NZ768960A - Tetrahydro-1h-pyrazino[2,1-a]isoindolylquinoline compounds for the treatment of autoimmune disease - Google Patents

Abstract

The present invention relates to compounds of formula (I), wherein R1 to R6, m and n are as described herein, and their pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds.

Description

/064323 TETRAHYDRO-1 H—PYRAZINO[2,1 -AJ|SO|NDOLYLQU|NOL|NE NDS FOR THE TREATMENT OF AUTOIMMUNE The present invention s to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to antagonist of TLR7 and/or TLR8 and/or TLR9 useful for treating systemic lupus erythematosus or lupus nephritis.

FIELD OF THE INVENTION Autoimmune connective tissue disease (CTD) include prototypical mune syndromes such as Systemic Lupus Erythematosus (SLE), primary Sjégren’s me (ij S), mixed connective tissue disease (MCTD), Dermatomyositis/Polymyositis (DM/PM), Rheumatoid Arthritis (RA), and systemic sclerosis (SSc). With the exception of RA, no really effective and safe therapies are available to ts. SLE ents the prototypical CTD with a prevalence of 20-150 per 100,000 and causes broad inflammation and tissue damage in distinct organs, from commonly observed ms in the skin and joints to renal, lung, or heart failure. Traditionally, SLE has been treated with nonspecific anti-inflammatory or immunosuppressive drugs. However, long term usage of suppressive drug, e.g. corticosteroids is only partially effective, and is associated with undesirable toxicity and side effects. Belimumab is the only FDA-approved drug for lupus in the last 50 years, despite its modest and delayed efficacy in only a fraction of SLE ts (Navarra, S. V. et al Lancet 2011, 377, 721.). Other biologics, such as anti-CD20 mAbs, mAbs against or soluble receptors of specific cytokines, have failed in most clinical studies. Thus, novel therapies are required that provide sustained improvement in a greater proportion of patient groups and are safer for chronic use in many autoimmune as well as auto- ation diseases.

Toll Like Receptors (TLR) are an important family of pattern ition receptors (PRR) which can initiate broad immune responses in a wide variety of immune cells. As natural host defense sensors, mal TLRs 7, 8 and 9 recognize nucleic acids derived from viruses, bacteria; specifically, TLR7/8 and TLR9 recognize single-stranded RNA (ssRNA) and single- stranded CpG-DNA, respectively. However, aberrant nucleic acid sensing of TRL7,8,9 is considered as a key node in a broad of autoimmune and auto-inflammatory diseases (Krieg, A.

M. et a]. Immunol. Rev. 2007, 220, 251. Jiménez—Dalmaroni, M. J. et al Autoimmun Rev. 2016, , 1. Chen, J. Q., et al. Clinical Reviews in Allergy & Immunology 2016, 50, 1.). Anti-RNA and anti-DNA antibodies are well established diagnostic markers of SLE, and these antibodies can deliver both self-RNA and self—DNA to endosomes. While self—RNA complexes can be recognized by TLR7 and TLR8, self-DNA complexes can trigger TLR9 activation. Indeed, defective clearance of self-RNA and self-DNA from blood and/or s is evident in SLE (Systemic Lupus Erythematosus) patients. TLR7 and TLR9 have been reported to be upregulated in SLE tissues, and correlate with chronicity and activity of lupus nephritis, tively. In B cells of SLE patients, TLR7 expression ates with anti-RNP antibody production, while TLR9 expression with lL-6 and anti~dsDNA antibody . Consistently, in lupus mouse , TLR7 is required for anti-RNA antibodies, and TLR9 is required for anti-nucleosome antibody. On the other hand, overexpression of TLR7 or human TLRS in mice promotes autoimmunity and autoinflammation. Moreover, tion of TLR8 cally contributes to inflammatory cytokine secretion of mDC/macrophages, neutrophil NETosis, induction of Th1 7 cells, and suppression of Treg cells. In addition to the described role of TLR9 in promoting autoantibody production of B cells, activation of TLR9 by self-DNA in pDC also leads to induction of type I IFNs and other inflammatory cytokines. Given these roles of TLR9 in both pDC and B cells, both as key contributors to the pathogenesis of autoimmune diseases, and the ive ce of self-DNA complexes that could readily activate TLR9 in many patients with mune diseases, it may have extra benefit to further block self—DNA mediated TLR9 pathways on top of inhibition of TLR7 and TLR8 pathways. Taken er, TLR7, 8, and 9 pathways represent new therapeutic targets for the treatment of mune and auto- inflammatory diseases, for which no effective steroid-free and non—cytotoxic oral drugs exist, and inhibition of all these pathways from the very upstream may deliver satisfying therapeutic effects. As such, we invented oral compounds that target and suppress TLR7, TLR8 and TLR9 for the treatment of autoimmune and auto-inflammatory diseases.

Y OF THE INVENTION The present invention relates to novel compounds of formula (1), NlRZ (R6 R4 (R )m (I), wherein R7 R7 R7 N R8 N R8 N R8 \ / \ / N \ / N/j:R9 R1 is , , , 9 R7 R7 R7 R7 / N N \ \> \> \> \ \ \ \N s 0 , , ; wherein R7 is C1_6alkyl, C]_éalkoxy, haloCLGalkyl, halogen, nitro or cyano; R8 is H or ium; R9 is H, deuterium or C1_6alkyl; R10 is H or halogen; R2 is H or Cmalkyl; R3 is H; R4 is H; R5 is H, piperazinyl, halogen, kyl, halopyrrolidinylamino or hydroxypyrrolidinle1_ 6alkylamino; R6 is H; (C1-6alkyl)2aminoC1.6alkoxy; (C1-6a1kyl)2aminoC1-6alkylamino; 1,2,3,4,6,6a-hexahydropyrrolo[3,4—c]pyrroly1 tuted by C1_6alkoxy; 1,4-diazepanyl substituted by one or two substituents independently selected from hydroxy and Cmalkyl; 1,4-oxazepanyl substituted by amino; 1 ,4-oxazepanylamino; 1,6-diazaspiro[3.3]heptanyl; 2,5-diazabicyclo[2.2. l ]heptanylcarbonyl; 2,6-diazaspiro[3.3]heptany1 unsubstituted or substituted by C]_6alkyl; 2-oxaazaspiro[3.4]octany1 substituted by amino; 3,4,4a,5,7,7a-hexahydro—2H-pyrrolo[3 ,4-b] [ l ,4]oxazinyl; 3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4—b][1,4]oxazinyl; 3,8—diazabicyclo[3 .2. l]octanylcarb0nyl; 3—oxa-7,9-diazabicyclo[3.3 . l ]nonany1; 3-oxo-1,5,6,7,8,8a-hexahydroi1nidazo[l ,5-a]pyraziny1; -oxa—2,8-diazaspiro[3.5]nonanyl; 9-0xa—3 ,7-diazabicyclo[3 .3. 1 ]nonanyl; amino(C1-6alky1)piperidinylcarbonyl; azetidinyl unsubstituted or substituted by one or two substituents independently ed from amino and C1-6alkyl; azetidinylamino; azetidinyloxy; C1-6alkoxypipefidinylamino; C1_6alkoxypyrrolidiny1(C1-6alkyl)amino; C1-6alkoxypyrrolidinylamino; etidinyl(C1-6a1kyl)amino; halopyrrolidinylarnino; 1 5 halopyrrolidinylcl-6alkoxy; halopyrrolidinle I .6alkylamino; halopyrrolidinyloxy; hydroxypyrrolidinleI-6alky1amino; morpholiny1C1-6alkylamin0; piperazinyl unsubstituted or substituted by C].6alkoxyC1_6alkyl, hydroxyC1-6alkyl or C1- 6alkyl; piperazinylcarbonyl; piperidinyl tituted or substituted by one or two substituents independently selected from amino, C1.6alkoxy and ky1; piperidinylamino; or pyrrolidinyl substituted by one, two or three substituents independently selected from amino, C1_6alkoxy, C1_6alkyl, C1-6alkylarnino, halogen, hydroxy and hydroxyC 1.6a1ky1; mis 0,1, 2, or3; nis 1,2, 3 or4; m+nS4; with the o that R5 and R6 are not H aneously; or a phannaceutically acceptable salt thereof.

WO 33941 2019/064323 Another object of the present invention is related to novel compounds of formula (I) or (Ia) or (Ib), their manufacture, medicaments based on a compound in accordance with the invention and their tion as well as the use of compounds of formula (I) or (Ia) or (lb) as TLR7 and/or TLR8 and/or TLR9 antagonist, and for the treatment or prophylaxis of systemic lupus erythematosus or lupus nephritis. The compounds of formula (I) or (Ia) or (lb) show superior TLR7 and/or TLR8 and/or TLR9 antagonism ty. In on, the nds of formula (I) or (Ia) or (lb) also show good hPBMC, cytotoxicity, solubility, human microsome ity and SDPK profiles, as well as low CYP tion.

DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS The term “Cmalkyl” denotes a saturated, linear or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. Particular “Cmalkyl” groups are methyl, ethyl and n-propyl.

The term “halogen” and “halo” are used interchangeably herein and denote fluoro, , bromo, or iodo.

The term “haloC1_6alky1” denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by same or different halogen atoms, particularly fluoro atoms. Examples of haloC1-6alkyl include monofluoro-, difluoro-or ro—methyl, - ethyl or —propyl, for example 3,3,3—trifluoropropyl, 2—fluoroethyl, 2,2,2—trifluoroethyl, fluoromethyl, difluoromethyl, trifluoromethyl and trifluoroethyl.

The term “oxy” denotes -O—.

The term lkoxy” denotes C1.6alkyl-O-.

The term “halopyrrolidinyl” denotes a pyrrolidinyl substituted once, twice or three times by halogen. Examples ofhalopyrrolidinyl include, but not limited to, difluoropyrrolidinyl and fluoropyrrolidinyl.

The term “haloazetidinyl” denotes a azetidinyl substituted once, twice or three times by halogen. Examples of halopyrrolidinyl include, but not limited to, difluoroazetidinyl and fluoroazetidinyl.

The term “enantiomer” denotes two stereoisomers of a compound which are non- superimposable mirror images of one another.

The term “diastereomer” denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling , spectral properties, and reactivities.

WO 33941 The term “as—isomers” and “trans-isomers” denote the relative stereochemistry of the molecule or moiety. For e: the starting material of Example 16 (trans(boc—amino) ; similarly, the starting material of Example 17 (cis(boc- >Lo fl 0%”Q amino)-4—methoxypyrrolid1ne, \ ) as the “cis-isomers” refers to a mixture of fl\O n >Lo n DAN/Q CANMO O\ é and \ . The way of showing relative stereochemistry also applies to the final compounds of this invention.

The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts e both acid and base addition salts.

The term “pharmaceutically acceptable acid addition salt” denotes those ceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, ic acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, liphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid.

The term “pharmaceutically acceptable base addition salt” denotes those pharrnaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include , ium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable c nontoxic bases includes salts of primary, secondary, and tertiary , substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethy1aminoethanol, trimethamine, ohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N—ethylpiperidine, and polyamine resins.

The term “A pharmaceutically active metabolite” denotes a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. After entry into the body, most drugs are substrates for chemical reactions that may change their physical properties and biologic s. These metabolic conversions, which usually affect the polarity of the compounds of the invention, alter the way in which drugs are distributed in and excreted from the body. However, in some cases, metabolism of a drug is required for eutic effect.

The term “therapeutically effective amount” denotes an amount of a compound or molecule of the t invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described . The therapeutically effective amount will vary depending on the compound, the disease state being d, the severity of the e treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.

The term “pharmaceutical composition” denotes a mixture or on comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable ents to be administered to a mammal, e.g., a human in need ANTAGONIST OF TLR7 AND/OR TLRS AND/OR TLR9 The present invention relates to (i) a compound of formula (I), N R (R n R4 (R )m (I), wherein R7 R7 R7 R7 8 8 8 N R N R N R \ / \ / N\ / N/\IR9 R1 is 7 9 9 7 R7 R7 R7 R7 N N N N / N/ / N/ \ \> \> \> \ \ \ \N s 0 , , ; wherein R7 is C1_6alkyl, C1_6alkoxy, haloC1-6alkyl, halogen, nitro or cyano; R8 is H or ium; R9 is H, deuterium or kyl; R10 is H or halogen; R2 is H or C1_6alkyl; R3 is H; R4 is H; R5 is H, piperazinyl, halogen, C1_6alky1, halopyrrolidinylamino or hydroxypyrrolidinle- 6alkylamino; R6 is H; (C1-6alkyl)2amin0C1.6alkoxy; (C 1 -6alkyl)2aminoC 1 -6alkylamino; 1,2,3,4,6,6a-hexahydropyrrolo[3,4-c]pyrroly1 substituted by C1_(,alkoxy; 1,4-diazepanyl substituted by one or two substituents independently ed from hydroxy and C1_6alkyl; 1,4-oxazepanyl substituted by amino; 1,4-oxazepanylamino; 1,6-diazaspir0[3.3]heptanyl; 2,5—diazabicyclo[2.2.1]heptanylcarbonyl; 2,6-diazaspiro[3.3]heptany1 tituted or substituted by CMalkyl; 2-oxaazaspiro[3.4]octany1 substituted by amino; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3 ,4—b][1,4]oxazinyl; 3,4a,5,6,7,7a~hexahydro-2H-pyrrolo[3 ,4-b] [1 ,4]oxaziny1; 3,8-diazabicyclo[3.2.1]octanylcarbony1; 3-oxa-7,9-diazabicyclo[3.3.1]nonany1; 3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazinyl; -oxa~2,8—diazaspiro[3.5]nonanyl; 9-0xa—3 ,7-diazabicyclo[3.3.1]nonany1; amino(C1-6alky1)piperidinylcarbonyl; azetidinyl unsubstituted or substituted by one or two substituents independently selected from amino and C1_6alkyl; azetidinylamino; inyloxy; C1.6a1koxypiperidinylamino; C] -6alkoxypyrrolidinyl(C1-6alky1)amino; C1-6alkoxypyrrolidinylamino; haloazetidinyl(C1-6alkyl)amino; halopyrrolidinylamino; halopyrrolidinle1-6alkoxy; halopyrrolidinleMalkylamino; halopyrrolidinyloxy; hydroxypyrrolidinle1-6alkylamino; morpholinylcl-6alkylamino; piperazinyl unsubstituted or substituted by C1.6alkoxyC1-6alkyl, hydroxyC1_6alkyl or C1- 6alky1; zinylcarbonyl; piperidinyl tituted or tuted by one or two tuents independently selected from amino, Cmalkoxy and C1-6alkyl; piperidinylamino; or pyrrolidinyl substituted by one, two or three substituents independently selected from amino, C1_6alkoxy, C]_6a1kyl, C1_6alkylamin0, halogen, hydroxy and hydroxyC1_6alkyl; m is 0,1, 2, or 3; nis 1,2,3 or4; m+nS4; with the proviso that R5 and R6 are not H simultaneously; or a pharmaceutically acceptable salt thereof.

Another embodiment of present invention is (ii) a compound of formula (Ia), (121)’ wherein R7 R7 R7 N R8 N R8 N j: N \ / N/\ \> / N/ R9 \ \ S R1 is or , , ; wherein R7 is C1-6alkyl, haloC._6alkyl, halogen or cyano; R8 is H or deuterium; R9 is H or deuterium; R10 is H or halogen; R2 is H or C;.6alkyl; R3 is H; R4 is H; R5 is H, piperazinyl, rrolidinylamino or hydroxypyrrolidinle1.6alkylamino; R6 is H; (C1-6alkyl)2aminoC1-6alkoxy; (C1-6alkyl)2aminoC1-6alkylamino; 1,2,3,4,6,6a-hexahydropyrrolo[3,4-c]pyrrolyl substituted by koxy; 1,4-diazepanyl substituted by one or two tuents independently selected from hydroxy and kyl; 1,4-oxazepanyl substituted by amino; 1,4-oxazepanylamino; 1,6-diazaspiro[3 .3]heptanyl; 2,5-diazabicyclo[2.2.1]heptany1carbonyl; 2,6—diazaspiro[3.3]heptanyl unsubstituted or substituted by C1_6alkyl; 2-oxa—7—azaspiro[3.4]octany1 substituted by amino; 3,4,4a,5,7,7a-hexahydro-2H—pyrrolo[3 ,4-b] [l ,4]oxaziny1; 3,4a,5,6,7,7a-hexahydro~2H—pyrrolo[3 ,4-b][1,4]oxazinyl; 3,8—diazabicyclo[3 .2. 1 ylcarbony1; 3—oxa—7,9—diazabicyclo[3.3. 1]nonany1; 3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyraziny1; S-oxa—2,8-diazaspiro[3.5]nonanyl; 9-oxa-3 ,7-diazabicyclo[3 .3 . l ]nonanyl; amino(C1-6alkyl)piperidinylcarbonyl; azetidinyl unsubstituted or substituted by one or two substituents independently selected from amino and C1.6alkyl; azetidinylamino; 1 5 azetidinyloxy; koxypiperidinylamino; C1-6alkoxypyrrolidinyl(C1-6alky1)amino; C1-6alkoxypyrrolidiny1amino; haloazetidinyl(CMalkyDamino; halopyrrolidinylamino; halopyrrolidinle1-6alkoxy; halopyrrolidinle]-6alkylamino; halopyrrolidinyloxy; hydroxypyrrolidinle1-6alkylamino; morpholinle1-6alkylamino; piperazinyl unsubstituted or substituted by C1.6alkoxyC1.6a1kyl, yC1.6alkyl or C1- 6alkyl; piperazinylcarbonyl; piperidinyl tituted or substituted by one or two tuents independently ed from amino, C1_6alkoxy and C1_6a1kyl; piperidinylamino; or idinyl substituted by one, two or three substituents independently selected from amino, CMalkoxy, Cmalkyl, C1_6a1kylamino, halogen, hydroxy and hydroxyC1_6alkyl; or a pharmaceutically acceptable salt thereof.

Another embodiment of present invention is (iii) a compound of a (1b), (lb), R7 R7 R7 a 8 N R N R N \ / /N \ \> / N/IR9 \ \ S Rlis or , , ; wherein R? is C1-6alkyl, haloCl-6alkyl, halogen or cyano; R8 is H or deuterium; R9 is H or deuterium; R10 is H or halogen; R2 is H or C1.6alky1; R3 is H; R4 is H; R5 is H, piperazinyl, halopyrrolidinylamino or hydroxypyrrolidinle 1-6alkylamino; R6 is H; 1ky1)2aminoC1-6alkoxy; (C1_6alkyl)2aminoC1.6alkylamino; 1,2,3,4,6,6a-hexahydropyrrolo[3,4-c]pyrroly1 substituted by Cliéalkoxy; 1,4-diazepany1 substituted by one or two substituents independently selected from y and C1_6alky1; 1,4-oxazepanyl substituted by amino; 1 ,4-oxazepanylamino; 1,6-diazaspiro[3 .3 ]heptanyl; 2,5-diazabicyclo[2.2.1]heptanylcarbonyl; 2,6-diazaspiro[3.3]heptany1 unsubstituted or substituted by C1-6alkyl; 2-oxaazaspiro[3.4]octanyl substituted by amino; 3,4,4a,5,7,7a-hexahydro—2H-pyrrolo[3,4-b][1,4]oxazinyl; 3,4a,5,6,7,7a—hexahydro—2H-pyrrolo[3,4—b] [l ,4]oxazinyl; 3,8—diazabicyclo[3.2.1]octanylcarbonyl; 7,9-diazabicyclo[3 .3 . l ]nonany1; 3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5—a]pyrazinyl; 5—oxa—2,8-diazaspir0[3.5]nonanyl; 9-oxa-3,7-diazabicyclo[3 .3. l yl; amino(C] 1)piperidinylcarbonyl; azetidinyl unsubstituted or substituted by one or two substituents ndently selected from amino and C1-6alky1; azetidinylamino; azetidinyloxy; C1-6alkoxypiperidinylamino; C1-6alkoxypyrrolidinyl(C1.6a1kyl)amino; C1-6alkoxypyrrolidinylamino; haloazetidinyl(C1.6alkyl)amino; halopyrrolidinylamino; halopyrrolidinleMalkoxy; rrolidinle 1 -6alkylamino; halopyrrolidinyloxy; hydroxypyrrolidiny1C1.6alkylamino; morpholinle1 -6alkylamino; piperazinyl unsubstituted or substituted by C1-6a1koxyC1-6alkyl, liydroxyC1-6alkyl or C]- éalkyl; piperazinylcarbonyl; piperidinyl unsubstituted or tuted by one or two substituents independently selected from amino, C1.6alkoxy and C1.6alkyl; piperidinylamino; or pyrrolidinyl substituted by one, two or three substituents independently selected from amino, C1_6alk0xy, C1_6alkyl, ky1amino, halogen, hydroxy and hydroxyCMalkyl; or a pharmaceutically acceptable salt thereof.

A fiirther embodiment of present invention is (iv) a compound of formula (I) or (Ia) or (Ib) according to any one of (i) to (iii), or a pharmaceutically acceptable salt thereof, wherein R6 is H; (C1_6alkoxyC1-6alky1)piperazinyl; (C1.6alkyl)2aminoC1.6alk0xy; lkyl)2aminoC 1 -6alkylamino; (hydroxyC1-6alkyl)piperazinyl; 1,4-oxazepanylamino; l,6-diazaspiro[3.3]heptany1; 2,5- diazabicyclo[2.2.1]heptanylcarbonyl; 2,6-diazaspiro[3.3]heptany1; 3,4,4a,5,7,7a—hexahydro-2H- pyrrolo[3 ,4-b] [ l zinyl; 3,4a,5,6,7,7a-hexahydro—2H-pyrrolo[3,4-b][1,4]oxazinyl; 3 ,8- diazabicyclo[3.2. l ]octanylcarbonyl; 7,9-diazabicyclo[3.3.1]nonanyl; 3-0xo-l ,5,6,7,8,8a— droimidazo[ l ,5-a]pyrazinyl; 2,8-diazaspiro[3 .5]nonanyl; 9-oxa-3,7- diazabicyclo[3.3 . l ]nonanyl; amino(C1-6alkoxy)piperidinyl; amino(C1-6alkoxy)pyrrolidinyl; amino(C1-6alkyl)azetidinyl; amino(C1-6alkyl)piperidinyl; amino(C1-6alkyl)piperidiny1carbonyl; amino(C1-6alkyl)pyrrolidinyl; amino(hydroxy)(C1-6alkyl)pyrrolidinyl; amino(hydroxy)pyrrolidiny1; amino(hydroxyC1-6alkyl)pyrrolidinyl; 1,4-oxazepanyl; amino-2—oxa—7-azaspiro[3.4]octany1; aminoazetidinyl; alopyrrolidinyl; aminopyrrolidinyl; azetidinyl; azetidinylamino; azetidinyloxy; C1-6alkoxy(C1-6alkylamino)pyrrolidinyl; C1_6alkoxy- l,2,3,4,6,6a—hexahydropyrrolo[3,4-c]pyrrolyl; C1-6alkoxypiperidinylamino; C1- 6a1koxypyrrolidiny1(C1-6alkyl)amino; C1-6alkoxypyrrolidinylamino; C1_6alkyl-2,6- diazaspiro[3.3]heptanyl; C1_6alkylpiperazinyl; haloazetidinyl(C1-6alkyl)amino; halopyrrolidinylamino; halopyrrolidinle1-6alkoxy; halopyrrolidinle1-6alkylamino; halopyrrolidinyloxy; y(C 1 -6a1kyl)-1 ,4-diazepanyl; hydroxy(C1-6alkylamino)pyrrolidinyl; hydroxy- l ,4-diazepanyl; hydroxypyrrolidinle1-6alkylamino; morpholinle1-6alkylamino; piperazinyl; piperazinylcarbonyl; dinyl or piperidinylamino.

A further embodiment of present invention is (v) a compound of formula (I) or (la) or (lb) according to any one of (i) to (iv), or a pharmaceutically acceptable salt thereof, wherein R6 is H; (hydroxymethyl)piperaziny1; 1,4-oxazepanylamino; l,6-diazaspiro[3.3]heptan-6—yl; 2- hylamino)ethoxy; 2-(dimethylamino)ethylamino; 2,5-diazabicyclo[2.2. 1 ]heptanyl carbonyl; 2,6-diazaspiro[3.3]heptanyl; 2—morpholinylethylamino; 3- (methoxymethyl)piperazin- l -yl; 3 ,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3 ,4—b] [ l ,4]oxazinyl; 3,4a,5,6,7,7a-hexahydro—2H-pyrrolo[3,4-b][l,4]oxazinyl; 3,8—diazabicyclo[3 .2. l]octanyl—3— carbonyl; 3a-methoxy-l,2,3,4,6,6a—hexahydropyrrolo[3,4-c]pyrrolyl; 3-amino—3- (hydroxymethyl)pyrrolidin-1—yl; omethyl-azetidin—l -yl; 3-a1ninomethy1-pyrrolidin— l—yl; 3-amin0fluoro-pyrrolidin-1 -yl; 3-amino—4-hydroxy-pyrrolidinyl; 3-aminomethoxy- 1-piperidinyl; 3-amino1nethoxy-pyrrolidinyl; 3-aminoazetidin-l-yl; 3-aminopyrrolidin-l-yl; 3 -fluoroazetidinylmethylamino; 3-hydroxy—4—(methylamino)pyrrolidin-1 —y1; 3- hydroxypyrrolidin-l -ylethy1amino; 3-methoxy—4-(methy1amino)pyrrolidin—l-yl; 3—methoxy piperidinylamino; 3 -1nethylpiperazin- l —yl; 3-0xa—7,9~diazabicyclo[3 .3. l ]nonanyl; 3—oxo- 1,5,6,7,8,8a-hexahydroimidazo[ 1 yrazinyl; 3 -piperidiny1amino; 4—aminohydroxy methyl—pyrrolidin- l -yl; 4-a1ninomethoxy—1-piperidinyl; 4-amino1nethyl-1—piperidinyl; 4— aminomethyl—piperidinyl—l-carbonyl; 4-fluoropyrrolidinylmethoxy; 4-fluoropyrrolidin ylmethylamino; 4-fluoropyrrolidinylamino; 4-fluoropyrrolidinyloxy; 4-methoxypyrrolidin- 3-yl(methyl)amino; 4-methoxypyrrolidinylamino; 5-aminooxaazaspiro[3.4]octanyl; -oxa—2,8-diazaspiro[3.5]nonan—2~yl; 5—oxa-2,8—diazaspiro[3.5]nonan~8—yl; 6-amino-1,4- oxazepanyl; 6-hydroxy—l,4-diazepan-l-yl; oxy—6-methyl-l ,4-diazepan-l-yl; 6—methyl— 2,6—diazaspiro[3.3]heptanyl; 9—oxa-3,7—diazabicyclo[3.3.l]n0nanyl; azetidin-3~yl; azetidin- 3-ylamino; azetidinyloxy; hydroxy—l ,4—diazepan- l -yl; morpholin-Z-ylmethylamino; liny1methylamino; piperazin-l -yl; piperazinyl- l -carbonyl or piperidinyl.

A further ment of present invention is (vi) a nd of formula (I) or (Ia) or (lb) according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein R1 R7 R7 N\ R8 / N/N / \ \ .

IS or ; wherein R7 is cyano; R8 is H or deuterium; R[0 is H or halogen.

A further embodiment of present invention is (vii) a compound of formula (I) or (la) or (lb) ing to any one of (i) to (vi), or a phannaceutically acceptable salt thereof, wherein R1 R7 R7 N R \ / N/ / \ \ R10 . , . . . . 8 IS 01‘ ; whereln R7 15 cyano; R is H or deuterium; R10 IS H or fluoro.

A r embodiment of present invention is (viii) a compound of formula (I) or (Ia) or (1b) according to any one of (i) to (vii), or a pharmaceutically acceptable salt thereof, wherein R2 is C1_6alkyl and R5 is H.

A r embodiment of present invention is (ix) a compound of formula (1) or (la) or (lb) according to (ii) or (iii), or a pharmaceutically acceptable salt f, wherein R6 is (C1_6alkyl)2aminoC1-6alkylamino; l,4—diazepanyl substituted by hydroxy; 1,4-oxazepanyl substituted by amino; 3,4,4a,5,7,7a-hexahydro—2H-pyrrolo[3,4—b] [l ,4]oxazinyl; 5-oxa-2,8-diazaspiro[3.5]nonanyl; 9-0xa-3 ,7-diazabicyclo[3 .3. l ]nonanyl; azetidinyl substituted twice by amino and C1_6alkyl; C1-6alkoxypyrrolidiny1amino; halopyrrolidinylamino; or pyrrolidinyl substituted by two or three substituents independently selected from amino, C1-6alkoxy, C1_6all<yl and hydroxy.

A further ment of present ion is (x) a compound of formula (I) or (la) or (lb) according to any one of (i) to (ix), or a pharmaceutically acceptable salt thereof, wherein R6 is (C1-6alky1)2aminoC1-6alkylamino; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; 5- 8-diazaspiro[3.5]nonanyl; 3,7-diazabicyclo[3.3. l ]nonanyl; C1- 6alkoxy)pyrrolidinyl; amino(C]-6alkyl)azetidiny1; amino(C1-6alkyl)pyrrolidinyl; amino(hydroxy)(C1-6alky1)pyrrolidinyl; amino(hydroxy)pyrrolidinyl; amino—1 ,4-oxazepanyl; C]- 6alkoxypyrrolidinylamino; halopyrrolidinylamino or hydroxy-1,4-diazepanyl.

A further embodiment of present invention is (xi) a compound of formula (I) or (la) or (lb) according to any one of (i) to (x), or a pharmaceutically acceptable salt thereof, wherein R6 is 2- (dimethylamino)ethylamino; 3 ,4,4a,5,7,7a—hexahydro-2H-pyrrolo[3,4~b] [ l ,4]oxazinyl; 3 - aminomethyl—azetidinyl; o—3—methyl-pyrrolidinyl; 3-aminohydroxy- pyrrolidin- 1 ~yl; 3—aminomethoxy—pyrrolidinyl; o—3—hydroxy-3 l-pyrrolidin-1 - yl; 4-fluoropyrrolidin-3—ylamino; 4-methoxypyrrolidiny1amino; 5-oxa-2,8- diazaspiro[3.5]nonan-2—yl; 5-oxa-2,8—diazaspiro[3.5]nonan—8—yl; 6~amino-1,4-oxazepanyl; 9- oxa-3 ,7-diazabicyclo[3 .3 . l ]nonan-3 -y1 or hydroxy-I ,4—diazepan— 1 -y1.

A further embodiment of present ion is (xii) a compound of formula (I) or (la) or (Ib) according to any one of (i) to (xi), or a pharrnaceutically acceptable salt thereof, wherein R7 R7 N\ R8 / N’N / \ \ R1 is or ; wherein R7 is cyano; R8 is H or deuterium; R10 is H or halogen; R2 is C1-6alkyl; R3 is H; R4 is H; R5 is H; R6 is (C1.6alkyl)2aminoC1.6alkylamino; 1,4-diazepanyl substituted by hydroxy; WO 33941 1,4-oxazepanyl substituted by amino; 3,4,4a,5,7,7a—hexahydro-2H-pyrrolo[3 ,4—b] [l ,4]oxaziny1; —0xa-2,8—diazaspiro[3.5]nonanyl; 9-oxa-3 ,7-diazabicyclo[3 .3. l ]nonanyl; azetidinyl substituted twice by amino and C1_(,alkyl; C1-6alkoxypyrrolidinylamino; halopyrrolidinylamino; or pyrrolidinyl substituted by two or three substituents independently selected from amino, C 1 -6alkoxy, C 1 .6alkyl and hydroxy; or a pharmaceutically acceptable salt f.

A further embodiment of present invention is (xiii) a compound of formula (I) or (Ia) or (Ib) according to any one of (i) to (xii), or a pharmaceutically acceptable salt f, wherein R7 R7 N R \ / N/ / \ \ R1 is or ; wherein R7 is cyano; R8 is H or deuterium; R10 is H or halogen; R2 is C1_6a1kyl; R3 is H; R4 is H; R5 is H; R6 is (C1_6alkyl)2aminoC1-6alkylamino; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][l ,4]oxazinyl; 5-oxa-2,8—diazaspiro[3.5]nonany1; 9—oxa-3,7—diazabicyclo[3 .3. l ]nonanyl; amino(C1_ 6alkoxy)pyrrolidinyl; amino(C1-6a1kyl)azetidinyl; a1nino(C1.6alky1)pyrrolidinyl; hydroxy)(C1-6alkyl)pyrrolidiny1; hydroxy)pyrrolidinyl; amino-l ,4- oxazepanyl; koxypyrrolidinylamino; halopyrrolidinylamino or hydroxy-l ,4- diazepanyl; or a pharmaceutically acceptable salt f.

A further embodiment of present invention is (xiv) a compound of formula (I) or (Ia) or (Ib) according to any one of (i) to (xiii), or a pharmaceutically acceptable salt thereof, wherein -1 g- R7 R7 N\ R8 / /N / \ \ R1 is or ; wherein R7 is cyano; R8 is H or deuterium; R10 is H or fluoro; R2 is methyl; R3 is H; R4 is H; R5 is H; R6 is 2-(dimethylamino)ethylamino; 3,4,4a,5,7,7a-hexahydro~2H-pyrrolo[3,4—b][1,4]oxazin-6—yl; 3-aminomethyl-azetidinyl; 3-aminomethyl-pyrrolidinyl; ohydroxy- pyrrolidin- l ~yl; 3—aminomethoxy—pyrrolidinyl; 4-amin0—3—hydroxy—3 -methy1- pyrrolidin-l-yl; 4-fluoropyrrolidinylamino; 4-methoxypyrrolidiny1amino; 5-oxa-2,8- diazaspiro[3.5]nonan—2-yl; 5-oxa-2,8~diazaspiro[3.5]nonan-8—yl; 6-amino-1,4-oxazepan yl; 9-oxa—3,7—diazabicyclo[3.3. l ]nonanyl or y-l ,4-diazepan-1 -y1; or a pharmaceutically acceptable salt thereof.

The t invention relates to (i’)a compound of formula (I), N R2 (R n R4 1 5 ( )m (I), wherein R7 R7 R7 R7 N N N N \ \j / N/ \ \> / N/ \ \ R1 is or , , ; wherein R7 is cyano; R2 is C1_Galky1; R3 is H; R4 is H; R5 is H or piperazinyl; R6 is H; (C1_6alkylamino)C1-6alkoxy; ((C]-6alkyl)2amino)Cl.6a1ky1amino; (C). 6alkoxypyrrolidinyl)amino; (halopyrrolidinyl)amino; xyC1-6alkyl)piperazinyl; 1,4- diazepanyl substituted by hydroxy; 2-oxaazaspiro[3.4]octanyl substituted by amino; 3- oxa-7,9-diazabicyclo[3 .3 . l ]nonanyl; 5-oxa-2,8—diazaspiro[3 .5]nonanyl; 3,7— icyclo[3 .3 . l ]nonanyl; aminoazetidinyl; aminopyrrolidinyl; azetidinyl; azetidinylamino; azetidinyloxy; piperazinyl; piperidinyl or pyrrolidinyl which is once or twice substituted by substituents independently selected from amino, hydroxy, yCl- 6alkyl, C1_6alkoxy and C1_6alky1amino; mis 0, 1, 2, or 3; nis 1,2, 3 or4; m+ns4; with the proviso that R5 and R6 are not H simultaneously; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment of present invention is (ii’) a compound of formula (la), (Ia), wherein R7 R7 R7 R7 N N /N N / N/ \ \ R] is or , , ;wherein R7 is cyano; R2 is C1-6alkyl; R3 is H; W0 33941 R4 is H; R5 is H or piperazinyl; R6 is H; (C1-6alkylamin0)C1-6a1k0xy; ((C1-6alky1)2amino)C1-6alky1amino; (C1. 6alkoxypy1rolidinyl)amin0; (halopyrrolidinyl)amino; (hydroxyC 1-éalky1)piperazinyl; 1,4- diazepanyl tuted by hydroxy; 2—oxaazaspiro[3.4]octanyl substituted by amino; 3- oxa—7,9—diazabicyclo[3.3.1]nonanyl; 5-oxa-2,8-diazaspiro[3.5]nonany1; 9-oxa-3,7- diazabicyclo[3 .3 .] ]nonanyl; aminoazetidinyl; aminopyrrolidinyl; azetidinyl; azetidinylamino; azetidinyloxy; piperazinyl; piperidinyl or pyrrolidinyl which is once or twice substituted by substituents independently ed from amino, hydroxy, hydroxyC1_ 6alkyl, C1_6alkoxy and kylamino; with the proviso that R5 and R6 are not H simultaneously; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment of present invention is (iii’) a compound of formula (Ib), l 5 wherein R7 R7 N N /N N \ j / N \ \> / N/ \ \ R1 is or ; wherein R7 is cyano; R2 is C1-6alkyl; R3 is H; R4 is H; R5 is H or piperazinyl; R6 is H; (C1.6alkylamino)C1.6alkoxy; alkyl)2amino)C1_6alkylamino; (C1- 6alkoxypyrrolidinyl)amino; (halopyrrolidinyl)amino; (hydroxyC 1.6alkyl)piperazinyl; 1,4- diazepanyl substituted by hydroxy; 2-oxaazaspiro[3.4]octany1 substituted by amino; 3- oxa-7,9-diazabicyclo[3.3.1]nonanyl; 5-oxa-2,8-diazaspiro[3.5]nonanyl; 9-oxa—3,7- diazabicyclo[3.3.1]nonanyl; aminoazetidinyl; aminopyrrolidinyl; azetidinyl; azetidinylamino; azetidinyloxy; piperazinyl; piperidinyl or pyrrolidinyl which is once or twice substituted by tuents independently selected from amino, hydroxy, hydroxyC1_ 6alkyl, C1_6alkoxy and C1_6alky1amino; with the proviso that R5 and R6 are not H simultaneously; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

A further embodiment of present invention is (iv’) a compound of formula (I) or (la) or (Ib) according to any one of (i’) to (iii’), wherein R6 is H; (C 1-6alkylamino)C1_6alkoxy; ((C1_ galkyl)2amino)C1.6alkylamino; (C1-6alkoxypyrrolidiny1)amino; (halopyrrolidinyl)amino; (hydroxyC1-6alkyl)piperaziny1; 1,4-diazepany1 substituted by hydroxy; 2-oxa azaspiro[3.4]octanyl substituted by amino; 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl; 5—oxa-2,8- diazaspiro[3 any1; 3 ,7-diazabicyclo[3 .3. 1 ]nonanyl; amino(C1-6alkoxy)pyrrolidinyl; amino(hydroxy)pyrrolidinyl; amino(hydroxyC1.6a1kyl)pyrrolidinyl; aminoazetidinyl; aminopyrrolidinyl; azetidinyl; azetidinylamino; inyloxy; C1_6alkoxy(C1_ 6alkylamino)pyrrolidiny1; piperazinyl or piperidinyl.

A fithher embodiment of present ion is (v’) a nd of formula (I) or (Ia) or (lb) according to any one of (i’) to (iv’), wherein R6 is alkyl)2amino)C1.6alkylamino; (C1- 6alkoxypyrrolidinyl)amino; (halopyrrolidinyl)amino; 1,4-diazepanyl substituted by hydroxy; 5- oxa—2,8—diazaspiro[3 .5]nonanyl; 9-oxa-3,7-diazabicyclo[3.3. l yl or amino(C1_ 6alkoxy)pyrrolidiny1.

A further embodiment of present invention is (vi’) a compound of formula (I) or (1a) or (lb) ing to any one of (i’) to (iv’), wherein R6 is 9-0xa—3,7-diazabicyclo[3.3.l]nonanyl; xypyrrolidinyl)amino; hydroxy—l ,4-diazepanyl; 2,8—diazaspiro[3 .5]nonanyl; (dimethylamino)ethylamino; (fluoropyrrolidinyl)amino or amino(methoxy)pyrrolidinyl.

A further embodiment of present invention is (vii’) a compound of formula (I) or (la) or (Ib) according to any one of (i’) to (vi’), wherein R1 is ; wherein R7 is cyano.

A further ment of present invention is (viii’) a compound of formula (I) or (Ia) or (lb) according to any one of (i’) to (vii’), wherein R5 is H.

A further embodiment of present invention is (ix’) a compound of formula (I) or (la) or (Ib) according to (ii’) or (iii’), wherein R1 is ; wherein R7 is cyano; R2 is C]_6alkyl; R3 is H; R4 is H; R5 is H; R6 is ((C1.6alkyl)2amino)C1-6alkylamino; (C1-6alkoxypyrrolidinyl)amino; (halopyrrolidinyl)amino; azepanyl substituted by hydroxy; 5-oxa-2,8-diazaspiro[3.5]nonanyl; 9-oxa-3,7- diazabicyclo[3 .3. ny1 or C1-6alkoxy)pyrrolidinyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

A further embodiment of present invention is (X’) a compound of formula (I) or (Ia) or (lb) according to any one of (i’) to (ix’), wherein R1 is ; wherein R7 is cyano; R2 is methyl; R3 is H; R4 is H; R5 is H; R6 is 9-oxa-3,7—diazabicyclo[3.3.1]nonanyl; xypyrrolidiny1)amino; hydroxy-1,4- diazepanyl; 5-oxa-2,8~diazaspiro[3.5]nonanyl; hylamino)ethylamino; (fluoropyrrolidinyl)amino or amino(methoxy)pyrrolidinyl; or a pharmaceutically able salt, enantiomer or diastereomer thereof.

Another embodiment of present invention is that (XV) compounds of formula (I) or (la) or (lb) are selected from the following: -23 _ -[(4R,10bS)—4-methy1piperazin—1-y1-3 ,4,6, 1 Ob-tetrahydro— 1 H-pyrazin0[2, 1 ind01— 2-y1]quinolinecarbonitrile; —[(4S, 1 ObR)-4—methy1—8-piperazin—1 —y1~3 ,4,6,1Ob—tetrahydro—1H—pyrazin0[2,1~a]isoindol- 2-y1]quinolinecarbonitrile; -(8—piperazin-1—y1—3,4,6,10b—tetrahydr0-1H—pyrazin0[2,1-a]isoi11d01—2-y1)quinoline—8— carbonitrile; 7—(8—piperaziny1-3,4,6,1Ob-tetrahydro-1H—pyrazino[2,1-a]isoind01—2-y1)—1,3— benzothiazolecarbonitrile; 4-[(4R,10bS)-4~methy1-8—piperaziny1-3,4,6,10b-tetrahydro-1H~pyrazino[2,1-a]isoindol- 2—y1]pyrazolo[1,5-a]pyridine-7—carbonitrile; 7~[(4R,1 0bS)-4—methy1~8-piperazin~1-y1-3,4,6,10b-tetrahydro-1H—pyrazino[2,1—a]isoindol— 2-y1]—1,3-benzothiazolecarbonitrile; 8-[(4R,10bS)methy1-8—piperazin—1—y1—3,4,6,10b-tetrahydro-1H—pyrazin0[2,1 —a]isoind01- 2-y1]quinoxaline-S-carb0nitrile; 5-[(4R,10bS)—4-methy1~7~piperazin-1—y1-3,4,6,lob—tetrahydro—lH-pyrazino[2,1~a]is0indol- 2-y1]quinolinecarb0nitrile; -[(4R,10bS)-4—methy1—8-(4-piperidy1)-3,4,6,10b-tetrahydro—1H—pyrazino[2,1~a]isoindol yl]quin01inecarbonitrile; - [(4R, 10195')—8~[(2R)(hydroxy1nethy1)pipcraziny1]methy1—3,4,6,1Ob—tetrahydro- azin0[2,1-a]isoindoly1]quinolinecarb0nitrile; —[(4R,10bS)—8~[(2S)(hydroxymethyl)piperaziny1]-4—methy1—3 ,4,6,10b-tetrahydr0~ 1H—pyrazino[2,1-a]isoindol-Z-yl]quinolinecarb0nitrile; ,10bS)[(3S)—3 —(hydroxymethy1)piperazinyl]methy1-3 ,4,6,10b-tetrahydr0- 1H—pyrazino[2,1-a]isoindol-2—y]]quinolinecarbonitrile; 5-[(4R,10bS)methy1—8-(3-oxa—7,9-diazabicyclo[3.3.1]n0nan—7-y1)-3,4,6,10b—tetrahydro- 1H-pyrazin0[2,1-a]isoindol-Z-yl]quinoline-S-carbonitrile; -[(4R,10bS)methy1~8-(9-oxa-3,7-diazabicyclo[3.3.1]n0nany1)-3,4,6,10b-tetrahydro- 1H—pyrazin0[2,1—a]isoindol-Z-y1]quinoline-8~carbonitrile; -[(4R,10bS)-8—(6-hydr0xy-1,4-diazepan—1-y1)—4-1nethy1-3 ,4,6,10b-tetrahydro-1H- pyrazino[2, 1 -a]isoindol-2—y1]quin01inecarbonitrile; -[(4R,10bS)—8—[transaminometh0xy—pyrrolidin—1-y1]methy1—3,4,6,1 rahydro- 1H—pyrazin0[2,1-a]isoindol-Z-yl]quinolinecarb0nitrile; -[(4R,10bS)~8—[(3S,4S)amin0methoxy-pyrr01idin-1—y1]—4—methy1—3 ,4,6,10b— ydro-1H-pyrazino[2, 1 -a]isoind01—2—y1]quinoline-S—carbonitrile; -[(4R,10bS)-8—[(3R,4R)aminomethoxy—pyrrolidiny1]—4~methyl-3,4,6,10b— tetrahydro-lH-pyrazino[2,1-a]is0indoly1]quinoline—8-carbonitrile; -[(4R,10bS)—8—[cisamino-4—methoxy—pyrrolidiny1]—4-methy1—3,4,6,10b-tetrahydro- 1H—pyrazino[2,1 -a]isoind01y]]quinoline-S—carbonitrile; —[(4R,101353—8—(5—amin00xa—7—azaspiro[3.4]octan—7-yl)—4~methy1-3,4,6, 10b—tetrahydro- 1H-pyrazino[2, 1 -a]isoind01y1]quinolinecarbonitrile; -[(4R,10bS)-8—[3-amino—3~(hydroxymethyl)pyrr01idiny1]methy1-3,4,6,1 Ob- tetrahydro- 1 H—pyrazino[2, 1 -a]isoindoly1] quinolinecarbonitrile; -[(4R,10bS)—8-[(3R)—3 pyrrolidiny1]-4—methy1—3 ,4,6,10b—tetrahydro-1H— pyrazino[2,1-a]isoindol-Z-yl]quinoline—8-carbonitrile; -[(4R,1 019$)[trans—3—aminohydr0xy-pyrrolidin—1—y1]~4~methy1-3,4,6,1Ob-tetrahydro~ 1H-pyrazino[2,1-a]is0ind01y1]quinolinecarbonitrile; -[(4R,10bS)—8—(3 -aminoazetidiny1)—4-methy1-3,4,6,10b-tetrahydro-1.H-pyrazin0[2,1— ndol-Z-yl]quinolinecarbonitrile; 5—[(4R, 1 ObS)—8—[(3S,4S)meth0xy(methy1amin0)pyrrolidin- 1 —y1]—4-methy1-3,4,6, 1 0b- tetrahydro-1H—pyrazino[2,] -a]isoindo1—2-yl]quinoline-S—carbonitrile; -[(4R,10bS)—4—methy1(5-oxa—2,8—diazaspir0[3.5]n0nanyl)-3,4,6,1Ob-tetrahydro-lH- pyrazino[2,1-a]isoindoly1]quinolinecarbonitrile; -[(4R,10bS)[2-(dimethy1amin0)eth0xy]methy1—3,4,6,1 Ob—tetrahydro— 1H— pyrazino [2, 1 -a]isoind01y1] inecarbonitrile; -[(4R, 1 ObS)[2—(dimethylamin0)ethylamino]—4—methy1—3,4,6,10b-tetrahydr0-1H— pyrazino[2,1-a]is0ind01y1]quinoline-S-carbonitrile; -[(4R,10bS)-8—(azetidin~3—y10xy)—4-methy1-3,4,6,1Ob-tetrahydro-1H-pyrazin0[2,1- a]isoind01—2-y1]quinoline—8-carb0nitrile; 5-[(4R,10bS)-8—(azetidin-3—y1amino)methy1-3 0b-tetrahydro-1H—pyrazino[2, 1— a]isoindoly1]quinoline—S-carbonitrile; -[(4R, 1 0bS)—8—(azetidin~3 -y1)methy1—3 ,4,6,10b-tetrahydro-1H-pyrazin0[2,1-a]isoind01- 2-y1]quino1inecarbonitrile; ,10b53—8-[[(3S,4R)—4—flu0ropyrrolidin—3~y1]arnin0]methy1-3,4,6,1Ob-tetrahydro- 1H-pyrazino[2,1 -a]isoind01y1]quinoline-S-carbonitrile; -[(4R,10bS)~8-[[(3S,4S)fluor0pyrr01idiny1]amino]—4-methy1-3 ,4,6,1 Ob-tetrahydro- 1H—pyrazin0[2,1-a]isoind01—2—y1]quinolinecarb0nitrile; ,1ObS)—8—[[(3R,4S)flu0ropyrrolidiny1]amin0]methy1-3 ,4,6,1 Ob-tetrahydro- 1H—pyrazin0[2,1-a]isoindol-Z—yl]quinoline-8—carbonitrile; -[(4R,1 0b5)—8~[[(3R,4R)fluoropyrrolidiny1]amino]-4—methy1—3,4,6,10b-tetrahydro- 1H—pyrazino[2, 1 -a]isoindoly1]quinoline-8—carbonitrile; —[(4R,10bS)—8—[[(3R,4R)-4~meth0xypyrrolidin—3-y1]amino]—4-methy1—3,4,6,10b- tetrahydro-1H—pyrazino[2,1-a]isoindoly1]quinoline—S-carbonitrile; -[(4R,10bS)—4-methy1~8—(5—0xa-2,8—diazaspiro[3.5]n0nany1)—3,4,6,10b—tetrahydro-1H— pyrazino[2,1—a]isoind01y1]quinoline—8-carbonitrile; ,10bS)—8-(2,6-diazaspir0[3.3]heptan~2-y1)—4-methy1—3,4,6,1Ob-tetrahydro-IH- pyrazino[2,1—a]isoind01y1]quinolinecarbonitrile; -[(4R,10bS)-8~(1,6-diazaspiro[3.3]heptany1)-4—methyl-3,4,6,10b-tetrahydro-IH- pyrazin0[2,1-a]isoindoly1]quinolinecarbonitrile; —[(4R,10bS)methy1~8—(6-methy1-2,6-diazaspiro[3.3]heptan~2-y1)-3,4,6,IOb-tetrahydro- 1H—pyrazino[2,1-a]isoindoly1]quinolinecarbonitrile; -[(4R,10bS)(3 -amino—3~methy1-azetidiny1)methy1-3,4,6,10b-tetrahydro—1H~ pyrazino[2,1-a]isoindol-Z-yl]quinolinecarb0nitrile; 5-[(4R,10bS)—8-[(3S,4S)-3—aminohydroxy-pyrr01idiny1]—4-methy1-3,4,6,10b- tetrahydro-1H—pyrazino[2,l -a]isoindol-Z-y1]quinolinecarbonitrile; ,10bS)-8—[(3R,4R)amino—4-hydr0xy—pyrr01idin—1—y1]methy1-3 ,4,6,1 0b- tetrahydro-lH-pyrazino[2,1-a]isoindol-Z-y1]quin01inecarbonitrile; -[(4R,10bS)(3a-methoxy—1,2,3,4,6,6a-hexahydr0pyrrolo[3 ,4—c]pyrroly1)methyl- 3,4,6,10b-tetrahydro-1H-pyrazino[2,1—a]isoindol-Z-yl]quinoline-S-carbonitrile; -[(4R,10bS)—8-[(3S,4S)hydr0xy—4—(methy1amin0)pyrrolidiny1]-4—methy1—3,4,6, 10b- tetrahydro-1H—pyrazino[2,1-a]isoind01-2~y1]quinolinecarbonitri1e; -[(4R,1ObS)—4—methy1—8-[(3R,4R)hydr0xy(methylamino)pyrr01idin—1-y1]-3,4,6,10b— tetrahydro-lH—pyrazino[2,1—a]isoindoly1]quinoline-8—carbonitrile; ,10bS)methy1~8-[(4aR,7aR)—3,4,4a,5,7,7a-hexahydr0—2H-pyrrolo[3,4— b][1,4]0xazin—6—y1]-3,4,6,1Ob-tetrahydro-1H—pyrazin0[2,1-a]isoind01y1]quinoline-8— itrile; -[(4R,10bS)methy1[trans—(3R,4R)-4—aminohydroxy—3—1nethy1-pyrrolidinyl]— 3,4,6,10b-tetrahydr0-1H—pyrazino[2,1 -a]isoind01—2-y1]quinoline-S-carbonitrile; 5—[(4.R,10bS)-8—[(3R,4R)—4-amino—3-hydr0xy—3—methy1—pyrr01idin-1~y1]-4—methyl— 3,4,6,10b—tetrahydro-1H—pyrazino[2,1 -a]isoindol—Z-yl]quinoline-S-carb0nitrile; —[(4R,10bS)—8—[(3 S,4S)-4—amino—3-hydroxy-3 —methy1-pyrr01idin— 1 -y1]methy1— 3,4,6,1Ob-tetrahydro-lH-pyrazin0[2,1-a]isoindol-Z-yl]quinoline-S-carb0nitrile; ~26- —[(4R,10bS)-8—[(3S,4R)amino—4—fluoro-pyrrolidin-1 —y1]—4-methy1-3,4,6,10b-tetrahydr0- 1H—pyrazino[2,1-a]isoindol-Z-y1]quinoline—S-carbonitfile; -[(4R,10bS)-8—[(3R,4S)—3 ~aminofluor0-py1rolidiny1]-4~methy1-3,4,6,1Ob-tetrahydro- 1H-pyrazino[2,1-a]isoindol—Z—yl]quinolinecarb0nitrile; -[(4R,10bS)[(3R,4R)amin0—4~fluor0-pyrr01idin-1—y1]—4-methy1-3,4,6,10b—tetrahydro- 1H—pyrazino[2, 1 -a]isoindoly1]quinolinecarb0nitrile; -[(4R,10bS)[(3S,4S)amin0—4-fluor0-pyrrolidiny1]methy]—3,4,6,10b-tetrahydro- 1H-pyrazino[2,1-a]isoindol-Z-yl]quinolinecarbonitrile; -[(4R,10bS)—8-[(3R)-3 -,(methoxymethy1)piperaziny1]methy1-3,4,6,1 Ob-tetrahydro— 1H—pyrazino[2,1-a]isoindol-Z—yl]quinolinecarb0nitrile; —[(4R,10bS)—8—(4-amino-4—methy1~1-piperidy1)—4-methy1—3,4,6,10b-tetrahydro-IH- pyrazino[2,1-a]isoindoly1]quinoline-S-carbonitrile; -[(4R,10bS)-8—(3,4a,5,6,7,7a—hexahydr0-2H—pyrro10[3 ,4—b] [1 ziny1)~4-methy1- 3 ,4,6,10b-tetrahydro-1H—pyrazino[2,1-a]isoindol—Z-yl]quinoline—8-carb0nitrile; 5—[(4R,10bS)—8-[(65)-6—hydr0xy—1,4—diazepan—1—y1]methyl-3,4,6,1 0b-tetrahydr0~1H~ pyrazino[2, l -a]isoindoly1]quinolinecarbonitrile; -[(4R,10bS)—8—[(6R)—6—hydr0xy—1,4—diazepany1]methy1—3,4,6,10b—tetrahydro—1H- pyrazin0[2,1-a]isoindol-Z-yl]quinoline-S-carbonitrile; —[(4R,10bS)-8—(6-amin0—1,4-oxazepany1)-4—methyl-3,4,6,10b-tetrahydro-IH- pyrazin0[2,1 indol—Z-yl]quinolinecarbonitrile; —[(4R,10bS)[(6R)amin0-1,4—0xazepan—4-y1]methy1-3,4,6,10b-tetrahydro-1H— pyrazino[2,1-a]isoindol—2-y1]quinoline»8-carbonitrile; —[(4R,10bS)—8-[(6S)—6-amino—1,4-oxazepan—4~y1]—4-methyl-3,4,6,10b-tetrahydro-IH- pyrazino [2, 1 -a]isoind01—2-y1] inecarbonitrile; 5-[(4R,10bS)(6-hydr0xy—6-methy1-1,4-diazepan—1—y1)methy1-3 ,4,6,10b-tetrahydr0- 1H—pyrazino[2,1-a]isoindol—Z-yl]quinoline-8—carbonitrile; -[(4R,10bSD[(6S)hydr0xy—6—methyl-1,4-diazepan—1—yl]methyl-3,4,6,10b~ tetrahydro-1H-pyrazin0[2, 1 -a]isoindol-2 -y1]quinolinecarbonitrile; ,10bS)-8—[(6R)~6—hydroxy-6—methy1-1,4-diazepan-1—y1]—4—methy1-3,4,6,10b- tetrahydro-1H—pyrazin0[2,1-a]isoindol-Z-yl]quin01inecarb0nitrile; -[(4R,10bS)methy1—8—(l ,4-0xazepan-6—y1amino)—3,4,6,1Ob-tetrahydro-1H—pyrazin0[2,1- ndolyl]quinoline-8—carbonitrile; -[(4R,10bS)methy1[[(6R)—1,4-oxazepany1]amin0]-3,4,6,10b-tetrahydro-1H— pyrazino[2,1-a]isoindol-Z-yl]quinoline—S-carbonitrile; -[(4R,1ObS)methy1[[(6S)—1,4-oxazepan-6—y1]amin0]6,4,6,1Ob-tetrahydro-IH- pyrazino[2,1-a]isoind01—2-y1]quinoline-S-carbonitrile; -[(4R,1 0bS)—4—methy1(m0rpholiny11nethy1amino)-3 ,4,6, 1 Ob-tetrahydro—IH— pyrazino[2,1-a]isoindol-Z—yl]quinolinecarb0nitrile; -[(4R,10bS)—4-methy1[[(2S)-morph01iny1]methy1amin0]-3,4,6,1Ob-tetrahydro-IH- pyrazino[2,1—a]isoindoly1]quinoline-S-carbonitrile; -[(4R,10bS)-4~methy1[[(2R)-m0rpholin-2—y1]methylamino]-3,4,6,10b—tetrahydr0—1H- pyrazino[2,1-a]isoindol-Z-yl]quinoline-8—carbonitrile; -[(4R,10bS)[[(35,4R)methoxypyrrolidin-3~yl]amino]-4—methyl-3,4,6,10b— tetrahydro-lH—pyrazin0[2,1-a]isoindol-2—yl]quinoline-S—carbonitrile; —[(4R,10bS)—8—[[(3R,4S)—4—meth0xypyrr01idiny1]amino]—4—methyl—3,4,6,1 Ob- tetrahydro-1H—pyrazino[2,1 ind01—2-yl]quinolinecarbonitrile; -[(4R,10bS)—8~[[(3S,4S)—4-methoxypyrrolidin—3 -y1] amino]methy1~3,4,6, 1 Ob—tetrahydro- 1H—pyrazin0[2,1 -a]isoindoly1]quinoline-S-carbonitrile; ,10bS)—8-[[(3R,4R)—4-methoxypyrrolidin~3 —y1]amino]—4,9-di1nethy1-3,4,6, 10b~ tetrahydro— 1H-pyrazino[2, 1 -a]isoind01y1] quinoline-S—carbonitrile; -[(4R,10bS)-8—[[(35,45)methoxypyrrolidin—3 ~y1]—methy1-amin0]-4—methy1—3,4,6, 1 Ob- tetrahydro-1H—pyrazino[2,1-a]isoindol-Z—yl]quinoline-8—carbonitrile; -[(4R,1ObS)methy1-8—[[(3R)-3~piperidy1]amin0]-3,4,6,1Ob-tetrahydro-lH-pyrazin0[2,1— a]isoindol-Z-yl]quinolinecarb0nitrile; -[(4R,10bS)[[(3S,4R)—3-methoxy-4—piperidy1]amin0]—4-methy1—3 ,4,6,10b-tetrahydro- azin0[2,1-a]isoindol-Z-yl]quinolinecarbonitrile; -[(4R,10bS)methy1~8-(2-morph01inoethylamino)-3,4,6,1 Ob-tetrahydro— 1H- pyrazino[2,1-a]isoindol—Z—yl]quinoline-S-carbonitrile; ,10bS)~8—[2-[(3S)-3—hydroxypyrrolidiny1]ethylamino]-4—methyl~3 ,4,6,10b- tetrahydro—lH—pyrazino[2,1-a]is0indol—2-y1]quinoline-S-carbonitrile; -[(4R,10bS)[(3-flu0roazetidiny1)methy1amino]-4—methy1-3,4,6,10b—tetrahydro—IH— pyrazin0[2,1 -a]isoindol~2-y1]quinolinecarb0nitrile; -[(4R,10bS)—8-[[(2S,4S)flu0r0pyrrolidin-2—yl]methylamino]methy1-3,4,6, 10b— tetrahydro—1H—pyrazin0[2,1—a]isoindoly1]quinoline—S—carbonitri]e; -[(4R,10bS)-8—[(8aS)-3 -0x0—1,5,6,7,8,8a-hexahydroimidaz0[1,5-a]pyrazin-2—y1]methy1- 3 ,4,6,10b-tetrahydro-1H—pyrazin0[2,1-a]isoindol-Z-yl]quinolinecarbonitrile; -[(4R,10bS)—8-H8aR)0xo—1,5,6,7,8,8a—hexahydroimidazo[1,5-a]pyrazin—2—y1]—4- -3,4,6,1 Ob—tetrahydro-1H—pyrazin0[2,1-a]isoind01y1]quinolinecarbonitrile; —[(4R,10bS)-8—[(3S,4S)—4-fluor0pyrrolidin~3-y1]0xy—4-methy1—3,4,6,10b-tetrahydro-IH- pyrazino[2,1-a]isoindol-Z-yl]quinoline-S-carbonitrile; -[(4R,10bS)-8—[[(2S,4S)flu0r0pyrr01idin—2-y1]methoxy]-4—methy1-3,4,6,1Ob—tetrahydro- 1H—pyrazino[2,1-a]isoindol-Z-yl]quinolinecarbonitrile; (4R,10bS)-N-[(3S,4R)—4—fluoropyrrolidin-3—y1]~4—methy1(8—methy1-5—quin01y1)- 3,4,6,10b-tetrahydro-lH-pyrazino[2,1-a]isoindolamine; (4R,10bS)-N-[(3S,4R)—4-flu0r0pyrrolidin-3 -yl]methy1—2—(8—methquuinoxalin—5~y1)~ 3 ,4,6,10b—tetrahydro-1H-pyrazin0[2,1-a]isoind01amine; (4R,1 ObS)-N—[(3S,4R)fluor0pyrrolidin~3~y1]—4-methy1[8-(trifluoromethy1)quinoxalin- 3,4,6,10b~tetrahydro-1H—pyrazin0[2,1-a]isoindol—8-amine; 7-[(4R,10bS)-8—[[(3S,4R)-4—flu0r0pyrr01idin-3~y1]amino]—4—methy1-3 ,4,6,10b-tetrahydro- 1H—pyrazino[2,1-a]isoindoly1]-1,3 -benzothiazolecarbonitri1e; (4R,10bS)(8-chlor0—5-quinoly1)—N-[(3S,4R)fluor0pyrr01idin-3 -y1]—4-methy1— 3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindolamine; 5-[(4R,10bS)-7—[2-[(3S)—3-hydr0xypyrrolidiny1]ethylamin0]—4-methyl-3 ,4,6,10b— ydro- 1H-pyrazino[2, 1 -a]isoind01y1]quin01inecarb0nitrile; -[(4R,10b5)-7~[[(3S,4R)fluoropyrrolidin—3 -y1]amin0]—4—methyl-3,4,6,10b-tetrahydr0— 1H-pyrazino[2,1-a]isoindol—Z-yl]quinolinecarb0nitrile; —[(4R,10bS)—8-[(3R,4R)-4—amin0-3~hydr0xy—3-methy1-pyrrolidin-1 —y1]fluoromethy1- 3,4,6,1 Ob-tetrahydro-1H-pyrazino[2,1 -a]isoindol—Z-y1]quinolinecarbonitrile; -[(4R,10bS)-8—[(3S,4S)-4—amino—3-hydr0xy—3—methy]—pyrr01idin—1~y1]—9—flu0r0—4-methyl- 3 ,4,6,10b-tetrahydro-1H—pyrazino[2,1-a]isoindol-Z-yl]quinolinecarbonitrile; —[(4R, 1 0bS)—8—(2,6—diazaspir0[3 .3]heptan-Z-y1)—9-fluoro—4-methyl-3,4,6,1 Ob—tetrahydro- 1H—pyrazin0[2,1—a]isoindol-Z-y1]quin01inecarb0nitrile; 5-[(4R,10bS)flu0r0-4—methy1(9-oxa—3 ,7—diazabicyclo[3 .3 . 1 ]n0nan—3 ~y1)—3 ,4,6,10b- tetrahydro- 1H-pyrazino[2, 1 -a]isoind01yl]quinolinecarbonitrile; -[(4R,10bS)methy1-8—(piperazine—1 -carbony1)—3,4,6, 1 rahydr0-1H—pyrazino[2, 1 — a]isoindoly1]quinolinecarb0nitrile; —[(4R,10bS)-8—[(1S,4S)-2,5—diazabicyclo[2.2. 1]heptanecarb0ny1]methy1-3 ,4,6,10b- ydro-1H—pyrazino[2,1-a]isoindol-Z—yl]quinoline-8—carb0nitrile; -[(4R,10bS)-8—(4-aminomethy1-piperidine—1—carbony1)methyl-3 ,4,6,10b-tetrahydro- azino[2,1-a]isoind01y1]quinoline-S-carb0nitrile; ,10bS)-8—(3,8-diazabicyclo[3.2.1]octane—3-carb0ny1)methy1-3,4,6,10b-tetrahydro- 1H—pyrazino[2,1—a]isoindol-Z-yl]quinoline—8-carb0nitrile; -[(4R,1ObS)-4—methy1(5—0xa—2,8—diazaspir0[3.5]nonan-2—yl)-3 0b-tetrahydro—1H— pyrazino[2, 1 -a]isoind01-2—y1]—2-deuterio-quinoline—8-carb0nitrile; ~[(4R,10bS)—8—[[(3S,4R)—4-flu0r0pyrr01idiny1]amino]—4—methyI-3,4,6,10b—tetrahydr0- 1H—pyrazin0[2,1-a]isoindol-Z-yl]deuteri0-quinoline-8—carbonitrile; —[(4R,10bS)—8-(3 -amino-3~methyl—azetidiny1)~4—methy1—3 ,4,6,10batetrahydro-1H- pyrazino[2,1-a]isoindolyl]-2—deuterio-quinolinecarbonitrile; -[(4R,10bS)methy1—8—(9-oxa-3 ,7-diazabicyclo [3 .3. 1 ]nonan-3 -y1)-3 ,4,6,10b-tetrahydro— 1H-pyrazino [2, 1 -a]isoindoly1] deuteri0-quinolinecarb0nitrile; 4-[(4R,1ObS)~8—[(3R,4R)—3-aminometh0xy—pyrrolidin-1~y1]—4-1nethy1—3,4,6,1Ob- tetrahydro-1H-pyrazino[2, 1-a]isoindol-Z-yl]pyrazolo[1,5-a]pyn'dine-7—carbonitrile; 4—[(4R,10bS)[(3S,4S)a1nin0—4—methoxypyrrolidiny1]—4—1nethy1~3,4,6,10b- tetrahydro-lH—pyrazino[2,1-a]isoindol-Z-yl]pyrazolo[1,5-a]pyridinecarbonitrile; 4-[(4R,1ObS)—8-[(3R)-3—aminopyrrolidiny1]-4—1nethy1-3,4,6,1Ob—tetrahydro-1H— pyrazino[2,1-a]isoindoly1]pyrazolo[1,5-a]pyridinecarbonitrile; 4-[(4R,10bS)methy1—8—[(3R)methylpiperazin—1-y1]—3,4,6,10b-tetrahydro-IH- pyrazino[2,1-a]isoindol-Z-yl]pyrazolo[1,5-a]pyridinecarb0nitrile; 4-[(4R,10bS)-8—[[(3S,4R)—4-fluoropyrrolidiny1]amino]—4-methy1-3 ,4,6,10b-tetrahydr0- 1H-pyrazino[2,1-a]isoindol-Z-yl]pyrazolo[1,5-a]pyridinecarbonitri1e; 4-[(4R,10bS)-8—[(312,4S)aminofluoro-pyrr01idin-1 ~y1]—4—methy1-3 ,4,6,10b-tetrahydro- 2O 1H—pyrazino[2,1-a]isoindol-Z-y1]pyrazolo[1,5-a]pyridinecarbonitrile; 4-[(4R,10bS)-8—(4-amino-4~methylpiperidy1)methy1—3 ,4,6,10b-tetrahydro-1H- no[2,1-a]isoindol-Z-y1]pyrazolo[1,5-a]pyridine—7-carb0nitrile; 4—[(4R,10bS)—8-[(6R)amino~1,4-0xazepan—4—y1]—4-methy1-3 ,4,6, 1 Ob—tetrahydro— 1H- pyrazin0[2,1-a]isoindol—Z-yl]pyrazolo[1,5—a]pyridine-7—carbonitri1e; 4—[(4R,10bS)—4-methy1—8-(5—oxa—2,8-diazaspiro[3.5]nonan-2»yl)-3 ,4,6,10b-tetrahydro-1H- pyrazin0[2,1-a]isoindol—2-y1]pyrazolo[1,5—a]pyridine-7—carbonitrile; ,10bS)[(3R)-3—amino—3~methy1-pyrrolidin—1-y1]methy1-3 0b—tetrahydro— 1H—pyrazino[2,1-a]isoind01yl]pyrazolo[1,5-a]pyridine—7—carb0nitrile; 4-[(4R,10bS)[(3R,4R)amin0—3-meth0xy—1~piperidy1]methy1-3 ,4,6,10b—tetrahydro~ 1H—pyrazino[2,1 -a]isoindolyl]pyrazolo[I ,5-a]pyridinecarbonitrile; 4-[(4R,10bS)[(3R,4S)—4-amin0—3—methoxy-1—piperidy1]—4-methy1-3 ,4,6,10b-tetrahydr0- 1H-pyrazino[2,1-a]isoind01-2—yl]pyrazolo[1,5-a]pyridinecarbonitrile; ,1 0bS)-8—[(3R,4S)amino-4—methoxypiperidy1]—4-1nethyl-3 ,4,6,10b-tetrahydro- 1H—py1‘azino[2,1-a]isoindol-2—y1]pyrazolo[1,5-a]pyridinecarb0nitri1e; -3 0- 4-[(4R,10bS)—4-methyl(9-oxa-3,7-diazabicyclo[3.3.l]nonan—3—y1)—3,4,6,lOb-tetrahydro— lH-pyrazino[2,1-a]isoindol-2—yl]pyrazolo[1,5-a]pyridinecarbonitrile; 4-[(4R, l 0bS)—8—[(3R,4R)—4-aminohydroxy—3 -methyl-pyrrolidin—l -yl]—4—methyl- 3 ,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-Z-yl]pyrazolo[1 ,5-a]pyridine—7-carbonitrile; 4—[(4R_,l 0bS)[(3S,4S)a1nino-3—hydroxy-3—methyl—pyrrolidin— l -yl] methy1- 3,4,6,10b-tetrahydro—lH-pyrazino[2,1 -a]isoindol-Z-yl]pyrazolo[l,5-a]pyridinecarbonitrile; 4-[(4R,10bS)—8—[(3R,4R)—3—aminohydroxy-pyrrolidin-l -yl]—4—methy1-3,4,6,1 0b- tetrahydro—lH—pyrazino[2,1-a]isoindol-Z-yl]pyrazolo[l ,5-a]pyridinecarbonitrile; 4—[(4R, l 0bS)—8~[(3S,4S)-3—amino—4-hydroxy-pyrrolidin—l -yl]—4-methyl-3 0b— tetrahydro-lH—pyrazino[2,1-a]isoindol-Z-yl]pyrazolo[1,5—a]pyridine—7—carbonitrile; 4-[(4R, l 0b5)[(3S,4S)amino~3—hydroxy—3-methy1~pyrrolidin-l -yl]—4-methyl- 3,4,6, 1 Ob-tetrahydro— 1 H-pyrazino[2, l -a]isoindolyl]—3 -pyrazolo[l ,5-a]pyridine-7— carbonitrile; and 4-[(4R, 1 0bS)[(3R,4R)-3—a1ninomethoxy-py1rolidin-l-y1]methyl-3,4,6,1 Ob- tetrahydro-1H—pyrazino[2,1-a]isoindoly1]—3-fluoro-pyrazolo[l,5~a]pyridine-7—carbonitrile; or a pharmaceutically acceptable salt, enantiomer or diastereomer f.

SYNTHESIS The nds of the present ion can be prepared by any tional means.

Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular, R] to R6 are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction ions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.

A general synthetic route for preparing the compound of formula (I) is shown in Scheme 1 below.

Scheme] II? Rs 8 Re If 9 9 I :I,——. IV—— IV —OH R/HVR o N R o N R N R9 R2 2 HN HN H2N R Iv HZN R2 IV v VI o o I FIRB N R9 'I 'I F? N N X—-R1 N XIII _—._... l 2 2 l2 N R l N R —‘ N R R R3 6 R3 (R n R4 (R n R4 (R (R )m )m xn I wherein X is halogen or g group, for example, OH or OMs; m is O, l, 2, or 3; n is l, 2, 3 or 4; m+nS4; R7 and R8 are protecting groups, for e, R7 is Boc and R8 is benzyl; R9 is alkylsilyl, for example, trimethylsilyl.

The amide coupling of protected amino acid (11) and silylamine (III) can be achieved using coupling reagents, such as HATU and DIPEA, to afford intermediate (IV). After R7 is removed by selective ection, the amide bond in the resulting intermediate (V) can be reduced under reductive conditions, such as treatment of LAH, to afford diamine (VI). Imine (VIII), which can be formed by condensation of aldehyde (VII) and diamine (VI) under typical dehydration conditions, is cyclized under photo-redox ions, which is catalyzed by blue light and Ir— based catalyst, such as [Ir(dtbbpy)(ppy)2][PF6], to afford lic lactam (IX). When d with reducing reagent, such as LAH, lactam (IX) can be reduced to compound of formula (X), in which both R3 and R4 are hydrogen atoms. Alternatively, lactam (IX) can also be treated with dimethyl titanocene, then reduced by hydrogenation to install an alkyl group at R3 or R4.

Compound of formula (X) can be used as a common intermediate for further functionalization under metal catalyzed coupling conditions, such as Buchwald-Hafiwig amination, Suzuki coupling, Negishi coupling, Stille coupling, or Pd-catalyzed C=O insertion. For example, under -3 2- Buchwald-Hartwig amination conditions (ref: Acc. Chem. Res. 1998, 31, 805-818; Chem. Rev. 2016, 116, 12564-12649; Topics in Current Chemistry, 2002, 219, 9; and references cited therein) with a catalyst, such as Ruphos Pd—G2, and a base, such as CszCO3, compound of formula (XI) can be generated from compound of formula (X). After selective deprotection of R8 group under typical ions (6.g. removal of benzyl protecting group by hydrogenation over catalytic amount of Palladium on carbon), the resulting compound of formula (XII) can be submitted to nucleophilic aromatic substitution conditions (6.g. heating with halide (XIII) in the ce of DIEPA in DMSO), or Buchwald-Hartwig amination conditions (6.g. g with halide (XIII) in the presence of a catalyst, such as Ruphos Pd-G2, and a base, such as CszCO3, to afford compound of formula (I). In some embodiment, the compound of a (XII) may contain a protecting group, e.g. Boc, which will be removed before affording the final compound of formula (1).

Scheme 2 x——R1 N -——> l2 N R (R n R4 (x )m (X)m .____. Ml N R2 (R R“ After R8 is removed from formula (X) by selective deprotection, the resulting nd of formula (XIV) can react with halide (XIII) to afford compound of formula (XV) by nucleophilic aromatic substitution in the presence of a base, such as DIEPA. nd of formula (I) can be ed from compound of formula (XV) via metal catalyzed coupling conditions: Buchwald- Hartwig amination in the presence of a catalyst, such as Ruphos Pd-G2, and a base, such as CszC03; Suzuki coupling with boronic acid, boronic ester, or potassium trifluoroborate, in the ce of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [l,l‘- bis(diphenylphosphino)ferrocene]dichloropalladium (ll), complex with dichloromethane and a base, such as potassium carbonate in solvent; Stille coupling with organotin reagent, in the presence of a palladium(0) catalyst, such as is(triphenylphosphine)palladium(0); or Negishi W0 2019/233941 coupling with organozinc reagent in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1 '—bis(diphenylphosphino)ferrocene] dichloropalladium (II). In some embodiment, the compound of a (XII) may contain a protecting group, e.g. Boc, which will be removed before affording the final compound of formula (1).

Compounds of this invention can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or SFC.

This invention also relates to a process for the preparation of a compound of formula (I), (la) or (lb) comprising any of the ing steps: a) the substitution reaction of compound of formula (XII), (R )m (:XH)7 and halide (XIII) in the presence of a base; b) the Buchwald—Hartwig amination reaction of compound of a (XII), (R )m (X11), and halide (XIII) in the presence of a st and a base; c) the Buchwald-Hartwig ion reaction of compound of formula (XV), N R2 (R n R4 (XV), and halide (XIII) in the presence of a catalyst and a base; d) the Suzuki coupling reaction of compound of formula (XV), Nj\R2 (R n R4 ( X )m (XV), and boronic reagent in the presence of a catalyst and a base; 6) the Stille coupling reaction of nd of formula (XV), (R n R4 (XV), and organotin reagent in the presence of a catalyst; f) the i coupling reaction of compound of formula (XV), (R n R4 ( X )m (xv), and organozinc t in the presence of a catalyst; wherein, in step a), the base can be, for example, DIPEA; in step b) and c), the catalyst can be, for example, Ruphos Pd-G2; the base can be, for example, CszC03; in step d), the catalyst can be, for example, tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II); the base can be, for example, K2CO3; in step e), the catalyst can be, for example, tetrakis(triphenylphosphine)palladium(0); in step t), the catalyst can be, for example, is(triphenylphosphine)palladium(0) or [ 1 , l '-bis(diphenylphosphino)ferrocene] dichloropalladium (II).

A compound of formula (I), (la) or (lb) when manufactured according to the above process with achiral or chiral starting materials is also an object of the invention.

INDICATIONS AND METHODS OF TREATMENT The present invention provides compounds that can be used as TLR7 and/or TLR8 and/or TLR9 antagonist, which inhibits pathway activation through TLR7 and/or TLR8 and/or TLR9 as well as respective downstream biological events including, but not d to, innate and adaptive immune ses mediated through the production of all types of cytokines and all forms of auto-antibodies. Accordingly, the compounds of the ion are useful for blocking TLR7 and/or TLR8 and/or TLR9 in all types of cells that s such receptor(s) including, but not limited to, plasmacytoid dendritic cell, B cell, T cell, macrophage, monocyte, neutrophil, keratinocyte, epithelial cell. As such, the compounds can be used as a therapeutic or prophylactic agent for systemic lupus erythematosus and lupus tis.

The present invention provides s for treatment or prophylaxis of systemic lupus erythematosus and lupus nephritis in a patient in need thereof. r embodiment includes a method of treating or preventing systemic lupus erythematosus and lupus tis in a mammal in need of such treatment, wherein the method -3 6- comprises administering to said mammal a eutically effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug or phannaceutically acceptable salt thereof.

EXAMPLES The invention will be more fully understood by reference to the ing examples. They should not, however, be construed as limiting the scope of the invention.

ABBREVIATIONS The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.

Abbreviations used herein are as follows: ACN: itrile B0020: di-tert—butyl dicarbonate TfZO: triflic anhydride DCM: dichloromethane DDI drug-drug-interaction DIPEA diethylisopropylamine DMA ylacetamide BA or EtOAc: ethyl acetate FA: formic acid HATU 1 -[Bis(dimethylamino)methylene]—1H-1,2,3 - triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate HLM human liver ome hr hour hrs hours lC50: half inhibition concentration LCMS liquid chromatography-mass spectrometry LYSA lyophilisation solubility assay MS: mass spectrometry PE: petroleum ether prep—HPLC: preparative high performance liquid chromatography rt: rt RT: retention time RuPhos Pd G2: chloro(2-dicyclohexylphosphino-2’,6'-diisopropoxy—l ,l ’- yl)[2-(2’-amino-1 ,1 ’-biphenyl)]palladium(ll) 2nd generation SFC: supercritical fluid chromatography WO 33941 TFA: trifluoroacetic acid v/v volume ratio GENERAL EXPERIMENTAL CONDITIONS Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and the Quad 12/25 Cartridge module. ii) ISCO combi-flash tography instrument. Silica gel brand and pore size: i) KP-SIL 60 A, particle size: 40-60 pm; ii) CAS registry NO: Silica Gel: 632314, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical C0,, Ltd, pore: 200300 or 300-400. ediates and final compounds were d by preparative HPLC on reversed phase column using XBridgeTM Prep-C18 (5 um, OBDTM 30 X 100 mm) column, SunFireTM 18 (5 um, OBDTM 30 X 100 mm) column, Phenomenex Synergi-Cl8 (10 um, 25 X 150 mm) or Phenomenex Gemini—C18 (10 um, 25 X 150 mm). Waters AutoP purification System (Sample Manager 2767, Pump 2525, Detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% um hydroxide in water; acetonitrile and 0.1% FA in water or acetonitrile and 0.1% TFA in water). Or Gilson-281 purification System (Pump 322, Detector: UV 156, solvent system: acetonitrile and 0.05% ammonium ide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water).

For SFC chiral separation, intermediates were ted by chiral column (Daicel chiralpak IC, 5 pm, 30 X 250 mm), AS (10 um, 30 X 250 mm) or AD (10 um, 30 >< 250 mm) using Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC or Thar 80 preparative SFC, solvent system: C02 and IPA (0.5% TEA in IPA) or C02 and MeOH (0.1% NH3'H20 in MeOH), back pressure 100bar, detection UV@ 254 or 220 nm.

LC/MS spectra of compounds were obtained using a LC/MS (WatersTM Alliance 2795— Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ or Agilent Alliance 6110-Micromass ZQ), LC/MS conditions were as follows (running time 3 or 1.5 mins): Acidic condition I: A: 0.1% TFA in H20; B: 0.1% TFA in acetonitrile; Acidic condition 11: A: 0,0375% TFA in H20; B: 0.01875% TFA in acetonitrile; Basic condition I: A: 0.1% 0 in H20; B: acetonitrile; Basic condition II: A: 0.025% NH3-H20 in H20; B: acetonitrile; Neutral condition: A: H20; B: acetonitrile.

Mass spectra (MS): lly only ions which te the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (MH)+.

W0 2019/233941 -38— NMR Spectra were obtained using Bruker Avance 400 MHz.

The microwave assisted reactions were d out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Reagents were used as received from cial ers without further purification unless otherwise noted.

PREPARATIVE EXAMPLES The following examples are intended to illustrate the meaning of the present invention but should by no means represent a limitation within the meaning of the present invention: Example 1 —[(4R,10bS)-4—methyl-S-piperazinyl—3,4,6,10b-tetrahydro-lH-pyrazino[2,1-a]isoindol—2- noline-S-carbonitrile The title compound was prepared according to the following scheme: Zn(CN))Ru:hos Pd G2 \ / / 70%HZSO4 OH Q/HwéNSV \F/Ql3/ M | L'A'H4 NS\/\ ————-——-—-—-——. OIVSKN - W / N 4/ HN HATU,D|EA THF A0 DMF,rt > LV \ 1 HZN 1d 19 1f 19 o o Br S[|r(dtbbpy)(ppy)2]P Fe NI N ——.7——. BHS/THF 4A molecular steves, ’lip/m\ _..__._.___..

CHSCN E (9: 1) N N Br 0\ blue light Br Br 1h 1i 1i (\NH Q >r ‘n’ N 0 1c Pd-C/H2 _.____.__....__.

XPhos Pd (53 052003 MBOH DIEA, DMSO dioxane, 80°C {(51.3 O 76‘ H N H ‘ ij TFA/DCM N ——-.~—————. Nj\ 1m Example 1 Step 1: preparation of 8—bromofluoro~quinoline (compound 1b) In a 100 mL haped flask, 2-bromofluoroaniline (2.0 g, 10.5 mmol), e-1,2,3- triol (969 mg, 10.5 mmol) and sodium 3-nitrobenzenesulfonate (2.4 g, 10.5 mmol) were combined with 70% H2804 (20 mL) to afford a dark brown solution, which Was heated to 150 0C and stirred for 3 hrs. After cooled to room temperature, the reaction e was poured into ice- water, and lized with sodium hydroxide solution. The resultant mixture was filtered. The filter cake was dissolved in EtOAc and filtered. The resultant filtrate was concentrated in vacuo.

The crude material was purified by flash tography (silica gel, 40 g, 0% to 30% EtOAc in PE) to afford compound lb (2.0 g, 84% yield). MS: calc’d 226 and 228 [(M+H)+], measured 226 and 228 [(M+H)+].

Step 2: preparation of S-fluoroquinoline—8—carbonitrile (compound 1c) To a solution of 8-bromo-5—fluoroquinoline (compound lb, 4.9 g, 21.7 mmol) in DMF (30 mL) was added dicyanozinc (5.0 g, 43.4 mmol) and RuPhos Pd 62 (CAS: 1375325—68-0, Aldrich, g: 753246, 842 mg, 1.1 mmol). The reaction mixture was stirred at 100 0C for 3 hrs, then cooled to room temperature. The reaction mixture was filtered and the filtrate was diluted with water (50 m1), then extracted with BA (80 mL) for three times. The combined organic layer was washed with brine, dried over Na2804, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 40 g, 0% to 70% EtOAc in PE) to afford compound 1c (3.0 g, 80 % yield). MS: calc’d l73 [(M+H)+], measured l73 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 5 ppm 9.11 (dd, J: 4.28, 1.71 Hz, 1 H), 8.64 (dd, .1: 8.56, 1.71 Hz, 1 H), 8.29 (dd, J: 8.19, 5.62 Hz, 1 H), 7.76 (dd, J: 8.56, 4.28 Hz, 1 H), 7.49 (dd, J: 9.35, 8.25 Hz, 1 H).

Step 3: ation of tert-butyl N-[(1R)—2-[benzyl(trimethylsilylmethyl)aminoI—l— methyl-Z-oxo-ethyl]carbamate (compound 1e) To a solution of (2R)—2—(tert—butoxycarbonylamino)propanoic acid (10.0 g, 52.9 mmol) in DMF (40 mL) was added N-benzyl—l—(trimethy1silyl)methanamine (10.2 g, 52.9 mmol), HATU (20.1 g, 52.9 mmol) and DIEA (13.6 g, 18.4 mL, 105.8 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (150 mL), and ted with DCM (100 mL) for three times. The combined organic layer was washed with brine, dried over Na2804, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 40 g, 0% to 30% EtOAc in PE) to afford compound 1e (13.1 g, 68 % yield). MS: calc’d 365 [(M+H)+], measured 365 [(M+H)+].

Step 4: preparation of (2R)amino—N—benzyl-N-(trimethylsilylmethyl)-propanamide (compound 11) To a solution of tert—butyl N-[(1R)[benzyl(trimethylsilylmethyl)amino]~l~1nethyl—2—oxo- ethyl]carbamate (compound 1e, 13.0 g, 35.7 mmol) in DCM (60 mL) was added TFA (10 mL).

The resultant mixture was stirred at room ature for 4 hrs, then concentrated in vacuo, and the residue was partitioned n sat. NaHCO3 (aq.) and EA. The c layer was separated and the basic aqueous layer was extracted with BA (80 mL) twice. The combined organic layer was dried over Na2804, filtered and concentrated in vacuo to afford compound 1f (91 g, 96 % yield) without further purification. MS: calc’d 265 [(M+H)+], measured 265 [(M+H)+].

Step 5: preparation of (2R)-N1-benzyl-N1-(trimethylsilylmethyl)propane-1,2-diamine (compound 1g) To an ice—cooled solution of (2R)amino-N-benzyl-N—(trimethylsilylmethyl)-propanamide (compound 1f, 9.0 g, 34.0 mmol) in anhydrous THF (100 mL) was added LiAlH4 (3.9 g, 102.0 mmol) slowly. After the addition was completed, the mixture was heated under reflux overnight, then cooled to room temperature and quenched with NaOH (10 mL, 20% aq. solution) before filtered and washed with EtOAc. The combined filtrate was concentrated in vacuo to afford compound 1g (5.7 g, 67% yield) without further purification. MS: calc’d 251 +], measured 251 [(M+H)+].

Step 6: preparation of bS)benzyl-S-bromomethyl-1,3,4,10b- ydropyrazino[l,2-b]isoindolone (compound 1i) A mixture of the (2R)-N1-benzyl—Nl-(trimethylsilylmethyl)propane-l,2—diamine (compound 1g, 3.0 g, 12.0 mmol), methyl 5-bromo—2-formylbenzoate (2.9 g, 12.0 mmol), and 4A MS (5.0 g) in MeCN (80 mL) under N2 was stirred overnight at room temperature. The reaction mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated in vacuo and the residue was re-dissolved in MeCN/TFE (45 mL/5 mL), followed by the addition of [lr(dtbbpy)(ppy)2][PF(,] (CAS: 6765252, TCI, Catalog: D4887, 109 mg, 120 umol). The reaction was d at room temperature under the exposure of blue LEDs (synLED—l6 A Discover, 12 W, wavelength 465-470 nm, purchased from SYNLED corp.) for 2 days. After the solvents were removed in vacuo, the residue was purified by flash chromatography (silica gel, 80 g, 20% to 70% BA in PE) to afford compound 1i (1.8 g, 42 % yield). The stereochemistry was ed by NOESY. MS: calc’d 371 and 373 [(M+H)+], measured 371 and 373 [(M+H)+]. 1H NMR (400 MHZ, METHANOL-d4) (5 ppm 7.75 (d, J: 1.71 Hz, 1 H), 7.63 (dd, J: 8.01, 1.77 Hz, 1 H), 7.19 - 7.35 (m, 6 H), 4.43 (dd, J: 10.88, 3.67 Hz, 1 H), 3.67 - 3.86 (in, 1 H), 3.56 (s, 2 H), 3.41 - 3.45 (m, l H), 2.79 - 2.87 (m, 1 H), 1.86 (t, J: 11.07 Hz, 1 H), 1.67 (d, J: 6.97 Hz, 3 H), 1.64 (t, J: 11.07 Hz, 1 H).

Step 7: preparation of (4R,10bS)benzyl—8-bromomethyl—3,4,6,10b-tetrahydro- 1H-pyrazino[2,l-a}isoindole (compound lj) A mixture of (4R,10bS)—2—benzyl-8—bromo—4—methyl-1,3,4,10b-tetrahydropyrazino[l,2- b]isoindol—6—one (compound 1i, 1.9 g, 5.0 mmol) and BH3 solution (1M in THF, 40 mL, 40 mmol) was stirred at 80 0C for 5 hrs. HCl solution (6 N, 10 mL) was added slowly to the reaction mixture at 0 0C. The ant mixture was stirred at room temperature overnight, then d with a NaOH solution (2 N) to pH 10. The mixture was extracted with EtOAc twice, and the combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography a gel, 40 g, 30% to 100% EtOAc in PE) to afford compound lj (1.5 g, 85 % yield). MS: calc’d 357 and 359 [(M+H)+], measured 357 and 359 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 5 ppm 7.49 (s, 1 H), 7.32 - 7.43 (m, 5 H), 7.26 - 7.32 (m, 1 H), 7.05 (d, J= 7.95 Hz, 1 H), 4.18 (d, J= 12.59 Hz, 1 H), 3.71 (br d, J: 10.51 Hz, 1 H), 3.55 (dd, J: 12.47, 2.32 Hz, 1 H), 3.36-3.31(m, l H), 2.97-2.89(m, 1 H), 2.77 - 2.87 (m, 1 H), 2.12 (t, J== 10.64 Hz, 1 H), 2.00 (t, 4 Hz, 1 H), 1.14 (d, J: 6.48 Hz, 3 H).

Step 8: preparation of tert-butyl 4-[(4R,10bS)benzylmethyl-3,4,6,10b- tetrahydro-lH—pyrazino[2,]-a]isoindolyl]piperazine-l-carboxylate (compound 1k) To a solution of (4R,10bS)—2-benzyl—8~bromo—4-methyl—3,4,6,l0b-tetrahydro-lH— pyrazino[2,1-a]isoindole (compound lj, 0.4 g, 1.1 mmol) in e (15 mL) was added tert- butyl piperazine—1-carboxylate (209 mg, 1.1 mmol), CszC03 (365 mg, 1.1 mmol) and XPhos Pd G3 (CAS: 14450851, BePharm, g: D449923, 94.8 mg, 0.1 mmol). The reaction e was stirred at 80 0C overnight, then cooled to room temperature, diluted with water (50 mL) and extracted with EA (50 mL) for three times. The combined organic layer was washed with brine, dried over Na2304, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 40 g, 0% to 100% EtOAc in PE) to afford compound 1k (420 mg, 81.1 % yield). MS: calc’d 463 [(M+H)+], measured 463 [(M+H)+].

Step 9: preparation of utyl 4—l'(4R,10bS)methyl—1,2,3,4,6,10b- hexahydropyrazino[2,l-a]isoindol—8-yl]piperazinc—l-carboxylate (compound 11) A mixture of tert—butyl 4-[(4R,10bS)—2~benzy1—4—methy1—3,4,6,10b-tetrahydro—lH- pyrazino[2,1-a]isoindol-S—yl]piperazine—1-carboxylate und 1k, 240 mg, 519 umol) and Pd-C (16.6 mg, 156 umol) in MeOH (20 mL) was hydrogenated with a hydrogen balloon at room temperature for 5 hrs. After the catalyst was filtered off, the filtrate was concentrated in vacuo to afford compound 11 (181 mg, 94 % yield) which was used directly for the next step without further purification. MS: calc’d 373 [(M+H)+], measured 373 [(M+H)+].

Step 10: preparation of tert—butyl 4-[(4R,10bS')(8—cyano-S-quinolyl)methyl- 3,4,6,10b-tetrahydro—lH—pyrazino[2,1-a]isoindol-8—yl]piperazine—l-carboxylate (compound 1m) To a solution of 5-fluoroquinolinecarbonitrile (compound 1c, 20.1 mg, 112 umol) in DMSO (3 mL) was added tert—butyl 4—[(4R,10bS)~4~methyl-1 ,6,10b- hexahydropyrazino[2,1-a]isoindolyl]piperazinecarboxylate (compound 11, 42 mg, 112 umol) and DIEA (73 mg, 560 umol). The on mixture was stirred at 120 0C for 5 hrs. After cooled to room temperature, the reaction was quenched with water (30 mL) and extracted with EA (50 mL) twice. The combined organic layer was washed with brine, dried over NaZSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 0% to 100% EtOAc in PE) to afford compound 1m (41 mg, 68 % yield). MS: calc’d 525 +], measured 525[(M+H)+].

Step 11: preparation of 5-[(4R,10bS)methylpiperazinyl-3,4,6,10b-tetrahydro- lH-pyrazino[2,1-a]isoindol-Z-yl]quinoline-S-carbonitrile (Example 1) To a solution of tert—butyl 4-[(4R,10bS)—2-(8-cyanoquinolyl)—4-methy1-3,4,6,10b- tetrahydro-1H—pyrazino[2,1-a]isoindolyl]piperazinecarboxylate (compound 1m, 100 mg) in DCM (10 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for min, then trated to afford a crude t, which was d by prep-HPLC to afford Example 1 (33 mg, 77 %). MS: calc’d 425[(M+H)+], measured 425[(M+H)+]. IH NMR (400 MHz, METHANOL—d4) 6 ppm 9.02 (dd, J: 4.22, 1.53 Hz, 1 H), 8.73 (dd, J: 8.56, 1.59 Hz, 1 H), 8.18 (d, J: 8.07 Hz, 1 H), 7.71 (dd, J: 8.56, 4.28 Hz, 1 H), 7.35 (d, J: 8.07 Hz, 1 H), 7.14 (d, J: 8.31 Hz, 1 H), 7.06 (s, 1 H), 6.88 (dd, J: 825, 2.02 Hz, 1 H), 4.29 (d, J: 12.10 Hz, 1 H), 4.10 (br d,J=10.51Hz, 1 H), 3.89 (br d, J: 11.49 Hz, 1 H), 3.70 (br (1, J== 11.86 Hz, 1 H), 3.46 (br (1, J: 11.74 Hz, 1 H), 3.34—3.38 (m, 1H), 3.07 — 3.19 (m, 4 H), 2.94 - 3.05 (m, 5 H), 2.73 - 2.92 (m, 1 H), 1.28 (d, J: 6.48 Hz, 3 H).

Example 2 -[(4S,10bR)methyl-S-piperazinyl-3,4,6, 1Oh-tetrahydro-1H-pyrazino[2,1-a]isoindol-Z- yl]quinoline—8-carbonitrile The title compound was prepared in y to the preparation of Example 1 by using (2.5')—2-(tert-butoxycarbonyla1nino)propanoic acid instead of (2R)—2-(tert- butoxyearbonylamino)propanoic acid (compound 1d). Example 2 (12 mg) was obtained. MS: calc’d 425[(M+H)+], measured 425[(M+H)+]. 1H NMR (400 MHz, METHANOL—a’4) 5 ppm 9.02 (dd, J= 4.28, 1.59 Hz, 1 H), 8.72 (dd, .1: 8.56, 1.47 Hz, 1 H), 8.19 (d, J = 7.95 Hz, 1 H), 7.72 (dd, J: 8.56, 4.28 Hz, 1 H), 7.35 (d, J: 8.07 Hz, 1 H), 7.14 (d, J: 8.3] Hz, 1 H), 7.05 (s, 1 H), 6.87 (dd, J= 8.31, 1.96 Hz, 1 H), 4.23 - 4.25 (m, 1 H), 4.28 (d, J=12.10 Hz, 1 H), 4.09 (br (1, .1: .51 Hz, 1 H), 3.88 (br (1, .1: 11.37 Hz, 1 H), 3.70 (br d, J: 11.98 Hz, 1 H), 3.45 (br d, J: 11.25 Hz, 1 H), 3.34-3.38 (m, 1H), 3.07 - 3.18 (m, 4 H), 2.96 - 3.06 (m, 5 H), 2.79 - 2.91 (In, 1 H), 1.28 (d, J: 6.36 Hz, 3 H).

Example 3 -(8-piperazinyl-3,4,6,10b-tetrahydro-lH-pyrazino[2,1-a]isoindol—Z-yl)quinoline carbonitrile W0 2019/233941 The title compound was ed in analogy to the preparation of Example 1 by using 2- (z‘ert-butoxycarbonylamino)acetic acid instead of (2R)(tert-butoxycarbonylamino)-propanoic acid (compound 1d). Example 3 (19.7 mg) was obtained. MS: calc’d 411[(M+H)+], ed 411 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 5 ppm 9.05 (dd, .1 = 4.28, 1.59 Hz, 1 H), 8.71 (dd, J: 8.62, 1.53 Hz, 1 H), 8.21 (d, J= 8.07 Hz, 1 H), 7.72 (dd, J: 8.68, 4.28 Hz, 1 H), 7.42 (dd, J: 8.25, 4.71 Hz, 2 H), 7.23 (s, 1 H), 7.13 (dd, J= 8.44, 2.08 Hz, 1 H), 5.31 (dd, J: 8.50, 4.46 Hz, 1 H), 4.91-4.96 (1n, 1H), 4.76 - 4.84 (1n, 1 H), 3.95 — 4.06 (m, l H), 3.87 (br d, J: .41 Hz, 1 H), 3.78 (br d,J= 13.33 Hz, 1 H), 3.37 - 3.64 (m, 11 H).

Example 4 7-(8—piperazin—1-yl—3,4,6,10b-tetrahydro-lH-pyrazino[2,1-a]isoindolyl)—1,3- benzothiazole-4—carbonitrile The title compound was prepared in analogy to the preparation of Example 3 by using 7- fluoro-l,3-benzothiazole-4—carbonitrile instead of 5-fluoroquinoline-8—carbonitrile (compound 1c). Example 4 (15 mg) was obtained. MS: calc’d 417 [(M+H)+], measured 417 [(M+H)+]. lH NMR (400 MHZ, METHANOL-d4) 0‘ ppm 9.46 (s, 1 H), 7.95 (d, J = 8.19 Hz, 1 H), 7.45 (d, J = 8.44 Hz, 1 H), 7.26 (d, J: 8.19 Hz, 1 H), 7.21 (s, 1 H), 7.13 (dd, J: 8.44, 2.20 HZ, 1 H), 5.19 (br s, 1 H), 4.81 (s, 2 H), .10 (m, 1 H), 3.76 - 3.92 (m, 1H), 3.55-3.65 (m, 2 H), 3.45 - 3.53 (m, 5 H), 3.37 - 3.44 (m, 5 H).

W0 2019/233941 —46- Example 5 4-[(4R,10bS)methyl—S-piperazinyl-3,4,6,1 Ob-tetrahydro-1H-pyrazino[2,1-a]isoindol-Z- yl] pyrazolo[1,5-a] pyridine-7—carbonitrile The title compound was prepared according to the following scheme: NN]\ / N’N\ N’N\ / \ \\ / N’N\ \ \\ \ \\ TFA/DCM RuPhos Pd 62 (—N CSZCOS, dioxane +9 NO 53 Example 5 Step 1: preparation of tert-butyl 4-[(4R,10bS)—2-(7-cyanopyrazolo[1,5—a]pyridinyl)— 4-methyl—3,4,6,10b-tetrahydro-lH-pyrazino[2,1-a]isoindol—8—yl]piperazine—l—carboxylate (compound 53) To a on of tert-butyl 4-[(4R,10bS)methyl-l,2,3,4,6,10b-hexahydropyrazino[2,l- a]isoindol-8—y1]piperazinecarboxylate (compound 11, 42.0 mg, 113 umol) in dioxane (5 mL) was added 4—chloropyrazolo[1,5-a]pyridinecarbonitrile (20 mg, 113 umol), RuPhos Pd G2 (CAS: 13753250, Sigma-Aldrich, Catalog: 753246; 8.7 mg, 11.3 umol) and CszC03 (110 mg, 338 umol). The reaction mixture was stirred at 90 0C for 20 hrs, then cooled to room temperature, diluted with water (20 mL), and ted with EA (30 mL) for three times. The combined organic layer was washed with brine, dried over , filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 0% to 100% EtOAc in PE) to afford compound Sa (15 mg, 26 % yield). MS: calc’d 514 [(M+H)+], ed 514 [(M+H)+l- Step 2: preparation of 4-[(4R,10bS)—4-methylpiperazinyl-3,4,6,10b-tetrahydro- lH-pyrazino[2,1-a]isoindolyl]pyrazolo[1,5-a]pyridinecarbonitrile (Example 5) To a solution of tert—butyl 4—[(4R,10bS)-2—(7-cyanopyrazolo[1,5-a]pyridinyl)—4-methyl- 3,4,6,10b-tetrahydro-1H—pyrazino[2,1-a]isoindolyl]piperazinecarboxylate (compound 5a, mg, 29.2 umol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 30 min, then concentrated to afford a crude product, which was purified by prep- HPLC to afford Example 5 (3.3 mg, 27 % yield). MS: calc’d 414 [(M+H)+], measured 414 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 5 ppm 7.96 (d, J = 2.32 Hz, 1 H), 7.39 (d, J = 8.07 Hz, 1 H), 7.09 (d, J: 8.31 Hz, 1 H), 6.94 (s, 1 H), 6.83 (d, J: 2.45 Hz, 1 H), 6.79 (dd, J: 8.31, 2.08 Hz, 1 H), 6.59 (d, J= 8.07 Hz, 1 H), 4.08 - 4.24 (m, 2 H), 3.67 - 3.88 (m, 2 H), 3.55 (br d, J: 13.33 Hz, 1 H), 2.97 - 3.13 (m, 5 H), 2.85 - 2.96 (m, 5 H), 2.73 (dd, J: 12.35, 10.51 Hz, 1 H), 1.18 (d, J= 6.48 Hz, 3 H).

Example 6 7-[(4R,10bS)—4-methyl—8—piperazinyl-3,4,6,10b—tetrahydr0—lH-pyrazino[2,1-a]isoindol—2— yl]-1,3-benzothiazole-4—carbonitrile The title compound was prepared in analogy to the preparation of Example 1 by using 7- fluoro-l,3-benzothiazolecarbonitrile instead of 5-fluoroquinolinecarbonitrile (compound 1c). Example 6 (15 mg) was obtained. MS: calc’d 431 [(M+H)+], ed 431 +]. IH NMR (400 MHz, METHANOL-d4) (5 ppm 9.44 (s, 1 H), 7.92 (d, J: 8.31 Hz, 1 H), 7.21 (d, J: 8.31 Hz, 1 H), 7.18 (d, J: 8.19 Hz,1 H), 7.05 (d, J= 1.47 Hz, 1H), 6.90 (dd, J: 8.31, 2.08 Hz, 1 H), 4.28 (d, J: 12.35 Hz, 1 H), 4.22 (br d, .1: 11.13 Hz, 1 H), 3.90 (br (1, J: 10.39 Hz, 1 H), 3.79 (br (1, .1: 11.74 Hz, 1 H), 3.67 (br d, J: 12.10 Hz, 1 H), 3.10 — 3.21 (m, 5 H), 2.94 — 3.07 (1n, 5 H), 2.83 - 2.92 (m, 1 H), 1.30 (d, J: 6.24 Hz, 3 H).

Example 7 8-[(4R,10bS)—4—methyl-8—piperazinyl-3,4,6,10b-tetrahydro—lH—pyrazino[2,1-a]is0indol—2- yl]quinoxaline—S-carbonitrile W 95.l N The title compound was prepared in analogy to the preparation of Example 5 by using 8- bromoquinoxaline—5-carbonitrile instead of 4-chloropyrazolo[1,5-a]pyridinecarbonitrile.

Example 7 (3.3 mg) was obtained. MS: calc’d 426 [(M+H)+], measured 426 +]. 1H NMR (400 MHz, METHANOL-d4)(5 ppm 8.85 (dd, J: 11.25, 1.71 Hz, 2 H), 8.04 (d, J: 8.31 Hz, 1 H), 7.21 (d, J: 8.31 Hz, 1 H), 7.06 (d, .1: 8.07 Hz, 1 H), 6.94 (s, 1 H), 6.78 (dd, J: 8.25, 2.02 Hz, 1 H), 4.58 (br (1, J = 11.13 Hz, 1 H), 4.10 - 4.21 (m, 2 H), 3.90 (br (1, J: 10.88 Hz, 1 H), 3.55 (br d, J: 12.72 Hz, 1 H), 3.13 — 3.18 (m, 1 H), 3.02 — 3.06 (m, 4 H), 2.98 (t, J: 11.07 Hz,1 H), 2.88 - 2.93 (m, 4 H), 2.78 - 2.86 (m, 1 H), 1.17 (d, J: 6.48 Hz, 3 H).

Example 8 -[(4R,10bS)—4-methylpiperazinyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol—2- yl]quinoline-S-carbonitrile The title compound was ed in analogy to the preparation of Example 1 by using methyl 2-bromo—6-formyl-benzoate instead of 5-bromoformy1benzoate. Example 8 (19.6 mg) was obtained. MS: calc’d 425 [(M+H)+], measured 425 [(M+H)+]. 1H NMR (400 MHZ, METHANOL-d4) 6 ppm 9.02 (dd, J: 4.28, 1.59 Hz, 1 H), 8.74 (dd, J: 8.56, 1.59 Hz, 1 H), 8.19 (d, J = 7.95 Hz, 1 H), 7.71 (dd, J = 8.56, 4.28 Hz, 1 H), 7.36 (d, J: 8.07 Hz, 1 H), 7.23 (t, J: 7.70 Hz, 1 H), 6.91 (d, J: 7.70 Hz, 2 H), 4.31 (d, J=11.98 Hz, 1 H), 4.15 (br d, J: 10.27 Hz,1 H), 3.93 (br d, J: 10.76 Hz, 1 H), 3.69 (dd, Jr- 11.98, 2.20 Hz, 1 H), 3.42 - 3.53 (m, 1 H), 3.35- 3.38 (m, 1H), 2.90 - 3.13 (m, 9 H), 2.85 (dd, J: 11.86, 10.27 Hz, 1 H), 1.30 (d, J: 6.36 Hz, 4 Example 9 —[(4R,10bS)-4—methyl(4-piperidyl)—3,4,6,10b-tetrahydro-lH-pyrazino[2,1-a]isoindol—Z- yl]quinoline-S—carbonitrile The title compound was prepared ing to the following scheme: Q N N 0% k °6 dppf.DCM KZCO3 MeOH e/water Br fl: 11‘ 9b IT N / 35:“: ——“-—""—’ _._____._... :50 DIEA DMSO MlN >Lo0a Examp|e9 Step 1: preparation of tert—butyl 4-[(4R,10bS)benzyl—4-methyl-3,4,6,10b-tetrahydro- lH-pyrazino[2,1-a]isoindol-S-yl]-3,6-dihydro-2H-pyridine-l-carboxylate (compound 9a) To a 10 mL microwave Vial was added tert—butyl ,5,5-tetramethyl-1,3,2-dioxaborolan— 2-yl)—3,6-dihydro-2H—pyridine-l-carboxylate (130 mg, 420 umol), (4R,lObS-Z-benzyl—S—bromo- 4-methyl-3,4,6,10b-tetrahydro-lH—pyrazino[2,l~a]isoindole (compound lj, 100 mg, 280 pmol), PdC12(dppt)'DCM adduct (20.5 mg, 28 pmol), and K2CO3 (77.4 mg, 560 umol) in dioxane (4 mL) and water (0.4 mL). The reaction mixture was heated in the microwave at 100 0C for 30 min, then cooled to room temperature, diluted with water (50 mL) and extracted with DCM (30 mL) for three times. The combined organic layer was washed with brine, dried over Na2804, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 40 g, 0% to 30% EtOAc in PE ) to afford compound 9a (83 mg, 64% yield). MS: calc’d 460 [(M+H)+], measured 460 [(M+H)+].

Step 2 : preparation of tert—butyl 4-[(4R,10bS)methyl-1,2,3,4,6,10b- hexahydropyrazino[2,1-a]isoindolyl]piperidine-l-carboxylate und 9b) A mixture of tert—butyl ,10bS)-2—benzylmethyl-3,4,6,lOb—tetrahydro—IH- pyrazin0[2,l—a]isoindolyl]-3,6-dihydro-2H-pyridine-l-carboxylate (compound 9a, 83 mg, 180 umol) and Pd(OH)2 (10 mg) in MeOH (20 mL) was hydrogenated with a hydrogen n at room temperature for 30 min. After the catalyst was filtered off, the filtrate was concentrated in vacuo to afford compound 9b (62 mg, 75% yield) which was directly used for the next step without further purification. MS: calc’d 372 [(M+H)+], measured 372 [(M+H)+].

Step 3: preparation of tert-butyl 4-[(4R,10bS)(8-cyano—5—quinolyl)—4-methyl- 3,4,6,10b-tetrahydro—lH-pyrazino[2,1—a]isoindolyl]piperidine-l-carboxylate (compound To a solution of oquinolinecarbonitrile (compound 1c, 19 mg, 113 umol) in DMSO (2 mL) was added tert-butyl 4-((4R,10bS)~4—methyl-1,2,3,4,6,10b- hexahydropyrazino[2,1-a]isoindolyl)piperidine-l-carboxylate (compound 9b, 42 mg, 113 umol) and DIEA (73 mg, 565 umol). The reaction e was stirred at 120 0C for 5 hrs, then cooled to room ature, diluted with water (10 mL), and extracted with EA (15 mL) twice.

The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 0% to 100% EtOAc in PE) to afford compound 9c (40 mg, 68% yield). MS: calc’d 524 [(M+H)+], measured 524 [(M+H)+].

Step 4: ation of ,10bS)methyl—8-(4—piperidyl)—3,4,6,10b-tetrahydro-1H— pyrazino[2,1-a]isoindol—2-yl]quinoline-S-carbonitrile (Example 9) To a on of tert—butyl 4-((4R,10bS)(8—cyanoquinolinyl)methyl-1,2,3,4,6,10b- hexahydropyrazino[2,1 -a]isoindoly1)piperidinecarboxylate (compound 9c, 40 mg, 76.4 mMMMEMOmeww®dWAUmUTMmmmmmmmMMmemmmmmbr 30 min, then concentrated to afford a crude product, which was purified by prep-HPLC to afford Example 9 (12 mg, 38 % yield). MS: calc’d 424 [(M+H)+], measured 424 [(M+H)+]. ‘H NMR (400 MHz, METHANOL-d4) 5 ppm 9.07 (dd, J: 4.22, 1.65 Hz, 1 H), 8.81 (dd, J: 862, 1.53 Hz, 1 H), 8.22 (d, J: 7.95 Hz, 1 H), 7.76 (dd, J: 8.56, 4.28 Hz, 1 H), 7.47 - 7.53 (m, 2 H), 7.35 - 7.45 (m, 2 H), 5.34-5.38 (m, 1 H), 4.98 (br (1, J: 13.69 Hz, 1 H), 4.68 (br d, J: 13.94 Hz, 1 H), 4.33 (br s, 1 H), 3.85-4.15 (m, 1 H), 3.65-3.72 (1n, 1 H), 3.54 (br d, J: 12.72 Hz, 2 H), 3.12 - 3.24 (in, 3 H), 2.96 - 3.09 (m, 1 H), 1.87 - 2.15 (m, 5 H), 1.56 (d, J: 6.72 Hz, 3 H).

Example 10 -[(4R,10bS)-8—[(2R)(hydr0xymethyl)piperazin-1—yl]methyl—3,4,6,lOb-tetrahydrO-IH- pyrazino[2,1-a]isoindol-Z-yl]quinoline—S-carbonitrile The title compound was prepared according to the following scheme: %ng:Qék;:;:::—~=—~~¥—~ @kiii; N II HO“ H /Z \—/z OA< N TFA/DCM ___.._.____. Nj\ tBuXPhos Pd G3, t~BuONa e HO HO‘ "v 10c Example 10 Step 1 : preparation of (4R, 1 0bS)bromomethyl-1,2,3,4,6,10b— hexahydropyrazino[2,1-a1isoindole (compound 10a) To a stirred solution of (4R,10bS)—2~benzylbr0mo—4-methy1~3,4,6,10b-tetrahydro-IH— pyrazino[2,1-a]isoindole (compound 1j, 900 mg, 2.4 mmol) in DCE (30 mL) at room temperature was added l—chloroethyl ochloridate (1.7 g, 12.1 mmol). The reaction mixture was heated under reflux overnight and cooled to room temperature before concentrated in vacuo.

The residue was dissolved in MeOH (20 mL) and heated under reflux for additional 2 hrs, then cooled to room temperature and concentrated in vacuo. The residue was diluted with water (10 mL), basified with aq. NaHC03, and ted with EtOAc twice. The ed organic layer was washed with brine, dried over Na2804, filtered and concentrated in vacuo to afford compound 10a (660 mg, 98% yield), which used directly to the next step. MS: calc’d 267 and 269 [(M+H)+], measured 267 and 269 +].

Step 2: preparation of 5-[(4R,10bS)-8—bromo-4—methyl-3,4,6,10b-tetrahydro—1H— pyrazino[2,1-a]isoindolyl]quinoline-S-carbonitrile (compound 10b) To a solution of 5-fluoroquinoline-8~carbonitrile (compound 1c, 258 mg, 1.5 mmol) in DMSO (10 mL) was added (4R,10bS)bromo—4-methyl-1,2,3,4,6,10b-hexahydropyrazino[2,1- a]isoindole (compound 103, 400 mg, 1.5 mmol) and DIEA (1.3 mL, 7.5 mmol). The reaction mixture was d at 120 0C for 5 hrs, then cooled to room temperature, quenched with water (50 mL), and extracted with BA (80 mL) twice. The combined organic layer was washed with brine, dried over Na2804, filtered and trated in vacuo. The residue was purified by flash chromatography to afford compound 10b (450 mg, 72 % yield). MS: calc’d 419 and 421 [(M+H)+], measured 419 and 421 [(M+H)+].

Step 3: preparation of tert—butyl (3R)—4-[(4R,10bS)—2-(8-cyano-5—quin01yl)—4-methyl- 3,4,6,10b-tetrahydr0-lH-pyrazino[2,1-a]isoindolyl](hydroxymethyl)—piperazine—1— ylate (compound 10c) To a solution of 5-[(4R,10bS)—8-bromomethyl-3,4,6,10b-tetrahydro—1H—pyrazino[2,1- ndol—Z-y1]quinoline-S—carbonitrile (compound 10b, 70 mg, 167 umol) in dioxane (10 mL) was added tert-butyl (3R)—3-(hydroxymethyl)piperazine—l—carboxylate (CAS: 2787882, Accela ChemBio, Catalog: SYOl7685, 43.2 mg, 200 umol), t—BuONa (32.1 mg, 334 umol) and tBuXPhos Pd G3 (CAS: 1447963—75-8, Sigma-Aldrich, Catalog: 762229, 13.3 mg, 167 umol).

The reaction e was stirred at 90 0C overnight, then cooled to room temperature, diluted with water (50 mL) and extracted with BA (30 mL) for three times. The combined organic layer was washed with brine, dried over , filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 40 g, 30% to 100% EtOAc in PE) to afford compound 10c (21 mg, 23 % yield). MS: calc’d 555 [(M+H)+], measured 555 [(M+H)+].

Step 4: preparation of ,10bS)[(2R)(hydroxymethyl)piperazinyl] methyl-3,4,6,l0b-tetrahydro-lH—pyrazino[2,1-a]isoindol—Z-yl]quinoline—8-earbonitrile (Example 10) To a solution of tert-butyl (3R)[(4R,10bS)(8-cyanoquinoly1)—4-methy1-3,4,6,10b- tetrahydro—1H—pyrazino[2,1~a]isoindol-8—yl]-3—(hydroxymethyl)—piperazine- 1 —earboxylate (compound 10c, 21 mg, 38 umol ) in DCM (2 mL) was added TFA (1 mL). The reaction mixture was d at room temperature for 30 min, then concentrated to afford a crude product, which was purified by PLC to afford Example 10 (8 mg, 46% yield). MS: calc’d 455 [(M+H)+], measured 455 +]. 1H NMR (400 MHz, METHANOL-d4) (5 ppm 9.01 (dd, J = 4.16, 1.47 Hz, 1 H), 8.73 (dd, J = 8.62, 1.53 Hz, 1 H), 8.19 (d, J = 7.95 Hz, 1 H), d, J= 8.56, 4.28 Hz, 1 H), 7.35 (d, J: 8.07 Hz, 1 H), 7.14 (d, J: 8.19 Hz, 1 H), 7.07 (s, 1 H), 6.90 (br d, J: 8.19 Hz, 1 H), 4.28 (d, J= 12.23 Hz, 1 H), 4.09 (br (1, J= 10.51 Hz, 1 H), 3.87 (br d, J: 10.76 Hz, 1 H), 3.61 — 3.78 (m, 3 H), 3.41 — 3.49 (m, 2 H), 3.14 - 3.25 (m, 2 H), 2.97 — 3.13 (m,5 H), 2.80 2.93 (m, 2 H), 1.28 (d, J= 6.36 Hz, 3H).

Example 11 -[(4R,10bS)[(ZS)(hydroxymethyl)piperazinyl]methyl-3,4,6,10b-tetrahydr0—1H— pyrazino[2,1-a]isoindol—2-yl]quinoline—S—carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert-butyl (3S)—3-(hydroxymethyl)piperazineCarboxylate (CAS: 3147417, Accela ChemBio, Catalog: SY020478) instead of tert-butyl (3R)—3-(hydroxymethyl)piperazine—1- carboxylate. Example 11 (24 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHZ, METHANOL—d4) (5 ppm 9.02 (dd, J = 4.16, 1.47 Hz, 1 H), 8.73 (dd, J: 8.62, 1.53 Hz, 1 H), 8.19 (d, J: 7.95 Hz, 1 H), 7.71 (dd, J: 8.56, 4.28 Hz, 1 H), 7.35 (d, J: 8.07 Hz, 1 H), 7.14 (d, J: 8.19 Hz, 1 H), 7.07 (s, 1 H), 6.90 (br (1, J: 8.19 Hz, 1 H), 4.28 (d, J= 12.23 Hz,1 H), 4.09 (br d, J=10.51 Hz, 1 H), 3.89 (br d, J: 10.76 Hz, 1 H), 3.61 - 3.78 (111,3 H), 3.41 — 3.49 (m, 2 H), 3.14 — 3.25 (m, 2 H), 2.96 — 3.12 (m,5 H), 2.80 — 2.93 (m, 2 H), 1.28 (d, J: 6.36 Hz, 3H).

Example 12 -['(4R,10bS)[(3S)—-3—(hydr0xymethyl)piperazin-l-yl]methyl-3,4,6,10b-tetrahydro-IH- pyrazino[2,1-a]isoindolyl]quinoline-S-carbonitrile The title compound was ed in analogy to the preparation of Example 10 by using tert-butyl (25)—2-(hydroxymethyl)piperazinecarboxy1ate (CAS: 10303779, Accela ChemBio, Catalog: SY018056) instead of utyl -(hydroxymethy1)piperazine-1~ carboxylate. Example 12 (8.6 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 6 ppm 9.07 (dd, J = 4.28, 1.59 Hz, 1 H), 8.80 (dd, J: 8.62, 1.53 Hz, 1 H), 8.22 (d, J= 7.95 Hz, 1 H), 7.75 (dd, .1: 8.56, 4.28 Hz, 1 H), 7.35 - 7.47 (m, 2 H), 7.24 (s, 1 H), 7.13 (dd, J: 8.50, 2.14 Hz, 1 H), 5.24—5.31 (m, 1 H), 4.95 (br d, J: 13.57 Hz, 1 H), 4.65 (br d, J: 13.69 Hz, 1 H), 4.34 (br s, 1 H), 3.82 - 3.95 (m, 4 H), 3.72-3.80 (m, 1 H), 3.67 (br s, 1 H), 3.46 - 3.56 (m, 3H), 3.34—3.39 (m, 1H), 2.96 — 3.24 (m, 3 H), 1.56 (d, J = 6.72 Hz, 3 H).

Example 13 -[(4R,10bS)methyl—8-(3—0xa—7,9—diazabicyclo[3.3.1]n0nan—7—yl)—3,4,6,IOb-tetrahydro— lH—pyrazino[2,1-a]isoindol—Z-yl]quinoline-S-carbonitrile (in);O The title compound was ed in analogy to the preparation of Example 10 by using tert-butyl 3 —oxa-7,9—diazabicyclo[3 .3. 1 ]nonanecarboxy1ate (CAS: 1251010-45—3, PharmaBlock, Catalog: PB07078) instead of utyl (3R)(hydroxymethyl)piperazine carboxylate. Example 13 (8.2 mg) was obtained. MS: calc’d 467 [(M+H)+], measured 467 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) (5 ppm 9.02 (dd, J = 4.28, 1.59 Hz, 1 H), 8.73 (dd, J: 8.56, 1.59 Hz, 1 H), 8.18 (d, J: 7.95 Hz, 1 H), 7.71 (dd, J: 8.62, 4.22 Hz, 1 H), 7.34 (d, J = 8.07 Hz, 1 H), 7.13 (d, J= 8.31 Hz, 1 H), 7.01 (d, J= 1.71 Hz, 1 H), 6.83 (dd, J= 8.31, 2.20 Hz, 1 H), 4.29 (d, J = 12.23 Hz, 1 H), 4.10 (b1 (1, J = 10.27 Hz, 1 H), .02 (m, 4 H), 3.77 - 3.91 (m, 3 H), 3.71 (br d, J= 12.23 Hz, 1 H), 3.46 (br d, J= 11.49 Hz, 1 H), 3.09 - 3.19 (111,2 H), 2.96 - 3.09 (m, 1 H), 2.93—3.07 (m, 3H), 2.82 - 2.92 (m, 1 H), 1.28 (d, J: 6.36 Hz, 3 H).

Example 14 -[(4R,10bS)—4-methyl(9-oxa-3,7-diazabicyclo[3.3.1]n0nanyl)-3,4,6,10b-tetrahydro- 1H-pyrazino[2,1-a]isoindol—Z-yl]quinoline-S-carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonanecarboxylate (CAS: 4786470, WuXi Pharma, Catalog: WX120052) instead of tert—butyl (3R)-3—(hydroxymethyl)piperazine—1- carboxylate. Example 14 (7.2 mg) was ed. MS: calc’d 467 [(M+H)+], measured 467 +]. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 9.02 (dd, J = 4.22, 1.53 Hz, 1 H), 8.71 (dd, J: 8.56, 1.47 Hz, 1 H), 8.18 (d, J = 7.95 Hz, 1 H), 7.72 (dd, J: 8.56, 4.28 Hz, 1 H), 7.33 (d, J: 8.07 Hz, 1 H), 7.14 (d, J= 8.31 Hz, 1 H), 7.09 (s, 1 H), 6.90 (dd, J2 8.25, 2.02 Hz, 1 H), 4.29 (d, J = 12.23 Hz, 1 H), 4.08 (br (1, J= 10.15 Hz, 1 H), 3.87 (br s, 3 H), 3.77 (br dd, J = 11.68, 6.17 Hz, 2 H), 3.69 (br d, J: 12.10 Hz, 1 H), 3.45 (br d, J: 11.74 Hz, 1 H), 3.24-3.35 (m, 3H), 3.09 - 3.23 (m, 4 H), 3.02 (t, J= 10.88 Hz, 1 H), 2.85 (t, J = 11.07 Hz, 1 H), 1.27 (d, J: 6.48 Hz, 3 H).

Example 15 -[(4R,10bS)(6-hydroxy-1,4-diazepan—1-yl)methyl-3,4,6,10b—tetrahydro—1H— pyrazino[2,1-a]isoindolyl]quinoline-S-carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using utyl 6—hydroxy—1,4-diazepane—1-earboxylate (CAS: 956317~40-1, WuXi Pharma, Catalog: WX604354) instead of tert-butyl (3R)(hydroxymethyl)piperazinecarboxy1ate. Example 15 (7.2 mg) was obtained. MS: calc’d 455 +], measured 455 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 0‘ ppm 9.00 (d, J: 3.06 Hz, 1 H), 8.69 (d, J: 8.56 Hz, 1 H), 8.15 (d, J = 8.07 Hz, 1 H), 7.69 (dd, J: 8.56, 4.28 Hz, 1 H), 7.30 (d, J: 8.07 Hz, 1 H), 7.04 (d, .1: 8.31 Hz, 1 H), 6.87 (s, 1 H), 6.68 (d, J: 8.31 Hz, 1 H), 4.23 (br d, J= 12.23 Hz, 1 H), 3.98 — 4.13 (m, 2 H), 3.76 - 3.94 (m, 2 H), 3.54 - 3.49 (m, 4 H), 2.92 - 3.08 (m, 3 H), 2.69 - 2.89 - 3.74 (m, 2 H), 3.33 (m, 3 H), 1.26 (d, J: 6.36 Hz, 3 H). -58— Example 16 -[(4R,10bS)[transaminomethoxy-pyrrolidinyl]methyl—3,4,6,10b-tetrahydro- 1H-pyrazin0[2,1-a]isoindoI-Z-yl]quinoline-S-carbonitrile The title nd was prepared in azalogy to the preparation of Example 10 by using trans(boc~amino)-4—meth0xypyrrolidine (CAS: 128739-924, PharmaBlock, Catalog: 21069) instead of tert—butyl (3R)(hydr0xymethyl)piperazine-1—carb0xylate. Example 16 (58 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 0‘ ppm 9.01 (dd, J = 4.22, 1.65 Hz, 1 H), 8.72 (dd, .1: 8.56, 1.59 Hz, 1 H), 8.17 (d, J: 7.95 Hz, 1 H), 7.70 (dd, J: 8.62, 4.22 Hz, 1 H), 7.34 (d, J: 8.19 Hz, 1 H), 7.07 (d, J = 8.07 Hz, 1 H), 6.64 (d, J: 1.47 Hz, 1 H), 6.46 (dd, J: 8.25, 2.02 Hz, 1 H), 4.26 (d, J: 12.10 Hz, 1 H), 4.08 (br d, J: 10.51 Hz, 1 H), 3.86 (br d,J= 11.13 Hz, 1 H), 3.77 — 3.83 (ml H), 3.64 - 3.74 (1n, 2 H), 3.49 - 3.57 (m, 2 H), 3.45-3.49(m, 1H), 3.44 (s, 3 H), 3.35-3.40 (in, 1H), 3.25 (dd, .1: 10.51, 2.81 Hz, 1 H), 3.06 - 3.17 (m, 1 H), 2.96 — 3.04 (m, l H), 2.80 - 2.92 (m, 1 H), 1.28 (d, .1: 6.48 Hz, 3 H). 2019/064323 Example 16A and 16B: 5-[(4R,10bS)—8-[(3S,4S)—3-amin0methoxy—pyrrolidin—1-yl]-4— methyl-3,4,6,10b-tetrahydro-lH-pyrazino[2,1—a]isoindol-Z-yl]quinoline—S-carbonitrile and -[(4R,10bS3-8—[(3R,4R)amino—4-methoxy-pyrrolidin-l-yl]—4—methyl—3,4,6,10b— tetrahydro—lH-pyrazino[2,1-a]isoindol—2-yl]quinoline-S—carbonitrile N N N\ N / / Preparation of Example 16A & 16B: N N N I I | I | | N N N \ \ \ / / / N N N j\ SFC chiral separation j\ + l N N N HN HN/O HN“'Q o 5 0/40 5 0’4 7g 0 \ 7g \ 7g 0 °\ 16c-a&16c-b TFA’DCM l TFA/DCM 16A&1GB Intermediate 16c (162 mg) was resolved by SFC to give two single isomers: 16c-a (faster eluting, 62 mg, yield: 38%) MS: calc'd 555 (M+H) +, measured 555 ; and compound 16c- b (slower eluting, 76 mg, yield: 47%) MS: calc'd 555 (M+H) +, measured 555 (M+H)+, with 40% l (0.25% )/C02 on OJ (5 pm, 250><20 mm) column.

To a on of compound 16c-a (62 mg, 112 umol) in DCM (4 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 30 min, then concentrated to afford a crude product, which was purified by prep-HPLC to afford Example 16A (42 mg, 82% yield). MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHZ, METHANOL— d4) 5 ppm 9.01 (dd, J = 4.22, 1.65 Hz, 1 H), 8.72 (dd, J= 8.56, 1.59 Hz, 1 H), 8.17 (d, J= 7.95 Hz, 1 H), 7.70 (dd, J: 8.62, 4.22 Hz, 1 H), 7.34 (d, J: 8.19 Hz, 1 H), 7.07 (d, J: 8.07 Hz, 1 H), 6.64 (d, J= 1.47 Hz, 1 H), 6.46 (dd, J= 8.25, 2.02 Hz, 1 H), 4.26 (d, J= 12.10 Hz, 1 H), 4.08 (br d, J: 10.51 Hz, 1 H), 3.86 (br d, J: 11.13 Hz, 1 H), 3.77 - 3.83 (m, 1 H), 3.64 - 3.74 (m, 2 H), 3.49 - 3.57 (m, 2 H), 3.45-3.49(m, 1H), 3.44 (s, 3 H), 3.35-3.40 (m, 1H), 3.25 (dd, J: 10.51, 2.81 Hz, 1 H), 3.06 - 3.17 (m, 1 H), 2.96 — 3.04 (m, l H), 2.80 - 2.92 (m, 1 H), 1.28 (d, J: 6.48 Hz, 3 H).

Example 16B was prepared in analogy to Example 16A (51 mg, 82% yield). MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 'H NMR (400 MHz, METHANOL-d4) 5 ppm 9.01 (dd, J: 4.28, 1.59 Hz, 1 H), 8.72 (dd, J: 8.68, 1.59 Hz, 1 H), 8.18 (d, J: 8.07 Hz, 1 H), 7.71 (dd, J = 8.56, 4.28 Hz, 1 H), 7.34 (d, .1: 8.07 Hz, 1 H), 7.06 (d, J = 8.19 Hz, 1 H), 6.64 (s, 1 H), 6.46 (dd, J: 8.25, 2.02 Hz, 1 H), 4.26 (d, J: 12.10 Hz, 1 H), 4.08 (hr (1, J: 10.27 Hz, 1 H), 3.86 (br d, J: 11.25 Hz, 1 H), 3.78 - 3.83 (m, 1 H), 3.63 - 3.75 (m, 2 H), 3.49 — 3.58 (m, 2 H), 3.40-3.47 (m, 1 H), 3.44 (s, 3 H), 3.35-3.38 (m, 1H), 3.24 (dd, J=10.51,2.81 Hz, 1 H), 3.07 — 3.17 (m, l H), 2.96 - 3.04 (m, 1 H), 2.78 — 2.93 (m, 1 H), 1.28 (d, J: 6.48 Hz, 3 H).

Example 17 -[(4R,10bS)—8-leisamino—4-methoxy-pyrrolidinyl]methyl-3,4,6,lOb-tetrahydro-IH- pyrazino[2,1-a]isoindol—Z-yl]quinoline-S—carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using cis- 3—(boc—amino)methoxypyrrolidine (CAS: 1287399, PharmaBlock, Catalog: PBXA8055) d of tert-butyl (3R)(hydroxymethy1)piperazine-1—carboxylate. Example 17 (36 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 5 ppm 9.02 (dd, J: 4.28, 1.59 Hz, 1 H), 8.72 (dd, .1: 8.62, 1.53 Hz, 1 H), 8.18 (d, J: 7.95 Hz, 1 H), 7.71 (dd, J = 8.56, 4.28 Hz, 1 H), 7.33 (d, .1: 8.07 Hz, 1 H), 7.05 (d, J = 8.07 Hz, 1 H), 6.60 (s, 1 H), 6.42 (dd, J: 8.25, 1.90 Hz, 1 H), 4.25 (d, J: 12.23 Hz, 1 H), 4.07 (br d, J: 10.27 Hz, 1 H), 3.91 (br (1, J: 293 Hz, 1 H), 3.85 (br (1, J: 11.00 Hz, 1 H), 3.67 (br d, J: 12.10 Hz, 1 H), 3.55 - 3.63 (m, 1 H), 3.39 — 3.54 (m, 8 H), 2.96 - 3.11 (m, 2 H), 2.79 - 2.91 (m, 1 H), 1.27 (d, J: 6.48 Hz, 3 H). e 18 -I(4R,10bS)(5-amin0oxaazaspiro[3.4]octanyl)methyl-3,4,6,10b-tetrahydro- 1H—pyrazin0[2,1-a]isoindol—Z-yl]quinoline-S-carbonitrile W0 2019/233941 The title compound was prepared in analogy to the preparation of Example 10 by using tert—butyl N—(2—oxaazaspiro[3.4]octany1)carbamate (CAS: 14224964, Block, Catalog: PBLG1162) instead of tert—butyl (3R)(hyd1'oxymethyl)piperazinecarboxy1ate.

Example 18 (12 mg) was ed. MS: cale’d 467 +], measured 467 [(M+H)+]. lH NMR (400 MHz, METHANOL-d4) (5 ppm 9.01 (dd, J: 4.28, 1.59 Hz, 1 H), 8.73 (dd, J = 8.56, 1.59 Hz, 1 H), 8.17 (d, J= 7.95 Hz, 1 H), 7.69 (dd, J= 8.62, 4.22 Hz, 1 H), 7.34 (d, J= 8.07 Hz, 1 H), 7.08 (d, J: 8.19 Hz, 1 H), 6.65 (s, 1 H), 6.47 (dd, J: 8.13, 1.90 Hz, 1 H), 4.96 (d, J z 6.72 Hz, 1 H), 4.54 — 4.68 (m, 3 H), 4.27 (d, J= 12.23 Hz, 1 H), 4.09 (br d, J: 10.03 Hz, 1 H), 3.87 (br d, J: 11.49 Hz, 1 H), 3.58 - 3.56 (m, 3 H), 3.07 — 3.17 (m, — 3.78 (m, 4 H), 3.42 1 H), 2.94 - 3.04 (m, 1 H), 2.80 - 2.92 (m, 1 H), 1.28 (d, J= 6.36 Hz, 3 H).

Example 19 ,10bS)—8-[3-amino-3—(hydroxymethyl)pyrrolidin-l—yl]methyl-3,4,6,10b-tetrahydrolH-pyrazino [2,1-alisoindolyl]quinoline-8—carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert-butyl N-[3-(hydroxymethyl)pyrrolidiny1]carbamate (CAS: No, PharmaBlock, Catalog: PBXA7029-l) instead of tert-butyl (3R)(hydroxymethyl)piperazine-l-carboxy1ate. Example 19 (7.7 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 9.06 (dd, J = 4.28, 1.59 Hz, 1 H), 8.79 (dd, J: 8.56, 1.34 Hz, 1 H), 8.21 (d, J = 7.95 Hz, 1 H), 7.75 (dd, J = 8.56, 4.28 Hz, 1 H), 7.41 (br (1, J = 5.62 Hz, 1 H), 7.36 (d, J: 8.44 Hz, 1 H), 6.82 (s, 1 H), 6.71 (dd, J: 8.44, 2.08 Hz, 1 H), 5.27 (br s, 1 H), 4.93 (br d, J: 13.57 Hz, 1 H), 4.62 (br (1, J: 13.82 Hz, 1 H), 4.33 (br s, l H), 3.78 (s, 2 H), 3.75-3.82 (m, 1H), 3.60 - 3.52 (m, 2H), 2.85-3.00 (m, 1H), 2.30 - 2.40 - 3.72 (in, 2 H), 3.54 (s, 2H), 3.43 (m, 1 H), 2.19 - 2.30 (m, l H), 1.55 (d, J: 6.72 Hz, 3 H). 2019/064323 Example 20 - [(4R,10bS)—8—[(3R)amin0pyrrolidin-l-yl}methyl-3,4,6,10b-tetrahydro-1H- pyrazino[2,1-alisoindol—2-yl]quinoline-8—carb0nitrile The title compound was prepared in 2analogy to the preparation of e 10 by using tert-butyl N—[(3R)—pyrrolidinyl]earbamate (CAS: 1225360, Accela ChemBio, Catalog: SY006424) instead of tert-butyl (3R)(hydroxymethyl)piperazinecarboxylate. Example 20 (8.6 mg) was obtained. MS: calc’d 425 [(M+H)+], measured 425 [(M+H)+]. 1H NMR (400 MHZ, METHANOL-d4) (3 ppm 9.06 (dd, .1: 4.28, 1.59 Hz, 1 H), 8.80 (d, J: 8.68 Hz, 1 H), 8.21 (d, J = 7.83 Hz, 1 H), 7.75 (dd, .1: 8.56, 4.28 Hz, 1 H), 7.40 (br s, 1 H), 7.36 (d, J: 8.44 Hz, 1 H), 6.82 (s, 1 H), 6.72 (dd, J: 8.38, 2.02 Hz, 1 H), 5.27 (br s, 1 H), 4.95 (br d, .1: 12.80 Hz, 1 H), 4.62 (br d, J== 13.94 Hz, 1 H), 4.32 (br s, 1 H), 4.08 (br s, 1 H), 3.56 - 3.87 (m, 5 H), 3.39 - 3.54 (m, 2 H), 2.85-3.10 (m, 1H), 2.45 — 2.58 (m, 1 H), 2.15 - 2.26 (m, 1 H), 1.55 (d, J: 672 Hz, 3 H). 1 5 Example 2 1 -[(4R,10bS)-8—[trans-3—amin0hydroxy-pyrrolidin-1~yl]methyl-3,4,6,10b—tetrahydr0- lH-pyrazino[2,l-a]isoindol—Z—yl]quinoline—S-carbonitrile The title compound was prepared in analogy to the preparation of e 10 by using trans(boc—amino)hydroxypyrrolidine (CAS: 8706326, PharmaBlock, Catalog: 2019/064323 —64- PB07572) d of tert—butyl (3R)—3~(hydroxymethyl)piperazine-l-carboxylate. Example 21 (8.6 mg) was obtained. MS: calc’d 441 [(M+H)+], measured 441 [(M+H)+]. ‘H NMR (400 MHz, METHANOL—d4) (5 ppm 9.01 (dd, J== 4.28, 1.59 Hz, 1 H), 8.72 (dd, .1: 8.56, 1.59 Hz, 1 H), 8.18 (d, J = 8.07 Hz, 1 H), 7.70 (dd, J: 8.62, 4.34 Hz, 1 H), 7.33 (d, J = 8.07 Hz, 1 H), 7.05 (d, J: 8.07 Hz, 1 H), 6.61 (s, 1 H), 6.31 - 6.53 (m, 1 H), 4.26 (d,J= 12.23 Hz, 1 H), 4.01 ~ 4.17 (m, 2 H), 3.85 (br d, J= 11.13 Hz, 1 H), 3.57 — 3.75 (m, 3 H), 3.45 (br d, J= 11.86 Hz, 1 H), .40 (m, 2H), 3.12 — 3.20 (m, 1 H), 3.05 - 3.12 (m, 1 H), 3.00 (br t, J: 12.00 Hz, 1 H), 2.86 (br t, J: 11.07 Hz, 1 H), 1.27 (d, J= 6.36 Hz, 3 H).

Example 22 -[(4R,1(le)—8—(3-amin0azetidin-1—yl)methyl—3,4,6,10b-tetrahydr0-lH-pyrazino[2,1- a]isoindol—Z-yl]quinoline-8—carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert—butyl N—(azetidin—3-y1)carbamate instead of tert—butyl (3R)~3—(hydroxymethyl)piperazine carboxylate. Example 22 (34 mg) was obtained. MS: calc’d 411 [(M+H)+], measured 411 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4)5 ppm 8.89 (dd, J = 4.28, 1.59 Hz, 1 H), 8.58 (dd, J: 8.56, 1.59 Hz, 1 H), 8.02 (d, J: 7.95 Hz, 1 H), 7.55 (dd, J: 8.56, 4.28 Hz, 1 H), 7.18 (d, J = 8.07 Hz, 1 H), 7.03 (d, J: 8.07 Hz, 1 H), 6.48 (d, J: 1.59 Hz, 1 H), 6.31 (dd, J: 8.07, 2.08 Hz, 1 H), 4.24 (d, .1: 12.59 Hz, 1 H), 4.04 — 4.16 (in, 3 H), 3.63 - 3.84 (m, 4 H), 3.27 — 3.44 (m, 3 H), 2.87 (t, J=11.13 Hz, 1 H), 2.74 - 2.82 (m, 1 H), 1.18 (d, J: 6.24 Hz, 3 H). -65— Example 23 -[(4R,10bS)[(3S,4S)meth0xy(methylamino)pyrrolidin-l-yl]—4-methyl-3,4,6,10b— tetrahydro-lH—pyrazino[2,1-a]isoindolyl]quinoline-S-carbonitrile The title compound was ed in analogy to the preparation of e 10 by using tert—butyl N—[(3S,4S)methoxypyrrolidiny1]-N—methyl-carbamate (CAS: 174727—04—9, PharrnaBlock, Catalog: PBN20121070) instead of tert—butyl (3R)-3~(hydroxymethyl)piperazine- oxylate. Example 23 (34 mg) was obtained. MS: calc’d 469 [(M+H)+], measured 469 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 9.02 (d, J = 3.06 Hz, 1 H), 8.71 (d, J = 8.68 Hz, 1 H), 8.19 (d, J: 7.95 Hz, 1 H), 7.72 (dd, J= 8.56, 4.28 Hz, 1 H), 7.18 - 7.47 (m, 1 H), 7.06 (d, J: 8.19 Hz, 1 H), 6.65 (s, 1 H), 6.47 (br d, J=8.19 Hz, 1 H), 4.26 (d, J: 11.98 Hz, 1 H), 4.07 (br d, J: 9.78 Hz, 1 H), 3.88 - 3.95 (m, 1 H), 3.85 (br d, .1: 11.37 Hz, 1 H), 3.62 - 3.71 (m, 2 H), 3.56 (dd, J= 9.72, 6.17 Hz, 1 H), 3.43-3.46 (m, 1 H), 3.44 (s, 3 H), 3.23-3.33 (m, 3H), 3.17 (dd, J: 9.78, 3.67 Hz, 1 H), 3.00 (t, J: 1100 Hz, 1 H), 2.86 (br t, J: 11.07 Hz, 1 H), 2.46 (s, 3 H), 1.27 (d, J= 6.36 Hz, 3 H).

Example 24 -[(4R,10bS)—4-methyl(5-oxa-2,8—diazaspiro[3.5]nonanyl)-3,4,6,10b-tetrahydro-IH- pyrazino[2,1-a]isoindol—2-yl]quinoline—8—carbonitrile -66— The title compound was prepared in analogy to the ation of Example 10 by using tert—butyl 5-oxa-2,8-diazaspiro[3.5]nonanecarboxylate (CAS: 18, PharmaBlock, Catalog: PBN20111063) instead of tert—butyl (3R)—3~(hydroxymethy1)piperazine-1—carboxylate.

Example 24 (16 mg) was obtained. MS: calc’d 467 [(M+H)+], measured 467 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) (5 ppm 9.04 (dd, J = 1.65, 4.22 Hz, 1H), 8.78 (dd, J: 1.59, 8.56 Hz, 1H), 8.19 (d, J = 7.95 Hz, 1H), 7.73 (dd, J: 4.28, 8.56 Hz, 1H), 7.32 - 7.46 (m, 2H), 7.20 (s, 1H), 7.09 (dd, J: 2.26, 8.50 Hz, 1H), 5.28 (br s, 1H), 4.93 (br d, J: 13.69 Hz, 1H), 4.62 (br (1, J: 13.82 Hz, 1H), 4.32 (br s, 1H), 4.04 - 4.19 (m, 4H), 3.51 - 4.03 (m, 4H), 3.40 (s, 2H), 3.14 - 3.21 (m, 1H), 2.90 - 3.23 (m, 1H), 1.54 (d, J= 6.85 Hz, 3H).

Example 25 -[(4R,10bS)[2-(dimethylamino)ethoxy]methyl—3,4,6,10b-tetrahydro—1H-pyrazino[2,l- a]isoindol—Z-yl]quinoline-S-carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using N,N-dimethylethanolamine (CAS: 1080, Aldrich, Catalog: 471453) d of tert—butyl (3R)—3—(hydroxymethyl)piperazine—1-carboxylate. Example 25 (9.4 mg) was ed. MS: calc’d 428 [(M+H)+], measured 428 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 5 ppm 8.99 (dd, J: 1.65, 4.22 Hz, 1H), 8.71 (dd, J: 1.6, 8.6 Hz, 1H), 8.15 (d, J: 7.95 Hz, 1H), 7.67 (dd, J: 4.22, 8.62 Hz, 1H), 7.32 (d, J: 8.1 Hz,1H), 7.15 (d, J: 8.19 Hz,1H), 7.00 (d, J: 1.96 Hz, 1H), 6.83 (dd, J: 2.32, 8.19 Hz, 1H), 4.28 (d, J: 12.35 Hz, 1H), 4.04 - 4.13 (m, 3H), 3.82 - 3.92 (m, 1H), 3.69 (br d, J: 12.23 Hz, 1H), 3.40 - 3.48 (m, 1H), 3.33 - 3.38 (m, 1H), 2.93 - 3.05 (m, 1H), 2.71 — 2.88 (m, 3H), 2.35 (s, 6H), 1.25 (d, J: 6.5 Hz, 3H). e 26 -[(4R,10bS)[2-(dimethylamino)ethylamino]methyl-3,4,6,10b-tetrahydro—IH- pyrazino[2,1-alisoindolyl]quinoline-S-carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using 2- ylaminoethylamine (CAS: 108~00-9, TCI, Catalog: D0719) instead of tert-butyl (3R) (hydroxymethyl)piperazine—1~carboxylate. Example 26 (19 mg) was obtained. MS: calc’d 427 [(M+H)+], measured 427 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) (5 ppm 8.98 (dd, J = 1.59, 4.28 Hz, 1H), 8.70 (dd, J: 1.59, 8.56 Hz, 1H), 8.15 (d, J = 8.07 Hz, 1H), 7.66 (dd, J: 4.22, 8.62 Hz, 1H), 7.31 (d, .1: 8.07 Hz, 1H), 7.00 (d, .1: 7.95 Hz, 1H), 6.69 (d, J: 183 Hz, 1H), 6.52 (dd, J: 2.02, 8.13 Hz, 1H), 4.22 (d, J: 12.10 Hz, 1H), 4.04 (br (1, J: 10.03 Hz, 1H), 3.84 (br d, J: 11.25 Hz,1H), 3.63 (br d, J: 11.98 Hz,1H), 3.33 - 3.38 (m, 1H), 3.43 (br (1, J: 11.49 Hz, 1H), 3.23 (t, J: 6.66 Hz, 2H), 2.98 (t, J: 1088 Hz, 1H), 2.83 (dd, .1: 10.33, 11.80 Hz, 1H), 2.58 (t, J: 6.66 Hz, 2H), 2.31 (s, 6H), 1.25 (d, J = 6.48 Hz, 3H).

Example 27 -[(4R,10bS)(azetidin—3-yloxy)methyl—3,4,6,10b-tetrahydro-lH-pyrazino{2,1- a]isoindol—Z-yl]quinoline-S—carbonitrile HNO‘O WO 33941 The title compound was prepared in analogy to the preparation of e 10 by using tert—butyl 3—hydroxyazetidine-l—carboxylate (CAS: 141699—55-0, PharmaBlock, Catalog: PB00001) instead of tert—butyl (3R)(hydroxymethyl)piperazine—1-carboxylate. Example 27 (13 mg) was obtained. MS: calc’d 412 [(M+H)+], measured 412 [(M+H)+]. 1H NMR (400MHz, METHANOL-d4) 6 ppm 8.90 (dd, J: 1.7, 4.2 Hz, 1H), 8.64 (dd, J: 1.7, 8.6 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.59 (dd, J: 4.2, 8.6 Hz, 1H), 7.27 (dd, J= 8.2, 18.3 Hz, 2H), 6.94 (d, J= 2.2 Hz, 1H), 6.78 (dd, J: 2.3, 8.4 Hz, 1H), 5.15 - 5.02 (m, 1H), 4.92 (dd, J: 3.7, 11.0 Hz, 1H), 4.69 (d, J: 13.6 Hz, 1H), 4.43 (d, J = 13.6 Hz, 1H), 4.03 - — - 4.54 (m, 2H), 4.33 4.11 (m, 2H), 3.94 4.02 (m, 1H), 3.80 - - 3.87 (m, 1H), 3.45 — 3.55 (1n, 1H), 2.96 3.13 (m, 2H), 1.37 (d, J: 6.6 Hz, 3H).

Example 28 ,10bS)—8-(azetidin—3-ylamino)—4-methyl-3,4,6,10b-tetrahydro—1H—pyrazino[2,1- a]isoindol—Z-yl]quinoline-S—carbonitrile HNO._§ The title compound was prepared in analogy to the preparation of Example 10 by using tert-butyl 3-aminoazetidinecarboxylate (CAS: 193269-78—2, PharmaBlock, Catalog: PB00002) instead of lert-butyl (3R)—3—(hydroxymethyl)piperazine-1~carboxylate. Example 28 (30 mg) was obtained. MS: calc’d 411 [(M+H)+], measured 411 +]. 1H NMR (400 MHz, METHANOL-d4) . 5 ppm 9.03 (dd, J: 1.7, 4.2 Hz, 1H), 8.76 (dd, J: 1.6, 8.6 Hz, 1H), 8.18 (d, J: 7.9 Hz, 1H), 7.72 (dd, J: 4.3, 8.6 Hz, 1H), 7.37 (d, J: 8.1 Hz, 1H), 7.23 (d, J: 8.3 Hz, 1H), 6.73 (d, J: 1.8 Hz, 1H), 6.61 (dd, J: 2.1, 8.3 Hz,1H), 4.93 - 4.96 (m, 1H), 4.71 (d, J: 13.3 Hz, 1H), 4.51 - 4.62 (m, 1H), 4.39 - 4.49 (1n, 2H), 4.34 (d, J: 13.4 Hz, 1H), 3.97 - 4.13 (m, 3H), 3.84 - 3.95 (1n, 1H), 3.51 — 3.6.5 (m, 1H), 3.03 - 3.24 (m, 2H), 1.47 (d, J: 6.7 Hz, 3H).

Example 29 - [(4R,10bS)(azetidin-S-yl)methyl-3,4,6,1 rahydro-lH-pyrazino [2, 1 -a] isoindol-Z- noline—S-carbonitrile The title compound was prepared according to the following scheme: 31):; | l MEL )40 N: !p \/2 <39 a 10b 293 H Example 29 Step 1: preparation of tert-butyl 3-[(4R,10bS)(8—cyanoquinolyl)methyl-3,4,6,10b- tetrahydro—lH-pyrazino[2,1-a]isoindolyl]azetidine-l-carboxylate (compound 29a) To a suspension of zinc (156 mg, 2.4 mmol) in DMF (3 mL) was added 1,2-dibromoethane (44.8 mg, 238 umol). The resultant mixture was heated at 60 0C for 10 min, and then cooled to room temperature. trimethylsilane (25.9 mg, 238 umol) was added to the mixture, stirred at 60 0C for 10 min, then cooled to room temperature. A solution of tert—butyl 3-iodoazetidine carboxylate (CAS: 254454-54—1, PharmaBlock, Catalog: PB00430, 675 mg, 2.4 mmol) in DMF (1 mL) was then added and the e was stirred at room temperature for 1 hr. 5-[(4R,lObS) bromo-4—methyl —3 ,4,6,10b-tetrahydro—1H-pyrazino[2,l -a]isoindol-Z-yl]quinoline-S-carbonitrile (compound 10b, 500 mg, 1.2 mmol) and Pd(PPh3)2Clz (83.7 mg, 0.1 mmol) were added sequentially and the reaction mixture was heated to 80 0C for 4 hrs, then cooled to room temperature and partitioned between EA and sat.NH4Cl on. The aqueous layer was extracted with EA twice, and the combined organic layer was washed with water and brine, dried over Na2804, d and concentrated in vacuo. The residue was purified by flash chromatography to afford compound 29a (202 mg, 34 % . MS: calc’d 496 [(M+H)+], measured 496 [(M+H)+].

Step 2: preparation of 5-[(4R,10bS)(azetidin~3-yl)—4-methyl—3,4,6,10b-tetrahydro—1H— pyrazino[2,1—a]isoindol-Z-yl]quinoline-S-carbonitrile (Example 29) To a solution of tert-butyl 3-[(4R,10bS)(8-cyano—5—quinolyl)—4-methyl-3,4,6,10b- tetrahydro-lH-pyrazino[2,1-a]isoindol-8—yl]azetidine-l-carboxylate und 29a, 42 mg, 85 umol ) in DCM (2 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 30 min, then trated to afford a crude product, which was purified by pre- HPLC to afford Example 29 (23 mg, 68 % yield). MS: calc’d 396 [(M+H)+], measured 396 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4)5 ppm 9.02 (dd, J = 1.71, 4.28 Hz, 1H), 8.79 (dd, J: 1.59, 8.56 Hz, 1H), 8.17 (d, J: 8.07 Hz, 1H), 7.73 (dd, J: 4.28, 8.56 Hz, 1H), 7.61 (s, 1H), 7.54 - 7.58 (m, 1H), 7.43 - 7.52 (m, 1H), 7.39 (d, J = 8.07 Hz, 1H), 5.41 (br dd, J=3.85, 11.19 Hz, 1H), 5.01 (d, J: 13.82 Hz, 1H), 4.72 (d, J: 13.94 Hz, 1H), 4.20 - 4.46 (m, 6H), 3.99 (br s, 1H), 3.68 (br d, .1: 12.96 Hz, 1H), 3.33 - 3.36 (m, 1H), 3.10 - 3.25 (m, 1H), 1.56 (d, J: 6.72 Hz, 3H). e 30 -[(4R,10bS)-8—| [(3S,4R)—4-fluoropyrrolidinyl]amino]methyl-3,4,6,10b-tetrahydro-IH- pyrazino[2,1-a]isoindol—Z-yl]quinoline-S-carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert-butyl (3S,4R)amino—4-fluoropyrrolidine-l -carboxylate (CAS: 1 1740204, PharmaBlock, Catalog: PB07374) instead of tert—butyl (3R)—3-(hydroxymethyl)piperazine ylate. Example 30 (46 mg) was obtained. MS: calc’d 443 [(M+H)+], measured 443 [(M+H)+]. 1H NMR (400 MHz, OL-d4) (5 ppm 9.02 (dd, J = 1.6, 4.3 Hz, 1H), 8.76 (dd, J: 1.6, 8.6 Hz, 1H), 8.16 (d, J: 7.9 Hz,1H), 7.71 (dd, J: 4.3, 8.6 Hz, 1H), 7.37 (d, J: 8.1 Hz, 1H), 7.26 (d, J: 8.3 Hz,1H), 6.92 (d, J: 1.8 Hz, 1H), 6.81 (dd, J: 2.1, 8.3 Hz, 1H), 5.21 - 5.44 (m, 1H), 5.12 (dd, J: 3.9, 11.0 Hz, 1H), 4.82 (d, J= 13.6 Hz, 1H), 4.38 ~ 4.55 (m, 2H), 4.10 - 4.26 (m, 1H), 3.85 = — 3.97 (m, 1H), 3.56 - 3.84(m, 4H), 3.20-3.30 (m, 2H), 3.12 (dd, J 11.2, 13.1 Hz,1H), 1.51 (d,J= 6.7 Hz, 3H).

Example 3 1 —[(4R,10bS)-8—[[(3S,4S)flu0r0pyrrolidinyl]amino]—4—methyl-3,4,6,10b-tetrahydro-1H- pyrazino[2,1-a]isoindol~2—yl]quinoline-8—carbonitrile @531 The title compound was prepared in analogy to the preparation of Example 10 by using tert-butyl )—3-aminofluoropyrrolidine—1 -carboxylate (CAS: 10090757, PharmaBlock, Catalog: PB07376) instead of tert-butyl (3R)-3~(hydroxymethyl)piperazine—l- carboxylate. Example 31 (46 mg) was obtained. MS: calc’d 443 [(M+H)+], ed 443 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 9.01 (d, J = 4.03 Hz, 1H), 8.71 (d, J = 8.19 Hz, 1H), 8.17 (d, J: 8.07 Hz, 1H), 7.70 (dd, J= 4.22, 8.62 Hz, 1H), 7.33 (d, J = 7.95 Hz, 1H), 7.03 (d, J: 8.19 Hz, 1H), 6.75 (s, 1H), 6.59 (br d, J: 8.07 Hz, 1H), 4.77 - 5.02 (m, 1H), 4.24 (d, J = 12.23 Hz, 1H), 4.06 (br d, J = 10.27 Hz, 1H), 3.89 - 4.00 (m, 1H), 3.85 (br d, J = 11.13 Hz, 1H), 3.66 (br d, J: 11.86 Hz, 1H), 3.41 - 3.52 (m, 2H), 2.93 - 3.17 (m, 3H), 2.85 (t, J =11.13 Hz,1H), 2.75 (dd, J: 4.28, 11.98 Hz, 1H), 1.27 (d, J= 6.36 Hz, 3H). 2019/064323 Example 32 -[(4R,10bS)—8-[[(3R,4S)fluoropyrrolidinyl] methyl—3,4,6,l0b-tetrahydro-1H— pyrazino[2,1-a]isoindol—2-yl]quinoline—S—carbonitrile . {Ml The title compound was prepared in analogy to the preparation of Example 10 by using tert—butyl (3R,4S)—3-aminofluoropyrrolidine—1-carb0xy1ate (CAS: 1009075~48—2, PharmaBlock, Catalog: PB07375) instead of tert—butyl (3R)-3—(hydroxymethyl)piperazine-1— carboxylate. Example 32 (26 mg) was obtained. MS: calc’d 443 [(M+H)+], ed 443 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 9.00 (dd, J = 1.28, 4.22 Hz, 1H), 8.72 (dd, J: 1.6, 8.6 Hz, 1H), 8.16 (d, J: 8.07 Hz, 1H), 7.69 (dd, .1: 4.28, 8.56 Hz, 1H), 7.32 (d, J: 8.07 Hz, 1H), 7.01 (d, .1: 8.07 Hz, 1H), 6.80 (s, 1H), 6.63 (br d, J: 8.07 Hz, 1H), 5.00—5.22 (1n, 1H), 4.22 (d, J: 12.23 Hz, 1H), 3.89 - 4.09 (in, 2H), 3.84 (br d, J: 11.37 Hz, 1H), 3.64 (br (:1, J = 11.86 Hz,1H), 3.43 (br d, J: 11.49 Hz,1H), 3.12 (t, J: 13.51 Hz, 1H), 2.94 - 3.04 (m, 1H), 2.84 (t, J: 11.13 Hz,1H), 2.71 (t, J: 10.27 Hz, 1H), 1.25 (d, J: 6.48 Hz, 3H).

WO 33941 Example 33 —[(4R,10bS)—8—[[(3R,4R)fluoropyrrolidinyl]amino]methyl-3,4,6,10b-tetrahydro-1H- pyrazino[2,1-alis0indolyl]quinoline—8-carbonitrile The title nd was prepared in analogy to the preparation of Example 10 by using tert—butyl (3R,4R)—3—a1ninofluoropyrrolidine—1-carboxy1ate (CAS: 14413923, PharmaBlock, Catalog: P807377) instead of tert-butyl (3R)(hydroxymethyl)piperazine—1- carboxylate. Example 33 (38 mg) was obtained. MS: calc’d 443 [(M+H)+], measured 443 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) (5 ppm 8.99 (dd, J = 1.59, 4.16 Hz, 1H), 8.70 (dd, J: 1.65, 8.62 Hz, 1H), 8.15 (d, J: 7.95 Hz, 1H), 7.68 (dd, J: 4.28, 8.56 Hz, 1H), 7.31 (d, J = 8.19 Hz, 1H), 7.02 (d, J= 8.19 Hz, 1H), 6.73 (d, J: 1.59 Hz, 1H), 6.57 (dd, J= 1.96, 8.07 Hz, 1H), 4.77 - 5.02 (m, 1H), 4.22 (d, J: 12.35 Hz, 1H), 4.04 (br d, J: 10.39 Hz, 1H), 3.93 (td, .12 .64, 18.43 Hz, 1H), 3.83 (br (1, J= 10.88 Hz,1H), 3.63 (br (1, J: 11.98 Hz,1H), 3.36 — 3.49 (m, 2H), 2.91 - 3.17 (m, 3H), 2.77 - 2.88 (m, 1H), 2.73 (dd, .1: 4.40, 12.10 Hz, 1H), 1.25 (d, J: 6.36 Hz, 3H).

Example 34 -[(4R,10bS)—8-[[(3R,4R)methoxypyrrolidinyl]amino]methyl-3,4,6,10b-tetrahydro— lH-pyrazino[2,1-a]isoindol—2~yl]quinoline-S-carbonitrile \ fifql The title compound was prepared in analogy to the preparation of Example 10 by using tert—butyl (3R,4R)—3 methoxypyrrolidine-1~carb0xy1ate (CAS: 1400562—12-0, PharmaBlock, Catalog: PBXA3109) instead of utyl (3R)—3-(hydroxymethy1)piperazine carboxylate. Example 34 (46 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4)(5 ppm 8.69 (dd, J = 1.59, 8.56 Hz, 1H), 8.14 (d, J = 7.95 Hz, 1H), 7.67 (dd, J = 4.28, 8.56 Hz, 1H), 7.30 (d, J = 8.07 Hz, 1H), 7.00 (d, J = 8.07 Hz, 1H), 6.71 (d, J: 1.59 Hz, 1H), 6.55 (dd, J: 2.02, 8.13 Hz, 1H), 4.20 (d, J: 12.10 Hz, 1H), 4.03 (br d, J: 10.15 Hz,1H), 3.83 (br (1, J= 11.25 Hz, 1H), 3.74 — 3.79 (m, 1H), 3.66 — 3.71 (m, 1H), 3.63 (br d, J: 11.86 Hz, 1H), 3.39 - 3.46 (m, 1H), 3.35 (s, 3H), 3.27 - 3.31 (m, 1H), 2.90 - 3.04 (m, 3H), 2.82 (dd, J: 10.45, 11.68 Hz, 1H), 2.67 (dd, J: 3.91, 11.98 Hz, 1H), 1.24 (d, J = 6.48 Hz, 3H). e 35 -[(4R,l0bS)-4—methyl-8—(5-oxa-2,8-diazaspiro[3.5]nonan-Z-yl)-3,4,6,10b-tetrahydro—1H— pyrazino[2,1-alisoindolyl]quinoline—8—carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert—butyl 5—oxa-2,8-diazaspiro[3.5]nonanecarboxylate (CAS: 1251005~61-4, PharmaBlock, Catalog: 11065—5G) instead of tert-butyl (3R)—3-(hydroxymethyl)piperazine~1- carboxylate. Example 35 (16 mg) was obtained. MS: calc’d 467 [(M+H)+], measured 467 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 8.89 (dd, J = 1.7, 4.2 Hz, 1H), 8.61 (dd, J: 1.6, 8.6 Hz, 1H), 8.06 (d, J: 8.1 Hz, 1H), 7.57 (dd, J= 4.2, 8.5 Hz, 1H), 7.22 (d, J= 8.1 Hz, 1H), 6.98 (d, J: 7.9 Hz, 1H), 6.48 (d, J: 1.3 Hz, 1H), 6.29 (dd, J = 2.0, 7.9 Hz, 1H), 4.15 (d, J = 12.3 Hz, 1H), 3.97 (br d, J: 10.5 Hz, 1H), 3.69 - 3.84 (m, 3H), 3.44 - 3.61 (1n, 5H), 3.34 (br d, J: 11.6 Hz, 1H), 3.23 = 6.4 - 2.96 (m, 3H), 2.67 - 2.78 (m, 3H), 1.16 (d, J - 3.28 (m, 1H), 2.84 Hz, 3H).

Example 36 -[(4R,10bS)—8-(2,6—diazaspir0[3.3]heptan-Z-yl)—4—methy1~3,4,6,10b-tetrahydro-1H— no[2,1—a]isoindol—2-yl]quinoline—8—carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert-butyl 2,6—diazaspiro[3.3]heptane~2-earboxylate oxalate (CAS: 10410263, Block, Catalog: PBO3883—1G) instead of tert—butyl ~(hydroxymethyl)piperazine—1»carboxylate.

Example 36 (19.2 mg) was obtained. MS: calc’d 437 [(M+H)+], measured 437 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 9.01 (dd, J = 1.5, 4.2 Hz, 1H), 8.71 (dd, J= 1.3, 8.6 Hz, 1H), 8.17 (d, J: 7.9 Hz, 1H), 7.70 (dd, J: 4.3, 8.6 Hz, 1H), 7.33 (d, J: 8.1 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.55 (s, 1H), 6.37 (dd, J: 1.7, 7.9 Hz, 1H), 4.25 (d, J: 12.3 Hz, 1H), 4.06 (br (1, J: 10.1 Hz, 1H), 3.92 (s, 4H), 3.78 — 3.88 (m, 1H), 3.77 (s, 4H), 3.65 (br d, J: 12.5 Hz, 1H), 3.34 — 3.48 (m, 2H), 2.99 (t, J: 10.9 Hz, 1H), 2.84 (br t, J: 11.1 Hz, 1H), 1.27 (d, J: 6.4 Hz, 3H).

Example 37 -{(4R,10bS)(1,6—diazaspiro[3.3]heptanyl)-4—methyl-3,4,6,10b—tetrahydro-1H- pyrazino[2,1-a1isoindolyl]quinoline-S-carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert—butyl 1,6~diazaspiro[3.3]heptanecarboxylate (CAS: 1330763-95—5, PharmaBlock, Catalog: PBN2011926-1G) instead of tert—butyl (3R) (hydroxymethyl)piperazineearboxylate.

Example 37 (8.8 mg) was obtained. MS: calc’d 437 +], ed 437 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 6 ppm 9.03 (dd, J: 1.7, 4.2 Hz, 1H), 8.75 (dd, J== 1.6, 8.6 Hz, 1H), 8.18 (d, J: 8.1 Hz, 1H), 7.71 (dd, J: 4.3, 8.6 Hz, 1H), 7.36 (d, J: 8.1 Hz,1H), 7.22 (d, J: 8.2 Hz, 1H), 6.66 (d, J: 1.7 Hz, 1H), 6.49 (dd, J: 2.1, 8.1 Hz, 1H), 4.50 - 4.64 (m, 2H), 4.35 (d, J: 10.0 Hz, 2H), 4.13 (d, J: 9.7 Hz, 2H), 4.08 (br d, J: 12.7 Hz, 1H), 3.95 - 4.03 (m, 2H), 3.86 - 3.93 (m, 1H), 3.71 — 3.80 (m, 1H), 3.52 — 3.59 (m, 1H), 2.98 — 3.11 (m, 2H), 2.79 - 2.91 (m, 2H), 1.39 (d, J: 6.6 Hz, 3H).

Example 38 -[(4R,10bS)methyl(6-methyl—2,6—diazaspiro[3.3]heptan-Z-yl)—3,4,6,10b-tetrahydro- 1H-pyrazino[2,1-a]isoindol—2—yl] quinoline—S-carbonitrile .530 The title nd was prepared in analogy to the preparation of Example 10 by using 2- methyl-2,6-diazaspiro[3.3]heptane (CAS: 12035676, Block, Catalog: PBLJ2831) instead of tert-butyl (3R)(hydroxymethy1)piperazine—1— carboxylate. Example 38 (16.0 mg) was obtained. MS: calc’d 451 [(M+H)+], measured 451 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 5 ppm 9.06 (dd, J = 1.6, 4.3 Hz, 1H), 8.80 (dd, J: 1.5, 8.6 Hz, 1H), 8.21 (d, J = 7.9 Hz, 1H), 7.75 (dd, J: 4.3, 8.6 Hz, 1H), 7.35 - 7.47 (m, 2H), 7.19 (s, 1H), 7.08 (dd, J: 2.2, 8.4 Hz, 1H), 5.24 = 13.8 Hz, 1H), 4.64 (br - 5.36 (m, 1H), 4.94 (d, J (:1, J: 13.7 Hz, 1H), 4.26 - 4.41 (m, 1H), 4.15 (s, 2H), 3.78 - 3.86 (m, 2H), 3.55 - 3.73 (m, 3H), 3.26 — 3.32 (m, 5H), 2.78 (s, 3H), 1.56 (d, J= 6.7 Hz, 3H).

Example 39 -[(4R,10bS)-8—(3-amin0-3—methyl—azetidinyl)methyl—3,4,6,10b-tetrahydro—1H— pyrazino[2,1-a]isoindol—2-yl]quinoline-S-carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert—butyl N-(3-methy1azetidinyl)carbamate (CAS: 10184430, PhannaBlock, Catalog: PB03046) instead of tert-butyl (3R)(hydroxymethyl)~ piperazine-l-carboxylate. Example 39 (30 mg) was obtained. MS: calc’d 425 [(M+H)+], measured 425 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 9.04 (dd, J = 1.6, 4.3 Hz, 1H), 8.76 (dd, J = 1.6, 8.6 Hz, 1H), 8.18 (d, J: 7.9 Hz,1H), 7.71 (dd, J= 4.3, 8.6 Hz, 1H), 7.37 (d, J= 8.1 Hz, 1H), 7.25 (d, J= 8.1 Hz, 1H), 6.66 (d, J: 1.7 Hz, 1H), 6.51 (dd, J: 2.1, 8.1Hz,1H), 4.73 - 4.81 (m, 1H), 4.64 (d, J: 13.2 Hz, 1H), 4.22 (d, J: 13.1 Hz, 1H), 3.99 - 4.09 (m, 2H), 3.87 - 3.97 (m, 4H), 3.53 - 3.65 (m, 1H), 3.02 - 3.16 (m, 2H), 1.70 (s, 3H), 1.43 (d, J: 6.6 Hz, 3H).

Example 40A and 40B -[(4R,10bS)I(3S,4S)—3-amin0—4-hydr0xy—pyrrolidin-l—yl]-4—methyl—3,4,6,10b—tetrahydro- 1H—pyrazin0[2,1-a]isoindol-Z-yl]quinoline-S-carbonitrile and 5-[(4R,10bS)[(3R,4R) aminohydroxy-pyrrolidinyl]—4-methyl—3,4,6,10b-tetrahydro-lH—pyrazino[2,1- a]isoindol—Z—yl]quinolinecarbonitrile N N N\ N / / N N HZN’O H2N““9 OH OH The title compound was prepared in analogy to the preparation of Example 16A and 16B by using trans—3—(boc-amino)—4-hydroxypyrrolidine (CAS: 870632—89-6, PharmaBlock, Catalog: PB07572) instead of 3-(boc—amino)methoxypyrrolidine. Example 40A (38 mg) was obtained. MS: calc’d 441 [(M+H)+], ed 441 +]. 1H NMR (400 MHZ, METHANOL-d4) 6 ppm 9.07 (dd, J: 1.3, 4.1 Hz, 1H), 8.79 (d, J: 8.3 Hz, 1H), 8.21 (d, J: 8.2 Hz, 1H), 7.75 (dd, J: 4.3, 8.6 Hz, 1H), 7.30 - 7.48 (m, 2H), 6.82 (s, 1H), 6.71 (dd, J: 1.5, 8.3 Hz, 1H), 5.14 - 5.40 (m, 1H), 4.89 - 4.96 (m, 2H), 4.55 — 4.66 (m, 1H), 4.43 - 4.51 (m, 1H), 4.20 - 3.29 (m, 2H), 1.55 (d, J: 6.7 Hz, - 3.52 (m, 2H), 3.15 - 4.37 (1n, 1H), 3.74 — 3.89 (m, 4H), 3.42 3H). e 408 (40 mg) was obtained. MS: calc’d 441 [(M+H)+], measured 44] [(M+H)+]. 1H NMR (400 MHZ, METHANOL-d4) 5 ppm 9.07 (dd, J: 1.3, 4.1 Hz, 1H), 8.79 (d, J: 8.3 Hz, 1H), 8.21 (d, J: 8.2 Hz, 1H), 7.75 (dd, J: 4.3, 8.6 Hz, 1H), 7.30 — 7.48 (m, 2H), 6.82 (s, 1H), 6.71 (dd, J: 1.5, 8.3 Hz, 1H), 5.14 — 5.40 (m, 1H), 4.89 — 4.96 (m, 2H), 4.55 — 4.66 (m, 1H), 4.43 - 3.52 (m, 2H), 3.15 — 3.29 (m, 2H), - 4.51 (m, 1H), 4.20 — 4.37 (m, 1H), 3.74 - 3.89 (m, 4H), 3.42 1.55 (d, J: 6.7 Hz, 3H).

Example 41 -[(4R,10bS)(3a-methoxy—1,2,3,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol—S-yl)—4—methyl— 3,4,6,10b-tetrahydr0-lH—pyrazino[2,1-a]isoindol—2-yl] quinoline-8—carbonitrile The title compound was prepared in analogy to the ation of Example 10 by using tert—butyl 3a—methoxy—1,2,3,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole—5-carboxylate instead of tert- butyl -(hydroxymethyl)piperazinecarboxylate. Example 41 (8.8 mg) was obtained. MS: calc’d 481 [(M+H)+], measured 481 [(M+H)+]. 1H NMR (400 MHZ, METHANOL—d4) 65 ppm 9.07 (dd, J: 1.6, 4.3 Hz, 1H), 8.80 (br (1, J: 8.3 Hz, 1H), 8.21 (br d, J: 7.8 Hz, 1H), 7.75 (dd, J = 4.3, 8.6 Hz, 1H), 7.23 - 7.49 (m, 2H), 6.75 (s, 1H), 6.65 (dd, J: 2.0, 8.4 Hz, 1H), 5.13 — 5.36 (m, 1H), 4.90 - 4.96 (m, 1H), 4.49 - 4.65 (1n, 1H), 4.23 - 4.39 (m, 1H), 3.74 - 3.83 (m, 2H), 3.57 — 3.06 (m, 2H), 1.55 (d, J: 6.7 Hz, — 3.68 (m, 1H), 3.47 - 3.56 (m, 2H), 3.23 - 3.43 (m, 9H), 2.91 3H).

W0 2019/233941 Example 42 -[(4R,10bS)[(3S,4S)hydr0xy(methylamino)pyrrolidin-l-yl]methyl—3,4,6, 10b- tetrahydro—lH—pyrazino[2,1-a]isoindolyl]quinoline-S-carbonitrile HO’Q The title compound was prepared in analogy to the preparation of Example 10 by using utyl N-[(3S,4S)hydroxypyrrolidiny1]-N—methy1-carbamate instead of utyl (3R)- 3~(hydroxymethyl)piperazinecarboxy1ate. Example 42 (46 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 6 ppm 9.04 (dd, J = 1.7, 4.2 Hz, 1H), 8.76 (dd, J: 1.6, 8.6 Hz, 1H), 8.19 (d, J: 7.9 Hz, 1H), 7.72 (dd, J: 4.2, 8.6 Hz, 1H), 7.37 (d, J: 8.1 Hz, 1H), 7.27 (d, J: 8.2 Hz, 1H), 6.79 (d, J: 1.7 Hz, 1H), 6.65 (dd, J = 2.2, 8.4 Hz, 1H), 4.75 = 13.2 Hz, 1H), 4.55 — 4.62 (m, 1H), 4.26 (d, J - 4.86 (m, 1H), 4.67 (d, J = 13.2 Hz, 1H), 3.88 — 4.02 (m, 2H), 3.69 — 3.86 (m, 3H), 3.51 - 3.64 (m, 2H), 3.20 - 3.28 (m, 1H), 3.04 — 3.17 (m, 2H), 2.88 (s, 3H), 1.45 (d, J: 6.6 Hz, 3H).

WO 33941 ~81- Example 43 -[(4R,10bS)—4—methyl[(3R,4R)—3-hydr0xy(methylamino)pyrrolidin-l-yl]—3,4,6,10b- tetrahydro-lH—pyrazino[2,l—a]isoindol—Z-yl]quinoline—8—carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert—butyl N—[(3S,4S)hydroxypyrrolidin-3—yl]-N-methy1-carbamate instead of tert-butyl (3R)- 3-(hydroxymethyl)piperazine-1~carboxylate. Example 43 (45 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 0‘ ppm 9.04 (dd, J= 1.6, 4.3 Hz, 1H), 8.76 (dd, J = 1.6, 8.6 Hz, 1H), 8.18 (d, J: 7.9 Hz, 1H), 7.72 (dd, J = 4.2, 8.6 Hz, 1H), 7.37 (d, J= 7.9 Hz, 1H), 7.28 (d, J: 8.3 Hz, 1H), 6.79 (d, J= 1.8 Hz, 1H), 6.65 (dd, J = 2.1, 8.4 Hz, 1H), 4.82 — 4.90 (m, 1H), 4.66 — 4.75 (m, 1H), 4.55 — 4.64 (m, 1H), 4.31 (d, J = 13.2 Hz, 1H), 3.95 - 4.09 (m, 1H), 3.88 - 3.94 (m, 1H), 3.69 - 3.86 (m, 3H), 3.52 - 3.63 (m, 2H), 3.22 - 3.28 (m, 1H), 3.04 ~ 3.20 (m, 2H), 2.88 (s, 3H), 1.46 (d, J: 6.7 Hz, 3H).

Example 44 -[(4R,10bS)—4—methyl—8—[(4aR,7aR)—3,4,4a,5,7,7a—hexahydro-2H—pyrrolo[3,4-b] xazin- 6-yl]-3,4,6,10b-tetrahydro-lH-pyrazino[2,1-a]isoindol-Z—yl]quinoline—S-carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert-butyl-(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H—pyrrolo[3 ,4-b] [1 ,4]oxazinecarboxylate instead of tert—butyl (3R)(hydroxymethyl)piperazine—1-carboxylate. Example 44 (8.8 mg) was obtained. MS: calc’d 467 [(M+H)+], measured 467[(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 6 ppm 9.03 (dd, J: 1.6, 4.3 Hz, 1H), 8.75 (dd, J: 1.7, 8.6 Hz, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.71 (dd, J: 4.2, 8.6 Hz, 1H), 7.36 (d, J: 8.1 Hz, 1H), 7.21 (d, J: 8.3 Hz, 1H), 6.70 (d, J: 1.6 Hz, 1H), 6.54 (dd, J: 2.0, 8.3 Hz, 1H), 4.47 - 4.68 (m, 2H), 4.15 - 4.25 (m, 1H), 4.11 (d, J: 13.2 Hz, 1H), 3.86 - 3.73 (m, 2H), 3.52 - - 3.84 (m, 1H), 3.64 - 4.03 (m, 3H), 3.74 3.60 (m, 1H), 3.38 - 3.12 (m, 2H), 1.40 (d, J: 6.5 Hz, - 3.47 (m, 1H), 3.23 - 3.37 (m, 4H), 2.95 3H). e 45 —[(4R,10bS)methyl[trans-(3R,4R)amino-3—hydroxy—3-methyl-pyrrolidin-l-yll- 3,4,6,10b-tetrahydro—lH-pyrazino[2,1-alisoindol—2-yl]quinoline—S-carbonitrile “02/? The title compound was prepared in analogy to the ation of Example 10 by using tert-butyl N—[trans-4—hydroxymethy1-pyrrolidin—3-y1]carbamate instead of tert-butyl (3R)-3— (hydroxymethyl)piperazine—1~carboxy1ate. e 45 (26 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) (5 ppm 9.04 (dd, J = 1.6, 4.3 Hz, 1H), 8.76 (dd, J== 1.6, 8.6 Hz, 1H), 8.18 (d, J= 8.1 Hz, 1H), 7.72 (dd, J: 4.3, 8.6 Hz, 1H), 7.37 (d, J: 7.9 Hz, 1H), 7.25 (d, J: 8.3 Hz, 1H), 6.73 (d, J: 1.6 Hz, 1H), 6.59 (dd, J = 2.1, 8.3 Hz, 1H), 4.76 (br d, J = 7.9 Hz, 1H), 4.64 (d, J = 13.1 Hz, 1H), 4.22 (d, J = 13.1 Hz, 1H), 3.81 - 3.51 - 4.02 (m, 3H), 3.67 - 3.75 (m, 1H), 3.54 - 3.63 (1n, 2H), 3.46 (1n, 1H), 3.38 (d, J = 10.4 Hz, 1H), 3.03 - 3.17 (in, 2H), 1.51 (s, 3H), 1.44 (d, J: 6.6 Hz, 3H).

Example 45A and 45B -[(4R,10bS)[(3R,4R)-4—amin0hydroxymethyl—pyrrolidinyl]methy1-3,4,6,10b- tetrahydro-lH—pyrazino[2,1—a]isoindol—2—yl]quinoline~8—carbonitrile and 5-[(4R,10bS)—8- [(3S,4S)—4-amin0-3—hydroxy—3-methyl—pyrrolidin-l—yl]methyl-3,4,6,lOb-tetrahydro-l H- no[2,1-a]isoindol—Z-yl]quinoline—S-carbonitrile N N I I | | N\ N\ / / N N H6 H0 5 NH2 NH2 The title compound was prepared in analogy to the preparation of Example 16A and 163 by using tert—butyl N-[trans—4-hydroxy-4—methyl-pyrrolidinyl]carbamate d of trans (boc-amino)—4-methoxypyrrolidine. Example 45A (18 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. ‘H NMR (400 MHZ, METHANOL—ab) 5 ppm lH NMR (400 MHz, CD3OD, 299 K) (5 (ppm) 9.04 (dd, J z 1.6, 4.3 Hz, 1H), 8.76 (dd, J = 1.6, 8.6 Hz, 1H), 8.18 (d, J: 8.1 Hz, 1H), 7.72 (dd, J: 4.3, 8.6 Hz,1H), 7.37 (d, J = 7.9 Hz,1H), 7.25 (d, J: 8.3 Hz, 1H), 6.73 (d, J = 1.6 Hz, 1H), 6.59 (dd, J = 2.1, 8.3 Hz, 1H), 4.76 (br d, J = 7.9 Hz, 1H), 4.64 (d, J: 13.1 Hz, 1H), 4.22 (d, J: 13.1 Hz, 1H), 3.81 - 4.02 (in, 3H), 3.67 - 3.75 (m, 1H), 3.54 - 3.63 (m, 2H), 3.46 — 3.51 (m, 1H), 3.38 (d, J: 10.4 Hz, 1H), 3.03 - 3.17 (m, 51 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H). Example 45B (19 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) (5 ppm 9.04 (dd, J x 1.6, 4.3 Hz, 1H), 8.76 (dd, J: 1.7, 8.6 Hz, 1H), 8.19 (d, J: 7.9 Hz, 1H), 7.72 (dd, J: 4.3, 8.6 Hz, 1H), 7.37 (d, J: 8.1 Hz, 1H), 7.26 (d, J: 8.3 Hz, 1H), 6.74 (d, J: 1.7 Hz, 1H), 6.59 (dd, J: 2.2, 8.3 Hz, 1H), 4.76 = 13.2 Hz, 1H), 4.25 - 3.98 (m, - 4.84 (m, 1H), 4.67 (d, J (d, J= 13.2 Hz, 1H), 3.83 3H), 3.65 - 3.73 (m, 1H), 3.55 — 3.64 (m, 2H), 3.46 - 3.53 (m, 1H), 3.38 (d, J = 10.5 Hz, 1H), 3.00 - 3.20 (m, 2H), 1.51 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H). 2019/064323 Example 46 -[(4R,10bS)—8—[(3S,4R)amino-4—fluoro-pyrrolidinyl]methyl—3,4,6,10b-tetrahydro- 1H-pyrazino[2,1-a]isoindol—Z-yl]quinoline-S-carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert—butyl N—[(3S,4R)-4—fluoropyrrolidin—3-yl]carbamate (CAS: 1033718-89—6, PharmaBlock, Catalog: PBO9206) instead of tert—butyl- (3R)(hydroxymethyl)—piperazinecarboxy1ate.

Example 46 (35 mg) was obtained. MS: calc’d 443 +], measured 443 [(M+H)+]. 'H NMR (400 MHz, METHANOL-d4) 5 ppm 9.05 (dd, J = 1.6, 4.3 Hz, 1H), 8.78 (dd, J: 1.7, 8.6 Hz, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.73 (dd, J: 4.3, 8.6 Hz, 1H), 7.39 (d, J: 8.1 Hz, 1H), 7.33 (d, J: 8.4 Hz, 1H), 6.80 (d, J: 1.8 Hz, 1H), 6.66 (dd, J: 2.2, 8.4 Hz, 1H), 5.38 - 5.63 (m, 1H), .05 - 5.16 (m, 1H), 4.83 (d, J= 13.6 Hz, 1H), 4.48 (d, J = 13.6 Hz, 1H), 4.12 - 4.25 (m, 2H), 3.68 - 3.53 (m, 1H), 3.19 - 3.28 (m, 1H), 3.08 — 3.17 (m, — 3.97 (m, 4H), 3.60 — 3.66 (m, 1H), 3.44 1H), 1.51 (d, J= 6.7 Hz, 3H). ~85- Example 47 -[(4R,l0bS)—8-[(3R,4S)aminofluor0-pyrrolidinyl]methyl-3,4,6,10b—tetrahydrolH-pyrazino [2,1-a]isoindol—2—yl]quinoline—S-carbonitrile The title compound was prepared in analogy to the ation of Example 10 by using tert—butyl N—[(3R,4S)—4-fluoropyrrolidin—3-y1]carbarnate (CAS: 1033718-91—0, PharmaBlock.

Catalog: PB09204) instead of tert—butyl-(3R)—3-(hydroxymethyl)pipcrazine-1—carboxy1ate.

Example 47 (31 mg) was obtained. MS: calc’d 443 +]. measured 443 [(M+H)+]. 'H NMR (400 MHz, METHANOL—d4) 6 ppm 9.04 (dd, J = 1.7, 4.2 Hz, 1H), 8.77 (dd, J = 1.7, 8.6 Hz, 1H), 8.19 (d, J: 8.1 Hz, 1H), 7.73 (dd, J: 4.3, 8.6 Hz, 1H), 7.38 (d, J: 7.9 Hz, 1H), 7.30 (d, J: 8.4 Hz, 1H), 6.78 (d, J: 1.8 Hz, 1H), 6.64 (dd, J: 2.2, 8.4 Hz, 1H), 5.38 - 5.61 (m, 1H), .05 — 5.16 (m, 1H), 4.73 (d, J: 13.3 Hz, 1H), 4.33 (d, J = 13.2 Hz, 1H), 4.09 - 4.23 (m, 1H), 3.97 - 3.53 (m, 1H), 3.04 - 3.22 (m, — 4.07 (m, 1H), 3.65 - 3.95 (m, 4H), 3.59 - 3.63 (m, 1H), 3.42 2H), 1.47 (d, J: 6.6 Hz, 3H).

Example 48 -[(4R,10bS)—8—[(3R,4R)—3-amino-4—fluor0-pyrrolidin—l—yl]methyl-3,4,6,lOb-tetrahydro- azin0[2,1-a]isoindol—Z-yl]quinoline—8—carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert-butyl ((3R,4R)-4—fluoropyrrolidinyl)carbamate hydrochloride (CAS: 20970614, BePharm, Catalog: BDOO765464) instead of tert—butyl ~ xymethyl)piperazine—1- carboxylate. Example 48 (8.8 mg) was obtained. MS: calc’d 443 [(M+H)+], measured 443 [(M+H)+]. 1H NMR (400 MHZ, METHANOL—d4) 5 ppm 9.03 (dd, J = 1.6, 4.3 Hz, 1H), 8.75 (dd, J=1.6, 8.6 Hz, 1H), 8.18 (d, J: 7.9 HZ, 1H), 7.71 (dd, J: 4.3, 8.6 Hz, 1H), 7.36 (d, J: 7.9 Hz, 1H), 7.26 (d, J: 8.2 Hz, 1H), 6.81 (d, J: 1.7 Hz, 1H), 6.66 (dd, J= 2.1, 8.4 Hz, 1H), 5.28 - 5.48 (m, 1H), 4.65 — 4.01 (m, 4H), — 4.73 (m, 1H), 4.61 (d, J: 13.0 Hz, 1H), 4.06 — 4.23 (m, 2H), 3.75 3.45 - 3.67 (m, 3H), 3.01 — 3.15 (1n, 2H), 1.42 (d, J: 6.5 Hz, 3H).

Example 49 -[(4R,10bS)-8—[(3S,4S)~3-aminofluoro—pyrrolidinyl]—4-methyl—3,4,6,10b-tetrahydro- 1H-pyrazino[2,1—a]isoindol—Z-yl]quinoline—S-carbonitrile The title compound was prepared in analogy to the ation of Example 10 by using tert—butyl N—[(3S,4S)—4-fluoropyrrolidiny1]carbamate (CAS: 2133888, PharmaBlock, Catalog: PB09205) instead of tert-butyl (3R)—3—(hydroxymethyl)piperazine-1—carboxy1ate.

Example 49 (58 mg) was ed. MS: calc’d 443 [(M+H)+], measured 443 [(M+H)+]. 1H NMR (400 MHz, METHANOL—da) 6 ppm 9.03 (dd, J: 1.6, 4.3 Hz, 1H), 8.75 (dd, J = 1.6, 8.6 Hz, 1H), 8.18 (d, J: 7.9 Hz, 1H), 7.71 (dd, J: 4.3, 8.6 Hz, 1H), 7.36 (d, J= 7.9 Hz, 1H), 7.26 (d, J: 8.2 Hz, 1H), 6.81 (d, J: 1.7 Hz, 1H), 6.66 (dd, J: 2.1, 8.4 Hz, 1H), 5.28 - 5.48 (1n, 1H), 4.65 (d, J = 13.0 Hz, 1H), 4.06 - 4.23 - 4.73 (m, 1H), 4.61 (1n, 2H), 3.75 - 4.01 (m, 4H), 3.45 - 3.67 (m, 3H), 3.01 - 3.15 (m, 2H), 1.42 (d, J: 6.5 Hz, 3H).

Example 50 -[(4R,10bS)-8—[(3R)(methoxymethyl)piperazin—1-yl]methyl-3,4,6,10b-tetrahydro-IH- pyrazino[2,1-a]isoindol—Z-yl]quinoline—S-carbonitrile eff”)N The title compound was prepared in analogy to the preparation of Example 10 by using tert-butyl (2R)(methoxymethyl)piperazinecarboxy1ate (CAS: 1023301-73—6, PharmaBlock, Catalog: 78) instead of tert-butyl (3R)(hydroxymethyl)piperazine—1-carboxylate.

Example 50 (5.4 mg) was obtained. MS: calc’d 469 [(M+H)+], measured 469 [(M+H)+]. lH NMR (400 MHz, METHANOL-d4) 6 ppm 8.91 (dd, J: 1.6, 4.3 Hz, 1H), 8.64 (dd, J: 1.7, 8.6 Hz, 1H), 8.05 (d, J: 7.9 Hz, 1H), 7.60 (dd, J = 4.3, 8.6 Hz, 1H), 7.25 (dd, J = 5.3, 8.2 Hz, 2H), 7.08 (d, J: 1.8 Hz, 1H), 6.94 (dd, J: 2.2, 8.4 Hz, 1H), 4.85 - 4.91 (m, 2H), 4.65 (d, J: 13.4 Hz, 1H), 4.27 (d, J: 13.4 Hz, 1H), 3.89 - 4.01 (m, 1H), 3.78 - 3.86 (1n, 1H), 3.67 — 3.76 (m, 2H), 3.45 - 3.26 (m, 1H), 2.85 - 3.11 - 3.64 (m, 4H), 3.36 - 3.42 (m, 1H), 3.30 - 3.38 (m, 2H), 3.22 (1n, 4H), 1.36 (d, J: 6.7 Hz, 3H).

Example 51 -[(4R,10bS)(4-aminomethylpiperidyl)methyl-3,4,6,10b-tetrahydro-1H- no[2,1-a]isoindol—Z-yl]quinoline—8-carbonitrile The title compound was prepared in analogy to the ation of Example 10 by using tert-butyl N-(4-methylpiperidin-4—yl)carbamate (CAS: 1632717, PharmaBlock, Catalog: PB02909) instead of tert-butyl (3R)—3~(hydroxymethyl)piperazinecarboxy1ate. Example 51 (40 mg) was obtained. MS: calc’d 453 [(M+H)+], measured 453 [(M+H)+]. 1H NMR (400 MHZ, METHANOL—d4) 5 ppm 9.05 (dd, J = 1.6, 4.3 Hz, 1H), 8.79 (dd, J: 1.7, 8.6 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H), 7.74 (dd, J: 4.3, 8.6 Hz, 1H), 7.38 (dd, J= 8.3,17.4 Hz, 2H), 7.18 (d, J: 1.8 Hz, 1H), 7.06 (dd, J: 2.2, 8.6 Hz, 1H), 6.94 (dd, J: 2.2, 8.4 Hz, 1H), 5.16 — 5.26 (m, 1H), 4.87 (d, J = 13.6 Hz, 1H), 4.58 (d, J: 13.6 Hz, 1H), 4.23 - 4.34 (m, 1H), 3.87 - 4.00 (m, 1H), 3.55 - 3.69 (m, 3H), 3.24 - 3.31 (m, 1H), 3.07 - 3.21 (m, 3H), 1.79 - 2.04 (m, 4H), 1.54 (d, J: 6.7 Hz, 3H), 1.47 (s, 3H). -89— Example 52 -[(4R,10bS)(3,4a,5,6,7,7a-hexahydro-ZH—pyrrolo[3,4-b] [1,4] yl)—4-methyl— 3,4,6,10b-tetrahydro—lH-pyrazino[2,1-a]isoindolyl]quinoline—S-carbonitrile The title compound was prepared in analogy to the preparation of e 10 by using tert-butyl octahydropyrrolo[3,4-b]morpholinecarboxylate (CAS: 13603641, PharinaBlock, Catalog: PBCS1406244) instead of tert—butyl (3R)(hydroxyrnethy1)piperazinecarboxy1ate.

Example 52 (18 mg) was obtained. MS: calc’d 467 [(M+H)+], measured 467 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) (5 ppm 9.03 (dd, J = 1.6, 4.3 Hz, 1H), 8.75 (dd, J = 1.6, 8.6 Hz, 1H), 8.18 (d, J: 7.9 Hz, 1H), 7.71 (dd, J: 4.3, 8.6 Hz, 1H), 7.36 (d, J: 8.1 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.25 (s, 1H), 7.09 (dd, J = 1.5, 7.9 Hz, 1H), 4.54 (br d, J: 12.7 Hz, 2H), 4.09 - 4.18 (m, 1H), 4.01 - 3.89 (m, 1H), 3.59 - 3.74 (m, — 4.08 (m, 1H), 3.89 - 4.00 (m, 2H), 3.79 3H), 3.51 - 3.58 (m, 1H), 3.18 - 3.31 (m, 2H), 2.87 - 3.13 (m, 5H),1.38(d, J: 6.4 Hz, 3H). 2019/064323 Example 53A and 53B -[(4R,10bS)-8—[(6S)—6-hydroxy-1,4—diazepan-l-yl]methyl-3,4,6,10b-tetrahydro-IH- pyrazinolZJ~a]isoindolyl]quinoline—S-carbonitrile and 5-[(4R,10bS)—8—[(6R)hydroxy- 1,4-diazepanyl]methyl-3,4,6,10b-tetrahydro-lH-pyrazino[2,1-a]isoindol yl]quinoline—S-carbonitrile N N I I | 1 N\ N\ / / N N N N N N H H The title compound was prepared in analogy to the preparation of Example 16A and 16B by using terz-butyl 6—hydroxy-1,4-diazepanecarboxylate (CAS: 9563171, WUXI APPTEC, Catalog: WX604354) instead of trans-3—(boc-amino)—4~1nethoxypyrrolidine. Example 53A (19.8 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHz, OL-d4) 6 ppm 8.91 (dd, J = 1.6, 4.3 Hz, 1H), 8.66 (dd, J = 1.5, 8.6 Hz, 1H), 8.05 (d, J: 8.1 Hz, 1H), 7.61 (dd, J: 4.3, 8.7 Hz, 1H), 7.36 - 7.17 (m, 2H), 6.94 (d, J= 1.3 Hz, 1H), 6.83 (dd, J: 2.3, 8.6 Hz, 1H), 5.17 (br d, J: 7.7 Hz, 1H), 4.73 - 4.81 (m, 1H), 4.50 (br d, J = 13.7 Hz, 1H), 4.27 - 4.34 (m, 1H), 4.15 - 4.26 (m, 1H), 3.70 - 3.86 (m, 3H), 3.47 - 3.66 (m, 3H), 3.36 - 3.45 (1n, 1H), 3.13 - 3.28 (m, 5H), 1.44 (d, J: 6.7 Hz, 3H). Example 53B (23.3 mg) was obtained. MS: calc’d 455 [(M+H)+], ed 455 [(M+H)+]. 1H NMR (400 MHZ, METHANOL-d4)5 ppm 8.91 (dd, J: 1.6, 4.2 Hz, 1H), 8.66 (dd, J: 1.5, 8.6 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.61 (dd, J: 4.3, 8.6 Hz, 1H), 7.17 - 7.34 (m, 2H), 6.95 (d, J: 1.3 Hz, 1H), 6.83 (dd, J: 2.3, 8.6 Hz, 1H), 5.10 - 5.22 (m, 1H), 4.78 - 4.82 (m, 1H), 4.50 (br d, J: 13.7 Hz, 1H), 4.28 - 3.86 (m, 3H), 3.46 - 3.66 (m, 3H), 3.35 - 3.44 (m, - 4.35 (m, 1H), 4.14 - 4.27 (m, 1H), 3.70 1H), 3.12 — 3.29 (in, 5H), 1.44 (d, J: 6.7 Hz, 3H). -91 _ Example 54 -[(4R,10bS)(6-amin0-1,4-oxazepan—4—yl)methyl—3,4,6,10b-tetrahydro-IH- pyrazino [2,1-a1isoindol-2—yl] quinoline—8-carbonitrile OJ(—N The title compound was prepared in y to the preparation of Example 10 by using tert-butyl N-(l,4-oxazepanyl)carbamate (CAS: 17829168, Block, Catalog: PB95734) instead of tert-butyl (3R)—3~(hydroxymethyl)piperazine—1—carboxy1ate. Example 54 (8.1 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. ‘H NMR (400 MHZ, METHANOL-d4) 5 ppm 9.04 (dd, J: 1.6, 4.3 Hz, 1H), 8.77 (dd, J: 1.7, 8.6 Hz, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.72 (dd, J= 4.3, 8.6 Hz, 1H), 7.37 (d, J: 8.1 Hz, 1H), 7.28 (d, J: 8.4 Hz, 1H), 7.02 (d, J: 2.0 Hz, 1H), 6.87 (dd, J: 2.3, 8.4 Hz, 1H), 4.80 - 4.87 (m, 1H), 4.69 (d, J: 13.2 Hz, 1H), 4.28 (d, J: 13.1 Hz, 1H), 4.13 - 4.21 (m, 1H), 3.71 - 4.08 (m, 7H), 3.45 - 3.68 (m, 4H), 3. 01 - 3.20 (m, 2H), 1.46 (d, J: 6.6 Hz, 3H).

Example 54A and 54B -[(4R,10bS)[(6R)amin0-1,4-0xazepan-4—y1]methyl-3,4,6,10b—tetrahydro-1H- pyrazin0[2,1-a]isoindolyl]quinoline—8-carbonitrile and 5-[(4R,10bS)—8-|(6S)—6—amin0—1,4- oxazepanyl]methyl—3,4,6,10b-tetrahydro-lH-pyrazino[2,1-a]isoindolyl]quinoline-S- carbonitrile N N l | I | N\ N\ / / N N The title compound was ed in analogy to the ation of Example 16A and 16B by using terZ-butyl -oxazepany1)carbamate (CAS: 17829168, PharmaBlock, Catalog: PB95734) instead of trans(boc-amino)-4—methoxypyrrolidine. Example 54A (29 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 6 ppm 9.04 (dd, J: 1.6, 4.3 Hz, 1H), 8.77 (dd, J: 1.7, 8.6 Hz, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.72 (dd, J: 4.3, 8.6 Hz, 1H), 7.37 (d, J: 8.1 Hz, 1H), 7.28 (d, J: 8.4 Hz, 1H), 7.02 (d, J: 2.0 Hz, 1H), 6.87 (dd, J: 2.3, 8.4 Hz, 1H), 4.80 — 4.87 (m, 1H), 4.69 (d, J: 13.2 Hz, 1H), 4.28 (d, J = 13.1 Hz, 1H), 4.13 - 4.21 (m, 1H), 3.71 - 4.08 (m, 7H), 3.45 - 3.68 (m, 4H), 3.01 - 3.20 (m, 2H), 1.46 (d, J= 6.6 Hz, 3H). Example 543 (36 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHZ, METHANOL—d4) 5 ppm 9.04 (dd, J: 1.6, 4.3 Hz, 1H), 8.77 (dd, J = 1.7, 8.6 Hz, 1H), 8.19 (d, J: 7.9 Hz, 1H), 7.72 (dd, J: 4.2, 8.6 Hz, 1H), 7.38 (d, J: 8.1 Hz, 1H), 7.28 (d, J: 8.4 Hz, 1H), 7.01 (d, J: 2.0 Hz, 1H), 6.86 (dd, J: 2.4, 8.5 Hz, 1H), 4.74 = 13.2 Hz, 1H), - 4.83 (m, 1H), 4.66 (d, J: 13.1 Hz, 1H), 4.25 (d, J 4.12 - 3.67 (m, 4H), 3.01 - 3.19 (m, 2H), 1.44 (d, J: - 4.21 (m, 1H), 3.73 — 4.08 (m, 7H), 3.45 6.6 Hz, 3H).

Example 55 -[(4R,10bS)—8-(6-hydroxymethyl-1,4-diazepanyl)—4—methyl-3,4,6,10b-tetrahydr0-1H- pyrazino[2,1-alis0indolyl]quinoline-S-carbonitrile ”bk/LW” The title compound was prepared in analogy to the preparation of Example 10 by using tert—butyl oxymethyl-1,4-diazepane—1—carboxy1ate (PharmaBlock, Catalog: PB96918) instead of utyl (3R)—3-(hydroxymethyl)piperazinecarboxy1ate. Example 55 (42 mg) was obtained. MS: calc’d 469[(M+H)+], measured 469 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 6 ppm 9.03 (dd, J: 1.7, 4.2 Hz, 1H), 8.73 (dd, J: 1.6, 8.6 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.70 (dd, J= 4.2, 8.6 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.18 (d, J: 8.4 Hz, 1H), 7.05 (d, J: 1.8 Hz, 1H), 6.88 (dd, J = 2.3, 8.4 Hz, 1H), 4.48 (br (1, J= 12.6 Hz, 2H), 3.96 — 4.09 (m, 2H), 3.81 - 3.90 (m, 2H), 3.61 - 3.73 (m, 3H), 3.49 - 3.55 (m, 1H), 3.38 - 3.44 (m, 1H), 3.25 - 3.33 (m, 2H), 3.10 — 3.17 (m, 1H), 2.95 - 3.05 (m, 2H), 1.38 (s, 3H),1.38(d, J: 6.7 Hz, 3H).

Example 55A and 55B -[(4R,10bS)[(6.5')hydroxymethyl—1,4-diazepan—1-yl]—4-methyl-3,4,6,10b-tetrahydro- lH-pyrazino[2,1-a]isoindolyl]quinoline-S-carbonitrile and 5-[(4R,10b.$')—8—[(6R)—6- hydroxy—6—methyl-l,4-diazepanyl}methyl-3,4,6,10b-tetrahydro-lH-pyrazino[2,1- a]isoindol—Z-yl]quinoline—S-carbonitrile N N I | I l N\ N\ / / N N Nj\ Nj\ The title compound was prepared in analogy to the preparation of e 16A and 16B by using tert—butyl 6-hydroxymethyl-1,4-diazepanecarboxylate (PharmaBlock, Catalog: P396918) instead of 3~(boc-amino)methoxypyrrolidine. Example 55A (26 mg) was obtained. MS: calc’d 469 [(M+H)+], measured 469 [(M+H)+]. 1H NMR (400 MHZ, METHANOL-d4) 6 ppm 9.03 (dd, J: 1.7, 4.2 Hz, 1H), 8.73 (dd, J: 1.6, 8.6 Hz, 1H), 8.17 (d, J = 8.1Hz,1H), 7.70 (dd, J: 4.2, 8.6 Hz,1H), 7.33 (d, J: 8.1 Hz, 1H), 7.18 (d, J: 8.4 Hz,1H), 7.05 (d, J: 1.8 Hz, 1H), 6.88 (dd, J: 2.3, 8.4 Hz, 1H), 4.48 (br (1, J: 12.6 Hz, 2H), 3.96 — 4.09 (m, 2H), 3.81 — 3.90 (m, 2H), 3.61 ~ 3.73 (m, 3H), 3.49 - 3.55 (m, 1H), 3.38 - 3.44 (m, 1H), 3.25 - 3.32 (m, 2H), 3.10 - 3.17 (m, 1H), 2.95 - 3.05 (m, 2H), 1.38 (s, 3H), 1.38 (d, J: 6.7 Hz, 3H). e 55B (23.8 mg) was obtained. MS: calc’d 469 [(M+H)+], measured 469 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 5 ppm 1H NMR (400 MHz, CD3OD, 298 K) (5 (ppm) = 9.05 (dd, J = 1.6, 4.3 Hz, 1H), 8.77 (dd, J: 1.7, 8.6 Hz, 1H), 8.19 (d, J: 7.9 Hz, 1H), 7.73 (dd, J: 4.3, 8.6 Hz, 1H), 7.37 (d, J: 8.1 Hz, 1H), 7.25 (d, J: 8.6 Hz, 1H), 7.07 (d, J: 2.1 Hz, 1H), 6.94 (dd, J: 2.3, 8.5 Hz, 1H), 4.70 (d, J: 13.2 Hz, 1H), 4.32 (d, J: 13.3 Hz, 1H), 3.95 - 4.13 (m, 2H), 3.80 — 3.94 (m, 2H), 3.54 - 3.75 (m, 3H), 3.38 — 3.44 (m, 1H), 3.23 - 3.32 (m,3H), 3.01 - 3.21 (m, 3H), 1.47 (d, J: 6.7 Hz, 3H), 1.38 (s, 3H).

Example 56 -[(4R,10bS)-4—methyl(1,4-oxazepan—6-ylamino)-3,4,6,10b-tetrahydro-lH-pyrazino[2,1- a]isoindol—Z-yl]quinoline-S-carbonitrile 752:1 HN\~/J The title compound was prepared in analogy to the preparation of Example 10 by using tert-butyl 6-amino-1,4-0xazepanecarb0xylate (CAS: 11703901, WUXI , g: WX601045) instead of tert-butyl (3R)-3—(hydroxymethyl)piperazine—1-carboxy1ate. Example 56 (49.4 mg) was obtained. MS: calc’d 455[(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHZ, METHANOL-d4) 6 ppm 9.03 (dd, J: 1.6, 4.3 Hz, 1H), 8.75 (dd, J = 1.7, 8.6 Hz, 1H), 8.17 (d, J = 7.9 Hz, 1H), 7.71 (dd, J: 4.3, 8.6 Hz, 1H), 7.36 (d, J: 8.1 Hz, 1H), 7.20 (d, J: 8.3 Hz, 1H), 6.85 (d, J: 1.8 Hz, 1H), 6.72 (dd, J: 2.1, 8.3 Hz, 1H), 4.76 ~ 4.86 (m, 1H), 4.65 (d, J: 13.1 Hz, 1H), 4.25 (d, J=13.1 Hz, 1H), 3.85 - 4.15 (m, 6H), 3.76 - 3.85 (m, 1H), 3.54 - 3.62 (m, 1H), 3.38 - 3.51 (m, 4H), 3.01 - 3.17 (m, 2H),1.45(d,J= 6.6 Hz, 3H). —96- Example 56A and 56B -[(4R,10bS)methyl—8-[{(6R)-1,4-oxazepanyl]amino]-3,4,6,10b-tetrahydro-1H- pyrazino[2,1-a]isoindolyl]quinoline—S-carbonitrile and 5-[(4R,10bS)—4-methyl{[(6S)- 1,4-oxazepanyl]amino]-3,4,6,10b-tetrahydro-1H—pyrazino[2,1-a]isoindol-Z-yl]quinoline- 8-carbonitrile N N I I I | N N \ \ / / N N Nj\ Nj\ HN HN ( O ( O ”Nd “Nd The title compound was ed in analogy to the preparation of Example 16A and 168 by using tert—b‘utyl o-1,4-oxazepaneearboxylate (CAS: 1170390—54-1, WUXI APPTEC, Catalog: WX601045) instead of trans(boc—amino)—4-methoxypyrrolidine. Example 56A (24 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455[(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 9.03 (dd, J: 1.6, 4.3 Hz, 1H), 8.75 (dd, J: 1.7, 8.6 Hz, 1H), 8.17 (d, J = 7.9 Hz, 1H), 7.71 (dd, J: 4.3, 8.6 Hz, 1H), 7.36 (d, J: 8.1 Hz, 1H), 7.20 (d, J: 8.3 Hz, 1H), 6.85 (d, J: 1.8 Hz, 1H), 6.72 (dd, J= 2.1, 8.3 Hz,1H), 4.76 - 4.86 (1n, 1H), 4.65 (d, J:13.1 Hz, 1H), 4.25 (d, J: 13.1 Hz, 1H), 3.85 - 4.15 (m, 6H), 3.76 - 3.85 (m, 1H), 3.54 — 3.62 (m, 1H), 3.38 — 3.51 (m, 4H), 3.01 - 3.17 (m, 2H), 1.45 (d, J: 6.6 Hz, 3H). e 56B (28 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHZ, METHANOL-d4) (5 ppm 1H NMR (400 MHz, CD3OD, 298 K) 6 (ppm) 9.03 (dd, J = 1.7, 4.2 Hz, 1H), 8.75 (dd, J: 1.7, 8.6 Hz, 1H), 8.18 (d, J: 8.1 Hz, 1H), 7.71 (dd, J: 4.2, 8.6 Hz, 1H), 7.36 (d, J: 8.1 Hz, 1H), 7.18 (d, J: 8.2 Hz, 1H), 6.83 (d, J2 1.7 Hz, 1H), 6.69 (dd, J: 2.1, 8.3 Hz, 1H), 4.60 — 4.69 (m, 1H), 4.56 (d, J = 13.1 Hz, 1H), 3.94 - 4.15 (m, 5H), 3.74 - 3.92 (m, 3H), 3.52 - 3.59 (m, 1H), 3.39 - 3.48 (1n, 4H), 2.94 — 3.12 (m, 2H), 1.40 (d, J: 6.6 Hz, 3H).

Example 57 -[(4R,10bS)—4-methyl(morph01inylmethylamino)-3,4,6,1Ob-tetrahydro-IH- pyrazino[2,1-a]is0indol—2-yl]quinoline-S-carbonitrile jENj\ 0 NH The title nd was prepared in analogy to the preparation of Example 10 by using tert-butyl 3~(aminomethyl)morpholinecarboxylate (CAS: -18—4, BePharm, Catalog: BD28817) instead of tert-butyl (3R)—3-(hydroxymethyl)piperazine-l~carboxylate. Example 57 (17.5 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) d ppm 9.01 (dd, J = 1.6, 4.3 Hz, 1H), 8.75 (dd, J = 1.7, 8.6 Hz, 1H), 8.15 (d, J: 7.9 Hz, 1H), 7.70 (dd, J: 4.3, 8.6 Hz, 1H), 7.35 (d, J: 7.9 Hz, 1H), 7.23 (d, J: 8.3 Hz, 1H), 6.85 (d, J: 1.8 Hz, 1H), 6.73 (dd, J: 2.1, 8.4 Hz, 1H), 5.02 - 5.12 (m, 1H), 4.78 (d, J: 13.6 Hz, 1H), 4.44 (d, J: 13.6 Hz, 1H), 4.15 — 4.21 (m, 1H), 4.07 - 4.14 (m, 1H), 3.96 — 4.03 (m, 1H), 3.86 - 3.92 (m, 1H), 3.73 — 3.82 (m, 1H), 3.50 — 3.67 (m, 3H), 3.40 - 3.45 (m, 2H), 3.32 — 3.38 (m, 1H), 3.16 - 3.26 (m, 2H), 3.05 — 3.14 (m, 1H), 1.49 (d, J= 6.7 Hz, 3H).

Example 58 -[(4R,10bS)methyl[[(2S)-morpholinyl]methylamino]-3,4,6,10b-tetrahydro—1H- pyrazino[2,1-a]isoindol—2—yl]quinoline—8—carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert—butyl N—[(2S)-morpholinylmethyl]carbamate (CAS: 875551-59—0, PharmaBlock, Catalog: PBN20121323) instead of tert-butyl -(hydroxymethyl)piperazinecarboxylate. Example 58 (28 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHZ, METHANOL-d4) 5 ppm 8.88 (dd, J = 1.7, 4.2 Hz, 1H), 8.60 (dd, J = 1.6, 8.6 Hz, 1H), 8.05 (d, J: 7.9 Hz, 1H), 7.56 (dd, J: 4.3, 8.6 Hz, 1H), 7.21 (d, J: 8.1 Hz, 1H), 6.89 (d, J: 8.1 Hz,1H), 6.60 (d, J: 1.7 , 6.43 (dd, J: 2.1, 8.1 Hz, 1H), 4.11 (d, J: 12.1 Hz,1H), 3.94 (br d, J: 10.1 Hz, 1H), 3.69 - 3.83 (m, 2H), 3.45 - 3.62 (m, 3H), 3.31 - 3.41 (m, 1H), 3.27 - 3.30 (m, 1H), 2.94 — 3.10 (m, 2H), 2.79 - 2.91 (m, 2H), 2.64 - 2.78 (m, 3H), 2.38 - 2.55 (m, 1H), 1.15 (d, J: 6.4 Hz, 3H).

Example 59 -[(4R,10bS)methyl[[(2R)-morpholinyl]methylamino]-3,4,6, 1 0b—tetrahydro-1H- pyrazino [2, 1 ~21]isoindol—2-yl] quinoline-8—carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert—butyl )—morpholiny1methyl]carbamate (CAS: 1862023, PharmaBlock, Catalog: PBN20121322) instead of tert~butyl (3R)—3-(hydroxymethyl)piperazine~1—carboxylate. Example 59 (8.8 mg) was ed. MS: calc’d 455 [(M+H)+], measured 455 +]. 1H NMR (400 MHz, METHANOL-d4) 5 ppm 8.88 (dd, J = 1.7, 4.2 Hz, 1H), 8.60 (dd, J = 1.6, 8.6 Hz, 1H), 8.05 (d, J: 7.9 Hz, 1H), 7.56 (dd, J: 4.3, 8.6 Hz, 1H), 7.21 (d, J: 8.1 Hz, 1H), 6.89 (d, J: 8.1 Hz, 1H), 6.60 (d, J: 1.7 Hz,1H), 6.43 (dd, J: 2.1, 8.1Hz,1H), 4.11 (d, J: 12.1 Hz, 1H), 3.94 (br d, J: 10.1 Hz, 1H), 3.69 - 3.83 (m, 2H), 3.45 - 3.62 (m, 3H), 3.31 - 3.41 (m, 1H), 3.27 - 3.30 (m, 1H), 2.94 - 3.10 (m, 2H), 2.79 - 2.91 (m, 2H), 2.64 - 2.78 (m, 3H), 2.38 - 2.55 (m, 1H), 1.15 (d, J: 6.4 Hz, 3H). -l 00- Example 60 - [(4R, 1 0bS)—8- [ [(3S,4R)methoxypyrrolidinyl] amino] methyl-3,4,6, 1Ob—tetrahydro— lH-pyrazino[2,1-a]isoindol—2-yl]quinolinecarbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using (3S,4R)—tert-butyl 3-amino~4-methoxypyrrolidine-1—carboxylate (CAS: 1482601, BePharm, Catalog: BD260807) instead of tert—butyl (3R)(hydroxymethyl)piperazinecarboxy1ate.

Example 60 (70 mg) was obtained. MS: calc’d 455 [(M+H)+], ed 455 [(M+H)+]. 1H NMR (400 MHZ, OL-d4) 8 ppm 9.03 (dd, J = 1.7, 4.2 Hz, 1H), 8.75 (dd, J: 1.7, 8.6 Hz, 1H), 8.18 (d, J: 8.1 Hz, 1H), 7.71 (dd, J= 4.3, 8.6 Hz,1H), 7.36 (d, J: 8.1 Hz, 1H), 7.19 (d, J: 8.3 Hz, 1H), 6.89 (d, J: 1.7 Hz, 1H), 6.75 (dd, J: 2.1, 8.3 Hz, 1H), 4.68 — 4.77 (m, 1H), 4.61 (d, J: 13.1 Hz, 1H), 4.29 - 4.21 (m, 2H), 3.81 - 3.95 (m, 2H), 3.52 - - 4.39 (m, 1H), 4.11 3.69 (m, 3H), 3.42 - 3.46 (m, 1H), 3.42 (s, 3H), 3.03 - 3.22 (m, 3H), 1.42 (d, J: 6.6 Hz, 3H).

Example 61 ,10bS)—8-[[(3R,4S)—4—methoxypyrrolidin—3-yl]amino]methyl—3,4,6,lOb-tetrahydro- lH—pyrazino[2,1-a]isoindol—Z-yl]quinoline-S-carbonitrile The title compound was ed in analogy to the preparation of Example 10 by using (3R,4S)—tert-butyl 3-aminomethoxypyrrolidinecarboxylate (CAS: 1482600, BePharm, Catalog: BD285562) instead of tert—butyl (3R)-3—(hydroxymethyl)piperazinecarboxylate. e 61 (61 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 8 ppm 9.03 (dd, J = 1.6, 4.3 Hz, 1H), 8.74 (dd, J: 1.6, 8.6 Hz, 1H), 8.18 (d, J= 7.9 Hz, 1H), 7.70 (dd, J= 4.2, 8.6 Hz, 1H), 7.35 (d, J= 8.1 Hz, 1H), 7.16 (d, J= 8.2 Hz, 1H), 6.88 (d, J: 1.8 Hz, 1H), 6.73 (dd, J= 2.1, 8.2 Hz, 1H), 4.48 - 4.59 (m, 2H), 4.28 - 3.93 (m, 1H), 3.69 - — 4.38 (m, 1H), 4.10 - 4.17 (m, 1H), 4.05 (d, J = 13.0 Hz, 1H), 3.85 3.79 (m, 1H), 3.58 - 3.67 (m, 2H), 3.51 — 3.57 (m, 1H), 3.41 ~3.45 (m, 1H), 3.42 (s, 3H), 3.13 - 3.22 (m, 1H), 2.96 - 3.09 (m, 2H), 1.39 (d, J: 6.5 Hz, 3H).

Example 62 -[(4R,10bS)—8—[[(3S,4S)methoxypyrrolidinyl]amino]methyl—3,4,6,10b—tetrahydrolH-pyrazino [2,1-a]isoindol-Z-yl]quinoline-S-carbonitrile @131 fwd“ The title compound was prepared in analogy to the preparation of Example 10 by using tert—butyl )aminomethoxypyrrolidinecarboxylate (CAS: 10016353, BePharm, g: BD260806) instead of tert—butyl (3R)—3—(hydroxymethyl)piperazine~1—carboxy1ate.

Example 62 (58 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 5 ppm 9.04 (dd, J = 1.7, 4.2 Hz, 1H), 8.77 (dd, J = 1.7, 8.6 Hz, 1H), 8.19 (d, J: 8.1 Hz, 1H), 7.73 (dd, J: 4.3, 8.6 Hz, 1H), 7.38 (d, J: 8.1 Hz, 1H), 7.25 (d, J= 8.2 Hz, 1H), 6.84 (d, J== 1.8 Hz, 1H), 6.72 (dd, J: 2.1, 8.3 Hz, 1H), 4.93 - 5.03 (m, 1H), 4.74 (d, J: 13.4 Hz, 1H), 4.38 (d, J: 13.3 Hz, 1H), 4.20 (br d, J: 5.4 Hz, 1H), 4.02 - 4.12 (m, 2H), 3.87 - 3.54 (m, 2H), 3.48 (s, - 3.95 (m, 1H), 3.67 - 3.75 (m, 1H), 3.58 - 3.65 (m, 1H), 3.50 3H), 3.37 (d, J: 2.1 Hz, 1H), 3.06 - 3.24 (m, 2H), 1.48 (d,J= 6.7 Hz, 3H). —l 02— Example 63 ,10bS)—8-[[(3R,4R)-4—meth0xypyrrolidinyl]amino]-4,9-dimethyl-3,4,6, 10b- tetrahydro—lH-pyrazino[2,1—a]isoindol—2-yl]quinoline—8-carbonitrile The title compound was prepared according to the following scheme: —103— N N II II N\ N / / (s 5 NBS I M M j\ HOAC N Pd(dppf)C|2.DCM Br K2C03 dioxane/water HN’ HN’ 0 O / N O / N o \(il/ Y H H N: N: @l @k )30-C‘Yo f+ ,-C‘ Example 63 Step 1: ation of tert—butyl (3R,4R)[[(4R,10bS)-9—bromo (8-cyano —5-quinolyl)methyl—3,4,6,10b—tetrahydro-1H—pyrazino[2,1—a]isoindol—S-yl]amino] methoxy—pyrrolidine—l-carboxylate (compound 63b) To a on of tert—butyl (3R,4R)[[(4R,10bS)(8-cyanoquinoly1)—4-methyl- 3 ,4,6,10b—tetrahydro-1H—pyrazino[2,1-a]isoindol-S—yl]amino]—4-methoxy—pyrrolidine—l- carboxylate (compound 63a, 200 mg, 361 umol) in Acetic Acid (5 mL) was added NBS (64.2 mg, 361 umol). The resultant mixture was stirred at room temperature for 2 hrs. The reaction was quenched with aqueous NaHCOg. The aqueous layer was extracted with EtOAc (10 mL) for three times. The combined organic layers were washed with water, brine, dried over NaZSO4 and concentrated in vacuo. The residue was purified by flash tography (silica gel, 12 g, 0% to 100% EtOAc in PE) to afford compound 63b (98 mg, 42.9 % yield). MS: calc’d 633 [(M+H)+], measured 633 [(M+H)+].

Step 2: preparation of tert—butyl (3R,4R)[[(4R,10bS)(8-cyano-S-quinolyl)—4,9- dimethyl—3,4,6,10b—tetrahydro-lH-pyrazino[2,1-a]isoindol—8-yl]amino]-4—methoxy- pyrrolidine—l-carboxylate (compound 63c) To a solution of tert-butyl (3R,4R)-3—[[(4R,10bS)-9—br0mo(8-cyano—5— quinoly1) methyl-3 0b-tetrahydro-1H—pyrazino[2,1-a]isoindol—8—yl]amino]—4- y—pyrrolidine-l - carboxylate (compound 63b, 98 mg, 155 umol) in dioxane (5 mL) and water (1 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (38.8 mg, 309 umol), K2CO3 (42.8 mg, 309 umol) and Pd(dppf)Cl-CH2C12 adduct (11.3 mg, 15.5 umol). The resultant mixture was stirred at 90 °C for 2 hrs. Then the e was cooled to room temperature, diluted with water (20 mL) and extracted with BA (20 mL) for three times. The combined organic layer was washed with brine, dried over Na2804, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 20 g, 30% to 100% EtOAc in PE) to afford compound 63c (53 mg, 60.3 % yield). MS: calc’d 569 [(M+H)+], measured 569 [(M+H)+].

Step 3: preparation of 5-[(4R,10bS)-8—[[(3R,4R)-4—methoxypyrrolidinyl]amino]—4,9- dimethyl-3,4,6,1 0b-tetrahydro-lH-pyrazinol2,1-a]isoindol-Z-yl]quinoline-S-carbonitrile (Example 63) To a solution of tert—butyl (3R,4R)—3-[[(4R,10bS)—2—(8-cyan0quinolyl)-4,9- dimethyl- 3 ,4,6, 1 0b—tetrahydro- 1 I—I-pyrazino[2, 1 ~a]isoindoly1] amino] hoxy—pyrrolidine- 1 — carboxylate und 63c, 53 mg, 93.2 pmol) in DCM (10 ml) was added TFA (5 ml). The reaction e was stirred at room temperature for 2 hrs, then concentrated to afford a crude product which was purified by pre-HPLC to afford Example 63 (32 mg, 58.9 % yield). MS: calc’d 469 [(M+H)+], measured 469 +]. 1H NMR (400 MHZ, METHANOL—d4) 5 ppm 9.03 (dd, J: 1.7, 4.2 Hz,1H), 8.75 (dd, J: 1.6, 8.6 Hz,1H), 8.18 (d, J: 8.1 Hz, 1H), 7.71 (dd, J = 4.3, 8.6 Hz, 1H), 7.36 (d, J: 8.1 Hz, 1H), 7.10 (s, 1H), 6.82 (s, 1H), 4.53 - 4.67 (m, 2H), 4.27 (br (1, J = 5.5 Hz, 1H), 4.08 - 4.17 (1n, 2H), 3.90 (br d, J: 12.1 Hz, 1H), 3.70 - 3.83 (m, 2H), 3.52 - 3.59 (m, 3H), 3.50 (s, 3H), 3.42 - 3.49 (m, 1H), 3.02 - 3.12 (m, 2H), 2.20 (s, 3H), 1.41 (d, J= 6.6 Hz, 3H). -105— Example 64 -[(4R,10bS)[[(3S,4S)methoxypyrrolidin—3-yl]-methyl-amino]methyl-3,4,6,10b- ydro—lH—pyrazino[2,1-a]isoindol—2-yl]quinoline—S-carbonitrile \ Mk 9 g 5 HD‘N\ The title compound was prepared in analogy to the preparation of Example 10 by using tert-butyl (3S,4S)~3-methoxy—4-(methylamino)pyrrolidinecarboxylate (CAS: 9603169, PharmaBlock, Catalog: 14) instead of tert-butyl (3R)-3—(hydroxymethyl)piperazine carboxylate. Example 64 (25 mg) was obtained. MS: calc’d 469 [(M+H)+], measured 469 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 9.04 (dd, J = 1.7, 4.3 Hz, 1H), 8.77 (dd, J: 1.7, 8.6 Hz,1H), 8.19 (d, J: 7.9 Hz,1H), 7.73 (dd, J= 4.2, 8.6 Hz,1H), 7.38 (d, J: 7.9 Hz, 1H), 7.33 (d, J: 8.3 Hz,1H), 7.16 (d, J= 1.8 Hz, 1H), 7.03 (dd, J: 2.2, 8.3 Hz, 1H), 4.82 - 4.87 (m,1H), 4.71 (d,J= 13.2 Hz, 1H), 4.40 - 4.47 (m, 1H), 4.31 (d, J = 13.1 Hz, 1H), 4.14 - 4.21 (m, 1H), 3.88 - 3.48 (m, 2H), 3.36 (s, 3H), 3.06 — 3.19 (m, — 4.04 (m, 2H), 3.51 - 3.69 (m, 3H), 3.37 2H), 2.91 (s, 3H), 1.46 (d, J: 6.7 Hz, 3H).

Example 65 —[(4R,10bS)-4—methyl—8—[[(3R)piperidyl]amino]-3,4,6,10b—tetrahydro-lH—pyrazino[2,1— a]isoindolyl]quinoline-S-carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using —106— tert-butyl (3R)aminopiperidine-1~carboxy1ate (CAS: 1881117, m, Catalog: BDO329) instead of tert-butyl (3R)(hydroxymethyl)piperazine-1—carboxy1ate. e 65 (27 mg) was obtained. MS: calc’d 439 [(M+H)+], measured 439 +]. ‘H NMR (400 MHZ, METHANOL-d4) 6 ppm 9.05 (dd, J= 1.7, 4.2 Hz, 1H), 8.77 (dd, J= 1.7, 8.6 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H), 7.73 (dd, J: 4.3, 8.6 Hz, 1H), 7.38 (d, J: 7.9 Hz, 1H), 7.32 (d, J: 8.4 Hz, 1H), 7.16 (d, J: 1.7 Hz, 1H), 7.03 (dd, J= 2.1, 8.5 Hz, 1H), 4.72 (d, J: 13.3 Hz, 1H), 4.33 (d, J= 13.4 Hz, 1H), 3.96 - 4.06 (m, 1H), 3.90 - 3.96 (m, 1H), 3.46 - 3.66 (m, 3H), 3.25 - 3.31 (m, 2H), 3.06 — 3.20 (m, 4H), 1.93 — 2.14 (m, 2H), 1.70 - 1.86 (m, 2H), 1.46 (d, J= 6.6 Hz, 3H).

Example 66 - [(4R,10bS)—8—| [(3S,4R)—3-methoxy—4-piperidyl]amino]methyl-3,4,6,10b—tetrahydro-1H- pyrazino[2,1-a]isoindolyl]quinoline—8—carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert—butyl (3S,4R)amino-3—methoxypiperidinecarboxy1ate(CAS: 1171125-92—0, PharmaBlock, Catalog: PBN20120813) instead of tert—butyl (3R)—3~(hydroxymethy1)piperazine- 1—carboxy1ate. Example 66 (28 mg) was ed. MS: calc’d 469 [(M+H)+], measured 469 [(M+H)+]. 1H NMR (400 MHZ, METHA‘NOL-d4) 0‘ ppm 8.87 (dd, J = 1.6, 4.3 Hz, 1H), 8.58 (dd, J=1.7, 8.6 Hz,1H), 8.02 (d, J: 7.9 Hz,1H), 7.55 (dd, J= 4.3, 8.6 Hz,1H), 7.19 (d, J: 8.1 Hz, 1H), 6.90 (d, J= 8.1 Hz, 1H), 6.67 (d, J: 1.5 Hz, 1H), 6.50 (dd, J = 2.0, 8.1 Hz, 1H), 4.10 (d, J = 12.1 Hz, 1H), 3.92 (br d, J: 10.4 Hz,1H), 3.73 (br (1, J = 11.0 Hz,1H), 3.52 (br d,J= 11.7 Hz, 1H), 3.42 - 3.20 (m, 2H), 2.81 - 2.96 (m, - 3.49 (m, 1H), 3.29 — 3.34 (m, 2H), 3.24 (s, 3H), 3.13 2H), 2.65 - 1.67 (1n, 2H), 1.14 (d, J: 6.5 Hz, 3H). - 2.76 (m, 1H), 2.44 - 2.61 (m, 2H), 1.48 -107— Example 67 -[(4R,10bS)methyl(2-m0rpholinoethylamino)—3,4,6,10b-tetrahydro-1H-pyrazino[2,l- a]isoindol—Z—yl]quinoline—S-carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using 2- morpholinoethanamine (CAS: 20381, BePharm, Catalog: 7) instead of Iert—butyl (3R)—3—(hydroxymethyl)piperazinecarboxy1ate. Example 67 (29 mg) was obtained. MS: calc’d 469 [(M+H)+], measured 469 [(M+H)+]. IH NMR (400 MHz, METHANOL—d4) 6 ppm 8.87 (dd, J= 1.7, 4.2 Hz, 1H), 8.57 (dd, J= 1.7, 8.6 Hz, 1H), 8.02 (d, J: 8.1 Hz, 1H), 7.55 (dd, J = 4.2, 8.6 Hz, 1H), 7.18 (d, J: 8.1 Hz, 1H), 6.88 (d, J: 8.1 Hz, 1H), 6.59 (d, J: 1.7 Hz, 1H), 6.42 (dd,J= 2.1, 8.1 Hz, 1H), 4.10 (d, J: 12.2 , 3.91 (br d,J= 10.3 Hz,1H),3.68 - 3.76 (m, 1H), 3.57 - 3.64 (m, 4H), 3.51 (br d, J: 11.6 Hz, 1H), 3.31 (br d,J=11.6 Hz, 1H), 3.16 — 3.19 (m, 1H), 3.13 (t, J: 6.5 Hz, 2H), 2.86 (t, J: 10.9 Hz, 1H), 2.67 - 2.74 (m, 1H), 2.50 (t, J: 6.5 Hz, 2H), 2.37 - 2.45 (m, 4H), 1.14 (d, J: 6.4 Hz, 3H). —108- Example 68 -[(4R,10bS)—8—[2-[(3S)hydroxypyrrolidin- l-yl]ethylamino]-4—methyl-3,4,6, 10b- tetrahydro-lH—pyrazino[2,1-a]isoindol—2—yl]quinoline-S-carbonitrile <1...

The title compound was prepared in analogy to the ation of Example 10 by using (3S)-1—(2-aminoethy1)pyrrolidinol (CAS: 540787—75—5, BePharm, Catalog: BD45313) instead of utyl (3R)(hydroxymethyl)piperazinecarboxylate. Example 68 (13 mg) was obtained. MS: calc’d 469 [(M+H)+], measured 469[(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 5 ppm 8.87 (dd, J= 1.6, 4.3 Hz, 1H), 8.58 (dd, J: 1.6, 8.6 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.55 (dd, J= 4.3, 8.6 Hz, 1H), 7.19 (d, J: 8.1 Hz, 1H), 6.89 (d, J: 8.1 Hz, 1H), 6.60 (d, J: 1.6 Hz, 1H), 6.43 (dd, J: 2.0, 8.1 Hz, 1H), 4.20 - 4.31 (m, 1H), 4.10 (d, J: 12.2 Hz, 1H), 3.92 (br d, J: 10.3 Hz, 1H), 3.72 (br (1, J=11.2 Hz,1H), 3.52 (br d, J: 12.0 Hz, 1H), 3.32 (br d, J= 11.6 Hz,1H), 3.16 - 3.20 (m, 1H), 3.13 (t, J: 6.6 Hz, 2H), 2.86 (t, J: 10.9 Hz,1H), 2.59 — 2.77 (m, 5H), 2.38 - 2.51 (m, 2H), 1.99 — 2.12 (m, 1H), 1.59 - 1.72 (m, 1H), 1.14 (d, J= 6.4 Hz, 3H). —109- Example 69 -[(4R,10bS)—8-[(3-fluoroazetidinyl)methylamino]methyl-3,4,6,10b-tetrahydro-1H- pyrazino[2,1-a]isoindol—2-yl]quinolinecarbonitrile The title compound was prepared in y to the preparation of Example 10 by using tert-butyl 3~(aminomethyl)—3-fluoroazetidinecarboxylate (CAS: 1083181—23—0, PharmaBlock, Catalog: PBN20120081) instead of utyl (3R)—3—(hydroxymethyl)piperazine-1~carboxylate.

Example 69 (10 mg) was obtained. MS: calc’d 443 [(M+H)+], measured 443 [(M+~H)+]. ‘H NMR (400 MHz, METHANOL-d4) 5 ppm 9.04 (dd, J: 1.6, 4.3 Hz, 1H), 8.76 (dd, J z 1.7, 8.6 Hz, 1H), 8.18 (d, J: 7.9 Hz, 1H), 7.72 (dd, J: 4.3, 8.6 Hz, 1H), 7.37 (d, J: 7.9 Hz, 1H), 7.22 (d, J: 8.3 Hz, 1H), 6.90 (d, J: 1.7 Hz, 1H), 6.77 (dd, J: 2.1, 8.3 Hz, 1H), 4.95 - 5.02 (m, 1H), 4.75 (d, J= 13.3 Hz, 1H), 4.24 - 4.46 (m, 5H), 4.06 - 4.18 (m, 1H), 3.86 - 3.95 (111, 1H), 3.69 (d, J: 19.8 Hz, 2H), 3.55 — 3.64 (m, 1H), 3.16 - 3.25 (m, 1H), 3.04 - 3.13 (m, 1H), 1.49 (d, J: 6.6 Hz, 3H).

Example 70 -[(4R,10bS)—8-[1(2S,4S)-4—fluoropyrrolidin-Z-yl]methylamino]methyl—3,4,6, rahydro —lH-pyrazino[2,1-a]isoindol-Z-yl]quinoline-S—carbonitrile “51.4ng —l l 0- The title compound was ed in analogy to the preparation of Example 10 by using tert-butyl (23,4S)(aminomethyl)fluoropyrrolidinecarboxy1ate (CAS: 10332453, Block, Catalog: PB05325) instead of tert-butyl (3R)-3—(hydroxymethyl)piperazine ylate. Example 70 (28 mg) was obtained. MS: calc’d 457 [(M+H)+], measured 457 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 6 ppm 9.03 (dd, J = 1.6, 4.3 Hz, 1H), 8.76 (dd, J=1.7, 8.6 Hz, 1H), 8.17 (d, J= 7.9 Hz, 1H), 7.72 (dd, J: 4.3, 8.6 Hz, 1H), 7.37 (d, J: 7.9 Hz, 1H), 7.24 (d, J: 8.3 Hz,1H), 6.87 (d, J: 1.7 Hz,1H), 6.74 (dd, J2 2.1, 8.3 Hz, 1H), 5.39 - 5.58 (m, 1H), 4.97 - 4.17 (m, — 5.04 (m, 1H), 4.76 (d, J: 13.4 Hz, 1H), 4.40 (d, J: 13.4 Hz, 1H), 4.04 2H), 3.84 — 3.78 (m, 1H), 3.40 - 3.65 (m, 4H), 3.17 - 3.27 (m, 1H), 3.06 - - 3.96 (m, 1H), 3.68 3.14 (m, 1H), 2.51 - 2.73 (m, 1H), 2.12 - 2.31 (m, 1H), 1.49 (d, J: 6.6 Hz, 3H).

Example 71 -[(4R,10bS)[(8aS)—3-oxo—1,5,6,7,8,82-hexahydr0imidazo[1,5-a]pyrazin-Z-yljmethyl- 3,4,6,10b—tetrahydro-lH-pyrazino[2,1-a]isoindolyl]quinoline—S-carbonitrile The title nd was prepared in analogy to the preparation of Example 10 by using tert—butyl (8aR)oxo-l,2,5,6,8,8a-hexahydroimidazo[l,5-a]pyrazine carboxylate instead of tert—butyl (3R)—3—(hydroxymethyl)piperazine—1-carboxylate. Example 71 (38 mg) was obtained.

MS: calc’d 480 [(M+H)+], measured 480 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 5 ppm 9.03 (dd, J: 1.7, 4.2 Hz, 1H), 8.77 (dd, J3 1.6, 8.6 Hz, 1H), 8.18 (d, J: 7.9 Hz, 1H), 7.86 (d, J: 1.3 Hz, 1H), 7.72 (dd, J: 4.3, 8.6 Hz, 1H), 7.51 (dd, J: 2.0, 8.4 Hz, 1H), 7.33 - 7.47 (m, 1H), 4.92 = 13.3 Hz, 1H), 4.06 — 4.22 (m, - 5.01 (m, 1H), 4.77 (d, J: 13.3 Hz, 1H), 4.38 (d, J 3H), 3.93 - 4.06 (m, 2H), 3.68 - 3.74 (m, 1H), 3.54 — 3.65 (m, 2H), 3.41 — 3.47 (m, 1H), 3.29 (br d, J: 3.3 Hz, 1H), 3.00 - 3.22 (m, 4H), 1.47 (d, J: 6.6 Hz, 3H). -1 1 1— Example 72 -[(4R,10bS)[(8aR)-3—0xo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-Z-yl]methyl- 3,4,6,10b-tetrahydro—lH-pyrazino[2,1-a]is0indolyl]quinoline-S-carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert—butyl (8aS)oxo-l,2,5,6,8,8a-hexahydroimidazo[l,5-a]pyrazine carboxylate instead of tert—butyl —(hydroxymethy1)piperazine-1~Carboxylate. Example 72 (8.8 mg) was obtained.

MS: calc’d 480 [(M+H)+], ed 480 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 0' ppm 9.02 (dd, J: 1.6, 4.3 Hz, 1H), 8.74 (dd, J: 1.7, 8.6 Hz, 1H), 8.18 (d, J: 8.1 Hz, 1H), 7.75 (d, J: 1.5 Hz, 1H), 7.70 (dd, J: 4.2, 8.6 Hz, 1H), 7.44 (dd, J: 2.0, 8.3 Hz, 1H), 7.27 - 7.38 (m, 2H), 4.41 - 4.15 (m, 3H), 3.90 — 4.01 (m, 2H), 3.49 - 3.70 (in, 4H), 3.37 - 4.54 (m, 2H), 4.04 3.44 (m, 1H), 3.24 - 3.30 (1n, 1H), 3.03 - 3.14 (m, 3H), 2.87 - 3.01 (m, 1H), 1.36 (d, J: 6.5 Hz, 3H).

Example 73 -[(4R,10bS)[(3S,4S)—4-flu0r0pyrrolidin—3-yl]oxymethyl-3,4,6,10b-tetrahydro-1H— pyrazino[2,1-a]isoindol—2-yl]quinoline-8—carbonitrile HNO‘0 The title nd was prepared in analogy to the preparation of Example 10 by using tert-butyl (3S,4.S')-3 -fluorohydroxypyrrolidinecarboxylate (CAS: 1 1740209, -1 12- PharmaBlock, Catalog: PB08192) instead of tert—butyl (3R)—3-(hydroxymethyl)piperazine-lcarboxylate.

Example 73 (18 mg) was obtained. MS: calc’d 444 [(M+H)+], measured 444 [(M+H)+]. 1H NMR (400 MHz, OL-d4) (5 ppm 9.02 (dd, J = 1.5, 4.2 Hz, 1H), 8.73 (dd, J=1.5, 8.6 Hz, 1H), 8.17 (d, J= 8.1 Hz, 1H), 7.69 (dd, J: 4.2, 8.6 Hz, 1H), 7.34 (d, J= 7.9 Hz, 1H), 7.28 (d, J: 8.1 Hz, 1H), 7.14 (s, 1H), 6.97 (br (1, J: 8.4 Hz, 1H), 5.37 — 5.57 (m, 1H), 5.25 - 5.34 (m, 1H), 4.41 (d, J: 12.6 Hz, 1H), 4.28 (br (1, J= 10.1 Hz, 1H), 3.62 - 3.95 (m, 6H), 3.49 (br d, J: 8.9 Hz, 2H), 3.03 (t, J: 11.1 Hz, 1H), 2.90 (t, J: 11.7 Hz, 1H), 1.32 (d, J= 6.2 Hz, 3H). 1 0 Example 74 -[(4R,10b.S)—8-[[(2S,4S)—4-fluoropyrrolidin-Z—yl]methoxy]methyl-3,4,6,10b-tetrahydro- 1H-pyrazino[2,1-a]isoindol-Z-yl]quinoline-S-carbonitrile The title compound was prepared in analogy to the preparation of Example 10 by using tert-butyl S)—4-fluoro~2—(hydroxymethyl)pyrrolidinecarboxy1ate (CAS: 3173567, PharmaBlock, Catalog: PB05324) instead of tert-butyl (3R)(hydroxymethyl)piperazine—1- carboxylate. Example 74 (12 mg) was obtained. MS: cale’d 458 [(M+H)+], measured 458 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 9.02 (dd, J = 1.6, 4.3 Hz, 1H), 8.74 (dd, J=1.6, 8.6 Hz, 1H), 8.17 (d, J: 8.1 Hz, 1H), 7.70 (dd, J: 4.3, 8.6 Hz,1H), 7.35 (d, J: 8.1Hz, 1H), 7.29 (d, J: 8.3 Hz, 1H), 7.12 (d, J: 2.1 Hz, 1H), 6.96 (dd, J: 2.3, 8.3 Hz, 1H), 5.35 - 5.63 (m, 1H), 4.36 - 3.95 (m, 1H), - 4.53 (m, 3H), 4.14 — 4.32 (m, 2H), 3.99 (d, J== 12.8 Hz, 1H), 3.88 3.71 - 3.09 (m, 2H), 2.60 - 2.81 (m, 1H), 2.16 - 2.34 (m, - 3.81 (m, 1H), 3.42 - 3.67 (m, 3H), 2.92 1H), 1.36 (d, J: 6.6 Hz, 3H). -l 1 3- Example 75 (4R,1 0bS)—N—[(3S,4R)-4—fluoropyrrolidinyl]methyl-Z-(8-methyl—5-quinolyl)-3,4,6,1 0b- tetrahydro—lH-pyrazino[2,1-a]isoind01—8—amine The title compound was prepared ing to the following : Q 13w Ni Q6 :j\ PdCIH2 XPhos Pd <32 oszco3 MeOH F N O dioxane, 80 00 F NYC Y 1i 75a 75b N \/2 N\ j\ N r TFA/DCM —-—-—-——> HN —————-———-> RuPhos Pd 62 C52003 dioxane, 90 0c F’t‘ ”N N o 750 Example 75 Step 1: preparation of tert-butyl (3S,4R)-3—(((4R,10bS)benzyl—4-methyl— 1,2,3,4,6,10b-hexahydropyrazino[2,1-a]is0indol—8—yl)amino)—4-flu0ropyrrolidine-l— carboxylate (compound 75a) To a solution of tert-butyl (3S,4R)amino—4-fluoropyrrolidine—l-carhoxy1ate (366 mg, 1.8 mmol) in dioxane (15 mL) was added (4R,lObS)benzyl— 8—bromomethyl-1,2,3,4,6,10b- hexahydropyrazino[2,1—a]isoindole (compound lj, 640 mg, 1.8 mmol, ), CsZCO3 (1.7 g, 5.4 mmol) and XPhos Pd G2 (152 mg, 179 mmol). The reaction mixture was stirred at 85 0C overnight. The mixture was cooled to room temperature, d with water (50 mL) and extracted with EA (80 mL) for three times. The combined organic layer was washed with brine, dried over NaZSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography a gel, 40 g, 0% to 100% EtOAc in DCM) to afford compound 75a (710 mg, 82.5 % yield). MS: calc’d 481 [(M+H)+], measured 481 [(M+H)+].

Step 2: preparation of tert-butyl (3R,4S)fluoro—4-(((4R,10bS)methyl- 1,2,3,4,6,10b-hexahydropyrazino[2,1—a]isoindolyl)amino)pyrrolidinecarboxylate (compound 75b) A mixture of utyl (3S,4R)-3—(((4R,10bS)—2-benzyl—4—methyl—l,2,3,4,6,10b— dropyrazino[2,1-a]isoindoly1)amino)fluoropyrrolidinecarboxy1ate (compound 7521, 710 mg, 1.5 mmol) and Pd-C (100 mg) in MeOH (80 mL) was hydrogenated by a hydrogen balloon at room temperature for 5 hrs. After the catalyst was filtered off, the filtrate was concentrated in vacuo to afford compound 75b (490 mg, 84.9 % yield) which was used directly for the next step without further purification. MS: calc’d 391 [(M+H)+], measured 39] [(M+H)+].

Step 3: preparation of tert-butyl )fluoro—4-(((4R,10bS)methyl-2— (8- methquuinolin-S-yl)—1,2,3,4,6,lOb-hexahydropyrazino[2,1-a]isoindol-S-yl)—amino)— pyrrolidine-l-carboxylate (compound 75c) To a solution of 5-bromomethquuinoline (CAS: 74316—55—5, BePharm, Catalog: BD239383, 34.1 mg, 154 umol) in e (5 mL) was added tert—butyl (3R,4S)-3—fluoro 10bS)—4-methyl-l ,2,3 ,4,6,10b-hexahydropyrazino[2,l-a]isoindol—8-yl)amino)pyrrolidine—l — carboxylate (compound 75b, 60 mg, 154 pmol), RuPhos Pd G2 (11.9 mg, 15.4 umol) and CszC03 (150 mg, 461 umol). The reaction mixture was stirred at 90 °C for 20 hrs. The mixture was cooled to room temperature, diluted with water (20 mL) and extracted with EA (20 mL) for three times. The combined organic layer was washed with brine, dried over Na2804, filtered and concentrated in vacuo. The residue was purified by flash tography (silica gel, 20 g, 0% to 100% EtOAc in PE) to afford compound 75c (39 mg, 47.7 % yield). MS: calc’d 532 [(M+H)+], measured 532 [(M+H)+].

Step 4: (412,10bS)—N—[(3S,4R)—4—flu0ropyrrolid'myl]methyl(8-methyl- -quinolyl)-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-alisoindol-8—amine (Example 75) To a solution of utyl (3R,4S)—3-fluoro(((4R,10bS)—4—methyl—2— (8-methquuinolin-5— y1)-l ,6,10b-hexahydropyrazino[2,l—a]isoindol-8—yl)amino)pyrrolidinecarboxylate (compound 75c, 39 mg, 73.4 umol) in DCM (8 mL) was added TFA (2 mL). The reaction -1 15- mixture was d at room temperature for 2 hrs, then concentrated to afford a crude product, which was purified by pre—HPLC to afford Example 75 (10 mg, 32% yield). MS: calc’d 432 [(M+H)+], measured 432 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 8.80 (dd, J = 1.7, 4.3 Hz, 1H), 8.68 (dd, J= 1.5, 8.5 Hz, 1H), 7.50 (dd, J: 4.3, 8.4 Hz, 1H), 7.45 (dd, J: 0.7, 7.7 Hz,1H), 7.16 (d, J: 7.6 Hz,1H), 7.13 (d, J: 8.4 Hz, 1H), 6.83 (d, J: 1.7 Hz, 1H), 6.70 (dd, J= 2.1, 8.4 Hz, 1H), 5.15 - 5.34 (m, 1H), 4.99 — 5.08 (m, 1H), 4.75 (d, J= 13.7 Hz, 1H), 4.31 - 4.47 (m, 2H), 4.06 - 4.19 (m, 1H), 3.54 — 3.74 (m, 4H), 3.31 (br d, J: 12.3 Hz, 1H), 3.03 - 3.18 (m, 2H), 2.85 - 2.98 (m, 1H), 2.61 (s, 3H), 1.40 (d, J= 6.7 Hz, 3H).

Example 76 (4R,10bS)—N-[(3S,4R)—4-fluoropyrrolidinyl]methyl(8-methquuinoxalin-5—yl)- 3,4,6,10b—tetrahydro—1H-pyrazino[2,1-a]isoindol—S-amine ($21“ F NH The title compound was prepared in analogy to the preparation of Example 75 by using 5- Bromo-8—methquuinoxa1ine (CAS: 13605994, BePharm, Catalog: BD00771201) instead of ~bromo-8—methquuinoline. Example 76 (11 mg) was obtained. MS: calc’d 433 +], ed 433 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) (5 ppm 8.84 - 8.98 (m, 2H), 7.53 - 7.69 (m, 1H), 7.31 (d, J: 7.8 Hz, 1H), 7.22 (d, J: 8.3 Hz, 1H), 6.92 (d, J: 1.6 Hz,1H), 6.80 (dd, J: 2.1, 8.2 Hz, 1H), 5.25 - 5.45 (m, 1H), 4.81 — 4.87 (m, 1H), 4.68 (d, J: 13.3 Hz, 1H), 4.40 — 4.56 (m, 1H), 4.18 - 4.33 (m, 2H), 3.88 — 4.03 (m, 2H), 3.62 ~ 3.83 (m, 3H), 3.25 (t, J: 11.2 Hz, 1H), 2.95 - 3.10 (m, 2H), 2.71 (s, 3H), 1.45 (d, J: 6.5 Hz, 3H).

WO 33941 -1 l 6- Example 77 (4R,l 0bS)-N- [(3S,4R)fluoropyrrolidinyl]methyl [8-(trifluoromethyl)quinoxalin yl] -3,4,6,10b-tetrahydro-1H—pyrazino[2,1-a]isoindolamine {5.1x F’GH The title compound was prepared in analogy to the preparation of Example 75 by using 5— bromo(trifluoromethyl)quinoxaline instead of 5-bromo1nethy1quinoline. Example 77 (21.2 mg) was obtained. MS: calc’d 487 [(M+H)+], measured 487 [(M+H)+]. IH NMR (400 MHz, METHANOL-d4) (5 ppm 8.86 - 9.04 (m, 2H), 8.11 (d, J = 8.4 Hz, 1H), 7.37 (d, J: 8.2 Hz, 1H), 7.24 (d, J: 8.3 Hz, 1H), 6.91 (d, J: 1.7 Hz, 1H), 6.79 (dd, J: 2.1, 8.3 Hz, 1H), 5.20 - 5.44 (m, 1H), 4.69 — 4.75 (m, 1H), 4.64 (d, J= 13.2 Hz, 1H), 4.38 - 4.59 (m, 2H), 4.17 - 4.29 (m, 2H), 3.84 - 3.94 (m, 1H), 3.65 - 3.83 (m, 3H), 3.25 (t, J: 11.2 Hz, 1H), 3.09 - 3.20 (m, 2H),1.45(d, J = 6.6 Hz, 3H).

Example 78 7—[(4R,10bS)[[(3S,4R)fluoropyrrolidin—yl]amino]methyl-3,4,6,10b-tetrahydro-1H- pyrazino[2,1-a]isoindol—Z-yl]—1,3-benzothiazolecarbonitrile . 6.3x The title compound was ed according to the following scheme: Nj\ N N Nl N S) F TFA/DCM D!EA,DMSO F'tr‘q 7513 Example 78 Step 1: preparation of tert-butyl (3S,4R)[[(4R,10bS)(4-cyano-l,3- benzothiazol yl)-4—methyl—3,4,6,10b-tetrahydro-lH-pyrazino[2,1-a]isoindol—S-yll—amino]fluoro— pyrrolidinecarboxylate (compound 78a) To a solution of 7-fluorobenzo[d]thiazolecarbonitrile (27.4 mg, 154 umol) in DMSO (2 ml) was added tert—butyl )—3-[[(4R,10bS)—4-methyl-l ,2,3 , 4,6,10b— dropyrazino[2,l -a]isoindolyl]amino]—4-fluoro-pyrrolidine-1 -carboxylate (compound 75b, 60 mg, 154 umol) and DIEA (99.3 mg, 768 umol). The resultant mixture was stirred at 120 °C ght. After cooled to room temperature, the reaction was quenched with water (20 mL) and extracted with BA (20 mL) twice. The combined organic layer was washed with brine, dried over NaZSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 20 g, 0% to 100% EtOAc in PE) to afford nd 78a (29 mg, 34.4 % yield). MS: calc’d 549 [(M+H)+], measured 549 [(M+H)+].

Step 2: preparation of 7—[(4R,10bS)—8-[[(3S,4R)flu0ropyrrolidin—3-yl]- amino]methyl-3,4,6,10b—tetrahydro-lH—pyrazino[2,1-a]isoindol—Z-yl]-1,3-benzothiazole— 4-carbonitrile le 78) To a solution of tert—butyl (3S,4R)—3—[[(4R,l0bS)(4-cyano-1,3-benzothiazol—7-yl)—4- methyl-3 ,4,6, l Ob-tetrahydro- 1H—pyrazino[2, 1 -a]isoindol-8—y1]amino]fluoro-pyrrolidine- l - carboxylate (compound 78a, 20 mg, 36.5 umol) in DCM (8 mL) was added TFA (2 mL). The reaction mixture was stirred at room ature for 2 hrs, then concentrated to afford a crude product, which was purified by pre-HPLC to afford Example 78 (11mg, 67% yield). MS: calc’d 449 [(M+H)+], measured 449 +]. ‘H NMR (400 MHz, METHANOL-d4) 0‘ ppm 9.33 (s, 1H), 7.81 (d, J: 8.2 Hz, 1H), 7.13 (dd, J: 4.0, 8.2 Hz, 2H), 6.81 (d, J: 1.6 Hz, 1H), 6.68 (dd, J = 2.0, 8.3 Hz, 1H), 5.11 - 4.45 (m, 1H), 4.02 - 5.34 (1n, 1H), 4.46 - 4.57 (m, 2H), 4.29 - 4.15 (m, 2H), 3.77 (br d, J = 12.7 Hz, 1H), 3.52 - 3.71 H), 2.96 — 3.16 (m, 3H), 1.35 (d, J: 6.5 Hz, 311).

Example 79 bS)(8-chloro—5—quinolyl)-N-[(3S,4R)fluoropyrrolidin—3-yl]-4—methyl—3,4,6,10b- tetrahydro—lH—pyrazino[2,1—a]isoindol-8—amine 32:1 The title compound was prepared in analogy to the preparation of Example 75 by using 5- Bromo-S-Chloroquinoline (CAS: 927800-41—7, BePharm, Catalog: BD3 8263) instead of 5- bromo-S-methquuinoline. Example 79 (12 mg) was obtained. MS: calc’d 452 [(M+H)+], measured 452 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) (5 ppm 8.99 (dd, J = 1.6, 4.3 Hz, 1H), 8.78 — 8.88 (m, 1H), 7.87 (d, J: 8.1 Hz, 1H), 7.71 (dd, J= 4.2, 8.5 Hz, 1H), 7.34 (d, J: 8.2 Hz, 1H), 7.23 (d, J: 8.2 Hz, 1H), 6.93 (d, J: 1.7 Hz, 1H), 6.80 (dd, J: 2.1, 8.3 Hz, 1H), 5.22 - .44 (m, 1H), 4.94 - 5.02 (m, 1H), 4.76 (d, J: 13.4 Hz, 1H), 4.32 - 4.55 (m, 2H), 4.08 (br d, J: 7.0 Hz, 1H), 3.61 - 3.85 (m, 4H), 3.45 (br d, J: 12.0 Hz, 1H), 3.25 (t, J: 11.2 Hz,1H), 3.00 - 3.18 (m, 2H), 1.48 (d, J: 6.7 Hz, 3H). -1 1 9- e 80 -[(4R,10bS)[2-[(3S)hydroxypyrrolidin-l-yl]ethylamino]methyl-3,4,6,10b- tetrahydro-lH—pyrazino[2,1-a]isoindolyl]quinoline-S-carbonitrile ”KRIS/OH The title compound was prepared in analogy to the preparation of Example 68. Example 80 (12 mg) was obtained. MS: calc’d 469 [(M+H)+], ed 469 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 8.97 - 9.05 (m, 1H), 8.73 — 8.78 (m, 1H), 8.17 (d, J: 8.1 Hz, 1H), 7.71 (dd, J: 4.3, 8.6 Hz, 1H), 7.37 (d, J: 8.1 Hz, 1H), 7.28 (t, J: 7.8 Hz, 1H), 6.70 - 6.83 (m, 2H), 4.96 — 5.01 (m, 1H), 4.56 - 4.69 (m, 2H), 4.31 (br (1, J= 13.0 Hz, 1H), 4.02 - 4.14 (m, 1H), 3.92 (br .1 Hz, 1H), 3.41 - 3.76 (m, 9H), 3.07 - 3.22 (m, 2H), 2.24 - 2.36 (m, 1H), 2.03 - 2.15 (m, 1H), 1.49 (d, J: 6.6 Hz, 3H).

Example 81 -[(4R,10bS)[[(3S,4R)—4-fluoropyrrolidin—3-yl]amino]-4—methyl—3,4,6,10b-tetrahydr0-1H- 1 5 pyrazino [2,1-a]isoindol-Z-yl]quinoline-S-carbonitrile The title compound was prepared in analogy to the preparation of Example 30. Example 81 (10 mg) was obtained. MS: calc’d 443 [(M+H)+], measured 443 [(M+H)+]. 1H NMR (400 MHZ, METHANOL—d4) 6 ppm 9.02 (dd, J = 1.6, 4.3 Hz, 1H), 8.74 (dd, J = 1.7, 8.6 Hz, 1H), -1 20— 8J6QLJ=T9HL1HL7JOM¢J=43,&6HL1HL736MHF=&1H;1HL727flJé78 &M¢J=82HL1HL6&(¢J=75H;1HL529¢J=29HL1HL484®r¢J =3IIHLZHD,464(dHI=13J.HA1fD,422(d“/=13JQHLllD,388—4Dl(nLZLD,368— 3.84 (m, 3H), 3.59 (br d, J= 12.5 Hz, 1H), 3.43 (t, J: 11.2 Hz, 1H), 3.02 — 3.19 (m, 2H), 1.45 (d, J: 6.6 Hz, 3H).

Example 82 -[(4R,10bS)I(3R,4R)—4-aminohydroxy—3-methyl—pyrrolidin-l-yl}—9—fluor0methyl- 3,4,6,10b-tetrahydro—lH-pyrazino[2,l-a]isoindol—Z-yl]quinoline-S-carbonitrile The title compound was prepared according to the following scheme: — l 21 - 0 OH H_______*__3______.so4NBS con (33200 Mel NBS BPO 0014 0 do Nvé’i: [|r(dtbbpy)(ppy)2]PFe AgNoa Z/ ——-——> F -PrOHIWa_—T—.er 4A molecular sieves, 0\ ACN/TFE (9:1) CHSCN blue light 82e 82f 829 I | m N\ N\ H / BHBITHF 1)ACE--c: DCE N F DIEA, DMSO Nj\ 2) MeOH 82i 82] H N H N | I HO,,,_ N\ NH / o=( A< _....._—_. :i TFA/DCM Nj\ tBuXPhos Pd GS, t-BuONa dioxane 0* 82k Example 82 Step 1: preparation of 5-bromofluoro-2—methyl-benzoic acid (compound 82b) To the solution of 4-fluoromethylbenzoic acid (compound 82a, 50.0 g, 324.38 mmol) in Con. H2SO4 (250.0 lnL) was added NBS (58.0 g, 325.88 mmol) in portions at 0 OC. Then the reaction mixture was stirred at 0-5 °C for 1 hr. The resultant mixture was poured into 2.5 L ice- water. The solid was collected by filtration. The collected solid was dried in air and then in vacuo to afford nd 82b (67 g, 88.6% . MS: calc’d 231, 233[(M-H)‘], measured 231, 233[(M—H)']. ~122— Step 2: preparation of methyl 5-bromo—4-fluoro—2-methyl-benzoate (compound 82c) To the stirred solution of 5-bromofluoromethyl-benzoic acid (compound 82b, 35.0 g, 150.2 mmol) in DMF (350 mL) was added cesium ate (73.5 g, 225.6 mmol) The resultant mixture was stirred for 30 minutes, followed by the addition of iodomethane (22.0 g, 155 mmol).

Then the e was d at 40 °C for 15 hrs. After cooled to room temperature, the on was quenched with water (1.5 L) and extracted with EA (800 mL) for three times. The ed organic layer was washed with brine, dried over Na2804, filtered and concentrated in vacuo to afford compound 82c (35 g, crude) which was used directly for the next step without further purification. MS: calc’d 247, 249[(M+H)+], measured 247, 249[(M+H)+].

Step 3: preparation of methyl 5-bromo-Z—(dibromomethyl)fluoro-benzoate und 82d) To the on of methyl 5-bromofluoro—2-methyl-benzoate (compound 82c, 35.0 g, crude) in carbon tetrachloride (200 mL) was added benzoylperoxide (3.43 g, 14.2 mmol) and NBS (77.0 g, 432.6 mmol). The resultant mixture was stirred at reflux for 18 hrs. The reaction mixture was d through Celite and washed with CC14. The filtrate was washed with the mixed solution of aq. NaHCO3/aq. Nazszo3 aq. (1:1, 200 mL) and brine (200 mL) subsequently, dried over Na2804, filtered and concentrated in vacuo afford compound 82d (51 g, crude). MS: calc’d 405, 407[(M+H)+], measured 325, 327[(M- Br)+].

Step 4: preparation of methyl 5-bromo-4—fluoro—2-formyl-benzoate (compound 82c) To a suspension of methyl 5—bromo—2-(dibromomethyl)~4~fluoro-benzoate (compound 82d, .0 g, crude) in 2-propanol (150 mL) was added a solution of silver nitrate (9.2 g, 54.16 mmol) in deionized water (20 mL) at room temperature in the absence of light under the protection of N2 over about 30 mins. The resultant mixture was stirred at room temperature for another 3 hrs in the absence of light. The reaction was quenched with 5 mL brine, the resultant mixture was filtered through Celite, and the filtrate was trated in vacuo. The residue was re—dissolved with DCM (500 mL), washed with aq.NaHCO3 (200 mL) and brine (300 mL) subsequently, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 120 g, 0% to 10% EtOAc in PE) to afford compound 82c (2.5 g, 31.9% yield for total three steps). MS: calc’d 261, 263[(M+H)+], measured 261,263[(M+H)+].

Step 5: preparation of (4R,10bS)benzyl—8-bromofluoro—4—methyl—1,3,4,10b- ydropyrazino[1,2-b]isoindolone (compound 82g) A mixture of the (2R)-N1-benzy1-N1~(trimethylsilylmethyl)propane—l,2-diamine (compound 1g, 1.0 g, 2.0 g, 8.0 mmol), methyl 5-bromofluoro—2-formyl-benzoate (compound 82c, 2.5 g, 7.6 mmol), and 4A MS (4.5 g) in MeCN (50 mL) under N2 was stirred overnight at WO 33941 2019/064323 room temperature. The reaction mixture was filtered through Celite and washed with DCM. The filtrate was concentrated in vacuo to afford the ediate compound 82f, and the residue was re-dissolved in MeCN/TFE (18 mL/2 mL), followed by the on of [1r(dtbbpy)(ppy)2][PF6] (CAS: 676525—77-2, TCI, Catalog: D4887, 120 mg, 130 umol). The reaction was stirred at room temperature under the exposure of blue LEDs (synLED-16 A Discover, 12 W, wavelength 465-470 nm, purchased from SYNLED corp.) for 24 hrs. After the solvents were removed in vacuo, the residue was purified by flash tography (silica gel, 40 g, 20% to 80% EA in PE) to afford compound 82g (0.9 g, 28.5 % . The stereochemistry was confirmed by NOESY. MS: calc’d 389 and 391 [(M+H)+], measured 389,391[(M+H)+].'H NMR (400 MHz, CHLOROFORM-a’) 5 ppm 7.97 (d, J: 6.0 Hz, 1H), 7.40 - 7.30 (m, 5H), 7.10 - 7.06 (m, 1H), 4.39 (dd, J: 3.2, 10.8 Hz, 1H), 3.86 - 3.75 (m, 1H), 3.66 - 3.55 (m, 2H), 3.34 ~— 3.30 (m, 1H), 2.89 - 2.85 (m, 1H), 1.98 (t, J: 11.0 Hz, 1H), 1.79 (d, J: 6.8 Hz, 3H), 1.76 — 1.73 (m, 1H).

Step 6: preparation of (4R,10bS)benzyl—8-bromofluoromethyl-3,4,6, 10b- tetrahydro—lH—pyrazino[2,1-a]isoindole (compound 82h) A mixture of (4R,10bS)—2-benzy1-8—bromo—9—fluoromethy1—1,3 ,4,10b- tetrahydropyrazino[1,2-b]isoindol—6-one (compound 82g, 0.9 g, 2.31 mmol) and BH3 solution (1M in THF, 40 mL, 40 mmol) was heated at 80 °C with stirring on for 15 hrs. HCl solution (6 Nu mL) was added slowly to the reaction mixture at 0 °C. The resultant mixture was stirred at room temperature overnight, then the mixture was basified with a NaOH on (2 N) to pH 10.

The mixture was extracted with EtOAc twice. The organic phases were combined and dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography a gel, 40 g, 30% to 100% EtOAc in PE) to afford compound 82h (0.5 g, 57.6 % yield). MS: calc’d 375,377 [(M+H)+], measured 375,377[(M+H)+].

Step 7: preparation of (4R,10bS)br0mo—9—fluoro—4-methyl—1,2,3,4,6,10b -hexahydropyrazino[2,1-a]isoindole (compound 82i) To a stirred solution of (4R,10bS)—2-benzy1br0mo—9-fluoromethy1—3,4,6,10b- tetrahydro-lH—pyrazino[2,1-a]isoindole (compound 82g, 0.5 g, 1.3 mmol) in DCE (15 mL) at room temperature was added 1—ch10roethy1 ochloridate (0.9 g, 6.6 mmol). The on mixture was heated under reflux overnight and cooled to room temperature before concentrated in vacuo. The residue was dissolved in MeOH (30 mL) and the resultant mixture was heated under reflux for additional 2 hrs. The mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with water (10 mL), and the solution was basified with aq.

NaHCOg. The ant mixture was extracted with EtOAc (50 mL) twice. The combined organic WO 33941 layer was washed with brine, dried over Na2804, d and concentrated in vacuo to afford compound 82i (290 mg, 77.6% yield) which used directly to the next step. MS: calc’d 285, 287 +], measured 285,287[(M+H)+].

Step 8: preparation of 5-[(4R,10bS)—8-brom0fluoro—4-methyl-3,4,6,10b - tetrahydro-lH-pyrazino[2,1—a]isoindol—2—yl]quinoline—8-carbonitrile (compound 82j) To a solution of 5-fluoroquinolinecarbonitrile (compound lo, 186 mg, 1.1 mmol) in DMSO (5 mL) was added (4R,l0bS)—8-bromofluoro—4-methyl-1,2,3,4, 6,10b- hexahydropyrazino[2,1-a]isoindole und 82i, 280 mg, 1.0 mmol) and (381 mg, 3.0 mmol).

The reaction mixture was stirred at 120 0C for 5 hrs. The mixture was cooled to room temperature, quenched with water (50 mL), and extracted with BA (60 mL) twice. The ed organic layer was washed with brine, dried over NaZSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography to afford compound 82j (150 mg, 32 % yield). MS: calc’d 437 and 439 [(M+H)+], measured 437 and 439 [(M+H)+].

Step 9: preparation of tert-butyl N-[(3R,4R)—l-[(4R,10b.”—2-(8-cyanoquinolyl) fluoro—4-methyl-3,4,6,10b-tetrahydro-lH-pyrazino[2,1-a]isoindol—8-yl]hydroxy—4- methyl-pyrrolidinyl]carbamate (compound 82k) To a solution of 5—[(4R,10bS)—8-bromofluoromethyl—3,4,6,lOb—tetrahydro —1H— no[2,1-a]isoindolyl]quinolinecarbonit1ile (compound 82j, 60.0 mg, 140 umol) in dioxane (5 mL) was added tert-butyl ,4R)hydroxy-4—methyl -pyrrolidin—3- y1]carbamate (45.0 mg, 210 umol), Cesium carbonate (90.0 mg, 280 umol) and tBuXPhos Pd G3 (CAS: 1447963—75—8, Sigma—Aldrich, Catalog: 762229, 24 mg, 30 umol). The reaction mixture was stirred at 90 OC overnight. The mixture was cooled to room temperature, diluted with water (10 mL) and extracted with EA (15 mL) for three times. The combined organic layer was washed with brine, dried over NaZSO4, filtered and trated in vacuo. The residue was purified by flash chromatography (silica gel, 12 g, 30% to 100% EtOAc in PE) to afford compound 82k (50 mg, 62% yield). MS: calc’d 573 [(M+H)+], measured 573 [(M+H)+].

Step 10: preparation of 5-[(4R,10bS)[(3R,4R)—4-aminohydroxy—3-methyl- pyrrolidinyl]-9—fluoromethyl—3,4,6,10b-tetrahydr0-lH-pyrazino[2,1-a]isoindol—2- yl]quinolinecarbonitrile (Example 82) To a solution of tert-butyl N—[(3R,4R)—l—[(4R,10bS)—2-(8-cyanoquinolyl)— 9-fluoro—4- methyl-3 ,4,6,1 rahydro—lH—pyrazino[2,1-a]isoindol—S-yl]~4—hydroxymethy1-pyrrolidin—3- yl]carbamate (compound 82k, 50.0 mg, 87 umol) in DCM (5 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hrs, then concentrated to afford a crude t, which was purified by pre-HPLC to afford Example 82 (5.9 mg, 14% yield). MS: —125— calc’d 473 [(M+H)*], measured 473 [(M+H)*]. 1H NMR (400 MHz, DMSO—d,) (5 ppm 9.05 (d, J = 3.2 Hz, 1 H), 8.60 (d, J: 8.8 Hz, 1 H), 8.23 (d, J= 8.4 Hz, 1 H), 7.70 (dd, J: 8.0, 4.0 Hz, 1 H), 7.28 (br 01, J = 8.0 Hz, 1 H) 7.00 (, J = 13.6 Hz, 1 H), 6.62 (d, J = 8.8 Hz, 1 H), 4.72 (s, 1 H), 4.05 — 4.12 (m, 2 H), 3.89 - 3.92 (m, 1 H), 3.87 (br d, J = 10.4 Hz, 1 H), 3.61 - 3.67 (m, 1 H), 3.50 - 3.53 (1n, 2 H), 3.16 — 3.20 (m, 2 H), 3.09 (br s, 1 H), 2.96 — 1, 1 H), 2.87 (t, J = 10.8 Hz, 1 H), 2.69 - 2.74 (m, 1 H), 1.20 (s, 3 H), 1.13 (br d, J = 6.0 Hz, 3 H).

Example 83 -[(4R,10bS)-8—{(3S,4S)—4—aminohydroxy—3~methyl-pyrrolidin-l—yl]fluoromethyl- 3,4,6, 1 Ob-tetrahydro-lH-pyrazino [2, l-a] isoindol—Z-yl] quinoline-S-carbonitrile F ”1‘ HO N The title compound was prepared in analogy to the preparation of Example 82 by using tert-butyl N—[(3S,4S)—4—hydroxymethyl -pyrrolidiny1]carbamate instead of utyl N— [(3R,4R)hydroxy—4-methy1-pyrrolidiny1]carbamate. Example 83 (8.1 mg) was ed.

MS: calc’d 473 [(M+H)+], measured 473 [(M+H)+]. 1H NMR (400 MHZ, DMSO'dé) 5 ppm 9.06 (dd, J: 1.6, 4.0 Hz, 1H), 8.61 (dd, J== 1.6, 8.4 Hz, 1H), 8.24 (d, J: 8.0 Hz, 1H), 7.70 (dd, J: 4.0, 8.4 Hz, 1H), 7.28 (d, J: 8.4 Hz, 1H), 7.01 (d, J = 13.6 Hz, 1H), 6.62 (d, J: 8.4 Hz, 1H), 4.70 (s, 1H), 4.11 (d, J: 12.0 Hz, 1H), 3.87 (br d, J: 9.2 Hz, 2H), 3.64 — 3.68 (m, 1H), 3.52 (br d, J: 11.6 Hz,1H), 3.36 - 3.43 (m, 2H), 3.16 (br dd, J= 2.8, 9.6 Hz, 2H), 3.06 - 3.11 (m, 1H), 2.97 - 3.00 (m, 1H), 2.86 (t, J: 11.2 Hz, 1H), 2.69 — 2.75 (m, 1H), 1.48 - 1.79 (m, 2H), 1.21 (s, 3H), 1.14 (d, J: 6.4 Hz, 3H). -126— Example 84 —[(412,10bS)(2,6-diazaspiro[3.3]heptan-Z-yl)fluoromethyl-3,4,6,10b-tetrahydro-1H— pyrazino[2,1-a]isoindolyl}quinolinecarbonitrile The title compound was prepared in y to the preparation of e 82 by using tert-butyl 2,6-diazaspiro[3.3]heptanecarboxylate instead of utyl N—[(3R,4R)hydroxy- yl~pyrrolidiny1]carbamate. Example 84 (10.4 mg) was obtained. MS: calc’d 455 [(M+H)+], measured 455 [(M+H)+]. 1H NMR (400 MHz, DMSO-d6) (5 ppm 9.12 (br d, J = 2.8 Hz, 1H), 8.68 (br s, 2H), 8.28 (br d, J: 8.0 Hz, 1H), 7.73 (dd, J: 4.0, 8.4 Hz, 1H), 7.25 —7.33 (m, 2H), 6.67 (br s, 1H), 4.75 - 5.25 (m, 1H), 4.31 - 4.60 (m, 1H), 4.17 (br 1, J: 5.6 Hz, 4H), 4.09 (br s, 4H), 3.68 - 3.92 (m, 1H), 3.45 — 3.59 (m, 2H), 3.19 - 3.27 (m, 2H), 2.86 ~2.96 (m, 1H), 1.33 (br s, 3H).

Example 85 5-[(4R,10bS)—9-fluoro—4—methyl-8—(9-oxa—3,7-diazabicyclo[3.3.1]nonan—3-yl)—3,4,6,10b— tetrahydro-lH—pyrazino[2,1-a]isoindol-Z—yl]quinoline-S-carbonitrile The title compound was prepared in analogy to the preparation of Example 82 by using tert—butyl 9-oxa—3,7-diazabicyclo[3.3.1]nonanecarboxylate instead of tert—butyl N-[(3R,4R)-4— hydroxy—4-methyl-pyrrolidinyl]carbamate. Example 85 (10.4 mg) was obtained. MS: calc’d 485 [(M+H)+], measured 485 [(M+H)+]. lH NMR (400 MHZ, DMSO'dé) (5 ppm 9.30 (br d, J = .8 Hz, 1H), 9.10 (dd, J: 1.3, 4.2 Hz, 1H), 8.73 (br d, J: 8.8 Hz, 1H), 8.30 (br d, J: 8.0 Hz, 2H), 7.75 (dd, J: 4.2, 8.6 Hz, 1H), 7.44 (br (1, J = 11.6 Hz, 1H), 7.34 (br (1, J: 7.2 Hz, 1H), 7.26 ~127- (br d, J: 7.6 Hz, 1H), 5.22 - 5.38 (m, 1H), 4.79 -. 4.91 (m, 1H), 4.43 - 4.59 (m, 1H), 4.10 - 4.28 (m, 4H), 3.64 - 3.10 (m, 1H), 1.37 - 4.00 (m, 2H), 3.37 - 3.43 (m, 6H), 3.19 — 3.27 (m, 2H), 2.93 (br (1, J= 6.0 Hz, 3H). e 86 5-[(4R,10bS)-4—methyl(piperazine—l-carbonyl)—3,4,6,l(lb-tetrahydro-lH-pyrazino[2,1— a] isoindol-Z-yl]quinoline-S-carbonitrile The title compound was prepared according to the following scheme: N N >1/ II // 0 0 N\ oven N / \ CI 01 0 N _ ___.___.__. _.________.

Pd(OAc)2,Xan1Phos, 0 CI N TEA,DMAP,THF N TEA, PhCFS 10b 86a N II IN\ N\ :j\ N TFA/DCM ______.___. > (>le \N HN o \——/ o 86b Example86 Step 1: preparation of (2,4,6-trichlorophenyl) bS)(8-cyano-S-quinolyl) methyl-3,4,6,1{lb-tetrahydro-lH-pyrazino[2,1-a]isoindole-S-carboxylate (compound 86a) The mixture of 5-[(4R,10bS)—8—bromo-4~methy1-3,4,6,10b-tetrahydro-1H- pyrazino[2,1— a]isoindolyl]quinoline—8-carbonitrile (compound 10b, 500 mg, 1.2 mmol), - trichlorophenyl) formate (1.6 g, 7.1 mmol), XantPhos (140 mg, 240 umol), Pd(OAc)2 (30.0 mg, —128- 0.130 mmol) and triethylamine (300 mg, 3.0 mmol) in PhCF3 (6.0 mL) was degassed and purged with N2 for 3 times. The resultant mixture was stirred at 60 °C for 16 hrs under N2 atmosphere.

The reaction mixture was diluted with DCM/MeOH (80 mL/10 mL), filtered, and the filtrate was trated in vacuo. The residue was purified by Prep-TLC (PE: EA=1 :1) to afford compound 86a (480 mg, 70.0% yield). MS calc’d 563 [(M+H) +1; ed 563 [(M+H) +].

Step 2: preparation of tert-butyl 4-[(4R,10bS)(8-cyanoquinolyl)methyl- 3,4,6,10b-tetrahydro-lH-pyrazino[2,1-a]isoindole-8—carbonyl]piperazine-l-carboxylatea (compound 86b) To a solution of (2,4,6-trichlorophenyl) (4R,l0bS)(8-cyanoquinolyl)—4-methyl- 3,4,6,lOb-tetrahydro-1H-pyrazino[2,1-a]isoindolecarboxylate (compound 86a, 120.0 mg, 210 umol) in THF (3 mL) was added DMAP (5.0 mg, 40umol), triethylamine (44.0 mg, 430 umol) and tert-butyl piperazine—l-carboxylate (60.0 mg, 320 umol). The resultant e was stirred at 50 °C for 16 hrs, then the mixture was concentrated in vacuo. The residue was purified by Prep-TLC to afford compound 86b (80 mg, 64.0% yield). MS calc’d 553 [(M+H) Jr]; measured 553 [(M+H) t] Step 3: preparation of 5-[(4R,l0bS)methyl(piperazinecarbonyl)—3,4,6,10b- tetrahydro-1H-pyrazino[2,1-a]isoindol-Z—yl]quinolinecarbonitrile (Example 86) To a solution of tert—butyl 4-[(4R,10bS)(8-cyanoquinolyl)methy1-3,4,6,10b- tetrahydro-1H—pyrazino[2,1—a]isoindolecarbony1]piperazinecarboxylate und 86b, 80.0 mg, 140 pmol) in DCM (5 mL) was added TFA (2 mL). The on mixture was stirred at room temperature for 2 hrs, then concentrated to afford a crude product, which was purified by pre-HPLC to afford Example 86 (34.5 mg, 51.0 % yield). MS: calc’d 453 [(M+H)+], ed 453 [(M+H)+]. 1H NMR (400 MHz, DMSO-dé) 6 ppm 9.06 (dd, J = 4.0, 1.6 Hz, 1H), 8.64 (dd, J = 8.8, 1.6 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 8.8, 4.0 Hz, 1H), 7.30 — 7.36 (m, 3H), 7.21 (d, J = 8.0 Hz, 1H), 4.25 (d, J = 12.4 Hz, 1H), 3.94 - 4.01 (m, 2H), 3.63 (dd, J = 12.4, 1.6 Hz, 1H), 3.50 — 3.57 (m, 1H), 3.39 - 3.49 (m, 2H), 3.23 - 3.26 (m, 1H), 3.14 - 3.23 (m, 2H), 2.97 (t, J = 11.2 Hz, 1H), 2.70 — 2.76 (m, 2H), 2.65 — 2.70 (m, 2H), 2.52 (d, J = 2.0 Hz, 2H), 1.16 (d, J = 6.4 Hz, 3H).

Example 87 ,10bS)[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-z-carbonyl]methyl-3,4,6,10b- tetrahydro-lH—pyrazino[2,1-a]isoindol-Z-yl]quinoline—S-carbonitrile H N H O The title compound was prepared in analogy to the preparation of Example 86 by using utyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptanecarboxylate instead of tert-butyl piperazine— l—carboxylate. Example 87 (46.1 mg) was ed. MS: calc’d 465 [(M+H)+], measured 465 [(M+H)+]. 1H NMR (400 MHz, DMSO-a’é) 6 ppm 9.07 (dd, J = 4.0, 1.6 Hz, 1H), 8.64 (dd, J = 8.4, 1.2 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 8.4, 4.0 Hz, 1H), 7.46 - 7.54 (m, 1H), 7.34 = 8.0 Hz, 1H), 4.33 - 4.76 (m, 1H), 4.24 - 4.32 (m, 1H), 4.12 - - 7.43 (m, 2H), 7.32 (d, J 4.22 (m, 1H), 3.99 (d, J = 8.8 Hz, 2H), 3.60 - 3.67 (m, 2H), 3.54 - 3.59 (m, 1H), 3.42 - 3.43 (m, 1H), 3.23 = 11.2 Hz, 1H), 2.73 (t,J= 11.2 Hz,1H), - 3.26 (m, 1H), 3.10 — 3.16 (m, 1H), 2.97 (t,J 2.51 = 6.4 Hz, 3H). - 2.53 (m, 2H), 1.92 — 2.06 (m, 1H), 1.67 — 1.84 (m, 1H), 1.17 (d, J Example 88 -[(4R,10bS)(4-aminomethy1-piperidinecarbonyl)methyl-3,4,6,10b-tetrahydro- lH-pyrazino[2,1-a]isoindol—2—yl]quinoline-S-carbonitrile fl 4 The title compound was prepared in analogy to the preparation of e 86 by using tert—butyl N—(4—methyl—4-piperidyl)carbamate instead of tert—butyl piperazine-l-carboxy1ate.

Example 88 (56.1 mg) was obtained. MS: calc’d 481 [(M+H)+], measured 481 [(M+H)+]. lH - 1 3 0— NMR (400 MHz, DMSO—a’b) (5 ppm 9.06 (d, J = 3.2 Hz, 1H), 8.64 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 8.8, 4.0 Hz, 1H), 7.30 - 7.36 (m, 3 H), 7.20 (d, J = 8.0 Hz, 1H), 4.25 (d, J = 12.4 Hz, 1H), 3.95 — 4.03 (m, 2H), 3.67 — 3.76 (m, 1H), 3.60 - 3.66 (m, 1H), 3.53 — 3.59 (m, 1H), 3.44 (d, J = 11.6 Hz, 2H), 3.15 — 3.24 (m, 2H), 2.97 (1, J = 11.2 Hz, 1H), 2.73 (t, J = 10.8 Hz, 1H), 2.54 — 2.61 (m, 2H), 1.37 - 1.54 (m, 4H), 1.16 (d, J = 6.4 Hz, 3H), 1.14 (s, 3H). e 89 -[(4R,10bS)(3,8—diazabicyclo[3.2.1]octanecarbonyl)—4-methyl—3,4,6,10b-tetrahydro- 1H-pyrazino[2,1-a]is0indol—2-yl]quinoline—S-carbonitrile <2) 8 The title compound was prepared in analogy to the preparation of Example 86 by using d of tert—butyl piperazine-l-carboxylate. Example 89 (34.3 mg) was obtained. MS: calc’d 479 [(M+H)+], measured 479 [(M+H)+]. 1H NMR (400 MHz, DMSO—dé) 6‘ ppm 9.07 (dd, J = 4.0m 1.6 Hz, 1H), 8.64 (dd, J = 8.4, 1.2 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 8.4, 4.0 Hz, 1H), 7.45 (s, 1H), 7.30 = 12.4 Hz, 1H), 3.95 - 7.37 (n1, 3H), 4.44 — 4.59 (m, 1H), 4.27 (d, J — 4.03 (m, 2H), 3.85 = 11.2 Hz, 1H), 3.15 - 3.94 (m, 1H), 3.59 - 3.67 (m, 1H), 3.45 (d, J — 3.28 (1n, 2H), 2.95 - 3.01 (m, 1H), 2.84 ~ 2.93 (m, 1H), 2.69 - 2.79 (m, 2H), 2.51 - 2.53 (m, 2H), 1.86 (s, 4H), 1.16 (d, J = 6.4 Hz, 3H). 2019/064323 -13 1— Example 90 -[(4R,10bS)—4-methyl(5-oxa—2,8-diazaspiro[3.5]n0nanyl)—3,4,6,10b-tetrahydro-IH- pyrazino[2,1-a]isoindolyl]deuterio—quinoline-S-carbonitrile HN/_©o \__/ The title compound was prepared according to the following scheme: -1 3 2- O O— / —<_< H NH2 N O 0— H2804 con --—----—> NaHMDS / 90a 90c N N Pd(PPh3)4 H H H H {228 pd/C Zn(<:N)2 "”e N o N o ,9 02 N D ——-—-—p —> \ :8 F —D \ DOM 0 EF DMF,100°C / / / 90e 90f H H Nj\ N D N / %O o L/N‘( os Pd G3, t—BuONa DIEA, DMSO dioxane N D \ H / TFA/DCM N D w———. #0 {in Example 90 )V 90h -l33- Step 1: Preparation of N—(Z—bromo—S-fluoro-phenyl)-3,3-dimethoxy-propanamide (compound 90b) To a solution of 2-bromofluoroaniline (50 g, 263 mmol) and methyl 3,3- dimethoxypropionate, (45 mL, 316 mmol) in THF (150 mL) was added NaHMDS in THF (394 mL, 394 mmol) dropwise at 0°C. The mixture was stirred at the temperature for 10 minutes, and then it was warmed up to 15 °C and stirred for 18 hrs. The reaction was quenched with sat. aqueous solution of NH4Cl and concentrated to about 300 mL. The solution was diluted with water and extracted with EtOAc. The organic layer was dried over NaQSO4 and concentrated to afford nd 90b (100 g, 90% yield). MS: calc’d 306 [(M+H)+], measured 306 [(M+H)+].

Step 2: Preparation of 8-bromofluoro-IH-quinolin-Z-one (compound 90c) A solution of N—(2—bromo~5—fluoro-phenyl)—3,3—dimethoxy-propanamide (compound 90b, 100 g, 238 mmol) in DCM (500 mL) was added to concentrated sulfuric acid (300 mL) at 0°C.

The mixture was stirred at 15 °C for 2 hrs. The mixture was poured slowly into 2000 mL ice- water, and a yellow precipitate appeared. The mixture was filtered, and the wet—cake was washed with 500 mL water, 200 mL isopropyl l and 300 mL PB. The solid was dried by sucking in vacuum to afford compound 90c (50 g, 86.5% yield). MS: calc’d 242 [(M+H)+], measured 242 [(M+H)+].

Step 3: Preparation of o—Z-oxo-lH-quinoline—8—carb0nitrile (compound 90d) A solution of 8-bromofluoro-lH-quinolin-Z-one und 90c, 50 g, 206 mmol), zinc cyanide (4820 mg, 412 mmol), Pd(PPh3)4 (2428 mg, 21 mmol) in DMF was stirred at 120 °C for hrs. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried and concentrated to give the crude product, which was d by flash column to afford compound 90d (29 g, 74.5% . MS: calc’d 189 [(M+H)+], measured 189 [(M+H)+].

Step 4: Preparation of (8-cyano-S-fluoro—Z-quinolyl) trifluoromethanesulfonate (compound 90e) To a solution of 5—fluorooxo-1H-quinolinecarbonitrile (compound 90d, 17 g, 90 mmol) and 2,6—dimethylpyridine (39 g, 361 mmol) in DCM was added trifluoromethanesulfonic ide (5] g, 181 mmol) se at 0 °C. The mixture was stirred at 0 °C for 1 hr, and then the reaction was diluted with water, extracted with DCM. The c layer was dried and concentrated. The residue was purified by flash column to give compound 90c (23.0 g, 80% yield). MS: calc’d 321 [(M+H)+], measured 321 [(M+H)+].

Step 5: Preparation of eriofluoro-quinoline-8—carbonitrile (compound 901) To a solution of nofluoro-2—quinolyl) trifluoromethanesulfonate (compound 90e, 23 g, 72 mmol) in THF (230 mL) and deuterium oxide (100 mL) was added potassium carbonate -l34- (20 g, 144 mmol) and Pd/C (6 g). The mixture was stirred at 40 °C for 5 hrs under deuterium atmosphere (balloon). The mixture was filtered, and the filtrate was concentrated and purified by flash column to afford compound 90f (11 g, 87.8% yield) which was used directly for the next step without further ation. MS: calc’d 174 [(M+H)+], measured 174 [(M+H)+].

Step 6: preparation of 5—[(4R,10bS)-8—bromo—4-methyl—3,4,6,10b—tetrahydro -1H-pyrazino[2,l-a]isoindol-Z-yl]deuterio-quinoline-8—carbonitrile und 90g) To a solution of (4R,10bS)bromo-4—methyl-1,2,3,4,6,lOb—hexahydropyrazino a]isoindole (compound 1021, 660 mg, 2.8 mmol) in DMSO (20 mL) was added 2-deuterio- ~fluoro-quinolinecarbonitrile (compound 90f, 350 mg, 2.0 mmol) and DIEA (1.3 g, 10.1 mmol). The resultant e was stirred at 120 °C overnight. After being cooled to room temperature, the reaction was quenched with water (50 mL) and extracted with BA (80 mL) twice. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 40 g, 0% to 100% EtOAc in PE) to afford compound 90g (810 mg, 95.3 % yield). MS: calc’d 420, 422[(M+H)+], measured 420, 422[(M+H)+].

Step 2: preparation of tert-butyl 2-[(4R,10bS)—2-(8-cyan0deuterio-S-quinolyl) methyl-3,4,6,10b-tetrahydro-1H—pyrazino[2,1-a]isoindol—8-yl]oxa-2,8— diazaspiro[3.5]nonane—S—carboxylate (compound 90h) To a solution of 5-[(4R,10bS)bromo—4—methyl-3,4,6,10b~tetrahydro~lH~ no-[2,l~ a]isoindolyl]deuterio-quinolinecarbonitrile (compound 90g, 100 mg, 238 umol) in dioxane (15 mL) was added t—BuONa (45.7 mg, 476 umol), utyl 5-oxa—2,8- diazaspiro[3.5]nonanecarboxylate (65.2 mg, 285 umol) and tBuXPhos Pd G3 (9.4 mg, 11.9 umol). The reaction e was stirred at 900C overnight. The mixture was cooled to room temperature, diluted with water (50 ml) and extracted with BA (50 mL) for three times. The combined organic layer was washed with brine, dried over Na2804 and concentrated in vacuo.

The residue was purified by flash chromatography (silica gel, 20 g, 0% to 100% EtOAc in PE) to afford compound 90h (80 mg, 59.2 % . MS: calc’d 568[(M+H)+], measured 568[(M+H)+].

Step 3: preparation of 5-[(4R,10bS)methyl—8-(5-oxa-2,8-diazaspiro[3.5]- nonan-Z—yl)—3,4,6,10b-tetrahydro-lH-pyrazino[2,1-a]isoindol-Z-yl]deuterio—quinoline carbonitrile (Example 90) To a solution of tert—butyl 2-[(4R,l0bS)—2-(8—cyano~2-deuterio—5-quinolyl)-4~methyl- 3,4,6,l0b-tetrahydro—1H—pyrazino[2,l -a]isoindolyl]oxa~2,8—diazaspiro[3.5]nonane—8— ylate (compound 90h, 80 mg, 141 umol) in DCM (8 mL) was added TFA (4 mL).The mixture was stirred at room temperature for 2 hrs. The reaction mixture was stirred at room temperature for 2 hrs, then concentrated to afford a crude product, which was purified by pre- HPLC to afford Example 90 (42 mg, ). MS: calc’d 468 [(M+H)+], measured 468 [(M+H)+]. 'H NMR (400 MHz, METHANOL-d4) (5 ppm 8.76 (d, J = 8.6 Hz, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.72 (d, J: 8.6 Hz, 1H), 7.37 (d, J: 7.9 Hz, 1H), 7.25 (d, J= 8.2 Hz, 1H), 6.66 (d, J: 1.8 Hz, 1H), 6.51 (dd, J: 2.1, 8.2 Hz, 1H), 4.77 — 4.84 (m, 1H), 4.66 (d, J: 13.2 Hz, 1H), 4.25 (d, J: 13.2 Hz, 1H), 4.06 (d, J= 8.6 Hz, 2H), 3.86 - 3.98 (m, 4H), 3.79 (d, J: 8.4 Hz, 2H), 3.58 (br d, J = 12.2 Hz, 1H), 3.54 (s, 2H), 3.23 - 3.29 (m, 2H), 3.01 — 3.17 (m, 2H), 1.44 (d, J: 6.6 Hz, 3H).

Example 91 5-[(4R,10bS)[[(3S,4R)—4-flu0r0pyrrolidin—3-yl]amino]methyl-3,4,6,10b—tetrahydro-1H— pyrazino[2,1-a]isoindol—2-yl]~2-deuterio—quinoline—8-carbonitrile N D Q5:1 The title nd was prepared in analogy to the preparation of e 90 by using tert—butyl (3S,4R)aminofluoropyrrolidinecarboxylate instead of tert—butyl 5-oxa-2,8- diazaspiro[3.5]nonanecarboxylate. e 91 (21.2 mg) was obtained. MS: calc’d 444 [(M+H)+], measured 444 [(M+H)+]. ‘H NMR (400 MHz, METHANOL-d4) 6 ppm 8.66 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.61 (d, J== 8.6 Hz, 1H), 7.27 (d, J: 8.1 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.84 (d, J: 1.8 Hz, 1H), 6.70 (dd, J: 2.2, 8.3 Hz, 1H), 5.14 - 5.36 (m, 1H), 4.88 - 4.48 (m, 2H), 3.95 - 4.10 (m, 1H), 3.74 — - 4.97 (m, 1H), 4.67 (d, J: 13.4 Hz, 1H), 4.28 3.84 (m, 1H), 3.45 - 3.72 (m, 4H), 3.07 - 3.18 (m, 2H), 2.95 - 3.05 (m, 1H), 1.39 (d, J: 6.7 Hz, 3H). -l 36— Example 92 —[(4R,10bS)(3-amino—3—methyl-azetidinyl)methyl-3,4,6,l rahydro-1H- pyrazino[2,1-a]isoindol—Z-yl]deuterio—quinolinecarbonitrile N D The title compound was prepared in analogy to the preparation of e 90 by using tert-butyl N—(3-methylazetidin-3—yl)carbamate instead of tert—butyl 2,8- diazaspiro[3.5]nonaneearboxylate. Example 92 (21.2 mg) was obtained. MS: ealc’d 426 [(M+H)+], measured 426 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 5 ppm 8.77 (d, J = 8.6 Hz, 1H), 8.19 (d, J: 8.1 Hz, 1H), 7.72 (d, J= 8.6 Hz,1H), 7.38 (d, J: 8.1 Hz, 1H), 7.27 (d, J: 8.2 Hz, 1H), 6.67 (d, J: 1.8 Hz, 1H), 6.53 (dd, J = 2.1, 8.2 Hz, 1H), 4.78 - 4.87 (m, 1H), 4.68 (d, J: 13.3 Hz, 1H), 4.27 (d, J: 13.3 Hz, 1H), 3.85 - 4.06 (m, 6H), 3.56 - 3.65 (m, 1H), 3.03 - 3.19 (m, 2H), 1.70 (s, 3H), 1.45 (d, J: 6.6 Hz, 3H).

Example 93 1 5 5-[(4R,10bS)methyl(9-oxa-3,7-diazabicyclo[3.3.1]nonanyl)—3,4,6,10b-tetrahydro- 1H-pyrazino[2,1-a]isoindol-Z-yl]-2—deuterio-quinoline—8-carb0nitrile The title compound was prepared in analogy to the preparation of Example 90 by using -137— tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonanecarboxylate instead of tert-butyl 5~oxa—2,8~ diazaspiro[3.5]nonane—8-carboxylate. Example 93 (21.2 mg) was obtained. MS: calc’d 468 [(M+H)+], measured 468 +]. 1H NMR (400 MHz, METHANOL—d4) 8 ppm 8.77 (d, J = 8.7 Hz, 1H), 8.19 (d, J: 7.9 Hz, 1H), 7.72 (d, J: 8.6 Hz, 1H), 7.37 (d, J= 7.9 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 1.7 Hz, 1H), 7.11 (dd, J = 2.2, 8.3 Hz, 1H), 4.54 - 4.65 (m, 2H), 4.23 - 3.98 (m, 1H), 3.71 - 3.86 - 4.31 (m, 1H), 4.28 (br s, 1H), 4.12 (br (1, J= 12.7 Hz, 1H), 3.88 (m, 3H), 3.51 - 3.66 (m, 5H), 3.20 - 3.28 (111,211), 3.01 ~ 3.14 (m, 2H), 1.41 (d, J: 6.5 Hz, 3H).

Example 94 1 O 4-[(4R,10bS)-8—[(3R,4R)—3-aminometh0xy—pyrrolidinyl]-4—methyl—3,4,6,l 0b- tetrahydro-lH-pyrazino[2,1-a]isoindolyl]pyrazolo[1,5-a]pyridinecarbonitrile / N,N The title compound was prepared ing to the following scheme: -138— F / \ Br O“ N perchloric acid 0‘ — / N+ ‘8 V0 N‘ ,8. ,‘s —’ I O d——-—- H2N\ “s .0 onane Q «0 DCM \ '0'“ 94a 94b 94° R Br ”0 § / N,N\ N Conc. H RWCNZZ” Pd()OAC / N’N\ —""—" \ \ Xantphos DMA \ \ \ \ water Br’< b NH N 0° N4 10a \ H O —-———-——-——————.

DIEA, DMSO WW os Pd G3. 082003 dioxane N\ "" N l TFA/DCM \ O N / N N ——————-------D HN 0., N k H2N 94h Example 94 Step 1: preparation of amino 2,4,6-trimethylbenzenesulfonate (compound 94b) A solution of ethyl (1E)~N—(2,4,6—trimethylphenyl)sulfonyloxyethanimidate (compound 94a, 200 g, 700 mmol) in 1,4-dioxane (500 mL) was added perchloric acid (110 mL) dropwise in 30 min and stirred for 1 hr at 0 °C. 1000 mL ice-water was added and the mixture was filtered. The filter cake was dissolved in 1.5 L EtOAc, then stirred for 30 minutes. The organic layer was concentrated (keep the temperature below 25 0C) to afford crude product. The crude product was recrystallized (petroleum/EtOAc=10/ 1) to afford compound 94b (110 g, 73% yield). MS: calc’d 216 +], measured 216 [(M+H)+]. - l 3 9- Step 2: preparation of 2-bromo—5-fluoro-pyridinium—1-amine 2,4,6— trimethylbenzenesulfonate (compound 94c) A solution of amino 2,4,6—trimethy1benzenesulfonate (compound 94b, 110 g, 511 mmol) and 2—bromofluoropyridine (60 g, 341 mmol) in DCM (1800 mL) was stirred at 10°C for 18 hrs. The mixture was concentrated, the residue was recrystallized in EtOAc to afford compound 94c (90 g, 92% yield). MS: calc’d 191 [(M+H)+], measured 191 [(M+H)+].

Step 3: preparation of ethyl 7-bromofluoro-pyrazolo[1,S—a]pyridine—3—carboxylate (compound 94d) A solution of 2-bromofluoro—pyridinium—1—amine; 2,4,6-trimethylbenzenesulfonate (compound 94c, 90 g, 230 mmol), K2CO3 (64 g, 460 mmol) and ethyl late (28 mL, 276 mmol) in DMF (1300 mL) was stirred at 10 °C for 18 hrs. The reaction was diluted with water, extracted with EtOAc. The organic layer was dried over Na2804, filtered and the filtrate was concentrated in vacuo. The e was purified by chromatography column to afford compound 94d (11 g, 16.7% yield). MS: calc’d 287 [(M+H)+], measured 287 [(M+H)+].

Step 4: preparation of 7—bromo—4-i'luoro-pyrazolo[1,5—a]pyridine (compound 94c) To a e of ethyl 7—bromo-4—fluoro-pyrazolo[l,5—a]pyridinecarboxylate und 94d, 8.0 g, 26.7 mmol) in acetic acid (48 mL) and water (48 mL) was added conc. HCl (36 mL, 432 mmol). The mixture was stirred at 100 °C for 18 hrs. The mixture was diluted with water (200 mL), basified with aq. NaOH (IN) to pH = 8, extracted with EA (200 mL) for three times.

The combined organic layers were washed with brine, dried over Na2804 and concentrated in vacuo to afford compound 94c (5 g, 86.9% yield) which was used directly for the next step.

MS: calc’d 215 [(M+H)+], measured 215 [(M+H)+].

Step 5: preparation of 4-fluoropyrazolo[1,5-a]pyridine-7—carbonitrile (compound 941) A mixture of 7-bromo-4—fluoro-pyrazolo[1,5-a]pyridine (compound 94e, 1000 mg, 4.6 mmol), zinc cyanide (880 mg, 7.5 mmol), zinc (31 mg, 0.5 mmol), XantPhos (1076 mg, 1.8 mmol) and Pd(OAc)2 (209 mg, 0.9 mmol) in DMA (10 mL) was degassed and purged with Ar for 3 times, and then the mixture was stirred at 120°C for 1 h under Ar here. The mixture was d with EA (150 mL), filtered and the filtrate was washed with water (50 mL), brine (50 mL x 3), dried over NaZSO4 and trated in vacuo. The residue was purified by LC (PE: EA=3:1) to afford nd 94f (600 mg, 68 % yield). MS: calc’d 162 [(M+H)+], measured 162 [(M+H)+]. -140— Step 6: preparation of 4—((4,R,10bS)bromo—4-methyl-3,4,6,10b- tetrahydropyrazino— ]isoindol—2(1H)-yl)pyrazolo[1,5-a]pyridine—7-carbonitrile (compound 94g) To a solution of 4-fluoropyrazolo[1 ,5—a]pyridinecarbonitrile und 94f, 750 mg, 4.6 mmol) in DMSO (30 mL) was added (4R,lObS)-8—bromomethy1-1,2,3,4,6,10b- hexahydropyrazino[2,l-a]isoindole (compound 103, 1.2 g, 4.6 mmol) and DIEA (3.0 g, 23.3 mmol). The reaction mixture was stirred at 100 0C for 20 hrs. After cooled to room temperature, the reaction was quenched with water (50 mL) and extracted with EA (100 mL) twice. The combined organic layer was washed with brine, dried over NaZSO4, filtered and concentrated in vacuo. The e was d by flash chromatography (silica gel, 80 g, 0% to 100% EtOAc in PE) to afford compound 94g (870 mg, 45.8 % yield). MS: calc’d 408, 410 [(M+H)+], measured 408, 410[(M+H)+].

Step 7: preparation of tert—butyl ((3R,4R)((4R,10bS)-2—(7—cyanopyrazolo- [1,5- a] pyridinyl)—4-methyl—1,2,3,4,6,10b-hexahydr0pyrazino[2,1-a]isoindolyl)—4- methoxypyrrolidinyl)carbamate (compound 94h) To a solution of 4-((4R,10bS)~8—bromomethyl-3,4,6,10b—tetr-ahydropyrazino [2,1- a]isoindol—2(lH)—yl)pyrazolo[1,5-a]pyridine-7—carbonitrile (compound 94g, 40 mg, 98 umol) in dioxane (6 mL) was added tert-butyl ((3R,4R)methoxypyrrolidin—3~yl)—carbamate (25.4 mg, 118 umol), C52C03 (95.8 mg, 294 umol) and tBuXPhos Pd G3 (7.8 mg, 9.8 umol). The on mixture was stirred at 90 0C overnight. The mixture was cooled to room temperature, diluted with water (30 mL) and extracted with BA (30 mL) for three times. The combined organic layer was washed with brine, dried over Na2804, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 12 g, 30% to 100% EtOAc in PE) to afford compound 94h (22 mg, 41.3 % yield). MS: calc’d 544[(M+H)+], ed 544[(M+H)+].

Step 3: preparation of 4-[(4R,10bS)—8-[(3R,4R)—3-aminomethoxy—pyrrolidinyl] methyl-3,4,6,10b-tetrahydro-lH—pyrazino[2,1-a]isoindol-Z-yl]-pyrazolo[l,5-a]pyridine-7— carbonitrile(Example 94) To a solution of tert—butyl ((3R,4R)-l-((4R,l0bS)~2-(7—cyanopyrazolo[1,5—a]— pyridiny1)- 4-methy1-1,2,3,4,6,10b—hexahydropyrazino[2,1-a]isoindol-S-y1)~4—meth-oxypyrrolidin-3 — bamate (compound 94h, 22 mg, 40.5 umol) in DCM (10 mL) was added TFA (3 mL). The e was stirred at room temperature for 2 hrs. The reaction mixture was stirred at room temperature for 2 hrs, then concentrated to afford a crude product, which was purified by pre— HPLC to afford Example 94 (12 mg, 66% yield). MS: calc’d 444[(M+H)+], measured 444[(M+H)+]. ]H NMR (400 MHz, METHANOL—d4) 8 ppm 8.08 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.23 (d, J: 8.2 Hz, 1H), 6.95 (d, J= 2.4 Hz, 1H), 6.74 (d, J: 1.7 Hz, 1H), 6.69 —141— (d, J: 8.1 Hz, 1H), 6.60 (dd, J: 2.1, 8.3 Hz, 1H), 4.33 — 4.41 (m, 1H), 4.24 — 4.31 (m, 1H), 4.07 - 4.16 (1n, 2H), 3.78 — 3.94 (m, 4H), 3.63 - 3.71 (m, 1H), 3.41 - 3.52 (1n, 1H), 3.48 (s, 3H), 3.24 - 3.33 (m, 2H), 2.98 - 3.06 (m, 1H), 2.86 - 2.96 (m, 1H), 1.34 (d, J: 6.5 Hz, 3H).

Example 95 4-[(4R,10bS)[(3S,4S)aminomethoxy-pyrrolidin-l—yl]methyl-3,4,6,10b- tetrahydro-lH—pyrazino[2,1-a]isoindol—Z-yl}pyrazolo[1,5-a]pyridinecarbonitrile / N,N The title compound was ed in analogy to the preparation of e 94 by using tert—butyl ((3S,4S)methoxypyrrolidin—3-y1)-carbamate instead of tert—butyl ((3R,4R) methoxypyrrolidin—3-y1)-carbamate. Example 95 (18 mg) was obtained. MS: calc’d 444 [(M+H)+], measured 444 [(M+H)+]. 1H NMR (400 MHZ, METHANOL-d4) 8 ppm 8.06 - 8.09 (m, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.75 (s, 1H), 6.70 (s, 1H), 6.57 = 12.7 Hz, 1H), 4.25 - 4.32 (m, 2H), 4.10 - 4.17 (m, - 6.65 (m, 1H), 4.46 (d, J 1H), 3.85 - 3.71 (m, 1H), 3.42 - 3.49 (m, 2H), 3.48 (s, 3H), 2.92 - 3.10 (m, — 3.97 (m, 5H), 3.63 2H), 1.37 (d, J: 6.5 Hz, 3H).

Example 96 4-[(4R,10bS)—8—[(3R)-3—aminopyrrolidinyl]methyl-3,4,6,10b—tetrahydr0-1H- pyrazino[2,1-a]isoindol—Z—yl]pyrazolo[1,5-a]pyridinecarbonitrile / ,N The title compound was prepared in analogy to the preparation of Example 94 by using tert-butyl N-[(3R)-pyrrolidiny1]carbamate instead of tert-butyl R)methoxypyrrolidin —carbamate. Example 96 (5.2 mg) was obtained. MS: calc’d 414 [(M+H)+], ed 414 [(M+H)+]. ‘H NMR (400 MHz, METHANOL-d4) 5 ppm 8.12 (d, J : 2.4 Hz, 1H), 7.54 (d, J : 7.9 Hz, 1H), 7.41 (br d, J: 8.2 Hz, 1H), 7.03 (d, J: 2.4 Hz, 1H), 6.70 - 6.84 (m, 3H), 4.54 - 4.64 (m, 1H), 4.04 - 4.23 (m, 3H), 3.58 - 3.72 (m, 2H), 3.40 - 3.53 (m, 2H), 2.43 - 2.64 (m, 1H), 2.13 - 2.28 (m, 1H), 1.56 (d, J: 6.7 Hz, 3H). e 97 4-[(4R,10bS)—4—methyl—8—[(3R)-3—methylpiperazin-1—yl]-3,4,6,10b-tetrahydr0-1H— 1 5 pyrazino [2, 1—a]isoindolyl] pyrazolo[1,5-a]pyridinecarbonitrile / N,N The title compound was prepared in analogy to the preparation of Example 94 by using tert—butyl (2R)—2-methylpiperazine—1-carboxylate instead of tert-butyl ((3R,4R)—4— methoxypyrrolidin yl)-carbamate. Example 97 (6.0 mg) was obtained. MS: calc’d 428 [(M+H)+], measured 428 [(M+H)+]. 'H NMR (400 MHz, METHANOL-d4) (5 ppm 8.08 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.26 (d, J: 8.6 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 6.93 - 7.00 (m, 2H), 6.70 (d, J: 8.1 Hz, 1H), 4.25 = 11.5 Hz, 1H), 3.69 — 4.36 (m, 2H), 4.00 (br d, J - 3.91 (m, 4H), 3.47 - 3.58 (111, 3H), 3.20 — 3.27 (m, 1H), 2.96 - 3.09 (m, 2H), 2.74 — 2.91 (m, 2H), 1.42 (d, J: 6.6 Hz, 3H), 1.31 (d, J: 6.5 Hz, 3H).

Example 98 4-[(4R,10bS)[[(3S,4R)—4-fluoropyrrolidinyl]amino]—4-methyI-3,4,6,l0b-tetrahydro—1H— pyrazino[2,1-a]is0indolyl]pyrazolo[1,5-a]pyridine-7—carbonitrile / N,N The title compound was ed in analogy to the preparation of Example 94 by using tert—butyl (3S,4R)amin0fluoro—pyrrolidine-l—carboxylate instead of tert—butyl ((3R,4R)-4— methoxypyrrolidin —3-yl)-carbamate. Example 98 (17 mg) was obtained. MS: calc’d 432 [(M+H)+], measured 432 [(M+H)+]. 1H NMR (400 MHz, OL—d4) 0‘ ppm 8.09 (d, J = 2.3 Hz, 1H), 7.51 (d, J: 7.9 Hz, 1H), 7.21 (d, J= 8.1 Hz, 1H), 6.97 (d, J= 2.4 Hz, 1H), 6.87 (d, J: 1.8 Hz, 1H), 6.76 (dd, J: 2.2, 8.3 Hz, 1H), 6.72 (d, J=~= 8.1 Hz, 1H), 5.24 - 5.45 (m, 1H), 4.47 (d, J: 13.0 Hz, 1H), 4.39 - 4.55 (m, 1H), 4.24 - 4.38 (m, 2H), 3.89 - 4.02 (m, 2H), 3.64 - 3.84 (m, 3H), 3.52 - 3.63 (rn, 1H), 3.24 (t, J=11.1_Hz, 1H), 2.96 - 3.11 (m, 2H), 1.39 (d, J: 6.5 Hz, 3H).

Example 99 4-[(4R,10bS)[(3R,4S)aminoflu0ro-pyrrolidinyl]methyl-3,4,6,10b-tetrahydro- lH-pyrazino[2,1-a]isoindol—Z-yl]pyrazolo[1,5-a]pyridinecarbonitrile The title nd was ed in analogy to the preparation of Example 94 by using tert—butyl N—[(3R,4S)fluoropyrrolidin—3—y1]carbamate instead of tert—butyl R) methoxypyrrolidin yl)-carbamate. Example 99 (17 mg) was obtained. MS: calc’d 432 [(M+H)+], measured 432 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 5 ppm 8.08 (d, J = 2.4 Hz, 1H), 7.50 (d, J: 8.1 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.66 — 6.73 (m, 2H), 6.56 (dd, J: 2.3, 8.1 Hz, 1H), 5.33 - 5.55 (m, 1H), 4.24 - 4.39 (m, 2H), 4.02 — 4.08 (m, 1H), 3.62 — 3.93 (m, 5H), 3.39 — 3.46 (m, 2H), 2.97 — 3.07 (m, 1H), 2.84 - 2.96 (m, 1H), 2.21 (t, J: 7.5 Hz, 1H), 1.32 (d, J: 6.5 Hz, 3H).

Example 100 4-[(4R,10bS)(4-aminomethyl—1-piperidyl)-4—methyl-3,4,6,10b-tetrahydro-1H- pyrazino[2,1-a]isoindolyl]pyrazolo[1,5-a]pyridine-7—carbonitrile /N\,N The title compound was prepared in analogy to the preparation of Example 94 by using tert—butylN—(4-methy1piperidyl)carbamate instead of tert-butyl ((3R,4R)-4—methoxypyrrolidin -145— -carbamate. Example 100 (9.0 mg) was obtained. MS: calc’d 442 +], measured 442 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) (5 ppm 8.09 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.30 (d, J: 8.4 Hz, 1H), 7.12 (d, J: 1.7 Hz, 1H), 7.00 ( (dd, J: 2.2, 8.2 Hz, 1H), 6.98 (d, J= 2.4 Hz, 1H), 6.73 (d, J: 7.9 Hz, 1H), 4.53 - 4.60 (m, 1H), 4.40 - 4.51 (m, 1H), 4.22 - 4.34 (m, 1H), 4.09 (d, J: 12.7 Hz, 1H), 3.90 - 3.99 (m, 1H), 3.61 - 3.70 (m, 1H), 3.52 - 3.60 (m, 2H), 2.98 - 3.17 (1n, 4H), 1.88 - 2.03 (m, 4H), 1.47 (s, 3H), 1.42 (d, J: 6.6 Hz, 3H).

Example 101 4-[(4R,10bS)-8—[(6R)—6-amino-1 ,4-oxazepanyl]methyl—3,4,6,lOb—tetrahydro—IH- pyrazino[2,1-a]isoindol—Z-yl}pyrazolo[1,5-a]pyridinecarbonitrile /N’\ The title compound was prepared in analogy to the preparation of Example 94 by using tert—butyl N—[(6R)-1,4—oxazepan—6-y1]carbamate instead of tert—butyl ((3R,4R) methoxypyrrolidin—3—y1)-carbamate. Example 101 (10.0 mg) was obtained. MS: calc’d 444 +], measured 444 [(M+H)+]. 1H NMR (400 MHZ, METHANOL—d4) (5 ppm 8.09 (d, J = 2.3 Hz, 1H), 7.50 (d, J: 7.9 Hz, 1H), 7.27 (d, J: 8.3 Hz, 1H), 6.92 - 7.03 (m, 2H), 6.84 (dd, J: 2.3, 8.3 Hz, 1H), 6.72 (d, J: 8.1 Hz, 1H), 4.48 (d, J = 12.6 Hz, 1H), 4.24 — 4.38 (m, 2H), 4.16 (dd, J: 5.7, 15.5 Hz, 1H), 4.01 — 4.09 (m, 1H), 3.89 — 4.00 (m, 4H), 3.74 — 3.87 (m, 2H), 3.46 — 3.68(m, 4H), 2.95 — 3.09 (m, 2H), 1.39 (d, J: 6.5 Hz, 3H).

Example 102 4-[(4R,10bS)methyl(5-oxa-2,8-diazaspirol3.5]nonanyl)—3,4,6,10b-tetrahydro-1H— pyrazino[2,1-a]isoindolyl]pyrazolo[1,5-a]pyridine-7—carbonitrile / N,N The title compound was prepared in analogy to the preparation of Example 94 by using tert-butyl 5-oxa—2,8-diazaspiro[3.5]nonanecarboxylate instead of terI—butyl ((3R,4R) methoxypyrrolidin y1)-carbamate. Example 102 (20.2 mg) was obtained. MS: calc’d 456 [(M+H)+], measured 456 +]. IH NMR (400 MHz, METI-IANOL-d4) 5 ppm 8.09 (d, J = 2.4 Hz, 1H), 7.51 (d, J: 7.9 Hz, 1H), 7.28 (d, J: 8.1 Hz, 1H), 6.98 (d, J: 2.4 Hz, 1H), 6.73 (d, J: 7.9 Hz, 1H), 6.64 (d, J: 1.7 , 6.52 (dd, J: 2.1, 8.2 Hz, 1H), 4.58 (d, J: 13.1 Hz, 1H), 4.50 - 4.54 (in, 1H), 4.24 — 4.34 (m, 1H), 4.12 (d, J: 13.0 Hz, 1H), 4.06 (d, J: 8.4 Hz, 2H), 3.90 = 8.4 Hz, 2H), 3.63 - 3.73 - 3.98 (m, 3H), 3.79 (d, J (1n, 1H), 3.54 (s, 2H), 3.23 — 3.29 (m, 2H), 3.04 - 3.11 (m, 2H), 1.43 (d, J: 6.5 Hz, 3H).

Example 103 4-[(4R,10bS)[(3R)—3-aminomethyl-pyrrolidin-l-yl]methyl-3,4,6,10b-tetrahydr0-1H- pyrazino[2,1-a]isoindol—2-yl]pyrazolo[1,5-a]pyridine-7—carbonitrile / N’N\ —l47- The title nd was prepared in y to the preparation of Example 94 by using tert—butyl N—[(3R)methylpyrrolidiny1]carbamate (CAS: —15-5, PharmaBlock, Catalog: PBXA3113) instead of tert-butyl ((3R,4R)methoxy~ pyrrolidinyl)-carbamate.

Example 103 (20 mg) was obtained. MS: calc’d 428 [(M+H)+], measured 428 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 8.08 (d, J = 2.3 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.20 (d, J= 7.9 Hz, 1H), 6.94 (d, J= 2.4 Hz, 1H), 6.71 (d, J: 1.8 Hz, 1H), 6.68 (d, J: 8.1 Hz, 1H), 6.57 (dd, J: 2.1, 8.3 Hz, 1H), 4.22 - 4.35 (m, 2H), 4.01 (br d, J: 10.8 Hz, 1H), 3.87 (br d, J: 12.3 Hz, 1H), 3.64 - 3.76 (m, 2H), 3.57 (d, J: 10.6 Hz, 1H), 3.39 - 3.47 (m, 2H), 3.22 - 3.31 (m, 1H), 2.95 - 3.05 (m, 1H), 2.84 ~ 2.91 (m, 1H), 2.18 — 2.33 (m, 2H), 1.60 (s, 3H), 1.31 (d, J: 6.5 Hz, 3H).

Example 104 ,10bS)—8—[(3R,4R)aminometh0xy—l-piperidyl]methyl—3,4,6,10b—tetrahydro— 1H—pyrazino[2,1-a]isoindol—Z-yllpyrazolo[1,5-a]pyridinecarbonitrile / N,N HZN 0‘ The title compound was prepared in analogy to the preparation of Example 94 by using tert— butyl N—[(3R,4R)—3-methoxypiperidinyl]carbamate (CAS: 9075447, PharmaBlock, Catalog: PB07428) instead of tert-butyl ((3R,4R)-4—methoxypyrrolidin ~3—yl)—carbamate.

Example 104 (10 mg) was obtained. MS: calc’d 458 [(M+H)+], measured 458 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 6 ppm 8.07 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.20 (d, J: 8.1 Hz, 1H), 7.07 (d, J: 1.6 Hz, 1H), 6.88 — 6.97 (m, 2H), 6.69 (d, J: 7.9 Hz, 1H), 4.27 (br d, J: 11.9 Hz, 2H), 3.95 - 4.04 (m, 1H), 3.81 - 3.93 (m, 2H), 3.59 - 3.70 (m, 2H), 3.52 (s, 3H), 3.13 — 2.88 (m, 3H), 2.41 - 2.53 (m, 1H), 1.97 - - 3.23 (m, 3H), 2.94 - 3.05 (m, 1H), 2.68 2.04 (m, 1H), 1.29 (d, J: 6.5 Hz, 3H). -148— Example 105 4-[(4R,10bS)—8—[(3R,4S)amin0methoxypiperidyl}methyl-3,4,6,10b-tetrahydro- 1H—pyrazino[2,1—a]isoindol—Z-yIIpyrazolo[1,5—a]pyridinecarbonitrile H2N 0‘ The title compound was prepared in analogy to the preparation of Example 94 by using bis(tert-butyl N—[(3R,4S)—3-methoxypiperidinyl]carbamate) oxalic acid (PharmaBlock, Catalog: PB97963-l) instead of tert-butyl R)-4—methoxypyrrolidin —carbamate.

Example 105 (10 mg) was obtained. MS: calc’d 458 [(M+H)+], measured 458 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 5 ppm 8.10 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.34 (d, J= 8.4 Hz, 1H), 7.13 (d, J: 1.6 Hz, 1H), 6.92 - 7.05 (m, 2H), 6.75 (d, J = 7.9 Hz, 1H), 4.61 = 13.2 Hz, 2H), 4.09 — 4.19 (m, 1H), 3.98 (br d, J = 12.7 Hz, — 4.79 (m, 2H), 4.30 (br d, J 1H), 3.84 - 3.91 (rn, 1H), 3.73 — 3.55 (m, 1H), 3.48 - 3.80 (m, 1H), 3.68 (br s, 1H), 3.47 (s, 3H), 3.9 — 1.96 (m, 1H), 1.48 (d, J: 6.6 ~ 3.21 (m, 2H), 2.85 - 2.99 (m, 2H), 2.05 - 2.18 (m, 1H), 1.86 Hz, 3H). -149— Example 106 ,10bS)[(3R,4S)aminometh0xypiperidyl]methyl-3,4,6,l 0b-tetrahydro- 1H-pyrazin0 [2,l-a]isoindol—Z—yl]pyrazolo[1,S-a]pyridine—7—carbonitrile H2Nm...ON The title compound was prepared in analogy to the preparation of Example 94 by using tert—butyl N—[(3R,4S)—4-methoxy-3~piperidyl]carbamate (CAS: 7—47—7, PharmaBlock, Catalog: PBZ5288—1) instead of tert—butyl ((3R,4R)-4—methoxypyrrolidinyl)-Carbamate.

Example 106 (10 mg) was obtained. MS: calc’d 458 [(M+H)+], measured 458 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 5 ppm 8.08 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.28 (d, J: 8.2 Hz, 1H), 7.12 (d, J: 1.7 Hz, 1H), 6.99 (dd, J: 2.3, 8.4 Hz, 1H), 6.96 (d, J: 2.4 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1H), 4.43 (d, J: 12.6 Hz, 1H), 4.27 — 4.33 (m. 1H), 4.22 (br d, J: .9 Hz, 1H), 3.86 — 3.96 (m, 2H), 3.59 - 3.75 (m, 2H), 3.36 - 3.49 (m, 3H), 3.48 (s, 3H), 3.23 - 3.30 (m, 1H), 3.00 - 3.12 (m, 2H), 2.89 — 2.98 (m, 1H), 1.96 - 2.09 (m, 2H), 1.36 (d, J: 6.5 Hz, 3H). -1 50— Example 107 4-[(4R,10bS)—4—methyl(9-0xa-3,7-diazabicyclo[3.3.1]nonanyl)-3,4,6,10b-tetrahydro- lH-pyrazino[2,1-a]isoindol—Z-yl]pyrazolo[1,5—a]pyridine—7—carb0nitrile / ,N The title compound was prepared in analogy to the preparation of Example 94 by using tert-butyl 9-0xa—3,7—diazabicyclo[3.3.1]nonanecarboxylate instead of tert-butyl ((3R,4R) methoxypyrrolidinyl)-carbamate. Example 107 (10 mg) was obtained. MS: calc’d 456 [(M+H)+], ed 456 [(M+1—1)+]. 1H NMR (400 MHZ, OL-d4) 5 ppm 8.08 (d, J = 2.3 Hz, 1H), 7.50 (d, J: 7.9 Hz, 1H), 7.29 (d, J: 8.2 Hz, 1H), 7.21 (d, J: 1.8 Hz, 1H), 7.06 (dd, J: 2.1, 8.3 Hz, 1H), 6.96 (d, J: 2.4 Hz,1H), 6.71 (d, J: 8.1 Hz,1H), 4.37 (d, J=12.5 Hz, 1H), 4.23 — 3.94 (m, 1H), 3.75 - 3.82 (m, 3H), 3.52 - - 4.33 (m, 3H), 4.08 (br d, J: 10.4 Hz, 1H), 3.87 3.64 (m, 5H), 3.19 — 3.28 (m, 2H), 2.99 - 3.06 (m, 1H), 2.84 - 2.94 (m, 1H), 1.33 (d, J: 6.4 Hz, 3H). 1 5 Example 108 4-[(4R,1 0bS)[(3R,4R)aminohydroxymethyl-pyrrolidinyl]methyl-3,4,6,1 0b- tetrahydro-lH-pyrazino[2,1-a]isoindol—2—yl]pyrazolo[1,5—a]pyridine-7—carbonitrile -1 51— The title nd was prepared in analogy to the preparation of Example 94 by using tert—butyl N-[(3R,4R)—4—hydroxymethyl-pyrrolidin-3~yl]carbamate instead of tert-butyl ((3R,4R)methoxypyrrolidin—3-y1)-carbamate. e 108 (10 mg) was obtained. MS: calc’d 444 [(M+H)+], measured 444 [(M+H)+]. 1H NMR (400 MHz, METHANOL-d4) 6 ppm 8.08 (d, J = 2.4 Hz, 1H), 7.50 (d, J= 7.9 Hz, 1H), 7.24 (d, J= 8.3 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.66 - 6.76 (m, 2H), 6.56 (dd, J = 2.1, 8.3 Hz, 1H), 4.45 (d, J = 12.7 Hz, 1H), 4.28 (br (1, J = 9.4 Hz, 2H), 3.78 = 10.4 Hz, - 3.98 (m, 3H), 3.63 - 3.74 (m, 1H), 3.59 (d, J 1H), 3.46 - 3.53 (m, 2H), 3.37 (d, J: 10.5 Hz, 1H), 2.92 - 3.10 (m, 2H), 1.51 (s, 3H), 1.37 (d, J: 6.6 Hz, 3H).

Example 109 4-[(4R,l0bS)[(3S,4S)aminohydroxymethyl-pyrrolidin-l-yl]methyl-3,4,6,10b- ydro—lH—pyrazino[2,l-a]isoindol-Z—yl]pyrazolo[1,5-a]pyridinecarbonitrile The title compound was prepared in analogy to the preparation of Example 94 by using tert-butyl N-[(3S,4S)-4—hydroxymethyl-pyrrolidinyl]carbamate instead of tert-butyl ((3R,4R)—4-methoxypyrrolidin-3~yl)-carbamate. Example 109 (27 mg) was obtained. MS: calc’d 444 [(M+H)+], measured 444 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 5 ppm 8.08 (d, J = 2.3 Hz, 1H), 7.50 (d, J: 8.1 Hz, 1H), 7.24 (d, J: 8.2 Hz, 1H), 6.96 (d, J: 2.4 Hz, 1H), 6.64 - 6.74 (m, 2H), 6.56 (dd, .1 = 2.1, 8.3 Hz, 1H), 4.47 (d, J = 12.6 Hz, 1H), 4.24 — 4.33 (m, 2H), 3.81 = 10.4 Hz, 1H), 3.46 - 3.54 (m, 2H), 3.37 (d, J: — 3.99 (m, 3H), 3.66 - 3.71 (m, 1H), 3.59 (d, J .4 Hz, 1H), 2.91 - 3.10 (m, 2H), 1.51 (s, 3H), 1.38 (d, J: 6.6 Hz, 3H).

Example 1 10 4-[(4R,10bS)[(3R,4R)aminohydroxy—pyrrolidinyl]methyl-3,4,6,10b- tetrahydro—lH—pyrazino[2,1-a]isoindol-Z-pryrazolo[1,5-a}pyridine—7—carbonitrile / ,N The title compound was prepared in analogy to the preparation of Example 94 by using utyl N—[(3R,4R)—4-methy1-pyrrolidin-3—yl]carbamate (CAS: 18205759, BePhann, Catalog: BD761646) instead of tert-butyl ((3R,4R)—4-methoxypyrrolidinyl)-carbamate.

Example 110 (40 mg) was obtained. MS: calc’d 430 +], measured 43o [(M+H)+]. 'H NMR (400 MHz, METHANOL-d4) 5 ppm 8.07 — 8.12 (m, 1H), 7.51 (d, J: 8.1 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.71 — 6.76 (m, 2H), 6.64 (dd, J = 2.1, 8.3 Hz, 1H), 4.46 - 4.63 (m, 3H), 4.25 - 4.33 (in, 1H), 4.15 (d, J: 13.1 Hz, 1H), 3.96 (br d, J: 12.5 Hz, 1H), 3.67 - 3.12 (m, 2H), 1.43 (d, J — 3.88 (m, 4H), 3.46 (d, .1: 6.6 Hz, 1H), 3.25 - 3.29 (m, 1H), 3.03 = 6.6 Hz, 3H).

Example 1 1 1 4- [(4R,l 0bS)[(3S,4S)—3-aminohydroxy—pyrrolidin-l-yl]-4—methyl-3,4,6,10b-tetrahydro- lH—pyrazino[2,1-a]isoindol—Z-yl]pyrazolo[1,5-a]pyridine—7-carbonitrile / ,N WO 33941 —1 53— The title compound was prepared in analogy to the preparation of Example 94 by using tert-butyl N—[(3S,4S)—4—hydroxy-pyrrolidin—3-yl]ca1'bamate (CAS: 8706320, BePharm, Catalog: BD447697 ) instead of tert-butyl ((3R,4R)—4—methoxypyrrolidinyl)-carbamate.

Example 111 (42 mg) was obtained. MS: calc’d 43o [(M+H)+], ed 430 [(M+H)+]. 1H NMR (400 MHz, METHANOL—d4) 5 ppm 8.09 (d, J: 2.3 Hz, 1H), 7.51 (d, J3 7.9 Hz, 1H), 7.28 (d, J= 8.3 Hz, 1H), 6.98 (d, J: 2.6 Hz, 1H), 6.70 - 6.76 (m, 2H), 6.62 (dd, J: 2.], 8.3 Hz, 1H), 4.36 - 4.58 (m, 3H), 4.30 (br d, J: 12.5 Hz, 1H), 4.04 (d, J: 13.0 Hz, 1H), 3.94 (br d, J: 12.8 Hz, 1H), 3.72 - 3.86 (m, 3H), 3.56 - 3.64 (m, 1H), 3.45 (d, J: 6.7 Hz, 1H), 3.24 - 3.29 (m, 1H), 3.00 — 3.10 (m, 2H), 1.41 (d, J: 6.5 Hz, 3H).

Example 112 4-[(4R,10bS)[(3S,4S)—4-aminohydroxymethyl—pyrrolidin-l-yl]methy1-3,4,6,10b- tetrahydro-lH-pyrazino[2,1-a]isoindol—2-yl]fluoro—pyrazolo[1,5—a]pyridine carbonitrile \ N\N HzN‘s The title nd was prepared according to the following scheme: -154— fluor, KF / N’N\ Zn(CN)2, -——-——> _—__.

Pd PPh( 3)4 F F 112b l l HN’BOC / N’ HNm8“ 10a (3,0 H,,, \ HN \ \ RuPhos Pd GZ DIEA DMA F F CsZCO3 dioxane 112C 112e Example 112 Step 1:preparation of 7-bromofluoro-pyrazolo[1,5-a]pyridine-3—carboxylic acid (compound 112a) The mixture of ethyl 7-bromofluoro—pyrazolo[1,5-a]pyridine-3—carboxylate (compound 94d, 5.2 g, 18.1 mmol), NaOH (2.1 g, 54.3 mmol) in EtOH (90.0 mL) and water (70.0 mL) was stirred at 60°C for 2 hrs. The reaction mixture was trated and then d with water.

After adjusting pH to 4 with 1 N HCl, grey solid was precipitated, which was collected by filtration to afford compound 112a (4.0 g, 85.6% . MS: calc’d 259 [(M+H)+], ed 259 [(M+H)+].

Step 2: preparation of 7—bromo—3,4-difluoro—pyrazolo[1,5—a]pyridine (compound 112b) To a solution of 7-bromo-4—fluoro-pyrazolo[1,5-a]pyridine—3-carboxylic acid (compound 112a, 4.0 g, 15.4 mmol) and KP (3.6 g, 61.8 mmol) in DCE (60.0 mL) and water (50.0 mL) was added Selectfluor (10.9 g, 30.9 mmol). The reaction was stirred at 70°C for 18 hrs. The reaction was quenched with water, extracted with DCM twice. The combined organic layers were dried over NaQSO4, filtered and the filtrate was concentrated in vacuo to afford crude compound 112b (2.8 g, 78% yield). MS: calc’d 233 [(M+H)+], measured 233 [(M+H)+]. -1 55- Step 3: preparation of 3,4-difluoropyrazolo[1,5-a}pyridine—7—carbonitrile (compound 112e) A on of 7-bromo-3,4-difluoro—pyrazolo[1,5-a]pyridine (compound 112b, 2.8 g, 12.0 mmol) and zinc cyanide (5.6 g, 48.0 mmol) in DMF (70.0 mL) was added tetrakis(tripheny1phosphine)palladium (1.4 g, 1.2 mmol). The reaction mixture was stirred at 120 °C for 18 hrs under N2 atmosphere. The mixture was quenched with water and ted with EtOAc twice. The combined organic layers were dried over , filtered and the filtrate was trated in vacuo. The residue was purified by column chromatography to afford compound 112c (810.0 mg, ) as a white solid. MS: calc’d 180 [(M+H)+], measured 180 [(M+H)+]. 1H NMR (400MHz, CHLOROFORM-d) (5 ppm 8.00 (d, J: 3.6 Hz, 1H), 7.31 (dd, J = 4.7, 8.0 Hz, 1H), 6.83 (t, J: 8.4 Hz, 1H).

Step 4: preparation of 4—[(4R,10bS)—8—bromomethyl—3,4,6,10b—tetrahydro-1H- pyrazino [2,1-a]isoindolyl]fluoro-pyrazolo[1,5—a]pyridine—7—carbonitrile (compound 1 12d) A mixture of 3,4—difluoropyrazolo[1,5~a]pyridinecarbonitrile (compound 112e, 200.0 mg, 1.12 mmol), (4R,10bS)—8—bromomethy1—1,2,3,4,6,10b-hexahydropyrazino [2,1-a]isoindole (compound 10a, 351.1 mg, 1.32 mmol) and DIEA (800.0 mg, 6.19 mmol) in DMA (20 mL) was stirred at 130 0C for 15 hrs. The reaction mixture was quenched with H20 (50 mL), extracted with EtOAc (50 mL) for three times. The combined organic layers were washed with brine, dried over Na2S04, filtered and the filtrate was concentrated in vacuo. The residue was purified by LC (PE: EA=1:1) to afford compound 112d (224.4 mg, 49.2% yield). MS: calc’d 426 and 428 [(M+H)+], measured 426 and 428 +].

Step 5: preparation of tert-butyl N—[(3S,4S)-l-[(4R,10bS)~2-(7-cyanofluoropyrazolo I 1 ,S—a] pyridinyl)-4—methyl-3,4,6,10b—tetrahydro-1H-pyrazino[2,1-a]isoindol-S- yl]hydroxy-4—methyl-pyrrolidinyl]carbamate (compound 112e) A mixture of tert-butyl N-[(3S,4S)-4—hydroxymethyl-pyrrolidin—3~yl]carbamate (31.0 mg, 140 umol), 4-[(4R,10bS)bromo-4—methyl—3,4,6,10b- tetrahydro—1H—pyrazino[2,1-a]isoindol-2— fluoro-pyrazolo[l,5—a]pyridinecarbonitrile und 112d, 50.0 mg, 120 umol), RuPhos Pd G2 (20.0 mg, 20 umol) and cesium carbonate (115.0 mg, 3501111101) in 1,4-dioxane (5 mL) was degassed and purged with Ar for 3 times, and then the mixture was stirred at 100 0C for 16 hrs under Ar atmosphere. The mixture was diluted with DCM (80 mL), filtered and the filtrate was concentrated in vacuo. The residue was purified by Prep—TLC (PE: EA=1 :2) to afford nd 112e (40 mg, 37 % yield). MS: calc’d 562 [(M+H)+], measured 562 [(M+H)+]. -1 5 6- Step 6: preparation of ,10bS)—8-[(3S,4S)-4—aminohydroxy—3-methylpyrrolidin-l —yl] methyl-3,4,6,10b-tetrahydro—1H-pyrazino[2,1-a]isoindol-Z-yl]fluoro- pyrazolo[1,S—a]pyridine—7—carbonitrile; 2,2,2-triflu0roacetic acid (Example 112) To a solution of tert-butyl ,4S)[(4R,l0b5)(7-cyanofluoro-pyrazolo [1 ,5- a]pyridinyl)—4-methyl-3 ,4,6,lOb-tetrahydro—1H—pyrazino[2,1-a]isoindolyl]hydroxy—4— methyl-pyrrolidinyl]carbamate (compound 112e, 40.0 mg, 70 umol) in DCM (10 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 2 hrs. The reaction mixture was stirred at room temperature for 2 hrs, then concentrated to afford a crude t, which was purified by pre—HPLC to afford Example 112 (5.5 mg, 17% yield). MS calc’d 462 [(M+H)+], measured 462.4 +]. 1H NMR (400 MHZ, DMSO-db) (5 ppm 8.31 (d, J = 3.6 Hz, 1H), 8.20 = 8.0 Hz, 1H), 7.28 (d, J: 6.8 Hz, 1H), 6.76 (d, J: 8.0 Hz, 1H), 6.63 - 8.24 (m, 3H), 7.73 (d, J (br s, 1H), 6.49 — 6.58 (m, 1H), 5.54 — 5.63 (m, 1H), 4.85 - 5.07 (s, 1H), 4.40 — 4.51 (1n, 1H), 3.85 - 4.06 (m, 1H), 3.71 (dd, J: 5.2, 10.8 Hz, 1H), 3.58 — 3.60 (1n, 1H), 3.45 — 3.49 (1n, 2H), 3.28 — 3.29 (m, 2H), 3.23 (d, J: 10.0 Hz, 2H), 2.95 - 3.10 (m, 2H), 1.36 -1.35 (m, 6H).

Example 1 13 4-[(4R,10bS)—8—[(3R,4R)aminomethoxy-pyrrolidin-l-yl]methyl—3,4,6,10btetrahydro-lH —pyrazino[2,1-a]isoindolyl]fluoro-pyrazolo[1,5-a]pyridine—7- carbonitrile The title compound was prepared in analogy to the preparation of Example 112 by using tert—butyl N~[(3R,4R)rnethoxypyrrolidinyl]carbamate instead of tert—butyl N—[(3S,4S)-4— hydroxy—4~methyl-pyrrolidin-3~yl]carbamate. Example 113 (70 mg) was obtained. MS: calc’d 462 [(M+H)+], measured 462 [(M+H)+]. 1H NMR (400 MHZ, OL-a’4) 5 ppm 8.06 (d, J = 3.5 Hz, 1H), 7.46 (d, J: 7.9 Hz, 1H), 7.22 (d, J: 8.3 Hz, 1H), 6.76 (d, J: 1.8 Hz,1H), 6.63 (d, J: 8.1 Hz, 2H), 4.48 (d, J: 12.6 Hz, 1H), 4.30 (br d, J: 10.0 Hz, 1H), 4.07 - 4.16 (m, 2H), 3.98 (br d, J: 12.6 Hz, 1H), 3.84 - 3.94 (m, 2H), 3.63 — 3.74 (m, 2H), 3.41 - 3.55 (m, 5H), 3.30 (br d, J: 3.5 Hz, 1H), 2.90 - 3.07 (m, 2H), 1.37 (d, J: 6.6 Hz, 3H). -l 57~ Example 1 14 The following tests were carried out in order to ine the activity of the nds of formula (I), (la) or (lb) in HEK293-Blue-hTLR—7/8/9 cells assay.

HEK293-Blue-hTLR—7 cells assay: A stable HEK293-Blue-hTLR-7 cell line was purchased from InVivoGen (Cat.#: hkb—htlr7, San Diego, California, USA). These cells were originally designed for studying the stimulation ofhuman TLR7 by monitoring the activation ofNF-KB. A SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of the IFN-B minimal promoter fused to five NF-KB and inding sites. The SEAP was induced by activating NF—KB and AP-l via stimulating HEK-Blue hTLR7 cells with TLR7 ligands. Therefore the reporter expression was declined by TLR7 antagonist under the stimulation of a ligand, such as R848 (Resiquimod), for incubation of 20 hrs. The cell culture supernatant SEAP er activity was determined using -BlueTM kit (Cat.#: rep-qbl, Invivogen, San Diego, Ca, USA) at a wavelength of 640 nm, a detection medium that turns purple or blue in the presence of alkaline phosphatase.

HEK293-Blue—hTLR7 cells were incubated at a density of 250,000~450,000 cells/mL in a volume of 170 uL in a 96-well plate in Dulbecco's Modified Eagle's medium (DMEM) ning 4.5 g/L glucose, 50 U/mL penicillin, 50 mg/mL omycin, 100 mg/mL Normocin, 2 mM L—glutamine, 10% (v/V) heat-inactivated fetal bovine serum with addition of 20 uL test compound in a serial dilution in the presence of final DMSO at 1% and 10 uL of 20uM R848 in above DMEM, perform incubation under 37 0C in a C02 tor for 20 hrs. Then 20 uL of the supernatant from each well was incubated with 180 uL Quanti-blue substrate solution at 37 0C for 2 hrs and the absorbance was read at 620~655 nm using a spectrophotometer. The signaling pathway that TLR7 activation leads to downstream NF-KB tion has been widely accepted, and therefore similar reporter assay was modified for evaluating TLR7 antagonist.

HEK293-Blue-hTLR-8 cells assay: A stable HEK293—Blue-hTLR~8 cell line was purchased from Gen (Cat.#: hkb—htlr8, San Diego, California, USA). These cells were originally designed for studying the stimulation of human TLR8 by monitoring the activation of NF-KB. A SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of the IFN-B minimal promoter fused to five NF-KB and AP—l-binding sites. The SEAP was induced by activating NF-KB and AP- 1 via stimulating HEK—Blue hTLR8 cells with TLR8 ligands. Therefore the reporter expression was declined by TLR8 nist under the ation of a ligand, such as R848, for incubation of 20 hrs. The cell culture supernatant SEAP reporter activity was ined using QUANTI- —l 5 8- BlueTM kit (Cat.#: rep-qbl, gen, San Diego, Ca, USA) at a wavelength of 640 nm, a detection medium that turns purple or blue in the presence of alkaline phosphatase.

HEK293—Blue—hTLR8 cells were incubated at a density of 250,000~450,000 cells/mL in a volume of 170 ML in a l plate in Dulbecco's Modified Eagle's medium (DMEM) containing 4.5 g/L glucose, 50 U/mL llin, 50 mg/mL streptomycin, 100 mg/mL Normocin, 2 mM L-glutamine, 10% (v/v) heat-inactivated fetal bovine serum with addition of 20 uL test compound in a serial dilution in the presence of final DMSO at 1% and 10 uL of 60uM R848 in above DMEM, perform incubation under 37 °C in a C02 incubator for 20 hrs. Then 20 uL of the supernatant from each well was incubated with 180 uL Quanti~blue substrate solution at 37°C for 2 hrs and the absorbance was read at 620~655 nm using a spectrophotometer. The signaling y that TLR8 activation leads to downstream NF-KB activation has been widely accepted, and therefore similar reporter assay was modified for evaluating TLR8 antagonist.

HEK293-Blue-hTLR-9 cells assay: A stable HEK293-Blue—hTLR-9 cell line was purchased from Gen (Cat.#: hkb-htlr9, San Diego, California, USA). These cells were originally ed for studying the stimulation ofhuman TLR9 by monitoring the activation of NF—KB. A SEAP (sccrctcd embryonic alkaline phosphatase) reporter gene was placed under the control of the lFN-B minimal promoter fused to five NF~KB and AP-l -binding sites. The SEAP was induced by activating NF—KB and AP- 1 via stimulating HEK-Blue hTLR9 cells with TLR9 ligands. Therefore the reporter expression was declined by TLR9 antagonist under the stimulation of a ligand, such as ODN2006 (Cat.#: tlrl-2006—l, Invivogen, San Diego, California, USA), for incubation of 20 hrs. The cell culture supernatant SEAP reporter activity was determined using QUANTl-BlueTM kit (Cat.#: rep~qbl, gen, San Diego, California, USA) at a wavelength of 640 nm, a ion medium that turns purple or blue in the presence of alkaline phosphatase.

HEK293-Blue-hTLR9 cells were incubated at a density of 0~450,000 cells/mL in a volume of 170 uL in a 96—well plate in Dulbecco’s Modified Eagle's medium (DMEM) containing 4.5 g/L glucose, 50 U/mL penicillin, 50 mg/mL streptomycin, 100 mgmL in, 2 mM L—glutamine, l0% (v/v) heat-inactivated fetal bovine serum with addition of 20 uL test compound in a serial dilution in the presence of final DMSO at 1% and 10 uL of 20uM ODN2006 in above DMEM, perform incubation under 37 °C in a C02 tor for 20 hrs. Then uL of the supernatant fi‘om each well was incubated with 180 ML -blue substrate on at 37 0C for 2 h and the absorbance was read at 620~655 nm using a spectrophotometer.

The signaling pathway that TLR9 activation leads to ream NF—KB activation has been 2019/064323 -159~ widely accepted, and therefore similar reporter assay was modified for evaluating TLR9 antagonist.

The nds of formula (I) have TLR7 and/or TLR8 inhibitory activities (IC50 value) <0.1 uM. Moreover, most compounds also have TLR9 inhibitory activity <0.3 uM. ty data of the compounds of the present invention were shown in Table 1.

Table 1: The activity of the compounds of present invention in HEK293—Blue-hTLR-7/8/9 cells assays HEK/hTLR7 HEK/hTLR8 HEK/hTLR9 Example No 1C50 (HM) IC50 (HM) ICSO (HM) <3.2 <3.2 106.0 \J u—a kl} /\5”N 125.0 . 87.7 101.0 132.7 156.3 99.2 150.3 130.2 92.5 92.0 71.2 81.1 83.2 95.2 113.4 97.5 81.0 114.1 65.3 86.9 56.1 103.7 92.4 90.5 115.7 55.8 .6 83.4 43.3 96.6 |._. 93.7 89.2 100.1 66.6 111.4 100.3 1 102.9 WO 33941 I * 38 1.7 <0.3 66.8 39 3.0 <0.3 122.6 41 . . 42 <32 <32 65.4 43 4.0 I <32 55.5 44 19.1 0.4 102.0 46 . 143.8 47 4.8 0.6 146.2 - . — . . 4.5 <32 543 5.7 <32 87.3 55A 7.7 <32 111.2 5513 16.1 <32 156.1 6.9 <3.2 103.4 11.1 <3.2 ‘1 83.0 563 4.5 <32 92.1 59 <32 <32 73.5 62 5.9 <32 84.5 64 <32 <32 125.3 65 4.4 <32 95.8 66 <32 <32 141.2 68 3.3 <3.2 73.5 69 18-2 <32 77 12.6 <3.2 140.7 78 1.2 0.4 83.6 79 7.6 2.8 113.4 ~16] - 63.6 126.0 Example 113 Human Microsomal Stability Assay Human liver microsomes (Cat.NO.: 452117, Corning, USA) were preincubated with test compound for 10 minutes at 370C in 100 mM potassium phosphate buffer, pH 7.4. The reactions were initiated by adding NADPH regenerating system. The final tion es contained 1 uM test compound, 0.5 mg/mL liver microsomal protein, 1 mM MgC12, 1 mM NADP, 1 unit/mL isocitric dehydrogenase and 6 mM isocitric acid in 100 mM potassium ate buffer, pH 7.4.

After incubation times of O, 3, 6, 9, 15 and 30 minutes at 37°C, 300 uL of cold ACN (including internal standard) was added to 100 uL incubation mixture to terminate the reaction. ing precipitation and centrifugation, IOOuL supernatant will be taken out and added 300uL water.

The amount of compound remaining in the samples was ined by MS. Controls of no NADPH regenerating system at zero and 30 minutes were also prepared and analyzed. The results were categorized as: low (<7.0 mL/min/kg), medium (7.0-16.2 mL/min/kg) and high (16.2—23.2 mL/min/kg). Test results were summarized in Table 2. 2019/064323 ~162— Table 2: Human microsomal stability results CL (h) (mL/min/kg) 21 6.2 27 7.7 28 8.7 8.8 32 8.7 36 6.2 37 6.5 38 6.2 39 6.2 40A 7.0 403 7.6 45 6.2 45A 6.2 4513 6.2 46 8.8 48 8.9 52 8.1 54 8.9 54A 7.5 54B 7.0 60 7.4 61 7.3 62 7.5 65 T 6 2 :] -l 63— 86 7.7 T Example 114 hERG Channel Inhibition Assay The hERG channel inhibition assay is a highly sensitive measurement that identifies compounds exhibiting hERG tion d to cardiotoxicity in vivo. The hERG KJr channels were cloned in humans and stably expressed in a CHO ( Chinese hamster ovary) cell line.

CHOhERG cells were used for clamp (voltage—clamp, Whole-cell) experiments. Cells were stimulated by a voltage pattern to activate hERG channels and conduct IKhERG currents (rapid delayed outward rectifier ium current of the hERG channel). After the cells were stabilized for a few minutes, the amplitude and kinetics of IKIIERG were recorded at a stimulation frequency of 0.1 Hz (6 bpm). Thereafter, the test compound was added to the ation at increasing concentrations. For each concentration, an t was made to reach a steady-state effect, usually, this was achieved within 3-10 min at which time the next highest concentration was applied. The amplitude and kinetics of lKhERG are recorded in each tration of the drug which were compared to the control values (taken as 100%). (references: Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie l, Palethorpe S, Siegl PK, Strang I, an AT, Wallis R, Camm AJ, Hammond TG. 2003; Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 58:32-45, netti MC, Tristani-Firouzi M. 2006; hERG potassium channels and cardiac arrhythmia. Nature 4402463- 469, Webster R, an D, Walker D. 2002; Towards a drug concentration effect relationship for QT prolongation and torsades de pointes. Curr. Opin. Drug Discov. Devel. 5:116-26). Results of hERG are given in Table 3.

Table 3: hERG results Example No 1 >10 >20 16 >10 >20 21 >10 >20 22 5.0 >20 -0 >20 >10 >20 >10 >20 37 8.6 >20 38 >10 >20 39 >10 >20 4013 >10 >20 >10 >20 6.7 >20 .2 >20 6.4 >20 45A >20 453 >10 >20 53A 6.6 >20 >10 >20 >10 >20 “ >10 >20 Example 115 3T3 in Vitro phototoxicity assay Phototoxicity is defined as a toxic response that is elicited after the first exposure of the skin to certain chemicals and subsequent exposure to 1ight, or that is d similarly by skin irradiation after systemic administration of a chemical substance. The assay used in this study is designed to detect the phototoxic potential of a chemical by using a simple in Vitro xicity assay with Balb/c 3T3 mouse asts. The principle of this test is a comparison of the cytotoxicity of a chemical when tested with and without exposure to a non-toxic dose of UVA- light. Cytotoxicity is expressed as a dose dependent reduction of the growth rate of cells as determined by uptake of the Vital dye Neutral Red one day after treatment.

Method Preparation of stock solution and dosage of test item A small amount of substance was d and formulated freshly in DMSO just before the start of the exposure of the cells. This stock solution or appropriate dilutions with DMSO were added to the cell suspensions to obtain the required final concentrations. All solutions were generally prepared in Eppendorf caps and discarded after use.

Reference substance Chlorpromazine (HCL) (Sigma, Batch/Lot No.2 120M1328V) test concentration: 300 ug/mL, Solvent: PBS / 3% DMSO Measurement of UV absorption spectrum The absorption spectra as such or with UV-A or with UV-B pro-irradiation were recorded between 240 nm and 400 nm with a Lambda-2 spectral photometer n Elmer).

UV radiation sources: for UV-A: Sol 500 with filter H1 Main um: 315—690 nm Irradiance: . 1.67 mW/cm2 Radiation dose : approx. 5 J/cm2 for UV-B: Philips TL 20W/ 12 Main um: 290—320 nm ance: approx. 0.083 mW/cm2 Radiation dose: approx. 0.05 J/cm2 Determination of oxicity For this study the Neutral Red uptake (NRU) assay of Borenfreund and Puerner (Borenfreund, E, Puerner JA. Toxicity determined in Vitro by morphological alterations and l Red absorption. Toxicology Lett. 1985; 24:119—124.) modified according to INVITTOX protocol No 78 (ERGATT/FRAME data bank of in Vitro techniques in toxicology. INVITTOX PROTOCOL No 78. 3T3 NRU oxicity Assay. March 1994) has been adapted to examine a possible phototoxic ial of the test item. This assay is based on the active uptake of the Neutral Red dye into the lysosomes of cultured murine fibroblasts. Because lysosomal membranes are known to be a site of action of many phototoxic compounds, this assay can provide a measure of potential for phototoxic injury.

Preparation of cell culture A murine fibroblasts clone A 31 (ATCC no. CCL 163 — passage No. 108) were cultured in 175 01112 tissue culture grade flasks, containing sDMEM cco’s Minimal Essential WO 33941 Medium, supplemented with 10% fetal calf serum, 2 mM L—glutamine, 100 ml Penicillin and 100 pig/ml streptomycin) at 37°C in a humidified atmosphere of 6% C02. Before cells approach confluence they were removed from flasks by trypsinisation. Prior to use in an assay, the cells were transferred to l microtiter plates at a tration of 1x 104 cells/well in 100 pl volumes of sDMEM and d to attach for 24 h.

Exposure to test item For incubation with murine fibroblasts, the test item was diluted in PBS / 3% DMSO (detailed concentrations see in results).

Culture medium (Dulbecco's Modified Eagle Medium(DMEM), GlutaMAX (Gibco Ref 21885-025), 10% Fetal Bovine Serum (FBS) (Gibco Ref 10270-106), lOOIU/ml Penicillin and 100 ug/ml Streptomycin (Gibco Ref 15140-122» was removed from the wells and murine asts were washed with PBS. Afterwards 100 uL ofPBS / 3% DMSO containing the test item was added and target cells were incubated for l h at 37°C with 6% CO2.

UV exposure For each test item the microtiter plates were prepared according to Table 4. “UVA plates” were exposed to approx. 5 J/cm2 UVA light, the “Dark plates” were kept in the dark and served as cytotoxicity control. Plates with chlorpromazine hydrochloride served as positive control. UV flux was measured with a UV-meter (Dr. Grobel RM2l).

Following UV irradiation, the test item was removed from the wells (one g step with PBS) and replaced with sDMEM. Target cells were then incubated overnight at 37°C in 6% C02.

Table 4. 96-well microtiter plate setup 1.0 ~ _ -_, U01 U02 U03 U04 U05 U06 U07 96-well microtiter plates were prepared as follows: - l 67— Each plate contained wells with cells and solvent but without test item which were either not incubated with Neutral Red on (0% standard - $1) or were stained with Neutral Red (100% standard —SZ) for calculation of the standard cell viability curve. Wells labeled with U01- U08 ned the different test item concentrations.

Neutral Red uptake The ready to use Neutral Red (NR) staining solution was freshly prepared as follows: ' 0.4% aqueous stock solution was shielded from light and filtered before use to remove NR crystals. 0 1:40 dilution of the stock solution was then prepared in sDMEM and added to the cells.

After the incubation the wells to be assayed were filled with 100 uL of the sDMEM containing Neutral Red. The target cells were incubated with the NR for 3 h at 37°C in 6% C02.

Measurement of Neutral Red uptake Unincorporated Neutral Red was removed from the target cells and the wells washed with at least 100 uL of PBS. 150 uL of l Red desorb solution (1% glacial acetic acid, 50% ethanol in aqua bidest) was then added to quantitatively t the incorporated dye. After at least 10 mins of vigorous shaking of the plates on a microtiter plate shaker until Neutral Red has been extracted from the cells and formed a homogeneous solution, the absorption of the resulting colored on was measured with a SPECTRAmaX PLUS microtiter plate reader (Molecular Devices) at 540 nm.

Calculation of cell ity Cell viability was calculated with the x Pro software package (Molecular Devices). First a two-point standard curve (0% and 100% viability) was calculated with the linear curve fit option of the m based on the following formula: Y = A + ( B >< X) (A = y-intercept of the line; B = slope of the line; 0% cell viability = cells with solvent, but t test item and l Red; 100% cell viability = cells with solvent and Neutral Red, but without test item) By this means the ity of the cells incubated with increasing concentrations of the test chemical was calculated. Chlorpromazine (HCl) served as positive control in the experiment.

Calculation of IC50 values All calculations were performed with the SOFTmax Pro analysis software package WO 33941 -1 68— (Molecular Devices ~ for details see: http://www.mbl.edu/jbpc/files/ZO14/05/SoftMax_Pro_User_Guide.pdf) Calculation of discrimination factor for phototoxicity For evaluation of phototoxic potential, the IC50 values determined with and without UV exposure were compared.

Factor = IC50 (-UV) / ICso (+UV) For discrimination between phototoxic and non—phototoxic test chemicals a cut-off factor of >5 was applied (Liebsch M, Spielmann H, Balls M, Brand M, Doring B, Dupuis J, Holzhfiter HG, Klecak G, L.Eplattenier H, Lovell W, Maurer T, hauer F, Moore L, Pape W, Pfannenbecker U, Potthast JM, De Silva O, Steiling W, Willshaw A. First results of the EC/COLIPA Validation Project. In Vitro Phototoxicity Testing. In: In Vitro Skin Toxicology: Irritation, Phototoxicity, Sensitization; Vol. 10. Alternative Methods in logy,-Eds.

Rougier A, Maibach HI, Goldberg AM; Mary Ann Liebert Pub1.: New York, USA 1994, pp. 243-251).

Test items which are not xic to murine fibroblasts even at the highest concentrations tested, but ShOW a strong dose dependent decrease in cell viability after UV exposure are considered also phototoxic (Spielmann H, Balls M, Dupuis J, Pape WJW, Pechovitch G, Silva DeO, Holzhfitter, HG, Clothier R, Desolle P, Gerberick F, Liebsch M, Lowell WW, Maurer T, Pfannenbecker U, Potthast JM, Csato M, Sladowski D, Steiling W, Brantom P. The international EU/COLIPA in vitro phototoxicity validation study: Results of phase II (blind . Part 1: The 3T3 NRU phototoxicity test. Toxicology in Vitro 1998, 12: 305—327).

The test s were shown below, the compounds of this invention showed very good phototoxicity profile.

Table 5. The 3T3 test results for the nd of this invention Example No oxicity factor IC50 (UV-A) (pg/inL) 14 1.00 >100 so >19 39 1.00 >100 54B 1.00

Claims (3)

1. A compound of a (I), (R n R4 (R )m (I), wherein R7 R7 R7 R7 N R8 N R8 N R8 N R8 \ N/ \ / \ / \ / N\ / N/j:Re R] is , a 9 9 R7 R7 R7 R7 \ \ \ \N s 0 , , ; wherein R7 is C1_6alkyl, C1_6alkoxy, haloC1_6alkyl, n, nitro or cyano; R8 is H or deuterium; R9 is H, deuterium or C1_6alkyl; R10 is H or halogen; R2 is H or C1_6alkyl; 10 R3 is H; R4 is H; R5 is H, piperazinyl, halogen, C1_6alky1, halopyrrolidinylamino or hydroxypy1‘rolidinle1_ balkylamino; R6 is H; 15 (Cl-(,alky1)2aminoC1-6alkoxy; (C1-éalky1)2aminoC1-6alkylamino; l,2,3,4,6,6a-hexahydropyrrolo[3,4-C]pyr1‘olyl substituted by C1_6alkoxy; -l 70- 1,4-diazepany1 substituted by one or two substituents independently selected from y and C1_6alky1; 1,4~oxazepanyl substituted by amino; 1,4-oxazepanylamino; 5 l,6-diazaspiro [3 .3]heptany1; 2,5-diazabicyclo[2.2. l ]heptanylcarbonyl; azaspiro[3.3]heptanyl unsubstituted or tuted by C1_6a1ky1; 2-oxaazaspiro[3.4]octany1 substituted by amino; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3 ,4—b] [1 ,4]oxazinyl; 10 3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxaziny1; 3,8-diazabicyclo[3 .2. l ]octanylcarbonyl; 3-oxa-7,9-diazabicyclo[3 .3 . 1 ]nonany1; 3-oxo—l ,5,6,7,8,8a—hexahydroimidazo[ 1 ,5-a]pyraziny1; 5-oxa-2,8-diazaspiro[3.5]nonanyl; 15 9-oxa—3 ,7—diazabicyclo[3 .3. 1 ]nonany1; a1nino(C1-6alkyl)piperidinylcarbonyl; inyl unsubstituted or substituted by one or two substituents independently selected from amino and C1-6a1kyl; inylamino; 20 inyloxy; C1-6alkoxypiperidiny1amino; C1-6alkoxypyrrolidinyl(C1-6a1kyl)amino; C1-6alkoxypyrrolidiny1a1nino; haloazetidinyl(C1.6alky1)amino; 25 halopyrrolidinylamino; halopyrrolidinleI-6alkoxy; halopyrrolidinle1-6alky1amino; halopyrrolidinyloxy; hydroxypyrrolidinlel.6alky1amino; 30 morpholinylcl-6alkylamino; piperazinyl unsubstituted or substituted by C1-6alkoxyC1-6a1ky1, hydroxyC1_6alkyl or C1- 6alkyl; piperazinylcarbonyl; -l 71 - piperidinyl unsubstituted or tuted by one or two substituents independently selected from amino, C1_6alkoxy and C1_6alkyl; piperidinylamino; or pyrrolidinyl substituted by one, two or three substituents independently selected from 5 amino, C1_6alkoxy, C1_6alkyl, C1-6alkylamino, halogen, hydroxy and hydroxyC1_6alkyl; m is 0,1, 2, or3; nis 1,2, 3 or4; m+ns4; with the proviso that R5 and R6 are not H simultaneously; 10 or a pharmaceutically acceptable salt thereof.

2. A nd of formula (Ia), (Ia), wherein R7 R7 R7 N R8 N R8 N j: N \ / N’ \ \> / N/ R9 \ \ 8 15 R1 is or ; wherein R7 is C1_6alkyl, haloCl_(,alkyl, halogen or cyano; R8 is H or deuterium; R9 is H or deuterium; R10 is H or halogen; R2 is H or C1_6alkyl; R3 is H; 20 R4 is H; R5 is H, zinyl, rrolidinylamino or hydroxypyrrolidinle1-6alkylamino; R6 is H; (C1-6alkyl)2aminoC1-6alkoxy; (C1_6alky1)2aminoC 1 -6a1ky1amino; l,2,3,4,6,6a—hexahydropyrrolo[3,4—c]pyrroly1 substituted by C._6alkoxy; 1,4-diazepanyl substituted by one or two substituents independently ed from hydroxy and C]_6alkyl; 5 1,4—oxazepanyl substituted by amino; 1 ,4-oxazepanylamino; 1,6-diazaspiro[3 .3]heptanyl; 2,5 -diazabicyclo [2 .2. 1 ]heptanylcarbonyl; 2,6—diazaspiro[3.3]heptanyl unsubstituted or substituted by C1_6alky1; 10 2-oxa—7—azaspiro[3.4]octanyl substituted by amino; 3,4,4a,5,7,7a-hexahydro-2H—pyrrolo[3,4-b] [ l ,4]oxazinyl; 3,4a,5,6,7,7a-hexahydro-ZH-pyrrolo[3,4-b] [ l ,4]oxazinyl; 3,8-diazabicyelo[3.2.1 ylcarbonyl;

3-0xa-7,9-diazabicyclo[3.3.1]nonanyl; 15 3-oxo—1,5,6,7,8,8a-hexahydroi1nidazo[1 ,5-a]pyrazinyl; 5-oxa-2,8-diazaspiro[3.5]nonanyl; 9-oxa-3 ,7—diazabicyclo[3 .3.l ]nonanyl; amino(C1.6alkyl)piperidinylcarbonyl; azetidinyl unsubstituted or substituted by one or two substituents independently selected 20 from amino and Cmalkyl; inylamino; inyloxy; C1-6alkoxypiperidinylamino; C1-6alkoxypyrrolidiny1(C1-6alkyl)amino; 25 C1-6alkoxypyrrolidinylamino; haloazetidinyl(C1-6a1ky1)amino; halopyrrolidinylamino; halopyrrolidinle1-6alk0xy; halopyrrolidinle1.6alkylamino; 30 halopyrrolidinyloxy; hydroxypyrrolidinle.6alkyla1nino; morpholinle1-6alkylamino; piperazinyl unsubstituted or substituted by C1_6alkoxyC1_6alkyl, yC1-6alkyl or CL 6alky1;