h g Ν^\ V χ'm<L_L, \ ₌ / ^Ν γ ΝΗ ₂ Intermediate A12-cis A19 I ~ά\ Intermediate connection A18 A21 θκ. vCw ^N ZZV ^N X' ^NH 2 ν—\ Υ 0 F Intermediate A20

Synthesis of the intermediate A15-cis benzyl(rac-(2R,3S,4R)-1-(1-(4-fluorophenyl)-1Nindazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5- oxopyrrolidin-3-yl)carbamate and intermediate A15-trans benzyl (rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4- methoxyphenyl)-4methyl-5-oxopyrrolidin-3-yl)carbamate.

Step 1. Synthesis of benzyl (rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)4-methyl-5-oxopyrrolidine -3-yl)carbamate and benzyl (rac-(2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)2-(4-methoxyphenyl)-4-methyl- 5-oxopyrrolidin-3-yl)carbamate. In a microwave-safe vessel, intermediate A14 (500 mg, 1.54 mmol) was added to 1-(4-fluorophenyl)-5-iodindazole (524 mg,

1.55 mmol, 1.1 eq.), K ₃ PO ₄ (599 mg, 2.82 mmol, 2.0 eq.) and CuI (53.7 mg, 0.282 mmol, 0.2 eq.). The vessel was hermetically sealed and purged with nitrogen. 1,4-Dioxane (14.1 mL) was then added sequentially to the mixture, followed by (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (80.3 mg, 0.564 mmol, 0.4 equiv .). The mixture was heated to 100°C overnight and to 110°C for 5 hours. After reaction control (UPLC) showed complete conversion of the starting material, the suspension was allowed to cool to room temperature and ethyl acetate was added, followed by the addition of us. NaHCO ₃ solution. The mixture was stirred for 5 minutes, the layers were separated and the aqueous layer was extracted once with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO ₄ . Flash chromatography (40 g silica gel cartridge, gradient cyclohexane/ethyl acetate eluent) of the crude material gave benzyl (rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1 H-indazole-5 -yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3 yl)carbamate (545 mg, 0.965 mmol, 68%) and epimeric benzyl (rac-(2R,3S,4R)-1- (1-(4-fluorophenyl)-1Hindazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate (116 mg, 0.206 mmol, 15%).

Step 2: Following the procedure described for Intermediate A9, Step 2, (rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2- (4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3yl)carbamate was used to prepare the intermediate A15-trans benzyl (rac(2R,3S,4S)-1-(1-(4-fluorophenyl)-1 H-indazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3 yl)carbamate.

Step 3: Following the procedure described for Intermediate A9, Step 2, (rac-(2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2- (4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3yl)carbamate was used to prepare the intermediate A15-cis benzyl ((2R,3S,4S)-1(1-(4-fluorophenyl)-1H-indazol- 5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate.

Synthesis of the intermediate A17-cis (3R,4S, 5S)-4-amino-5-(5-chlorothiophen-2-yl)-1-(1-(4fluorophenyl)-1H-indazol-5-yl)-3- methyln-pyrrolidin-2-one and intermediate A17-trans (3S,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol- 5-yl)-3-methylpyrrolidin-2-one.

Step 1. Synthesis of benzyl (rac-(2S,3S,4S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5yl)-4-methyl- 5-oxopyrrolidin-3-yl)carbamate and benzyl (rac-(2S, 3S,4R)-2-(5-chlorothiophen-2-yl)-1-(1-(4fluorophenyl)-1H-indazol-5-yl )-4-methyl-5-oxopyrrolidin-3-yl)carbamate: By analogy with the procedure described for intermediates A15-trans and A15-cis Stepa 1, intermediate A16 (500 mg, 1.37 mmol) was bound to 1-(4-fluorophenyl)-5-iodindazole (510 mg, 1.51 mmol, 1.1 eq.) to give benzyl(rac-(2S,3S,4S)-2-(5-chlorothiophen-2-yl )-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)4-methyl-5-oxopyrrolidin-3-yl)carbamate (644 mg, 1.12 mmol, 82%) and epimeric benzyl ( rac(2S,3S,4R)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxopyrrolidin-3yl )carbamate (118 mg, 0.205 mmol, 15%).

Step 2: Following the procedure described for Intermediate A9, Step 2, with ((2S,3S,4S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)- 1H-Indazol-5-yl)-4-methyl-5-oxopyrrolidin-3yl)carbamate was deprotected to give intermediate A17-trans (3S,4S,5S)-4amino-5-(5-chlorothiophen-2-yl )-1-(1 -(4-fluorophenyl)-1 N-indazol-5 -yl)-3 -methylpyrrolidin-2-one.

Step 3: Following the procedure described for Intermediate A9, Step 2, with ((2S,3S,4R)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)- 1H-Indazol-5-yl)-4-methyl-5-oxopyrrolidin-3yl)carbamate was deprotected to give intermediate A17-cis(3R,4S,5S)-4amino-5-(5-chlorothiophen-2-yl )-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylpyrrolidin-2-one.

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Synthesis of 1-(4-fluorophenyl)-5-iodo-III-indole (intermediate B1).

Step 1. 5-Bromo-III-indole (750.0 mg, 3.826 mmol, 1.0 eq.), 1-fluoro-4-iodobenzene (891.7 mg, 4.017 mmol, 1.05 eq.), K ₃ PO ₄ (1624.1 mg, 6.513 mmol, 2.0 eq.) and copper iodide (582.9 mg, 3.061 mmol, 0.8 eq.) were weighed into the flask, a magnetic stir bar was added, the flask was sealed and purged with nitrogen. 1,4-Dioxane (19.1 mL) and trans-N,N-dimethylcyclohexane-1,2-diamine (54.4 mg, 0.3826 mmol, 0.1 eq.) were then added and the reaction mixture was heated to 100°C for 16 hours. The reaction mixture was then cooled to ambient temperature, diluted with DCM and sat. NaHCO ₃ solution and filtered through a hydrophobic frit. The organic solvent was removed and the residues were purified by silica gel chromatography to give 5-bromo-1-(4-fluorophenyl)-1H-indole in 35% yield.

Step 2. 5-Bromo-1-(4-fluorophenyl)indole (2300 mg, 7.927 mmol, 1.0 eq.), NaI (5941 mg, 39.6 mmol, 5.0 eq.), K3PO4 (3365 mg , 15.8 mmol, 2.0 eq.) and copper iodide (1207 mg, 6.3419 mmol, 0.8 eq.) were weighed into the flask, a magnetic stir bar was added, the flask was sealed and purged with nitrogen. Then 1,4-dioxane (58.4 ml) and trans-N,N-dimethylcyclohexane-1,2-diamine (112.8 mg,

0.793 mmol, 0.1 eq.), and the reaction mixture was heated to 100°C. for one week. The reaction mixture was then cooled to ambient temperature, diluted with DCM and sat. NaHCO3 solution and filtered through a hydrophobic frit. The organic solvent was removed and the residues were purified by silica gel chromatography to give 1580 mg of intermediate B1 (53%).

Synthesis of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine (intermediate B2).

Step 1: Intermediate B2 was prepared similarly to the synthesis of intermediate B4, using 5-bromo-2-fluoropyridine-3-carbaldehyde instead of 6-bromo-3-fluoropyridine-2-carbaldehyde. Yield: 66%.

Synthesis of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine (intermediate B3).

Intermediate 'r connection VZ

Step 1: Intermediate B3 was prepared similarly to the synthesis of intermediate B4, using 2-bromo-5-fluoropyridine-4-carbaldehyde instead of 6-bromo-3-fluoropyridine-2-carbaldehyde. Yield: 79%.

Synthesis of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (intermediate B4).

connection B4

Step 1: 6-Bromo-3-fluoropyridine-2-carbaldehyde (300.0 mg, 1.471 mmol, 1.0 eq.) and (4fluorophenyl)hydrazine hydrochloride (239.1 mg, 1.471 mmol, 1.0 eq.) were dissolved in NMP (3.0 ml) and the reaction mixture was stirred for 90 min. CS2CO3 (1437.8 mg, 4.412 mmol, 3.0 eq) was then added and the reaction mixture was heated to 115°C for 90 min. The reaction mixture was then allowed to warm to ambient temperature and diluted with EtOAc and water. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO ₄ and the solvent was removed under reduced pressure. The resulting residue was then purified by LC to obtain 297.0 mg (69%) of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine.

Synthesis of the intermediate compound C1 N-((2R,3S)-1-(1-(4-fluorophenyl)-lH-indazol-5-yl)-5-oxo-2phenylpyrrolidin-3-yl)cyclopropanecarboxamide.

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Step 1. Maleic anhydride (9.8 g, 100 mmol, 1.0 eq.), p-thiocresol (12.4 g, 100 mmol, 1.0 eq.), ammonium acetate (7.8 g, 100 mmol , 1.0 equiv.) and benzaldehyde (10 ml, 100 mmol, 1.0 equiv.) were placed in a sealed tube and 100 ml of toluene was added. The reaction mixture was stirred at room temperature for 1 hour and then stirred at 150°C for 16 hours. After cooling to RT, the solvent was evaporated under reduced pressure, the residue was made basic with saturated NaHCO3 solution and extracted with DCM. The aqueous layer was acidified with 2N HCl while cooling with ice, and the crude product was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give crude 5-oxo-2-phenyl-3-(rtolylthio)pyrrolidine-3-carboxylic acid (10.0 g, crude).

Step 2: To a stirred solution of crude 5-oxo-2-phenyl-3-(p-tolylthio)pyrrolidine-3carboxylic acid (10.0 g, 30.58 mmol, 1.0 eq.) in acetone (100 ml) was added at 0°C potassium carbonate (16.8 g, 122.32 mmol, 4.0 eq.) and methyl iodide (7.6 ml, 122.32 mmol, 4.0 eq.), and the reaction mixture was stirred for 16 h at room temperature. The solvent was removed under reduced pressure and the residue was partitioned between DCM and water. The aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (100-200 silica gel, 50% EtOAc:hexanes) to give methyl 5-oxo-2-phenyl-3-(p-tolylthio)pyrrolidine-3-carboxylate (4.0 g, 38%) as an off-white solid.

Step 3: To a stirred solution of methyl 5-oxo-2-phenyl-3-(p-tolylthio)pyrrolidine-3carboxylate (4.0 g, 11.73 mmol, 1.0 eq.) in EtOH:THF (100 ml , 2:1), Raney Nickel (1 g) was added and the reaction mixture was stirred for 2 hours at room temperature. Once complete, the reaction mixture was filtered through a pad of celite and the celite pad was washed 2-3 times with EtOAc. The combined organic layers were concentrated and the crude product was purified by column chromatography (100200 silica gel, 50% EtOAc:hexanes) to give methyl 5-oxo-2-phenylpyrrolidine-3-carboxylate (2.2 g, 88%, syn:anti, mixture 1: 1) in the form of an off-white solid.

Step 4: To a stirred solution of methyl 5-oxo-2-phenylpyrrolidine-3-carboxylate (1.0 g, 4.56 mmol, 1.0 eq) in MeOH (25 ml) was added 2 N NaOH (5 ml ) and the reaction mixture was stirred at 80°C for 2 hours. After completion of the reaction (under LCMS control), the reaction mixture was concentrated and acidified with 2 N HCl solution and extracted with 30% isopropanol-DCM. The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain the desired trans-5-oxo-2-phenylpyrrolidine-3-carboxylic acid (0.8 g, 85%).

Step 5: To a stirred solution of trans-5-oxo-2-phenylpyrrolidine-3-carboxylic acid (0.5 g, 2.43 mmol, 1.0 eq.) in benzene:THF (25 ml, 4:1) was added TEA (0.68 mL, 4.87 mmol, 2.0 eq.) and DPPA (0.68 mL, 3.17 mmol, 1.3 eq.), and the reaction mixture was stirred at room temperature for 2 h. Benzyl alcohol (0.33 mL, 3.17 mmol, 1.3 eq.) was then added and the reaction mixture was refluxed for 16 hours. Once complete, the reaction mixture was concentrated under reduced pressure to give the crude compound, which was extracted with water and EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel 100-200 mesh; 2% MeOH-DCM; R _r value 0.5) to give trans-benzyl (5-oxo-2phenylpyrrolidin-3-yl)carbamate (0.38 g, 50%).

Step 6: To a stirred solution of trans-benzyl(5-oxo-2-phenylpyrrolidin-3-yl)carbamate (1.7 g, 5.48 mmol, 1.0 eq.) in MeOH (20 ml, 2:1) , Pd/C (0.058 g, 0.548 mmol, 0.1 eq.) was added and the reaction mixture was stirred with a balloon of hydrogen for 2 hours at room temperature. After completion, the reaction mixture was filtered through a layer of celite, and the celite layer was washed 2-3 times

EtOAc. The combined organic layers were concentrated to give the desired trans-4-amino-5phenylpyrrolidin-2-one as a brown gum (0.9 g, 93%).

Step 7: To a stirred solution of cyclopropanecarboxylic acid (0.59 g, 6.818 mmol, 1.2 eq.) in DMF (15 ml) was added HATU (4.32 g, 11.363 mmol, 2.0 eq.), DIPEA (5 .0 ml, 28.409 mmol, 5.0 eq.) and intermediate A2 (1.00 g, 5.681 mmol, 1.0 eq.) at 0°C, and the reaction mixture was then stirred at ambient temperature for 16 h After completion of the reaction (TLC control, TLC system 5% MeOH in DCM, Rf-0.3), the reaction mixture was diluted with EtOAc (35 ml) and washed with ice water (3x25 ml), dried over Na ₂ SO ₄ and concentrated at reduced pressure to give the crude product, which was purified by column chromatography (silica gel 230400 mesh; 0 to 4% MeOH-DCM) to give K-(trans-5-oxo-2-phenylpyrrolidin-3yl)cyclopropanecarboxamide (0.45 g, 32 %).

Step 8: Stirred solution of N-(trans-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (0.450 g, 1.844 mmol, 1.0 eq.), 1-(4-fluorophenyl)-5-iodo-1H -indazole (0.748 g, 2.213 mmol, 1.2 eq.) and K ₃ PO ₄ (0.781 g, 3.688 mmol, 2.0 eq.) in 1,4-dioxane (30 ml) were degassed with argon for 30 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (0.104 g, 0.737 mmol, 0.4 eq.) and CuI (0.070 g, 0.368 mmol, 0.2 eq.) were then added and the reaction mixture was stirred for 16 hours at 90°C in a sealed tube. After completion of the reaction (TLC control, TLC system 5% MeOH in DCM, Rf-0.4), the reaction mixture was filtered through a pad of celite and the celite pad was washed 2-3 times with 1,4-dioxane. The combined organic layers were concentrated to give the crude product, which was purified by column chromatography (silica gel 230-400 mesh; 0 to 2% MeOH in DCM) to give the racemic product. Further separation of enantiomers was carried out by preparative chiral HPLC to obtain pure N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-undazol-5-yl)-5-oxo-2phenylpyrrolidin-3-yl)cyclopropanecarboxamide (0.267 g, 32%; RT=5.56 min; column name: Chiralpak IA (250x4.6 mm) 5 µm, mobile phase: hexane/uzopropanol/DCM/DEA: 70/15/15/0.1, speed flow: 1.0 ml/min) and intermediate C1 -ent1 N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5yl)-5-oxo-2-phenylpyrrolidine- 3-yl)cyclopropanecarboxamide (0.254 g, 30%; RT=7.13 min; column name: Chiralpak IA (250x4.6 mm) 5 µm, mobile phase: hexane/isopropanol/DCM/DEA: 70/15/15/ 0.1, flow rate: 1.0 ml/min).

Examples 1 and 2. N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-undazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3- yl)cyclopropanecarboxamide (example 1) and N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidine-3 -yl)cyclopropanecarboxamide (example 2).

Intermediate Prior 1 Example 2, compound A2

Step 1: Stirred solution of intermediate A2 (0.35 g, 1.286 mmol, 1.0 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole (0.520 g, 1.54 mmol, 1.0 eq.), 2 eq.), K ₃ PO ₄ (0.545 g 2.572 mmol, 2.0 eq.) in 1,4-dioxane (20 ml) was degassed with argon for 30 min. Trans-N,N'dimethylcyclohexane-1,2-diamine (0.073 g, 0.514 mmol, 0.4 eq) and CuI (0.049 g, 0.257 mmol, 0.2 eq) were then added and the reaction mixture was stirred for 16 h at 90°C in a sealed tube. After completion of the reaction (TLC control, TLC system 5% MeOH in DCM, Rf-0.4), the reaction mixture was filtered through a pad of celite, which was then washed 2-3 times with 1,4-dioxane.

The combined organic layers were concentrated to give the crude product, which was purified by column chromatography (silica gel 230-400 mesh; 0 to 2% MeOH in DCM) to give the racemic compound, and further separation of the enantiomers was carried out using Rev. chiral HPLC (column: Chiralpak IC (4.6x250 mm), 5 µm, mobile phase: hexane: ethyl acetate: EtOAc: isopropylamine 70:15:15:0.1, flow rate: 1.0 ml/min) to obtain an example 1 (0.055 g, 9%, retention time: 4.62 min) and example 2 (0.057 g, 9%, retention time 6.48 min). ^1H NMR (400 MHz, DMSO-d6): δ= 8.46 (d, 1H), 8.29 (s, 1H), 7.74-7.71 (m, 3H), 7.67 (d , 1H), 7.46 (m, 1H), 7.39 (d, 2H), 7.34-7.32 (m, 2H), 7.22 (t, 2H), 7.14 (t, 2H), 5.11 (d, 1H), 4.29 (t, 1H), 1.69-1.63 (m, 1H), 1.21 (s, 3H), 1.12 (s, 3H ), 0.7-0.52 (m, 4H).

Example 5. n-trans-(5-(1-(4-Fluorophenyl)-1H-indol-5-yl)-4-oxo-6-phenyl-5-azaspiro[2,4]heptan-7yl)cyclopropanecarboxamide.

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-yellow Intermediate ^F Example 5 compound Bl compound A5

Step 1: Intermediate A5 (50.0 mg, 0.185 mmol, 1.0 eq), Intermediate B1 (65.5 mg, 0.194 mmol, 1.05 eq), _K3PO4 ( _78.5 mg , 0.370 mmol, 2.0 eq.) and copper iodide (28.2 mg, 0.148 mmol, 0.8 eq.) were weighed into the vial, a stir bar was added, the vial was sealed and purged with nitrogen. Then 1,4-dioxane (0.9 ml) and trans-N,N'dimethylcyclohexane-1,2-diamine (2.5 mg, 0.019 mmol, 0.1 eq.) were added and the reaction mixture was heated to 100° C within six days. The reaction mixture was then cooled to ambient temperature, diluted with DCM and sat. NaHCO ₃ solution and filtered through a hydrophobic frit. The organic solvent was removed and the residues were purified by silica gel chromatography to give 4.0 mg (4%) of the compound of Example 5. ¹ H NMR (DMSO-d ₆ ) δ: 8.88 (d, 1H), 7.74-7. 70 (m, 1H), 7.62-7.54 (m, 3H), 7.45 -7.35 (m, 6H), 7.33 (dd, 2H), 7.27-7.19 ( m, 1H), 6.63 (d, 1H), 5.22 (d, 1H), 4.01 (dd, 1H), 1.72-1.64 (m, 1H), 1.28-1 .05 (m, 2H), 0.97-0.89 (m, 2H), 0.79-0.73 (m, 1H), 0.73 -0.68 (m, 3H).

Example 7. N-((2R, 3S)-4,4-dimethyl-1-(1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indazol-5yl)- 5-oxo-2-phenylpyrrolidin-3-yl)-5-methylisoxazole-3-carboxamide.

Step 1: 5-Methylisoxazole-3-carboxylic acid (22.3 mg, 0.175 mmol, 1.5 eq.) was dissolved in DCM (1.2 ml) followed by the addition of triethylamine (0.05 ml, 0.351 mmol, 3. 0 eq.). A solution of propylphosphonic anhydride (>50 wt% in ethyl acetate, 0.14 mL, 2.0 eq.) was then added and the mixture was stirred at ambient temperature for 20 minutes. Intermediate A4 ent1 (50.0 mg, 0.117 mmol, 1.0 eq) was then added and the mixture was stirred for 48 hours at ambient temperature. Saturated NaHCO ₃ solution and more DCM were then added and the mixture was stirred for 10 minutes. The mixture was then filtered through a hydrophobic frit and then the organic solvent was removed. The crude residues were purified by silica gel chromatography to give 36.0 mg (57%) of the compound of Example 7. ¹ H NMR (DMSO-d6) δ: 9.09 (d, 1H), 8.26 (d, 1H), 8. 17 (d, 1H), 7.72-7.67 (m, 2H), 7.59 (d, 1H), 7.39 (dd, 1H), 7.38-7.36 (m, 2H) , 7.26-7.20 (m, 2H), 7.18-7.12 (m, 1H), 6.54 (d, 1H), 6.51 (d, 1H), 5.50 (d , 1H), 4.47 (t, 1H), 3.50 (s, 3H), 2.47 (d, 3H), 1.32 (s, 3H), 1.17 (s, 3H).

Example 31 2,4]heptan-7-yl)1cyclopropanecarboxamide.

Step 1. 5-Bromo-1-(4-fluorophenyl)pyrazolo[3,4-b]pyridine (64.8 mg, 0.222 mmol, 1.2 eq.), intermediate A5 (50.0 mg, 0.185 mmol , 1.0 eq.), K3PO4 (78.5 mg, 0.370 mmol, 2.0 eq.), CuI (7.0 mg, 0.037 mmol, 0.2 eq.) and NaI (55.4 mg, 0.370 mmol, 2.0 eq.) were weighed into a microwave-safe container. A stir bar was added, the tube was capped and purged with nitrogen. Then 1,4-dioxane (1.0 ml) and trans-X,N'-dimethylcyclohexane-1,2-diamine (0.012 ml, 0.074 mmol, 0.4 eq.) were added and the mixture was stirred at 110°C for 16 hours. The mixture was then allowed to cool to ambient temperature and diluted with sat. a solution of NaHCO ₃ and DCM. The mixture was then filtered through a hydrophobic frit. The organic layer was evaporated under reduced pressure and the residue was purified by LC to give 42.0 mg (47%) N-[rac-((6R,7S)-5-(1-(4-fluorophenyl)-1H-pyrazolo[3 ,4-b]pyridin-5yl)-4-oxo-6-phenyl-5-azaspiro[2,4]heptan-7-yl)]cyclopropanecarboxamide. Ή NMR (DMSO-d ₆ ): δ= 8.928.86 (m, 2H), 8.44 (d, 1H), 8.40 (s, 1H), 8.25-8.16 (m, 2H) , 7.44-7.37 (m, 4H), 7.35 (t, 2H), 7.29-7.23 (m, 1H), 5.37 (d, 1H), 4.13 (dd , 1H), 1.71-1.63 (m, 1H), 1.25 (dd, 1H), 1.18-1.11 (m, 1H), 1.05-0.96 (m, 2H ), 0.78-0.68 (m, 4H)

Example 32 - 42 044347

5-azaspiro[2,4]heptan-7-yl)]cyclopropanecarboxamide.

Example 32 was prepared similarly to the synthesis described for Example 31, using intermediate B3 instead of intermediate B2 and requiring additional HPLC purification. Yield: 35%. ^1H NMR (DMSO- _d6 ): δ= 8.99 (p, 1H), 8.90 (d, 1H), 8.76 (q, 1H), 8.54 (q, 1H), 7. 88-7.81 (m, 2H), 7.437.36 (m, 2H), 7.36-7.26 (m, 4H), 7.23-7.17 (m, 1H), 5.79 ( s, 1H), 3.95 (dd, 1H), 1.72-1.64 (m, 1H), 1.25-1.12 (m, 2H), 1.04-0.91 (m, 2H), 0.81-0.66 (m, 4H).

Example 33. N-[rac-((6R,7S)-5-(1-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-4-oxo-6-phenyl5 -azaspiro[2,4]heptan-7-yl)]cyclopropanecarboxamide.

Example 33 was prepared similarly to the synthesis described for Example 31, using intermediate B4 instead of intermediate B2. Yield: 32%. ^1H NMR (DMSO- _d6 ): δ= 8.91 (d, 1H), 8.62 (d, 1H), 8.39-8.34 (m, 2H), 7.84-7.77 (m, 2H), 7.47-7.40 (m, 2H), 7.40-7.34 (m, 2H), 7.32 (t, 2H), 7.22 (t, 1H), 5.80 (d, 1H), 3.98-3.94 (m, 1H), 1.72-1.62 (m, 1H), 1.26-1.14 (m, 2H), 1. 05-0.96 (m, 2H), 0.83 -0.75 (m, 1H), 0.75-0.65 (m, 3H).

Example 34a. N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3-yl)methanesulfonamide.

connection M anti Prmer 34a

Step 1. (4S,5R)-4-Amino-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-5-phenylpyrrolidin2-one (50.0 mg, 0.121 mmol, 1.0 eq) was weighed into the vial under nitrogen followed by the addition of DCM (1.2 mL) and triethylamine (0.067 mL, 0.483 mmol, 4.0 eq). The mixture was then cooled to 0°C, then methanesulfonyl chloride (0.019 ml, 0.241 mmol, 2.0 eq.) was added and the mixture was left stirring for 10 minutes at this temperature. The reaction mixture was then diluted with us. a solution of NaHCO ₃ and DCM. The mixture was then filtered through a hydrophobic frit and the organic layer was evaporated to dryness under reduced pressure. The resulting residue was purified by LC to give 59.4 mg (76%) N((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4- dimethyl-5-oxo-2-phenylpyrrolidin-3 yl)methanesulfonamide. ^1H NMR (DMSO- _d6 ): δ= 8.28 (d, 1H), 8.02 (d, 1H), 7.76-7.69 (m, 3H), 7.69-7.63 (m, 1H), 7.52-7.47 (m, 2H), 7.44-7.35 (m, 3H), 7.29 (dd, 2H), 7.23-7.18 (m , 1H), 5.07 (d, 1H), 3.70 (t, 1H), 2.03 (s, 3H), 1.26 (s, 3H), 1.14 (s, 3H).

The examples in the following table were synthesized similarly to example 34a described above using various intermediates. Reaction times may vary.

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Approx. No. Intermediate connection (INT) Structure Exit (%) II NMR 34a Intermediate, conn. A7 ent 2 0 ό F 52 *H NMR (OMZO-D): δ= 8.28 (d, W), 8.02 (d, 1H), 7.76 - 7.69 (m, 3H), 7.69 - 7.63 ( m, 1H), 7.52 - 7.47 (m, 2H), 7.44 - 7.35 (m, 3H), 7.29 (dd, 2H), 7.23 - 7.18 (m, 1H), 5.07 (d, 1H), 3.70 (t, 1H), 2.03 (s, 3H), 1.26 (s, 3H), 1.14 (s, 3H) 35a Intermediate, conn. A7 ent 1 0 0 F 13 *H NMR (DMSO-<4): δ= 8.28 (d, 1H), 7.95 (d, 1H), 7.76 - 7.68 (m, 3H), 7.65 (dd, 1H ), 7.49 - 7.44 (m, 2H), 7.43 - 7.35 (m, 3H), 7.26 (t, 2H), 7.20 - 7.14 (m, 1H), 5.09 (d, 1H), 3.74 (t, 1H), 1.46 (tt, 1H), 1.28 (s, 3H), 1.15 (s, 3H), 0.70 - 0 .49 (m, 2H), 0.49 0.25 (m, 2H) 35b Intermediate, conn. A7 ent 2 oh.....$0 <R g 8 *H NMR (DMSO-<4): δ= 8.28 (d, 1H), 7.95 (d, 1H), 7.76 - 7.68 (m, 3H), 7.65 (dd, 1H ), 7.49 - 7.44 (m, 2H), 7.43 - 7.35 (m, 3H), 7.26 (t, 2H), 7.20 - 7.14 (m, 1H), 5.09 (d, 1H), 3.74 (t, 1H), 1.46 (tt, 1H), 1.28 (s, 3H), 1.15 (s, 3H), 0.70 - 0 .49 (m, 2H), 0.49 0.25 (m, 2H) 61 A9 o /=\ А.о ω ^χ /ъ 74 *H NMR (DVI 50-%) δ: 8.28 (d, 1H), 7.99 (d, 1H), 7.76 - 7.69 (m, 3H), 7.65 (dt, 1H) , 7.48 - 7.42 (m, 3H), 7.42 - 7.35 (m, 2H), 7.30 7.25 (m, 2H), 7.22 - 7.17 (m, 1H ), 5.10 (d, 1H), 3.61 (dt, 1H), 2.68 (dq, 1H), 2.26 (s, 3H), 1.31 (d, 3H)

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62 A11-trans 0 / ^χ^ °V° n -J n 0 JUF 50 *H NMR (DMSOX δ: 8.29 (s, 1H), 7.96 (d, 1H), 7.77 - 7.71 (m, 3H), 7.69 - 7.64 (m, 1H) , 7.44 (dd, 1H), 7.44 - 7.36 (m, 2H), 7.27 (d, 1H), 7.25 - 7.21 (m, 1H), 7.16 (t , 1H), 7.01 (d, 1H), 5.05 (d, 1H), 3.58 (dt, 1H), 2.67 (dq, 1H), 2.26 (s, 3H), 2 .22 (s, 3H), 1.31 (d, 3H) 76 A11-cis o g N YyN0-„ _N ^ ^N T ^H 0 JU F 40 *H NMR (DMSOX δ: 7.89 (dd, 1H), 7.79 7.68 (m, 5H), 7.44 - 7.37 (m, 2H), 7.24 (t, 1H), 7.19 (d, 1H), 7.17 - 7.13 (m, 1H), 7.08 (ddd, 1H), 5.24 (d, 1H), 3.97 (d, 1H), 3 .01 (p, 1H), 2.87 (s, 3H), 2.27 (s, 3H), 1.18 (d, 3H) 86 A13-cis O.g N JTVN N—\ UT ^H 0 XF 35 *H NMR (DMSOX δ: 8.35 (d, 1H), 8.19 (d, OH), 7.87 (dd, 1H), 7.80 - 7.73 (m, 3H), 7.65 (dd, 1H), 7.54 - 7.48 (m, 1H), 7.44 - 7.37 (m, 2H), 7.37 - 7.28 (m, 3H), 5.58 (d , 1H), 4.09 (s, 1H), 3.04 (p, 1H), 2.95 (s, 3H), 1.20 (d, 3H) 91 A21 0. > °v° N~< JIH 0 ¹ F 42 *H NMR (DMSOX δ: 8.40 (d, 1H), 7.87 7.76 (m, 4H), 7.72 (d, 1H), 7.45 (ddd, 3H), 7.40 - 7.33 (m, 4H), 7.26 (It, 1H), 4.07 (td, 1H), 3.62 (ddd, 1H), 3.15 (dd, 1H), 3.09 (dd , 1H), 2.96 (q, 1H), 2.79 (s, 3H), 1.51 (ddd, 1H), 1.22 (dp, 1H), 0.40 (t, 3H) 93 A13-trans O. / M v ^N T ^H 0 0 F 19 *H NMR (Chloroform-^) δ: 8.10 (d, 1H), 7.68 (dd, 1H), 7.64 - 7.58 (m, 2H), 7.55 (dd, 1H), 7.38 (dd, 2H), 7.31 (d, 1H), 7.26 - 7.18 (m, 4H), 5.68 (s, 1H), 4.79 (d, 1H), 2 .72 (dq, 1H), 2.51 (s, 3H), 1.55 (d, 3H), 0.97 - 0.77 (m, 1H) 99 A15-trans 0. / N JV ^N J+n^ ^S ^ ^N— xU T ^H 0 ό ^f J 13 *H NMR (DMSOX δ: 8.28 (d, 1H), 7.93 (d, 1H), 7.75 - 7.72 (m, 2H), 7.71 (dd, 1H), 7.65 (dt, 1H), 7.43 - 7.34 (m, 5H), 6.85 - 6.79 (m, 2H), 5.03 (d, 1H), 3.65 (s, 3H), 3.59 (dt, 1H), 2.65 (dt, 1H), 2.29 (s, 3H), 1.31 (d, 3H) 114 A17-trans o T ω XX ^Ω -4 ,ο / ^s o 25 *H NMR (DMSOX δ: 8.34 (d, 1H), 7.98 (d, 1H), 7.81 - 7.74 (m, 3H), 7.72 (dt, 1H), 7.47 - 7.38 (m, 3H), 7.14 (d, 1H), 6.89 (d, 1H), 5.34 (d, 1H), 3.68 (dt, 1H), 2.70 ( dq, 1H), 2.64 (s, 3H), 1.31 (d, 3H) 122 A19 °U °/ 0 0 F 47 *H NMR (DMSOX δ: 8.31 (t, 1H), 7.92 (d, 1H), 7.79 - 7.73 (m, 2H), 7.72 (dd, 1H), 7.69 (dd, 1H), 7.52 (d, 1H), 7.45 - 7.37 (m, 3H), 6.27 (dd, 1H), 5.11 (d, 1H), 3.79 ( q, 1H), 3.70 (s, 3H), 2.67 2.59 (m, 1H), 2.46 (s, 3H), 1.30 (d, 3H)

Examples 95 and 96 yl)carbamoyl)cyclopropan-1-ylium (Example 95) and N-((2R,3R)-4,4-difluoro-1-(1-(4fluorophenyl)-III-indazol-5-yl)-5-oxo -2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (example 96)

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Step 1: In a dried vessel, intermediate C1-ent 1 (150 mg, 0.33 mmol) was dissolved in dry THF (3.3 ml) under an inert atmosphere. The solution was cooled to -78°C and LDA solution (1M in THF/heptanes/ethylbenzene, 1.32 mL, 4.0 eq.) was added dropwise. After stirring for 15 min at -78°C, N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (NFSI, 229 mg, 0.726 mmol, 2.2 eq.) dissolved in dry THF (1.7 ml) was added dropwise. . The mixture was stirred for two hours at -78°C, and then additional amounts of LDA (330 μl, 1 eq.) and NFSI (100 mg, 1 eq.) were added. After stirring for another 30 minutes at -78°C, the reaction was quenched with sat. NH4Cl solution and after stirring for 5 minutes, ethyl acetate was added. The layers were separated, the organic layer was dried over sodium sulfate and the solvent was removed in vacuo. The crude material was purified by flash chromatography (silica, cyclohexane/ethyl acetate gradient eluent) followed by preparative mmol, 16%) and high-pressure HPLC (water/acetonitrile gradient) to give Example 95 (25.5 mg, 0.054 of Example 96 (3.0 mg, 0.006 mmol, 2%) as a white solid.

Example 95: Ή NMR (Chloroform-d^δ: 8.07 (d, 1H), 7.76 (dd, 0.7 Hz, 1H), 7.67 -7.50 (m, 2H), 7.587, 45 (m, 1H), 7.39 (dd, 1H), 7.41-7.06 (m, 6H), 6.31 (d, 1H), 5.86 (dd, 1H), 5.54 (dd, 1H), 3.98 (dq, 1H), 1.44 (tt, 1H), 0.86 (dtd, 2H).

Example 96: ^1H NMR (Chloroform^) δ: 8.10 (s, 1H), 7.52 (d, 1H), 7.41 (dd, 1H), 7.43-7.19 (m, 5H ), 7.28-7.11 (m, 2H), 6.42 (s, 1H), 5.14 (d, 1H), 4.88 (dddd, 1H), 1.51 (tq, 1H) , 1.05 (tq, 1H), 0.96-0.74 (m, 2H).

Example 100 2,2-Difluoro-n-(trans-1 -(1 -(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-oxo-2phenylpyrrolidin-3-yl)propanamide.

Intermediate Prier 100 connection Av

Step 1: To a stirred solution of intermediate A6 (1 g, 3.08 mmol, 1.0 eq) in methanol (30 ml) was added Pd-C (820 g, 10%, wet) and the reaction mixture was stirred with a hydrogen balloon for 2 hours at RT. Once complete (TLC monitoring, TLC system 5% MeOH in DCM, Rf-0.2), the reaction mixture was filtered through a pad of celite and washed 2-3 times with MeOH. The filtrate was concentrated to give the desired trans-4-amino-5-methyl-5-phenylpyrrolidin-2-one as an off-white solid (0.693 g, 94%).

Step 2: To a stirred solution of 2,2-difluoropropanoic acid (0.304 g, 2.759 mmol, 1.5 eq.) in DMF (10 ml), DIPEA (1.6 ml, 9.14 mmol, 5. 0 eq.), HATU (1.4 g, 3.678 mmol, 2.0 eq.) and trans-4-amino-5-methyl-5-phenylpyrrolidin-2-one (350 mg, 1.839 mmol, 1 eq.) and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.3), the reaction mixture was diluted with EtOAc (20 ml) and washed with ice water (3 x 25 ml ), dried over Na ₂ SO ₄ and concentrated to give the crude product, which was purified by column chromatography (silica gel 230-400 mesh; 0 to 2% MeOH-DCM) to give 2,2-difluoro-N-(trans- 2-methyl-5-oxo-2-phenylpyrrolidin-3yl)propanamide (0.350 g, 67%).

Step 3. Stirred solution of 2,2-difluoro-N-(trans-2-methyl-5-oxo-2-phenylpyrrolidone-3y1)propanamide (0.250 g, 0.885 mmol, 1 eq), 1-(4-fluorophenyl)- 5-iodo-1H-indazole (0.359 g, 1.0627 mmol, 1.2 eq.) and K ₃ PO ₄ (0.376 g, 1.770 mmol, 2 eq.) in 1,4-dioxane (10 ml) were degassed with argon within 30 min. Trans-N,N'-dimethylcyclohexane-1,2-diamine (0.032 g, 0.354 mmol, 0.4 eq.) and CuI (0.033 g, 0.177 mmol, 0.2 eq.) were then added and the reaction mixture was stirred for 72 hours at 90°C in a sealed tube. After completion of the reaction (TLC monitoring, TLC system, 5% MeOH in DCM, Rf-0.4), the reaction mixture was filtered through a pad of celite and washed 2-3 times with dioxane. The combined organic layer was concentrated to give the crude product, which was purified by column chromatography (silica gel 230-400 mesh; 0 to 2% MeOH in DCM) to give 2,2-difluoro-N-(trans-1-(1-( 4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-oxo-2-phenylpyrrolidin3-yl)propanamide (0.046 g, 11%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.49 (d, J= 8.84 Hz, 1H), 8.32 (s, 1H), 7.78-7.73 (m, 3H), 7.49-7.30 (m, 9H), 4.53-4.49 (m, 1H), 3.00-2.93 (m, 1H), 2.47-2.42 (m, 1H ), 1.78 (t, J= 19.52 Hz, 3H), 1.44 (s, 3H).

Example 101 n-(trans-1-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-oxo-2-phenylpyrrolidin-3yl)cyclopropanecarboxamide.

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Step 1: To a stirred solution of trans-4-amino-5-methyl-5-phenylpyrrolidin-2-one (350 mg, 1.84 mmol, 1 eq.) in DMF (10 ml) TEA (1.2 ml, 9 .14 mmol, 5.0 eq.), cyclopropanecarbonyl chloride (288 mg, 2.76 mmol, 1.5 eq.) was added under ice cooling and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC , TLC system 5% MeOH in DCM, R _r 0.3) the reaction mixture was diluted with EtOAc (50 ml) and washed with ice water (3x25 ml), dried over Na ₂ SO ₄ and concentrated to give the crude product, which was purified using a column chromatography (silica gel 230-400 mesh; 0 to 2% MeOH-DCM) to give N-(trans-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (350 mg, 74%).

Step 2: Stirred solution of N-(trans-2-methyl-5-oxo-2-phenylπpyrrolidin-3yl)cyclopropanecarboxamide (0.250 g, 0.967 mmol, 1 eq.), 1-(4-fluorophenyl)-5-iodo-1H -indazole (0.393 g, 1.16 mmol, 1.2 eq.), K ₃ PO ₄ (0.410 g, 1.93 mmol, 2 eq.) in 1,4-dioxane (10 ml) was degassed with argon for 30 min. N,N'-dimethylethylenediamine (0.034 g, 0.387 mmol, 0.4 eq.) and CuI (0.037 g, 0.193 mmol, 0.2 eq.) were added and the reaction mixture was stirred for 72 hours at 90°C in a sealed tube . After completion of the reaction (TLC monitoring, TLC system, 5% MeOH in DCM, Rf-0.4), the reaction mixture was filtered through a pad of celite and washed 2-3 times with dioxane. The combined organic layer was concentrated to give the crude product, which was purified by column chromatography (silica gel 230-400 mesh; 0 to 2% MeOH in DCM) to give N(trans-1-(1-(4-fluorophenyl)-1H -indazol-5-yl)-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (0.046 g, 10%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.81 (d, J= 8.88 Hz, 1H), 8.35 (s, 1H), 7.79-7.74 (m, 3H) , 7.52 (s, 1H), 7.48-7.32 (m, 8H), 4.50-4.45 (m, 1H), 2.912.85 (m, 1H), 2.30- 2.26 (m, 1H), 1.66-1.63 (m, 1H), 1.44 (s, 3H), 0.69 (d, J= 6.2 Hz, 4H).

Example 121 yl)cyclopropanecarboxamide.

Stage-1. Synthesis of methyl 3-cyclopropyl-2-(nitromethyl)propanoate. To a stirred solution of methyl 3-nitropropanoate (15 g, 112.74 mmol) in THF (105 ml) was added LDA (2M in THF, 112.7 ml, 225.5 mmol) at -78°C, and the resulting solution was stirred in for 1 hour at the same temperature. (Bromomethyl)cyclopropane (21.28 ml, 225.5 mmol) was added at -78°C. The reaction mixture was allowed to gradually reach room temperature and stirring was continued for 16 hours. The reaction mixture was quenched with aqueous NH ₄ Cl at 0°C. The layers were separated and the aqueous portion was extracted with ethyl acetate (600 ml x3). The combined organic layers were washed with brine (300 ml), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (using 100-200 mesh silica gel, 6-8% ethyl acetate-hexanes as eluant) to give 3-cyclopropyl-2-(nitromethyl)propanoate as a brown oil.

Stage-2. Synthesis of rac-(3S,4S,5R)-3-(cyclononylmethyl)-1-(4-methoxybenzyl)-4-nitro-5-phenylpyrrolidin-2-one. To a stirred solution of benzaldehyde (6.07 mL, 60.09 mmol) in toluene (112.5 mL) was added 4-methoxybenzylamine (8.24 g, 60.09 mmol) at room temperature and stirred for 2 hours. methyl 3-cyclopropyl-2-(nitromethyl)propanoate (7.5 g, 40.06 mmol) was added to the mixture, followed by benzoic acid (7.34 g, 60.09 mmol), and the resulting mixture was stirred for 7-8 hours at 70°C. After completion of the reaction (under LCMS monitoring), the mixture was diluted with ethyl acetate (300 ml) and washed with water (200 ml) and then with saturated NaHCO ₃ (100 ml x2). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (using 100-200 mesh silica gel; 12-15% ethyl acetate in hexane as eluent) to give 4 rac-(3S, 4S, 5R)-3-(cyclopropylmethyl)-1-(4-methoxybenzyl )-4-nitro-5-phenylpyrrolidin2-one (7.5 g, 49.1%) as a brown oil.

Stage-3. rac-(3S,4S,5R)-3-(Cyclopropylmethyl)-4-niΊro-5-phenylpyrrolidin-2-one. To a stirred solution of rac-(3S,4S,5R)-3-(cyclopropylmethyl)-1-(4-methoxybenzyl)-4-nitro-5-phenylpyrrolidin-2-one (6 g, 15.77 mmol) in acetonitrile (120 ml), a solution of CAN (25.93 g, 47.31 mmol) in water (120 ml) was added dropwise at 0°C. The reaction mixture was slowly heated to 10-15°C and stirring was continued for 3-4 hours. After completion of the reaction (TLC control, 30% ethyl acetate/hexane, Rf 0.3), the mixture was diluted with ethyl acetate (400 ml) and washed with water (200 ml) and then brine (200 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude material was purified by column chromatography (using 100-200 mesh silica gel; 25-30% ethyl acetate in hexane as eluent) to give rac-(3S,4S,5R)-3-(cyclopropylmethyl)-4-nitro-5-phenylpyrrolidine -2-one (3.51 g, 85.6%) as a colorless oil.

Stage-4. rac-(3S,4S,5R)-4-Amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-one. To a stirred solution of rac-(3S,4S,5R)-3-(cyclopropylmethyl)-4-nitro-5-phenylpyrrolidin-2-one (4 g, 15.36 mmol) in ethyl acetate-methanol (360 ml, 2:1 ) added 6 N aq. HCl (118 ml) at 0°C. Zinc dust (60.29 g, 922.04 mmol) was added in portions at the same temperature. The resulting suspension was stirred at room temperature for 16 hours. Once the reaction was complete (monitored by LCMS), it was quenched with saturated NaHCO ₃ solution at 0°C, stirred for 1 hour, filtered through celite and washed with ethyl acetate-methanol (500 ml, 2:1). The filtrate was concentrated to give rac-(3S,4S,5R)-4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-one (3.53 g crude, considered 100% yield) as a crude solid. white, which was used in the next step without further purification.

Stage-5. Synthesis of tert-butyl (rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3yl)carbamate. To a stirred suspension of rac-(3S, 4S, 5R)-4-amino-3-(cyclopropylmethyl)-5phenylpyrrolidin-2-one (3.53 g crude, 15.34 mmol) in THF-water (1:1, 400 ml) sodium bicarbonate (3.86 g, 46.04 mmol) was added at 0° C. and the resulting mixture was stirred for 30 minutes at the same temperature. Di-tert-butyl dicarbonate (10.6 mL, 46.04 mmol) was added to the reaction mixture at 0° C., and stirring was continued for 16 hours at room temperature. After completion of the reaction (under LCMS monitoring), the mixture was diluted with water (200 ml) and extracted with ethyl acetate (3 x 300 ml). The combined organic layers were washed with water (300 ml) and then brine (300 ml). After drying over Na2SO4 and concentration, the crude material was purified by column chromatography (using 100-200 mesh silica gel; 1.5-2% MeOH in DCM as eluent) to give (rac-(2R,3S,4S)-4-(cyclopropylmethyl )-5-oxo-2-phenylpyrrolidin-3-yl)carbamate (3.52 g, 69.5%) as an off-white solid.

Stage-6. Synthesis of rac-(3S,4S,5R)-4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2one hydrochloride. To a stirred suspension of (rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3yl)carbamate (2 g, 6.05 mmol) in 1,4-dioxane (10 ml) 4 N HCl in 1,4-dioxane was added at 0°C and stirring was continued at room temperature for 16 hours. After completion of the reaction (under LCMS control), the mixture was concentrated and triturated with ether to obtain rac(3S,4S,5R) hydrochloride -4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-one (1.62 g, crude) as an off-white solid.

Stage-7. Synthesis of N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide. Et ₃ N (2.54 mL, 18 .21 mmol) at 0°C, and the resulting mixture was stirred at the same temperature for 20 minutes. A solution of cyclopropanecarbonyl chloride (0.56 ml, 6.06 mmol) in DCM (5 ml) was added and stirring was continued at 0-10°C for 3 hours. After complete consumption of the starting material (monitored by LCMS), the reaction mixture was diluted with H2O, the resulting precipitate was filtered off and washed with cold water and then with pentane ether to give N-(rac-(2R,3S,4S)-4(cyclopropylmethyl)-5- oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (1.41 g, 78%) as an off-white solid.

Step 8. C-N-coupling was carried out similarly to the procedure described for example 7 Step 1, using N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide . Yield 53%. 1H NMR (DMSO-d6) δ: 8.59 (d, 1H), 8.29 (s, 1H), 7.79 (d, 1H), 7.77-7.70 (m, 2H), 7 .68 (d, 1H), 7.51 (dd, 1H), 7.43-7.36 (m, 2H), 7.32 (d, 2H), 7.25 (t, 2H), 7. 19-7.13 (m, 1H), 5.21 (d, 1H), 4.33 (q, 1H), 2.83 (dt, 1H), 1.67 1.59 (m, 2H), 1.57 (ddd, 1H), 0.90 (ddt, 1H), 0.73-0.60 (m, 4H), 0.50-0.32 (m, 2H), 0.18-0, 01 (m, 2H).

Example 127 ; and example 130: N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazole- 48 044347

5-yl)-5-oxo-4-phenethyl-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide, diastereomer 1.

In a dried vessel, intermediate C1-ent 1 (150 mg, 0.33 mmol) was dissolved in dry THF (3.3 ml) under an inert atmosphere. The solution was cooled to -78°C and a solution of freshly prepared LDA (1M in THF, 0.825 mL, 2.5 eq.) was added dropwise. After stirring for 15 min at -78°C, (2-iodoethyl)benzene (99.6 mg, 0.429 mmol, 1.3 eq.) dissolved in dry THF (1.7 ml) was added dropwise. The mixture was left to warm to -20°C overnight and cooled again to -60°C before adding (2-iodoethyl)benzene (99.6 mg, 0.429 mmol, 1.3 eq) and LDA (1M in THF, 0.682 ml. 2.0 eq.). After stirring for 90 min at -60°C, a third amount of (2-iodoethyl)benzene (99.6 mg, 0.429 mmol, 1.3 eq.) followed by LDA (1M in THF, 0.34 mL, 1 ,0 eq.). The mixture was again stirred overnight at -20°C and quenched with a saturated solution of NH ₄ Cl at this temperature before the mixture was diluted with ethyl acetate. The crude material was purified by flash chromatography (silica, cyclohexane/ethyl acetate gradient eluent) followed by preparative HPLC (water/acetonitrile gradient) to give Example 127 (N-((2R,3S)-1-(1-( 4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4phenethyl-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide, second eluting diastereomer, 6 mg, 0.011 mmol, 3%) and example 130 (N-( (2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2phenylpyrrolidin-3-yl)cyclopropanecarboxamide, first eluting diastereomer, 12.0 mg , 0.021 mmol, 6%) as a white solid. Example 127: ^1H NMR (DMSO- _d6 ) δ: 8.94 (d, 1H), 8.35-8.28 (m, 1H), 8.01 (d, 1H), 7.83 (dd , 1H), 7.80-7.63 (m, 3H), 7.44-7.23 (m, 9H), 7.26-7.16 (m, 1H), 7.19-7.13 (m, 2H), 7.15-7.03 (m, 1H), 5.26 (d, 1H), 4.52 (ddd, 1H), 2.93 (tdd, 1H), 2.65- 2.52 (m, 2H), 1.85-1.68 (m, 2H), 1.24 (s, 1H), 1.18 (s, 1H), 0.90-0.69 (m, 3H).

Example 128: ^1H NMR (DMSO- _d6 ) δ: 8.66 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 1.3 Hz, 1H), 7.79 ( d, J = 1.9 Hz, 1H), 7.74 (ddd, 2H), 7.68 (d, 1H), 7.54 7.48 (m, 1H), 7.43 7.36 (m , 2H), 7.36 7.28 (m, 4H), 7.26 (t, 2H), 7.23 7.14 (m, 4H), 5.21 (d, 1H), 4.22 ( td, 1H), 2.76 (t, 2H), 2.70 (td, 1H), 2.18 2.06 (m, 2H), 1.88 (dq, 1H), 1.58 (tt, 1H), 0.77 0.62 (m, 4H).

Examples 128 3-yl)cyclopropanecarboxamide and Example 129 N-((2R,3R,4S)-4-fluoro-1-(1-(4fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2 -phenylpyrrolidin-3-yl)cyclopropanecarboxamide.

Step 1: In a 250 mL round bottom flask, a solution of intermediate A8 (2370 mg, 7.31 mmol) in acetonitrile (120 mL) was added to sodium iodide (6570 mg, 43.8 mmol, 6 eq.) under nitrogen. Trimethylsilyl chloride (3.71 mL, 29.2 mmol, 4.0 eq.) was added dropwise to the resulting mixture. After stirring overnight at room temperature, the reaction mixture was added dropwise to ethanol (142 ml) and filtered through celite. The filtrate was loaded into a strong cation exchanger cartridge (SCX, 5 g), washed twice with ethanol (15 ml each) and eluted with 2 M NH3 in methanol (2x10 ml). This procedure was repeated with product containing fractions twice. The pure fractions were combined and the solvent was removed in vacuo to give rac-(3S,4S,5R)-4-amino-3-methyl-5phenylpyrrolidin-2-one (296 mg, 1.56 mmol, 21%) as a colorless gum .

Stage-2. rac-(3S,4S,5R)-4-Amino-3-methyl-5-phenylpyrrolidin-2-one (328 mg, 1.72 mmol) and cyclo

- 49 044347 propanecarboxylic acid (297 mg, 3.45 mmol, 2.0 eq.) was dissolved in dichloromethane (17.2 ml) at room temperature. Triethylamine (689 mg, 6.90 mmol, 4.0 eq) was added dropwise to the mixture and stirred until all starting materials were dissolved. A solution of propylphosphonic anhydride (>50 wt% in ethyl acetate, 2.57 mL, 4.31 mmol, 2.5 eq) was added to the reaction mixture and stirring was continued at room temperature. After 3 hours, reaction control (UPLC) showed complete consumption of the starting materials, and the reaction was quenched with 1 M Na ₂ CO ₃ solution. After stirring for one hour, the product precipitated and was filtered to give N-(rac-(2R,3S,4S)-4-methyl-5-oxo-2phenylpyrrolidin-3-yl)cyclopropanecarboxamide (264 mg, 1.02 mmol , 59%) as a white solid. The resulting material was used at the next stage without additional purification.

Step 3. To a suspension of N-(rac-(2R,3S,4S)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (263 mg, 1.02 mmol), triethylamine (206 mg, 2.04 mmol, 2.0 eq.) and 4-dimethylaminopyridine (12.4 mg, 0.102 mmol, 0.1 eq.) in acetonitrile (10 ml), a solution of di-tert-butyl dicarbonate (244 mg, 1.12 mmol) was added , 1.1 eq.) in acetonitrile (2 ml) in a sealed tube. The reaction mixture was heated to 80°C for 30 min and stirred overnight at room temperature. Additional di-tert-butyl dicarbonate (133 mg, 0.611 mmol, 0.6 eq) in acetonitrile (2 mL) was added and stirring was continued at room temperature until reaction monitoring (UPLC) confirmed completion of the reaction (2 h). . Dichloromethane and saturated NaHCO ₃ solution were added to the reaction mixture, the layers were separated, and the aqueous layer was extracted once with dichloromethane. The combined organic layers were dried over magnesium sulfate and the solvent was removed in vacuo. The crude material was purified by flash chromatography (12 g silica, cyclohexane/ethyl acetate gradient eluent) and tert-butyl rac-(3S,4S,5R)-4-(cyclopropanecarbonylamino)-3methyl-2-oxo-5- Phenylpyrrolidine-1-carboxylate (234 mg, 0.653 mmol, 64%) was obtained as a white solid.

Stage-4. In a dried vessel, tert-butyl rac-(3S,4S,5R)-4-(cyclopropanαcarbonylamino)-3-methyl-2oxo-5-phenylpyrrolidine-1-carboxylate (80 mg, 0.223 mmol) was dissolved in dry THF (2.2 ml) in an inert atmosphere. The solution was cooled to -78°C and a solution of lithium bis(trimethylsilyl)amide (1M in THF, 0.446 mL, 0.446 mmol, 2.0 eq.) was carefully added. After stirring for 15 min at -78 °C, a solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (70.4 mg, 0.223 mmol, 1.0 eq) in THF (1 ml) was added dropwise. After stirring for 45 min at this temperature, another amount of Nfluoro-N-(phenylsulfonyl)benzenesulfonamide (35.0 mg, 0.111 mmol, 0.5 eq.) in THF (0.5 ml) was added and stirring was continued for 30 min. . The reaction was quenched at -78°C using us. NH ₄ Cl solution diluted with DCM and quickly poured onto the hydrophobic frit before the mixture can heat up. The organic layer was washed with water and separated again. The crude product was purified by flash chromatography (12 g silica, cyclohexane/ethyl acetate gradient eluent) to give tert-butyl (4R,5R)-4-(cyclopropanecarboxamido)-3-fluoro-3-methyl-2-oxo-5 -phenylpyrrolidine-1carboxylate (47 mg, 0.125 mmol, 56%) as a mixture of epimers (3:1).

Step 5. To a solution of tert-butyl(4R,5R)-4-(cyclopropanecarboxamido)-3-fluoro-3-methyl-2-oxo-5phenylpyrrolidine-1-carboxylate (46.0 mg, 0.122 mmol) in dichloromethane (1 .22 mL), trifluoroacetic acid (0.094 mL, 1.22 mmol, 10.0 eq.) was added at room temperature. After stirring for 30 min, reaction control (UPLC) confirmed completion of the reaction and the mixture was quenched using us. NaHCO ₃ solution. DCM was added to the mixture and the layers were separated using a hydrophobic frit. Evaporation of the organic layer gave N-((2R,3R)-4-fluoro-4-methyl-5-oxo-2-phenylpyrrolidin-3yl)cyclopropanecarboxamide (27 mg, 0.098 mmol, 80%) as a brown oil, which was used without additional cleaning.

Step 6. In a sealed tube, N-((2R,3R)-4-fluoro-4-methyl-5-oxo-2-phenylpyrrolidin-3yl)cyclopropanecarboxamide (27.0 mg, 0.098 mmol), 1-(4-fluorophenyl )-5-iodindazole (36.3 mg, 0.107 mmol, 1.1 eq), K3PO4 (41.5 mg, 0.195 mmol, 2.0 eq) and CuI (3.7 mg, 0.020 mmol, 0. 2 eq.) was dissolved in degassed 1,4-dioxane (1 ml). (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (5.6 mg, 0.039 mmol, 0.4 eq.) was added to the mixture and the reaction mixture was heated to 100°C overnight and to 120 °C for 5 hours. The reaction was quenched with sat. NaHCO ₃ solution and diluted with dichloromethane. The layers were separated using a hydrophobic frit, and the aqueous layer was washed repeatedly with DCM. The organic layers were combined and the solvent was evaporated. The crude material was purified by flash chromatography (silica, cyclohexane/ethyl acetate gradient eluent) followed by preparative HPLC (water/acetonitrile gradient) to give Example 128 N-((2R,3R,4R)-4-fluoro-1 -(1-(4fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (1.8 mg, 0.003 mmol, 4%) and example 129 N -((2R,3R,4S)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide ( 5.8 mg, 0.012 mmol, 12%).

Example 128: 1H NMR (DMSO-d6) δ: 8.11 (d, 1H), 7.78 (dd, 1H), 7.67-7.59 (m, 2H), 7.56 (dt, 1H ), 7.48 (dd, 1H), 7.39-7.19 (m, 6H), 7.26-7.16 (m, 1H), 6.29-6.20 (m, 1H), 5.15 (d, 1H), 4.66 (ddd, 1H), 1.69 (d, 3H), 1.47 (tt, 1H), 1.01 (dddd, 1H), 0.95-0 .90 (m, 1H),0.82 (m, 2H).

Example 129: 1H NMR (DMSO-d6) δ: 8.69 (dd, 1H), 8.33 (d, 1H), 7.87 (d, 1H), 7.82-7.67 (m, 3H ), 7.51

- 50 044347 (dd, 1H), 7.45-7.30 (m, 4H), 7.26 (t, 2H), 7.22-7.13 (m, 1H), 5.12 (dd, 1H), 4.68 (ddd, 1H), 1.66 (tt, 1H), 1.54 (d,

3H), 0.77-0.65 (m, 3H), 0.58 (dtd, 1H).

Example 131 2phenylpyrrolidin-3-yl)cyclopropanecarboxamide and Example 132 N-((2R,3S,4R)-4-(2,2-difluoroethyl)-1-(1(4-fluorophenyl)-1H-indazol-5-yl)- 5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide.

In a dried vessel, intermediate C1-ent 1 (150 mg, 0.33 mmol) was dissolved in dry THF (3.3 ml) under an inert atmosphere. The solution was cooled to -78°C and a solution of freshly prepared LDA (1M in THF, 0.825 mL, 2.5 eq.) was added dropwise. After stirring for 15 min at -78°C, 1,1-difluoro-2-iodoethane (82.4 mg, 0.429 mmol, 1.3 eq.) dissolved in dry THF (1.7 ml) was added dropwise. The mixture was heated to -40°C and stirred overnight at this temperature. Another amount of 1,1-difluoro-2-iodoethane (82.4 mg, 0.429 mmol, 1.3 eq) was added and the mixture was heated to -20°C. At this temperature they added us. NH ₄ Cl solution and stirring was continued before diluting the mixture with ethyl acetate. After layer separation, the organic layers were dried over sodium sulfate and the solvent was removed in vacuo. The crude material was purified by flash chromatography (12 g silica, cyclohexane/ethyl acetate gradient eluent) to give Example 131 N((2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1 -(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3yl)cyclopropanecarboxamide (9.0 mg, 0.017 mmol, 5%) and example 132 N-((2R,3S, 4R)-4-(2,2-difluoroethyl)1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (7.0 mg , 0.014 mmol, 4%) as a white solid.

Example 131: 1H NMR (DMSO- _d6 ) δ: 8.30 (d, J = 1.0 Hz, 1H), 7.85-7.64 (m, 3H), 7.68 (d, 1H) , 7.56-7.21 (m, 6H), 7.36-7.07 (m, 3H), 5.24 (d, 1H), 4.25 (q, 1H), 2.97 (q , 1H), 2.54-2.34 (m, 1H), 1.25 (s, 2H), 0.81-0.52 (m, 3H).

Example 132: 1H NMR (DMSO- _d6 ) δ: 8.95 (d, 1H), 8.33 (s, 1H), 8.02 (d, 1H), 7.85 (dd, J=9, 2, 2.1 Hz, 1H), 7.87-7.67 (m, 3H), 7.51-7.19 (m, 7H), 5.28 (s, 1H), 4.42 (t , 1H), 3.22-3.02 (m, 1H), 2.25-2.02 (m, 1H), 1.24 (s, 2H), 0.96-0.63 (m, 4H ).

Example 134 2phenylpyrrolidin-3-yl)cyclopropanecarboxamide.

1>“ρ“ Πρ“Φ·134

Step 1: In a dried vessel, Example 46 (50 mg, 0.107 mmol) was dissolved in dry THF (1.1 ml) under an inert atmosphere. The solution was cooled to -78°C and a solution of freshly prepared LDA (1M in THF, 0.267 mL, 2.5 eq.) was added dropwise. After stirring for 15 min at -78°C, iodoethane (25.0 mg, 0.160 mmol, 1.5 eq.) dissolved in dry THF (0.5 ml) was added dropwise. The mixture was heated to -60°C and stirred for 90 minutes at this temperature. The reaction mixture was then cooled again to -78°C before adding more iodoethane (12.5 mg, 0.080 mmol, 0.75 eq.) dissolved in dry THF (0.5 ml). After stirring for 1 hour at -78°C, the reaction was quenched with saturated NH ₄ Cl solution and diluted with dichloromethane after stirring for 5 minutes. The layers were separated using a hydrophobic frit. The organic layer was washed with water, separated again and dried over sodium sulfate. After removal of the solvent, the crude material was purified by flash chromatography (silica, cyclohexane/ethyl acetate gradient eluent) followed by preparative HPLC (water/acetonitrile gradient) to give Example 134 N-(rac(2R,3S,4R)-4 -ethyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3yl)cyclopropanecarboxamide (6 mg, 0.012 mmol, 11%) as colorless resin.

1H NMR (DMSO- _d6 ) δ 8.47 (d, 1H), 8.30 (d, 1H), 7.77-7.71 (m, 3H), 7.68 (d, 1H), 7 .46 (dd, 1H), 7.39 (dd, 2H), 7.36-7.33 (m, 2H), 7.24 (t, 2H), 7.15 (td, 1H), 5, 15 (d, 1H), 4.33 (t, 1H), 1.72-1.63 (m, 2H), 1.54 (dq, 1H), 1.24 (s, 3H), 0.95 (d, 2H), 0.73-0.67 (m, 1H), 0.63 (qt, 2H), 0.59-0.50 (m, 1H).

Example 135 -8yl)cyclopropanecarboxamide.

- 51 044347

In a dried vessel, intermediate C1-ent 1 (150 mg, 0.33 mmol) was dissolved in dry THF (3.3 ml) under an inert atmosphere. The solution was cooled to -78°C and a solution of freshly prepared LDA (1M in THF, 0.825 mL, 2.5 eq.) was added dropwise. After stirring for 15 min at -78°C, 1,3-dibromopropane (93.3 mg, 0.462 mmol, 1.3 eq.) dissolved in dry THF (1.7 ml) was added dropwise. The mixture was warmed to room temperature overnight. The mixture was again cooled to -20°C before adding additional amounts of LDA (1M in THF, 0.330 ml, 1.0 eq.) and 1,3-dibromopropane (71.8 mg, 0.355 mmol, 1.0 eq.). After stirring for 15 min, another amount of LDA (1M in THF, 0.495 mL, 1.5 eq.) was added. The mixture was allowed to return to room temperature overnight and quenched under saturation. NH ₄ Cl solution. Stirring was continued for 5 minutes, after which the mixture was diluted with ethyl acetate. After layer separation, the organic layers were dried over sodium sulfate and the solvent was removed in vacuo. The crude material was purified by flash chromatography (12 g silica, cyclohexane/ethyl acetate gradient eluent) to give Example 135 N((7R,8S)-6-(1-(4-fluorophenyl)-III-indazole-5 -yl)-5-oxo-7-phenyl-6-azaspiro[3,4]octan-8-yl)cyclopropanecarboxamide (11 mg, 0.022 mmol, 7%) as a colorless resin. 1H NMR (DMSO- _d6 ) δ: 8.09 (d, 1H), 7.99 (dd, 1H), 7.81 (dd, 1H), 7.63 (ddd, 2H), 7.56 ( dt, 1H), 7.43-7.39 (m, 2H), 7.35-7.30 (m, 3H), 7.28-7.24 (m, 1H), 7.24-7, 20 (m, 2H), 6.03 (d, 1H).

Example 137 3-yl)cyclopropanecarboxamide.

Step 1: In a dried vessel, Example 106 (70 mg, 0.141 mmol) was dissolved in dry THF (1.4 ml) under an inert atmosphere. The solution was cooled to -78°C and a solution of freshly prepared LDA (1M in THF, 0.352 mL, 2.5 eq.) was added dropwise. After stirring for 15 min at -78°C, N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (NFSI, 66.7 mg, 0.211 mmol, 1.5 eq.) dissolved in dry THF (0.7 ml). The mixture was stirred for 15 minutes at -78°C and quenched with a saturated solution of NH ₄ Cl. After stirring for 5 minutes, the mixture was diluted with ethyl acetate and the layers were separated. After removal of the solvent, the crude material was purified by flash chromatography (silica, cyclohexane/ethyl acetate gradient eluent) to give Example 137 N-(rac(2R,3R,4S)-4-benzyl-2-ethyl-4-fluoro -1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3yl)cyclopropanecarboxamide (4 mg, 0.008 mmol, 6%) as a colorless oil. 1H NMR (Chloroform-d ₃ ) δ: 8.19 (d, 1H), 7.67 (dd, 3H), 7.57 (d, 1H), 7.39-7.34 (m, 3H ), 7.32 (dd, 2H), 7.28-7.25 (m, 2H), 7.22 (dd, 1H), 6.01 (t, 1H), 4.97-4.86 ( m, 1H), 3.51-3.42 (m, 1H), 3.34 (dd, 1H), 3.17-3.08 (m, 1H), 1.54 (qd, 2H), 1 .42 (tt, 1H), 1.15 -1.09 (m, 1H), 1.10-1.05 (m, 1H), 0.94-0.88 (m, 1H), 0.85 (dddd, 1H), 0.75 (t, 3H).

Example 138 -5 yl)methyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide.

Example 138

Example 138 was prepared similarly to the synthesis described for Example 131 using 5(bromomethyl)-3-methyl-1,2,4-oxadiazole instead of 1,1-difluoro-2-iodoethane. Yield: 9%. 1H NMR (DMSO- _d6 ) δ: 8.55 (d, 1H), 8.29 (d, 1H), 7.77-7.70 (m, 3H), 7.70-7.64 (m , 1H), 7.47-7.36 (m, 5H), 7.24 (t, 2H), 7.17-7.10 (m, 1H), 5.27 (d, 1H), 4, 41 (q, 1H), 3.46 -3.36 (m, 1H), 2.35 (s, 3H), 1.50 (tt, 1H), 0.71-0.50 (m, 4H) .

Example 139a. N-((2R,3S,4S)-1 -(1 -(4-Fluorophenyl)-1 H-indazol-5 -yl)-4-(( 1 -methyl-1 H-pyrazol-4- 52 044347 yl )methyl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide and Example 139b N-((2R,3S,4R)-1-(1(4-fluorophenyl)-1 H-indazol-5-yl) -4-(( 1 -methyl-1 H-pyrazol-4-yl)methyl)-5-oxo-2-phenylpyrrolidin-3 yl)cyclopropanecarboxamide.

Examples 139a and 139b were prepared similarly to the synthesis described for Examples 131 and 132 using 5.0 eq. LDA and 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide instead of 1,1-difluoro-2iodoethane. Yields: 7% (139a) and 6% (139b). Example 139a 1H NMR (Chloroform-d ₃ ) δ: 8.06 (d, 1H), 7.68 (d, 1H), 7.61-7.54 (m, 2H), 7.51-7.43 (m, 2H), 7.37 (dd, 1H), 7.29 (d, 1H), 7.25-7.13 (m, 5H), 7.07-7.00 (m, 2H), 6.13 (d, 1H), 5.13 (d, 1H), 4.23 (dt, 1H), 3.87 (s, 3H), 3.08-2.98 (m, 3H), 1 .38 (tt, 1H), 1.05-0.93 (m, 2H), 0.79 (ddddd, 2H).

Example 139b: 1H NMR (Chloroform-da) δ: 8.07 (d, 1H), 7.95 (d, 1H), 7.69 (dd, 1H), 7.64-7.58 (m, 2H ), 7.51 (d, 1H), 7.42-7.33 (m, 5H), 7.32-7.27 (m, 1H), 7.26 (s, 1H), 7.25 - 7.19 (m, 2H), 6.58 (d, 1H), 5.17 (s, 1H), 4.58 (t, 1H), 3.84 (s, 3H), 3.21-3 .11 (m, 2H), 2.92 -2.83 (m, 1H), 1.50 (tt, 1H), 1.16-1.07 (m, 2H), 0.94-0.81 (m, 2H).

Example 148 methyl5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide.

Step 1: In a dried vessel, Example 46 (71 mg, 0.152 mmol) was dissolved in dry THF (1.5 ml) under an inert atmosphere. The solution was cooled to -78°C and a solution of freshly prepared LDA (1M in THF, 0.379 mL, 2.5 eq.) was added dropwise. After stirring for 15 min at -78°C, 1,1-difluoro-2-iodoethane (43.6 mg, 0.160 mmol, 1.5 eq.) dissolved in dry THF (0.75 ml) was added dropwise. The mixture was heated to -50°C and stirred for 45 minutes at this temperature. Another amount of 1,1-difluoro-2-iodoethane (11.4 mg, 0.110 mmol, 0.75 eq) dissolved in dry THF (0.5 ml) was then added. After stirring for 1 hour at -78°C, the reaction was quenched with a saturated solution of NH ₄ Cl and diluted with dichloromethane after stirring for 5 minutes. The layers were separated using a hydrophobic frit. The organic layer was washed with water, separated again and dried over sodium sulfate. After removal of the solvent, the crude material was purified by preparative HPLC (water/acetonitrile gradient) to give Example 148 N-(rac-(2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4 -fluorophenyl)-1Hindazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide 3.0 mg 0.0056 mmol, 3.7%) as a colorless resin. 1H NMR (Chloroform-da) δ: 8.07 (d, 1H), 7.63 (d, 1H), 7.60-7.56 (m, 2H), 7.50 (dt, 1H), 7 .32 (dd, 1H), 7.29-7.25 (m, 4H), 7.23-7.18 (m, 3H), 6.43 (tdd, 1H), 5.91 (dd, 1H ), 4.92 (d, 1H), 4.78 (t, 1H), 2.50-2.39 (m, 1H), 2.39-2.27 (m, 1H), 1.43- 1.37 (m, 1H), 1.36 (s, 3H), 0.97 (dddd, 1H), 0.86 (dddd, 1H), 0.83-0.77 (m, 1H), 0 .74 (dddd, 1H).

Example 149 2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide.

Example 121 Example 149

Step 1: In a dried vessel, Example 121 (150 mg, 0.295 mmol) was dissolved in dry THF (3 ml) under an inert atmosphere. The solution was cooled to -78°C and a solution of freshly prepared LDA (1M in THF, 0.737 mL, 2.5 eq.) was added dropwise. After stirring for 15 minutes at -78°C, iodomethane (62.8 mg, 0.442 mmol, 1.5 eq.) was added dropwise. The mixture was stirred at this temperature for 45 minutes. Another amount of iodomethane (42 mg, 0.110 mmol, 1 eq.) was then added. After stirring for 1 hour at -78°C, the reaction was quenched with a saturated solution of NH ₄ Cl and diluted with dichloromethane after stirring for 5 minutes. The layers were separated using a hydrophobic frit. The organic layer was washed with water, separated again and dried over sodium sulfate. After removal of the solvent, the crude material was purified by preparative HPLC (water/acetonitrile gradient) to give Example 149N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H -indazol-5yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (14.0 mg, 0.0268 mmol, 9%) as a colorless resin. 1H NMR (DMSO- _d6 ) δ: 8.44 (d, 1H), 8.30 (d, 1H), 7.79-7.70 (m, 3H), 7.68 (d, 1H), 7.47 (dd, 1H), 7.43-7.33 (m, 4H), 7.23 (t, 2H), 7.15 (td, 1H), 5.23 (d, 1H), 4 .34 (t, 1H), 1.85 (dd, 1H), 1.69 (ddd, 1H), 1.30 (s, 3H), 1.13 (dd, 1H), 1.05 (tt, 1H), 0.71 (tdd, 1H), 0.68-0.58 (m, 2h), 0.55 (tdt, 1H), 0.45-0.36 (m, 2H), 0.08 -0.05 (m, 2H).

Example 150 pyrrolidin-3-yl)cyclopropanecarboxamide.

Example 150

Step 1: In a dried vessel, intermediate C1-ent 1 (150 mg, 0.295 mmol) was dissolved in dry THF (4.7 ml) under an inert atmosphere. The solution was cooled to -78°C and a solution of freshly prepared LDA (1M in THF, 1.32 mL, 4 eq.) was added dropwise. After stirring for 15 minutes at -78°C, 2-(chloromethyl)-1,3-thiazole hydrochloride (67 mg, 0.396 mmol, 1.2 eq.) was added as a solid. The mixture was kept for one hour at -40°C. Another amount of LDA (1M in THF, 0.165 mL, 1 eq) was then added, followed by 2-(chloromethyl)-1,3-thiazole hydrochloride (28.1 mg, 0.165 mmol, 0.5 eq). After stirring overnight at -40°C, the reaction was quenched with saturated NH ₄ Cl solution and diluted with dichloromethane after stirring for 5 minutes. The layers were separated using a hydrophobic frit. The organic layer was washed with water, separated again and dried over sodium sulfate. After removal of the solvent, the crude material was purified by preparative HPLC (water/acetonitrile gradient) to give Example 150. N-((2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl )-5oxo-2-phenyl-4-(thiazol-2-ylmethyl)pyrrolidin-3-yl)cyclopropanecarboxamide (26.3 mg, 0.0477 mmol 14%) as an off-white solid. 1H NMR (600 MHz, Chloroform- _d3 ) δ: 9.22 (d, 1H), 8.06 (d, 1H), 7.77 (d, 1H), 7.72 (d, 1H), 7 .65-7.58 (m, 2H), 7.53-7.46 (m, 2H), 7.45-7.40 (m, 2H), 7.37-7.31 (m, 3H) , 7.31-7.26 (m, 1H), 7.24-7.18 (m, 2H), 5.09 (d, 1H), 4.72 (td, 1H), 3.71 (dd , 1H), 3.58 (td, 1H), 3.44 (dd, 1H), 1.56 (tt, 1H), 1.09-1.02 (m, 2H), 0.85-0, 78 (m, 2H).

Example 151 3-yl)cyclopropanecarboxamide.

Step 1: To a stirred solution of 1-(5-chlorothiophen-2-yl)ethan-1-one (20 g, 125 mmol, 1.0 eq.) in

EtOAc (250 ml) at room temperature, add NaOAc (50.6 g, 625 mmol, 5.0 eq.) and NH2OH.HCl (25.7 g, 375 mmol, 3.0 eq.) and stir for 16 h at 80°C. The progress of the reaction was monitored using TLC. The reaction mixture was evaporated, diluted with H2O and the resulting precipitate was washed with H2O (100 ml) and dried in vacuum to give (E)-1-(5-chlorothiophen-2-yl)ethan-1-one oxime (20 g, 94%) in in the form of a brown liquid.

Step 2: To a stirred solution of compound (E)-1-(5-chlorothiophen-2-yl)ethan-1-one oxime (10 g, 57.14 mmol, 1.0 eq.) in DCM (100 ml) at -40°C, TEA (9.2 ml, 68.57 mmol, 1.2 eq.) was added and

- 54 044347 the mixture was stirred for 15 minutes before adding chlorodiphenylphosphine (13.8 g, 62.85 mmol, 1.1 eq.). The reaction mixture was allowed to warm slowly to room temperature and stirred for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with H ₂ O (100 ml) and extracted with DCM (2 x 200 ml). The combined organic layer was washed with brine (100 ml), dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash chromatography (silica 40-60% EtOAc in petroleum ether as eluent) to give (E)-N-(1-(5chlorothiophen-2-yl)ethylidene)-P,P-diphenylphosphine amide ( 15 g, 73%) as a brown solid.

Step 3: To a stirred solution of compound (E)-N-(1-(5-chlorothiophen-2-yl)ethylidene)-P,Pdiphenylphosphine amide (15 g, 41.71 mmol, 1.0 eq.) in THF ( 200 ml) at room temperature under a nitrogen atmosphere, Cu(OAc) ₂ (0.377 g, 2.85 mmol, 0.05 eq.), TPP (1.0 g, 4.16 mmol, 0.1 eq.) was added. The mixture was stirred for 15 min before diethyl fumarate (18 mL, 104 mmol, 2.5 eq.) and pinacolborane (14.8 mL, 116 mmol, 2.8 eq.) were added. Stirring was continued for 16 hours at room temperature. The progress of the reaction was monitored using TLC. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with brine (100 ml), dried (Na2SO4) and evaporated. The crude compound was purified by flash chromatography (silica 40-60% EtOAc in petroleum ether as eluent) to give the compound ethyl 2-(5chlorothiophen-2-yl)-1-(diphenylphosphoryl)-2-methyl-5-oxopyrrolidine-3 -carboxylate (15 g, ~75%) as a white solid.

Step 4: To a stirred solution of the compound ethyl 2-(5-chlorothiophen-2-yl)-1(diphenylphosphoryl)-2-methyl-5-oxopyrrolidine-3-carboxylate (15 g, 30.80 mmol, 1.0 eq. ) in EtOAc (150 ml) at room temperature was added conc. HCl (15 ml) and stirred for 16 hours at 90°C. The progress of the reaction was monitored by TLC. The reaction mixture was evaporated, diluted with water (50 ml), made basic with saturated NaHCO ₃ (pH = 8) and extracted with EtOAc (2 x 200 ml). The combined organic layers were washed with brine (100 ml), dried (Na ₂ SO ₄ ) and evaporated. The crude compound was purified by flash chromatography (silica 60-70% EtOAc in petroleum ether as eluent) to give ethyl rac-(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5 -oxopyrrolidine 3-carboxylate (7.0 g, ~81%) as a white solid.

Step 5: To a stirred solution of ethyl (2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl5-oxopyrrolidine-3-carboxylate (7 g, 24.39 mmol, 1.0 eq.) LiOH*H ₂ O (1.7 g, 48.78 mmol, 2.0 eq.) was added to THF/MeOH/H ₂ O (1:1:1, 75 ml) at room temperature and stirring was continued at the same temperature. The progress of the reaction was monitored by TLC. The reaction mixture was evaporated, diluted with water (30 ml) and extracted with Et ₂ O (2x50 ml). The aqueous layer was acidified with 1 N HCl (pH=4-5), and the resulting precipitate was filtered and dried to obtain the compound (2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidine-3 -carboxylic acid (3.5 g, ~97%) as a white solid.

Step 6: To a stirred solution of the compound rac-(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5oxopyrrolidine-3-carboxylic acid (3.4 g, 13.12 mmol, 1. 0 eq) in toluene (70 ml) at room temperature, add TEA (2.0 ml, 13.78 mmol, 1.05 eq), DPPA (3.4 ml, 15.74 mmol, 1.2 eq) . Stirring was continued for 2 hours at 90°C, then the mixture was cooled to room temperature before adding BnOH (3 ml, 26.25 mmol, 2.0 eq.). The resulting mixture was heated for 16 hours to 120°C. The progress of the reaction was monitored using TLC. The reaction mixture was evaporated, diluted with water (50 ml) and extracted with EtOAc (2x100 ml). The combined organic layers were washed with brine (50 ml), dried (Na2SO4) and evaporated. The crude compound was purified by flash chromatography (silica 70-90% EtOAc in petroleum ether as eluent) to give benzyl(rac(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5 -oxopyrrolidin-3-yl)carbamate (2.0 g, ~41%) as an off-white solid.

Step 7: Stirred solution of benzyl(rac-(2S,3S)-2-(5-chlorothiophen-2-yl)-2methyl-5-oxopyrrolidin-3-yl)carbamate (2.0 g, 5.49 mmol, 1.0 eq.) in HBr in AcOH (20 ml) at RT, stirred for 2 hours at RT. The progress of the reaction was monitored using TLC. The reaction mixture was quenched with NaHCO ₃ solution and extracted with EtOAc (4x 100 ml). The combined organic layers were washed with brine (50 ml), dried (Na ₂ SO ₄ ) and evaporated. The crude compound was purified by flash chromatography (silica 70-80% EtOAc in petroleum ether as eluent) to give the compound rac-(4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-5-methylpyrrolidin- 2-one (1.0 g, ~41%) as an off-white solid.

Step 8: To a stirred solution of the compound rac-(4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-5methylpyrrolidin-2-one (400 mg, 1.739 mmol, 1.0 eq.) and cyclopropanecarboxylic acid (224 mg, 2.608 mmol, 1.5 eq.) in DMF (10 ml) at 0°C under nitrogen, add HATU (0.90 g, 2.608 mmol, 1.5 eq.), DIPEA (0 .9 ml, 5.217 mmol, 3.0 eq.) and stirred for 16 hours at room temperature. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (20 ml), dried

- 55 044347 (Na ₂ SO ₄ ) and evaporated. The crude compound was purified by flash chromatography (silica 7090% EtOAc in petroleum ether as eluent) to give N-(rac(2S,3S)-2-(5chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidin- 3-yl)cyclopropanecarboxamide (210 mg, ~40%).

Step 9. To a stirred solution of the compound N-(rac(2S,3S)-2-(5-chlorotuophene-2-ul)-2-methyl-5oxopyrrolidin-3-yl)cyclopropanecarboxamide (200 mg, 0.671 mmol, 1.0 eq.) and compound 1-(4fluorophenyl)-5-iodo-1H-indazole (249 mg, 0.738 mmol, 1.5 eq.) in dioxane (10 ml) under a nitrogen atmosphere was added CuI (127 mg, 0.671 mmol, 1 .5 eq.), DMEDA (59 mg, 0.671 mmol, 1 eq.) and K2CO3 (277 mg, 2.013 mmol, 3.0 eq.) and stirred at 130°C for 16 hours. The progress of the reaction was monitored using TLC. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (2x20 ml). The combined organic layers were washed with brine (20 ml), dried (Na ₂ SO ₄ ) and evaporated. The crude compound was purified by flash chromatography (silica 70-90% EtOAc in petroleum ether as eluent) followed by preparative HPLC to give Example 151 N-((2S,3S)-2-(5-chlorothiophen-2-yl)- 1-(1-(4fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide (50 mg, -53%).

^1H NMR (500 MHz, DMSO- _d6 ): δ 8.77 (d, 1H), 8.39 (s, 1H), 7.80-7.76 (m, 3H), 7.58 (d , 1H), 7.63 (s, 1H), 7.44-7.40 (m, 2H), 7.22 (dd, 1H), 7.01 (d, 1H), 6.93 (d, 1H), 4.71-4.67 (m, 1H), 3.10 (dd, 1H), 2.43-2.36 (m, 1H), 1.64-1.61 (m, 1H) , 1.48 (s, 3H), 0.72-0.6 (m, 4H).

The examples in the following table were synthesized similarly to example 1 described above using various intermediates.

Note No. Intermediate connection (INT) Structure Exit (%) II NMR 4 Intermediate, conn. AZ CO'V'A 0 0 F 12 *H NMR (DMSO-0): δ= 9.08 (d, 1H), 8.31 (s, 1H), 7.72-7.69 (m, 4H), 7.41-7.34 ( m, 5H), 7.24(s, 2H), 7.17(m, 1H), 5.41 (d, 1H), 4.26 (t, 1H), 1.71 (t, 3H), 1.27(s, 3H), 1.13(s, 3H). 9 Intermediate, conn. AZ O I % 1— o NW 1 ^N FF -0 O O 10 *H NMR (DMSO-d ₆ ): δ= 9.07 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 7.68-7.58 (m, 3H ), 7.34-7.17 (m, 6H), 6.51 (s, 1H), 5.39 (s, 1H), 4.25 (s, 1H), 3.48 (s, 3H) , 1.71 (t, 3H), 1.27 (s, 3H), 1.13 (s, 3H) 10 Intermediate, conn. AZ 0^0 '' F 13 % NMR (DMSO4): δ= 9.08 (d, 1H), 8.31 (s, 1H), 7.72-7.69 (m, 4H), 7.41-7.34 (m, 5H ), 7.24(s, 2H), 7.17(m, 1H), 5.41 (d, 1H), 4.26 (t, 1H), 1.71 (t, 3H), 1.27 (s, 3H), 1.13 (s, 3H).

The examples in the following table were synthesized similarly to example 5 described above using various intermediates.

Approx. No. Intermediate connection (INT) Structure Exit (%) II NMR 3 Intermediate, conn. A5 OU. 10*·o Ο^γ^ <0 ό F 10 *H NMR (DMSO-0) δ: 8.90 (d, 1H), 8.30 (t, 1H), 7.93 (dd, 1H), 7.79 - 7.69 (m, 4H), 7.43 - 7.37 (m, 4H), 7.34 (t, 2H), 7.28 - 7.21 (m, 1H), 5.29 (d, 1H), 4.03 (dd, 1H), 1.68 (tt, 1H), 1.31 - 0.91 (m, 4H), 0.80 - 0.62 (m, 4H) thirty Intermediate, conn. A5 1 s SkX iz 4 *H NMR (DMSO4) δ: 8.89 (d, 1H), 8.25 (d, 1H), 8.18 (d, 1H), 7.92 (dd, 1H), 7.71 (ddd, 2H), 7.61 (dt, 1H), 7.41 - 7.36 (m, 2H), 7.33 (t, 2H), 7.27 - 7.21 (m, 1H), 6.54 (dd, 1H), 5.28 (d, 1H), 4.03 (dd, 1H), 3.50 (s, 3H), 1.72 - 1.64 (m, 1H), 1.26 - 1.15 (m, 1H), 1.16 - 1.08 (m, 1H), 0.95 (q, 2H), 0.74 (ddd, 1H), 0.73 - 0.68 (m, 3H)

The examples in the following table were synthesized similarly to example 7 described above using various intermediates.

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Approx. No. Intermediate connection (INT) Structure Exit (%) II NMR 6 Intermediate, conn. A 4 ent 1 1 ΖΖ \=о ^z =\ Y 31 'n NMR (DMSO-<7) δ: 9.11 (d, 1H), 8.26 (d, 1H), 8.17 (d, 1H), 7.78 (t, 1H), 7.72 - 7.67 (m, 2H), 7.59 (d, 1H), 7.40 (d, 1H), 7.39 - 7.35 (m, 2H), 7.22 (t, 2H), 7.17 - 7.11 (m, 1H), 6.54 (d, 1H), 5.63 (d, 1H), 4.46 (t, 1H), 3.50 (s, 3H), 2 .52 (s, 3H), 1.32 (s, 3H), 1.18 (s, 3H) 12 Intermediate, conn. A 4 ent 1 1 3 ζζ \=ο ο ^χ ζ' 1 80 *H NMR (DMSO-Y) δ: 8.39 (d, 1H), 8.25 (d, 1H), 8.17 (d, 1H), 7.78 (d, 1H), 7.72 - 7.68 (m, 2H), 7.59 (d, 1H), 7.40 (dd, 1H), 7.38 - 7.35 (m, 2H), 7.21 (t, 2H), 7 .15 - 7.10 (m, 1H), 6.57 (d, 1H), 6.54 (d, 1H), 5.59 (d, 1H), 4.50 (t, 1H), 3, 96 (s, 3H), 3.50 (s, 3H), 1.30 (s, 3H), 1.17 (s, 3H) 13 Intermediate, conn. A 4 ent 1 1 Υ ---- ζ ΙΖ 2=0 ο 85 *H NMR (DMSOO _d ) δ: 8.96 (dd, 1H), 8.60 (s, 1H), 8.26 (d, 1H), 8.18 (d, 1H), 7.83 (s , 1H), 7.73 (d, 1H), 7.70 (dd, 1H), 7.62 - 7.57 (m, 1H), 7.41 (dd, 1H), 7.39 - 7, 36 (m, 2H), 7.23 (t, 2H), 7.18 - 7.12 (m, 1H), 6.54 (d, 1H), 5.41 (d, 1H), 4.48 (t, 1H), 3.50 (s, 3H), 1.31 (s, 3H), 1.18 (s, 3H) 14 Intermediate, conn. A 4 ent 1 1 ο ^ζ Υ ζζ \=ο ri ^ο ^ζ 64 *H NMR (DMSO-Y) δ: 9.38 (d, 1H), 8.26 (d, 1H), 8.18 (d, 1H), 7.72 - 7.67 (m, 2H), 7.62 - 7.57 (m, 1H), 7.41 7.37 (m, 3H), 7.24 (t, 2H), 7.18 - 7.13 (m, 1H), 6.54 (d, 1H), 5.55 (d, 1H), 4.50 (t, 1H), 3.50 (s, 3H), 2.69 (s, 3H), 1.33 (s, 3H) , 1.18 (s, 3H) 15 Intermediate, conn. A 4 ent 1 1 7 ^! .---- ζ ΙΖ \=ο 70 *H NMR (DMSO-Y) δ: 9.25 (d, 1H), 8.95 (dd, 1H), 8.60 (s, 1H), 8.26 (d, 1H), 8.18 ( d, 1H), 7.75 (dd, 1H), 7.74 - 7.67 (m, 1H), 7.60 (dd, 1H), 7.46 7.41 (m, 1H), 7, 39 (dd, 2H), 7.24 (t, 2H), 7.18 - 7.12 (m, 1H), 6.54 (d, 1H), 5.36 (d, 1H), 4.51 - 4.45 (m, 1H), 3.50 (d, 3H), 1.32 (s, 3H), 1.20 (s, 3H) 16 Intermediate, conn. A 4 ent 1 0 60 *H NMR (DMSO4) δ: 9.08 (s, 1H), 8.61 (dd, 1H), 8.25 (d, 1H), 8.18 (d, 1H), 7.73 (d, 1H), 7.70 (dd, 1H), 7.59 (d, 1H), 7.42 (dd, 1H), 7.40 - 7.37 (m, 2H), 7.25 (t, 2H ), 7.20 - 7.14 (m, 1H), 6.54 (d, 1H), 5.37 (d, 1H), 4.47 (t, 1H), 3.50 (s, 3H) , 2.51 (s, 3H), 1.34 (s, 3H), 1.18 (s, 3H) 17 Intermediate, conn. A 4 ent 1 ω A Up to 7 _g ^X 'z' ^x ^o 1 87 *H NMR (DMSO-Y) δ: 9.25 (d, 1H), 8.79 (d, 1H), 8.30 (d, 1H), 8.26 (d, 1H), 8.17 ( d, 1H), 7.72 - 7.68 (m, 2H), 7.61 - 7.57 (m, 1H), 7.41 (dd, 1H), 7.39 - 7.36 (m, 2H), 7.21 (t, 2H), 7.15 - 7.10 (m, 1H), 6.54 (d, 1H), 5.64 (d, 1H), 4.53 (t, 1H ), 3.50 (s, 3H), 1.33 (s, 3H), 1.19 (s, 3H)

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18 Intermediate, conn. A 4 ent 1 -00¾ 0 73 *H NMR (DMSO-0) δ: 9.08 (s, 1H), 8.61 (dd, 1H), 8.25 (d, 1H), 8.18 (d, 1H), 7.73 ( d, 1H), 7.70 (dd, 1H), 7.61 - 7.57 (m, 1H), 7.42 (dd, 1H), 7.40 7.36 (m, 2H), 7, 25 (t, 2H), 7.20 - 7.14 (m, 1H), 6.54 (d, 1H), 5.37 (d, 1H), 4.47 (t, 1H), 3.50 (s, 3H), 2.51 (s, 3H), 1.34 (s, 3H), 1.18 (s, 3H) 21 Intermediate, conn. A 4 ent 2 0 O o 77 *H NMR (DMSO-0) δ: 8.95 (dd, 1H), 8.60 (s, 1H), 8.26 (d, 1H), 8.17 (d, 1H), 7.83 ( s, 1H), 7.74 - 7.72 (m, 1H), 7.70 (dd, 1H), 7.62 - 7.57 (m, 1H), 7.41 (dd, 1H), 7 .39 - 7.36 (m, 2H), 7.23 (t, 2H), 7.17 - 7.12 (m, 1H), 6.54 (d, 1H), 5.41 (d, 1H ), 4.48 (t, 1H), 3.50 (s, 3H), 1.31 (s, 3H), 1.18 (s, 3H) 22 Intermediate, conn. A 4 ent 2 1 O.....0 IZ s=° Η 80 *H NMR (DMSO-0) δ: 9.08 (d, 1H), 8.25 (d, 1H), 8.17 (d, 1H), 7.72 - 7.67 (m, 2H), 7.59 (d, 1H), 7.42 - 7.35 (m, 3H), 7.23 (t, 2H), 7.18-7.12 (m, 1H), 6.53 (d, 1H), 6.50 (t, 1H), 5.50 (d, 1H), 4.47 (t, 1H), 3.50 (s, 3H), 2.47 (d, 3H), 1, 32 (s, 3H), 1.17 (s, 3H) 24 Intermediate, conn. A 4 ent 2 0 0 o' 78 *H NMR (DMSO-0) δ: 9.25 (d, 1H), 8.95 (dd, 1H), 8.60 (s, 1H), 8.26 (d, 1H), 8.18 ( d, 1H), 7.76 - 7.73 (m, 1H), 7.70 (dd, 1H), 7.62 - 7.57 (m, 1H), 7.43 (dd, 1H), 7 .41 - 7.37 (m, 2H), 7.24 (t, 2H), 7.18 - 7.12 (m, 1H), 6.54 (d, 1H), 5.36 (d, 1H ), 4.48 (t, 1H), 3.50 (s, 3H), 1.32 (s, 3H), 1.20 (s, 3H) 26 Intermediate, conn. A 4 ent 2 -0 o 63 *H NMR (DMSO-0) δ: 9.10 (d, 1H), 8.26 (d, 1H), 8.17 (d, 1H), 7.80 - 7.75 (m, 1H), 7.72 - 7.67 (m, 2H), 7.61 7.56 (m, 1H), 7.41 - 7.35 (m, 3H), 7.22 (t, 2H), 7.17 - 7.11 (m, 1H), 6.53 (d, 1H), 5.62 (d, 1H), 4.45 (t, 1H), 3.50 (s, 3H), 2.53 - 2.51 (m, 3H), 1.32 (s, 3H), 1.18 (s, 3H) 36a Intermediate, conn. A7 ent 1 0 0 ' F 86 *H NMR (DMSO-0) δ: 8.97 (d, 1H), 8.60 (s, 1H), 8.31 (d, 1H), 7.83 (s, 1H), 7.76 - 7.72 (m, 3H), 7.70 (dd, 1H), 7.46 (dd, 1H), 7.43 - 7.35 (m, 4H), 7.23 (dd, 2H), 7 .17 - 7.12 (m, 1H), 5.42 (d, 1H), 4.49 (t, 1H), 1.31 (s, 3H), 1.18 (d, 3H)

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36b Intermediate, conn. A7 ent 2 V4-° 0 O F 40 'n NMR (DVISO-O) δ: 8.97 (d, 1H), 8.60 (s, 1H), 8.31 (d, 1H), 7.83 (s, 1H), 7.76 - 7.72 (m, 3H), 7.70 (dd, 1H), 7.46 (dd, 1H), 7.43 - 7.35 (m, 4H), 7.23 (dd, 2H), 7 .17 - 7.12 (m, 1H), 5.42 (d, 1H), 4.49 (t, 1H), 1.31 (s, 3H), 1.18 (d, 3H) 37 Intermediate, conn. A7 ent 1 W s ^1st O 0 O F 71 *H NMR (DVISO-O) δ: 8.40 (d, 1H), 8.31 (d, 1H), 7.78 (d, 1H), 7.76 - 7.71 (m, 3H), 7.69 (dd, 1H), 7.44 (dd, 1H), 7.41 - 7.35 (m, 4H), 7.24 - 7.18 (m, 2H), 7.16 - 7, 10 (m, 1H), 6.58 (dd, 1H), 5.59 (dd, 1H), 4.51 (t, 1H), 3.96 (d, 3H), 1.31 (d, 3H ), 1.17 (s, 3H) 38a Intermediate, conn. A7 ent 2 h 0g'AA-\ 0 0 ^L F 44 *H NMR (DVISO-O) δ: 9.08 (s, 1H), 8.67 - 8.57 (m, 1H), 8.31 (d, 1H), 7.80 - 7.64 (m , 4H), 7.46 (dd, 1H), 7.42 7.35 (m, 4H), 7.25 (dd, 2H), 7.19 7.13 (m, 1H), 5.38 ( d, 1H), 4.47 (t, 1H), 2.51 (s, 3H), 1.34 (s, 3H), 1.18 (s, 3H) 38b Intermediate, conn. A7 ent 1 0 0 ^L F 92 *H NMR (DVISO-O) δ: 9.08 (s, 1H), 8.67 - 8.57 (m, 1H), 8.31 (d, 1H), 7.80 - 7.64 (m , 4H), 7.46 (dd, 1H), 7.42 7.35 (m, 4H), 7.25 (dd, 2H), 7.19 7.13 (m, 1H), 5.38 ( d, 1H), 4.47 (t, 1H), 2.51 (s, 3H), 1.34 (s, 3H), 1.18 (s, 3H) 39a Intermediate, conn. A7 ent 1 0 .----< z lm? ZZ \=о ω^ ^ζ 88 *H NMR (DVISO-O) δ: 9.08 (s, 1H), 8.63 - 8.58 (m, 1H), 8.31 (d, 1H), 7.78 - 7.72 (m , 3H), 7.70 (dd, 1H), 7.46 (dd, 1H), 7.43 - 7.36 (m, 4H), 7.25 (t, 2H), 7.17 (t, 1H), 5.38 (d, 1H), 4.47 (t, 1H), 2.52 (s, 3H), 1.34 (s, 3H), 1.18 (s, 3H) 39b Intermediate, conn. A7 ent 2 W χ 0 0 ^Λ F 51 *H NMR (DVISO-O) δ: 9.08 (s, 1H), 8.63 - 8.58 (m, 1H), 8.31 (d, 1H), 7.78 - 7.72 (m , 3H), 7.70 (dd, 1H), 7.46 (dd, 1H), 7.43 - 7.36 (m, 4H), 7.25 (t, 2H), 7.17 (t, 1H), 5.38 (d, 1H), 4.47 (t, 1H), 2.52 (s, 3H), 1.34 (s, 3H), 1.18 (s, 3H)

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40a Intermediate, conn. A7 ent 1 0 0^° IZ 2=0 GA z^ / O 98 *H NMR (DVISO-O) δ: 9.37 (d, W), 8.64 (d, 1H), 8.31 (d, 1H), 7.78 (dd, 1H), 7.77 - 7.71 (m, 2H), 7.70 (dd, 1H), 7.47 (dd, 1H), 7.43 - 7.35 (m, 4H), 7.24 (dd, 2H), 7 ,19-7.13 (m, 1H), 5.25 (d, 1H), 4.46 (t, 1H), 2.30 (s, 3H), 1.31 (s, 3H), 1, 18 (s, 3H) 40b Intermediate, conn. A7 ent 2 °h 1% 1—· o '„D Ύ g y T> 0 0 ^l F 62 *H NMR (DVISO-O) δ: 9.37 (d, 1H), 8.64 (d, 1H), 8.31 (d, 1H), 7.78 (dd, 1H), 7.77 - 7.71 (m, 2H), 7.70 (dd, 1H), 7.47 (dd, 1H), 7.43 - 7.35 (m, 4H), 7.24 (dd, 2H), 7 ,19 - 7.13 (m, 1H), 5.25 (d, 1H), 4.46 (t, 1H), 2.30 (s, 3H), 1.31 (s, 3H), 1, 18 (s, 3H) 41a Intermediate, conn. A7 ent 1 Hl x JY ⁿ L, ^N 0 0 'F 79 *H NMR (DVI SO-0) δ: 8.31 (d, 1H), 8.26 (d, 1H), 8.16 (s, 1H), 7.88 (d, 1H), 7.78 - 7.71 (m, 3H), 7.73 - 7.68 (m, 1H), 7.46 (dd, 1H), 7.43 - 7.33 (m, 4H), 7.22 (dd , 2H), 7.17 - 7.11 (m, 1H), 5.30 (d, 1H), 4.47 (t, 1H), 3.87 (s, 3H), 1.29 (s, 3H), 1.15 (s, 3H) 41b Intermediate, conn. A7 ent 2 oo ° 0 0 F 35 *H NMR (DMSO-0) δ: 8.31 (d, 1H), 8.26 (d, 1H), 8.16 (s, 1H), 7.88 (d, 1H), 7.78 - 7.71 (m, 3H), 7.73 - 7.68 (m, 1H), 7.46 (dd, 1H), 7.43 - 7.33 (m, 4H), 7.22 (dd, 2H), 7.17 - 7.11 (m, 1H), 5.30 (d, 1H), 4.47 (t, 1H), 3.87 (s, 3H), 1.29 (s, 3H ), 1.15 (s, 3H) 42a Intermediate, conn. A7 ent 1 ZI V Ta 89 *H NMR (DMSO-0) δ: 9.02 (d, 1H), 8.96 - 8.91 (m, 1H), 8.77 - 8.72 (m, 1H), 8.32 (d , 1H), 8.21 - 8.16 (m, 1H), 7.78 (d, 1H), 7.76 - 7.73 (m, 2H), 7.71 (d, 1H), 7, 55 (dd, 1H), 7.48 (dd, 1H), 7.43 - 7.36 (m, 4H), 7.27 - 7.21 (m, 2H), 7.18 - 7.12 ( m, 1H), 5.41 (d, 1H), 4.55 (t, 1H), 1.34 (s, 3H), 1.21 (s, 3H) 42b Intermediate, conn. A7 ent 2 A 0.....0 ΙΖ 27 *H NMR (DMSO-0) δ: 9.02 (d, 1H), 8.96 - 8.91 (m, 1H), 8.77 - 8.72 (m, 1H), 8.32 (d , 1H), 8.21 - 8.16 (m, 1H), 7.78 (d, 1H), 7.76 - 7.73 (m, 2H), 7.71 (d, 1H), 7, 55 (dd, 1H), 7.48 (dd, 1H), 7.43 - 7.36 (m, 4H), 7.27 - 7.21 (m, 2H), 7.18 - 7.12 ( m, 1H), 5.41 (d, 1H), 4.55 (t, 1H), 1.34 (s, 3H), 1.21 (s, 3H)

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43a Intermediate, conn. A7 ent 1 sgA ³ F 96 *H NMR (DMSO-%) δ: 9.23 (d, 1H), 9.00 (d, 2H), 8.31 (d, 1H), 7.76 (dd, 1H), 7.73 ( ddd, 3H), 7.70 (dd, 1H), 7.46 (dd, 1H), 7.43 - 7.36 (m, 4H), 7.22 (t, 2H), 7.16 - 7 .11 (m, 1H), 5.64 (d, 1H), 4.56 (dd, 1H), 1.35 (s, 3H), 1.22 (s, 3H) 43b Intermediate, conn. A7 ent 2 0 0 F 35 *H NMR (DMSO-%) δ: 9.23 (d, 1H), 9.00 (d, 2H), 8.31 (d, 1H), 7.76 (dd, 1H), 7.73 ( ddd, 3H), 7.70 (dd, 1H), 7.46 (dd, 1H), 7.43 - 7.36 (m, 4H), 7.22 (t, 2H), 7.16 - 7 .11 (m, 1H), 5.64 (d, 1H), 4.56 (dd, 1H), 1.35 (s, 3H), 1.22 (s, 3H) 44a Intermediate, conn. A7 ent 1 <ryV'-'N^vVm—-'LJ I ⁿ U 0 0 F 90 *H NMR (DMSO-%) δ: 8.81 (dd, 1H), 8.31 (s, 1H), 7.77 - 7.65 (m, 5H), 7.45 (dd, 1H), 7.43 - 7.35 (m, 4H), 7.23 (t, 2H), 7.18 - 7.12 (m, 1H), 5.41 (d, 1H), 4.48 (t, 1H), 2.51 (s, 3H), 1.30 (s, 3H), 1.17 (s, 3H) 44b Intermediate, conn. A7 ent 2 0 0 F 37 *H NMR (DMSO-%) δ: 8.81 (dd, 1H), 8.31 (s, 1H), 7.77 - 7.65 (m, 5H), 7.45 (dd, 1H), 7.43 - 7.35 (m, 4H), 7.23 (t, 2H), 7.18 - 7.12 (m, 1H), 5.41 (d, 1H), 4.48 (t, 1H), 2.51 (s, 3H), 1.30 (s, 3H), 1.17 (s, 3H) 45a Intermediate, conn. A7 ent 1 0 0 ^Λ F 89 *H NMR (DMSO-%) δ: 8.77 (d, 1H), 8.50 (s, 1H), 8.31 (t, 1H), 7.77 - 7.72 (m, 3H), 7.70 (dd, 1H), 7.44 (dd, 1H), 7.42 - 7.35 (m, 4H), 7.23 (t, 2H), 7.18 - 7.12 (m, 1H), 5.51 (d, 1H), 4.49 (t, 1H), 2.32 (s, 3H), 1.32 (s, 3H), 1.17 (s, 3H) 45b Intermediate, conn. A7 ent 2 °o ° \ 05.....o 0 ² XX 62 *H NMR (DMSO-%) δ: 8.77 (d, 1H), 8.50 (s, 1H), 8.31 (t, 1H), 7.77 - 7.72 (m, 3H), 7.70 (dd, 1H), 7.44 (dd, 1H), 7.42 - 7.35 (m, 4H), 7.23 (t, 2H), 7.18 - 7.12 (m, 1H), 5.51 (d, 1H), 4.49 (t, 1H), 2.32 (s, 3H), 1.32 (s, 3H), 1.17 (s, 3H)

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46 A9 F 26 *H NMR (DVISOA) δ: 8.57 (d, 1H), 8.29 (t, 1H), 7.78 (d, 1H), 7.77 - 7.71 (m, 2H), 7. 68 (d, 1H), 7.51 (dd, 1H), 7.39 (Id, 2H), 7.33 (d, 2H), 7.24 (t, 2H), 7.19 - 7.11 (m, 1H), 5.19 (d, 1H), 4.04 (Id, 1H), 2.78 - 2.70 (m, 1H), 1.57 (tt, 1H), 1.24 ( d, 3H), 0.74 - 0.58 (m, 4H). 47 A13-trans O _h ✓ ΥΥ o ^N .00V ^N -A'nA< T ^HFF 0 U F 43 *H NMR (DVISOA) δ: 9.21 (s, 1H), 8.33 (s, 1H), 7.73 (dt, 4H), 7.53 - 7.46 (m, 1H), 7. 45 - 7.32 (m, 3H), 7.27 7.15 (m, 2H), 5.85 (s, 1H), 4.16 (s, 1H), 2.96 (dd, 1H), 2.55 (d, OH), 1.73 (t, 3H), 1.28 (d, 3H) 60 A9 , W A J 0 0 F thirty *H NMR (DMSO-A) δ: 9.08 (s, 1H), 8.70 (d, 1H), 8.29 (d, 1H), 7.80 (dd, 1H), 7.76 - 7.72 (m, 2H), 7.68 (dt, 1H), 7.51 (dd, 1H), 7.43 - 7.34 (m, 4H), 7.28 - 7.22 (m, 2H), 7.20 - 7.14 (m, 1H), 5.33 (d, 1H), 4.27 (td, 1H), 2.89 (dq, 1H), 2.56 (s, 3H ), 1.31 (d, 3H) 63 All-trans Ok ✓ γγ ° 0 JU F 55 *H NMR (DVISOA) δ: 8.56 (d, 1H), 8.30 (d, 1H), 7.79 (dd, 1H), 7.77 - 7.71 (m, 2H), 7. 69 (dd, 1H), 7.56 - 7.48 (m, 1H), 7.43 - 7.36 (m, 2H), 7.17 - 7.07 (m, 3H), 6.97 ( ddt, 1H), 5.15 (d, 1H), 4.01 (td, 1H), 2.76 - 2.68 (m, 1H), 2.20 (s, 3H), 1.57 (tt , 1H), 1.23 (d, 3H), 0.74 0.58 (m, 4H) 64 A9 Q>Ya\y 0 ό F 28 *H NMR (DVISOA) δ: 8.60 (d, 1H), 8.29 (d, 1H), 7.78 (d, 1H), 7.77 - 7.70 (m, 3H), 7. 68 (dt, 1H), 7.46 (dd, 1H), 7.43 - 7.36 (m, 2H), 7.34 - 7.29 (m, 2H), 7.21 (dd, 2H) , 7.16 - 7.10 (m, 1H), 6.56 (d, 1H), 5.37 (d, 1H), 4.34 (td, 1H), 3.94 (s, 3H), 2.92 (dq, 1H), 1.26 (d, 3H) 65 A9 0^0 F 44 *H NMR (DVISOA) δ: 9.11 (d, 1H), 9.07 - 8.99 (m, 1H), 8.74 (dd, 1H), 8.30 (d, 1H), 8. 23 8.18 (m, 1H), 7.82 (dd, 1H), 7.78 - 7.71 (m, 2H), 7.70 (dt, 1H), 7.57 - 7.51 (m , 2H), 7.43 - 7.36 (m, 4H), 7.24 (dd, 2H), 7.19 - 7.13 (m, 1H), 5.38 (d, 1H), 4, 32 (td, 1H), 2.92 (dq, 1H), 1.32 (d, 3H)

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66 A9 0^0 F 35 *H NMR (DMSO4) δ: 9.45 (d, 1H), 9.00 (d, 2H), 8.30 (d, 1H), 7.78 - 7.69 (m, 4H), 7. 68 (dd, 1H), 7.48 (dd, 1H), 7.44 - 7.36 (m, 2H), 7.36 - 7.32 (m, 2H), 7.24 - 7.19 ( m, 2H), 7.17 - 7.11 (m, 1H), 5.44 (d, 1H), 4.40 (td, 1H), 3.02 - 2.94 (m, 1H), 1 .30 (d, 3H) 67 All-trans C>✓ VV o , :W00 A F 43 *H NMR (DMSO-X) δ: 9.08 (s, 1H), 8.70 (d, 1H), 8.30 (d, 1H), 7.80 (d, 1H), 7.77 - 7.71 (m, 2H), 7.69 (d, 1H), 7.51 (dd, 1H), 7.45 - 7.36 (m, 2H), 7.18 (d, 1H), 7 .17 - 7.10 (m, 2H), 6.98 (dt, 1H), 5.28 (d, 1H), 4.23 (td, 1H), 2.94 - 2.78 (m, 1H ), 2.57 (s, 3H), 2.20 (s, 3H), 1.31 (d, 3H) 68 All-trans ^0U0xF 54 *H NMR (DMSO4) δ: 9.10 (d, 1H), 9.04 (d, 1H), 8.74 (dd, 1H), 8.31 (d, 1H), 8.20 (dt, 1H), 7.82 (d, 1H), 7.78 7.72 (m, 2H), 7.71 (dd, 1H), 7.57 7.51 (m, 2H), 7.43 - 7 .36 (m, 2H), 7.21 (t, 1H), 7.19 - 7.10 (m, 2H), 6.97 (d, 1H), 5.33 (d, 1H), 4, 30 (td, 1H), 2.90 (dq, 1H), 2.19 (s, 3H), 1.32 (d, 3H) 69 All-trans 0 00° F 23 *H NMR (DMSO4) δ: 9.47 9.42 (m, 1H), 9.00 (d, 1H), 8.31 (s, 1H), 7.78 7.73 (m, 2H), 7.76 - 7.69 (m, 2H), 7.69 (d, 1H), 7.48 (dd, 1H), 7.43 - 7.36 (m, 2H), 7.18 - 7, 07 (m, 4H), 6.95 (d, 1H), 5.39 (d, 1H), 4.39 (td, 1H), 2.97 (dq, 1H), 2.17 (s, 3H ), 1.30 (d, 3H) 70 All-cis Ok g N__*' O 0 JUF 52 *H NMR (DMSO-X) δ: 8.76 (d, 1H), 8.32 (s, 1H), 7.96 (d, 1H), 7.80 (ddd, 1H), 7.79 - 7.71 (m, 3H), 7.44 - 7.37 (m, 2H), 7.22 (t, 1H), 7.18 (d, 1H), 7.14 - 7.09 (m, 1H), 7.07 (d, 1H), 5.15 (d, 1H), 4.35 (ddd, 1H), 3.04 (p, 1H), 2.27 (s, 3H), 1, 78 - 1.68 (m, 1H), 1.11 (d, 3H), 0.80 - 0.73 (m, 1H), 0.76 0.70 (m, 2H) 71 All-cis Ok <·' 0__ί Oh , 0 JJ F 49 *H NMR (DMSO-X) δ: 9.08 (s, OH), 9.01 (d, 1H), 8.32 (d, 1H), 7.94 (dd, 1H), 7.79 - 7.71 (m, 4H), 7.44 - 7.36 (m, 2H), 7.26 - 7.21 (m, 2H), 7.20 7.15 (m, 1H), 7.08 (ddt, 1H), 5.32 (d, 1H), 4.52 (td, 1H), 3.16 (p, 1H), 2.60 (s, 3H), 2.28 (d, 3H) , 2.08 (s, 1H), 1.16 (d, 3H)

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72 All-cis O _ch g Ν_ί 0 Ογύ'/χν 0 JU F 48 1H NMR (DMSO-d6) δ: 8.79 (d, 1H), 8.32 (s, 1H), 7.91 (dd, 1H), 7.81 - 7.67 (m, 6H), 7 .44 - 7.36 (m, 2H), 7.23 7.13 (m, 3H), 7.07 - 7.02 (m, 1H), 6.66 (d, 1H), 5.40 ( d, 1H), 4.57 (Id, 1H), 3.93 (s, 3H), 3.12 (p, 1H), 2.25 (s, 3H), 1.11 (d, 3H) 73 All-cis θκ g Ν__¢- Ο ^Ν '00\-' ^Ν χ/'Ν^^Ν Ν-χ^ Υ Η Η 1 0 JU F 45 1H NMR (DMSO-d6) δ: 9.28 (d, 1H), 9.09 (d, 1H), 8.74 (dd, 1H), 8.32 (t, 1H), 8.27 (dt , 1H), 7.98 (d, 1H), 7.80 (dd, 1H), 7.78 - 7.71 (m, 3H), 7.54 (ddd, 1H), 7.44 - 7, 37 (m, 2H), 7.27 7.21 (m, 2H), 7.21 - 7.16 (m, 1H), 7.08 (d, 1H), 5.37 (d, 1H), 4.62 (ddd, 1H), 3.19 (p, 1H), 2.28 (s, 3H), 1.17 (d, 3H) 74 All-cis C) <' ⁿ OtV ⁿ UnU% ν-\ / Y η 1 0 Ό F 49 1H NMR (DMSO-d6) δ: 9.53 (d, 1H), 9.00 (dd, 1H), 9.90 - 6.59 (m, OH), 8.32 (d, 1H), 7 .93 (dd, 1H), 7.79 - 7.69 (m, 6H), 7.44 - 7.36 (m, 2H), 7.25 7.16 (m, 3H), 7.06 ( dd, 1H), 5.45 (d, 1H), 4.62 (Id, 1H), 3.24 - 3.16 (m, 1H), 2.26 (s, 3H), 1.15 (d , 3H) 75 All-trans VY ⁰ 0 JU F 86 *H NMR (DMSO-</jδ: 8.59 (d, 1H), 8.30 (d, 1H), 7.78 (d, 1H), 7.78 - 7.71 (m, 3H) , 7.69 (dt, 1H), 7.46 (dd, 1H), 7.43 - 7.31 (m, 2H), 7.16 - 7.07 (m, 3H), 6.97 - 6 .92 (m, 1H), 6.57 (d, 1H), 5.33 (d, 1H), 4.32 (td, 1H), 3.94 (s, 3H), 2.90 (dq, 1H), 2.17 (s, 3H), 1.26 (d, 3H) 77 All-cis U ^ots w ZI J 54 *H NMR (DMSO-rf _d ) δ: 9.45 (d, 1H), 8.33 (d, 1H), 7.92 (t, 1H), 7.81 - 7.69 (m, 4H) , 7.47 - 7.35 (m, 2H), 7.29 7.16 (m, 2H), 7.16 - 7.10 (m, 1H), 7.10 - 7.03 (m, 1H ), 5.28 (d, 1H), 4.41 (td, 1H), 3.16 (p, 1H), 2.26 (s, 3H), 1.81 (t, 3H), 1.08 (d, 3H) 78 A13-cis o ZI X ^z ' χχ 41 1H NMR (DMSO-d6) δ: 8.82 (d, 1H), 8.36 (d, 1H), 7.97 (d, 1H), 7.82 - 7.73 (m, 4H), 7 .51 (dd, 1H), 7.44 - 7.38 (m, 2H), 7.38 - 7.26 (m, 4H), 5.50 (d, 1H), 4.49 (ddd, 1H ), 3.03 (p, 1H), 1.68 (tt, 1H), 1.05 (d, 3H), 0.77 - 0.67 (m, 4H)

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79 A13-cis С> g У,__О 40tv ⁿ v^''nA< / ^N ϊ Н FF 0 ”Ό F 54 *H NMR (DMSO-A) δ: 9.58 (d, 1H), 8.36 (d, 1H), 7.95 (dd, 1H), 7.83 - 7.69 (m, 4H), 7.52 (dt, 1H), 7.46 - 7.35 (m, 2H), 7.38 - 7.25 (m, 3H), 5.62 (d, 1H), 4.48 (t, 1H), 3.22 3.11 (m, 1H), 1.82 (t, 3H), 1.11 - 1.01 (m, 4H) 80 A9 ^N. JV ^N Un'U / ^Ν Ά^ I ^hf f 0 0 F 33 *H NMR (DMSO-A) δ: 9.17 (d, 1H), 8.29 (s, 1H), 7.79 - 7.70 (m, 3H), 7.68 (d, 1H), 7.47 (dd, 1H), 7.44 - 7.35 (m, 2H), 7.35 - 7.29 (m, 2H), 7.24 (t, 2H), 7.20 - 7, 12 (m, 1H), 5.27 (d, 1H), 4.12 (q, 1H), 2.87 (dq, 1H), 1.73 (t, 3H), 1.26 (d, 3H ) 81 All-trans O, ✓ Ai Τ ^h ff 0 JU F 62 *H NMR (DMSO-A) δ: 9.16 (d, 1H), 8.30 (d, 1H), 7.78 - 7.72 (m, 3H), 7.69 (d, 1H), 7.48 (dd, 1H), 7.44 - 7.35 (m, 2H), 7.15 - 7.08 (m, 3H), 6.98 (dt, 1H), 5.22 (d, 1H), 4.14 - 4.04 (m, 1H), 2.85 (dq, 1H), 2.20 (s, 3H), 1.73 (t, 3H), 1.26 (d, 3H ) 82 A15-trans O ₄ / yv ⁰ i 0 Q ^F °x 23 *H NMR (DMSO-A) δ: 9.07 (s, 1H), 8.65 (d, 1H), 8.30 (s, 1H), 7.79 - 7.71 (m, 3H), 7.68 (d, 1H), 7.48 (dd, 1H), 7.40 (t, 2H), 7.29 (d, 2H), 6.79 (d, 2H), 5.25 (d , 1H), 4.26 (td, 1H), 3.64 (s, 3H), 2.87 (dq, 1H), 2.57 (s, 3H), 1.31 (d, 3H) 83 A15-trans /=\ and n/U IZ Uo d z \ 18 *H NMR (DMSO-A) δ: 8.54 (d, 1H), 8.29 (d, 1H), 7.79 - 7.73 (m, 2H), 7.75 - 7.70 (m , 2H), 7.67 (dt, 1H), 7.43 (dd, 1H), 7.43 7.36 (m, 2H), 7.27 - 7.21 (m, 2H), 6.79 - 6.73 (m, 2H), 6.56 (d, 1H), 5.30 (d, 1H), 4.33 (td, 1H), 3.94 (s, 3H), 3.63 ( s, 3H), 2.90 (dq, 1H), 1.26 (d, 3H)

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84 A15-trans С> ✓ N_/ О Ν—Υ Н | I 0 o ^F thirty 'Η NMR (DMSO-ίή;) δ: 9.08 - 9.02 (m, 2H), 8.74 (dd, 1H), 8.31 (d, 1H), 8.20 (ddd, 1H) , 7.79 (dd, 1H), 7.78 - 7.72 (m, 2H), 7.69 (dt, 1H), 7.54 (ddd, 1H), 7.50 (dd, 1H), 7.43 - 7.36 (m, 2H), 7.33 - 7.28 (m, 2H), 6.81 - 6.76 (m, 2H), 5.30 (d, 1H), 4, 32 (tdd, 1H), 3.64 (s, 3H), 2.89 (dq, 1H), 1.32 (d, 3H) 85 A15-trans Z3 \=z ^o= \ZI Y5-<y° ^{x 7} O thirty *H NMR (DMSO-ίή;) δ: 9.39 (d, 1H), 8.99 (dd, 2H), 8.30 (d, 1H), 7.76 - 7.73 (m, 3H) , 7.71 (Id, 1H), 7.68 (dd, 1H), 7.44 (dd, 1H), 7.43 - 7.36 (m, 2H), 7.29 - 7.24 (m , 2H), 6.79 - 6.73 (m, 2H), 5.36 (d, 1H), 4.40 (Id, 1H), 3.63 (d, 3H), 2.97 (dq, 1H), 1.30 (d, 3H) 87 A13-cis Och O 0__¢- o n—\ 0 ϊ η Η 1 0 “Ό F 42 *H NMR (DMSO-ίή;) δ: 9.35 (d, 1H), 9.09 (dd, 1H), 8.75 (dd, 1H), 8.37 (s, 1H), 8.27 (dt, 1H), 8.00 (t, 1H), 7.83 7.74 (m, 4H), 7.58 - 7.50 (m, 2H), 7.44 - 7.37 (m, 2H), 7.33 (did, 3H), 5.71 (d, 1H), 4.77 - 4.71 (m, 1H), 3.19 (p, 1H), 1.12 (d, 3H ) 88 A13-cis 0 0 F 41 *H NMR (DMSO-ίή;) δ: 9.73 (d, 1H), 9.00 (d, 2H), 8.36 (d, 1H), 7.98 (d, 1H), 7.77 (tq, 4H), 7.71 (t, 1H), 7.53 7.47 (m, 1H), 7.44 - 7.34 (m, 3H), 7.34 - 7.28 (m, 2H), 5.80 (d, 1H), 4.72 (s, 1H), 3.24 - 3.16 (m, 1H), 1.12 (d, 3H) 89 A21 S/Ο. ✓ Ν_/ Ο ^Ν γ ' ^Ν ^00^ ^Ν ν-\ 0 Τ η 1 ϊ 0 ' F 41 *H NMR (DMSO-<4) δ: 8.89 (dd, 1H), 8.82 (d, 1H), 8.72 (dd, 1H), 8.40 (d, 1H), 8.08 (dt, 1H), 7.86 - 7.78 (m, 4H), 7.51 (ddd, 1H), 7.48 - 7.41 (m, 3H), 7.39 - 7.34 (m , 2H), 7.28 (t, 2H), 7.19 7.13 (m, 1H), 4.45 (td, 1H), 4.14 (td, 1H), 3.20 - 3.09 (m, 2H), 3.05 (dd, 1H), 1.47 (ddd, 1H), 1.24 (dp, 1H), 0.52 (t, 3H)

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90 A21 Q Οχ > ⁰ n-\ / Y n 1 0 ^J F 55 *H NMR (DMSOO δ: 9.26 (d, 1H), 8.98 (d, 2H), 8.40 (d, 1H), 7.85 - 7.79 (m, 3H), 7.76 (dd, 1H), 7.71 (t, 1H), 7.48 - 7.39 (m, 3H), 7.38 - 7.33 (m, 2H), 7.29 - 7.23 (m , 2H), 7.17 - 7.11 (m, 1H), 4.47 (Id, 1H), 4.20 (Id, 1H), 3.27 - 3.20 (m, 1H), 3, 09 (dd, 1H), 3.01 (dd, 1H), 1.41 (ddt, 1H), 1.26 1.15 (m,lH), 0.46(1, 3H) 92 A13-trans 0 F 73 *H NMR (DMSO4) δ: 9.16 (s, 1H), 9.01 (d, 1H), 8.74 (dd, 1H), 8.34 (s, 1H), 8.17 (dt, 1H), 7.78 (s, 1H), 7.77 7.71 (m, 3H), 7.58 - 7.50 (m, 2H), 7.46 (s, 1H), 7.43 - 7.36 (m, 2H), 7.32 (d, 1H), 7.23 (td, 1H), 7.18 (t, 1H), 5.93 (s, 1H), 4.36 (s , 1H), 3.01 (dq, 1H), 1.34 (d, 3H) 94 A13-cis Duu° IZ ^=° z' \ 12 *H NMR (DMSO-A δ: 8.99 (d, 1H), 8.36 (d, 1H), 7.98 - 7.95 (m, 1H), 7.81 - 7.72 (m, 3H), 7.48 (dt, 1H), 7.43 7.38 (m, 2H), 7.35 (dd, 1H), 7.30 (dd, 2H), 6.66 (d, 1H) , 5.77 (d, 1H), 4.67 (s, 1H), 3.93 (s, 2H), 3.13 (dd, 1H), 1.08 (d, 3H) 97 A15-cis A ^N . jV ⁿ An-V 0(0 ^F Οχ 60 1H NMR (DMSO-rf _d ) δ: 9.39 (d, 1H), 8.32 (d, 1H), 7.89 (d, 1H), 7.81 - 7.71 (m, 3H), 7.68 (dd, 1H), 7.45 - 7.35 (m, 2H), 7.32 - 7.23 (m, 2H), 6.92 - 6.83 (m, 2H), 5, 28 (d, 1H), 4.41 (td, 1H), 3.69 (s, 3H), 3.13 (p, 1H), 1.80 (t, 3H), 1.09 (d, 3H ) 98 A15-trans 0' /== /'“Crvk IZ l^ ⁰ 24 *H NMR (DMSO-U) δ: 9.11 (d, 1H), 8.29 (d, 1H), 7.78 - 7.70 (m, 3H), 7.68 (d, 1H), 7.48 - 7.35 (m, 3H), 7.29 7.20 (m, 2H), 6.83 - 6.74 (m, 2H), 5.19 (d, 1H), 4.11 (q, 1H), 3.65 (s, 3H), 2.84 (dq, 1H), 1.73 (t, 3H), 1.26 (d, 3H)

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108 A17-trans 0 F 27 *H NMR (DMSO-<4) δ: 8.56 (d, 1H), 8.34 (s, 1H), 7.81 (d, 1H), 7.78 (ddd, 2H), 7.73 (d, 1H), 7.48 (dd, 1H), 7.44 - 7.40 (m, 2H), 6.96 (d, 1H), 6.85 (dd, 1H), 5.38 ( d, 1H), 4.16 4.09 (m, 1H), 2.76 (dq, 1H), 1.58 (ddd, 1H), 1.24 (d, 3H), 0.75 - 0, 70 (m, 3H), 0.68 (Id, 1H) 109 A17-trans /CI F 33 *H NMR (DMSO-<4) δ: 9.47 (d, 1H), 9.01 (dd, 2H), 8.35 (d, 1H), 7.80 - 7.77 (m, 3H) , 7.75 (d, 1H), 7.73 (Id, 1H), 7.47 (dd, 1H), 7.45 - 7.39 (m, 2H), 6.98 (d, 1H), 6.83 (d, 1H), 5.63 (d, 1H), 4.48 (Id, 1H), 3.02 (dq, 1H), 1.29 (d, 3H) BY A17-trans A /~~(l IZ \=about fi Z 1 31 *H NMR (DMSO-<4) δ: 8.62 (d, 1H), 8.35 (d, 1H), 7.81 - 7.76 (m, 4H), 7.74 (dt, 1H) , 7.45 (dd, 1H), 7.45 - 7.39 (m, 2H), 6.96 (d, 1H), 6.82 (d, 1H), 6.61 (d, 1H), 5.56 (d, 1H), 4.42 (Id, 1H), 3.94 (s, 3H), 2.94 (dq, 1H), 1.25 (d, 3H) 111 A17-trans °N l / Cl F 36 *H NMR (DMSO-<4) δ: 9.11 (d, 1H), 9.06 (dd, 1H), 8.76 (dd, 1H), 8.36 (d, 1H), 8.22 (dt, 1H), 7.85 (d, 1H), 7.80 7.75 (m, 3H), 7.56 (dd, 1H), 7.52 (dd, 1H), 7.45 - 7 .39 (m, 2H), 7.02 (d, 1H), 6.85 (dd, 1H), 5.57 (d, 1H), 4.40 (td, 1H), 2.95 (dq, 1H), 1.32(d, 3H) 112 A13-trans C> ✓ νΎ ⁰ ν^νΛα ν—< J Υ Η V 0 UF 32 *H NMR (DMSO-<4) δ: 8.54 (d, 1H), 8.31 (s, 1H), 7.77 - 7.68 (m, 3H), 7.43 (s, 2H) , 7.42 - 7.35 (m, 2H), 7.33 (d, 1H), 7.19 (dt, 2H), 5.81 (s, OH), 4.04 (s, OH), 2.85 (p, 1H), 1.55 (p, 1H), 1.26 (d, 3H), 0.72 - 0.64 (m, 3H), 0.61 (s, 1H) 113 A17-trans Na/ 0^φ ^Η ^ / Cl F 28 *H NMR (DMSO-<4) δ: 9.09 (s, 1H), 8.70 (d, 1H), 8.35 (d, 1H), 7.84 (d, 1H), 7.80 - 7.76 (m, 2H), 7.75 (d, 1H), 7.50 (dd, 1H), 7.45 - 7.39 (m, 2H), 7.01 (d, 1H), 6.86 (d, 1H), 5.53 (d, 1H), 4.35 (q, 1H), 2.91 (dq, 1H), 2.60 (s, 3H), 1.31 (d , 3H)

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115 A19 F 51 *H NMR (DMSO4) δ: 8.55 (d, 1H), 8.32 (t, 1H), 7.80 - 7.73 (m, 3H), 7.70 (dd, 1H), 7. 48 - 7.44 (m, 2H), 7.44 7.40 (m, 2H), 6.15 (d, 1H), 5.17 (d, 1H), 4.21 (td, 1H), 3.68 (s, 3H), 2.71 2.63 (m, 1H), 1.56 (ddd, 1H), 1.26 (d, 3H), 0.72 - 0.65 (m, 4H ) 116 A19 A/ 0ΆF 35 *H NMR (DMSO-A) δ: 9.07 (s, 1H), 8.67 (d, 1H), 8.33 (d, 1H), 7.80 - 7.73 (m, 3H), 7.71 (dt, 1H), 7.50 - 7.45 (m, 2H), 7.45 - 7.38 (m, 2H), 6.19 (d, 1H), 5.30 (d, 1H), 4.43 (td, 1H), 3.68 (s, 3H), 2.82 (dq, 1H), 2.59 (s, 3H), 1.33 (d, 3H) 117 A19 \ z o ZI z 41 *H NMR (DMSO4) δ: 8.54 (d, 1H), 8.32 (d, 1H), 7.80 - 7.74 (m, 3H), 7.73 - 7.68 (m, 2H ), 7.47 - 7.42 (m, 1H), 7.44 - 7.38 (m, 3H), 6.59 (dd, 1H), 6.20 (d, 1H), 5.35 ( d, 1H), 4.52 (td, 1H), 3.93 (d, 3H), 3.65 (d, 3H), 2.85 (dq, 1H), 1.27 (d, 3H) 118 A19 ^ν .'^τλ- ^| Ο·.. _ν Α^ν 0^/ A F 29 *H NMR (DMSO-A) δ: 9.10 (d, 1H), 9.04 (dd, 1H), 8.74 (dd, 1H), 8.33 (d, 1H), 8.21 ( dt, 1H), 7.81 - 7.74 (m, 3H), 7.74 - 7.69 (m, 1H), 7.57 - 7.52 (m, 1H), 7.52 - 7, 46 (m, 2H), 7.45 7.38 (m, 2H), 6.21 (d, 1H), 5.35 (d, 1H), 4.49 (q, 1H), 3.67 ( s, 3H), 2.85 (p, 1H), 1.34 (d, 3H) 119 A19 ^Ό F 44 *H NMR (DMSO4) δ: 9.41 (d, 1H), 8.99 (dd, 2H), 8.33 (d, 1H), 7.80 - 7.68 (m, 5H), 7. 48 - 7.38 (m, 4H), 6.23 (t, 1H), 5.41 (dd, 1H), 4.59 (td, 1H), 3.64 (d, 3H), 2.98 - 2.83 (m, 1H), 1.31 (dd, 3H) 120 A19 ^\°HI ^N . jV V'nV ν-\0 T ^h f F /j V0 F 48 *H NMR (DMSO-A) δ: 9.14 (d, 1H), 8.32 (d, 1H), 7.81 - 7.71 (m, 3H), 7.71 (d, 1H), 7.50 - 7.36 (m, 4H), 6.16 (d, 1H), 5.25 (d, 1H), 4.29 (td, 1H), 3.68 (s, 3H), 2 .78 (dq, 1H), 1.75 (t, 3H), 1.31 1.14 (m, 3H)

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Human glucocorticoid receptor (hGR) ligand binding assay.

The human lymphoblast cell line IM9 (ATCC, Bethesda, MD) was cultured in RPMI 1640 medium containing 10% fetal bovine serum, penicillin (100 U/ml), streptomycin (100 μg/ml) and 2 mM L-glutamine at 37°C. and 7% CO ₂ in a humidified incubator. Cells were centrifuged for 10 min at 1500 g, washed with PBS and repelled. Cells were then resuspended in homogenization buffer consisting of: 10 mM TES, 10 mM sodium molybdate, 1 mM EDTA, pH 7.4, 20 mM 2-mercaptoethanol and 10% glycerol. Cell disruption was performed using nitrogen cavitation using 2x15 minutes at 600 to 750 psi nitrogen pressure. inch in cavitator N2 at 0°C. The cell preparation was then centrifuged at 27,000 g for 15 min, and the resulting supernatant (= cytosol of IM9 cells) was centrifuged at 103,000 g for 60 min at 4°C. The amount of protein in the supernatant fraction was determined using a BCA assay kit, and aliquots were flash frozen in a dry ice-acetone bath and stored at -70°C. Competitive binding assays were performed in duplicate in homogenization buffer with a total volume of 200 μl. For this purpose, 1 mg of cytosol IM9, 0.05 μCi (1.5 nM) 3H-dexamethasone and unlabeled compounds of the example as competitor compounds were mixed at a concentration of 1 μM. The reaction was stopped after incubation at 0°C for 16-18 hours by adding 100 μl of an activated carbon-dextran mixture (2% activated carbon, 0.5% dextran in 10 mM Tris, 1 mM EDTA, pH 7.4). After a further incubation step at 0°C for 10 minutes, the samples were centrifuged for 5 minutes at 8200 g (100 μl of supernatant) and finally analyzed for radioactivity using liquid scintillation spectrometry and the percentage inhibition of 3H-dexamethasone binding was calculated.

GRE agonist.

The CHO-Gal4/GR reporter cell line consisted of a Chinese hamster ovary (CHO) cell line (Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures GmbH: ACC-110) containing the firefly luciferase gene under the control of the GR ligand binding domain fusion with the DNA-binding domain (DBD) of GAL4 (GAL4 DBD-GR), is stably integrated into CHO cells. This cell line was generated by stably transfecting CHO cells with a GAL4-UAS-luciferase reporter construct. In the next step, the GR ligand binding domain cloned into pIRES2-EGFP-GAL4 containing the GAL4 DNA binding domain from pFA-AT2 was transfected. This fusion construct activated the expression of firefly luciferase under the control of the multimerized GAL4 activation sequence (UAS). The emitted luminescence signal was detected by the FLIPR instrument. This allowed the specific detection of ligand-induced GR activation and, consequently, the identification of compounds with agonistic properties. The GAL4/UAS reporter was premixed with a vector that constitutively expressed Renilla luciferase, which

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The complete culture medium for analysis was:

DMEM F-12 (1:1) MIXTURE (LONZA Cat. No.: BE04-687F/U1) 500 ml, ml 100 mM sodium pyruvate (LONZA Cat. No.: BE 12-115E), ml 7.5% sodium bicarbonate ( LONZA, cat. No. BE17-613E),

6.5 ml 1 M Hepes (LONZA cat. no. BE17-737E), ml 100X penicillin/streptomycin (LONZA cat. no. DE17-602E), ml fetal bovine serum (Euroclone, cat. no. ECS 0180L),

0.25 ml Puromycin 10 mg/ml (InvivoGen cat. no.: ant-pr-1),

0.5 ml Zeocin 100 mg/ml (InvivoGen cat. no.: ant-zn-1).

Cryopreserved CHO-Gal4/GR cells were suspended in complete medium and 5000 cells/25 μl/well were seeded into the wells of 384-well polystyrene assay plates (Thermo Scientific, catalog no. 4332) and cultured at 37°C, 5% CO2 and 95% humidity. After 24 hours, the growth medium was carefully removed and replaced with 30 μl of Opti-MEM (GIBCO, catalog no. 31985062) as assay buffer. To test compounds, a semi-log 8-point compound dilution curve was generated in 100% DMSO starting with a 2 mM stock solution and then the compounds were diluted 1:50 in Opti-MEM. 10 μL of compounds were then added to wells containing 30 μL of Opti-MEM, resulting in a final assay concentration range of 10 μM to 0.003 μM in 0.5% DMSO. Compounds were tested at 8 concentrations at four data points. Cells were incubated for 6 hours with compounds and beclomethasone (Sigma, cat. no. Y0000351) as a control compound at 37°C, 5% CO ₂ and 95% humidity in a total volume of 40 μl. Finally, the cells were lysed with 20 μl of Triton/luciferin solution and the emitted luminescence signal was recorded on FLIPRTETRA for 2 min.

Relative compound potency (% effect) was calculated based on the total effect of the agonist beclomethasone:

% effect = ((connection - min.)/(max. - min.)) x 100

[min = Opti-MEM only, max = beclomethasone]

To calculate the _EC50 , max, min and slope coefficient for each compound, a concentration response curve was constructed by plotting the % effect versus compound concentration using a 4-parameter logistic equation:

y = A + (B-A)/(l+((10C)/x)D)

[A=min y, B=max y, CMogECso, O=slope]

GRE antagonist.

The CHO-Gal4/GR reporter cell line consisted of a Chinese hamster ovary (CHO) cell line (Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures GmbH: ACC-110) containing the firefly luciferase gene under the control of the GR ligand binding domain fusion with the DNA-binding domain (DBD) of GAL4 (GAL4 DBD-GR), is stably integrated into CHO cells. This cell line was generated by stably transfecting CHO cells with a GAL4-UAS-luciferase reporter construct. In the next step, the GR ligand binding domain cloned into pIRES2-EGFP-GAL4 containing the GAL4 DNA binding domain from pFA-AT2 was transfected. This fusion construct activated the expression of firefly luciferase under the control of the multimerized GAL4 activation sequence (UAS). The emitted luminescence signal was detected by the FLIPRTETRA instrument. This allowed specific detection of the antagonistic properties of compounds by measuring ligand-induced GR inhibition activated by beclomethasone. The GAL4/UAS reporter was premixed with a vector that constitutively expressed Renilla luciferase, which served as an internal positive control for transfection efficiency.

The complete culture medium for analysis was:

MIXTURE DMEM F-12 (1:1) (LONZA, cat. no.: BE04-687F / U1) 500 ml, ml 100 mM sodium pyruvate (LONZA cat. no.: BE12-115E), ml 7.5% sodium bicarbonate ( LONZA, cat. No. BE17-613E),

6.5 ml 1 M Hepes (LONZA, cat. no. BE17-737E), ml 100X penicillin/streptomycin (LONZA, cat. no. DE17-602E), ml fetal bovine serum (Euroclone, cat. no. ECS 0180L),

0.25 ml puromycin 10 mg/ml (InvivoGen cat. no.: ant-pr-1),

0.5 ml Zeocin 100 mg/ml (InvivoGen cat. no: ant-zn-1).

Cryopreserved CHO-Gal4/GR cells were suspended in complete medium and 5000 cells/25 μl/well were seeded into the wells of 384-well polystyrene assay plates (Thermo Scientific, catalog no. 4332) and cultured at 37°C, 5% CO ₂ and 95 % humidity. After 24 hours, the growth medium was carefully removed and replaced with 20 μl of Opti-MEM (GIBCO, catalog no. 31985062) as assay buffer. For the tested compounds, a dilution curve of the compound from the floor was constructed

- 72 044347 logarithmic curve with 8 points in 100% DMSO, starting with a 2 mM stock solution, and then the compounds were diluted 1:50 in Opti-MEM. To test compounds in antagonist mode, 10 μl of compounds were then added to wells containing 20 μl of Opti-MEM and incubated for 10 min. Following this preincubation, 10 μL of the reference agonist beclomethasone (Sigma, catalog no. Y0000351) was added at an EC50 of 2.5 nM, resulting in a final assay concentration range of 10 μM to 0.003 μM in 0.5% DMSO in a total volume of 40 μL. Compounds were tested at 8 concentrations at four data points. Cells were incubated for 6 hours with the compounds and mifepristone control (Sigma, cat. no. M8046) at 37°C, 5% CO2 and 95% humidity. Finally, the cells were lysed with 20 μl of Triton/luciferin solution and the emitted luminescence signal was recorded on a FLIPR ^tetra for 2 min.

Relative compound potency (% effect) was calculated based on the total effect of the mifepristone antagonist:

% effect = ((connection - min.)/(max. - min.))x-100

[min = Opti-MEM only, max = mifepristone]

To calculate the _IC50 , max, min, and slope coefficient for each compound, a concentration response curve was constructed by plotting the % effect versus compound concentration using a 4-parameter logistic equation:

y = A + (B-A)/(l +((10C)/x)D)

[A = min. Y,B = max. Y, OlogICso, D = slope] Table summarizing biological data

Conn. No. IC50 or EC50 A <100 nM, B = 100 nM-l µM, C = 1 µM-15 µM % hGR inhibition at 1 µM Conn. No. IC50 or EC50 A <100 nM, B = 100 nM-l µM, C = 1 µM-15 µM % hGR inhibition at 1 µM 1 A 99 71 IN But. 2 IN 91 72 A But. 3 A 98 73 A But. 4 IN 95 74 IN But.

- 73 044347

5 IN 95 75 A But. 6 IN 97 76 A But. 7 With 96 77 A But. 8 on the. 12 82 IN But. 9 on the. 86 83 A But. 10 on the. 100 84 IN But. 12 on the. 83 85 IN BUT. 13 on the. 20 86 A But. 14 on the. 84 87 A But. 15 on the. 87 88 A But. 16 on the. thirty 90 WITH But. 17 on the. 80 91 WITH But. 18 on the. 29 92 A But. 21 on the. 22 93 A But. 22 on the. 18 94 A But. 24 on the. 12 95 A But. 26 on the. 28 96 A But. thirty on the. 27 98 A But. 31 IN But. 100 A But. 33 WITH But. 101 IN But. 34a A But. 104 WITH But. 34b IN But. 107 WITH But. 35a A But. 108 A But. 36a IN But. 109 A But. 36b IN But. 110 A But. 37 A But. 111 A But. 38a IN But. 112 IN But. 38b A But. 113 IN But. 39a A But. 114 V But. 40a A But. 120 With But. 40b IN But. 121 A But. 41b WITH But. 123 A But. 42a A But. 124 A But. 42b IN But. 125 A But. 43a A But. 126 A But. 43b WITH But. 127 IN But. 44a A But. 128 IN But. 44b IN But. 129 A But. 45a A But. 130 IN But. 45b IN But. 131 IN But. 46 A But. 132 A But. 47 A But. 133 IN But. 60 IN But. 134 IN But. 61 IN But. 135 A But. 62 IN But. 136 A But. 63 V But. 137 A But. 64 A But. 138 IN But. 65 A But. 139a WITH But. 66 A But. 139b With But. 67 A But. 148 A But. 68 IN But. 149 A But. 69 A But. 150 IN But. 70 A But. 151 IN But.

NA: Not active in GR cell-based assays, neither agonist nor antagonist. N.A.: not defined

Prophetic examples.

The prophetic examples given in the following table can be synthesized by analogy with example 7 described above. A person skilled in the art should know how to select suitable

-

Claims (12)

intermediate compounds to obtain any of the prophetic examples shown in the table. below. In any of the tables above, exemplary compounds in which the substituents attached to the central pyrrolidone have different relative orientations, such as the phenyl moiety and methyl moiety up (bold bond) and the amide moiety down (shaded ''' bond) or vice versa are a trans diastereomer, which is a racemic mixture of two corresponding trans enantiomers. CLAIM 1. Compound of general formula (I), (I) where R ₁ represents phenyl; 5-membered heteroaryl; or -C _1-4 -alkyl; Rr represents H; -C _1-4 -alkyl; or -C _3-4 -cycloalkyl; R2 represents -C(=O)-C _1-4 -alkyl; -C(=O)-cyclopropyl; -C(=O)-oxetanyl; -C(=O)-(5 or 6 membered heteroaryl); -S(=O) ₂ -C _1-4 -alkyl; -S(=O) ₂ -cyclopropyl; R3 and _R3 ' independently represent H; F; Cl; -C _1-4 -alkyl; -C _3-6 -cycloalkyl; -CH ₂ -C _3-6 -cycloalkyl; -CH ₂ -phenyl; or -CH2-(5-membered heteroaryl); or R3 and _R3 ' together with the carbon atom to which they are bonded form _C3-6 -cycloalkyl; R4 is fluorophenyl or N-methyl-2-oxopyridyl; A, X, Y and Z independently represent N or CH; where at least one of R ₁ ', R 3 and R ₃ ' is not H; where -C _1-4 -alkyl is in each case, independently of each other, linear or branched, - 75 044347 saturated or unsaturated; where -Cm-alkyl, -C _3-6 -cycloalkyl, cyclopropyl and oxetanyl are in each case independently unsubstituted or mono- or disubstituted with one or more substituents selected from -F; -Cl; -Br; -I; wherein the phenyl and the 5- or 6-membered heteroaryl are in each case independently of each other unsubstituted or monosubstituted with one substituent selected from -F; -Cl; -Br; -I; -C ₁ _ ₆ -alkyl; O-C ₁ - ₄ -alkyl; where 5- or 6-membered heteroaryl means a 5- or 6-membered cyclic aromatic residue containing at least 1 heteroatom selected from the group consisting of S, N and O; in the form of the free compound or a physiologically acceptable salt thereof; provided that the following connections are excluded: N-[(2R,3 S)-4,4-dimethyl-1-[1-(1 -methyl-6-oxo-1 H-pyridin-3 -yl)-1 H-indazol-5-yl] - 5-oxo-2-phenylpyrrolidin-3-yl]-cyclopropanecarboxylic acid amide; N-[(2S,3R)-4,4-dimethyl-1-[1-(1 -methyl-6-oxo-1 H-pyridin-3 -yl)-1 H-indazol-5-yl] -5 -oxo-2-phenylpyrrolidin-3-yl]-cyclopropanecarboxylic acid amide; N-[(2S,3R)-4,4-dimethyl-1-[1-(1 -methyl-6-oxo-1 H-pyridin-3-yl)-1 H-indazol-5-yl] -5 -oxo-2-phenylpyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic acid amide; N-[(2S,3R)-4,4-dimethyl-1-[1-(1 -methyl-6-oxo-1 H-pyridin-3-yl)-1 H-indazol-5-yl] -5 -oxo-2-phenylpyrrolidin-3-yl]-5-methyl-[1,2,4]oxodiazole-3-carboxylic acid amide; N-[(2S,3R)-4,4-dimethyl-1-[1-(1 -methyl-6-oxo-1 H-pyridin-3-yl)-1 H-indazol-5-yl] -5 -oxo-2-phenylpyrrolidin-3-yl]-4-methyl-thiazol-5-carboxylic acid amide; N-[(2S,3R)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo -2-phenylpyrrolidin-3-yl]thiazol-4-carboxylic acid amide; And N-[(2S,3R)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo -2-phenylpyrrolidin-3-yl]-5-methyl-thiazol-4-carboxylic acid amide. 2. A compound according to claim 1, which has stereochemistry in accordance with the general formula (II) or (VI). 3. Connection according to claim 1 or 2, where A is N, X is CH, Y is CH; and Z represents CH; or A is N, X is N, Y is CH; and Z represents CH; or A is N, X is CH, Y is N; and Z represents CH; or A is N, X is CH, Y is CH; and Z is N; or A is N, X is N, Y is N; and Z represents CH; or A is N, X is N, Y is CH; and Z is N; or A is N, X is CH, Y is N; and Z is N; or A is N, X is N, Y is N; and Z is N; or A is CH, X is CH, Y is CH; and Z represents CH; or A is CH, X is N, Y is CH; and Z represents CH; or A is CH, X is CH, Y is N; and Z represents CH; or A is CH, X is CH, Y is CH; and Z is N; or A is CH, X is N, Y is N; and Z represents CH; or - 76 044347 A is CH, X is N, Y is CH; and Z is N; or A is CH, X is CH, Y is N; and Z is N; or A is CH, X is N, Y is N; and Z represents N. 4. Connection according to any of the previous points, where Ri represents phenyl; and/or R ₁ ' represents H, CH ₃ or cyclopropyl. 5. A compound according to any of the preceding claims, wherein R ₃ and R ₃ are both -C ₁ - ₄ -alkyl. 6. A compound according to any one of claims 1 to 3, where R ₁ represents phenyl, unsubstituted or monosubstituted with a substituent independently selected from the group consisting of -F, -Cl -Br, -OCH3 and -CH3. 7. A compound according to any one of claims 1 to 3, where R2 represents - C(=O)-C _1-4 -alkyl, unsubstituted or mono- or disubstituted with substituents independently selected from the group consisting of -F, -Cl and -Br; - C(=O)-cyclopropyl, unsubstituted or mono- or disubstituted with substituents independently selected from the group consisting of -F, -Cl, -Br; - C(=O)-(5-6-membered heteroaryl), where said 5-6-membered heteroaryl is selected from the group consisting of thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1-oxa-2,4-diazolyl, 1, 2,5-oxadiazolyl and isothiazolyl, wherein in each case said 5-6 membered heteroaryl is an unsubstituted or monosubstituted substituent independently selected from the group consisting of -F, -Cl Br, -CH3 and -OCH3; unsubstituted -S(=O) ₂ -C ₁ . ₄ -alkyl; unsubstituted -S(=O) ₂ -cyclopropyl. 8. A compound according to any of the preceding claims, wherein R ₃ and R ₃ · are both -CH ₃ . 9. Connection according to any one of claims 1-3, where R ₁ represents phenyl, unsubstituted or monosubstituted with a substituent independently selected from the group consisting of -F, -Cl, -Br, -CH ₃ and -OCH ₃ ; and/or R _r is H, CH ₃ or cyclopropyl; and/or R2 represents _-C (=O)-C _{1_4} -alkyl; -C(=O)-cyclopropyl; or -C(=O)-(5-6 membered heteroaryl), unsubstituted or monosubstituted with a substituent independently selected from the group consisting of -F, -Cl, -Br and -CH ₃ ; and/or R4 is fluorophenyl or N-methyl-2-oxopyridyl. 10. A compound according to any of the previous paragraphs, selected from the group consisting of: 1 N-[(2R,3S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidin-3-yl] cyclopropanecarboxylic acid amide; 2 N-[(2S,3R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-oxo-2-phenyl-pyrrolidin-3-yl] cyclopropanecarboxylic acid amide; 3 N-[rac-(6R,7S)-5-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-oxo-6-phenyl-5-azaspiro[2,4]heptane- 7-yl]cyclopropanecarboxylic acid amide; 4 2,2-difluoro-N-[(2S,3R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-oxo-2-phenylpyrrolidin- 3-yl]-propionamide; 5 N-[rac-(6R,7S)-5-[1-(4-fluorophenyl)-1H-indol-5-yl]-4-oxo-6-phenyl-5-azaspiro[2,4]heptane- 7-yl]cyclopropanecarboxylic acid amide; 6 N-[(2R,3S)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5- oxo-2phenyl-pyrrolidin-3-yl]-5-methyl-thiazol-2-carboxylic acid amide; 7 N-[(2R,3S)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5- oxo-2phenyl-pyrrolidin-3-yl]-5-methyl-isoxazole-3-carboxylic acid amide; 8 N-[(2S,3R)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5- oxo-2phenyl-pyrrolidin-3-yl]-2,2-difluoropropionamide; 9 N-[(2R,3S)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5- oxo-2phenyl-pyrrolidin-3-yl]-2,2-difluoropropionamide; 10 2,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4,4-dimethyl-5-oxo-2phenyl-pyrrolidin- 3-yl]-propionamide; 12 N-[(2R,3S)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5- oxo2-phenyl-pyrrolidin-3-yl]-1-methyl-1 H-pyrazole-3-carboxylic acid amide; 13 N-[(2R,3S)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5- oxo2-phenyl-pyrrolidin-3-yl]-oxazol-5-carboxylic acid amide; 14 N-[(2R,3S)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5- oxo2-phenyl-pyrrolidin-3-yl]-5-methyl-[1,2,4]oxodiazole-3-carboxylic acid amide; 15 N-[(2R,3S)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5- oxo2-phenyl-pyrrolidin-3-yl]-thiazol-5-carboxylic acid amide; - 77 044347 16 N-[(2R,3S)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-III-pyridin-3-yl)-III-indazol-5-yl]-5- oxo2-phenyl-pyrrolidin-3-yl]-4-methyl-thiazol-5-carboxylic acid amide; 17 N-[(2R,3S)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-III-pyridin-3-yl)-III-indazol-5-yl]-5- oxo2-phenyl-pyrrolidin-3-yl]-thiazol-4-carboxylic acid amide; 18 N-[(2R,3S)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5- oxo2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazol-4-carboxylic acid amide; 21 N-[(2S,3R)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-III-pyridin-3-yl)-III-indazol-5-yl]-5- oxo2-phenyl-pyrrolidin-3-yl]-oxazol-5-carboxylic acid amide; 22 N-[(2S,3R)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5- oxo2-phenyl-pyrrolidin-3-yl]-5-methyl-isoxazole-3-carboxylic acid amide; 24 N-[(2S,3R)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-III-pyridin-3-yl)-III-indazol-5-yl]-5- oxo2-phenyl-pyrrolidin-3-yl]thiazol-5-carboxylic acid amide; 26 N-[(2S,3R)-4,4-dimethyl-1-[1-(1-methyl-6-oxo-III-pyridin-3-yl)-1H-indazol-5-yl-5-oxo -2phenyl-pyrrolidin-3-yl]-5-methyl-thiazol-2-carboxylic acid amide; 30 N-[rac-(6R,7S)-5-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-4-oxo-6- phenyl5-azaspiro[2,4]heptan-7-yl]-cyclopropanecarboxylic acid amide; 31 N-[rac-(6R,7S)-5-[1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-4-oxo-6-phenyl-5azaspiro[ 2,4]heptan-7-yl]cyclopropanecarboxylic acid amide; 32 N-[rac-(6R,7S)-5-[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl]-4-oxo-6-phenyl-5azaspiro[ 2,4]heptan-7-yl]cyclopropanecarboxylic acid amide; 33 N-[rac-(6R,7S)-5-[1-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-4-oxo-6-phenyl-5azaspiro[ 2,4]heptan-7-yl]cyclopropanecarboxylic acid amide; 34a N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3 -yl)methanesulfonamide; 34b N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3 -yl)methanesulfonamide; 35a N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3 -yl)cyclopropanesulfonamide; 35b N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3 -yl)cyclopropanesulfonamide; 36a N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3 -yl)oxazol-5 - carboxamide; 36b N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3 -yl)oxazol-5 - carboxamide; 37 N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin-3-yl)1 - methyl-1H-pyrazole-3-carboxamide; 38a N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3-yl)-4-methylthiazole -5-carboxamide; 38b N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3-yl)-4-methylthiazole -5-carboxamide; 39a N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3-yl)-5-methylthiazole -4-carboxamide; 39b N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3-yl)-5-methylthiazole -4-carboxamide; 40a N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3 -yl)-3-methylisoxazole -4-carboxamide; 40b N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3 -yl)-3-methylisoxazole -4-carboxamide; 41a N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3-yl)-1-methyl -1H-pyrazole-4-carboxamide; 41b N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3-yl)-1-methyl -1H-pyrazole-4-carboxamide; 42a N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3-yl)nicotinamide; 42b N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3-yl)nicotinamide; 43a N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3-yl)pyrimidin-2- carboxamide; 43b N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3-yl)pyrimidin-2- carboxamide; 44a N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3-yl)-2-methyloxazole -5-carboxamide; - 78 044347 44b N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3-yl)-2-methyloxazole -5-carboxamide; 45a N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3-yl)-4-methyloxazole -5-carboxamide; 45b N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-phenylpyrrolidin3-yl)-4-methyloxazole -5-carboxamide; 46 N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenylpyrrolidin-3yl]cyclopropanecarboxylic acid amide; 47 N-[rac-(2R,3S,4S)-2-(2-)chlorophenyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxopyrrolidin- 3-yl]-2,2-difluoropropionamide; 48 N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(3-methoxyphenyl)-4-methyl-5-oxopyrrolidin- 3-yl]cyclopropanecarboxylic acid amide; 49 N-[rac-(2R,3S,4S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxopyrrolidin- 3-yl]cyclopropanecarboxylic acid amide; 60 N-[rac(2R,3S,4S)-1-[1 -(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3yl]- 4-methyl-thiazole-5-carboxylic acid amide; 61 N-[rac-(2R,3 S,4S)-1-[1 -(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3yl ]methanesulfonic acid amide; 62 N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin- 3yl]methanesulfonic acid amide; 63 N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxopyrrolidine-3- yl]cyclopropanecarboxylic acid amide; 64 N-[rac-(2R,3S,4S)-1-[1 -(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3yl] -1-methyl-1H-pyrazole-3-carboxylic acid amide; 65 N-[rac-(2R,3S,4S)-1-[1 -(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3yl] pyridine-3-carboxylic acid amide; 66 N-[rac-(2R,3S,4S)-1-[1 -(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2-phenyl-pyrrolidin-3yl] pyrimidine-2-carboxylic acid amide; 67 N-[rac-(2R,3S,4S)-1-[1 -(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin- 3yl]-4-methyl-thiazol-5-carboxylic acid amide; 68 N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxopyrrolidine-3- yl]-pyridine-3-carboxylic acid amide; 69 N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxopyrrolidine-3- yl]pyrimidine-2-carboxylic acid amide; 70 N-[rac-(2R,3S,4R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxopyrrolidine-3- yl]cyclopropanecarboxylic acid amide; 71 N-[rac-(2R,3S,4R)-1-[1 -(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin- 3yl]-4-methyl-thiazol-5-carboxylic acid amide; 72 N-[rac-(2R,3S,4R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin- 3yl]-1-methyl-1H-pyrazole-3-carboxylic acid amide; 73 N-[rac-(2R,3S,4R)-1-[1 -(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin- 3yl]-pyridine-3-carboxylic acid amide; 74 N-[rac-(2R,3S,4R)-1-[1 -(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin- 3yl]-pyrimidine-2-carboxylic acid amide; 75 N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin- 3yl]-1-methyl-1H-pyrazole-3-carboxylic acid amide; 76 N-[rac-(2R,3S,4R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl-5-oxo-pyrrolidin- 3yl]methanesulfonic acid amide; 77 2,2-difluoro-N-[rac-(2R,3 S,4R)-1-[1 -(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl -5-oxopyrrolidin-3-yl]propionamide; 78 N-[rac-(2R,3S,4R)-2-(2-chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxopyrrolidin- 3-yl]cyclopropanecarboxylic acid amide; 79 N-[rac-(2R,3S,4R)-2-(2-)chlorophenyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxopyrrolidin- 3-yl]-2,2-difluoropropionamide; 80 2,2-difluoro-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2- phenylpyrrolidin-3-yl]propionamide; 81 2,2-difluoro-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-m-tolyl- 5-oxopyrrolidin-3-yl]propionamide; 82 N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5oxo-pyrrolidin- 3-yl]-4-methyl-thiazol-5-carboxylic acid amide; 83 N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin- 3-yl]-1-methyl-1H-pyrazole-3-carboxylic acid amide; - 79 044347 84 N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin- 3-yl]pyridine-3-carboxylic acid amide; 85 N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5oxo-pyrrolidin- 3-yl]pyrimidin-2-carboxylic acid amide; 86 N-[rac-(2R,3S,4R)-2-(2-chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxopyrrolidin- 3-yl]methanesulfonic acid amide; 87 N-[rac-(2R,3S,4R)-2-(2-chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxopyrrolidin- 3-yl]pyridine-3-carboxylic acid amide; 88 N-[rac-(2R,3S,4R)-2-(2-chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxopyrrolidin- 3-yl]pyrimidin-2-carboxylic acid amide; 89 N-[rac-(2R,3S,4S)-4-benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3yl] pyridine-3-carboxylic acid amide; 90 N-[rac-(2R,3S,4S)-4-benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3yl] pyrimidine-2-carboxylic acid amide; 91 N-[rac-(2R,3S,4S)-4-benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3yl] methanesulfonic acid amide; 92 N-[rac-(2R,3S,4S)-2-(2-chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxopyrrolidin- 3-yl]-pyridin-3-carboxylic acid amide; 93 N-[rac-(2R,3S,4S)-2-(2-chlorophenyl)-1-[1-(4-Fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxopyrrolidin- 3-yl]methanesulfonic acid amide; 94 N-[rac-(2R,3S,4R)-2-(2-chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxopyrrolidin- 3-yl]-1-methyl-1H-pyrazole-3-carboxylic acid amide; 95 N-((2R,3R,4S)-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin3 -yl)cyclopropanecarboxamide; 96 N-((2R,3R)-4,4-difluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin3-yl)cyclopropanecarboxamide; 97 2,2-difluoro-N-[rac-(2R,3S,4R)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)4-methyl -5-oxo-pyrrolidin-3-yl]propionamide; 98 2,2-difluoro-N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)4-methyl -5-oxo-pyrrolidin-3-yl]propionamide; 99 N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin- 3-yl]methanesulfonic acid amide; 100 2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-methyl-5-oxo-2phenyl-pyrrolidin- 3-yl]propionamide; 101 N-[rac-(2R,3S)-1-[1 -(4-fluorophenyl)-1 H-indazol-5-yl]-2-methyl-5-oxo-2-phenyl-pyrrolidin-3yl]cyclopropanecarboxylic acid amide; 102 2,2-difluoro-N-[rac-(2R,3S)-2-methyl-1-[1-(1 -methyl-6-oxo-1 H-pyridin-3 -yl)-1 H-indazole -5-yl]5-oxo-2-phenyl-pyrrolidin-3-yl]propionamide; 103 N-[rac-(2R,3S)-2-methyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5- oxo2-phenyl-pyrrolidin-3-yl]cyclopropanecarboxylic acid amide; 104 N-[rac-(2R,3S,4S)-4-benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3yl] -1-methyl-1H-pyrazole-3-carboxylic acid amide; 105 N-[rac-(2R,3S,4S)-4-benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3yl] -4-methyl-thiazole-5-carboxylic acid amide; 106 N-[rac-(2R,3S,4S)-4-benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3yl] cyclopropanecarboxylic acid amide; 107 N-[rac-(2R,3S,4S)-4-benzyl-2-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-pyrrolidin-3yl] -2,2-difluoropropionamide; 108 N-[rac-(2S,3S,4S)-2-(5-chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4- methyl 5oxo-pyrrolidin-3-yl]cyclopropanecarboxylic acid amide; 109 N-[rac-(2S,3S,4S)-2-(5-chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4- methyl 5oxo-pyrrolidin-3-yl]pyrimidine-2-carboxylic acid amide; 110 N-[rac-(2S,3S,4S)-2-(5-chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4- methyl 5oxo-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic acid amide; 111 N-[rac-(2S,3S,4S)-2-(5-chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4- methyl 5oxo-pyrrolidin-3-yl]pyridine-3-carboxylic acid amide; 112 N-[rac-(2R,3S,4S)-2-(2-chlorophenyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxopyrrolidin- 3-yl]cyclopropanecarboxylic acid amide; 113 N-[rac-(2S,3S,4S)-2-(5-chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4- methyl-5oxo-pyrrolidin-3-yl]-4-methyl-thiazol-5-carboxylic acid amide; 114 N-[(2S,3S,4S)-2-(5-chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl- 5-oxopyrrolidin-3-yl]methanesulfonic acid amide; - 80 044347 115 N-[rac-(2S,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3 -yl)5-oxo-pyrrolidin-3-yl]cyclopropanecarboxylic acid amide; 116 N-[rac-(2S,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3 -yl)5-oxo-pyrrolidin-3-yl]-4-methyl-thiazol-5-carboxylic acid amide; 117 N-[rac-(2S,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3 -yl)5-oxo-pyrrolidin-3-yl]-1-methyl-1 H-pyrazole-3-carboxylic acid amide; 118 N-[rac-(2S,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3 -yl)5-oxo-pyrrolidin-3-yl]pyridin-3-carboxylic acid amide; 119 N-[rac-(2S,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3 -yl)5-oxo-pyrrolidin-3-yl]pyrimidin-2-carboxylic acid amide; 120 2,2-difluoro-N-[rac-(2S,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl -1Hpyrazol-3-yl)-5-oxo-pyrrolidin-3-yl]propionamide; 121 N-[rac-(2R,3S,4S)-4-(cyclopropyl-methyl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-2phenyl-pyrrolidin- 3-yl]cyclopropanecarboxylic acid amide; 122 N-[rac-(2S,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-2-(1-methyl-1H-pyrazol-3 -yl)5-oxo-pyrrolidin-3-yl]methanesulfonic acid amide; 123 N-[rac-(2S,3S,4S)-2-(5-chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4- methyl-5oxo-pyrrolidin-3-yl]-2,2-difluoropropionamide; 124 N-[rac-(2S,3S,4R)-2-(5-chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4- methyl 5oxo-pyrrolidin-3-yl]cyclopropanecarboxylic acid amide; 125 N-[rac-(2S,3S,4R)-2-(5-chloro-thiophen-2-yl)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4- methyl-5oxo-pyrrolidin-3-yl]-2,2-difluoropropionamide; 126 N-[rac-(2R,3S,4S)-4-ethyl-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3yl] cyclopropanecarboxylic acid amide; 127 N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phenylpyrrolidin3-yl)cyclopropanecarboxamide, diastereomer 2; 128 N-[rac-(2R,3R,4R)-4-fluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2phenyl-pyrrolidin- 3-yl]cyclopropanecarboxylic acid amide; 129 N-[rac-(2R,3R,4S)-4-fluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methyl-5-oxo-2phenyl-pyrrolidin- 3-yl]cyclopropanecarboxylic acid amide; 130 N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-4-phenethyl-2-phenylpyrrolidin3-yl)cyclopropanecarboxamide, diastereomer 1; 131 N-((2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin- 3-yl)cyclopropanecarboxamide; 132 N-((2R,3S,4R)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin- 3-yl)cyclopropanecarboxamide; 133 N-[rac-(2R,3S,4S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin- 3-yl]cyclopropanecarboxylic acid amide; 134 N-(rac-(2R,3S,4R)-4-ethyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin- 3-yl)cyclopropanecarboxamide; 135 N-((7R,8S)-6-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-7-phenyl-6-azaspiro[3,4]octan-8yl) cyclopropanecarboxamide; 136 N-(rac(2R,3S,4S)-4-(2,2-difluoroethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo -2phenylpyrrolidin-3-yl)cyclopropanecarboxamide; 137 N-(rac-(2R,3R,4S)-4-benzyl-2-ethyl-4-fluoro-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin- 3-yl)cyclopropanecarboxamide; 138 N-((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-undαzol-5-yl)-4-((3-methyl-1,2,4-oxαduαzol-5- yl)methyl)5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide; 139 N-((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((1-methyl-1H-pyrazol-4-yl)methyl) 5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide; 142 N-(rac-(2R,3S)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3yl)cyclopropanecarboxamide; 143 N-(rac-(2R,3R)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3yl)cyclopropanecarboxamide; 144 N-(rac-(2R,3S)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3yl)-2,2 -difluoropropanamide; 145 N-(rac-(2R,3R)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3yl)-2,2 -difluoropropanamide; 146 N-(rac-(2R,3S)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3yl)oxetane-3- carboxamide; 147 N-(rac-(2R,3R)-2-cyclopropyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin3-yl)oxetan-3- carboxamide; - 81 044347 148 N-(pac-(2R,3S,4S)-4-(2,2-diτopoethyl)-l-(1-(4-fluorophenyl)-1 H-indazol-5-yl)-4-methyl-5 -oxo-2phenylpyrrolidin-3-yl)cyclopropanecarboxamide; 149 N-(pap-(2R,3S, 48)-4-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5oxo-2-phenylpyrrolidin- 3-yl)cyclopropanecarboxamide; 150 N-((2R,3 S,4R)-1-(1 -(4-fluorophenyl)-1 H-indazol-5-yl)-5 -oxo-2-phenyl-4-(thiazol-2-ylmethyl )pyrrolidin-3-yl)cyclopropanecarboxamide; 151 M-((28.38)-2-(5-chlorothiophen-2-yl)-1 -(1 -(4-fluorophenyl)-111-indazol-5-yl)-2-methyl-5-oxopyrrolidine3 - yl)cyclopropanecarboxamide, in each case in the form of the free compound or a physiologically acceptable salt thereof. 11. Pharmaceutical dosage form containing a compound according to any one of claims 1 to 10 and one or more pharmaceutical excipients. 12. Use of a compound according to any one of claims 1 to 10 for the treatment and/or prevention of pain and/or inflammation. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2