Pyrrolidine compounds as proteasome stimulators

Abstract

The present invention relates to compounds of formula (I) or a stereoisomer, tautomer, prodrug, hydrate, solvate, racemic mixture, polymorph or pharmaceutically acceptable salt thereof. Further, the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula I as well as the compound of formula I for use in medicine.

Description

[0001] - 1 - 17 April 2025 5Our reference: B17987WO / JUM----------------------------------------------------------------------------------------------------- Booster Therapeutics GmbH10 Schlueterstrasse 36, 10629 Berlin, Germany------------------------------------------------------------------------------------------------------ Novel compounds as proteasome stimulators ------------------------------------------------------------------------------------------------------15 Field of the inventionThe present invention relates to compounds of formula I or a stereoisomer, tautomer, prodrug, hydrate, solvate, racemic mixture, polymorph or pharmaceutically acceptable salt thereof. Further, the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of the20 compound of formula I as well as the compound of formula I for use in medicine.Background of the invention The major protein degradation pathway in cells is the ubiquitin-proteasome system (UPS). This system involves a network of proteins to polyubiquitinate and degrade protein substrates. Proteins are tagged for25 degradation with small protein called ubiquitin. The tagging reaction is catalyzed by enzymes called ubiquitinligases. Once a protein is tagged with a single ubiquitin molecule, this is a signal to other ligases to attach additional ubiquitin molecules. The result is a polyubiquitin chain that is bound by the proteasome, allowing it to degrade the tagged protein. The degradation process is performed by the 26S proteasome, which is comprised of a 19S regulatory30 particle (19S RP) and a 20S core particle (20S CP). The 20S CP is responsible for the hydrolysis activity,degrading proteins into shorter peptides, and is regulated by the 19S RP, which recognizes ubiquitinated substrates, removes ubiquitin, and coordinates the movement of the substrate in the catalytic core particle for degradation. The 20S CP alone can accept and degrade proteins in a ubiquitin-independent system (UIPS). In this case,35 proteins are not ubiquitinated and must be disordered enough to enter the catalytic core without beingdenatured by the 10S RP. The UIPS has been shown to paly an important role in the degradation of oxidatively damaged proteins during times of cellular stress. - 2 - Aging is a natural process accompanied by a progressive accumulation of damage in all constituent macromolecules (nucleic acids, lipids and proteins). Accumulation of damage in proteins leads to failure of proteostasis (or vice versa) due to increased levels of unfolded, misfolded or aggregated proteins and, in turn, to aging and / or age-related diseases. 5The proteasome and the lysosome have been shown to dysfunction during aging and age-related diseases,Parkinson’s, and Alzheimer’s disease. Regarding the proteasome, it is well established that it can be activated either through genetic manipulation or through treatment with natural or chemical compounds that eventually result to extension of lifespan or deceleration of the progression of age-related diseases. Stimulation of the 20S CP has recently been shown to be promoted by small molecules (see, for example,10 Coleman, Rachel A, et al.; Protein degradation profile reveals dynamic nature of 20S proteasome smallmolecule stimulation.2021, 636-644, RSC Chem. Biol.2, doi:10.1039 / D0CB00191K). Njomen and Tepe (in: Proteasome Activation as a New Therapeutic Approach To Target Proteotoxic Disorders. J Med Chem. 2019; 62(14):6469-6481. doi:10.1021 / acs.jmedchem.9b00101) review current approaches, genetic manipulation, posttranslational modification, and small molecule proteasome agonists15 used to increase proteasome activity, challenges facing the field, and applications beyond aging andneurodegenerative diseases. WO2021 / 034627 A1 relates to series compounds and methods of use for the treatment of a disease caused by abnormal regulation of the ubiquitin-proteasome system (UPS), and wherein said compound is an effective stimulator of the 20S core particle (CP) of the UPS.20 In contrast thereto, the compounds of formula I of the present invention function independently ofubiquitination. Coleman RA, et al. (in: Protein degradation profile reveals dynamic nature of 20S proteasome small molecule stimulation. RSC Chem Biol. 2021 Jan 5; 2(2):636-644.doi:10.1039 / d0cb00191k. PMID: 34458805; PMCID: PMC8341874) discuss that small molecules have been discovered to stimulate the 20S core particle (CP) of the proteasome to degrade proteins. They evaluate the effects of two stimulators on the25 whole cellular proteome in HEK-293T cells using label-free quantitative proteomic analysis for a broaderunderstanding on their impact. The development of more effective and selective molecules mediating proteasome degradation of undesired proteins is needed if they are to become useful in the treatment and / or prevention of diseases where30 undesired proteins and protein accumulation plays a role.The development of more effective and selective molecules mediating proteasome degradation of undesired proteins is needed if they are to become useful in the treatment and / or prevention of diseases where undesired proteins and protein accumulation plays a role. Accordingly, there is a need for compounds or agents mediating proteasome degradation of undesired35 proteins for use in the treatment and / or prevention of diseases where undesired proteins and proteinaccumulation plays a role. - 3 - It has recently been shown (Goldberg et al, Nature 2025, https: / / www.nature.com / articles / s41586-025-08615- w) that the body’s natural antibiotic peptides that fight infection are produced by the immune systems enhanced proteasome breakdown of the appropriate proteins. It follows that the proteasome enhancers that are the subject of this invention may promote the formation of these natural antibiotics and may have use in 5the treatment of bacterial infections.Objects and Summary of the Invention It is therefore an object of the present invention to provide compounds that can be used for the prevention and treatment of such conditions and diseases that can be treated / prevented by inducing and / or stimulating10 proteasome degradation, in particular age-related diseases, such as neurological diseases. In this regard, itis desired to provide compounds with a high activity. It is another object of the present invention, to provide compounds, which are suitable for use as a medicament. It is another object of the present invention, to provide compounds which are capable of preventing and treating conditions and diseases linked with undesired proteins and protein accumulation.15 It is still another object of the present invention, to provide compounds, which are suitable for the treatment ofa disease selected from the group consisting of a disease or condition caused by an undesired proteinaceous target molecule, caused by an accumulated pathological protein, proteopathies, alpha-synucleinopathies, tauopathies, neurodegenerative diseases associated with alpha-synuclein accumulation or aggregation, neurodegenerative diseases associated with tau accumulation or aggregation, neurodegenerative diseases20 associated with beta-amyloid accumulation or aggregation, Parkinson’s disease, Alzheimer's disease,dementia, dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, Pick's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxias, prion diseases, cystic fibrosis, alpha 1 antitrypsin deficiency, diabetes type-2, retinitis pigmentosa, cataracts, amyloidosis, desmin- related cardiomyopathy, multiple system atrophy, cancer, cancer tumor metastasis, and aging.25 The above objects can be achieved by the compounds of formula I as defined herein as well aspharmaceutical compositions comprising the same, and by the medical uses thereof. The inventors of the present invention inter alia surprisingly found that the compounds of formula I as defined herein below stimulate / induce proteasome degradation. Accordingly, the compounds of formula I or a pharmaceutical composition comprising a compound of formula I, as defined herein below, can be used as a30 medicament, preferably for the treatment of diseases that can be treated / prevented by inducing and / orstimulating proteasome degradation, in particular age-related diseases, such as neurological diseases. Therefore, in a first aspect, the present invention relates to a compound of formula I - 4 - A X m N R I or a stereoisomer, tautomer, prodrug mixture, polymorph or pharmaceutically acceptable salt thereof, wherein 5A is selected from the group consisting ofO O O N A5), 14), 19), H 10 - 5 - Z Z Z N 1 (Z )n Z ZA34),R R 5X is CH2, C(=O)NH, or C(=O);Z is C1-C4-alkyl, C1-C4-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl, wherein said C1-C4-alkyl, C1-C4-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl group is independently unsubstituted or substituted with one or more, same or different substituents selected from halogen; Z1is independently of each other selected from CH, CF, CCH3, C-O-(C1-C2-alkylene)-C1-C2-alkoxy, and10 C-O-C1-C4-alkyl;Z2is N, CH, or CCH3; Z l; Z Z15 ZZ Z8is phenyl or pyridinyl, wherein said phenyl or pyridinyl group is independently unsubstituted or substituted with one or more, same or different substituents selected from halogen, and C1-C4-haloalkyl; Z9is H, C1-C4-alkyl, or tetrahydropyranyl;20 Z10 is H, or C1-C4-alkyl;Z11is independently of each other selected from halogen, C1-C4-alkyl, and C1-C4-haloalkoxy, mis 0 or 1; andn is 0, 1 or 2.25 In another aspect, the present invention relates to a compound of formula II o , , prodrug, hydrate, solvate, racemic mixture, polymorph or pharmaceutically - 6 - acceptable salt thereof, wherein Ais selected from the group consisting ofO O O NH O (A5), 5(A9),A14), A19), R 10 R1, R2 are independently of each other selected from H, and C1-C4-alkyl;X is CH2, or C(=O);Z is pyridinyl, or phenyl, wherein said pyridinyl or phenyl group is independently unsubstituted orsubstituted with one or more, same or different substituents selected from halogen; Z1is independently of each other selected from CH, CF, and C-O-C1-C4-alkyl;15 Z2 is CH, or CCH3;Z3is H, or C1-C4-alkyl; Z4is N, CH, or C-O-C1-C4-alkyl; Z5is N, CH, CF, or C-O-C1-C4-alkyl; Z6is N, CH or C-O-C1-C4-alkyl; and20 m is 0 or 1.In a preferred embodiment, Ris H, F, Cl or CH3. - 7 - In another preferred embodiment, Ris H, or CH3.In another preferred embodiment, R1, R2are independently of each other selected from H and CH3, 5preferably R1, R2 are CH3.In one preferred embodiment, mis 0 and X is absent.In another preferred embodiment, mis 1, and10 X is CH2 or C(=O).In a more preferred embodiment, mis 1, andX is C(=O).In one preferred embodiment,15 A is selected from the group consisting ofO O O N (A9), I Ais selected from the group consisting ofZ20Z A10), (A8), In one preferred embodiment, the compound is not any one of - 8 - O F O N NH NH , ,5, - 9 - F , , O , 5 , - 10 - O O N N , I ble: O F - 11 - N N (R,S) N (R,S) (RS)* - 12 - (R,S) N H (R,S) N N (R,S) * N In another particularly preferred embodiment the compound is selected from the compounds in the following table: O - 13 - F (R,S) (R,S) N (R,S) N N N N F - 14 - (R,S) N O (R,S) N (R,S) O*O * NN - 15 - F O F N In a second aspect, the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I as defined above and optionally a pharmaceutically acceptable carrier, diluent or excipient. In a preferred embodiment, the present invention 5relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound offormula I as defined above and a pharmaceutically acceptable carrier, diluent or excipient. In a third aspect, the present invention relates to a compound of formula I as defined above, or a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I as defined above, for use in medicine.10 In another embodiment, the present invention relates to a compound of formula I as defined above or apharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I as - 16 - defined above, for use in the treatment of a disease selected from the group consisting of a disease or condition caused by an undesired proteinaceous target molecule, caused by an accumulated pathological protein, proteopathies, alpha-synucleinopathies, tauopathies, neurodegenerative diseases associated with alpha-synuclein accumulation or aggregation, neurodegenerative diseases associated with tau accumulation 5or aggregation, neurodegenerative diseases associated with beta-amyloid accumulation or aggregation,Parkinson’s disease, Alzheimer's disease, dementia, dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, Pick's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxias, prion diseases, cystic fibrosis, alpha 1 antitrypsin deficiency, diabetes type-2, retinitis pigmentosa, cataracts, amyloidosis, desmin-related cardiomyopathy, multiple system atrophy, cancer, cancer10 tumor metastasis, and aging.In another embodiment, the present invention relates to a compound of formula I as defined above or a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I as defined above, for use in the treatment of a disease selected from the group consisting of a disease or condition caused by an undesired proteinaceous target molecule, caused by an accumulated pathological15 protein, proteopathies, alpha-synucleinopathies, tauopathies, neurodegenerative diseases associated withalpha-synuclein accumulation or aggregation, neurodegenerative diseases associated with tau accumulation or aggregation, neurodegenerative diseases associated with beta-amyloid accumulation or aggregation, Parkinson’s disease, Alzheimer's disease, dementia, dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, Pick's disease, amyotrophic lateral sclerosis, Huntington's disease,20 spinocerebellar ataxias, prion diseases, cystic fibrosis, alpha 1 antitrypsin deficiency, diabetes type-2, retinitispigmentosa, cataracts, amyloidosis, desmin-related cardiomyopathy, multiple system atrophy, cancer, cancer tumor metastasis, aging, and bacterial infections. The compounds of the present invention have been shown to stimulate proteasomal activity in a E3 ubiqutin25 ligase independent manner and in a ubiquitin independent manner in an in vitro setting. Further, thecompounds of the present invention have been shown to stimulate proteasomal activity in an ATP independent manner. Definitions 30 Within the meaning of the present invention the following definitions apply, unless specified otherwise and when appropriate, terms used in the singular will also include the plural and vice versa. The term “compound(s) of the present invention” is to be understood as equivalent to the term “compound(s)35 according to the invention”, and also covers the stereoisomer, tautomer, prodrug, hydrate, solvate, racemicmixture, polymorph or pharmaceutically acceptable salt thereof. - 17 - Solvates, hydrates as well as anhydrous forms of the salt are also encompassed by the invention. The solvent included in the solvates is not particularly limited and can be any pharmaceutically acceptable solvent. Examples include water and C1–4 alcohols (such as methanol or ethanol). The term “hydrate” of the 5compound of formula I according to the present invention refers to the hydration, i.e., addition of water or ofthe elements of water to the compound of formula I, forming the hydrate thereof. The state of hydration of an active pharmaceutical ingredient can have an effect on e.g., the solubility and dissolution rate of said active ingredient and therefore its bioavailability.10 The term “salt” or “salts” refers to an acid addition or base addition salt of a compound of the presentinvention. “Salts” include in particular “pharmaceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of the invention and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or15 carboxyl groups or groups similar thereto."Pharmaceutically acceptable salts" are defined as derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or20 organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable saltsinclude the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid and the like; and the salts prepared from organic acids such as, but not25 limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic acid, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting30 the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two. Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts can be found in Remington’s Pharmaceutical Sciences, 23rd ed., Mack Publishing Company, Easton, PA, 2020, the disclosure of which is hereby incorporated by reference. 35 Depending on the substitution pattern, the compounds according to the invention may have one or more - 18 - centres of chirality, including axial chirality. The invention provides both, pure enantiomers or pure diastereomers, of the compounds according to the invention, and their mixtures, including racemic mixtures. Suitable compounds according to the invention also include all possible geometrical stereoisomers (cis / trans isomers or E / Z isomers) and mixtures thereof. E / Z-isomers may be present with respect to, e.g., an alkene, 5carbon-nitrogen double bond or amide group.The term “(±)-trans” indicated in the structural formula of the compounds of formula I of the present invention denotes in each case the two possible enantiomers for the chiral centres which are marked on the respective carbon atom with *. 10 Tautomers may be formed, if a substituent is present at the compound of formula I, which allows for the formation of tautomers such as keto-enol tautomers, imine-enamine tautomers, amide-imidic acid tautomers or the like.15 The term “prodrug” refers to any compound which is converted under physiological conditions or by solvolysisto any of the compounds of the formula I of the invention. A prodrug may be inactive prior to administration but may be converted to an active compound of the invention in vivo. In other words, the term “prodrug” according to the present invention refers to any compound that undergoes biotransformation to any of the compounds of formula I of the present invention before exhibiting pharmacological effects. 20 The term “substituted”, as used herein, means that a hydrogen atom bonded to a designated atom is replaced with a specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise indicated, a substituted atom may have one or more substituents and each substituent is independently selected. 25 The term “substitutable”, when used in reference to a designated atom, means that attached to the atom is a hydrogen, which can be replaced with a suitable substituent. When it is referred to certain atoms or moieties being substituted with “one or more” substituents, the term “one or more” is intended to cover at least one substituent, e.g., 1 to 10 substituents, preferably 1, 2, 3, 4 or 530 substituents, more preferably 1, 2 or 3 substituents, most preferably, 1 or 2 substituents. When neither theterm “unsubstituted” nor “substituted” is explicitly mentioned concerning a moiety, said moiety is to be considered as unsubstituted. The compounds according to the present invention may be amorphous or may exist in one or more different35 crystalline states (polymorphs), which may have different macroscopic properties such as stability or showdifferent biological properties such as activities. The present invention relates to amorphous and crystalline - 19 - forms of the compounds of formula I, mixtures of different crystalline states of the compounds of formula I, as well as amorphous or crystalline salts thereof. The organic moieties mentioned in the above definitions of the variables are – like the term halogen – 5collective terms for individual listings of the individual group members. The prefix Cn-Cm indicates in eachcase the possible number of carbon atoms in the group. The term “alkyl” as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms, preferably 1 to 5 or 1 to 4 carbon atoms, more preferably 1 to 3 or 1 or 2 carbon10 atoms. The hydrocarbon chain radical consists solely of carbon and hydrogen atoms, containing nounsaturation, having preferably from 1 to 4 carbon atoms, and which is attached to the rest of the molecule by a single bond. Examples of C1-C4-alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), or n-butyl; preferably methyl.15 The term “haloalkyl” as used herein denotes in each case a straight-chain or branched alkyl group havingusually from 1 to 4 carbon atoms, preferably 1 to 3 or 1 or 2 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms. Exemplified haloalkyl moieties are selected from C1-C4-haloalkyl, preferably C1-C3-haloalkyl, more preferably C1-C2-haloalkyl, in particular such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,20 pentafluoroethyl, and the like.The term “alkylene” as used herein refers to a linking straight-chain or branched alkylene group having usually from 1 to 2 carbon atoms. The alkylene group bridges a certain group to the remainder of the molecule or bridges two groups. Preferred alkylene groups include methylene (CH2), ethylene (CH2CH2), and25 the like. A skilled person understands that, if it is referred to e.g., CH2 that the carbon atom being tetravalenthas two valences left for forming a bridge (-CH2-). The term “alkoxy” us used herein denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom and has usually from 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, more30 preferably 1 to 2 carbon atoms. Examples of an alkoxy group are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert.-butyloxy, and the like. The term “haloalkoxy” as used herein denotes in each case a straight-chain or branched alkoxy group having from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, wherein the35 hydrogen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms.Preferred haloalkoxy moieties include C1-haloalkoxy, in particular C1-fluoroalkoxy, such as trifluoromethoxy - 20 - and the like. The term “halogen” or “halo” refers to bromo, chloro, fluoro or iodo. Preferably, “halo” is fluoro. 5It must be noted that as used herein and in the appended claims, the singular forms "a", "an" and "the"include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes reference to one or more compounds; and so forth. The terms “about” and “approximately” in the context of the present invention denotes an interval of accuracy10 that a person skilled in the art will understand to still ensure the technical effect of the feature in question. Theterm typically indicates a deviation from the indicated numerical value of ±10% and preferably ±5%. It needs to be understood that the term “comprising” is not limiting. For the purposes of the present invention, the term “consisting of” is considered to be a preferred embodiment of the term “comprising of”. If hereinafter15 a group is defined to comprise at least a certain number of embodiments, it is also meant to encompass agroup which preferably consists of these embodiments only. The term “pharmaceutically acceptable excipient” as used herein refers to compounds commonly comprised in pharmaceutical composition, which are known to the skilled person. Examples of suitable excipients are20 exemplary listed further below. Typically, a pharmaceutically acceptable excipient can be defined as beingpharmaceutically inactive. The term “treatment” is to be understood as also including the option of “prophylaxis”. Thus, whenever reference is made herein to a “treatment” or “treating”, this is to be understood as “treatment and / or25 prophylaxis” or “treating and / or preventing”."Pharmaceutically acceptable" is defined as those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication30 commensurate with a reasonable benefit / risk ratio.The patients or subjects in the present invention are typically animals, particularly mammals, more particularly humans.35 “Therapeutically effective amount” or “pharmaceutically effective amount” means an amount of compound ofthe invention that is sufficient, when administered to a subject suffering from a disease, disorder, and / or - 21 - abnormality to treat, reduces the incidence and / or severity of, and / or delays onset of, one or more symptoms of this disease, disorder, and / or this abnormality. The term "subject" refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, rats and 5mice. Preferably, the subject is a human or an animal. More preferably, the subject is a human.As defined herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.10 The term “pharmaceutical combination” or “combination” refers to a product that results from the mixing orcombining of more than one therapeutic agent and includes both fixed combination into one dosage unit form, and non-fixed combination of the therapeutic agents, or a kit of parts for the combined administration, or a combined administration where a compound of the present invention and a combination partner (e.g. another drug as explained below, also referred to as "therapeutic agent") may be administered independently at the15 same time or separately within time intervals, especially where these time intervals allow that the combinationpartners show a cooperative, e.g. synergistic effect. The single components may be packaged in a kit or separately. One or both of the components (e.g. powders or liquids) may be reconstituted or diluted to a desired dose prior to administration. The term "fixed combination" means that the therapeutic agents, e.g. a compound of the present invention and a combination partner, are both administered to a patient20 simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that thetherapeutic agents, e.g. a compound of the present invention and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of25 three or more therapeutic agent.The definitions and preferred definitions given in the "Definition"-section apply to all of the embodiments described below unless stated otherwise.30 Detailed descriptionIn the following, preferred embodiments of the substituents in the above formula I are described in further detail. It is to be understood that each preferred embodiment is relevant on its own as well as in combination with other preferred embodiments, Furthermore, it is to be understood that the preferences in each case also35 apply to the stereoisomer, tautomer, prodrug, hydrate, solvate, racemic mixture, polymorph orpharmaceutically acceptable salt of the compounds of the invention. - 22 - As indicated above, the present invention relates to a compound of formula I A X m N R I or a stereoisomer, tautomer, prodrug mixture, polymorph or pharmaceutically 5acceptable salt thereof, wherein Ais selected from the group consisting ofO O O N A5),10 14),19), H - 23 - Z Z Z N 1 (Z )n Z ZA34),R R , , 5X is CH2, C(=O)NH, or C(=O);Z is C1-C4-alkyl, C1-C4-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl, wherein said C1-C4-alkyl, C1-C4-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl group is independently unsubstituted or substituted with one or more, same or different substituents selected from halogen; Z1is independently of each other selected from CH, CF, CCH3, C-O-(C1-C2-alkylene)-C1-C2-alkoxy, and10 C-O-C1-C4-alkyl;Z2is N, CH, or CCH3; Z3is H, C(=O)-C1-C4-alkyl; or C1-C4-alkyl; Z4is N, CH, CF, or C-O-C1-C4-alkyl; Z5is N, CH, CF, or C-O-C1-C4-alkyl;15 Z6 is N CH or C-O-C -C -alk l;Z Z8is phenyl or pyridinyl, wherein said phenyl or pyridinyl group is independently unsubstituted or substituted with one or more, same or different substituents selected from halogen, and C1-C4-haloalkyl; Z9is H, C1-C4-alkyl, or tetrahydropyranyl;20 Z10 is H, or C1-C4-alkyl;Z11is independently of each other selected from halogen, C1-C4-alkyl, and C1-C4-haloalkoxy, mis 0 or 1; andn is 0, 1 or 2.25 In another embodiment, present invention relates to a compound of formula II or a stereoisomer, tautomer, prodrug, hydrate, solvate, racemic mixture, polymorph or pharmaceutically - 24 - acceptable salt thereof, wherein Ais selected from the group consisting ofO O O NH O (A5), 5 (A9), A14), A19), R 10 R1, R2 are independently of each other selected from H, and C1-C4-alkyl;X is CH2, or C(=O);Z is pyridinyl, or phenyl, wherein said pyridinyl or phenyl group is independently unsubstituted orsubstituted with one or more, same or different substituents selected from halogen; Z1is independently of each other selected from CH, CF, and C-O-C1-C4-alkyl;15 Z2 is CH, or CCH3;Z3is H, or C1-C4-alkyl; Z4is N, CH, or C-O-C1-C4-alkyl; Z5is N, CH, CF, or C-O-C1-C4-alkyl; Z6is N, CH or C-O-C1-C4-alkyl; and20 m is 0 or 1. - 25 - In the following, preferred embodiments of the substituent R in the above formula I are described in further detail. In this regard, it is to be understood that the preferred embodiments for R are preferred alone and in combination with the below preferred embodiments regarding the substituents R1, R2, A, X and m. 5In one embodiment of the present invention,R is H, C1-C4-alkyl, or C1-C4-alkoxy.In a preferred embodiment, Ris H, C1-C3-alkyl, or C1-C3-alkoxy.In a more preferred embodiment,10 R is H, or C1-C3-alkyl.In an even more preferred embodiment, Ris H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2.In another more preferred embodiment, Ris H, CH3 or CH2CH3.15 In a particularly preferred embodiment,R is H, or CH3.In an even more particularly preferred embodiment, Ris CH3.20 In another embodiment of the present invention,R is H, halogen, C1-C4-alkyl, or C1-C4-alkoxy.In a preferred embodiment, Ris H, halogen, or C1-C4-alkyl.In a more preferred embodiment,25 R is H, halogen, or C1-C2-alkyl.In an even more preferred embodiment, Ris H, F, Cl, CH3, or CH2CH3.In a particularly preferred embodiment, Ris H, F, Cl or CH3.30 In the following, preferred embodiments of the substituents R1and R2in the above formula I are described in further detail. In this regard, it is to be understood that the preferred embodiments for R1and R2are preferred alone and in combination with the above preferred embodiments regarding the substituents R, as well as the preferred embodiments regarding the substituents A, X and m as described further below. 35 In one embodiment, in the compound of formula I - 26 - A X m N I R ach other selected from H, and C1-C4-alkyl. I R1, R2are independently of each other selected from H, and C1-C3-alkyl. 5In one preferred embodiment,R1is H, or C1-C3-alkyl; and R2is H, or C1-C3-alkyl. In another preferred embodiment, R1is H, or C1-C2-alkyl; and10 R2 is H, or C1-C2-alkyl.In a more preferred embodiment of the present invention, R1is H, CH3or CH2CH3; and R2is H, CH3or CH2CH3. Thus, the following combinations of meanings for R1and R2according to embodiments A-1 to A-6 according15 to Table A are preferred in connection with the compounds of formula I.Table A No. R1 R2 In a more preferred embodiment of the present invention, R1, R2are independently of each other selected from H and CH3.20 Thus, in another more preferred embodiment of the present invention,R1is H or CH3; and R2is H or CH3. In a particularly preferred embodiment of the present invention, the combination of R1and R2refers to embodiment A-4 in Table A, wherein25 R1 is CH3; and - 27 - R2is CH3. In the following, preferred embodiments of the substituents A, X and m in the above formula I are described in further detail. In this regard, it is to be understood that the preferred embodiments for A, X and m are 5preferred alone and in combination with the above preferred embodiments regarding the substituents R, R1and R2. In one embodiment of the present invention, in the compound of formula I A X m10(A5), 14), 19), NH 15 - 28 - O Z O 7 NH N N N NH A34),5nI wing meanings: Zis C1-C4-alkyl, C1-C4-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl, wherein said C1-C4-alkyl, C1-10 C4-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl group is independently unsubstituted or substitutedwith one or more, same or different substituents selected from halogen; Z1is independently of each other selected from CH, CF, CCH3, C-O-(C1-C2-alkylene)-C1-C2-alkoxy, and C-O-C1-C4-alkyl; Z2is N, CH, or CCH3;15 Z3 is H, C(=O)-C1-C4-alkyl; or C1-C4-alkyl;Z4is N, CH, CF, or C-O-C1-C4-alkyl; Z5is N, CH, CF, or C-O-C1-C4-alkyl; Z6is N, CH or C-O-C1-C4-alkyl; Z7is H, or C1-C4-alkyl,20 Z8 is phenyl or pyridinyl, wherein said phenyl or pyridinyl group is independently unsubstituted orsubstituted with one or more, same or different substituents selected from halogen, and C1-C4-haloalkyl; Z9is H, C1-C4-alkyl, or tetrahydropyranyl; Z10is H, or C1-C4-alkyl; and Z11is independently of each other selected from halogen, C1-C4-alkyl, and C1-C4-haloalkoxy. 25 In a preferred embodiment of the present invention, Ais selected from the group consisting of - 29 - O O O NH NH O (A5), (A9), 14), 19), 5 n I 10 Z is C1-C4-alkyl, C1-C4-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl, wherein said C1-C4-alkyl, C1-C4-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl group is independently unsubstituted or substituted with one or more, same or different substituents selected from halogen; Z1is independently of each other selected from CH, CF, CCH3, C-O-(C1-C2-alkylene)-C1-C2-alkoxy, and C-O-C1-C4-alkyl;15 Z2 is N, CH, or CCH3;Z3is H, C(=O)-C1-C4-alkyl; or C1-C4-alkyl; Z4is N, CH, CF, or C-O-C1-C4-alkyl; Z -alkyl; and Z l.20 In ano er pre erre em o men of the present invention,A is selected from the group consisting of - 30 - O O O NH NH O (A5), (A9), 14), 19), 5 n I 10 Z is C1-C4-alkyl, C1-C4-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl, wherein said C1-C4-alkyl, C1-C4-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl group is independently unsubstituted or substituted with one or more, same or different substituents selected from halogen; Z1is independently of each other selected from CH, CF, CCH3, C-O-(C1-C2-alkylene)-C1-C2-alkoxy, and C-O-C1-C4-alkyl;15 Z2 is N, CH, or CCH3;Z3is H, C(=O)-C1-C4-alkyl; or C1-C4-alkyl; Z4is N, CH, or C-O-C1-C4-alkyl; Z5is N, CH, CF, or C-O-C1-C4-alkyl; and Z6is N, CH or C-O-C1-C4-alkyl. 20 In a preferred embodiment of the present invention, Ais selected from the group consisting of - 31 - O O N O O NH Z7NH 30),5), 5nI ings: Zis C1-C4-alkyl, C1-C4-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl, wherein said C1-C4-alkyl, C1-10 C4-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl group is independently unsubstituted or substitutedwith one or more, same or different substituents selected from halogen; Z1is independently of each other selected from CH, CF, CCH3, C-O-(C1-C2-alkylene)-C1-C2-alkoxy, and C-O-C1-C4-alkyl; Z C(=O)-C1-C4-alkyl; or C1-C4-alkyl;15 Z , or C1-C4-alkyl,Z8is phenyl or pyridinyl, wherein said phenyl or pyridinyl group is independently unsubstituted or substituted with one or more, same or different substituents selected from halogen, and C1-C4-haloalkyl; Z9is H, C1-C4-alkyl, or tetrahydropyranyl; Z10is H, or C1-C4-alkyl; and20 Z11 is independently of each other selected from halogen, C1-C4-alkyl, and C1-C4-haloalkoxy.In a more preferred embodiment of the present invention, Ais selected from the group consisting of - 32 - O O N O O NH Z7NH 30),5), 5nI ings: Zis C1-C3-alkyl, C1-C3-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl, wherein said C1-C3-alkyl, C1-10 C3-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl group is independently unsubstituted or substitutedwith one or more, same or different substituents selected from F and Cl; Z1is independently of each other selected from CH, CF, CCH3, C-O-(C1-C2-alkylene)-C1-C2-alkoxy, and C-O-C1-C3-alkyl; Z C(=O)-C1-C3-alkyl; or C1-C3-alkyl;15 Z , or C1-C3-alkyl,Z8is phenyl or pyridinyl, wherein said phenyl or pyridinyl group is independently unsubstituted or substituted with one or more, same or different substituents selected from F, Cl, and C1-C3-haloalkyl; Z9is H, C1-C3-alkyl, or tetrahydropyranyl; Z10is H, or C1-C3-alkyl; and20 Z11 is independently of each other selected from F, Cl, C1-C3-alkyl, and C1-C3-haloalkoxy.In an even more preferred embodiment of the present invention, Ais selected from the group consisting of - 33 - O O N O O NH Z7NH 30),5), 5nI ings: Zis C1-C2-alkyl, C1-C2-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl, wherein said C1-C2-alkyl, C1-10 C2-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl group is independently unsubstituted or substitutedwith one or more, same or different substituents selected from F; Z1is independently of each other selected from CH, CF, CCH3, C-O-(C1-C2-alkylene)-C1-C2-alkoxy, and C-O-C1-C2-alkyl; Z3is H, C(=O)-C1-C2-alkyl; or C1-C2-alkyl;15 Z7 is H, or C1-C2-alkyl,Z8is phenyl or pyridinyl, wherein said phenyl or pyridinyl group is independently unsubstituted or substituted with one or more, same or different substituents selected from F, and C1-C2-haloalkyl; Z9is H, C1-C2-alkyl, or tetrahydropyranyl; Z10is H, or C1-C2-alkyl; and20 Z11 is independently of each other selected from F, C1-C2-alkyl, and C1-C2-haloalkoxy.In connection with the above embodiments, it is preferred that X, m and n have the following meanings: Xis CH2, C(=O)NH, or C(=O);m is 0 or 1; and - 34 - nis 0, 1 or 2.In a more preferred embodiment, Xis CH2, or C(=O);m is 0 or 1; and5 n is 0, 1 or 2.In an even more preferred embodiment, mis 0, i.e., X is absent; andn is 0, 1 or 2.In another even more preferred embodiment,10 X is CH2, or C(=O);m is 1; andn is 0, 1 or 2.In connection with the above embodiments and preferred embodiments, it is to be understood that the curled line in the structural formula of the substituent A indicates the attachment to the remainder of the molecule. 15 In one embodiment of the present invention, in the compound of formula I A X (A5),20 (A9),A14), - 35 - O Z2Z Z1NH Z1Z1A19), 5IZ py y, p y, py y p y g p p y ed orsubstituted with one or more, same or different substituents selected from halogen; Z1is independently of each other selected from CH, CF, and C-O-C1-C4-alkyl; Z2is CH, or CCH3;10 Z3 is H, or C1-C4-alkyl;Z4is N, CH, or C-O-C1-C4-alkyl; Z5is N, CH, CF, or C-O-C1-C4-alkyl; Z6is N, CH or C-O-C1-C4-alkyl.15 In a preferred embodiment of the present invention,A is selected from the group consisting ofO O O (A5), (A9), 14), - 36 - O Z2Z Z1NH Z1Z1A19), 5I d Z6h g g Zis pyridinyl, or phenyl, wherein said pyridinyl or phenyl group is independently unsubstituted orsubstituted with one or more, same or different substituents selected from halogen; Z1is independently of each other selected from CH, CF, and C-O-C1-C4-alkyl;10 Z2 is CH, or CCH3;Z3is H, or C1-C4-alkyl; Z4is N, CH, or C-O-C1-C4-alkyl; Z5is N, CH, CF, or C-O-C1-C4-alkyl; Z6is CH or C-O-C1-C4-alkyl. 15 In connection with the above embodiments it is to be understood that the curled line in the structural formula of the substituent A indicates the attachment to the remainder of the molecule. In a first alternative embodiment regarding the substituents A, X and m the following meanings with regard to20 m and X are preferred:m is 0 and X is absent.In connection with this first alternative embodiment, the following definitions with regard to the substituent A are preferred: Ais selected from the group consisting of - 37 - O O O N NH N NH (A9), In , , , wing 5meanings:Z1is independently of each other selected from CH, CF, and C-O-C1-C4-alkyl; Z2is CH, or CCH3; Z4is N, CH, or C-O-C1-C4-alkyl; Z l.10 P llowing meanings:Z 1is independently of each other selected from CH, and CF; Z2is CH, or CCH3; Z4is N, or CH; Z5is N, CH, or CF.15 More preferably, Z1, Z2, Z4 and Z5 have the following meanings:Z1is independently of each other selected from CH, and CF; Z2is CH, or CCH3; Z4is CH; Z5is CH, or CF. 20 In view of the above, in a particularly preferred embodiment of the invention, in the compounds of formula I as defined above, Ais selected from the group consisting ofO (A9), 256-3), - 38 - O O F O NH 7-3), I mula o . 5 Thus, particularly preferred compounds of the invention are compounds of formula I as compiled in the tables below. Table 1 Compounds of the formula I, in which m is 0 and X is absent, R is CH3, R1is H, and R2and A correspond in10 each case to one row of Table B.Table 2 Compounds of the formula I, in which m is 0 and X is absent, R is CH3, R1is CH3, and R2and A correspond in each case to one row of Table B. Table B No. R2 A - 39 - No. R2 AB-15 CH3 A1 d in the Tables above, it is to be understood that the compounds may be present in the form of the corresponding pharmaceutically acceptable salt, preferably in the form of the formic acid salt. 5In a second alternative embodiment regarding the substituents A, the following meanings with regard to mand X are preferred: mis 1, andX is CH2 or C(=O).Preferably, m and X have the following meanings:10 m is 1, andX is C(=O).In connection with this second alternative embodiment, the following definitions with regard to the substituent A are preferred: Ais selected from the group consisting of - 40 - Z Z Z 12F N N Z 10), (A8),I wing 5m Zis pyridinyl, or phenyl, wherein said pyridinyl or phenyl group is independently unsubstituted orsubstituted with one or more, same or different substituents selected from halogen; Z1is independently of each other selected from CH, CF, and C-O-C1-C4-alkyl; Z2is CH, or CCH3;10 Z3 is H, or C1-C4-alkyl;Z6is CH or C-O-C1-C4-alkyl. Preferably, Z, Z1, Z2, Z3and Z6have the following meanings: Zis pyridinyl or phenyl, wherein said phenyl group is independently unsubstituted or substituted withone or more, same or different substituents selected from halogen;15 Z1 is independently of each other selected from CH, CF, and C-O-C1-C2-alkyl;Z2is CH, or CCH3; Z3is H, or C1-C2-alkyl; Z6is CH or C-O-C1-C2-alkyl. Particularly preferably, Z, Z1, Z2, Z3and Z6have the following meanings:20 Z is pyridinyl or phenyl, wherein said pyridinyl or phenyl group is independently unsubstituted orsubstituted with one or more, same or different substituents selected from F; Z1is independently of each other selected from CH, CF, and C-O-C1-alkyl; Z2is CH, or CCH3; Z3is H, or C1-alkyl;25 Z6 is CH or C-O-C1-alkyl.In connection with A being selected from A14 or A15 it is to be understood that the substituent Z is preferably in 4-, or 5- position relative to the heteroatom of said 5-membered ring, more preferably in 4-position relative to the heteroatom of said 5-membered ring. - 41 - Further, in connection with the above embodiments it is to be understood that the curled line in the structural formula of the substituent A indicates the attachment to the remainder of the molecule. In view of the above, in a particularly preferred embodiment of the invention, in the compounds of formula I as 5defined above,A is selected from the group consisting ofF 9-4), F F 9-8), 0-3), 10 0-7), F -11), 3-2),4-2), - 42 - F 6-2), 6-5), F 8-7), 5 -11), -15), 5-1), In co eco e a oe e o e s, s o e u esoo a e cu e e e s ucua omula10 of the substituent A indicates the attachment to the remainder of the molecule.Thus, particularly preferred compounds of the invention are compounds of formula I as compiled in the tables below. - 43 - Table 3 Compounds of the formula I, in which m is 1 and X is CH2, R is CH3, R1is H, and R2and A correspond in each case to one row of Table C. Table 4 5Compounds of the formula I, in which m is 1 and X is CH2, R is CH3, R1 is CH3, and R2 and A correspond ineach case to one row of Table C. Table 5 Compounds of the formula I, in which m is 1 and X is C(=O), R is CH3, R1is H, and R2and A correspond in each case to one row of Table C.10 Table 6Compounds of the formula I, in which m is 1 and X is C(=O), R is CH3, R1is CH3, and R2and A correspond in each case to one row of Table C. Table C 15 No. R2 A No. R2 AC-1 H A19-1 C-21 H A20-12 - 44 - No. R2 A No. R2 AC-41 H A18-7 C-74 CH3 A20-10 - 45 - No. R2 AC-107 CH3 A21

[0002] - 46 - With regard to the compounds compiled in the Tables above, it is to be understood that the compounds may be present in the form of the corresponding pharmaceutically acceptable salt, preferably in the form of the formic acid salt. 5The compounds of formula I as defined in the above tables are particularly advantageous for mediatingproteasome degradation of undesired proteins for use in the treatment and / or prevention of diseases where undesired proteins and protein accumulation plays a role (Njomen and Tepe (in: Proteasome Activation as a New Therapeutic Approach To Target Proteotoxic Disorders. J Med Chem. 2019; 62(14):6469-6481. doi:10.1021 / acs.jmedchem.9b00101); Opoku-Nsiah K. A. et al., CellPress Translational Research, Aim for10 the core: suitability of the ubiquitin-independent 20S proteasome as a drug target in neurodegeneration(2018); Chondrogianni N. et al., Ageing Research Reviews, Proteasome activation: An innovative promising approach for delaying aging and retarding age-related diseases (2014); Coleman R.A. et al., ACS Pharmacology & Translational Science, All about the core: A Therapeutic strategy to prevent protein accumulation with proteasome core particle stimulators (2018)). Therefore, the compounds of formula I as15 defined in the above tables may particularly advantageously be used in the pharmaceutical compositions ofthe present invention as well as the medical uses as defined herein. In one embodiment the present invention refers to the use of the compound of formula I provided herein for an in vitro method for mediating proteasome stimulation. 20 In another embodiment of the present invention, the compounds of formula I provided herein stimulate proteasome activation in the 20S CP assay by at least 30 % over a non-stimulating control compound (.e.g., DMSO).25 In one embodiment, the compound of formula I stimulates proteasomal activity of the 20S CP (core particle)of the proteasome by at least 50% over basal activity. In another embodiment, the compound of formula I stimulates proteasomal activity of the 20S CP (core particle) of the proteasome by at least 100% over basal activity. In a preferred embodiment, the compound of formula I stimulates proteasomal activity of the 20S CP of the proteasome by at least 150% over basal activity. In an even more preferred embodiment, the30 compound of formula I stimulates proteasomal activity of the 20S CP of the proteasome by at least 200%over basal activity. Proteasomal activity of the compound of formula I may be measured using purified 20S CP of the proteasome, wherein the concentration of the 20S CP of the proteasome is 5 nM. Incubation of the35 compound of formula I with the 20S CP of the proteasome and an activity probe (e.g. labeled protein orartificial substrate) may occur for e.g. 1h at 37°C. DMSO or any other suitable agent may be used as a - 47 - control for measuring basal activity. Degradation of the activity probe serves as a readout and may be measured by any suitable method. In the context of the above described assays, basal activity of the proteasome is considered to be 100%. For example, stimulation by 50% over basal activity thus refers to 150% activity. 5 In one embodiment, the 20S CP of the proteasome is the 20S CP of the human proteasome. Therefore, the compound of formula I of the present invention is preferably a compound of any one of tables 1 to 6 as defined above, and the present invention preferably relates to pharmaceutical compositions10 comprising the same and to medical uses thereof.However, it is preferred that the compound of formula I of the present invention is not any one of O F O N , 15 , - 48 - In other words, this means that the compound of formula I of the present application is not O NH is , N is not , 5 is not, is not , is not r - 49 - O NH i . I the compound of formula I of the present invention is not any one of O F O N , , 5

[0003] - 50 - O N , O , , , 5 In particularly preferred embodiments, the compound of formula I is a compound selected from the compounds in the following table: - 51 - N O (R,S) N *NHHCOOH (RS) - 52 - (R,S) N (R,S) N (R,S N) In further particularly preferred embodiments, the compound of formula I is a compound selected from the compounds in the following table: - 53 - O (R,S) N NHN * HCOOH (RS) F - 54 - N N (R,S N (R,S) (R,S) ) - 55 - F O F N In to be understood that “(±)-trans” indicated in the structural formula of the compounds of formula I of the present invention denotes in each case the two possible trans enantiomers for the chiral centers which are marked on the respective carbon atom with *. 5 In a further embodiment of the present invention, the compound of formula I is a compound selected from compounds 37 to 108 as referred to in the example section. In this connection, it is to be understood that compounds 37 to 108 include the enantiopure isomers, which are referred to in the example section as A and B of the respective compound and which are directed to one embodiment of the present invention. 10 - 56 - In a particularly preferred embodiment of the present invention, the compound of formula I is a compound selected from the compounds of Table 2 in combination with Table B-24, Table 4 in combination with Table C-69 and Table 6 in combination with Table C-75. 5In one embodiment, the present invention relates to the following compoundsF N or use in medicine. In , p es to the following compounds F or use in the treatment of a disease selected from the10 g y an undesired proteinaceous target molecule, caused by an accumulated pathological protein, proteopathies, alpha-synucleinopathies, tauopathies, neurodegenerative diseases associated with alpha-synuclein accumulation or aggregation, neurodegenerative diseases associated with tau accumulation or aggregation, neurodegenerative diseases associated with beta-amyloid accumulation or aggregation, Parkinson’s disease, Alzheimer's disease,15 dementia, dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, Pick'sdisease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxias, prion diseases, cystic fibrosis, alpha 1 antitrypsin deficiency, diabetes type-2, retinitis pigmentosa, cataracts, amyloidosis, desmin- related cardiomyopathy, multiple system atrophy, cancer, cancer tumor metastasis, and aging.20 In one embodiment, the present compounds of formula I as defined above stimulate proteasome activity.In a preferred embodiment, the present compounds of formula I as defined above stimulate the 20S proteasome subunit. Description of pharmaceutical compositions according to the present invention 25 In one embodiment, the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I as defined above and optionally a - 57 - pharmaceutically acceptable carrier, diluent or excipient. In another embodiment, the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I as defined above and a pharmaceutically acceptable carrier, diluent or excipient. 5Pharmaceutically acceptable excipients are well known in the pharmaceutical art, and are described, forexample, in Remington's Pharmaceutical Sciences, 15thEd., Mack Publishing Co., New Jersey (1975). The pharmaceutical excipient can be selected with regard to the intended route of administration and standard pharmaceutical practice. The excipient must be acceptable in the sense of being not deleterious to the recipient thereof. 10 The pharmaceutical compositions of the present invention can be produced in a manner known per se to the skilled person as described, for example, in Remington's Pharmaceutical Sciences, 15thEd., Mack Publishing Co., New Jersey (1975).15 Pharmaceutically useful excipients that may be used in the formulation of the pharmaceutical composition ofthe present invention may comprise, for example, carriers, vehicles, diluents, solvents such as monohydric alcohols such as ethanol, isopropanol and polyhydric alcohols such as glycols and edible oils such as soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, sesame oil, oily esters such as ethyl oleate, isopropyl myristate, binders, adjuvants, solubilizers, thickening agents, stabilizers, disintegrants, glidants,20 lubricating agents, buffering agents, emulsifiers, wetting agents, suspending agents, sweetening agents,colorants, flavors, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-ß-cyclodextrin, polyvinylpyrrolidone, low melting waxes, and ion exchange resins. 25 The routes for administration (delivery) of the compounds of formula I of the invention include, but are not limited to, one or more of: oral (e. g. as a tablet, capsule, or as an ingestible solution), topical, mucosal (e. g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e. g. by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial,30 intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (includingintravitreal or intracameral), transdermal, rectal, buccal, epidural and sublingual. For example, the compounds of the present invention can be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for35 immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications. - 58 - The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, D-ɑ-tocopheryl polyethylene glycol succinate (TPGS), disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates,and granulation binders such as polyvinylpyrrolidone, 5hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia.Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the agent may be combined with various sweetening or10 flavoring agents, coloring matter or dyes, with emulsifying and / or suspending agents and with diluents suchas water, ethanol, propylene glycol and glycerin, and combinations thereof. If the compounds of the present invention are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally,15 intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administeringthe compounds; and / or by using infusion techniques. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under20 sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilledin the art. As indicated, the compounds of the present invention can be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a25 pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e.g.dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container, pump, spray or nebulizer may contain a30 solution or suspension of the active compound, e. g. using a mixture of ethanol and the propellant as thesolvent, which may additionally contain a lubricant, e. g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.35 Alternatively, the compounds of the present invention can be administered in the form of a suppository orpessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or - 59 - dusting powder. The compounds of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch. They may also be administered by the pulmonary or rectal routes. They may also be administered by the 5ocular route. For ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic,pH was adjusted, sterile saline, or, preferably, as solutions in isotonic, pH was adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.10 For application topically to the skin, the compounds of the present invention can be formulated as a suitableointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid15 paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.The compounds of the invention may also be used in combination with other therapeutic agents. When a compound of the invention is used in combination with a second therapeutic agent active against the same disease, the dose of each compound may differ from that when the compound is used alone. 20 Thus, the invention relates to a combination comprising a therapeutically effective amount of a compound of formula (I), and one or more therapeutic agents. The one or more therapeutic agents can be selected, for example, from the group consisting of compounds against oxidative stress; anti-amyloid drug; anti-apoptotic compounds; metal chelators; inhibitors of DNA repair such as pirenzepine and metabolites; 3-amino-1-25 propanesulfonic acid (3APS); 1,3-propanedisulfonate (1,3PDS); alpha-secretase activators; beta- andgamma-secretase inhibitors including BACE1; Tau proteins; neurotransmitters; beta-sheet breakers; attractants for amyloid beta clearing / depleting cellular components; inhibitors of N-terminal truncated amyloid beta including pyroglutamated amyloid beta 3-42; anti-inflammatory molecules; cholinesterase inhibitors (ChEIs) such as tacrine, rivastigmine, donepezil, and / or galantamine; M1 agonists; amyloid-beta or30 Tau modifying drugs; nutritive supplements; neurological drugs; corticosteroids, antibiotics, antiviral agents.The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route. When35 administration is sequential, either the compound of the invention or the second therapeutic agent may beadministered first. When administration is simultaneous, the combination may be administered either in the - 60 - same or different pharmaceutical composition. When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art. 5 Further, the pharmaceutical composition according to the present invention may also contain the compound of formula I according to the present invention as a prodrug. The prodrug may be inactive prior to administration but may be converted to an active compound of the invention in vivo. In other words, the term “prodrug” according to the present invention refers to any compound that undergoes biotransformation to any10 of the compounds of formula I of the present invention before exhibiting pharmacological effects.Indications, for which the compounds of formula I of the present invention may be used. In one embodiment, the present invention relates to a compound of formula I as defined above or a15 pharmaceutical composition as defined above for use in medicine.In one embodiment, the present invention provides a method for treating any of the conditions referred to herein, wherein the method comprises administering a pharmaceutically effective amount of a compound of formula I to a patient in need thereof. 20 In one embodiment, the present invention relates to a compound of formula I as defined above for use as an inducer / stimulator of proteasomal degradation. In another embodiment, the present invention encompasses the use of a compound of formula I as defined above or the pharmaceutical composition as defined above for improving proteasome function. The uses may be a cosmetic use and / or in vivo and / or in vitro, for example in25 an in vitro assay.Modified or altered proteasomal degradation has been shown to be relevant in neurodegenerative disease, as demonstrated by the accumulation of protein aggregates, for example in Alzheimer disease and Parkinson’s disease.30 Therefore, in one embodiment of the present invention the compounds of formula I as defined above or thepharmaceutical composition as defined above are for use in the treatment of a disease selected from the group consisting of a disease or condition caused by an undesired proteinaceous target molecule, caused by an accumulated pathological protein, proteopathies, alpha-synucleinopathies, tauopathies, neurodegenerative diseases associated with alpha-synuclein accumulation or aggregation,35 neurodegenerative diseases associated with tau accumulation or aggregation, neurodegenerative diseasesassociated with beta-amyloid accumulation or aggregation, Parkinson’s disease, Alzheimer's disease, - 61 - dementia, dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, Pick's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxias, prion diseases, cystic fibrosis, alpha 1 antitrypsin deficiency, diabetes type-2, retinitis pigmentosa, cataracts, amyloidosis, desmin- related cardiomyopathy, multiple system atrophy, cancer, cancer tumor metastasis, and aging. 5 In another embodiment, the present invention relates to a compound of formula I as defined above or a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I as defined above, for use in the treatment of a disease selected from the group consisting of a disease or condition caused by an undesired proteinaceous target molecule, caused by an accumulated pathological10 protein, proteopathies, alpha-synucleinopathies, tauopathies, neurodegenerative diseases associated withalpha-synuclein accumulation or aggregation, neurodegenerative diseases associated with tau accumulation or aggregation, neurodegenerative diseases associated with beta-amyloid accumulation or aggregation, Parkinson’s disease, Alzheimer's disease, dementia, dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, Pick's disease, amyotrophic lateral sclerosis, Huntington's disease,15 spinocerebellar ataxias, prion diseases, cystic fibrosis, alpha 1 antitrypsin deficiency, diabetes type-2, retinitispigmentosa, cataracts, amyloidosis, desmin-related cardiomyopathy, multiple system atrophy, cancer, cancer tumor metastasis, aging, and bacterial infections. By “treatment” or “treating” is meant any treatment of a disease or disorder, in a mammal, including:20 preventing or protecting against the disease or disorder, that is, causing, the clinical symptoms of the diseasenot to develop; inhibiting the disease, that is, arresting or suppressing the development of clinical symptoms; and / or relieving the disease, that is, causing the regression of clinical symptoms. By “amelioration” is meant the prevention, reduction or palliation of a state, or improvement of the state of a subject; the amelioration of a stress is the counteracting of the negative aspects of a stress. Amelioration includes but does not require25 complete recovery or complete prevention of a stress. Amelioration includes in particular the removal of anundesired protein through proteasomal degradation according to the present invention. In another embodiment of the present invention, the compound of formula I as defined above is for use according to the present invention, wherein said prevention and / or treatment comprises a combination of at30 least two compounds for use according to the present invention, and / or a combination with at least oneadditional pharmaceutically active substance for said undesired protein-related disease or condition. It is to be understood that the present compound of formula I as defined above or the pharmaceutical composition as defined above comprising the compound of formula I as defined above is for use to be administered to a human patient. The term “administering” means administration of a sole therapeutic agent35 or in combination with another therapeutic agent. It is thus envisaged that the pharmaceutical composition ofthe present invention is employed in co-therapy approaches, i.e. in co-administration with other medicaments - 62 - or drugs and / or any other therapeutic agent which might be beneficial in the context of the methods of the present invention. Nevertheless, the other medicaments or drugs and / or any other therapeutic agent can be administered separately from the compound for use of the present invention, if required, as long as they act in combination (i.e., directly and / or indirectly) with the present compounds for use. 5 In another embodiment of the present invention, a method for treating or preventing a disease or condition in a mammalian subject, such as a human, is provided, comprising administering to a subject in need of said treatment or prevention an effective amount of the compound of formula I as defined above or the pharmaceutical composition as defined above, wherein the disease is selected from the group consisting of a10 disease or condition caused by an undesired proteinaceous target molecule, caused by an accumulatedpathological protein, proteopathies, alpha-synucleinopathies, tauopathies, neurodegenerative diseases associated with alpha-synuclein accumulation or aggregation, neurodegenerative diseases associated with tau accumulation or aggregation, neurodegenerative diseases associated with beta-amyloid accumulation or aggregation, Parkinson’s disease, Alzheimer's disease, dementia, dementia with Lewy bodies, frontotemporal15 dementia, progressive supranuclear palsy, Pick's disease, amyotrophic lateral sclerosis, Huntington'sdisease, spinocerebellar ataxias, prion diseases, cystic fibrosis, alpha 1 antitrypsin deficiency, diabetes type- 2, retinitis pigmentosa, cataracts, amyloidosis, desmin-related cardiomyopathy, multiple system atrophy, cancer, cancer tumor metastasis, and aging. In another embodiment of the present invention, a method for treating or preventing a disease or condition in20 a mammalian subject, such as a human, is provided, comprising administering to a subject in need of saidtreatment or prevention an effective amount of the compound of formula I as defined above or the pharmaceutical composition as defined above, wherein the disease is selected from the group consisting of a disease or condition caused by an undesired proteinaceous target molecule, caused by an accumulated pathological protein, proteopathies, alpha-synucleinopathies, tauopathies, neurodegenerative diseases25 associated with alpha-synuclein accumulation or aggregation, neurodegenerative diseases associated withtau accumulation or aggregation, neurodegenerative diseases associated with beta-amyloid accumulation or aggregation, Parkinson’s disease, Alzheimer's disease, dementia, dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, Pick's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxias, prion diseases, cystic fibrosis, alpha 1 antitrypsin deficiency, diabetes type-30 2, retinitis pigmentosa, cataracts, amyloidosis, desmin-related cardiomyopathy, multiple system atrophy,cancer, cancer tumor metastasis, aging, and bacterial infections. Thus, it has surprisingly been found that the compounds of formula I as defined above were shown to be effective inducers / stimulators of the proteasome.35 The present invention is further illustrated by the following examples. - 63 - Examples The compounds of the present invention may be prepared in accordance with the definition of a compound of formula I, as defined herein, by the routes described in the following Schemes or Examples. All methods described herein can be performed in any suitable order unless otherwise indicated herein, or otherwise 5clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g. "such as")as used herein is intended to merely illustrate the invention and does not pose a limitation on the scope claimed. In the following general methods, R, R1and R2are as previously defined in the above embodiments or limited to the designations in the Schemes. Unless otherwise stated, starting materials are either commercially available or are prepared by known methods. 10 General synthetic schemes for the preparation of building blocks of this invention: 1.1. General synthetic schemes for the preparation of the preparative examplesScheme 1 ns R trans15 F or example, commercially available (E)-(2-nitrovinyl)benzene-type derivative 1 with substituents R, asindicated in Scheme 1 can be stirred with commercially available N-benzyl-1-methoxy-N- ((trimethylsilyl)methyl)methanamine in the presence of a suitable acid (e.g. TFA.) in a suitable solvent (e.g. DMC, etc.) to afford product 2. The NO2-moiety can be reduce to NH2with Zn dust and ammonium chloride in - 64 - a suitable solvent mixture (e.g. THF,H2O) to afford compound 3. N-Alkylation of the NH2-moiety of 3 under reductive amination conditions with an appropriate aldehyde (e.g formaldehyde), reductive agents (eg NaCNBH3) in the presence of suitable acid (e.g. TFA) in a suitable solvent (e.g. DMC, etc.) affords compound 4. Cleavage of the Benzyl protecting group employing a catalyst system (eg Pd(OH2) and 5poly(methylhydrosiloxane) followed by Boc-protection with commercial available Boc-anhydride in a suitablesolvent (e.g. MeOH) affords compound 5. A Boc-cleavage by acid treatment affords 6 as a HCl-salt. Scheme 2 Cl O base N Y solvent N Cl Cl 7 Y=Fluorobenzene, 1H-pyrazole,10 1-methyl-1H-pyrazole For example, commercially available 2,4-dichloropyrimidine derivative 7 as indicated in Scheme 2 can be reacted with a suitable base (e.g. sodium hydroxide) in a suitable solvent (e.g. dioxane) to afford products 8.15 1.2. General synthetic schemes for the preparation of the ExamplesScheme 3

[0004] - 65 - Z O A R 6 Z 21 2O Xm N N N H 13 H Y1T (e.g. compounds 8) or commercially available compounds 9 and 10 with compound (6) using a suitable base (e.g.potassium carbonate) in a suitable solvent (e.g. DMF) as described in the examples of the present5 invention. In another example, compound of formula (I) can be obtained by reacting 11 or 12 or 13 withcompound 6 employing the reductive amination conditions in a suitable solvent (e.g. CH2Cl2, MeOH) to afford compound of formula (I). Scheme 4

[0005] - 66 - HO O O OH Z 19 H Alternatively, 6 can be reacted with carboxylic acid 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 employing the amide coupling reagent conditions (e.g HOBt, EDC, HATU, T3P) a suitable base (e.g. triethylamine, DIPEA, ) 5in a suitable solvent (e.g. DMF, THF) to afford compound of formula (I).10 15 - 67 - Scheme 5 (±)-trans R R2 N R1 R I ected pyrrolo[2,3-b]pyridine derivatives 24 and 26 with 6 employing catalyst / ligand system (e.g. Pd2(dba)3, 5Xantphos), a base (e.g. Cs2CO3 and a suitable solvent e.g. dioxane, water) to afford the palladium couplingproduct 25 and 27 with final removal of tosyl moiety with a suitable base (e.g. NaOH) in a suitable solvent (e.g. dioxane, water). Scheme 6 R2 Boc R1 R2 N R1 R 10 As reported in Scheme 6 appropriate commercially available indole 28 and 31 can be protected with Boc- anhydride in a suitable solvent (e.g. THF) affords compounds 29 and 32. The aldehyde moieties can be reacted with compound 6 employing the reductive amination conditions (e.g. NaCNBH3) MeOH in a suitable15 solvent (e.g. MeOH) to afford compound of formula (I) after final Boc-celavage using suitable base (e.g. HCl)in a suitable solvent (e.g.DCM). - 68 - Scheme 7 R R2 O N R1 R 5A agentconditions (e.g HATU) a suitable base (e.g. DIPEA, ) in a suitable solvent (e.g. DMF, THF). The halogenated compounds 35, 37, 39 as indicated in the Scheme 7 can be reacted with commercially available boronic acid or ester under a Suzuki coupling employing a catalyst / ligand system (e.g. PdCl2(dppf)2XCH2Cl2) a base (e.g. Cs2CO3) and a suitable solvent (e.g. dioxane, water) to afford compound of formula (I).Trans and cis racemic10 mixture were separated using chiral chromatography to afford enantiopure compounds of formula (I).EXAMPLES EXEMPLIFICATION OF THE INVENTION The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be15 construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to beunderstood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims. 20 - 69 - Compounds of the present disclosure may be prepared by methods known in the art of organic synthesis. In all of the methods, protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (2014) Protective Groups in Organic 5Synthesis, 5th edition, John Wiley & Sons). These groups are removed at a convenient stage of thecompound synthesis using methods that are readily apparent to those skilled in the art. Unless otherwise stated, all reagents and solvents were obtained from commercial sources and used without further purification. All starting materials, building blocks, reagents, acids, bases, dehydrating agents,10 solvents, and catalysts utilized to synthesize the compounds of the present invention are either commerciallyavailable or can be produced by organic synthesis methods known to one of ordinary skill in the art. The chemical names were generated using ChemDraw Professional v21.0.0.28 from PerkinElmer.15 Temperatures are given in degrees Celsius. If not mentioned otherwise, all evaporations are performed underreduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20- 133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art. 20 Abbreviations ACN Acetonitrile - 70 - H2O2Hydrogen peroxide H2SO4Sulfuric acid ith - 71 -THF TetrahydrofuranTLC Thin layer chromatography - 72 - Rt Retention timeXantphos 4,5-Bis-(diphenylphosphino)-9,9-dimethylxanthen NMR: 1H-NMR spectra were recorded on Bruker AVANCE NEO 400MHz spectrometers in deuterated solvents. Chemical shifts (δ) are reported in parts per million and coupling constants (J values) in hertz. Spin 5multiplicities are indicated by the following symbols: s (singlet), d (doublet), t (triplet), q (quartet), m(multiplate), bs (broad singlet). Deuterated solvents are given in parentheses and have a chemical shifts of dimethyl sulfoxide (δ 2.50 ppm), methanol (δ 3.32 ppm), chloroform (δ 7.28 ppm), or other solvent as indicated in NMR spectral data.10 MS: Mass Spectra were obtained on Waters Acquity QDa spectrometer with empower and a water Acquity H-class equipped with PDA spectrometer with empower software. chromatography was performed using c18 column and suitable solvent as indicated in specific examples. Flash Column Chromatography System: Flash purification was conducted with a Biotage Isolera with HP-Sil15 or KP-NH SNAP cartridges (Biotage) and Combi-flash RF+ TELE DYNE ISCO. The solvent gradient isindicated in specific examples. Thin layer chromatography (TLC): TLC was carried out on silica gel plates with UV detection.20 LCMS methodsColumn ped °C, cid bile min ent B); in, and - 73 - Negative, Cone voltage :-30 and 10 V, capillary voltage:- 3.0 KV, Extractor Voltage:-2 V, Rf Lens:- 0.1 V, Temperature of source:- 120°C,Temperature of Probe:- 400 °C,Cone Gas Flow:- 100 L / Hr, ped re: % B: 0.8 t to = 3 B) 0.8 0.8 ass ive, ctor ce:- lt , and 0.8 of w:- with uto d in Milli 0.8 t to = 3 B) 0.8 0.8 ion and KV, ce:- w: - with °C, mic cid 0.8 t to = 3 B) 0.8 - 74 - mL / min; end of run at T = 4 min (97% A, 3% B), Flow rate: 0.8 mL / min, Run Time:- 4 min. UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation: positive and ctor C, NA. with °C, mic cid 0.8 t to = 3 B) 0.8 0.8 and ctor C, NA. hed on, 0C, by d in A, 0% .01 B), od: tive 0.8 ce: lt , d in rile. A, T = ent end un - 75 - Default , Desolvation Gas flow:-Default. Machine Details: Waters AQUITY with PDA detector and QDA Performance, Column temperature: Milli min 0.8 ; T 0% A, ion d in rile. A, T = d of un and 0.8 of w:- d in rile. A, T = end in, and 0.8 of w:- SYNTHESIS OF THE PREPARATIVE EXAMPLES Preparative Example 1: (±)-trans-N,N-dimethyl-4-(p-tolyl)pyrrolidin-3-amine hydrochloride - 76 - ON Sihyde, 3 c,OH,P Step A To a stirred solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (29.09 g, 122.56 mmol) 5and (E)-1-methyl-4-(2-nitrovinyl)benzene (20 g, 122.56 mmol) in DCM (250 mL) was added TFA (1.41 g,12.25 mmol) dropwise at 0°C. The resulting reaction mixture was stirred at rt for 5 h. The reaction mixture was poured into 5% NaHCO3solution (250 mL) and extracted with DCM (3 x 300 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (Silica; 0 to 5% ethyl acetate in n-hexane) to afford (±)-trans-1-benzyl-3-10 nitro-4-(p-tolyl)pyrrolidine (20.0 g, 67.48 mmol, 44 % yield).LCMS Method: UC01_FAR1; Rt: 1.479 min; MS: 297 [M + H]+ Step B To a stirred solution of (±)-trans-1-benzyl-3-nitro-4-(p-tolyl)pyrrolidine from Step A (14.5 g, 48.92 mmol) in15 THF: water (1:1; 145 mL) was added ammonium chloride (26.18 g, 489.2 mmol) followed by Zn-dust (31.03g, 489.2 mmol) and stirred at rt for 2 h. The reaction mixture was filtered through a celite bed and the filtrate was extracted with ethyl acetate (2 × 150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (±)-trans-1-benzyl-4-(p-tolyl)pyrrolidin-3-amine (17 g, crude) which was used in the next step without purification.20 LCMS Method: UC01_FAR1; Rt: 0.877 min; MS: 266.9 [M + H]+Step C - 77 - To a stirred solution of (±)-trans-1-benzyl-4-(p-tolyl)pyrrolidin-3-amine from Step B (17 g, 63.90 mmol) in MeOH (170 mL) was added formaldehyde (33% solution; 15.32 g, 511.20 mmol) followed by acetic acid (3.64 mL, 63.90 mmol) and stirred at rt for 2 h, then NaCNBH3(6.02 g, 95.85 mmol) was added and the mixture stirred at rt for a further 2 h. The reaction mixture was concentrated under reduced pressure. The 5resulting crude material was diluted with water and extracted with EtOAc (2 x 200 mL). The combinedorganic layers were dried over Na2SO4, filtered and concentrated under a reduced pressure to afford (±)- trans-1-benzyl-N,N-dimethyl-4-(p-tolyl)pyrrolidin-3-amine (11 g, 37.35 mmol, 76% over two steps). LCMS Method: UC01_FAR1; Rt: 6.86 min; MS: 295.1 [M + H]+10 Step DTo a solution of (±)-trans-1-benzyl-N,N-dimethyl-4-(p-tolyl)pyrrolidin-3-amine from Step C (11.0 g, 37.41 mmol) in MeOH (100 mL) was added Pd(OH)2(11.0 g, 100% w / w) and stirred at rt for 10 mins. To this reaction mixture poly(methylhydrosiloxane) (11 g, 100% w / w) was added and further stirred at rt for 10 mins. After 10 mins, Boc-anhydride (11.0 g, 54.25 mmol) was added and stirred at rt for 5 h. After that, the reaction15 mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure. Theresulting crude was purified by column chromatography (Silica; 0 to 12% ethyl acetate in n-hexane) to afford (±)-trans-tert-butyl-3-(dimethylamino)-4-(p-tolyl)pyrrolidine-1-carboxylate (6.0 g, 19.70 mmol, 53% yield). LCMS Method: UC01_FAR1; Rt: 1.37 min; MS: 305 [M + H]+20 Step ETo a solution of (±)-trans-tert-butyl-3-(dimethylamino)-4-(p-tolyl)pyrrolidine-1-carboxylate compound from Step D (6.0 g, 19.70 mmol) in DCM (50 mL) was added 4M HCl in dioxane (12 mL, 2 vol) drop-wise and stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure and the solid material was triturated with EtOAc to afford as trans racemic mixture (±)-trans-N,N-dimethyl-4-(p-tolyl)pyrrolidin-3-amine25 hydrochloride (4.0 g, 16.61 mmol, 84% yield).1H NMR (DMSO-d6): δ 11.54 (s, 1H), 10.05 (s, 1H), 9.72 (s, 1H), 7.44 (d, J = 8 Hz, 2H), 7.24 (d, J = 7.6 Hz, 2H), 4.24 - 4.24 (m, 1H), 3.87 - 3.73 (m, 4H), 3.14 (t, J = 10.4 Hz, 1H), 2.66 (bs, 6H), 2.30 (s, 3H). LCMS Method: UC01_FAR1; Rt: 0.538 min; MS: 204.9 [M + H]+30 Preparative Example 2: 2-chloro-8-fluoroquinazolin-4(3H)-oneH Cl Preparative Example 2Step A - 78 - To a stirred solution of 2,4-dichloro-8-fluoroquinazoline ( 0.3 g, 1.38 mmol) in dioxane (3 mL) was added 1M NaOH (10 vol) at rt and stirred for 2 h. The reaction mixture was diluted with water (10 mL) acidified with 1N HCl, and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-chloro-8-fluoroquinazolin-4(3H)-one (0.2 g, 1.007 mmol, 573% yield).1H NMR (400 MHz, DMSO-d6): δ 13.48 (s, 1H) 7.90 (d, J = 8 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.56 - 7.51 (m, 1H). Preparative Example 3: 6-chloro-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Cl5 M NaOHO 55 °C, 2 h NHCl 10Preparative Example 3Step A A stirred solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (0.2 g, 1.05 mmol) in 5M NaOH (20 vol) was heated at 55 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting crude material was purified by normal phase column chromatography (silica; 0 to 5% methanol in DCM) to afford 6-15 chloro-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.15 g, 0.879 mmol, 83% yield).LCMS Method: UC01_FAR1; Rt: 0.49 min; MS: 168.9 [M - H]+Preparative Example 4: 6-chloro-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 1N NaOHCl O H Cl Preparative Example 420 Step ATo a stirred solution of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (0.3 g, 1.47 mmol) in dioxane (10 vol) was added 1N NaOH (3 mL) at rt and stirred for 2 h. After that, the reaction mixture was diluted with water (10 mL) acidified with 1N HCl and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-chloro-1-methyl-1,5-25 dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.2 g, 1.08 mmol, 73% yield).1H NMR (400 MHz, DMSO-d6): δ 13.21 (s, 1H) 8.06 (s, 1H), 3.97 (s, 3H). - 79 - Preparative Example 5: 6-chloro-1-(4-fluorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one Cl O N Cl O NHClample 5St ep To a stirred solution of (4-fluorophenyl) hydrazine (1 g, 7.92 mmol) in EtOH (15 mL) was added TEA (3.30 5mL, 23.78 mmol) at -20 °C followed by 2,4,6-trichloropyrimidine-5-carbaldehyde (1.67 g, 7.92 mmol) and themixture was stirred at -20 °C for 1 h then concentrated under vacuum and poured into water (150 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by normal phase column chromatography (Silica; 0 to 40% ethyl acetate in n-hexane) to afford 4,6-dichloro-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]10 pyrimidine (1 g, 3.53 mmol, 44 % yield) as an off white solid.LCMS Method: LCMS_Method_A, Rt: 2.65 min; MS: 285.1 [M + H]+. Step B A solution of 4,6-dichloro-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d] pyrimidine (0.50 g, 0.76 mmol) in15 4M NaOH (10 mL) was stirred at 60°C for 4 h then the mixture was acidified with acetic acid. Thesolid precipitate was filtered, washed with water and dried under vacuum to afford 6-chloro-1-(4- fluorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.120 g, 0.45 mmol, 50 % yield) as an off white solid. LCMS Method: LCMS_Method_A, Rt: 1.90 min; MS: 263 [M - H]+20 Preparative Example 7: (±)-trans4-(4-fluorophenyl)-N, N-dimethylpyrrolidin-3-amine - 80 - F hyde, cH O3, H,h NF dioxane, DCM, N F2 oc)2O, MeOH, N FPd(OH) , (Brt(RS) (R,S) 25h 12 hP Step A To a stirred solution of (E)-1-fluoro-4-(2-nitrovinyl) benzene (20 g, 119.66 mmol) and N-benzyl-1-methoxy-N- ((trimethylsilyl)methyl) methenamine (28.4 g, 119.66 mmol) in THF (300 mL) was added TFA (4.57 mL, 99.83 5mmol) dropwise at 0°C and the mixture was stirred at rt for 16 h then concentrated under vacuum. The crudeproduct was purified by normal phase column chromatography (Silica; 0 to 10% ethyl acetate in n-hexane) to afford (±)-trans-1-benzyl-3-(4-fluorophenyl)-4-nitropyrrolidine (12 g, 40 mmol, 33% yield). LCMS Method: UC_06_FAR1; Rt: 1.73 min; MS: 301.3 [M + H]+10 Step BTo a stirred solution of (±)-trans-1-benzyl-3-(4-fluorophenyl)-4-nitropyrrolidine (12 g, 39.93 mmol) from Step A in THF: water (1:1; 120 mL) was added NH4Cl (21.37 g, 399.56 mmol) followed by Zn-dust (25.32 g, 399.56 mmol) and the mixture was stirred at rt for 12 h then filtered through a celite bed. The filtrate was poured into water and extracted with ethyl acetate (2 × 500 mL). The combined organic layers were dried15 over Na2SO4, filtered and concentrated under vacuum to afford crude (±)-trans-1-benzyl-4-(4-fluorophenyl)pyrrolidin-3-amine (12.25 g). LCMS Method: UC_07_FAR1; Rt: 1.19 min; MS: 271.1 [M + H]+Step C - 81 - To a stirred solution of (±)-trans-1-benzyl-4-(4-fluorophenyl) pyrrolidin-3-amine (12.25 g, 45.31 mmol) from Step B in MeOH (120 mL) was added formaldehyde (33% solution in water; 30 mL, 44.24 mmol) followed by acetic acid (2.72 mL, 43.31 mmol) and the mixture was stirred at rt for 3 h then NaCNBH3(4.27 g, 67.96 mmol) was added and the mixture was stirred at rt for 12 h then concentrated under vacuum, poured into 5water (500 mL) and extracted with DCM (2 x 500 mL). The combined organic extracts were dried overNa2SO4, filtered and concentrated under vacuum to afford crude (±)-trans-1-benzyl-4-(4-fluorophenyl)-N, N- dimethylpyrrolidin-3-amine (7.5 g). LCMS Method: UC_01_FAR1; Rt: 1.73 min; MS: 299 [M + H]+10 Step DTo a solution of (±)-trans-1-benzyl-4-(4-fluorophenyl)-N, N-dimethylpyrrolidin-3-amine (3.5 g, 11.74 mmol) from Step C in MeOH (35 mL) was added Pd(OH)2(3.59 g, % w / w) and the mixture was stirred at rt for 10 minutes then poly(methylhydrosiloxane) (3.59 g, % w / w) was added and further stirred at rt for 10 minutes. Di-tert-butyl dicarbonate (3.59 g) was added and the mixture was stirred at rt for 12 h then filtered through a15 celite bed and the filtrate was concentrated under vacuum. The crude product was purified by normal phasecolumn chromatography (Silica; 0 to 10% methanol in dichloromethane) to afford (±)-trans-tert-butyl 3- (dimethyl amino)-4-(4-fluorophenyl) pyrrolidine-1-carboxylate (5 g, 16.23 mmol, Quantitative). LCMS Method: UC_01_FAR1; Rt: 1.24 min; MS: 308.8 [M + H]+20 Step ETo a solution of (±)-trans-tert-butyl 3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidine-1-carboxylate (2.1 g, 6.81 mmol) from Step D in DCM (21 mL) was added 4M HCl in dioxane (10.5 mL) dropwise and the mixture was stirred at rt for 5 h then concentrated under vacuum to afford the trans racemic mixture (±)-trans4-(4- fluorophenyl)-N, N-dimethylpyrrolidin-3-amine (2.5 g, 16.61 mmol, 84% yield).25 LCMS Method: UC_01_FAR1; Rt: 0.19 min; MS: 208.9 [M + H] +Preparative Example 8: 5-chloro-1,6-dihydro-7H-pyrazolo[4,3-d] pyrimidin-7-one Cl5M NaOHO H Cl Preparative Example 830 Step AA stirred solution of 5,7-dichloro-1H-pyrazolo[4,3-d] pyrimidine (0.22 g, 1.16 mmol) in 5M aqueous NaOH solution (2.5 mL) was stirred at 55 °C for 2 h then poured into cold water (10 mL), acidified with 1N HCl and - 82 - the solid precipitate was filtered and dried under vacuum to afford 5-chloro-1,6-dihydro-7H-pyrazolo[4,3-d] pyrimidin-7-one (0.18 g, 1.06 mmol, 90 % yield). 1H NMR: (400 MHz, DMSO-d6): δ 14.28 (s, 1H), 13.26 - 12.89 (m, 1H), 8.33 - 7.99 (m, 1H) LCMS Method: LCMS_Method_A; Rt: 0.84 min; MS: 168.88 [M - H]+5 Preparative Example 9: (±)-trans-4-(4-chlorophenyl)-N,N-dimethylpyrrolidin-3-amine Clhyde, cH O3, H,h NCl 4 M HC N ClP Po dl (y O(m H)e 2t ,h (y Blh oy cd )2ro Os ,il Mox ea On He) ,N Cll in dioxane,R Step A To a stirred solution of (E)-1-chloro-4-(2-nitrovinyl) benzene (10 g, 54.4 mmol) and N-benzyl-1-methoxy-N-10 ((trimethylsilyl)methyl) methenamine (15.51 g, 65.36 mmol) in THF (100 mL) was added TFA (0.62 g, 5.44mmol) dropwise at 0 °C and the mixture was stirred at rt for 16 h then poured into water (250 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by normal phase column chromatography (Silica; 0 to 10% ethyl acetate in n-hexane) to afford (±)-trans-1-benzyl-3-(4-chlorophenyl)-4-nitropyrrolidine15 (6.5 g, 20.56 mmol, 52 % yield).LCMS Method: LCMS_Method_A, Rt: 1.65 min; MS: 316.64 [M + H]+Step B To a stirred solution of (±)-trans-1-benzyl-3-(4-chlorophenyl)-4-nitropyrrolidine (6.5 g, 20.56 mmol) from Step20 A in THF: water (1:1; 140 ml) was added NH4Cl (11 g, 205.64 mmol) followed by Zn-dust (13.03 g, 205.59mmol) and the mixture was stirred at rt for 3 h then filtered through a celite bed. The filtrate was poured into - 83 - water (500 mL) and extracted with ethyl acetate (2 × 500 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum to afford crude (±)-trans-1-benzyl-4-(4-chlorophenyl) pyrrolidin-3-amine (5.6 g). LCMS Method: LCMS_Method_A, Rt: 1.52 min; MS: 287.2 [M + H]+5 Step C To a stirred solution of (±)-trans-1-benzyl-4-(4-chlorophenyl) pyrrolidin-3-amine (7 g, 24.47 mmol) from Step B in MeOH (80 mL) was added formaldehyde (33% solution in water; 5.87 g, 195.80 mmol) followed by acetic acid (1.46 gm, 24.31 mmol) and the mixture was stirred at rt for 2 h then NaCNBH3(3.07 g, 48.85 mmol) was10 added and the mixture was stirred at rt for 2 h then concentrated under vacuum, poured into water andextracted with ethyl acetate (2 x 200 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum to afford (±)-trans-1-benzyl-4-(4-chlorophenyl)-N, N-dimethylpyrrolidin-3- amine (6.5 g, 20.70 mmol, 76% yield over two steps). LCMS Method: LCMS_Method_A, Rt: 1.28 min; MS: 314.7 [M + H]+15Step D To a solution of (±)-trans-1-benzyl-4-(4-chlorophenyl)-N, N-dimethylpyrrolidin-3-amine (1.2 g, 3.82 mmol) from Step C in MeOH (20 mL) was added Pd(OH)2(1.2 g, % w / w) and the mixture was stirred at rt for 10 minutes then poly(methylhydrosiloxane) (1.2 g, % w / w) was added and the mixture was further stirred at rt for20 10 minutes. Di-tert-butyl dicarbonate (1.2 g) was added and the mixture was stirred at rt for 5 h then filteredthrough a celite bed and the filtrate was concentrated under vacuum. The crude product was purified by reverse phase column chromatography (Water / ACN) to afford (±)-trans-tert-butyl 3-(4-chlorophenyl)-4- (dimethyl amino) pyrrolidine-1-carboxylate (0.3 g, 0.92 mmol, 24 % yield). LCMS Method: LCMS_Method_A, Rt: 1.79 min; MS: 325.2 [M + H]+25Step E To a stirred solution of (±)-trans-tert-butyl 3-(4-chlorophenyl)-4-(dimethyl amino) pyrrolidine-1-carboxylate (0.3 g, 0.92 mmol) from Step D in DCM (5 mL) was added 4M HCl in dioxane (3 mL) drop-wise and the mixture was stirred at rt for 2 h then concentrated under vacuum. The crude product was triturated with ethyl acetate30 to afford the trans racemic mixture (±)-trans-4-(4-chlorophenyl)-N,N-dimethylpyrrolidin-3-amine (0.250 g, 0.69mmol, 96 % yield). LCMS Method: LCMS_Method_A, Rt: 0.78 min; MS: 225.2 [M + H]+Preparative Example 10: (±)-cis-N, N-dimethyl-4-(p-tolyl) pyrrolidin-3-amine hydrochloride - 84 - MgBr Cuprous iodide,S) O )-cis , Pd / CStep D MeOH, rt, 1 h Formaldeh de ,S) PrepaStep A To a stirred solution of p-tolylmagnesium bromide (1 M in THF, 10.54 g, 54.05 mmol) in 2-methyl tetrahydrofuran (100 mL) was added CuI (1.02 g, 5.40 mmol) at rt and the mixture was stirred at 0°C for 15 5minutes then tert-butyl 6-oxa-3-azabicyclo [3.1.0] hexane-3-carboxylate (10 g, 54.05 mmol) was addeddropwise at 0°C and the mixture was stirred at rt for 16 h then the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were dried over Na2SO4and concentrated under vacuum. The crude product was purified by normal phase column chromatography (silica; 0 to 30% ethyl acetate in n-hexane) to afford (±)-trans-tert-butyl 3-hydroxy-4-(p-tolyl)pyrrolidine-1-10 carboxylate as light brown sticky solid. (4.8 g, 17.32 mmol, 32% yield).LCMS Method: LCMS_Method_A; Rt: 1.69 min; MS: 221.88 [M - 56] + Step B To a stirred solution of (±)-trans-tert-butyl 3-hydroxy-4-(p-tolyl)pyrrolidine-1-carboxylate (4.8 g, 17.32 mmol)15 from Step A in DCM (50 mL) were added TEA (5.25 g, 51.98 mmol) and Mesyl chloride (2.96 g, 25.99 mmol)at 0°C and the mixture was stirred at rt for 1h then the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over Na2SO4and concentrated under vacuum. The crude product was purified by normal phase column chromatography (silica; 0 to 30% - 85 - ethyl acetate in n-hexane) to afford (±)-trans-tert-butyl 3-((methylsulfonyl)oxy)-4-(p-tolyl)pyrrolidine-1- carboxylate as light brown sticky. (4.2 g, 11.81 mmol, 62% yield). LCMS Method: LCMS_Method_A; Rt: 1.90 min; MS: 255.3 [M - 100] + 5Step CTo a stirred solution of (±)-trans-tert-butyl 3-((methylsulfonyl)oxy)-4-(p-tolyl)pyrrolidine-1-carboxylate (3 g, 8.45 mmol) in DMF (30 mL) was added NaN3(1.64 g, 25.35 mmol) at rt and the mixture was stirred at 90°C for 16 h then the mixture was diluted with cold water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over Na2SO4and concentrated under vacuum to afford (±)-cis-tert-10 butyl 3-azido-4-(p-tolyl)pyrrolidine-1-carboxylate as light brown sticky (2.1 g, 6.95 mmol, 82% yield).LCMS Method: LCMS_Method_C; Rt: 8.12 min; MS: 203 [M - 100] + Step D To a stirred solution of (±)-cis-tert-butyl 3-azido-4-(p-tolyl)pyrrolidine-1-carboxylate (2.1 g, 6.95 mmol) in15 MeOH (20 mL) was added 10% palladium on carbon (2.1 g, % w / w) at rt and stirred for 1 h under hydrogenatmosphere then the mixture was filtered through a celite bed and washed with MeOH. The filtrate was concentrated under vacuum to afford (±)-cis-tert-butyl 3-amino-4-(p-tolyl)pyrrolidine-1-carboxylate as light brown sticky (1.8 g, 6.52 mmol, 93% yield). LCMS Method: LCMS_Method_C; Rt: 5.47 min; MS: 221 [M - 56] + 20 Step E To a stirred solution of (±)-cis-tert-butyl 3-amino-4-(p-tolyl)pyrrolidine-1-carboxylate (1.8 g, 6.52 mmol) and formaldehyde (1.56 g, 52.17 mmol) in MeOH (20 mL) was added acetic acid (0.2 mL) and stirred at rt for 2 h then NaCNBH3(0.8 g, 13.04 mmol) was added to the reaction mixture and stirred at rt for 3 h then the25 mixture was concentrated under vacuum. The crude product was purified by normal phase columnchromatography (silica; 0 to 10% MeOH in DCM) to afford (±)-cis-tert-butyl 3-(dimethylamino)-4-(p- tolyl)pyrrolidine-1-carboxylate as light brown solid (1.5 g, 4.93 mmol, 75% yield). LCMS Method: LCMS_Method_A; Rt: 1.25 min; MS: 248.93 [M - 56] +30 Step FTo a stirred solution of (±)-cis-tert-butyl 3-(dimethylamino)-4-(p-tolyl)pyrrolidine-1-carboxylate (1.5 g, 4.93 mmol) in DCM (15 mL) was added 4M HCl in dioxane (15 mL) at rt and stirred at rt for 2 h then the mixture was concentrated under vacuum. The crude product was triturated using diethylether and dried under vacuum to afford cis racemic mixture (±)-cis-N, N-dimethyl-4-(p-tolyl) pyrrolidin-3-amine hydrochloride35 as light brown solid (1.15 g, 4.16 mmol, 84% yield).Preparative Example 11: (±)-cis-4-(4-fluorophenyl)-N, N-dimethylpyrrolidin-3-amine hydrochloride - 86 - F MgBr F F F iiO isd / Crt, 1 h Step A To a stirred solution of p-tolylmagnesium bromide (1M in THF; 15.05 g, 75.67 mmol) in 2-methyl 5tetrahydrofuran (70 mL) was added CuI (0.35 g, 1.89 mmol) at rt and stirred at 0°C for 15 minutes then tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (7 g, 37.83 mmol) was added dropwise at 0°C and the mixture was stirred at rt for 16 h then the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were dried over Na2SO4and concentrated under vacuum. The crude product was purified by normal phase column chromatography (silica; 0 to 30% ethyl10 acetate in n-hexane) to afford (±)-trans-tert-butyl 3-(4-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (5 g,17.77 mmol, 47 % yield). LCMS Method: UC01_FAR1; Rt: 1.77 min; MS: 225.9 [M - 56] + Step B15 To a stirred solution of (±)-trans-tert-butyl 3-(4-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (5 g, 17.77mmol) from Step A in DCM (50 mL) were added TEA (7.41 ml, 5.33 mmol) and methane sulfonyl chloride (3.05 g, 26.66 mmol) and the mixture was stirred at 0 °C for 30 minutes then poured into water (250 mL) and extracted with DCM (3 x 300 mL). The combined organic extracts were dried over Na2SO4,filtered and concentrated under vacuum. The crude product was purified by normal phase column chromatography - 87 - (silica; 0 to 25% ethyl acetate in n-hexane) to afford (±)-trans-tert-butyl 3-(4-fluorophenyl)-4-(methylsulfonyl) oxy) pyrrolidine-1-carboxylate (5.5 g, 15.30 mmol, 86 % yield). LCMS Method: UC01_FAR1; Rt: 2.04 min; MS: 259.8 [M -100] + 5Step CTo a stirred solution of (±)-trans-tert-butyl 3-(4-fluorophenyl)-4-(methylsulfonyl)oxy)pyrrolidine-1-carboxylate (3.8 g, 10.58 mmol) from Step B in DMF (40 mL) was added NaN3(2.75 g, 42.33 mmol) and the mixture was stirred at 100°C for 16 h then diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum to afford (±)-cis-10 tert-butyl 3-azido-4-(4-fluorophenyl)pyrrolidine-1-carboxylate (5 g).LCMS Method: UC01_FAR1; Rt: 2.22 min; MS: 250.9 [M - 56] + Step D To a solution of (±)-cis-tert-butyl 3-azido-4-(4-fluorophenyl)pyrrolidine-1-carboxylate (5 g, 16.32 mmol) from15 Step C in MeOH (50 mL) was added Pd / C (5 g, % w / w) and H2 gas was purged at rt for 3 h then the mixturewas filtered through a celite bed and concentrated under vacuum to afford (±)-cis-tert-butyl 3-amino-4-(4- fluorophenyl)pyrrolidine-1-carboxylate (3.4 g). LCMS Method: UC01_FAR1; Rt: 1.17 min; MS: 224.9 [M - 56] +20 Step ETo a stirred solution of (±)-cis-tert-butyl 3-amino-4-(4-fluorophenyl)pyrrolidine-1-carboxylate (3.4 g, 12.12 mmol) from Step D in MeOH (40 mL) was added formaldehyde (33% solution; 2.91 g, 96.90 mmol) then acetic acid (0.72 g, 11.36 mmol) and the mixture was stirred at rt for 2 h then NaCNBH3(1.52 g, 24.25 mmol) was added and the mixture was stirred at rt for 1 h then the concentrated under vacuum. The crude product25 was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organicextracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by normal phase column chromatography (silica; 0 to 10% MeOH in DCM) to afford (±)-cis-tert-butyl 3- (dimethylamino)-4-(4-fluorophenyl)pyrrolidine-1-carboxylate (1.5 g, 4.86 mmol, 40 % yield). LCMS Method: UC01_FAR1; Rt: 1.26 min; MS: 308.94 [M + H] + 30 Step F To a solution of (±)-cis-tert-butyl 3-(dimethylamino)-4-(4-fluorophenyl)pyrrolidine-1-carboxylate (1.5 g, 4.86 mmol) from Step E in DCM (15 mL) was added 4M HCl in dioxane (7 mL) drop-wise and the mixture was stirred at rt for 2 h then the mixture was concentrated under vacuum. The crude product was triturated with35 ethyl acetate to afford cis racemic mixture (±)-cis-4-(4-fluorophenyl)-N, N-dimethylpyrrolidin-3-aminehydrochloride (1.2 g, 4.87 mmol, 90 % yield). - 88 - LCMS Method: UC01_FAR1; Rt: 0.17 min; MS: 209 [M + H]+ Preparative Example 12: (±)-trans N,N-dimethyl-4-phenylpyrrolidin-3-amine hyde, H3 cO, H repara ve xamp e5 Step ATo a stirred solution of (E)-(2-nitrovinyl) benzene (10 g, 67.04 mmol) and N-benzyl-1-methoxy-N- ((trimethylsilyl)methyl) methanamine (15.91 g, 67.01 mmol) in THF (120 mL) was added TFA (2.56 ml, 33.52 mmol) dropwise at 0°C and the mixture was stirred at rt for 16 h then concentrated under vacuum. The crude product was purified by normal phase column chromatography (silica; 0 to 5 % ethyl acetate in n-hexane) to10 afford (±)-trans1-benzyl-3-nitro-4-phenylpyrrolidine (3.50 g, 18.71 mmol, 27.91 % yield).LCMS Method: UC01_FAR1; Rt: 1.35 min, MS: 283.14 [M + H] + Step B To a stirred solution of (±)-trans1-benzyl-3-nitro-4-phenylpyrrolidine (2.5 g, 8.86 mmol) from Step A in THF:15 water (1:1; 25 mL) was added NH4Cl (4.74 g, 88.61 mmol) then Zn-dust (5.58 g, 88.04 mmol) and the mixturewas stirred at rt for 8 h then filtered through a celite bed. The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum to afford (±)-trans-1-benzyl-4-phenylpyrrolidin-3-amine (2g). LCMS Method: UC01_FAR1; Rt: 0.78 min; MS: 253.13 [M + H] + 20 - 89 - Step C To a stirred solution of (±)-trans-1-benzyl-4-phenylpyrrolidin-3-amine (2 g, 7.93 mmol) from Step B in MeOH (20 mL) was added formaldehyde (33% solution; 5.1 mL, 63.49 mmol) then acetic acid (0.47 mL, 7.93 mmol) and the mixture was stirred at rt for 3 h then NaCNBH3(0.74 g, 11.90 mmol) was added and the mixture was 5stirred at rt for 2 h then concentrated under vacuum. The crude product was diluted with water (200 mL) andextracted with ethyl acetate (2 x 200 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by normal phase column chromatography (silica; 0 to 10 % MeOH in DCM ) to afford (±)-trans-1-benzyl-N,N-dimethyl-4-phenylpyrrolidin-3-amine (1 g, 3.56 mmol, 44% yield).10 LCMS Method: UC01_FAR1; Rt: 0.92 min; MS: 281.14 [M + H] +Step D To a stirred solution of (±)-trans-1-benzyl-N,N-dimethyl-4-phenylpyrrolidin-3-amine (0.8 g, 2.85 mmol) from Step C in MeOH (80 mL) was added Pd / C (0.8 g, % w / w) and the mixture was stirred at 90°C for 18 h in15 hydrogenator under 40 psi then filtered through a celite bed. The filtrate was concentrated under vacuum toafford trans racemic mixture (±)-trans N,N-dimethyl-4-phenylpyrrolidin-3-amine (0.6 g). LCMS Method: UC01_FAR1; Rt: 0.19 min; MS: 191.18 [M + H] + Preparative Example 13:6-chloro-2-(4-fluorophenyl)-2,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one F HCl l H, °C,4hl 203 - 90 - To a stirred solution 2,4,6-trichloropyrimidine-5-carbaldehyde (5 g, 23.6 mmol) in toluene (30 mL) were added trimethoxymethane (15 mL) and H2SO4(0.5 mL) at rt and the mixture was stirred at rt for 1.5 h then basic Al2O3(10 g) was added and the mixture was stirred at rt for 1.5 h then filtered by a celite bed and washed with ethyl acetate (200 ml). The filtrate was concentrated under vacuum to afford 2,4,6-trichloro-5- 5(dimethoxymethyl)pyrimidine as a cream solid (5.8 g, 22.52 mmol, 95 % yield).1H NMR: (400 MHz, CDCl3): δ 5.71 (s, 1H), 3.51 (s, 6H). Step B To a stirred solution of (4-fluorophenyl)hydrazine hydrochloride (1.13 g, 6.99 mmol) in MeOH (2 mL) was10 added 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (1 g, 3.88 mmol) from Step A followed by addition ofTEA (1.08 mL, 7.76 mmol) at 0°C and the mixture was stirred at 0°C for 1 h then concentrated under vacuum to afford yellow solid. Toluene (2.4 mL) was added to the residue followed by addition of TFA (1.03 g, 13.5 mmol) at rt and the mixture was stirred at rt for 2 h. The mixture was added drop-wise into a solution of K3PO4(3.25 g, 15.5 mmol) in water (8.1 mL) and stirred at rt for 10 minutes then the biphasic mixture was15 separated by partitioning between water (100 mL) and ethyl acetate (100 mL). The organic extract was driedover Na2SO4, filtered and concentrated under vacuum. The crude product was purified by normal phase column chromatography (Silica; 0 to 13% ethyl acetate in hexane) to afford 4,6-dichloro-2-(4-fluorophenyl)- 2H-pyrazolo[3,4-d]pyrimidine as a yellow solid (0.35 g, 1.24 mmol, 31% yield). 1H NMR: (400 MHz, CDCl3): δ 8.61 (s, 1H), 798 - 7.95 (m, 2H), 7.34 - 7.28 (m, 2H).20 LCMS Method: LCMS_Method_A, Rt: 2.22 min; MS: 283.1 [M + H] +, 285.1 [M + 2] +Step C To a stirred solution of 4,6-dichloro-2-(4-fluorophenyl)-2H-pyrazolo[3,4-d]pyrimidine (0.35 g, 1.23 mmol) from Step B in THF (3.5 mL) was added 4M NaOH (3.5 mL) at rt and the reaction mixture was stirred at 60°C for 425 h then neutalized using 1M HCl.The mixture was poured into water (100 mL) and extracted with ethyl acetate(3 x 125 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum to afford 6-chloro-2-(4-fluorophenyl)-2,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one as an off white solid (0.24 g, 0.90 mmol, 73% yield). LCMS Method: LCMS_Method_A; Rt: 1.79 min; MS: 265.1 [M + H]+30 Preparative Example 14: 6-chloro-1-(5-fluoropyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4- one - 91 - Cl O N Cl N Cl ep ,60 °C, 4 h.Preparative Example 1l Step A To the stirred solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (3 g, 14.18 mmol) in DMF (15 mL) was added 5-fluoro-2-hydrazinylpyridine (1.80 g, 14.18 mmol) at rt and the mixture was stirred at rt for 16 h then 5diluted with saturated NaHCO3 solution (200 mL).The solid precipitate was filtered and dried under vacuum toafford 2,4,6-trichloro-5-((2-(5-fluoropyridin-2-yl) hydrazono) methyl) pyrimidine as a pale-yellow solid (4 g, 12.48 mmol, 88 % yield) LCMS Method: LCMS_Method_A; Rt: 2.36 min; MS: 322.2 [M + H] +10 Step BA solution of 2,4,6-trichloro-5-((2-(5-fluoropyridin-2-yl) hydrazono) methyl) pyrimidine (4 g, 12.47 mmol) from Step A in ACN (80 mL) was heated at 100oC for 16 h then the mixture was concentrated under vacuum. The crude product was purified by normal phase column chromatography (silica; 0 to 15 % ethyl acetate in n- hexane) to afford 4,6-dichloro-1-(5-fluoropyridin-2-yl)-1H-pyrazolo[3,4-d] pyrimidine as a pale-yellow solid (1.815 g, 6.34 mmol, 51 % yield).LCMS Method: LCMS_Method_A; Rt: 2.11 min; MS: 284.1 [M + H] +, 286.1 [M + 2] + Step C A solution of 4,6-dichloro-1-(5-fluoropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.8 g, 6.33 mmol) from Step B in 4M NaOH aqueous solution (18 mL) was stirred at 100oC for 2 h then the mixture was acidified with acetic20 acid until pH ~5 was attained and extracted with ethyl acetate (3 X 150 mL). The combined organic extracts - 92 - were dried over Na2SO4 and evaporated under vacuum to afford 6-chloro-1-(5-fluoropyridin-2-yl)-1,5- dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one as an off-white solid (0.8 g, 3.01 mmol, 48 % yield). LCMS Method: LCMS_Method_A; Rt: 1.59 min; MS: 266.0 [M + H] +, 268.1 [M + 2] + 5Preparative Example 15:6-chloro-1-(5-(trifluoromethyl) pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Cl O N N Cl OH,, 1 hl Step A To the stirred solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (5 g, 23.69 mmol) in DMF (25 mL) was10 added 2-hydrazinyl-5-(trifluoromethyl) pyridine (4.19 g, 23.69 mmol) at 0oC and the mixture was stirred at rtfor 16 h then diluted with saturated NaHCO3solution (200 mL).The solid precipitate was filtered and dried under vacuum to afford 2,4,6-trichloro-5-((2-(5-(trifluoromethyl)pyridin-2-yl)hydrazono)methyl)pyrimidine as a yellow solid (4 g, 10.80 mmol, 46 % yield) LCMS Method: LCMS_Method_A; Rt: 2.60 min; MS: 370.1 [M + H] +, 372.1 [M + 2] + 15 Step B A solution of 2,4,6-trichloro-5-((2-(5-(trifluoromethyl) pyridin-2-yl) hydrazono) methyl) pyrimidine (3 g, 8.10 mmol) from Step A in ACN (90 mL) was heated at 100oC for 16 h then the mixture was concentrated under vacuum. The crude product was purified by normal phase column chromatography (silica; 0 to 13 % ethyl20 acetate in n-hexane) to afford 4,6-dichloro-1-(5-(trifluoromethyl) pyridin-2-yl)-1H-pyrazolo[3,4-d] pyrimidine asan off-white solid (1.9 g, 5.69 mmol, 70 % yield). - 93 - LCMS Method: LCMS_Method_A; Rt: 2.35 min; MS: 334.1 [M + H] +,336.1 [M + 2] + Step C A solution of 4,6-dichloro-1-(5-(trifluoromethyl) pyridin-2-yl)-1H-pyrazolo[3,4-d] pyrimidine (1.9 g, 5.68 mmol) 5from Step B in 4M NaOH aqueous solution (19 mL) was stirred at 100oC for 2 h then the mixture wasacidified with acetic acid until pH ~5 was attained.The solid precipitate was filtered and dried under vacuum to afford 6-chloro-1-(5-(trifluoromethyl) pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one as a pale yellow solid (1.2 g, 3.80 mmol, 67 % yield). LCMS Method: LCMS_Method_A; Rt: 1.84 min; MS: 316.1 [M + H] +, 318.1 [M + 2] + 10 Preparative Example 16:6-chloro-1-(pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one Cl O N Cl OH,4 hStep A To the stirred solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (2 g, 9.45 mmol) in DMF (20 mL) was15 added 2-hydrazinylpyridine (1.12 g, 10.40 mmol) at 0oC and the mixture was stirred at rt for 16 h then dilutedwith saturated NaHCO3solution (50 mL).The solid precipitate was filtered and dried under vacuum to afford 2,4,6-trichloro-5-((2-(pyridin-2-yl)hydrazono)methyl)pyrimidine as a brown solid (1.9 g, 6.28 mmol, 66 % yield) LCMS Method: LCMS_Method_A; Rt: 1.90 min; MS: 301.9 [M + H] +, 303.8 [M + 2] +20 Step B - 94 - A solution of 2,4,6-trichloro-5-((2-(pyridin-2-yl) hydrazono) methyl) pyrimidine (2.5 g, 8.26 mmol) from Step A in ACN (75 mL) was heated at 110oC for 12 h then the mixture was concentrated under vacuum. The crude product was purified by normal phase column chromatography (silica; 0 to 18 % ethyl acetate in n-hexane) to afford 4,6-dichloro-1-(pyridin-2-yl)-1H-pyrazolo[3,4-d] pyrimidine as a light brown solid (0.8 g, 3.01 mmol, 36 5% yield).LCMS Method: LCMS_Method_A; Rt: 2.00 min; MS: 266.1 [M + H] +, 268.1 [M + 2] + Step C A solution of 4,6-dichloro-1-(pyridin-2-yl)-1H-pyrazolo[3,4-d] pyrimidine (0.4 g, 1.50 mmol) from Step B in 4M10 NaOH aqueous solution (4 mL) was stirred at 90oC for 3 h then the mixture was acidified with acetic acid untilpH ~5 was attained.The solid precipitate was filtered and dried under vacuum to afford 6-chloro-1-(pyridin-2- yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one as a light brown solid (0.3 g, 1.21 mmol, 80 % yield). LCMS Method: LCMS_Method_A; Rt: 1.53 min; MS: 248.1 [M + H] +, 250.2 [M + 2] +15 Preparative Example 17: (±)-cis-N, N-dimethyl-4-phenylpyrrolidin-3-amine hydrochlorideMgBr O C Ms-Cl, T NaN3, DM02-°mCettohyrtl,T1H6Fh,DCM, 0 °C 100 °C, 1 ,S)Step A Step B Step CO O (±)-tran s H2, Pd / C Me OH, 3 rth, dOeHh( p p Step A To a stirred suspension of phenyl magnesium bromide in THF (1M, 81 mL, 80.98 mmol) in 2-methyl THF (150 mL) was added cuprous iodide (1.54 g, 80.98 mmol) at 0oC. After 10 minutes tert-butyl 6-oxa-3- - 95 - azabicyclo [3.1.0] hexane-3-carboxylate (15 g, 80.98 mmol) was added dropwise at same temperature. The mixture was stirred at rt for 16 h then poured into water (300 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by normal phase column chromatography (Silica; 0 to 40 % ethyl acetate in 5hexane) to afford (±)-trans-tert-butyl 3-hydroxy-4-phenylpyrrolidine-1-carboxylate as a pale-yellow oil (18 g,68.35 mmol, 84 % yield). LCMS Method: LCMS_Method_A; Rt: 2.07 min; MS: 208.3 [M - 56]+Step B10 To a stirred solution of (±)-trans-tert-butyl 3-hydroxy-4-phenylpyrrolidine-1-carboxylate (18 g, 68.35 mmol)from Step A in DCM (180 mL) was added TEA (28.6 mL, 205.05 mmol) then mesyl chloride (7.98 g, 102.52 mmol) dropwise at 0 °C and mixture was stirred at rt for 1 h then poured into water (250 mL) and extracted with DCM (3 x 200 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum to afford (±)-trans-tert-butyl 3-((methyl sulfonyl) oxy)-4-phenylpyrrolidine-1-carboxylate (25 g). 15 Step C To a stirred solution of (±)-trans-tert-butyl 3-((methyl sulfonyl) oxy)-4-phenylpyrrolidine-1-carboxylate (25 g, 73.22 mmol) from Step B in DMF (250 mL) was added NaN3(19.04 g, 292.89 mmol) and mixture was stirred at 100 °C for 16 h then poured into cold water (800 mL) and extracted with ethyl acetate (3 x 400 mL). The20 combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum to afford (±)-cis-tert-butyl 3-azido-4-phenylpyrrolidine-1-carboxylate (22 g). Step D To a stirred solution of (±)-cis-tert-butyl 3-azido-4-phenylpyrrolidine-1-carboxylate (20 g, 69.36 mmol) from25 Step C in MeOH (200 mL) was added Pd / C (10 g) and purged with H2 gas at rt for 3 h then mixture wasfiltered through celite bed and the filtrate was concentrated under vacuum. The crude product was purified by normal phase column chromatography (Silica; 0 to 5 %; MeOH in DCM) to afford (±)-cis-tert-butyl 3-amino-4- phenylpyrrolidine-1-carboxylate (7.2 g, 27.44 mmol, 40 % yield). LCMS Method: LCMS_Method_B, Rt: 1.48 min; MS: 207.1 [M - 56]+. 30 Step E To a stirred solution of (±)-cis-tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate (7.2 g, 27.44 mmol) from Step D in MeOH (72 mL) was added formaldehyde (33% solution in water; 5.40 mL, 219.5 mmol) followed by acetic acid (1.57 mL, 27.44 mmol) and stirred at rt for 3 h then NaCNBH3(3.44 g, 54.88 mmol) was added35 and stirred at rt for 5 h then concentrated under vacuum. The crude was partitioned between water (200 mL)and DCM (3 X 200 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated - 96 - under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford (±)-cis-tert-butyl 3-(dimethyl amino)-4-phenylpyrrolidine-1-carboxylate (4.75 g, 16.36 mmol, 60% yield). LCMS Method: LCMS_Method_A; Rt: 1.61 min; MS: 291.3 [M + H]+5Step FTo a stirred solution of (±)-cis-tert-butyl 3-(dimethyl amino)-4-phenylpyrrolidine-1-carboxylate (4.7 g, 16.18 mmol) from Step E in DCM (47 mL) was added 4M HCl in dioxane (47 mL) drop-wise and stirred at rt for 2 h then mixture was concentrated under vacuum. The crude product was triturated with n-pentane to afford cis racemic mixture of (±)-cis-N, N-dimethyl-4-phenylpyrrolidin-3-amine hydrochloride (3.5 g, 15.44 mmol, 95 %10 yield).LCMS Method: LCMS_Method_A, Rt: 1.04 min; MS: 191.2 [M + H]+SYNTHESIS OF THE EXAMPLES Example 1: (±)-trans-2-(3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)quinazolin-4(3H)-one formate O OH N 15 Step A To a stirred solution of Preparative Example 1 (4.06 g, 19.93 mmol) and 2-chloroquinazolin-4(3H)-one (3.0 g, 16.61 mmol) in DMF (30 mL, 10 vol) was added K2CO3(6.87 g, 49.83 mmol) at rt. The reaction mixture was heated at 90 °C for 2 h. The reaction mixture was added to ice-cold water. The white solid precipitate20 was filtered and dried under reduced pressure to afford trans racemic mixture Example 1 (2.0 g, 5.07 mmol,30 % yield).1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 8.14 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.29 - 7.22 (m, 3H), 7.15 - 7.09 (m, 3H), 4.01 - 3.99 (m, 1H), 3.84 - 3.80 (m, 1H), 3.53 - 3.38 (m, 4H), 2.28 (s, 3H), 2.16 (s, 6H). LCMS Method: LC07_MSR2; Rt: 8.208 min; MS: 349.3 [M + H]+.25 Example 1A and 1B: trans enantiopure 2-(3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)quinazolin-4(3H)-one formate - 97 - O O O NH HCOOH NH NH N Step The enantiopure compounds were obtained as white solids by chiral prep HPLC separation of trans racemic mixture of Example 1 (144 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UV DETECTOR. 5For separation HYPERSIL Chiral-ICT (250mm x 30mm x 5µm) column was used using mobile phase A: NAand mobile phase B: 0.1% (7M Methanolic Ammonia) in HEP_IPA: ACN (70:30), Isocratic ratio: NA:100 (v / v). Flow rate: 40 ml / min, UV detection was carried at 210 nm and 275 nm First eluting peak: trans enantiopure 2-(3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)quinazolin-4(3H)-10 one : Chiral HPLC Rt: 2.72 min, 100 % ee, 12.59 mg1H NMR: (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 7.89 (dd, J1 = 1.2 Hz, J2 = 8 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.28 (d, J = 8 Hz, 3H), 7.16 - 7.08 (m, 3H), 4.00 - 3.97 (m, 1H), 3.85 - 3.80 (m, 1H), 3.52 - 3.34 (m, 4H), 2.29 (s, 3H), 2.15 (s, 6H). LCMS Method: LCMS_Method_MSR2; Rt: 4.95 min; MS: 349.4 [M + H]+15 Second eluting peak: trans enantiopure 2-(3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)quinazolin- 4(3H)-one : Chiral HPLC Rt: 2.99 min, 100 % ee, 18.7 mg 1H NMR: (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 7.89 (dd, J1 = 1.6 Hz, J2 = 8 Hz, 1H), 7.57 - 7.53 (m, 1H), 7.27 (d, J = 8 Hz, 3H), 7.16 - 7.08 (m, 3H), 4.00 - 3.97 (m, 1H), 3.85 - 3.80 (m, 1H), 3.52 - 3.34 (m, 4H), 2.2920 (s, 3H), 2.15 (s, 6H).LCMS Method: LCMS_Method_MSR2; Rt: 5.41 min; MS: 349.4 [M + H]+Following the coupling, procedure and chiral separation as described in Example 1, 1A and 1B the following compounds were prepared. 25 - 98 - Startin1. Yield; %Example gMaterial Starting Material Product2.1H-NMR 3. MH+ (ESI) Hz, H), H), H), J = (m, Hz, H), 1 - H), Hz, .55 (m, Hz, Hz, (t, t, J .34 .31 Hz, J = J = .47 Hz, H), H), 0 - 3.3 .29

[0006] - 99 - 1.20% 2. 1H NMR (400 MHz, DMSO-d6): δ 8.01 (d, J = .56 = H), .29 .14 .99 4 - (m, H), .29 min Hz, J = .55 (m, Hz, Hz, H), 9 - .39 .18 Rt: min = , ), , , 9 - 3 .13 Rt: M + - 100 - 1.11% 2. 1H NMR (400 MHz, Example 6 DMSO-d6): δ 7.98 (d, J = .62 8.0 8.0 7.6 8.0 (m, H), .34 .18 min Hz, J = .62 Hz, Hz, Hz, Hz, H), .39 (m, (s, Rt: M + .08 Hz, J = .62 8.4 Hz, Hz, Hz, H), .47 (m, (s, Rt: - 101 - Example 7 1.25% 2. 1H NMR (400 MHz, (±)-trans-6-(3- O DMSO-d6): δ 10.68 (s, (d, d, J .99 (m, 0 - .39 .13 min Hz, (s, (d, J = H), .68 (m, (s, Rt: min Hz, (s, (d, d, J (s, H), = 8 (m, (s, Rt: Example 8: (±)-trans-2-(3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)-8-fluoroquinazolin-4(3H)-one formate - 102 - Preparative Example 2O NH OH N Step A To a stirred so u on o repara ve xampe ( . g, . mmo) an repara ve xample 2 (0.165 g, 1.18 mmol) in DMF (2.5 mL) was added DIPEA (0.447 mL, 2.49 mmol) at rt. The reaction mixture was heated 5at 80 °C for 2 h then cooled to rt, diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). Thecombined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (Silica; 0 to 5% methanol in dichloromethane) to afford the trans racemic mixture Example 8 (0.070 g, 0.169 mmol, 14 % yield).1H NMR (400 MHz, DMSO-d6): δ 11.33 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.44 (m, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.1410 (d, J = 8.0 Hz, 2H), 7.06 - 7.03 (m, 1H), 4.02 (m, 1H), 3.85 (m, 1H), 3.49 (m, 1H), 3.42 - 3.32 (m, 3H), 2.28 (s,3H), 2.15 (s, 6H) LCMS Method: UC01_FAR1; Rt: 1.28 min; MS: 367 [M + H]+ Following the coupling, procedure as described in Example 8 the following compound was prepared. 15 1. Yiel lSt rtin M t ri l Stard; % Ex m ting Pr d t2 1HNMR Hz, H), H), .14 5 - (m, .28 - 103 - Example 9A First eluting: -Chiral HPLC Rt: .7.67 min trans O -ee: 99.04 % SO- (s, J = Hz, .78 .36 Hz, .07 in SO- (s, H), .89 H), (s, .00 E xample 10: (±)-trans-1-((5-fluoro-1H-indazol-3-yl)methyl)-N,N-dimethyl-4-(p-tolyl)pyrrolidin-3-amine H P reparat ve xamp e xamp e 0Step A5 To a stirred solution of 5-fluoro-1H-indazole-3-carbaldehyde (0.2 g, 1.219 mmol) in DCE (4 mL) was addedAcOH (0.2 mL, 2.42 mmol) followed by Preparative Example 1 (0.351 mg, 1.96 mmol) and DIPEA (0.41 mL, 2.72 mmol) and stirred for 2 h, then NaBH(OAc)3(0.051 mg, 2.42 mmol) was added at rt and the mixture stirred for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). - 104 - The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by reverse phase chromatography (Water / ACN) to afford the trans racemic mixture Example 10 (0.080 g, 0.227 mmol, 18 % yield).1H NMR (400 MHz, DMSO-d6): δ 12.91 (s, 1H), 7.61 - 7.59 (m, 1H), 7.52 - 7.49 (m, 1H), 7.25 - 7.20 (m, 3H), 7.04 (d, J = 7.6 Hz, 2H), 3.94 (d, J = 13 Hz, 51H) 3.84 (d, J = 13 Hz, 1H), 3.12 (bs, 1H), 2.91 - 2.85 (m, 3H), 2.44 - 2.40 (m, 2H), 2.23 (s, 3H), 2.05 (s, 6H).LCMS Method: LC01_MSR2; Rt: 7.01 min; MS: 353.4 [M + H]+. Example 11: (±)-trans-1-((5-fluoro-3-methyl-1H-indol-2-yl)methyl)-N,N-dimethyl-4-(p-tolyl)pyrrolidin-3- amine FO10P p p pStep A A solution of Preparative Example 1 (0.48 g, 2.2 mmol) and 5-fluoro-3-methyl-1H-indole-2-carbaldehyde (0.35 g, 1.9 mmol) in MeOH (4.8 mL) was stirred at rt for 2 h and then NaBH3CN (0.15 g, 2.4 mmol) was15 added. The reaction mixture was stirred at rt for 3 h then diluted with water (50 mL) and extracted with EtOAc(3 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by Prep HPLC (Column ID: YMC C18, 120gm, mobile phase A: 0.05% NH4OH in water and mobile phase B: ACN) to afford the trans racemic mixture Example 11 (0.1 g, 0.274 mmol, 14 % yield) as an off-white solid..1H NMR (400 MHz, DMSO-d6): δ 10.6220 (s, 1H), 7.29 - 7.25 (m, 3H), 7.16 - 7.09 (m, 3H), 6.87 - 6.82 (m, 1H), 3.76 (s, 2H), 3.31 (bs, 2H), 2.99 - 2.93(m, 2H), 2.82 - 2.77 (m, 2H), 2.34 (s, 6H), 2.27 (s, 3H), 2.21 (s, 3H). LCMS Method: UC06_FAR1; Rt: 1.91 min; MS: 366.2 [M + H]+. 25 - 105 - Following the coupling, procedure as described in Example 11 the following compounds were prepared. A 1. Yield; % Example Amine Derivative ldehydeDerivative Product2.1H-NMR 3. MH+ (ESI) 400 δ (d, .67 .45 .22 J = 1 - 2 - 8 - 0 - (s, 400 δ .23 H), Hz, 7.6 J = 7 - (s, H), 7 - 0 - 4(s, H), Examples 14-28. The Examples of this invention were prepared following the general procedures for amide couplings. The 5specific procedures used are:General procedure 1 To a stirred solution of acid component (1 eq; indicated in Table below) and amine component (1.3 eq; indicated in Table below) in DMF (10 vol) was added HOBt (1.5 eq) followed by EDC.HCl (1.5 eq) at 0 °C.10 The resulting reaction mixture was stirred at rt for 16 h. After that, the reaction mixture was cooled to rt,diluted with water, and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash column - 106 - chromatography (Normal or Reverse phase) or alternatively preparative HPLC to obtain the final compounds as indicated in the Table below as formate salts. General procedure 2 5To a stirred solution of acid component (1 eq; indicated in Table below) and amine component (1.3 eq;indicated in Table below) in DMF (10 vol) was added HATU (2.0 eq) followed by DIPEA (1.5 eq) at rt. The resulting reaction mixture was stirred at rt for 3 h to 16 h. The reaction mixture was cooled to rt, diluted with water, and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash column10 chromatography (Normal or Reverse phase) or alternatively preparative HPLC to obtain the final compoundas indicated in the Table below as formate salt. General procedure 3 To a stirred solution of acid component (1 eq; indicated in Table below) and TEA (3.0 eq) in THF was added15 T3P (2.0 eq) at 0 °C. After 2 h, amine component (1.5 eq; indicated in Table below) was added at rt. Theresulting reaction mixture was stirred at rt for 3 h to 16 h then cooled to rt, diluted with water, and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography (Normal or Reverse phase) or alternatively preparative HPLC to obtain the final compound as indicated in the Table20 below as formate salt.1. Yield; % 2.1H-NMR Hz, (s, (m, .01 .80 .60 .51 .37 H), - 107 - 1.30% 2.1H NMR (400 MHz, Example 15 DMSO-d6): δ 8.14 (s, .47 .31 .18 .04 .90 .68 H), (s, 5.4 Hz, 0 - 6 - 9 - 9 - 0 - .67 .33 .23 .17 ) + .98 Hz, 0 - 7 - 9 - 2 - .03 .59 .44 H), H), _C; + - 108 - 1.46% 2.1H NMR (400 MHz, DMSO-d6): δ 11.47 (s, H), H), H), Hz, (m, .23 5 - 4 - 6 - (s, Hz, (s, .55 J = d, J 2 - 6 - 2 - 9 - 4 - 3 - (s, Hz, (s, .62 H), Hz, 8.0 .17 .98 .11 .87 .69 H), - 109 - 1.58% 2.1H NMR (400 MHz, DMSO-d6): δ 8.23 - (s, (m, (m, (m, (m, (m, (m, (m, (m, .29 Hz, (s, .84 H), H), H), H), H), H), (s, : . Hz, .66 J = t, J 8 - (d, .61 .97 .69 .33 H), + - 110 - yl)methanone using mobile phase A: 0.1% (7 Second eluting: formic salt M METHANOLIC AMMONIA) in -Chiral HPLC Rt: . HEXANE and mobile phase B: 11.10 min Hz, .66 J = t, J 8 - (d, 6 - 4 - 0 - 4 - (s, _C; MS: Hz, 2 - 4 - 0 - 3 - 4 - 6 - 8 - 1 - 5 - (s, Hz, (s, .90 1 = Hz, (m, 8.0 J = - 9 - 3 - 0 - 4 - (s, - 111 - 1.35% 2.1H NMR (400 MHz, DMSO-d6): δ 7.33 - (s, (m, (m, (m, (m, (m, (m, H), Hz, (s, 7.6 .22 .12 H), H), H), H), H), (s, Hz, (s, (m, (m, (m, (m, (m, (m, (m, (m, .22 - 112 - 1.12% 2.1H NMR (400 MHz, DMSO-d6): δ 8.89 (d, 3 - 6 - Hz, 6 - 9 - 8 - Hz, , J 5 - 9 - 2 - 1 - (s, , J Hz, 9 - (d, 3 - 3 - 9 - 8 - 2 - (s, 0.4 Hz, (s, 9.6 .64 .27 J = 2 - 5 - 8 - 8 - (d, .15 Example 29: (±)-trans-N,N-dimethyl-1-(9H-pyrrolo[2,3-b:4,5-c']dipyridin-2-yl)-4-(p-tolyl)pyrrolidin-3- amine - 113 - (R,S) N * 5Step ATo a stirred solution of 2-bromo-9-tosyl-9H-pyrrolo[2,3-b:4,5-c']dipyridine (synthesis reported in WO2017009454)(0.12 g, 0.298 mmol) and Preparative Example 1(0.1g, 0.447 mmol) in dioxane were added Cs2CO3(0.29 g, 0.894 mmol) followed by Xantphos (0.02g, 0.029 mmol) at rt. The reaction mixture was purged with N2gas and then Pd2(dba)3was added. The resulting reaction mixture was heated at 100 °C10 for 16 h then was cooled to rt, diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). Thecombined organic extracts were dried over Na2SO4,filtered and concentrated under reduced pressure to afford (±)-trans-N,N-dimethyl-4-(p-tolyl)-1-(9-tosyl-9H-pyrrolo[2,3-b:4,5-c']dipyridin-2-yl)pyrrolidin-3-amine (0.3 g). This material was carried forward for the next step without purification. LCMS Method: UC01_FAR1; Rt: 1.37 min; MS: 526.0 [M + H]+ 15 Step C To a stirred solution of (±)-trans-N,N-dimethyl-4-(p-tolyl)-1-(9-tosyl-9H-pyrrolo[2,3-b:4,5-c']dipyridin-2- yl)pyrrolidin-3-amine compound from Step B (0.3 g, 0.570 mmol) in dioxane was added 1N NaOH (0.9 mL) at rt. The reaction mixture was heated at 120 °C for 4 h in a microwave. The reaction mixture was cooled to rt20 and concentrated under reduced pressure. The crude material was purified by Prep HPLC (using Column ID:YMC,120GM, mobile phase A: 0.05% NH4OH in water and mobile phase B: ACN) to afford the trans racemic mixture Example 29 (0.04 g, 0.107 mmol, 36% yield, over two steps). 1H NMR: (400 MHz, DMSO-d6): δ 11.94 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8 Hz, 2H), 7.15 (d, J = 7.6 Hz, 2H), 6.57 (s , 3H), 6.51 (d, J = 8.4 Hz, 1H), 3.54 - 3.35 (m, 6H), 2.33 (s, 3H), 2.22 (s, 6H).25 LCMS Method: LC-01_MSR2; Rt: 5.286 min; MS: 372.5 [M + H]+Example 30: (±)-trans-N,N-dimethyl-1-(1H-pyrrolo[2,3-b]pyridin-6-yl)-4-(p-tolyl)pyrrolidin-3-amine - 114 - (R,S) N 2HCl* ans ch4l-oTroidluee,nNeasuHl,foDnMylF (R,S) 10p0 °C,18 h, N N N NHN Br e Step A To a stirred solution of 6-bromo-1H-pyrrolo[2,3-b]pyridine (0.15 g, 0.761 mmol) in DMF was added NaH (60% in mineral oil; 0.043g, 1.142 mmol) followed by 4-toluenesulfonyl chloride (0.174g, 0.913 mmol) at 0 °C. The 5reaction mixture was stirred at rt for 1 h then diluted with water (10 mL) and extracted with EtOAc (3 x 15mL). The combined organic extracts were dried over Na2SO4,filtered and concentrated under reduced pressure to afford 6-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.16g, 0.457 mmol, 60 % yield). LCMS Method: UC01_FAR1; Rt: 2.36 min; MS: 350.8 [M + H]+10 Step BTo a stirred solution of 6-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine compound from Step A (0.16 g, 0.455 mmol) and Preparative Example 1 (0.13g, 0.546 mmol) in dioxane were added Cs2CO3(0.445 g, 1.365 mmol) followed by Xantphos (0.013g, 0.022 mmol) at rt. The reaction mixture was purged with N2gas and then Pd2(dba)3(0.02 g, 0.022 mmol) was added. The resulting reaction mixture was heated at 100 °C for 18 h15 then cooled to rt, diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organicextracts were dried over Na2SO4,filtered, and concentrated under reduced pressure. The resulting crude material was purified by normal phase column chromatography (silica; 0 to 70% EtOAc in n-hexane) to afford (±)-trans-N,N-dimethyl-4-(p-tolyl)-1-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)pyrrolidin-3-amine (0.24 g). This material was carried forward for next step without purification.20 LCMS Method: UC01_FAR1; Rt: 1.77 min; MS: 475.5 [M + H]+Step C - 115 - To a stirred solution of (±)-trans-N,N-dimethyl-4-(p-tolyl)-1-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)pyrrolidin-3- amine compound from Step B (0.2 g, 0.505 mmol) in dioxane was added 1N NaOH (2 mL) at rt. The resulting reaction mixture was heated at 120 °C for 4 h in a microwave. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude material was purified by Prep HPLC (using Column Xtimate 5C18 (250mm x 21.2mm x 5µm), mobile phase A:0.05% NH4OH in water and mobile phase B: ACN) to affordtrans racemic mixture Example 30 (0.03 g, 0.093 mmol, 20% yield, over two steps). 1H NMR: (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8 Hz, 2H), 7.20 (d, J = 7.6 Hz, 2H), 7.03 (t, J = 2.4 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 6.24 - 6.25 (m, 1H), 4.21 - 3.80 (m, 5H), 3.34 (s, 1H), 2.54 - 2.49 (m, 6H), 2.30 (s, 3H).10 LCMS Method: LC-01_MSR2; Rt: 6.8 min; MS: 321.4 [M + H]+Example 31: (±)-trans-1-((1H-indol-5-yl)methyl)-N,N-dimethyl-4-(p-tolyl)pyrrolidin-3-amine El 1(±)-trans Step A 15 To a solution of 1H-indole-5-carbaldehyde (3.0 g, 20.68 mmol) in DCM (30 mL) was added TEA (8.6 g, 62.06mmol), DMAP (0.126 g, 1.03 mmol) and di-tert-butyl dicarbonate (5.41 g, 24.82 mmol) then the mixture was stirred at rt for 5 h The reaction mixture was diluted with water (500 mL) and extracted with DCM (2 x 500 mL). The combined organic extracts were dried over Na2SO4,filtered, and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (Silica; 0 to 10% ethyl acetate20 in n-hexane) to afford tert-butyl 5-formyl-1H-indole-1-carboxylate (3.0 g, 8.69 mmol, 59% yield).LCMS Method: UC01_FAR1; Rt: 2.25 min; MS: 246 [M + H]+Step B - 116 - To a stirred solution of tert-butyl 5-formyl-1H-indole-1-carboxylate compound from Step A (0.35 g, 1.42 mmol) in MeOH (7.0 mL) was added acetic acid (0.171 g, 2.8 mmol) followed by Preparative Example 1 (0.43 g, 2.14 mmol) and reaction mixture was stirred at rt for 3 h. To this solution, sodium cyanoborohydride (0.132 g, 2.14 mmol) was added at 0 °C and the mixture stirred at rt for 12 h. The reaction mixture was 5diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic extracts were driedover Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by normal phase column chromatography (silica; 0 to 5% methanol in dichloromethane) to afford (±)-tert-butyl 5- ((3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)methyl)-1H-indole-1-carboxylate (0.275 g, 0.63 mmol, 44% yield).10 LCMS Method: UC01_FAR1; Rt: 1.64 min; MS: 434.1 [M + H]+Step C To a stirred solution of (±)-tert-butyl 5-((3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)methyl)-1H-indole-1- carboxylate compound from Step B (0.275 g, 0.63 mmol) in DCM (5 mL) was added TFA (5 mL, 20 vol)15 dropwise and the mixture stirred at rt for 2 h then concentrated under reduced pressure. The resulting crudematerial was purified by reverse phase chromatography (0.05% NH3 in water / ACN) to afford the trans racemic mixture Example 31 (0.025 g, 0.075 mmol, 11 % yield).1H NMR: (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 7.44 (s, 1H), 7.30 (m, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.08 (m, 3H), 6.37 (s, 1H), 4.06 - 4.02 (m, 2H), 3.68 (d, J = 12.4 Hz, 1H), 3.53 (d, J = 12.4 Hz, 1H), 3.11 (m, 1H), 2.82 (m, 3H), 2.50 (m, 1H), 2.24 (s, 3H), 2.06 (s,20 6H).LCMS Method: LC01_MSR2; Rt: 5.83 min; MS: 334.4 [M + H]+Example 32: (±)-trans-1-((1H-indol-2-yl)methyl)-N,N-dimethyl-4-(p-tolyl)pyrrolidin-3-amine

[0007] - 117 - (R,S) N 2HCl* rt, 3h Step A To a stirred solution of 1H-indole-2-carbaldehyde (0.2 g, 1.37 mmol) in THF (4 mL), DIPEA (0.356 g, 2.75 mmol) was added and stirred at rt for 5 min. di-tert-butyl dicarbonate (0.360 g, 1.65 mmol) and DMAP (0.008 5g, 0.068 mmol) were added and the reaction mixture was stirred at rt for 20 min. The reaction mixture wasdiluted with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under a reduced pressure to afford tert-butyl 2-formyl-1H-indole-1- carboxylate (0.37 g, 1.51 mmol). LCMS Method: UC01_FAR1; Rt: 2.3 min; MS: 189.8 [M - 56]+10 Step B A stirred solution of tert-butyl 2-formyl-1H-indole-1-carboxylate from Step A (0.2 g, 0.815 mmol) and DIPEA (0.522 g, 4.07 mmol) in DCE (5 mL) was added Preparative Example 1 (0.43 g, 1.05 mmol) and stirred at rt for 3 h. The reaction mixture was cooled to 0 - 10 °C and sodium cyanoborohydride (0.075 g, 1.22 mmol) was15 added and the mixture stirred at rt for 16 h. The reaction mixture was diluted with water (30 mL) andextracted with EtOAc (3 x 150 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (Silica; 0 to 2% methanol in dichloromethane) to afford (±)-tert-butyl 2-((3-(dimethylamino)-4-(p- tolyl)pyrrolidin-1-yl)methyl)-1H-indole-1-carboxylate (0.15 g, 0.346 mmol, 35% yield).20 LCMS Method: UC01_FAR1; Rt: 1.77 min; MS: 434.1 [M + H]+Step C - 118 - To a stirred solution of (±)-tert-butyl 2-((3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)methyl)-1H-indole-1- carboxylate compound from Step B (0.15 g, 0.346 mmol) in DCM (4 mL) was added 4M HCl in dioxane (3 mL) dropwise then stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure. The resulting crude material was purified by Prep HPLC (using Column ID YMC C18, 120gm, 50um, mobile 5phase A: 0.05 % NH4OH in water, mobile phase B: ACN) to afford trans racemic mixture Example 32 (0.03 g,0.081 mmol, 23% yield). 1H NMR: (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 7.44 - 7.31 (m, 2H), 7.25 (d, J = 7.2 Hz, 2H), 7.08 - 6.99 (m, 2H), 6.94 - 6.91 (m, 2H), 6.26 (bs, 1H), 3.76 - 3.64 (m, 2H), 3.50 - 3.35 (m, 2H), 3.13 (bs, 1H), 2.88 - 2.86 (m, 3H), 2.24 (bs, 3H), 2.07 (s, 6H). 10 LCMS Method: UC01_FAR1; Rt: 1.34 min; MS: 333.9 [M + H]+Example 33: (±)-trans-(3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)(5-phenylthiophen-2-yl)methanone (R,S) N O trans15 S To a stirred solution of 5-bromothiophene-2-carboxylic acid (CAS: 7311-63-9; 0.5 g, 2.41 mmol) and DIPEA (1.24 mL, 7.24 mmol) in DMF (5 mL) was added HATU (1.37 g, 3.62 mmol) and stirred at rt for 15 min. Preparative Example 1 (0.73 g, 3.62 mmol) was added and the mixture stirred at rt for 1 h. The reaction mixture was poured into ice-cold water. The resulting precipitate was filtered and dried under reduced20 pressure to afford (±)-(5-bromothiophen-2-yl)(3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)methanone (0.9 g,2.29 mmol, 95% yield). LCMS Method: UC01_FAR1; Rt: 1.529 min; MS: 392.8 / 394.7 [M + H]+Step B25 To a stirred solution of (±)-(5-bromothiophen-2-yl)(3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)methanone fromStep A (0.2 g, 0.50 mmol), phenylboronic acid (CAS: 98-80-6; 0.093 g, 0.76 mmol) and Cs2CO3(0.490 g, 1.52 mmol) in dioxane: water (8 : 1; 2.5 mL) was purged with nitrogen gas for 10 min. PdCl2(dppf).DCM (0.02 g, 0.025 mmol) was added and reaction mixture was heated at 110 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried - 119 - over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography using (Combi-flash; 0 to 10% methanol in DCM) to afford trans racemic mixture Example 33 (0.07 g, 0.179 mmol, 35% yield).1H NMR: (400 MHz, DMSO-d6): δ 7.73 (s, 3H), 7.57 (s, 1H), 7.44 (d, J = 5.2 Hz, 2H), 7.38 (s, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 4.32 - 4.19 (m, 2H), 53.94 (s, 1H), 3.94 - 3.77 (m, 3H), 2.33 (s, 3H), 2.15 (s, 6H).LCMS Method: UC01_FAR1; Rt: 1.71 min; MS: 390.9 [M + H]+Example 34: (±)-trans-(-3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)(4-(4-fluorophenyl)-1H-pyrrol-2- yl)methanone (R,S) N F H 10 S To a stirred solution of 4-bromo-1H-pyrrole-2-carboxylic acid (1.0 g, 5.26 mmol) and DIPEA (2.72 mL, 15.78 mmol) in DMF (10 mL) was added HATU (3.0 g, 7.89 mmol) and the mixture stirred at rt for 15 min. Preparative Example 1 (1.61 g, 7.89 mmol) was added and the mixture stirred at rt for 2 h. The reaction15 mixture was poured into ice-cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combinedorganic extracts were dried using sodium sulphate and concentrated under reduced pressure. The resulting crude material was purified by normal phase column chromatography (silica; 0 to 12% MeOH in DCM) to afford (±)-(4-bromo-1H-pyrrol-2-yl)(3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)methanone (0.4 g, 1.06 mmol, 20% yield).20 LCMS Method: UC01_FAR1; Rt: 1.40 min; MS: 375.9 / 377.8 [M + H]+Step B A stirred solution of (±)-(4-bromo-1H-pyrrol-2-yl)(3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)methanone from Step A (0.1 g, 0.26 mmol), (4-fluorophenyl)boronic acid (0.075 g, 0.53 mmol) and Cs2CO3(0.260 g, 0.7925 mmol) in dioxane: water (4 : 1; 2 mL) was purged with nitrogen for 10 min. PdCl2(dppf). DCM (0.010 g, 0.013mmol) was added at rt and reaction mixture was heated at 110 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by Prep HPLC (using Column ID: YMC,120GM, mobile phase A: 0.05% NH4OH in water and mobile phase B:30 ACN) to afford trans racemic mixture Example 34 (0.02 g, 0.051 mmol, 19 % yield). - 120 - 1H NMR: (400 MHz, DMSO-d6): δ 11.65 (s, 1H), 7.70 - 7.62 (m, 2H), 7.36 (s, 1H), 7.28 (d, J = 7.2 Hz, 2H), 7.15 - 7.08 (m, 4H), 6.93 (s, 1H), 4.23 (s, 1H), 4.03 - 3.95 (m, 1H), 3.78 (s, 2H), 3.50 - 3.47 (m, 2H), 2.28 (s, 3H), 2.14 (s, 6H). LCMS Method: UC06_FAR1; Rt: 1.92 min; MS: 392.4 [M + H]+5 Example 35: (±)-trans-3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)(4-(pyridin-3-yl)thiophen-2- yl)methanone (R,S) N10 T oa stirred solution of 4-bromothiophene-2-carboxylic acid (0.2 g, 0.966 mmol) and Preparative Example 1(0.28 g, 1.16 mmol) in DMF (2 mL) was added HATU (0.55 g, 1.44 mmol) followed by DIPEA (0.375 g, 2.89 mmol) at rt. The resulting reaction mixture was stirred at rt for 2 h. The reaction mixture was cooled to rt, diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (±)-(4-bromothiophen-2-yl)(3-15 (dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)methanone (0.07 g, 0.178 mmol, 18% yield).LCMS Method: UC01_FAR1; Rt: 1.468 min; MS: 392.8 [M + H]+Step B To a stirred solution of (±)-(4-bromothiophen-2-yl)(3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)methanone from20 Step A (0.07 g, 0.178 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.054 g, 0.26 mmol)in dioxane: water (1:1; 2 mL) was added Cs2CO3(0.173 g, 0.53 mmol ) and purged with nitrogen gas for 10 min. PdCl2(dppf).DCM (0.001 g, 0.0089 mmol ) was added and the mixture heated at 110 °C for 1 h. The reaction mixture was cooled to rt, diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The25 resulting crude material was purified by reverse phase column (ACN / water) to afford the trans racemicmixture Example 35 (0.025 g, 0.063 mmol, 35% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.06 - 8.99 (m, 1H), 8.53 - 8.49 (m, 1H), 8.27 - 8.13 (m, 2H), 8.02 (s, 1H), 7.47 - 7.41 (m, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 7.2 Hz, 2H), 4.25 - 4.08 (m, 1H), 3.92 - 3.75 (m, 2H), 3.55 - 3.50 (m, 3H), 2.28 (s, 3H), 2.15 (s, 6H).30 LCMS Method: UC01_FAR1; Rt: 1.01 min; MS: 392.8 [M + H]+ - 121 - Example 36: (±)-trans-3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)(4-phenylthiophen-2-yl)methanone O B Example 36Step A 5To a stirred solution of (±)-(4-bromothiophen-2-yl)(3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)methanone (0.3g, 0.76 mmol) and phenyl boronic acid (1.39 g, 4.83 mmol) in dioxane: water (1:1, 2 mL) was added Cs2CO3(0.62 g, 1.90 mmol ) and nitrogen gas was purged for 10 min. Pd(PPh3)4(0.088 g, 0.076 mmol ) was added and the mixture heated at 110 °C for 12 h. The reaction mixture was poured into ice-cold water and purified in reverse phase chromatography (ACN / water) to afford the trans racemic mixture Example 36 as a white solid10 (0.1 g, 0.256 mmol, 33% yield). 1H NMR: (400 MHz, DMSO-d6): δ 8.12 - 8.04 (m, 2H), 7.92 (s, 1H), 7.80 -7.71 (m, 2H), 7.44 - 7.27 (m, 4H), 7.14 (d, J = 7.6 Hz, 2H), 4.27 - 4.21 (m, 1H), 3.97 - 3.93 (m, 1H), 3.92 - 3.77 (m, 2 H), 3.54 - 3.34 (m, 2 H), 2.28 (s, 3H), 2.15 (s, 6H). LCMS Method: UC01_FAR1; Rt: 1.602 min; MS: 390.9 [M + H]+15 Following the coupling procedure as described in Example 36 the following compounds were prepared.1. Yield xample Am; % Eine Boronic acid Product2 1H-NMR Hz, .16 H), d, J (d, .24 H), (s, Example 38: (±)-trans-(5-(1H-pyrazol-4-yl) thiophen-2-yl) (3-(dimethylamino)-4-(p-tolyl) pyrrolidin-1-yl) methanone - 122 - O N O B S T p y y p y py din-1- yl)methanone (0.2 g, 0.50 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 52-yl)-1H-pyrazole (0.19 g, 0.712 mmol) in 1,4-dioxane (2.4 mL) was added Cs2CO3 (0.49 g, 1.52 mmol) andwater (0.6 mL) then the mixture was purged with N2for 10 minutes. PdCl2dppf.DCM (0.020 g, 0.025 mmol) was added and the mixture was stirred at 80 °C for 1 h then poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum to afford crude (±)-trans-(3-(dimethylamino)-4-(p-tolyl)pyrrolidin-1-yl)(5-(1-(tetrahydro-2H-10 pyran-2-yl)-1H-pyrazol-4-yl)thiophen-2-yl)methanone (0.25 g).LCMS Method: UC01_FAR1; Rt: 1.45 min; MS: 465.0 [M + H] + Step B To a solution of (±)-trans-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl) (5-(1-(tetrahydro-2H-pyran-2-yl)-1H-15 pyrazol-4-yl) thiophen-2-yl) methanone (0.25 g, 0.53 mmol) in DCM (4 mL) was added 4M HCl in dioxane (3mL) dropwise at 0 °C and the mixture was stirred at rt for 3 h then concentrated under vacuum. The crude product was purified by Prep-HPLC (0.05% FA IN WATER: ACN) to afford trans racemic mixture Example 38 (0.031 g, 0.078 mmol, 15% yield) as light brown solid. 1H NMR: (400 MHz, DMSO) δ 13.12 (s, 1H), 8.20 (bs, 1H), 7.86 (bs, 1H), 7.55 (s, 1H), 7.32 - 7.27 (m, 2H),20 7.22 - 7.13 (m, 3H), 4.18 (s, 1H), 3.96 (m, 1H), 3.76 (s, 1H), 3.43 - 3.28 (m, 3H), 2.47 (s, 3H), 2.40 (s, 6H)LCMS Method: UC01_FAR1; Rt: 1.45 min; MS: 380.9 [M + H] + Example 39: (±)-trans-(3-(dimethylamino)-4-(p-tolyl) pyrrolidin-1-yl) (4-(pyrimidin-5-yl)-1H-pyrrol-2-yl) methanone - 123 - N N OH B N N S T py y y p y py y e (0.2 g, 0.53 mmol) in THF (4 mL) was added TEA (1.4 mL, 1.06 mmol) and DMAP (0.003 g, 0.026 mmol) at rt 5followed by di-tert-butyl dicarbonate (0.13 g, 0.63 mmol) was added dropwise at 0 °C and reaction mixturewas stirred at rt for 3 h then diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by normal phase column chromatography (Silica; 0 to 10 % methanol in dichloromethane) to afford (±)-trans-tert-butyl 4-bromo-2-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidine-1-10 carbonyl)-1H-pyrrole-1-carboxylate (0.2 g, 0.4 mmol, 79% yield).LCMS Method: UC01_FAR1; Rt: 1.59 min; MS: 477.73 [M + H] + Step B To a stirred solution of (±)-trans-tert-butyl 4-bromo-2-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidine-1-carbonyl)-15 1H-pyrrole-1-carboxylate (0.2 g, 0.42 mmol) and pyrimidin-5-ylboronic acid (0.10 g, 0.84 mmol) in 1,4-dioxane (1.6 mL) was added Cs2CO3(0.41 g, 1.26 mmol) and water (0.4 mL) then the mixture was purged with N2for 10 minutes. PdCl2dppf.DCM (0.017 g, 0.021 mmol) was added and the mixture was stirred at 100 °C for 8 h then poured into water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by20 Prep-HPLC using (mobile phase A: 0.05% AMMONIUM HYDROXIDE IN WATER mobile phase B: 20% ALINE IN ACETONITRILE+ Additional THF) to afford the Example 39 (0.023 g, 0.061 mmol, 14 %) as a white solid. 1H NMR: (400 MHz, DMSO) δ 11.93 (s, 1H), 9.17 (s, 1H), 9.09 (s, 1H), 8.93 (d, J = 20.4 Hz, 1H), 7.66 (d, J = 10.4 Hz, 1H), 7.28 - 7.14 (m, 5H), 4.25 (t, J = 9.2 Hz, 1H), 4.03 - 3.93 (m, 1H), 3.79 - 3.74 (m, 2H), 3.53 - 3.4025 (m, 2H), 2.31 (s, 3H), 2.18 (d, J = 20.4 Hz, 6H)LCMS: UC01_FAR; Rt: 1.09 min, MS: 375.9 [M + H] + Example 40: (±)-trans-2-(3-(dimethyl amino)-4-(4-fluorophenyl) pyrrolidin-1-yl) quinazolin-4(3H)-one - 124 - O NH O S) N F Step A To a stirred solution . , . zolin-4(3H)-one (0.43 g, 0.09 mmol) in DMF (10 mL) was added K2CO3(1.32 g, 0.38 mmol) at rt and the mixture was heated at 90 °C 5for 3 h then poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organicextracts were dried using Na2SO4,filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford trans racemic mixture of Example 40 (0.200 g, 0.77 mmol, 28 % yield) as a white solid. 1H NMR: (400 MHz, DMSO) δ 11.10 (s, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.56 (t, J = 6.8 Hz, 1H), 7.45 (t, J = 5.610 Hz, 2H), 7.28 - 7.26 (m, 1H), 7.19 - 7.09 (m, 3H), 4.04 - 4.00 (m, 1H), 3.84 - 3.80 (m, 1H), 3.53 - 3.34 (m, 4H),2.15 (s, 6H). LCMS Method: LC01_MSR2; Rt: 5.43 min; MS: 353.28 [M + H] + Example 40A and 40B: trans enantiopure 2-(3-(dimethyl amino)-4-(4-fluorophenyl) pyrrolidin-1-yl)15 quinazolin-4(3H)-oneO O O N F Example 40A / 40BStep A20 The enantiopure compounds were obtained as a white solid material by chiral prep HPLC separation ofracemic mixture of Example 40 (100 mg) using WELCH PREP SAIL1000 WITH UV DETECTOR. For separation, YMC CELLULOSE SC (250 x 50mm x 5μm) column was used using mobile phase A: NA and - 125 - Mobile Phase B: 0.1% (7 M METHANOLIC AMMONIA) in HEPTANE_IPA:ACN(70:30)_90_10 Flow rate: 20 ml / min, Isocratic ratio: 0:100 (v / v). UV detection was carried out at 210 nm. First eluting peak: trans enantiopure 2-(3-(dimethyl amino)-4-(4-fluorophenyl) pyrrolidin-1-yl) 5quinazolin-4(3H)-one: Chiral HPLC Rt: 2.85 min, 100 % ee, 20 mg1H NMR: (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 6.4 Hz, 2H), 7.25 - 7.07 (m, 4H), 4.07 (t, J = 8.8 Hz, 1H), 3.82 (t, J = 7.2, 1H), 3.54 - 3.34 (m, 4H), 2.16 (s, 6H). LCMS Method: UC01_FAR1; Rt: 1.00 min; MS: 353 [M + H]+10 Second eluting peak: trans enantiopure 2-(3-(dimethyl amino)-4-(4-fluorophenyl) pyrrolidin-1-yl) quinazolin-4(3H)-one: Chiral HPLC Rt: 3.32 min, 96.11% ee, 20 mg 1H NMR: (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 7.91 - 7.87 (m, 1H), 7.58 - 7.54 (m, 1H), 7.50 - 7.43 (m, 2H), 7.25 - 7.07 (m, 4H), 4.30 (t, J = 7.6 Hz, 1H), 3.82 (t, J = 7.2, 1H), 3.54 - 3.29 (m, 4H), 2.16 (s, 6H).15 LCMS Method: UC01_FAR1; Rt: 0.99 min; MS: 353.0 [M + H] +Examples 41-54. Following the coupling, procedure and chiral separation as described in Example 40, 40A and 40B the20 following compounds were prepared.. eStart1. Yield; % Exampl ing Starting Material Product2.1H-NMR - 126 - First eluting: -Chiral HPLC Rt: . 4.16 Example 41A min Hz, (s, .76 (m, Hz, H), 3 - H). .83 min Hz, (s, .76 (m, Hz, H), 1 - H). od: 2.7 - 127 - Example 42A First eluting: -Chiral HPLC Rt: . 6.20 trans- min O z, ), 3 8 , s, ), 9 n z, s, - = 1 , - ) : 7

[0008] - 128 - First eluting: O -Chiral HPLC Rt: . 5.22 NH ) ,S min R Hz, (s, Hz, H), H), .03 6 - .29 .20 min Hz, bs, Hz, H), H), 6 - .82 (m, od: .19 + Hz, (s, 5 - .14 (m, (m, 1 - H) - 129 - First eluting: -Chiral HPLC Rt: . 5.83 O Example 44A min Hz, (s, 6 - J = (m, H), 5 - H). Rt: M + min Hz, (s, 9 - J = .94 (m, H), Rt: M + - 130 - First eluting: O H -Chiral HPLC Rt: . 7.84 N NH min Hz, (s, .66 Hz, Hz, H), .62 (m, Rt: M + min Hz, (s, .64 (m, Hz, H), 9 - H). Rt: M + Hz, (s, 5 - J = .92 .75 .34 (m, - 131 - First eluting: O -Chiral HPLC Rt: . 7.59 Example 46A N NH ) min Hz, (s, 5 - J = .92 .80 .45 (m, Rt: M + min Hz, (s, 5 - J = .91 .75 .41 (m, Rt: M + Hz, J = J = .46 Hz, H), 1 - H), .18 - 132 - 1.31% 2. 1H NMR: (400 MHz, Example 48 DMSO-d 6): δ 11.29 - .88 (m, H), 0 - .83 1.2 (m, Hz, H), H), .82 Hz, (s, 1.2 9 - .23 (m, H), H), H), H), .09 Rt: M + min Hz, (s, Hz, Hz, H), H), .75 .64 J = .95 Rt: M + - 133 - Example 49 min Hz, bs, H), J = = 8 7.6 H), .52 (s, (s, Rt: min Hz, bs, H), J = = 8 7.6 H), .52 .34 .13 Rt: - 134 - 1.21% Example 50 2. 1H NMR: (400 MHz, O DMSO) δ 11.4 (bs, 1H), J1 Hz, Hz, Hz, H), 5 - H), Hz, (s, Hz, Hz, H), H), H), 4 - .47 (m, -4H- p , O F P xamp eStep A 5To a stirred solution of 2-chloroquinazolin-4(3H)-one (0.43 g, 0.09 mmol) and Preparative Example 7 (0.330g, 1.178 mmol) in DMSO (3 mL) was added DIPEA (0.82 mL 4.714 mmol) at rt and the mixture was heated at 120 °C for 4 h then poured into water (100 mL) and extracted using ethyl acetate (2 x 100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The resulting crude product was purified by reverse column chromatography (Water / ACN) to afford trans racemic mixture of10 Example 52 (0.200 g, 0.77 mmol, 28 % yield) as a black solid.LCMS Method: LCMS_Method_A; Rt: 1.025 min; MS: 341.9 [M + H]+ - 135 - 1H NMR: (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 10.43 (s, 1H), 7.45 - 7.41 (m, 2H), 7.18 - 7.14 (m, 2H), 6.65 - 6.63 (m, 1H), 6.21 - 6.20 (m, 1H), 3.95 - 3.91 (m, 1H), 3.75 - 3.70 (m, 1H), 3.50 - 3.48 (m, 2H), 3.45 - 3.34 (m, 2H), 2.15 (s, 6H). Example 52A and 52B: trans enantiopure 2-(3-(dimethyl amino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-3,7- 5dihydro-4H-pyrrolo[2,3-d] pyrimidin-4-one O O O NH ) Chiral NH NH F m Step A The enantiopure compounds were obtained as dark coloured solids by chiral prep HPLC separation of10 racemic mixture of Example 52 (122 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UVDETECTOR. For separation, Chiralpak IG Repack (250mm x 30mm x 5µm) column was used using mobile phase A: 0.1 % (7 M METHANOLIC AMMONIA) in n-HEPTANE and mobile phase B 0.1% (7 M METHANOLIC AMMONIA) in METHANOL: TERT-BUTYL METHYL ETHER (50:50), Isocratic ratio: 65:35 (v / v). Flow rate: 35 ml / min, UV detection was carried out at 210 nm and 262 nm 15 First eluting peak: trans enantiopure 2-(3-(dimethyl amino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-3,7- dihydro-4H-pyrrolo[2,3-d] pyrimidin-4-one : Chiral HPLC Rt: 3.52 min, 100 % ee, 19 mg 1H NMR: (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 10.41 (s, 1H), 7.45 - 7.41 (m, 2H), 7.16 (t, J = 8.8 Hz, 2H), 6.64 - 6.63 (m, 1H), 6.21 - 6.20 (m, 1H), 3.15 - 3.91 (m, 1H), 3.74 - 3.70 (m, 1H), 3.05 - 3.44 (m, 2H), 3.41 -20 3.34 (m, 2H), 2.15 (s, 6H).LCMS Method: LCMS_Method_C, Rt: 3.31 min; MS: 342.3 [M + H]+Second eluting peak: trans enantiopure 2-(3-(dimethyl amino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-3,7- dihydro-4H-pyrrolo[2,3-d] pyrimidin-4-one: Chiral HPLC Rt: 6.33 min, 97.87% ee, 19 mg25 1H NMR: (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 10.41 (s, 1H), 7.45 - 7.41 (m, 2H), 7.18 - 7.14 (m, 2H), 6.64- 6.03 (m, 1H), 6.21 - 6.20 (m, 1H), 3.95 - 3.91 (m, 1H), 3.74 - 3.70 (m, 1H), 3.49 - 3.44 (m, 2H), 3.34 - 3.33 (m, 2H), 2.14 (s, 6H). LCMS Method: LCMS_Method_C, Rt: 3.31 min; MS: 342.3 [M + H]+30 Examples 53-54 - 136 - Following the coupling, procedure and chiral separation as described in Example 52, 52A and 52B the following compounds were prepared. 1. Yiel ple Stard; % Exam tingMaterial Starting Material Product2.1H-NMR 3. MH+ (ESI) Hz, (s, H), .95 3 - .68 (m, H), .59 Hz, (s, Hz, (t, d, J .88 (m, H), .15 Rt: M +

[0009] - 137 - trans- INFINITY-II WITH UV Second euting: enantiopure - DETECTOR. For separation, -Chiral HPLC Rt: 10.56 2-(3-(dimethyl Chiralpak IG (250mm x 30mm x min Hz, (s, 5.6 .14 2.8 (m, H), 9 - H). Rt: [M .73 Hz, (s, Hz, Hz, Hz, H), .74 .56 .93 .09 od: .37 + - 138 - tolyl) was used using mobile phase A: Second eluting: pyrrolidin-1- 0.1% (7 M METHANOLIC O -Chiral HPLC Rt: 7.25 min yl) AMMONIA) in n-HEXANE and NH -ee: 91.06% Hz, (s, Hz, Hz, Hz, H), .74 .55 .92 .09 od: .37 + N- dimethylpyrrolidin-3-amine N O F N F N Preparative example 7 Example 555 Step ATo a stirred solution of 1-(3-fluorophenyl)-1H-pyrazole-4-carbaldehyde (0.4 g, 2.10 mmol) and Preparative Example 7 (0.65 g, 3.15 mmol) in DCE (4 mL) was added STAB (0.3 g, 0.14 mmol) at rt and the mixture was stirred for 12 h then poured into water (50 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude was purified by10 reverse column chromatography (water / ACN) to afford Example 55 (0.250 g, 0.65 mmol, 31% yield).LCMS Method: UC01_FAR1; Rt: 1.23 min; MS: 383.1 [M + H]+Example 55A and 55B: trans enantiopure 4-(4-fluorophenyl)-1-((1-(3-fluorophenyl)-1H-pyrazol-4-yl) methyl)-N, N-dimethylpyrrolidin-3-amine 15 - 139 - F F F (R Chiral N F Ste Th were obtained as orange oils by chiral prep HPLC separation of the racemic mixture of Example 55 (103 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UV DETECTOR. 5For separation, Chiralpak IB N-5 (250mm x 10mm x 5µm) column was used using mobile phase A: NA andMobile phase B: 0.1 % METHANOLIC AMMONIA n-HEPTANE_2-PROPANOL: TERT-BUTYL METHYL ETHER (50:50) 98_02 (PREMIX). Flow rate: 4 ml / min, Isocratic ratio: 0:100 (v / v). UV detection was carried out at 263 nm.10 First eluting peak: trans enantiopure 4-(4-fluorophenyl)-1-((1-(3-fluorophenyl)-1H-pyrazol-4-yl)methyl)-N, N-dimethylpyrrolidin-3-amine: Chiral HPLC Rt: 9.34 min, 100 % ee, 20 mg 1 38 (m, 2H), 7.14 - 7.07 (m, 3H), 3.58 - 3.46 (m, 2H), 3.34 - 3.17 (m, 3H), 2.89 - 2.84 (m, 2H), 2.49 - 2.46 (m, 1H), 2.06 (s, 6H).15 LCMS: Method: UC08_MSR2, Rt: 6.11 min; MS: 383.3 [M + H]+.Second eluting peak: trans enantiopure 4-(4-fluorophenyl)-1-((1-(3-fluorophenyl)-1H-pyrazol-4-yl) m h l N N i h l lidin i hiral HPLC Rt: 10.57 min, 96.4 1 2 1 6): δ 8.49 (s, 1H), 7.72 - 7.69 (m, 3H), 7.55 - 7.51 (m, 1H), 7.41 - 7.38 (m, 2H),20 7.14 - 7.07 (m, 3H), 3.58 - 3.46 (m, 2H), 3.34 - 3.19 (m, 3H), 2.88 - 2.84 (m, 2H), 2.49 - 2.44 (m, 1H), 2.08 (s,6H). LCMS: Method: UC07_MSR2, Rt: 6.11 min; MS: 383.3 [M + H]+Example 56: (±)-trans-2-(3-(dimethyl amino)-4-phenylpyrrolidin-1-yl) quinazolin-4(3H)-one - 140 - O NH O S) N PreStep A To a stirred solution of Preparative Example 12 (0.31 g, 1.66 mmol) and 2-chloroquinazolin-4(3H)-one (0.2 g, 1.10 mmol) in DMF (10 mL) was added TEA (0.5 mL, 3.32 mmol) and the mixture was stirred at 90 °C for 2 5h then diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layerswere dried over Na2SO4and concentrated under a vacuum. The crude product was purified by normal phase column chromatography (silica; 0 to 5 % methanol in dichloromethane) to afford Example 56 (0.09 g, 0.26 mmol, 15 % yield) as a white solid. LCMS: Method: LC01_MSR2, Rt: 5.23 min, [M + H]: 335.39;10 1H NMR: (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 7.90 (d, J = 8 Hz, 1H), 7.58 (t, J = 8.4 Hz, 1H), 7.44 - 7.32(m, 4H),7.24 (t, J = 7.2 Hz, 2H), 7.09 (t, J = 7.2 Hz, 1H), 4.03 – 3.99 (m, 1H), 3.83 (m, 1H), 3.55 - 3.48 (m, 4H), 2.16 (s, 6H). Example 56A and 56B: trans enantiopure 2-(3-(dimethyl amino)-4-phenylpyrrolidin-1-yl) quinazolin-15 4(3H)-oneO O O N Example 56A / 56BStep A The enantiopure compounds were obtained as white solids material by chiral prep HPLC separation of the racemic mixture of Example 56 (47 mg) using WELCH PREP SAIL1000 WITH UV DETECTOR. For20 separation, SC (250 x 10 mm, 5μm) column was used using mobile phase A: NA and mobile phase B: 0.1%(7 M METHANOLIC AMMONIA) in HEPTANE:IPA_(75:25). Flow rate: 20 ml / min, Isocratic ratio: 0:100 (v / v). UV detection was carried out at 275 nm. - 141 - First eluting peak: trans enantiopure 2-(3-(dimethyl amino)-4-phenylpyrrolidin-1-yl) quinazolin-4(3H)- one : Chiral HPLC Rt: 8.05 min, 100% ee, 5 mg 1H NMR: (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 7.91 - 7.87 (m, 1H), 7.58 - 7.54 (m, 1H), 7.44 - 7.32 (m, 4H), 7.25 (t, J = 7.2 Hz, 2H), 7.09 (t, J = 7.2 Hz, 1H), 4.04 - 4.00 (m, 1H), 3.86 - 3.81 (m, 1H), 3.55 - 3.45 (m, 4H) 52.16 (s, 6H).LCMS Method: UC01_FAR1; Rt: 0.96 min; MS: 334.9 [M + H]+Second eluting peak: trans enantiopure 2-(3-(dimethyl amino)-4-phenylpyrrolidin-1-yl) quinazolin- 4(3H)-one: Chiral HPLC Rt: 8.49 min, 95.29 % ee, 5 mg10 1H NMR: (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.41 - 7.32 (m,4H), 7.25 (t, J = 8.4 Hz, 2H), 7.09 (t, J = 7.2 Hz, 1H), 4.05 - 4.01 (m, 1H), 3.86 - 3.81 (m, 1H), 3.55 - 3.45 (m, 4H), 2.16 (s, 6H). LCMS Method: UC01_FAR1; Rt: 0.96 min; MS: 335.0 [M + H]+15 Example 57: (±)-trans-(3-(dimethylamino)-4-(4-fluorophenyl)pyrrolidin-1-yl)(5-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)methanone F B F a p eStep A To a stirred solution of methyl 5-bromo-4H-1,2,4-triazole-3-carboxylate (2 g, 9.71 mmol) and (4-fluorophenyl)20 boronic acid (1.63 g, 11.65 mmol) in 1,4 dioxane (16 mL) was added K3PO4 (6.18 g, 29.12 mmol) and water(4 mL) then the mixture was purged with N2for 5 minutes. Brettphos-PdG3(0.88 g, 0.97 mmol) was added then the resulting mixture was stirred at 110 °C for 4 h then poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (0.1 % NH4OH in25 Water / ACN) to afford methyl 5-(4-fluorophenyl)-4H-1,2,4-triazole-3-carboxylate (0.25 g, 1.13 mmol, 12 %yield). 1H NMR: (400 MHz, DMSO-d6): δ 8.02 - 7.98 (m, 2H), 7.17 - 7.11 (m, 2H), 3.72 (s, 3H); - 142 - LCMS Method: UC01_FAR1; Rt: 1.18 min; MS: 221.88 [M + H]+Step B To a stirred solution of methyl 5-(4-fluorophenyl)-4H-1,2,4-triazole-3-carboxylate (0.15 g, 0.67 mmol) and 5Preparative Example 7 (0.24 g, 0.88 mmol) in toluene (2 mL) was added trimethylaluminum solution (2.0 Min toluene; 0.67 mL, 1.35 mmol) at 0 °C and the mixture was heated at 80 °C for 2 h. The cooled mixture was treated with aqueous NH4Cl solution (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (0.1 % in NH4OH in H2O / ACN) to afford trans racemic10 mixture of Example 57 (0.090 g, 0.22 mmol, 33% yield) as a white solid.1H NMR: (400 MHz, DMSO-d6): δ 14.9 (bs, 1H), 8.11 - 8.07 (m, 1H), 8.02 - 7.99 (m, 1H), 7.49 - 7.44 (m, 2H), 7.39 - 7.28 (m, 2H), 7.19 (t, J = 8.8 Hz, 2H), 4.61- 4.35 (m, 1H), 4.06 - 3.91 (m, 1H), 3.87 - 3.80 (m, 1H), 3.56 - 3.46 (m, 3H), 2.17 - 2.16 (m, 6H). LCMS Method: UC07_MSR2; Rt: 6.13 min; MS: 398.33 [M + H]+15 Example 57A and 57B: trans enantiopure (3-(dimethylamino)-4-(4-fluorophenyl)pyrrolidin-1-yl)(5-(4- fluorophenyl)-4H-1,2,4-triazol-3-yl)methanone ( , RS)N F F S 20 The enantiopure compounds were obtained as off-white solids by chiral prep HPLC separation of the racemicmixture of Example 57 (85 mg) using PHP-02-SHIMADZU LC20AP WITH UV DETECTOR. For separation, Chiralpak IG (250mm x 30mm x 5μm) column was used using mobile phase A: 0.1% (7 M METHANOLIC AMMONIA) in METHANOL and mobile phaseB: 0.1% (7 M METHANOLIC AMMONIA) in 2-PROPANOL, Isocratic ratio: 70:30 (v / v). Flow rate : 15 ml / min, UV detection was carried out at 240 nm 25 First eluting peak: trans enantiopure (3-(dimethylamino)-4-(4-fluorophenyl)pyrrolidin-1-yl)(5-(4- fluorophenyl)-4H-1,2,4-triazol-3-yl)methanone : Chiral HPLC Rt: 6.28 min, 100 % ee, 19 mg 1H NMR (400 MHz, CDCl3): δ 8.15 (dd, J1 = 5.2 Hz, J2 = 8.4 Hz, 1H), 8.08 (dd, J1 = 5.6 Hz, J2 = 8.8 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.18 - 6.98 (m, 4H) 4.95 - 4.72 (m, 1H), 4.32 - 4.19 (m, 1H), 4.14 - 4.03 (m, 1H),30 3.81 - 3.66 (m, 1H), 3.55 - 3.40 (m, 2H), 2.35 - 2.25 (m, 6H).LCMS Method:LCMS_Method_C, Rt: 4.57 min; MS: 398.31 [M + H]+ - 143 - Second eluting peak: trans enantiopure (3-(dimethylamino)-4-(4-fluorophenyl)pyrrolidin-1-yl)(5-(4- fluorophenyl)-4H-1,2,4-triazol-3-yl)methanone : Chiral HPLC Rt: 6.66 min, 95.21% ee, 17 mg 1H NMR (400 MHz, CDCl3): δ 8.15 (dd, J1 = 5.2 Hz, J2 = 8.4 Hz, 1H), 8.08 (dd, J1 = 5.2 Hz, J2 = 8.4 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.18 - 7.05 (m, 4H) 4.96 - 4.72 (m, 1H), 4.33 - 4.19 (m, 1H), 4.16 - 4.03 (m, 1H), 53.81 - 3.66 (m, 1H), 3.58 - 3.30 (m, 2H), 2.35 - 2.25 (m, 6H).LCMS: Method: LCMS_Method_C, Rt: 4.57 min; MS: 398.31 [M + H]+Example 58: (±)-trans-4-(4-fluorophenyl)-N,N-dimethyl-1-(1H-pyrazolo[3,4-b]pyridin-6-yl)pyrrolidin-3- amine N F 10Pre Step A To a stirred solution of 6-chloro-1H-pyrazolo[3,4-b] pyridine (0.5 g, 3.26 mmol) and Preparative Example 7 (0.91 g, 3.26 mmol) in DMSO (5 mL) was added K3PO4(3.46 g, 16.33 mmol) then the mixture was purged15 with N2 for 10 minutes. CuI (0.13 g, 0.7 mmol) and L-proline (0.56 g, 4.90 mmol) were added. The resultingmixture was stirred at 100 °C for 16 h then poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford trans racemic mixture of Example 58 (0.140 g, 0.43 mmol, 13% yield) as an off-white solid.20 1H NMR: (400 MHz, DMSO-d6): δ 12.82 (s, 1H), 7.87 - 7.85 (m, 1H), 7.78 (s, 1H), 7.48 - 7.44 (m, 2H), 7.19 -7.11 (m, 2H), 6.48 - 6.45 (m, 1H), 3.99 - 3.95 (m, 1H), 3.78 - 3.76 (m, 1H), 3.57 - 3.35 (m, 4H), 2.18 (m, 6H). LCMS Method: UC07_MSR2; Rt: 5.24 min; MS: 326.3 [M + H]+Example 58A and 58B: trans enantiopure 4-(4-fluorophenyl)-N,N-dimethyl-1-(1H-pyrazolo[3,4-25 b]pyridin-6-yl)pyrrolidin-3-amine - 144 - N (R ,S)seChiral N N NparationN N * F NHNNF N NNF Step A The enantiopure compounds were obtained as off-white solids by chiral prep HPLC separation of the racemic 5mixture of Example 58 (99 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UV DETECTOR.For separation, Chiralpak IG (250mm x 50mm x 5μm) column was used using mobile phase A: 0.1 % (7 M METHANOLIC AMMONIA) in METHANOL and mobile phase B: 0.1% (7 M METHANOLIC AMMONIA) in ACETONITRILE, Isocratic ratio: 50:50 (v / v). Flow rate: 40 ml / min, UV detection was carried out at 210 nm and 324 nm 10 First eluting peak: trans enantiopure 4-(4-fluorophenyl)-N,N-dimethyl-1-(1H-pyrazolo[3,4-b]pyridin-6- yl)pyrrolidin-3-amine: Chiral HPLC Rt: 9.54 min, 92.35 % ee, 16 mg 1H NMR: (400 MHz, DMSO-d6): δ 12.68 (s, 1H), 7.87 - 7.85 (m, 1H), 7.78 (s, 1H), 7.48 - 7.44 (m, 2H), 7.16 (t, J = 8 Hz, 2H), 6.48 - 6.45 (m, 1H), 3.99 - 3.94 (m, 1H), 3.78 - 3.76 (m, 1H), 3.57 - 3.50 (m, 1H), 3.48 - 3.4315 (m, 2H), 3.40 - 3.34 (m, 1H), 2.18 (s, 6H).LCMS Method: LCMS_METHOD_C, Rt: 3.77 min; MS: 326.3 [M + H]+Second eluting peak: trans enantiopure 4-(4-fluorophenyl)-N,N-dimethyl-1-(1H-pyrazolo[3,4-b]pyridin- 6-yl)pyrrolidin-3-amine: Chiral HPLC Rt: 15.53 min, 93.83 % ee, 13 mg20 1H NMR: (400 MHz, DMSO-d6): δ 10.37 (s, 1H), 7.87 - 7.85 (m, 1H), 7.78 (s, 1H), 7.48 - 7.44 (m, 2H), 7.19 -7.14 (m, 2H), 6.48 - 6.45 (m, 1H), 3.99 - 3.94 (m, 1H), 3.78 - 3.76 (m, 1H), 3.57 - 3.50 (m, 1H), 3.48 - 3.43 (m, 2H), 3.40 - 3.34 (m, 1H), 2.18 (s, 6H). LCMS Method: LCMS_METHOD_C, Rt: 3.77 min; MS: 326.3 [M + H] +25 Example 59: (±)-trans-4-(4-fluorophenyl)-1-(5-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-N, N-dimethylpyrrolidin-3-amine - 145 - N F NNaNO2, CuBr2F3,4 DHP, pTSANH20°C, aq HCl, 1 hNTHF, 60°C, 3 hN N N F F lple 7Ste To a stirred solution of 5-(4-fluorophenyl)-4H-1,2,4-triazol-3-amine (2 g, 11.22 mmol) in aqueous HCl (20 mL) was added a solution of NaNO2(3 g, 44.90 mmol) in water (2 mL) dropwise at -10 °C followed by a solution 5of CuBr2 (7.5 g, 33.6 mmol) in aqueous HCl (5 mL). The mixture was stirred at -10 °C for 30 minutes thenpoured into aqueous Na2S2O3solution (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over Na2SO4and concentrated under vacuum. The crude product was purified by normal phase column chromatography (silica; 0 to 20% ethyl acetate in hexane) to afford 3-bromo-5-(4- fluorophenyl)-4H-1,2,4-triazole (0.8 g, 3.30 mmol, 29%) as white solid.10 1H NMR: (400 MHz, DMSO-d6): δ 14.83 (s, 1H), 8.00 - 7.98 (m, 2H), 7.43 - 7.39 (m, 2H)Step B To a stirred solution of 3-bromo-5-(4-fluorophenyl)-4H-1,2,4-triazole (0.3 g, 1.23 mmol) in THF (3 mL) was added 3,4-DHP (0.15 g, 1.85 mmol) followed by pTSA (0.021 g, 0.12 mmol) and the mixture was stirred at 6015 °C for 2 h then poured into water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organicextracts were dried using Na2SO4and concentrated under vacuum. The crude product was purified by normal phase column chromatography (silica;0 to 10% ethyl acetate: hexane) to afford 3-bromo-5-(4-fluorophenyl)-4- (tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole (0.34 g, 0.21 mmol, 85% yield) as an off white solid. 1H NMR: (400 MHz, DMSO-d6): δ 8.02 - 7.79 (m, 2H), 7.48 - 7.30 (m, 2H), 5.62 - 5.39 (m, 1H), 4.12 - 3.9820 (m, 1H), 3.80 - 3.62 (m, 1H), 2.41 - 1.98 (m, 3H), 1.72 - 1.46 (m, 2H). - 146 - Step C To a stirred solution of 3-bromo-5-(4-fluorophenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole (0.2 g, 0.61 mmol) and Preparative Example 7 (0.16 g, 0.67 mmol) in DMSO (2 mL) was added K2CO3(0.29 g, 2.14 mmol) then the mixture was purged with N2for 15 minutes. CuI (0.023 g, 0.12 mmol) and L-proline (0.028 g, 50.24 mmol) were added. The resulting mixture was stirred at 100 °C for 12 h then poured into water (50 mL)and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford (±)-trans-4-(4-fluorophenyl)-1-(5-(4-fluorophenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H- 1,2,4-triazol-3-yl)-N, N-dimethylpyrrolidin-3-amine (0.15 g, 0.31 mmol, 53% yield) as an off white solid.10 LCMS Method: LCMS_Method_A; Rt: 2.019 min; MS: 454.3 [M + H] +Step D To a stirred solution of (±)-trans-4-(4-fluorophenyl)-1-(5-(4-fluorophenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H- 1,2,4-triazol-3-yl)-N, N-dimethylpyrrolidin-3-amine (0.15 g, 0.33 mmol) in DCM (1.5 mL) was added 4M HCl in15 dioxane (1.5 mL) dropwise and the mixture was stirred at rt for 2 h then concentrated under vacuum. Thecrude product was triturated using diethyl ether and pentane to afford the trans racemic mixture Example 59 (0.1 g, 0.31 mmol, 81% yield) as off white solid. LCMS Method: LCMS_Method_A; Rt: 1.679 min; MS: 370.3 [M + H] +20 Example 59A and 59B: trans enantiopure 4-(4-fluorophenyl)-1-(5-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-N N-dimeth l rrolidin-3-amine F F F Example 59 Example 59A / 59BStep A The enantiopure compounds were obtained as off white solids by Chiral prep HPLC separation of the racemic25 mixture of Example 59 (100 mg) using Prep WATERS SFC 350 WITH 2489 UV Detector. For separation,Chiralpak IG (250mm x 50mm x 5µm) column was used using mobile phase A: LIQ. CO2 and Mobile Phase B: 0.1% (7 M METHANOLIC AMMONIA) in METHANOL. Flow rate: 150 ml / min, Isocratic ratio: 75:25 (v / v). UV detection was carried out at 230 nm. - 147 - First eluting peak: trans enantiopure 4-(4-fluorophenyl)-1-(5-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-N, N-dimethylpyrrolidin-3-amine: Chiral HPLC Rt: 6.20 min, 100 % ee, 20 mg 1H NMR: 400 MHz DMSO d6: δ 1250 1H 797 793 m 2H 744 t J = 8 Hz 2H 724 714 (m, 4 5L-yl)- 1 4H),10 3 LCMS Method: LCMS_Method_C; Rt: 3.94 min; MS: 370.3 [M + H] + Example 60: (±)-trans-4-(4-fluorophenyl)-1-(1H-indazol-3-yl)-N,N-dimethylpyrrolidin-3-amine I F 15 Step ATo a stirred solution of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.3 g, 0.91 mmol) and Preparative Example 7 (0.20 g,0.1 mmol) in toluene (3 mL) was added Cs2CO3(1.19 g, 3.65 mmol) then the mixture was purged with N2for 15 minutes. Pd2(dba)3(0.041 g, 0.045 mmol) and Xantphos (0.052 g, 0.091 mmol) were added. The resulting mixture was stirred at 100 °C for 4 h then poured into water (50 mL) and extracted with20 ethyl acetate (3 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered and concentratedunder vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford (±)-trans-4-(4-fluorophenyl)-N, N-dimethyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl) pyrrolidin-3- amine (0.16 g, 0.39 mmol, 42% yield) as an off-white solid. LCMS Method: LCMS_Method_A; Rt: 1.92 min; MS: 409.4 [M + H]+25 Step B - 148 - To a stirred solution of (±)-trans-4-(4-fluorophenyl)-N, N-dimethyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 3-yl) pyrrolidin-3-amine (0.15 g, 0.36 mmol) in DCM (2 mL) was added 4M HCl in dioxane (1.5 mL) dropwise and the mixture was stirred at rt for 1 h then concentrated under vacuum. The crude product was triturated using diethyl ether and pentane to afford trans racemic mixture Example 60 (0.13 g, 0.40 mmol, 91% yield) 5as off white solid.LCMS Method: LCMS_Method_A; Rt: 1.74 min; MS: 325.2 [M + H]+Example 60A and 60B: trans enantiopure 4-(4-fluorophenyl)-1-(1H-indazol-3-yl)-N,N- dimethylpyrrolidin-3-amine 10 , ( S)R N F Example 60Step A The enantiopure compounds were obtained as off-white solids by Chiral HPLC separation of the racemic mixture of Example 60 (100 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UV DETECTOR.15 For separation, Chiralpak IG (250mm x 30mm x 5µm) column was used using mobile phase A: NA andmobile phase B: 0.1 % (7 M METHANOLIC AMMONIA) in MEOH. Flow rate: 30 ml / min, Isocratic ratio: 100:0 (v / v). UV detection was carried out at 210 nm. First eluting peak: trans enantiopure 4-(4-fluorophenyl)-1-(1H-indazol-3-yl)-N,N-dimethylpyrrolidin-3-20 amine: Chiral HPLC Rt: 2.49 min, 100 % ee, 25 mg1H NMR: (400 MHz, DMSO-d6) (High temperature): δ 11.59 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.47 - 7.44 (m, 2H), 7.38 - 7.30 (m, 1H), 7.26 - 7.23 (m, 1H), 7.13 (t, J = 8.8 Hz, 2H), 6.91 (t, J = 7.6 Hz, 1H), 4.02 (t, J = 8Hz, 1H), 3.84 (t, J = 9.6 Hz, 1H), 3.642 (t, J = 6.8Hz, 1H), 3.54 - 3.36 (m, 3H), 2.24 - 2.21 (m, 6H) LCMS Method: LCMS_Method_C; Rt: 4.13 min; MS: 325.3 [M + H] + 25 Second eluting peak: trans enantiopure 4-(4-fluorophenyl)-1-(1H-indazol-3-yl)-N,N-dimethylpyrrolidin- 3-amine: Chiral HPLC Rt: 3.36 min, 100 % ee, 25 mg 1H NMR: (400 MHz, DMSO-d6) (High temperature): δ 11.57 (s, 1H), 7.79 (d, J = 8 Hz, 1H), 7.47 - 7.44 (m, 2H), 7.30 - 7.22 (m, 2H), 7.13 (t, J = 8.8 Hz, 2H), 6.91 (t, J = 7.2 Hz, 1H), 4.02 (t, J = 7.6 Hz, 1H), 8.84 (t, J =30 9.2 Hz, 1H), 3.64 (t, J = 6.8 Hz, 1H), 3.56 - 3.38 (m, 3H), 2.24 (s, 6H)LCMS Method: LCMS_Method_C; Rt: 4.14 min; MS: 325.3 [M + H] + - 149 - Example 61: (±)-trans-(3-(dimethyl amino)-4-(4-fluorophenyl) pyrrolidin-1-yl) (5-(4-fluorophenyl)-1- methyl-1H-1,2,4-triazol-3-yl) methanone O OH N OH F P5 StTo a stirred suspension of 5-bromo-1-methyl-1H-1,2,4-triazole-3-carboxylic acid (0.3 g, 1.45 mmol) and Preparative Example 7 (0.42 g, 1.74 mmol) in THF (3 mL) was added TEA (0.44 g, 4.36 mmol) at 0oC followed by T3P (50% solution in ethyl acetate,1.85 g, 2.91 mmol) and the mixture was stirred at rt for 2 h then poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic10 extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified bytrituration using diethyl ether to afford (±)-trans-(5-bromo-1-methyl-1H-1,2,4-triazol-3-yl) (3-(dimethyl amino)- 4-(4-fluorophenyl) pyrrolidin-1-yl) methanone (0.35 g, 0.88 mmol, 61 % yield) as an off white solid. LCMS Method: LCMS_Method_A, Rt: 1.566 min; MS: 396.0 [M + H]+15 Step BTo a stirred solution of (±)-trans-(5-bromo-1-methyl-1H-1,2,4-triazol-3-yl) (3-(dimethyl amino)-4-(4- fluorophenyl)pyrrolidin-1-yl)methanone (0.25 g, 0.63 mmol) and (4-fluorophenyl)boronic acid (0.22 g, 1.58 mmol) in 1,4-dioxane (2.4 mL) was added Cs2CO3(0.61 g, 1.89 mmol) and water (0.6 mL). The mixture was purged with N2for 10 minutes and then Pd(dppf)Cl2.DCM (0.041 g, 0.05 mmol) was added. The resulting20 mixture was stirred at 110°C for 2 h then poured into water (100 mL) and extracted with ethyl acetate (2 x 100mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford trans racemic mixture of Example 61 (0.16 g, 0.38 mmol, ~61 % yield) as a light green solid. LCMS Method: LCMS_METHOD_A; Rt: 1.714 min; MS: 412.4 [M + H]+25 Example 61A and 61B: trans enantiopure (3-(dimethyl amino)-4-(4-fluorophenyl) pyrrolidin-1-yl) (5-(4- fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl) methanone - 150 - (R F ,S O ) * F F F St The enantiopure compounds were obtained as green solids by chiral SFC separation of the racemic mixture 5of Example 61 (100 mg) using WATERS SFC 350 WITH 2489 UV Detector. For separation, Chiralpak IG(250mm x 50mm x 5µm) column was used using mobile phase A: Liquid CO2and mobile phase B: 0.1% (7 M METHANOLIC AMMONIA) in ISOPROPANOL:ACETONITRILE(70:30). Flow rate: 150 ml / min, Isocratic ratio: 60:40 (v / v). UV detection was carried out at 210 nm10 First eluting peak: trans enantiopure (3-(dimethyl amino)-4-(4-fluorophenyl) pyrrolidin-1-yl) (5-(4-fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl) methanone: Chiral HPLC Rt: 6.57 min, 100 % ee, 30 mg 1H NMR: (400 MHz, DMSO-d6): δ 7.92 - 7.81 (m, 2H), 7.47 - 7.38 (m, 4H), 7.19 - 7.12 (m, 2H), 4.31 - 4.07 (m, 1H), 4.03 - 3.97 (m, 3H), 3.83 - 3.74 (m, 1H), 3.68 (t, J = 10.4 Hz, 1H), 3.53 - 3.38 (m, 3H), 2.14 (d, J = 3.6 Hz, 6H).15 LCMS Method: LCMS_Method_C; Rt: 4.36 min; MS: 412.1 [M + H]+Second eluting peak: trans enantiopure (3-(dimethyl amino)-4-(4-fluorophenyl) pyrrolidin-1-yl) (5-(4- fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl) methanone: Chiral HPLC Rt: 6.75 min, 100 % ee, 35 mg 1H NMR: (400 MHz, DMSO-d6): δ 7.91 - 7.81 (m, 2H), 7.47 - 7.38 (m, 4H), 7.19 - 7.12 (m, 2H), 4.12 - 3.9720 (m, 4H), 3.83 - 3.76 (m, 1H), 3.68 (t, J = 10 Hz, 1H), 3.53 - 3.38 (m, 3H), 2.14 (d, J = 3.6 Hz, 6H).LCMS Method: LCMS_Method_C; Rt: 4.36 min; MS: 412.1 [M + H] + Examples 62-84. The Examples of this invention were prepared following the general procedures for amide couplings. The25 specific procedures used are:General procedure 1 To a stirred solution of acid component (1 eq; indicated in Table below) and amine component (1.3 eq; indicated in Table below) in DMF (10 vol) was added HOBt (1.5 eq) followed by EDC.HCl (1.5 eq) at 0 °C and30 the mixture was stirred at rt for 16 h then diluted with water and extracted with ethyl acetate. The combined - 151 - organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash column chromatography (normal or reverse phase) or alternatively preparative HPLC to obtain the final compounds as indicated in the Table below. 5General procedure 2To a stirred solution of acid component (1 eq; indicated in Table below) and amine component (1.3 eq; indicated in Table below) in DMF (10 vol) was added HATU (2.0 eq) followed by DIPEA (1.5 eq) at rt and mixture was stirred at rt for 3 h to 16 h then diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was10 purified by flash column chromatography (normal or reverse phase) or alternatively preparative HPLC toobtain the final compound as indicated in the Table below. General procedure 3 To a stirred solution of acid component (1 eq; indicated in Table below) and TEA (3.0 eq) in THF was added15 T3P (2.0 eq) at 0 °C, after 2 h amine component (1.5 eq; indicated in Table below) was added at rt and themixture was stirred at rt for 3 h to 16 h then diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash column chromatography (normal or reverse phase) or alternatively preparative HPLC to obtain the final compound as indicated in the Table below. 20 General procedure 4 To a stirred solution of methyl ester component (1 eq.) and amine component (1 eq) in THF (10 vol) was added TMA (2 eq) dropwise at rt and the mixture was stirred at 80 °C for 2 h then poured into water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered25 and concentrated under vacuum. The crude was purified by flash column chromatography (normal or reversephase) or alternatively preparative HPLC to obtain the final compound as indicated in the Table below. 30 1. Yield; % re - 152 - Example 62 F ) F S N Hz, - 9 - 4 - 4 - 5 - 6 - 7 - 5 - 5 - 1 - Hz, 8 - 4 - 8 - 2 - 0 - – 7 - 4 - 9 - 8 - 7 - 4 - - 153 - 1.49% Example 65 2.1H NMR: (400 MHz, DMSO-d6): δ 14.41 (s, (m, (m, Hz, (m, (m, (m, 12 Hz, 7 - 6 - 7 - 9 - 5 - 3 - 3 - (s, Hz, (d, .80 H), H), H), H), H), H), (s, Hz, 3 - 4 - 4 - 3 - 6 - 4 - 3 - (s, - 154 - 1.62% 2.1H NMR: (400 MHz, DMSO-d6): δ 8.93 - 4 - (d, (d, 6 - 0 - t, J (t, 8 - 3 - 2 - (s, Hz, 9 - 6 - 9 - 5 - 7 - 5 - 9 - 2 - (d, Hz, 6 - 2 - 0 - 1 - 9 - 7 - 8 - 7 - 9 - 6 - - 155 - 1.52% 2.1H NMR: (400 MHz, Example 72 DMSO-d6): δ 8.77 - 9 - 8 - 4 - 7 - 0 - 3 - 6 - 5 - (d, Hz, 8 - 4 - 5 - 2 - 6 - 5 - (s, Hz, 5 - 9 - 7 - 6 - 4 - (s, Hz, (s, (m, (m, (m, (m, (m, (m, - 156 - 1.72% 2.1H NMR: (400 MHz, Example 76 DMSO-d6): δ 11.70 (s, F (m, 8.8 .93 .77 .34 .17 Hz, (s, (m, (m, (m, (m, (m, (m, (m, (m, Hz, .29 .06 H), H), H), H), H), H), H), H), (s, - 157 - 1.10% 2.1H NMR: (400 MHz, DMSO) δ 11.46 (s, (m, 7.6 .97 H), 1 - 9 - (s, .20 Hz, .12 .95 .30 .00 J = (s, Hz, (m, Hz, (s, 7.6 J = (s, .90 .34 .41 H),

[0010] - 158 - 1.46% 2.1H NMR: (400 MHz, DMSO) δ 13.06 (s, 7.66 (d, .32 .17 .70 (m, (m, (m, (m, .29 Hz, (s, (m, (m, Hz, (m, Hz, (m, (m, (m, (m, Hz, (m, 0.8 H), Above racemate compounds were separated by the chiral separation method which is described the Table below. 5 10 - 159 - 1. Chiral HPLC Rt 2. ee; % Example Starting Material Product3. Quantity, mg Hz, igh (s, 6 - bs, Hz, 5 - H). .19 +. Hz, igh (s, 5 - bs, H), .21 .29 Hz, igh - J = H), .96 (m, H), 0 - .87 .32 8 - .07 - 160 - fluorophenyl) was used using mobile phase A: Second eluting: pyrrolidin-1- Liquid CO2 and Mobile phase B: 1.4.46 min yl)(1-ethyl-3- 0.1 % (7 M METHANOLIC 2.100% Hz, igh – J = H), 6 - .72 (m, H), 2 - .21 (m, .05 Hz, igh bs, H), H), .23 (m, H), (s, ). .44 Hz, igh bs, H), H), .20 (m, H), (s, ). .44 - 161 - First eluting: Example 65A 1.4.69 min 2.100 % O Hz, (s, H), .14 (m, H), .16 .71 Hz, (s, H), .14 (m, H), .16 .71 Hz, bs, 7.6 H), 8 - .13 H), 4 - .16 .12 - 162 - (dimethylamino separation, CHIRALPAK IG (250Examples 66A / 66B Second eluting:)-4-(4- x 50 mm x 5um) column was used 1.9.70 min fluorophenyl)using mobile phase A: Liquid CO22.100%quid CO2 andHz, bs, 6.4 H), .17 6 - .74 (m, ). .12 Hz, J = J = .26 (m, H), 6 - H), H] Hz, .79 (m, H), 5 - .66 (m, (s, Rt: - 163 - First eluting: 1.4.52 min O 2.100 % Hz, .37 (m, H), 6 - .34 (m, Rt: M + Hz, .37 (m, H), 6 - .34 (m, Rt: [M Hz, .86 (m, Hz, Hz, H), .17 7 - .95 (m, H), H). Rt: M + - 164 - fluorophenyl)p (250mm x 20mm x 5μm) column Second eluting: yrrolidin-1- was used using mobile phase A: 1.6.35 min yl)(1-phenyl- NA and mobile phase B; 0.1 % 2.98.73% Hz, .86 (m, Hz, Hz, H), .17 7 - .95 (m, H), H). Rt: M + Hz, .91 (m, H), 7 - .14 (m, H), .27 Hz, .91 (m, H), 8 - .19 (m, H), .29 - 165 - First eluting: 1.4.76 min 2.100 % 7 , ), 9 - 8 , ), H) 8 7 , ), 9 - 8 , ), H); 7 Hz, .73 (m, H), .37 0 - .03 (m, H), .17 .76 - 166 - )-4-(4- CHIRAL ART cellulose-SC Second eluting: fluorophenyl)p (250mm x 20mm 5μm) column 1.6.36 min yrrolidin-1- was used using mobile phase A: 2.90.63 % Hz, .73 (m, H), .37 0 - .03 (m, H), 6 - .77 Hz, H), 4 - .34 Hz, H), .09 .58 Hz, H), 4 - .34 Hz, 6 - bs, .59 - 167 - First eluting: O ) 1.4.04 min Example 74A F ON,S (RF2.96.87 % Hz, .24 (m, H), 4 - H), .86 + Hz, .24 (m, H), 4 - H), .87 Hz, (s, H), 2 - .94 (m, H), 9 - H), .25 - 168 - )-4-(4- HYPERSIL Chiral-ICT (250 mm x Second eluting: fluorophenyl) 50mm x 5μm) column was used 1.5.98 min pyrrolidin-1-yl) using mobile phase A: NA and 2.96.47% Hz, (s, H), 2 - .94 (m, H), 7 - H), .23 Hz, (s, H), H), 4 - .34 12 .38 Hz, (s, H), H), 9 - .34 12 .38 - 169 - First eluting: 1.4.50 min 2.98.41 % Hz, igh (s, H), 2 - .08 (m, H), 4 - .21 .19 Hz, igh (s, H), 2 - .04 (m, H), 4 - .23 .19 Hz, bs, (t, 7 - .49 (m, H), 9 - .17 .95 Rt: M + - 170 - )-4-(4- CHIRALPAK IG (250 mm x 50 Second eluting: fluorophenyl) mm x 5um) column was used 1.6.63 min pyrrolidin-1-yl) using mobile phase A: 0.1 % (7 M 2.100% Hz, bs, .81 (m, H), 5 - .56 (m, H), ). S: Hz, bs, H), 7 - J = (m, H), 2 - H), . Rt: Hz, bs, H), 7 - J = (m, H), 2 - H), Rt: - 171 - First eluting: 1.3.22 min 2.100 % Hz, (bs, H), H), 66 - J = .11 (m, H), .27 .15 Rt: M + Hz, (bs, H), H), 67a-ndJ = .11 (m, H), .27 .15 Rt: Example 81: (±)-trans-1-((5-(2-methoxyethoxy)-3-methyl-1H-indol-2-yl) methyl)-N, N-dimethyl-4-(p-tolyl) pyrrolidin-3-amine

[0011] - 172 - H N OOPO S To a stirred solution of 5-methoxy-3-methyl-1H-indole-2-carbaldehyde (0.81 g, 4.28 mmol) in MeOH (10 mL) was added Preparative Example 1 (1 g, 3.57 mmol) and the mixture was stirred at rt for 5 h then NaCNBH35 (0.44 g, 7.10 mmol) was added and the mixture was stirred at rt for 16 h then concentrated under vacuum.The crude product was purified by reverse phase column chromatography (0.05 % NH4OH in water / ACN) to afford (±)-trans-1-((5-methoxy-3-methyl-1H-indol-2-yl) methyl)-N, N-dimethyl-4-(p-tolyl) pyrrolidin-3-amine. (0.700 g, 1.85 mmol, 44% yield). LCMS Method: UC01_FAR1; Rt:1.39 min; MS: 378.1 [M + H] + 10 Step B To a stirred solution of (±)-trans-1-((5-methoxy-3-methyl-1H-indol-2-yl) methyl)-N, N-dimethyl-4-(p-tolyl) pyrrolidin-3-amine (1 g, 2.65 mmol) in DCM (10 mL) was added BBr3(5 mL) dropwise at 0 °C and the mixture was stirred at rt for 2 h then poured into water (100 mL) and extracted with DCM (2 x 100 mL). The combined15 organic extracts were dried over Na2SO4 and concentrated under vacuum. The crude product was purified byreverse phase column chromatography (water / ACN) to afford (±)-trans-2-((3-(dimethylamino)-4-(p-tolyl) pyrrolidin-1-yl) methyl)-3-methyl-1H-indol-5-ol. (0.3 g, 0.8 mmol, 31 % yield). LCMS Method: UC01_FAR1; Rt:1.10 min; MS: 364.1 [M + H] +20 Step C - 173 - To a stirred solution of (±)-trans-2-((3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl) methyl)-3-methyl-1H-indol-5- ol (0.3 g, 0.82 mmol) in DMF (5 mL) was added NaH (60% dispersion in mineral oil, 0.049 g, 1.23 mmol) at 0 °C. After 5 minutes 1-iodo-2-methoxyethane (0.15 g, 0.82 mmol) was added and the mixture was stirred at rt for 30 minutes then poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined 5organic extracts were dried over Na2SO4 and concentrated under vacuum. The crude product was purified byreverse phase column chromatography (0.05 % NH4OH in water / ACN) to afford the trans racemic mixture of Example 81 (0.030 g, 0.071 mmol, 9 % yield) as dark brown solid. 1H NMR: (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 7.23 (d, J = 8 Hz, 2H), 7.16 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8 Hz, 2H), 6.90 (d, J = 2 Hz, 1H), 6.68 - 6.65 (m, 1H), 4.07 (t, J = 4.4 Hz, 2H), 3.67 - 3.65 (m, 4H), 3.33 (d, J = 610 Hz, 3H), 3.10 (bs, 1H), 2.87 - 2.82 (m, 3H), 2.50 - 2.43 (m, 2H), 2.24 (s, 3H), 2.18 (s, 3H), 2.05 (s, 6H).LCMS: Method: UC07_MSR2, Rt: 6.66 min, MS: 422.5 [M + H] + Example 82: (±)-trans-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)-3-(dimethylamino)-4-(p-tolyl)pyrrolidine- 1-carboxamide O NH2 O O p15Preparative Example 1Step A To a stirred solution of 2,3-dihydrobenzo[b] [1,4] dioxin-6-amine (0.14 g, 0.95 mmol) in THF (5 mL) was added CDI (0.15 g, 0.95 mmol) at 0 °C. After 10 minutes Preparative Example 1 (0.19 g, 0.95 mmol) was added and the mixture was stirred at 0 °C for 15 minutes then poured into water (100 mL) and extracted with20 ethyl acetate (2 x 100 mL). The combined organic extracts were dried over Na2SO4 and concentrated undervacuum. The crude product was purified by reverse phase column chromatography (0.05 % NH4OH in water / ACN) to afford the trans racemic mixture of Example 82 (0.250 g, 0.65 mmol, 68 % yield) as brown solid. 1H NMR: (400 MHz, DMSO) δ 8.04 (s, 1H), 7.29 (d, J = 8 Hz, 2H), 7.16 (d, J = 8 Hz, 2H), 7.10 (d, J = 2.4Hz, 1H), 6.90 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.20 - 4.16 (m, 4H), 3.88 - 3.84 (m, 1H),25 3.80 - 3.76 (m, 1H), 3.55 - 3.48 (m, 1H), 3.36 - 3.29 (m, 3H), 2.32 (s, 9H)Following the coupling, procedure as described in Example 82 the following compounds were prepared. - 174 - Amine1. Yield; % Example Derivative Boronic acid / ester Product2.1H-NMR 3. MH+ (ESI) 400 .33 .50 J = d, J 9 - 3 - .72 .55 .30 H), azin- 4(3H)-one O Pre 5Step ATo a stirred solution of Preparative Example 1 (0.2 g, 0.83 mmol) in THF (2 mL) was added TEA (0.42 g, 4.16 mmol) and the mixture was stirred at rt for 15 minutes then 2-chloropyrrolo[2,1-f] [1,2,4] triazin-4(3H)- one (0.21 g, 1.24 mmol) was added and the mixture was heated at 100 °C for 16 h then diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over Na2SO4,10 filtered and concentrated under vacuum. The crude was purified by reverse phase column chromatographyusing (ACN / water) to afford trans racemic mixture Example 84 as a yellow solid (0.1 g, 0.29 mmol, 25 % yield). LCMS Method: LCMS_Method_C; Rt: 3.77 min; MS: 338.3 [M + H]+15 Example 84A and 84B: trans enantiopure -2-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl) pyrrolo[2,1-f] [1,2,4] triazin-4(3H)-one - 175 - O O O NH Chiral NH NH Step 5The enantiopure compounds were obtained as yellow solids by chiral prep HPLC separation of racemicmixture of Example 84 (95 mg) using PHP-02-SHIMADZU LC20AP WITH UV DETECTOR. For separation, CHIRALPAK IG (250mm x 50mm x 5µm) column was used using mobile phase A: 0.1% (7 M METHANOLIC AMMONIA) in METHANOL:ACETONITRILE(50:50) and Mobile Phase B: NA .Flow rate: 30 ml / min, Isocratic ratio: 100:00 (v / v). UV detection was carried out at 210 nm and 235 nm 10 First eluting peak: trans enantiopure 2-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl) pyrrolo[2,1-f] [1,2,4] triazin-4(3H)-one: Chiral HPLC Rt: 7.91 min, 97.97 % ee, 20 mg 1H NMR: (400 MHz, DMSO-d6): δ 10.89 (s, 1H), 7.31 - 7.24 (m, 3H), 7.13 (d, J = 7.6 Hz, 2H), 6.71 - 6.70 (m, 1H), 6.34 - 6.32 (m, 1H), 3.86 - 3.81 (m, 1H), 3.68 - 3.64 (m, 1H), 3.46 - 3.37 (m, 2H), 3.34 - 3.30 (m, 2H),15 2.28 (s, 3H), 2.13 (s, 6H)LCMS Method: LCMS_Method_C; Rt: 3.77 min; MS: 338.3 [M + H]+Second eluting peak: trans enantiopure (3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl) pyrrolo[2,1-f] [1,2,4] triazin-4(3H)-one: Chiral HPLC Rt: 9.53 min, 97.14 %, 20 mg20 1H NMR: (400 MHz, DMSO-d6): δ 10.89 (s, 1H), 7.30 (t, J = 2 Hz, 1H), 7.25 (d, J = 8 Hz, 2H), 7.13 (d, J = 7.6Hz, 2H), 6.70 - 6.68 (m, 1H), 6.33 - 6.31 (m, 1H), 3.85 - 3.81 (m, 1H), 3.68 - 3.64 (m, 1H), 3.45 - 3.37 (m, 2H), 3.34 - 3.29 (m, 2H), 2.28 (s, 3H), 2.13 (s, 6H) LCMS Method: LCMS_Method_C; Rt: 3.76 min; MS: 338.3 [M + H]+25 Example 85: (±)-trans-N, N-dimethyl-1-(quinoxalin-2-yl)-4-(p-tolyl) pyrrolidin-3-amine - 176 - N Pre para ve xample 1Example 85Step A To a stirred solution of Preparative Example 1 (0.20 g, 0.71 mmol) in ( m ) was added NaH (60% dispersion in mineral oil, 0.069 g, 2.89 mmol) at 0 °C. After stirring for 10 minutes 2-bromoquinoxaline (0.2 g, 50.96 mmol) was added at 0 °C and the mixture was stirred at rt for 24 h then diluted with water (30 mL) andextracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The resulting crude product was purified by reverse phase column chromatography (water / ACN) to afford trans racemic mixture Example 85 (0.115 g, 0.34 mmol, 46 % yield) as an off white solid.10 LCMS: Method: LC01_MSR2, Rt: 7.07 min; MS: 333.2 [M + H] +1H NMR: (400 MHz, DMSO) δ 8.52 (s, 1H), 7.82 (d, J = 8 Hz, 1H), 7.62 - 7.57 (m, 2H), 7.38 - 7.29 (m, 3H), 7.16 (d, J = 7.6 Hz, 2H), 4.16 - 4.15 (m, 1H), 4.00 - 3.95 (m, 1H), 3.67 - 3.63 (m, 1H), 3.56 - 3.46 (m, 3H), 2.33 (s, 3H), 2.24 (s,6H)15 Example 86:(±)-trans-1-((6-methoxy-3-methyl-1H-indol-2-yl) methyl)-N, N-dimethyl-4-(p-tolyl)pyrrolidin-3-amine

[0012] - 177 - Preparative Example 1O pStep A A solution of POCl3(0.3 mL) in DMF (0.3 mL) was stirred at 0 °C for 10 minutes and 6-methoxy-3-methyl-1H- 5indole (0.3 g, 1.85 mmol) was added and the mixture was stirred at rt for 2 h then poured into cold water (20mL). The solid precipitate was filtered and dried under vacuum to afford 6-methoxy-3-methyl-1H-indole-2- carbaldehyde (0.050 g, 0.2 mmol, 14.3%). LCMS Method: UC01_FAR2, Rt: 1.66 min, MS:190 [M+H] +10 Step BA solution of 6-methoxy-3-methyl-1H-indole-2-carbaldehyde (0.2 g, 1.05 mmol) and Preparative Example 1 (0.25 g, 1.26 mmol) in MeOH (2 mL) was stirred at rt for 2 h and NaCNBH3(0.13 g, 2.10 mmol) was added and the mixture was stirred at rt for 12 h then concentrated under vacuum. The crude product was purified using Prep-HPLC (0.05% NH4OH IN WATER: ACETONITRILE: METHANOL) to afford trans racemic mixture15 Example 86 (0.032 g, 0.08 mmol, 9% yield) as ant orange solid.1H NMR: (400 MHz, DMSO) δ 10.58 (s, 1H), 7.28 (d, J = 6.4 Hz, 3H), 7.11 (d, J = 8 Hz, 2H), 6.79 (d, J = 1.6 Hz, 1H), 6.62 - 6.56 (m, 1H), 3.72 (s, 4H), 3.07 - 3.03 (m, 2H), 2.94 (s, 2H), 2.67 (s, 3H), 2.50 - 2.18 (m, 12H). LCMS: Method: LC01_MSR2, Rt: 7.61 min, MS: 378.40 [M+H] +20 Example 87: (±)-trans-1-(1H-benzo[d]imidazol-2-yl)-N,N-dimethyl-4-(p-tolyl)pyrrolidin-3-amine - 178 - N Br N Pre Step A To the stirred solution of Preparative Example 1 (0.13 g, 0.63 mmol) in 1,4-dioxane (1.3 mL) were added 2- bromo-1H-benzo[d]imidazole (0.24 g, 1.27 mmol) followed by DIPEA (0.33 mL, 1.91 mmol) under N2and the 5mixture was purged with N2 for 15 minutes. CuI (0.012 g, 0.96 mmol) was added and the mixture was heatedat 140oC for 18 h then directly purified by normal phase column chromatography (Silica; 0 to 7% methanol in dichloromethane) to afford trans racemic mixture Example 87 as a white solid (0.100 g, 0.31 mmol, 49 % yield) 1H NMR: (400 MHz, DMSO) δ 11.68 (s, 1H), 7.29 (d, J = 8 Hz, 2H), 7.19 - 7.14 (m, 4H), 6.94 - 6.90 (m, 2H),10 3.94 - 3.90 (m, 1H), 3.81 - 3.76 (m, 1H), 3.53 - 3.35 (m, 4H), 2.28 (s, 3H), 2.20 (s, 6H)LCMS Method: LC01_MSR2; Rt: 4.95 min; 321.3 [M + H]+ Example 88: (±)-trans-1-(6-fluoro-1H-indazol-3-yl)-N, N-dimethyl-4-(p-tolyl) pyrrolidin-3-amine I OH (±)-trans (±)-trans Preparative Example 115 Step ATo a stirred solution of 6-fluoro-3-iodo-1H-indazole (0.3 g, 1.14 mmol) and Preparative Example 1 (0.58 g, 2.86 mmol) in DMSO (5 mL) was added K3PO4(0.60 g, 2.86 mmol) then purged with N2for 10 minutes, CuI (0.065 g, 0.034 mmol) and L-proline (0.19 g, 1.71 mmol) were added. The resulting mixture was stirred at 100 °C for 16 h then the mixture was poured into water (50 mL) and extracted with DCM (2 x 50 mL). The20 combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude - 179 - product was purified by Prep-HPLC (0.05% Formic in water: ACN) to afford trans racemic mixture of Example 88 as a brown solid (0.020 g, mmol, 5%). LCMS Method: UC01_FAR1; Rt: 1.41 min; MS: 339 [M+H] + 1H NMR: (400 MHz, DMSO-d6): δ 11.84 (s, 1H),8.16 (s,1H), 7.84 - 7.81 (m, 1H), 7.29 (d, J = 8 Hz, 2H), 7.13 5(d, J = 8 Hz, 2H), 7.04 (dd, J1 = 4 Hz, J2 = 12 Hz, 1H), 6.77 - 6.72 (m, 1H), 3.95 - 3.95 (m, 1H), 3.80 - 3.79(m, 1H), 3.58 (m, 1H), 3.48 - 3.35 (m, 2H), 2.28 (s, 3H), 2.18 (s, 6H). Example 88A and 88B: trans enantiopure 1-(6-fluoro-1H-indazol-3-yl)-N, N-dimethyl-4-(p-tolyl) pyrrolidin-3-amine 10 N N xamp e 88Step A The enantiopure compounds were obtained as brown solid materials by chiral SFC separation of racemic mixture of Example 88 (100 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UV DETECTOR.15 For separation, Chiralpak IG (250mm x 50mm x 5µm) column was used using mobile phase A: 0.1 % (7 MMETHANOLIC AMMONIA) in MEOH and Mobile Phase B: 0.1 % (7 M METHANOLIC AMMONIA) in ACN. Flow rate: 40 ml / min, Isocratic ratio: 50:50 (v / v). UV detection was carried out at 210 nm and 238 nm. First eluting peak: trans enantiopure 1-(6-fluoro-1H-indazol-3-yl)-N, N-dimethyl-4-(p-tolyl) pyrrolidin-3-20 amine: LC Rt: 4. 24 % ee, 20 mg 1H NMR: (400 MHz, DMSO-d6) (High temperature): δ 11.28 (s, 1H), 7.81 (q, J1 = 5.2 Hz, J2 = 8.8 Hz, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 7.6 Hz, 2H), 7.02 (d, J = 9.2 Hz, 1H), 6.75 (t, J = 9.2 Hz, 1H), 3.98 (s, 1H), 3.83 (t, J = 8 Hz, 1H), 3.62 (t, J = 6.8 Hz, 1H), 3.48 - 3.45 (m, 2H), 3.40 - 3.36 (m, 1H), 2.29 (s, 3H), 2.13 (s, 6H)25 LCMS Method: LCMS_Method_C; Rt: 4.51 min; MS: 339.4 [M + H] +Second eluting peak: trans enantiopure 1-(6-fluoro-1H-indazol-3-yl)-N, N-dimethyl-4-(p-tolyl) p HPLC Rt: 6 .11 min, 100 % ee, 20 mg 1 H NMR: (400 MHz, DMSO-d6) (High temperature): δ 10.09 (s, 1H), 7.82 - 7.78 (m, 1H), 7.28 (d, J = 7.6 Hz,30 2H), 7.14 (d, J = 7.6 Hz, 2H), 7.02 (d, J = 9.6 Hz, 1H), 6.76 (t, J = 1.6 Hz, 1H), 3.99 (t, J = 12.4 Hz, 1H), 3.83 - 180 - (t, J = 9.6 Hz, 1H), 3.62 (t, J = 7.2 Hz, 1H), 3.48 (d, J = 5.2 Hz, 2H), 3.40 - 3.34 (m, 1H), 2.29 (s, 3H), 2.22 (s, 6H). LCMS Method: LCMS_Method_C; Rt: 4.39 min; MS: 339.3 [M + H]+5 Following the coupling, procedure as described in Example 88 the following compounds were prepared.1. Yield ple Amine; % ExamHalo Derivative Derivative Product2.1H-NMR 3. MH+ (ESI) Hz, (s, .79 .30 .25 .14 .90 .97 .83 .61 52 - (s, Above racemate compounds were separated by the chiral separation method which is described below. 1. Chiral HPLC Rt 2. ee; % Hz, (s, Hz, H), H), H), 83 - .57 (m, H), H) Rt: - 181 - dimethyl-4-(p- racemic mixture of Example 89 Second eluting: tolyl) (100 mg) using PHP-04-AGILENT Example 89A / 89B 1.8.65 min pyrrolidin-3- 1260 SERIES INFINITY-II WITH 2.100% ee Hz, (s, Hz, Hz, Hz, Hz, Hz, Hz, Hz, Hz, H), H). ydro- 4H-pyrazolo[3,4-d] pyrimidin-4-one Preparative Example 135 Step ATo a stirred solution of Preparative Example 13 (0.24 g, 0.90 mmol) in DMF (2.4 mL) was added K2CO3(0.37g, 2.72 mmol) and Preparative Example 1 (0.22 g, 1.08 mmol) then the mixture was stirred at 90 °C for 2 h and poured into water (100 mL) and extracted using ethyl acetate (3 x 100 mL). The combined organic extracts were dried over Na2SO4,filtered and concentrated under vacuum. The resulting crude product was10 purified by reverse phase column chromatography (water / ACN) to afford trans racemic mixture Example 90as an off-white solid (0.13 g, 0.30 mmol, 33 % yield). LCMS Method: LCMS_Method_C; Rt: 4.95 min; MS: 433.3 [M + H]+ - 182 - Example 90A and 90B: trans enantiopure 6-(3-(dimethylamino)-4-(p-tolyl) pyrrolidin-1-yl)-2-(4- fluorophenyl)-2,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one O O O (±)-trans NH ( Chiral RFNHFNH F 5 S The enantiopure compounds were obtained as off-white solids by chiral prep HPLC separation of the racemic mixture of Example 90 (100 mg) using PHP-10-SHIMADZU LC20AP WITH UV DETECTOR. For separation,10 Chiral ART cellulose-SC (250mm x 20mm 5µm) column was used using mobile phase A: 0.1% (7 MMETHANOLIC AMMONIA) in n-HEXANE; mobile phase B: 0.1% (7 M METHANOLIC AMMONIA) IN 2- PROPANO:ACETONITRILE(70:30); with run time 28 min, Flow rate: 20 ml / min, Isocratic ratio: 75:25 (v / v). UV detection was carried out at 210 nm and 248 nm.15 First eluting peak: trans enantiopure 6-(3-(dimethylamino)-4-(p-tolyl) pyrrolidin-1-yl)-2-(4-fluorophenyl)-2,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one: Chiral HPLC Rt: 2.94 min; 100% ee; 30 mg 1H NMR: (400 MHz, DMSO-d6): δ 10.70 (s, 1H), 9.06 (s, 1H), 8.00 - 7.96 (m, 2H), 7.38 (t, J = 8.8 Hz, 2H), 7.27 (d, J = 8 Hz, 2H), 7.15 (d, J = 7.6 Hz, 2H), 4.01 - 3.94 (m, 1H), 3.82 - 3.77 (m, 1H), 3.53 - 3.46 (m, 1H),20 3.43 - 3.41 (m, 2H), 3.39 - 3.36 (m, 1H), 2.28 (s, 3H), 2.14 (s, 6H)LCMS Method: LCMS_Method_C, Rt: 4.39 min; MS: 433.3 [M + H] + Second eluting peak: trans enantiopure 6-(3-(dimethylamino)-4-(p-tolyl) pyrrolidin-1-yl)-2-(4- fluorophenyl)-2,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one: Chiral HPLC Rt: 3.35 min; 96.2 % ee; 37 mg25 1H NMR: (400 MHz, DMSO-d6): δ 10.70 (s, 1H), 9.06 (s, 1H), 8.00 - 7.96 (m, 2H), 7.38 (t, J = 8.8 Hz, 2H),7.27 (d, J = 8 Hz, 2H), 7.15 (d, J = 7.6 Hz, 2H), 4.01 - 3.94 (m, 1H), 3.82 - 3.77 (m, 1H), 3.53 - 3.48 (m, 1H), 3.43 - 3.41 (m, 2H), 3.39 - 3.37 (m, 1H), 2.28 (s, 3H), 2.15 (s, 6H) LCMS Method: LCMS_Method_C, Rt: 4.40 min; MS: 433.3 [M + H] +30 Example 91: (±)-trans-6-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one - 183 - Preparative Example 1Step A To a stirred solution o reparatve xampe (0. g, 0. mmo) and 6-c oro-1-phenyl-1,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-one (0.15 g, 0.60 mmol) in DMF (1.5 mL) was added K2CO3(0.25 g, 1.82 mmol) at 5rt and heated at 110 °C for 2 h then the mixture was poured into water (50 mL) and extracted with ethylacetate (3 x 30 mL). The combined organic extracts were dried using Na2SO4, filtered and concentrated under vacuum. The crude product was triturated with n-pentane to afford trans racemic mixture Example 91 as an off white solid (0.12 g, 0.28 mmol, 47 % yield). LCMS Method: LCMS_Method_C, Rt: 4.52 min; MS: 415.3 [M + H] + 10 Example 91A and 91B: trans enantiopure 6-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl)-1-phenyl- 1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one O O O15 St The enantiopure compounds were obtained as off-white solids by chiral SFC separation of the racemic mixture of Example 91 (100 mg) using WATERS SFC 350 WITH 2489 UV Detector. For separation, Chiral Pak IG (250mm x 50mm x 5µm) column was used using mobile phase A: Liquid CO2and mobile phase B: 0.1% (7 M METHANOLIC AMMONIA) in METHANOL: ACETONITRILE; with run time 26 min, Flow rate: 15020 ml / min, Isocratic ratio: 60:40 (v / v). UV detection was carried out at 210 nm. - 184 - First eluting peak: enantiopure 6-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl)-1-phenyl-1,5-dihydro- 4H-pyrazolo[3,4-d] pyrimidin-4-one: Chiral HPLC Rt: 2.31 min; 100% ee; 35 mg 1H NMR: (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 8.15 (d, J = 8 Hz, 2H), 8.01 (s, 1H), 7.47 (t, J = 8 Hz, 2H) 7.29 - 7.22 (m, 3H), 7.15 (d, J = 8 Hz, 2H), 4.03 (bs, 1H), 3.87 - 3.83 (m, 1H), 3.54 - 3.42 (m, 4H), 2.28 (s, 53H), 2.14 (s, 6H).LCMS Method: LCMS_Method_C, Rt: 4.90 min; MS: 415.4 [M + H] + Second eluting peak: enantiopure 6-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl)-1-phenyl-1,5- dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one : Chiral HPLC Rt: 2.41 min; 98.38 % ee; 34 mg 1H NMR: (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 8.15 (d, J = 8 Hz, 2H), 8.03 (s, 1H), 7.47 (t, J = 6 Hz, 2H)10 7.29 - 7.22 (m, 3H), 7.15 (d, J = 8 Hz, 2H), 4.03 (bs, 1H), 3.87 - 3.83 (m, 1H), 3.54 - 3.44 (m, 4H), 2.28 (s,3H), 2.14 (s, 6H). LCMS Method: LCMS_Method_C, Rt: 4.87 min; MS: 415.4 [M + H] + Example 92:(±)-trans-6-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl)-1-(5-fluoropyridin-2-yl)-1,5-15 dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-onePreparative Example 1Step A To a stirred solution of Preparative Example 14 (0.25 g, 0.94 mmol) and Preparative Example 1 (0.24 g, 1.03 mmol) in DMF (2.5 mL) was added K2CO3(0.38 g, 2.82 mmol) at rt and heated at 100°C for 2 h then the20 mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organicextracts were dried using Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford trans racemic mixture Example 92 as a white solid (0.110 g, 0.25 mmol, 27% yield). LCMS Method: LCMS_Method_A, Rt: 1.67 min; MS: 434.4 [M + H] + 25 - 185 - Example 92A and 92B: trans enantiopure 6-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl)-1-(5- fluoropyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one O O O chiral NH NH NH 5ST p p y p p p racemic mixture of Example 92 (100 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UV DETECTOR. For separation, Chiralpak IG (250mm x 50mm x 5µm)column was used using mobile phase A: 0.1 % (7 M Methanolic Ammonia) in n-Hexane and mobile phase B: 0.1% (7 M Methanolic Ammonia) in 2-10 propanol:Methanol (50:50) Flow rate: 40 ml / min, Isocratic ratio: 45:55 (v / v). UV detection was carried out at210 nm and 280 nm. First eluting peak: 6-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl)-1-(5-fluoropyridin-2-yl)-1,5-dihydro- 4H-pyrazolo[3,4-d] pyrimidin-4-one: Chiral HPLC Rt: 2.54 min; 100 % ee; 25 mg15 1H NMR: (400 MHz, DMSO-d6): δ 10.99 (bs, 1H), 8.53 (d, J = 2.8 Hz, 1H), 8.19 - 8.16 (m, 1H), 8.03 (s, 1H),7.95 - 7.93 (m, 1H), 7.26 (d, J = 8 Hz, 2H), 7.13 (d, J = 8 Hz, 2H), 4.01 - 3.81 (m, 2H), 3.51 - 3.36 (m, 4H), 2.27 (s, 3H), 2.12 (s, 6H). LCMS Method: LCMS_Method_C; Rt:3.92 min; 434.3; MS: [M + H] +20 Second eluting peak: 6-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl)-1-(5-fluoropyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one : Chiral HPLC Rt: 2.66 min; 90.2 % ee; 25 mg 1H NMR: (400 MHz, DMSO-d6): δ 11.01 (bs, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.15 - 8.14 (m, 1H), 8.05 (s, 1H), 7.95 - 7.94 (m, 1H), 7.27 (d, J = 8 Hz, 2H), 7.14 (d, J = 7.6 Hz, 2H), 4.03 (bs, 1H), 3.87 (bs, 1H), 3.53 - 3.42 (m, 4H), 2.27 (s, 3H), 2.16 (s, 6H).25 LCMS Method: LCMS_Method_C; Rt:3.98 min; 434.2; MS: [M + H] +Example 93: (±)-trans-6-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl)-1-(5-(trifluoromethyl) pyridin-2- yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one - 186 - Step A To a stirred solutio n o repara ve xampe ( . g, . mmo) an repara ve Example 1 (0.27 g, 1.14 mmol) in DMF (3 mL) was added K2CO3(0.39 g, 2.85 mmol) at rt and heated at 110 °C for 2 h then the 5mixture was poured into water (60 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organicextracts were dried using Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford trans racemic mixture Example 93 as a white solid (0.100 g, 0.20 mmol, 22 % yield). LCMS Method: LCMS_Method_A, Rt: 1.81 min; MS: 484.4 [M + H] +10 Example 93A and 93B: trans enantiopure 6-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl)-1-(5-(trifluoromethyl) pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one O O O S ep15 The enantiopure compounds were obtained as off-white solids by chiral prep HPLC separation of the racemicmixture of Example 93 (100 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UV DETECTOR. For separation, Chiralpak IG (250mm x 50mm x 5µm) column was used using mobile phase A: 0.1 % (7 M Methanolic Ammonia) in n-Hexane; mobile phase B: 0.1 % (7 M Methanolic Ammonia) in 2- PROPANOL:METHANOL(50:50); with run time 68 min, Flow rate: 40 ml / min, Isocratic ratio: 50:50 (v / v). UV20 detection was carried out at 210 nm and 244 nm - 187 - First eluting peak: 6-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl)-1-(5-(trifluoromethyl) pyridin-2-yl)- 1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one: Chiral HPLC Rt: 2.30 min; 100 % ee; 24 mg 1H NMR (400 MHz, DMSO-d6): δ 11.16 (bs, 1H), 8.92 (bs, 1H), 8.52 (bs, 1H), 8.42 (bs, 1H), 8.12 (s, 1H), 7.29 (d, J = 7.6 Hz, 2H), 7.15 (d, J = 8 Hz, 2H), 4.07 (bs, 1H), 3.87 - 3.86 (m, 1H), 3.55 - 3.45 (m, 4H), 2.29 5(s, 3H), 2.14 (s, 6H)LCMS Method: LCMS_Method_C; Rt: 4.68 min; MS: 484.2 [M + H] + Second eluting peak: 6-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl)-1-(5-(trifluoromethyl) pyridin-2- yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one: Chiral HPLC Rt: 2.57 min; 94.46 % ee; 25 mg10 1H NMR (400 MHz, DMSO-d6): δ 10.20 (bs, 1H), 8.91 (s, 1H), 8.56 (bs, 1H), 8.43 - 8.39 (m, 1H), 8.08 (s,1H), 7.28 (d, J = 7.6 Hz, 2H), 7.15 (d, J = 8 Hz, 2H), 4.06 (bs, 1H), 3.87 (bs, 1H), 3.54 - 3.34 (m, 4H), 2.28 (s, 3H), 2.14 (s, 6H) LCMS Method: LCMS_Method_C; Rt: 4.66 min; MS: 484.2 [M + H] +15 Example 94: (±)-trans-6-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl)-1-(pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one Step A To a stirred solution of Preparative Example 16 (0.2 g, 0.80 mmol) and Preparative Example 1 (0.23 g,20 0.96 mmol) in DMF (1.5 mL) was added K2CO3 (0.33 g, 2.42 mmol) at rt and heated at 110 °C for 2 h thenthe mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried using Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford trans racemic mixture Example 94 as a white solid (0.105 g, 0.20 mmol, 31 % yield).25 LCMS Method: LCMS_Method_A, Rt: 1.60 min; MS: 416.4 [M + H] +Example 94A and 94B: trans enantiopure 6-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl)-1-(pyridin-2- yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one - 188 - O O O NH NH NH N The enantiopure compounds were obtained as white solids by chiral prep HPLC separation of the racemic mixture of Example 94 (105 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UV DETECTOR. 5For separation, Chiralpak IG (250mm x 50mm x 5µm) column was used using mobile phase A: 0.1 % (7 MMethanolic Ammonia) in n-Hexane and mobile phase B: 0.1 % (7 M Methanolic Ammonia) in 2- PROPANOL:METHANOL(50:50); with run time 62 min, Flow rate: 40 ml / min, Isocratic ratio: 50:50 (v / v). UV detection was carried out at 210 nm and 275 nm10 First eluting peak: 6-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl)-1-(pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one: Chiral HPLC Rt: 4.29 min; 100 % ee; 20 mg 1 3 (s, 1 .01 - 315 L-4H- p 1 7.9320 ( (m,1 L -1H-25 1 , , - 189 - B S To a stirred suspension of 5-bromo-1-methyl-1H-1,2,4-triazole-3-carboxylic acid (0.3 g, 1.45 mmol) and 5Preparative Example 1 (0.52 g, 2.18 mmol) in THF (3 mL) was added TEA (0.6 mL, 4.36 mmol) at 0oCfollowed by T3P (1.8 mL, 2.91 mmol) and the mixture was stirred at rt for 1 h then poured into water (50 mL)and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum to afford (±)-trans-(5-bromo-1-methyl-1H-1,2,4-triazol-3-yl) (3- (dimethylamino)-4-(p-tolyl) pyrrolidin-1-yl) methanone (0.3 g).10 LCMS Method: LCMS_Method_A; Rt: 1.59 min; MS: 392.2 [M + H] +, 394.1 [M + 2] +Step B To a stirred solution of (±)-trans-(5-bromo-1-methyl-1H-1,2,4-triazol-3-yl)(3-(dimethylamino)-4-(p- tolyl)pyrrolidin-1-yl)methanone (0.3 g, 0.76 mmol) from Step A and (4-fluorophenyl)boronic acid (0.16 g, 1.1415 mmol) in 1,4-dioxane (2.4 mL), was added Cs2CO3 (0.74 g, 2.29 mmol) and water (0.6 mL) then purged withN2for 10 minutes, PdCl2(dppf)DCM (0.043 g, 0.05 mmol) was added and the mixture was stirred at 100 °C for 1 h then the mixture was cooled to rt and poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford trans20 racemic mixture Example 95 as a yellow solid (0.120 g, 0.29 mmol, 39 % yield).LCMS Method: LCMS_Method_C; Rt: 4.64 min; MS: 408.3 [M + H]+Example 95A and 95B: trans enantiopure (3-(dimethylamino)-4-(p-tolyl) pyrrolidin-1-yl) (5-(4- fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl) methanone 25 - 190 - (R, O S) O O F Step A The enantiopure compounds were obtained as off-white solids by chiral prep HPLC separation of the racemic mixture of Example 95 (119 mg) using PHP-10-SHIMADZU LC20AP WITH UV DETECTOR. For separation, 5Hypersil Chiral-ICT (250mm x 50mm x 5µm) column was used using mobile phase A: 0.1 % (7 M MethanolicAmmonia) in n-Hexane and mobile phase B: 0.1 % (7 M Methanolic Ammonia) in 2- PROPANOL:ACETONITRILE(70:30); with run time 55 min, Flow rate: 35 ml / min, Isocratic ratio: 60:40 (v / v). UV detection was carried out at 210 nm and 225 nm10 First eluting peak: (3-(dimethylamino)-4-(p-tolyl) pyrrolidin-1-yl) (5-(4-fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl) methanone: Chiral HPLC Rt: 2.51 min; 100 % ee; 35 mg 1H NMR (400 MHz, DMSO-d6): δ 7.91 - 7.88 (m, 1H), 7.84 - 7.81 (m, 1H), 7.47 - 7.38 (m, 2H), 7.28 - 7.25 (m, 2H), 7.13 (t, J = 9.2 Hz, 2H), 4.26 - 4.07 (m, 1H), 4.03 (s, 1H), 3.97 (s, 2H), 3.84 - 3.74 (m, 1H), 3.69 - 3.64 (m, 1H), 3.52 - 3.49 (m, 1H), 3.41 - 3.34 (m, 2H), 2.27 (d, J = 8.4 Hz, 3H), 2.13 (d, J = 3.6 Hz, 6H)15 LCMS Method: LCMS_Method_C; Rt: 5.09 min; MS: 408.3 [M + H] +Second eluting peak: (3-(dimethylamino)-4-(p-tolyl) pyrrolidin-1-yl) (5-(4-fluorophenyl)-1-methyl-1H- 1,2,4-triazol-3-yl) methanone: Chiral HPLC Rt: 2.65 min; 90.44 % ee; 35 mg 1H NMR (400 MHz, DMSO-d6): δ 7.91 - 7.88 (m, 1H), 7.84 - 7.81 (m, 1H), 7.47 - 7.38 (m, 2H), 7.28 - 7.2520 (m, 2H), 7.13 (t, J = 8.4 Hz, 2H), 4.29 - 4.07 (m, 1H), 4.03 (s, 1H), 3.97 (s, 2H), 3.84 - 3.76 (m, 1H), 3.66 -3.64 (m, 1H), 3.52 - 3.47 (m, 1H), 3.39 - 3.34 (s, 2H), 2.27 (d, J = 8.4 Hz, 3H), 2.13 (d, J = 3.6 Hz, 6H) LCMS Method: LCMS_Method_C; Rt: 5.07 min; MS: 408.3 [M + H] + Example 96: (±)-trans-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl) (1-phenyl-1H-1,2,3-triazol-4-yl)25 methanone - 191 - Preparative Example 1Step A To a stirred solution of methyl 1-phenyl-1H-1,2,3-triazole-4-carboxylate (0.2 g, 0.98 mmol) and Preparative Example 1 (0.23 g, 0.98 mmol) in THF (2 mL) was added TBD (0.68 g, 4.92 mmol) at rt and the mixture was 5stirred for 1 h then poured into water (60 mL) and extracted with ethyl acetate (3 x 60 mL). The combinedorganic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford trans racemic mixture Example 96 as an off-white solid (0.1 g, 0.26 mmol, 27% yield). LCMS Method: LCMS_Method_C; Rt: 4.83 min; MS: 376.3 [M + H] + 10 Example 96A and 96B: trans enantiopure (3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl) (1-phenyl-1H- 1,2,3-triazol-4-yl) methanone15 S tep AThe enantiopure compounds were obtained as off-white solids by chiral SFC separation of the racemic mixture of Example 96 (102 mg) using WATERS SFC 350 WITH 2489 UV Detector. For separation, Hypersil Chiral IC-T (250mm x 50mm x 5µm) column was used using mobile phase A: Liquid CO2and mobile phase B: 0.1% (7 M METHANOLIC AMMONIA) in METHANOL: ACETONITRILE (50:50) Flow rate: 150 ml / min,20 Isocratic ratio: 60:40 (v / v). UV detection was carried out at 245 nm. - 192 - First eluting peak: (3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl) (1-phenyl-1H-1,2,3-triazol-4-yl) methanone: Chiral HPLC Rt: 2.27 min; 94.82 % ee; 35 mg 1H NMR: (400 M Hz DMSOd6: δ 9.33 (d, J = 8.8 H z 1H 802 796 m 2H 765 752 m 3H 729 (d, J = 8 Hz, 2H), 7.15 (d, J = 7.6 Hz, 2H), 4.45 - 4.25 (m, 1H), 4.03 - 3.91 (m, 1H), 3.85 (t, J = 10.4 Hz, 1H), 3.55 - 53.34 (m, 3H), 2.28 (s, 3H), 2.15 (d, J = 4.8 Hz, 6H).LCMS Method: LCMS_Method_C; Rt: 4.59 min; MS: 376.3 [M + H] + Second eluting peak: (3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl) (1-phenyl-1H-1,2,3-triazol-4-yl) methanone: Chiral HPLC Rt: 2.43 min; 86.36 % ee; 35 mg 1H NMR: (400 MHz, DMSO-d6): δ 9.33 (d, J = 8.8 Hz, 1H), 8.02 - 7.96 (m, 2H), 7.65 - 7.52 (m, 3H), 7.29 (d, J10 = 7.6 Hz, 2H), 7.15 (d, J = 7.6 Hz, 2H), 4.48 - 4.25 (m, 1H), 4.02 - 3.94 (m, 1H), 3.85 (t, J = 10.4 Hz, 1H), 3.55- 3.34 (m, 3H), 2.28 (s, 3H), 2.15 (d, J = 4.8 Hz, 6H). LCMS Method: LCMS_Method_C; Rt: 4.59 min; MS: 376.3 [M + H] + Example 97: (±)-trans-6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-phenyl-1,5-dihydro-15 4H-pyrazolo[3,4-d] pyrimidin-4-oneF F S) N s T -phenyl-1,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-one (0.25 g, 1.01 mmol) in DMF (2.5 mL) was added K2CO3(0.42 g, 3.04 mmol) at20 rt and heated at 110 °C for 2 h then the mixture was poured into water (50 mL) and extracted with ethylacetate (2 x 50 mL). The combined organic extracts were dried using Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford trans racemic mixture Example 97 as a light brown solid (0.11 g, 0.26 mmol, 26 % yield). LCMS Method: LCMS_Method_A, Rt:1.76 min; MS:419.4 [M + H] + 25 - 193 - Example 97A and 97B: trans enantiopure 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1- phenyl-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one F F F O N N xampl5 S The enantiopure compounds were obtained as off-white solids by chiral prep HPLC separation of the racemic mixture of Example 97 (100 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UV DETECTOR. For separation, Chiralpak IG (250mm x 50mm x 5µm) column was used using mobile phase A: 0.1 % (7 M METHANOLIC AMMONIA) in n- HEXANE and mobile phase B: 0.1 % (7 M METHANOLIC10 AMMONIA) in 2-PROPANOL: METHANOL(50:50) Flow rate: 40 ml / min, Isocratic ratio: 60:40 (v / v). UVdetection was carried out at 210 nm and 240 nm. First eluting peak: 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-phenyl-1,5-dihydro-4H- pyrazolo[3,4-d] pyrimidin-4-one: Chiral HPLC Rt: 2.19 min; 99.07% ee; 14 mg15 1H NMR: (400 MHz, DMSO-d6): δ 1H NMR: (400 MHz, DMSO-d6): δ 10.97 (bs, 1H), 8.14 (d, J = 8 Hz, 2H),8.05 (s, 1H), 7.51 - 7.44 (m, 4H), 7.26 (t, J = 7.2 Hz, 1H), 7.18 (t, J = 8.8 Hz, 2H), 4.09 - 4.05 (m, 1H), 3.87 - 3.83 (m, 1H), , 3.57 - 3.44 (m, 4H), 2.16 (s, 6H) LCMS Method: LCMS_Method_C, Rt:4.32 min; MS:419.2 [M + H] +20 Second eluting peak: 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one: Chiral HPLC Rt: 2.28 min; 91.63 % ee; 35 mg; 1H NMR: (400 MHz, DMSO-d6): δ 10.99 (bs, 1H), 8.14 (d, J = 8 Hz, 2H), 8.06 (s, 1H), 7.51 - 7.44 (m, 4H), 7.26 (t, J = 7.2 Hz, 1H), 7.18 (t, J = 8.8 Hz, 2H), 4.09 - 4.04 (m, 1H), 3.87 - 3.83 (m, 1H), 3.56 - 3.43 (m, 4H), 2.16 (s, 6H)25 LCMS Method: LCMS_Method_C; Rt: 4.41 min; MS: 419.2 [M + H] +Example 98: (±)-trans-6-(3-(dimethyl amino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(4-fluorophenyl)-1,5- dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one - 194 - Preparative Example 7N F(R,S) **(R,S) F PrepStep A To a stirred solution of Preparative Example 7 (0.22 g, 0.90 mmol) and Preparative Example 5 (0.200 g, 50.75 mmol) in DMF (2 mL) was added K2CO3 (0.31 g, 2.24 mmol) at rt and heated at 110 °C for 2 h then themixture was poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried using Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford trans racemic mixture Example 98 as a orange solid (0.1 g, 0.2 mmol, 30 % yield).10 LCMS Method: LCMS_Method_A, Rt:1.80 min; MS:437.4 [M + H] +Example 98A and 98B: trans enantiopure 6-(3-(dimethyl amino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(4- fluorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one O O O F F 15 Step A The enantiopure compounds were obtained as orange solids by chiral prep HPLC separation of the racemic mixture of Example 98 (100 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UV DETECTOR. For separation, Chiralpak IG (250mm x 50mm x 5µm) column was used using mobile phase A: 0.1 % (7 M20 METHANOLIC AMMONIA) in n-HEXANE and mobile phase B: 0.1% (7 M METHANOLIC AMMONIA) in 2-PROPANOL:METHANOL(50:50) Flow rate: 40 ml / min, Isocratic ratio: 70:30 (v / v). UV detection was carried out at 210 nm & 240 nm. - 195 - First eluting peak: 6-(3-(dimethyl amino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(4-fluorophenyl)-1,5- dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one: Chiral HPLC Rt:2.08 min; 95.45 % ee; 20 mg 1H NMR: (400 MHz, DMSO-d6): δ 10.96 (bs, 1H), 8.17 - 8.13 (m, 2H), 8.05 (s, 1H), 7.48 - 7.44 (m, 2H), 7.34 5(t, J = 8.4 Hz, 2H), 7.18 (t, J = 8.8 Hz, 2H), 4.06 (t, J = 10 Hz, 1H), 3.87 - 3.82 (m, 1H), 3.56 - 3.43 (m, 4H),2.15 (s, 6H) LCMS Method: LCMS_Method_C, Rt:4.46 min; MS:437.2 [M + H] + Second eluting peak: 6-(3-(dimethyl amino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(4-fluorophenyl)-1,5-10 dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one: Chiral HPLC Rt:2.15 min; 97.74 % ee; 20 mg1H NMR: (400 MHz, DMSO-d6): δ 10.86 (bs, 1H), 8.17 - 8.13 (m, 2H), 8.05 (s, 1H), 7.47 - 7.44 (m, 2H), 7.34 (t, J = 8.4 Hz, 2H), 7.18 (t, J = 8.8 Hz, 2H), 4.06 (t, J = 9.6 Hz, 1H), 3.86 - 3.82 (m, 1H), 3.56 - 3.43 (m, 4H), 2.15 (s, 6H) LCMS Method: LCMS_Method_C, Rt:4.46 min; MS:437.2 [M + H] + 15 Example 99: (±)-trans-(6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(5-fluoropyridin-2-yl)- 1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one Preparative Example 7N FF Step A20 To a stirred solution of Preparative Example 7 (0.25 g, 0.94 mmol) and Preparative Example 14 (0.25 g,1.03 mmol) in DMF (2.5 mL) was added K2CO3(0.39 g, 2.82 mmol) at rt and heated at 100 °C for 2 h then the mixture was poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried using Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford trans racemic mixture Example 9925 as a white solid (0.1 g, 0.22 mmol, 24 % yield).LCMS Method: LCMS_Method_A, Rt:1.63 min; MS:438.4 [M + H] + Example 99A and 99B: trans enantiopure (6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(5- fluoropyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one - 196 - O O O NH ( NH NH N R N N F of the 5racemic mixture of Example 99 (100 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UVDETECTOR. For separation, Chiralpak IH (250mm x 30mm 5µm) column was used using mobile phase A: 0.1 % (7 M METHANOLIC AMMONIA) in n-HEXANE and mobile phase B: 0.1% (7 M METHANOLIC AMMONIA) in 2-PROPANOL:METHANOL(50:50) Flow rate: 30 ml / min, Isocratic ratio: 85:15 (v / v). UV detection was carried out at 210 nm & 240 nm. 10 First eluting peak: (6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(5-fluoropyridin-2-yl)-1,5- dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one: Chiral HPLC Rt:7.59 min; 100 % ee; 32 mg 1H NMR: (400 MHz, DMSO-d6): δ 11.05 (bs, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.16 - 8.15 (m, 1H), 8.07 (s, 1H), 7.96 - 7.93 (m, 1H), 7.48 - 7.45 (m, 2H), 7.19 (t, J = 8.4 Hz, 2H), 4.01 - 3.89 (m, 2H), 3.58 - 3.45 (m, 4H), 2.2215 (bs, 6H).LCMS Method: LCMS_Method_C, Rt: 3.84 min; MS:438.2 [M + H] + Second eluting peak: (6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(5-fluoropyridin-2-yl)- 1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one : Chiral HPLC Rt:8.12 min; 99.53 % ee; 35 mg20 1H NMR: (400 MHz, DMSO-d6): δ 11.02 (bs, 1H), 8.54 (bs, 1H), 8.16 - 8.15 (m, 1H), 8.07 (s, 1H), 7.97 - 7.93(m, 1H), 7.47 - 7.44 (m, 2H), 7.18 (t, J = 8.4 Hz, 2H), 4.05 - 3.86 (m, 2H), 3.51 - 3.44 (m, 4H), 2.16 (bs, 6H). LCMS Method: LCMS_Method_C, Rt: 3.86 min; MS:438.2 [M + H] + Example 100: (±)-trans-6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(5-(trifluoromethyl)25 pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one - 197 - Preparative Example 7N F(R,S) O (R,S) O * F Step A To a stirred solutio p p . g, . p e Example 7 (0.18 g, 0.76 mmol) in DMF (2 mL) was added K2CO3(0.26 g, 1.90 mmol) at rt and heated at 100 °C for 2 h then the 5mixture was poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organicextracts were dried using Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford trans racemic mixture Example 100 as an off-white solid (0.1 g, 0.20 mmol, 32 % yield). LCMS Method: LCMS_Method_A, Rt:1.74 min; MS:488.6 [M + H] + 10 Example 100A and 100B: trans enantiopure 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1- (5-(trifluoromethyl) pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one O O O F F15 S The enantiopure compounds were obtained as off-white solids by chiral prep HPLC separation of the racemic mixture of Example 100 (100 mg) using PHP-10-SHIMADZU LC20AP WITH UV DETECTOR. For separation, Chiralpak IG (250mm x 50mm x 5µm) column was used using mobile phase A: 0.1 % (7 M METHANOLIC AMMONIA) in n-HEXANE and mobile phase B: 0.1% (7 M METHANOLIC AMMONIA) in 2-20 PROPANOL:METHANOL(50:50) Flow rate: 40 ml / min, Isocratic ratio: 50:50 (v / v). UV detection was carriedout at 210 nm & 244 nm. - 198 - First eluting peak: 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(5-(trifluoromethyl) pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one: Chiral HPLC Rt: 2.15 min; 98.10 % ee; 23 m 1 1H), 57.48 - 7.44 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 4.10 (bs, 1H), 3.86 (bs, 1H), 3.56 - 3.45 (m, 4H), 2.16 (s, 6H)LCMS Method: LCMS_Method_C, Rt: 4.53 min; MS:488.3 [M + H] + Second eluting peak: 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(5-(trifluoromethyl) pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one:Chiral HPLC Rt:2.32 min; 95.61 % ee; 1910 mg1H NMR: (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.93 (bs, 1H), 8.50 - 8.41 (m, 2H), 8.14 (s, 1H), 7.48 - 7.45 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 4.09 (bs, 1H), 3.87 (bs, 1H), 3.57 - 3.48 (m, 4H), 2.16 (s, 6H) LCMS Method: LCMS_Method_C, Rt:4.54 min; MS:488.4 [M + H] +15 Example 101: (±)-trans-(3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl) (1-phenyl-1H-1,2,3-triazol-4-yl)methanone Preparative Example 7N FF ( )-trans Step A To a stirred solution of methyl 1-phenyl-1H-1,2,3-triazole-4-carboxylate (0.2 g, 0.98 mmol) and Preparative20 Example 7 (0.24 g, 0.98 mmol) in THF (2 mL) was added TBD (0.68 g, 4.92 mmol) at rt and the mixture wasstirred for 2 h then poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford trans racemic mixture Example 101 as105 an off-white solid (0.118 g, 0.31 mmol, 32% yield).25 LCMS Method: LCMS_Method_A; Rt: 1.74 min; MS: 380.4 [M + H] +Example 101A and 101B: trans enantiopure (3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl) (1-phenyl- 1H-1,2,3-triazol-4-yl) methanone - 199 - F F F ( , RS O)O O S ep The enantiopure compounds were obtained as off-white solids by chiral prep HPLC separation of the racemic mixture of Example 101 (105118 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UV 5DETECTOR. For separation, Chiralpak IG (250mm x 50mm x 5µm) column was used using mobile phase A:0.1 % (7 M Methanolic Ammonia) in Methanol and mobile phase B: 0.1% (7 M Methanolic Ammonia) in Acetonitrile Flow rate: 40 ml / min, Isocratic ratio: 50:50 (v / v). UV detection was carried out at 210 nm and 230 nm.10 First eluting peak: (3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl) (1-phenyl-1H-1,2,3-triazol-4-yl)methanone: Chiral HPLC Rt: 4.30 min; 100 % ee; 40 mg 1H NMR: (400 MHz, DMSO-d6): δ 9.32 (d, J = 9.2 Hz, 1H), 8.01 - 7.95 (m, 2H), 7.64 - 7.60 (m, 2H), 7.58 - 7.51 (m, 1H), 7.50 - 7.46 (m, 2H), 7.16 (t, J = 8.8 Hz, 2H), 4.50 - 4.24 (m, 1H), 4.04 - 3.91 (m, 1H), 3.87 - 3.81 (m, 1H), 3.55 - 3.42 (m, 3H), 2.17 (d, J = 5.6 Hz, 6H)15 LCMS Method: LCMS_Method_C; Rt: 4.32 min; MS: 380.2 [M + H] +Second eluting peak: (3-(dimethyl amino)-4-(p-tolyl) pyrrolidin-1-yl) (1-phenyl-1H-1,2,3-triazol-4-yl) methanone: Chiral HPLC Rt: 5.77 min; 100 % ee; 40 mg 1H NMR: (400 MHz, DMSO-d6): δ 9.32 (d, J = 9.2 Hz, 1H), 8.01 - 7.95 (m, 2H), 7.64 - 7.60 (m, 2H), 7.58 -20 7.51 (m, 1H), 7.47 - 7.44 (m, 2H), 7.16 (t, J = 8.4 Hz, 2H), 4.50 - 4.24 (m, 1H), 4.04 - 3.91 (m, 1H), 3.87 -3.81 (m, 1H), 3.55 - 3.42 (m, 3H), 2.17 (d, J = 5.6 Hz, 6H) LCMS Method: LCMS_Method_C; Rt: 4.38 min; MS: 380.2 [M + H] + Example 102: (±)-trans-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl) (1-(4-fluorophenyl)-1H-25 1,2,3-triazol-4-yl) methanone - 200 - Preparative Example 7N F(R,S) F Step A To a stirred suspension of 1-(4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid (0.2 g, 0.96 mmol) and Preparative Example 7 (0.28 g, 1.15 mmol) in THF (2 mL) was added TEA (0.6 mL, 2.89 mmol) at 0oC 5followed by T3P (1.8 mL, 2.89 mmol) and the mixture was stirred at rt for 2 h then poured into water (50 mL)and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (water / ACN) to afford trans racemic mixture Example 102 as an off-white solid (0.1 g, 0.25 mmol, 26 % yield).10 Example 102A and 102B: trans enantiopure (3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl) (1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl) methanone F F F F Example 102 Example 102A / 102BStep A15 The enantiopure compounds were obtained as off-white solids by chiral prep HPLC separation of racemicmixture of Example 102 (100 mg) using PHP-10-SHIMADZU LC20AP WITH UV DETECTOR. For separation, Chiralpak IH (250mm x 30mm x 5µm) column was used using mobile phase A: 0.1 % (7 M Methanolic Ammonia) in HEXANE and mobile phase B: 0.1% (7 M Methanolic Ammonia) in 2- PROPANOL:METHANOL(50:50) Flow rate: 25 ml / min, Isocratic ratio: 75:25 (v / v). UV detection was carried20 out at 210 nm and 245 nm.First eluting peak: (3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl) (1-(4-fluorophenyl)-1H-1,2,3- triazol-4-yl) methanone:Chiral HPLC Rt: 3.43 min; 100 % ee; 29 mg - 201 - 1H NMR: (400 MHz, DMSO-d6): δ 9.31 (d, J = 9.6 Hz, 1H), 8.07 - 8.00 (m, 2H), 7.52 - 7.45 (m, 4H), 7.17 (t, J = 8.4 Hz, 2H), 4.50 - 4.24 (m, 1H), 4.05 - 3.93 (m, 1H), 3.87 - 3.82 (m, 1H), 3.56 - 3.42 (m, 3H), 2.17 (d, J = 5.2 Hz, 6H) LCMS Method: LCMS_Method_C; Rt:4.58 min; MS: 398.3 [M + H] + 5 Second eluting peak: (3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl) (1-(4-fluorophenyl)-1H- 1,2,3-triazol-4-yl) methanone:Chiral HPLC Rt: 4.22 min; 100 % ee; 26 mg 1H NMR: (400 MHz, DMSO-d6): δ 9.31 (d, J = 9.6 Hz, 1H), 8.07 - 8.00 (m, 2H), 7.52 - 7.47 (m, 4H), 7.17 (t, J = 8.8 Hz, 2H), 4.50 - 4.25 (m, 1H), 4.05 -3.92 (m, 1H), 3.87 - 3.82 (m, 1H), 3.56 - 3.43 (m, 3H), 2.18 (d, J =10 4.4 Hz, 6H)LCMS Method: LCMS_Method_C; Rt: 4.58 min; MS: 398.3 [M + H] + Example 103: (±)-trans-6-(3-(dimethylamino)-4-phenylpyrrolidin-1-yl)-1-(4-fluorophenyl)-1,5-dihydro- 4H-pyrazolo[3,4-d] pyrimidin-4-one Preparative Example 12(RS N) O O K2CO3, DMF,Cl90°C, 4 h 15Preparative a p e Step A To a stirred solution of Preparative Example 12 (0.200 g, 0.88 mmol) and Preparative Example 5 (0.23 g, 0.88 mmol) in DMF (2 mL) was added K2CO3(0.36 g, 2.64 mmol) at rt and heated at 90°C for 4 h then the mixture was poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic20 extracts were dried using Na2SO4, filtered and concentrated under vacuum. The crude product was purifiedby reverse phase column chromatography (water / ACN) to afford trans racemic mixture Example 103 as an off-white solid (0.09 g, 0.21 mmol, 4 % yield). LCMS Method: LCMS_Method_C, Rt:4.40 min; MS:419.2 [M + H] + Example 103A and 103B: trans enantiopure 6-(3-(dimethylamino)-4-phenylpyrrolidin-1-yl)-1-(4-25 fluorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one - 202 - O O O N NH N NH N NH F S T he enantiopure compounds w acemic mixture of Example 103 (90 mg) using PHP-10-SHIMADZU LC20AP WITH UV DETECTOR. For separation, 5Chiralpak IG (250mm x 50mm x 5µm) column was used using mobile phase A: 0.1 % (7 M MethanolicAmmonia) in n-Hexane and mobile phase B: 0.1% (7 M Methanolic Ammonia) in 2- PROPANOL:METHANOL(50:50) Flow rate: 40 ml / min, Isocratic ratio: 50:50 (v / v). UV detection was carried out at 256 nm.10 First eluting peak: 6-(3-(dimethylamino)-4-phenylpyrrolidin-1-yl)-1-(4-fluorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one :Chiral HPLC Rt: 2.19 min; 100 % ee; 26 mg 1H NMR: (400 MHz, DMSO-d6): δ 10.91 (bs, 1H), 8.18 - 8.15 (m, 2H), 8.01 (s, 1H), 7.42 - 7.40 (m, 2H), 7.36 - 7.31 (m, 4H), 7.27 - 7.23 (m, 1H), 4.15 - 4.07 (m, 1H), 3.87 - 3.83 (m, 1H), 3.55 - 3.47 (m, 4H), 2.15 (m, 6H). LCMS Method: LCMS_Method_C; Rt: 4.59 min; MS: 419.4 [M + H] + 15 Second eluting peak: 6-(3-(dimethylamino)-4-phenylpyrrolidin-1-yl)-1-(4-fluorophenyl)-1,5-dihydro-4H- pyrazolo[3,4-d] pyrimidin-4-one:Chiral HPLC Rt: 2.29 min; 91.98 % ee; 27 mg 1H NMR: (400 MHz, DMSO-d6): δ 10.98 (bs, 1H), 8.20 - 8.18 (m, 2H), 7.97 (s, 1H), 7.41 - 7.40 (m, 2H), 7.36 - 7.30 (m, 4H), 7.27 - 7.23 (m, 1H), 4.06 - 4.05 (m, 1H), 3.87 - 3.83 (m, 1H), 3.54 - 3.44 (m, 4H), 2.15 (m, 6H).20 LCMS Method: LCMS_Method_C; Rt: 4.58 min; MS: 419.4 [M + H] +Example 104: (±)-cis-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl) (1-(4-fluorophenyl)-1H- 1,2,3-triazol-4-yl) methanone Prepparative Example 11N FF 25 Step A - 203 - To a stirred solution of 1-(4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid (0.25 g, 1.20 mmol) in DMF (2.5 mL) was added HATU (0.68 g, 1.81 mmol) at 0oC followed by Preparative Example 11 (0.38 g,1.56 mmol) and DIPEA (0.82 mL, 4.82 mmol) and the mixture was stirred at rt for 2 h then diluted with water (10 mL). The solid precipitates were filtered and dried under vacuum. The crude product was purified by reverse phase 5chromatography (Water / ACN) to afford cis racemic mixture Example 104 as an off-white solid (0.1 g, 0.25mmol, 21 % yield). LCMS Method: LCMS_Method_A; Rt: 1.75 min; MS: 398.4 [M + H]+Example 104A and 104B: trans enantiopure (3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl) (1- (4-fluorophenyl)-1H-1,2,3-triazol-4-yl) methanone 10 F F F ,S)O(RO O Step A The enantiopure compounds were obtained as off-white solids by chiral prep HPLC separation of racemic15 mixture of Example 104 (100 mg) using PHP-10-SHIMADZU LC20AP WITH UV DETECTOR. Forseparation, Chiralpak IG (250mm x 50mm x 5µm) column was used using mobile phase A: 0.1 % (7 M Methanolic Ammonia) in Acetonitrile and mobile phase B: 0.1% (7 M Methanolic Ammonia) in Methanol Flow rate: 40 ml / min, Isocratic ratio: 50:50 (v / v). UV detection was carried out at 210 nm and 255 nm.20 First eluting peak: (3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl) (1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl) methanone: Chiral HPLC Rt: 1.80 min; 100 % ee; 35 mg 1H NMR: (400 MHz, DMSO-d6): δ 9.37 - 9.31 (m, 1H), 8.08 - 7.99 (m, 2H), 7.52 - 7.45 (m, 2H), 7.33 - 7.24 (m, 2H), 7.24 - 7.11 (m, 2H), 4.30 - 3.97 (m, 2H), 3.94 - 3.85 (m, 1H), 3.78 - 3.66 (m, 1H), 3.62 - 3.55 (m, 1H), 3.05 - 2.99 (m, 1H), 2.10 (d, J = 3.2 Hz, 6H). 25 LCMS Method: LCMS_Method_C; Rt: 4.29 min; MS: 398.2 [M + H] + Second eluting peak: (3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl) (1-(4-fluorophenyl)-1H- 1,2,3-triazol-4-yl) methanone:Chiral HPLC Rt: 1.87 min; % ee; 35 mg;30 1H NMR: (400 MHz, DMSO-d6): δ 9.36 - 9.31 (m, 1H), 8.08 - 7.99 (m, 2H), 7.52 - 7.45 (m, 2H), 7.33 - 7.24(m, 2H), 7.15 - 7.11 (m, 2H), 4.31 - 3.97 (m, 2H), 3.94 - 3.85 (m, 1H), 3.78 - 3.66 (m, 1H), 3.62 - 3.55 (m, 1H), 3.05 - 2.99 (m, 1H), 2.10 (d, J = 2.8 Hz, 1H). - 204 - LCMS Method: LCMS_Method_C; Rt: 4.31 min; MS: 398.2 [M + H] + Example 105: (±)-cis-6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(4-fluorophenyl)-1,5- dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one Prepparative Example 11N FO (R,S) O NH* *F 55 T Example 11 (0.20 g, 0.81 mmol) and Preparative Example 5 (0.23 g, 0 .90 mmol) in DMF (4 mL) was added K2CO3 (0.33g, 2.45 mmol) at rt and heated at 100 °C for 2 h then the mixture was poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic10 extracts were dried using Na2SO4, filtered and concentrated under vacuum. The crude product was purifiedby trituration using MeOH to afford cis racemic mixture Example 105 as a white solid (0.1 g, 0.22 mmol, 4 % yield). LCMS Method: LCMS_Method_A, Rt:1.75 min; MS:437.4 [M + H] + Example 105A and 105B: trans enantiopure 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-15 (4-fluorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one ) O O O F F Step A The enantiopure compounds were obtained as off-white solids by chiral prep HPLC separation of racemic20 mixture of Example 105 (100 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UVDETECTOR. For separation, Chiralpak IH (250mm x 30mm 5µm) column was used using mobile phase A: 0.1 % (7 M Methanolic Ammonia) in n-Hexane and mobile phase B: 0.1% (7 M Methanolic Ammonia) in 2- Propanol:Methanol (50:50) Flow rate: 30 ml / min, Isocratic ratio: 80:20 (v / v). UV detection was carried out at 210 nm and 240 nm. - 205 - First eluting peak: 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(4-fluorophenyl)-1,5- dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one:Chiral HPLC Rt: 1.71 min; 100% ee; 35 mg 1H NMR 4 MH DM 11 7 1H 17 2H s, 1H), 7.34 (m, 2H), 7.27 - 7.23 (m, 52 H), 3.65 (bs, 1H), 3.57 - 3.55 (m, 1H),3.04 (m, 1H), 2.09 (s, 6H) LCMS Method: LCMS_Method_C; Rt: 4.38 min; MS: 437.2 [M + H] + Second eluting peak: 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(4-fluorophenyl)-1,5-10 dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one:Chiral HPLC Rt: 1.89 min; 100% ee; 30 mg;1H NMR: (400 MHz, DMSO-d6): δ 11.06 (bs, 1H), 8.17 (bs, 2H), 8.06 (s, 1H), 7.34 (m, 2H), 7.27 - 7.23 (m, 2H), 7.11 (t, J = 8.8 Hz, 2H), 3.96 - 3.85 (m, 2H), 3.77 (d, J = 11.2 Hz, 1H), 3.65 (bs, 1H), 3.57 - 3.53 (m, 1H), 3.04 - 2.98 (m, 1H), 2.09 (s, 6H) LCMS Method: LCMS_Method_C; Rt: 4.36 min; MS: 437.2 [M + H] + 15 Example 106: (±)-cis 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(5-fluoropyridin-2-yl)- 1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one Preparative Example 11N FF Prepar ative Example 14Step A20 To a stirred solution of Preparative Example 14 (0.20 g, 0.75 mmol) and Preparative Example 11 (0.18 g,0.75 mmol) in DMF (2 mL) was added K2CO3(0.31 g, 2.25 mmol) at rt and heated at 110 °C for 1 h then the mixture was poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried using Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase chromatography (Water / ACN) to afford cis racemic mixture Example 106 as a white solid25 (0.1 g, 0.22 mmol, 30 % yield).LCMS Method: LCMS_Method_A, Rt:1.57 min; MS:438.3 [M + H] + - 206 - Example 106A and 106B: trans enantiopure 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1- (5-fluoropyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one F 5 S ep The enantiopure compounds were obtained as off-white solids by chiral prep HPLC separation of racemic mixture of Example 106 (100 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UV DETECTOR. For separation, Chiralpak IK (250mm x 30mm x 5µm) column was used using mobile phase A:10 0.1 % (7 M Methanolic Ammonia) in n-Hexane and mobile phase B: 0.1% (7 M Methanolic Ammonia) in 2-propanol : Acetonitrile Flow rate: 30 ml / min, Isocratic ratio: 70:30 (v / v). UV detection was carried out at 210 nm and 240 nm. First eluting peak: 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(5-fluoropyridin-2-yl)-1,5-15 dihydro-4H-pyrazolo[34-d] pyrimidin-4-one:Chiral HPLC Rt: 695 min; 100 % ee; 30 mg1 7 t, J = L 20 -yl)- 1 1 O-d6) (bs, 1H), 8.55 (s, 1H), 8.18 (bs, 1H), 8.07 (s, 1H), 7.94 (bs, 1H), 7 , J = 8.8 Hz, 2H), 3.99 - 3.84 (m, 2H), 3.77 - 3.74 (m, 1H), 3.63 (bs, 1H), 3.40 (t, J25 = (m, 1H), 2.08 (s, 6H).L thod_C; Rt: 3.97 min; MS: 438.4 [M + H] + 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(5-(trifluoromethyl) p 4H -pyrazolo[3,4-d] pyrimidin-4-one - 207 - Preparative Example 11N F(R,S) O* *R O F PrStep A To a stirred solution of Preparative Example 15 (0.20 g, 0.63 mmol) and Preparative Example 11 (0.17 g, 0.69 mmol) in DMF (2 mL) was added K2CO3(0.26 g, 1.90 mmol) at rt and heated at 100 °C for 2 h then the 5mixture was diluted with water (10 mL). The solid precipitates were filtered and dried under vacuum. Thecrude product was purified by trituration using MeOH to afford cis racemic mixture Example 108 as an off- white solid (0.11 g, 0.20 mmol, 32 % yield). LCMS Method: LCMS_Method_A, Rt:1.71 min; MS:488.3 [M + H] + Example 107A and 107B: trans enantiopure 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-10 (5-(trifluoromethyl) pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-oneO O O F F S The enantiopure compounds were obtained as off-white solids by chiral prep HPLC separation of racemic15 mixture of Example 107 (100 mg) using PHP-10-SHIMADZU LC20AP WITH UV DETECTOR. Forseparation, Chiralpak IK (250mm x 30mm x 5µm) column was used using mobile phase A: 0.1 % (7 M Methanolic Ammonia) in n-Hexane and mobile phase B: 0.1% (7 M Methanolic Ammonia) in 2-propanol : Acetonitrile (70:30) Flow rate: 30 ml / min, Isocratic ratio: 70:30 (v / v). UV detection was carried out at 210 nm and 245 nm. 20 First eluting peak: 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(5-(trifluoromethyl) pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one:Chiral HPLC Rt: 2.57 min; 100 % ee; 39 mg - 208 - 1H NMR: (400 MHz, DMSO-d6): δ 11.20 (bs, 1H), 8.94 (bs, 1H), 8.51 - 8.39 (2H), 8.15 (s, 1H), 7.28 - 7.24 (m, 2H), 7.11 (t, J = 8.8 Hz, 1H), 3.97 - 3.83 (m, 3H), 3.70 - 3.56 (m, 2H), 3.05 - 2.99 (m, 1H), 2.10 (s, 6H). LCMS Method: LCMS_Method_C; Rt: 4.46 min; MS: 488.3 [M + H] + 5Second eluting peak: 6-(3-(dimethylamino)-4-(4-fluorophenyl) pyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one:Chiral HPLC Rt: 2.74 min; 100 % ee; 32 mg; 1H NMR: (400 MHz, DMSO-d6): δ 11.20 (bs, 1H), 8.93 (bs, 1H), 8.61 - 8.39 (2H), 8.15 (s, 1H), 7.28 - 7.24 (m, 2H), 7.11 (t, J = 8.8 Hz, 1H), 3.97 - 3.83 (m, 3H), 3.75 - 3.56 (m, 2H), 3.05 - 2.99 (m, 1H), 2.10 (s, 6H). LCMS Method: LCMS_Method_C; Rt: 4.53 min; MS: 488.3 [M + H] + 10 Example 108: (±)-cis-6-(3-(dimethylamino)-4-phenylpyrrolidin-1-yl)-1-(4-fluorophenyl)-1,5-dihydro-4H- pyrazolo [3,4-d] pyrimidin-4-one Preparative Example 17 Preparative Example 5Step A15 To a stirred solution of Preparative Example 5 (0.25 g, 0.94 mmol) and Preparative Example 17 (0.25 g,1.13 mmol) in DMF (2.5 mL) was added K2CO3(0.39 g, 2.83 mmol) at rt and heated at 110 °C for 1 h then the mixture was poured into water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried using Na2SO4, filtered and concentrated under vacuum. The crude product was purified by reverse phase column chromatography (Water / ACN) to afford cis racemic mixture Example 10820 as a white solid (0.1 g, 0.23 mmol, 25 % yield).LCMS Method: LCMS_Method_C, Rt: 4.29 min; MS:419.2 [M + H] + Example 108A and 108B: trans enantiopure 6-(3-(dimethylamino)-4-phenylpyrrolidin-1-yl)-1-(4- fluorophenyl)-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one - 209 - O O O NH (R N NH N NH N S The enantiopure compounds were obtained as off-white solids by chiral prep HPLC separation of racemic mixture of Example 108 (100 mg) using PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UV 5DETECTOR. For separation, Cpreparativehiralpak IK (250mm x 30mm x 5µm) column was used usingmobile phase A: 0.1 % (7 M Methanolic Ammonia) in n-Hexane and mobile phase B: 0.1% (7 M Methanolic Ammonia) in 2-PROPANOL:ACETONITRILE (70:30) Flow rate: 27 ml / min, Isocratic ratio: 75:25 (v / v). UV detection was carried out at 210 nm and 240 nm.10 First eluting peak: 6-(3-(dimethylamino)-4-phenylpyrrolidin-1-yl)-1-(4-fluorophenyl)-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one:Chiral HPLC Rt: 2.31 min; 100 % ee; 29 mg 1H NMR: (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.17 (s, 2H), 8.07 (s, 1H), 7.34 - 7.20 (m, 7H), 3.97 - 3.93 (m, 2H), 3.88 - 3.61 (m, 3H), 3.04 - 3.02 (m, 1H), 2.10 (s, 6H). LCMS Method: LCMS_Method_C; Rt: 4.28 min; MS: 419.2 [M + H] + 15 Second eluting peak: 6-(3-(dimethylamino)-4-phenylpyrrolidin-1-yl)-1-(4-fluorophenyl)-1,5-dihydro-4H- pyrazolo [3,4-d] pyrimidin-4-one:Chiral HPLC Rt: 2.45 min; 100 % ee; 28 mg 1H NMR: (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.17 (s, 2H), 8.06 (s, 1H), 7.34 - 7.18 (m, 7H), 3.97 - 3.86 (m, 2H), 3.81 - 3.55 (m, 3H), 3.06 - 3.00 (m, 1H), 2.10 (s, 6H).20 LCMS Method: LCMS_Method_C; Rt: 4.25 min; MS: 419.2 [M + H] +BIOLOGICAL ASSAY DESCRIPTION Proteasome activity measurement 25 Proteasome activity of compounds may be measured using purified 20S CP of the proteasome, wherein the concentration of the 20S CP of the proteasome is 5 nM, and the concentration of the compound is 0.1-60µM. Incubation of the compound at the different concentrations with the 20S CP of the proteasome and an activity probe (e.g., labelled protein or artificial substrate) may occur for, e.g., 30min at room temperature. DMSO or30 any other suitable agent may be used as a control for measuring basal activity. Degradation of the activityprobe serves as a readout and may be measured by any suitable method. - 210 - The following example compounds were measured and reported in the Table below: Example 20S Maximum activation (%) 20S Activation EC50 (µM)1 ++ +++ - 211 - 33 + +++34 +++ ++ - 212 - 52A +52B + - 213 - 71A ++71B + + - 214 - 92A ++ ++92B ++ uM. Legend: +++ % > 350; ++ % 250<x<350; + %150<x<250. - 215 - Neuroprotection assessment The neuroprotective effects of compounds of the invention were evaluated in relevant models of Parkinson's disease using a primary culture of mesencephalic neurons from rats. Neurons were subjected to injury 5through the application of alpha-synuclein pre-formed fibrils (PFFs) or MPP+, both of which cause the deathof dopaminergic neurons and lead to the aggregation of alpha-synuclein (a-Syn). Neurons were injured with either a-Syn PFFs or MPP+ and treated with compounds of the invention. Subsequently, the neurons were immunostained using antibodies against Tyrosine Hydroxylase (TH), which identifies dopaminergic neurons, and against a-Syn. The number of TH-positive neurons and the level of a-Syn aggregation in these neurons10 were quantified through automated imaging analysis. Neuroprotective effects were indicated by an increasein the number of TH-positive neurons and a reduction in a-Syn aggregation. Compounds 3, 1B, 1A, 76B, 20, 54A, 54B, 42B and 1 were tested and exhibited neuroprotective effects in the µM-range, some of the tested compounds even exhibited an effect <0.5 µM.15 In particular, the present invention relates to the following items:1. A compound of formula IAX R I or a stereoisomer, tautomer, prodrug mixture, polymorph or pharmaceutically acceptable salt thereof,20 whereinA is selected from the group consisting ofO O N (A5), - 216 - F Cl N N 14), Z A19), R5 R1, p y , 1 4 yX is CH2, or C(=O);Z is pyridinyl, or phenyl, wherein said pyridinyl or phenyl group is independently unsubstituted orsubstituted with one or more, same or different substituents selected from halogen; Z1is independently of each other selected from CH, CF, and C-O-C1-C4-alkyl;10 Z2 is CH, or CCH3;Z3is H, or C1-C4-alkyl; Z4is N, CH, or C-O-C1-C4-alkyl; Z5is N, CH, CF, or C-O-C1-C4-alkyl; Z6is N, CH or C-O-C1-C4-alkyl; and15 m i 1 2. The compound according to item 1, whereinR is H, or CH3.20 3. The compound according to item 1 or 2, whereinR1, R2are independently of each other selected from H and CH3, preferably R1, R2are CH3. 4. The compound according to any one of items 1 to 3, wherein25 m is 0 and X is absent.5. The compound according to any one of items 1 to 3, whereinm is 1, and - 217 - Xis CH2 or C(=O).6. The compound according to item 5, whereinm is 1, and5 X is C(=O).7. The compound according to any one of items 1 to 4, whereinA is selected from the group consisting ofO O O N (A9),108 .The compound according to any one of items 1 to 3, 5 or 6, whereinA is selected from the group consisting ofZ Z A10),15 (A8), 9. The compound according to any one of items 1 to 8, wherein the compound is not any one of - 218 - O F O N NH NH , , 5 10. A compound according to any one of items 1 to 9, wherein the compound is selected from thecompounds in the following table: O - 219 - O O O N NH HCOOH F - 220 - (R,S) (R,S) N N N (R,S) O 11. A pharmaceutical composition comprising a pharmaceutically effective amount of a compoundaccording to any one of items 1 to 10 and optionally a pharmaceutically acceptable carrier, diluent or excipient. 5 12. A compound according to any one of items 1 to 10 or a pharmaceutical composition according to item11 for use in medicine. 13. A compound according to any one of items 1 to 10 or a pharmaceutical composition according to item10 11 for use in the treatment of a disease selected from the group consisting of a disease or condition causedby an undesired proteinaceous target molecule, caused by an accumulated pathological protein, proteopathies, alpha-synucleinopathies, tauopathies, neurodegenerative diseases associated with alpha- synuclein accumulation or aggregation, neurodegenerative diseases associated with tau accumulation or aggregation, neurodegenerative diseases associated with beta-amyloid accumulation or aggregation, - 221 - Parkinson’s disease, Alzheimer's disease, dementia, dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, Pick's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxias, prion diseases, cystic fibrosis, alpha 1 antitrypsin deficiency, diabetes type-2, retinitis pigmentosa, cataracts, amyloidosis, desmin-related cardiomyopathy, multiple system atrophy, cancer, cancer5 tumor metastasis, and aging.

Claims

- 222 - Claims 1. A compound of formula IAX m N R I 5or a stereoisomer, tautomer, prodrug mixture, polymorph or pharmaceuticallyacceptable salt thereof,wherein Ais selected from the group consisting ofO O O N A5),1014), 19), H- 223 - Z Z Z N (Z ) Z1 n ZA34),R R, , 5X is CH2, C(=O)NH, or C(=O);Z is C1-C4-alkyl, C1-C4-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl, wherein said C1-C4-alkyl, C1-C4-haloalkyl, pyridinyl, pyrimidinyl, pyrazolyl, or phenyl group is independently unsubstituted or substituted with one or more, same or different substituents selected from halogen; Z1is independently of each other selected from CH, CF, CCH3, C-O-(C1-C2-alkylene)-C1-C2-alkoxy, and10 C-O-C1-C4-alkyl;Z2is N, CH, or CCH3; Z3is H, C(=O)-C1-C4-alkyl; or C1-C4-alkyl; Z4is N, CH, CF, or C-O-C1-C4-alkyl; Z5is N, CH, CF, or C-O-C1-C4-alkyl;15 Z6 is N CH or C-O-C -C -alk l;ZZ8is phenyl or pyridinyl, wherein said phenyl or pyridinyl group is independently unsubstituted or substituted with one or more, same or different substituents selected from halogen, and C1-C4-haloalkyl; Z9is H, C1-C4-alkyl, or tetrahydropyranyl;20 Z10 is H, or C1-C4-alkyl;Z11is independently of each other selected from halogen, C1-C4-alkyl, and C1-C4-haloalkoxy, mis 0 or 1; andn is 0, 1 or 2.25 2. The compound according to claim 1, whereinR is H, F, Cl or CH3.

3. The compound according to claim 1 or 2, whereinR1, R2are independently of each other selected from H and CH3,30 preferably R1, R2 are CH3.- 224 - 4. The compound according to any one of claims 1 to 3, whereinm is 0 and X is absent.5 5. The compound according to any one of claims 1 to 3, whereinm is 1, andX is CH2 or C(=O).

6. The compound according to claim 5, wherein10 m is 1, andX is C(=O).

7. The compound according to any one of claims 1 to 4, whereinA is selected from the group consisting ofO O O N15 (A9),8. The compound according to any one of claims 1 to 3, 5 or 6, whereinA is selected from the group consisting ofZ20Z A10), (A8),- 225 - 9. The compound according to any one of claims 1 to 8, wherein the compound is not any one ofO F O , , , O 5 , ,- 226 - O O N N , 10. A compound according to any one of claims 1 to 9, wherein the compound is selected from the5 compounds in the following table:O (R,S) N N- 227 - O (R,S) N N NH N (R,S*) **F- 228 - (R,S) N H (R,S) N N N (R,S) * N* N11., m thecompounds in the following table: N O N- 229 - O O O N NH HCOOH F- 230 - (R,S) N (R,S) N N O (R,S)- 231 - O O O N NH NH 12.p a aceu ca co pos o co p s g a p a aceu ca y e ec e a ou o a compoundaccording to any one of claims 1 to 11 and optionally a pharmaceutically acceptable carrier, diluent or excipient. 5 13. A compound according to any one of claims 1 to 11 or a pharmaceutical composition according toclaim 12 for use in medicine.

14. A compound according to any one of claims 1 to 11 or a pharmaceutical composition according to10 claim 12 for use in the treatment of a disease selected from the group consisting of a disease or conditioncaused by an undesired proteinaceous target molecule, caused by an accumulated pathological protein, proteopathies, alpha-synucleinopathies, tauopathies, neurodegenerative diseases associated with alpha- synuclein accumulation or aggregation, neurodegenerative diseases associated with tau accumulation or aggregation, neurodegenerative diseases associated with beta-amyloid accumulation or aggregation,15 Parkinson’s disease, Alzheimer's disease, dementia, dementia with Lewy bodies, frontotemporal dementia,progressive supranuclear palsy, Pick's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxias, prion diseases, cystic fibrosis, alpha 1 antitrypsin deficiency, diabetes type-2, retinitis- 232 - pigmentosa, cataracts, amyloidosis, desmin-related cardiomyopathy, multiple system atrophy, cancer, cancer tumor metastasis, and aging.

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