Substituted tetrahydropyrazolo[3,4-d]pyrimidines and tetrahydropyrazolo[4,3-d]pyrimidines as C5A receptor modulators

Abstract

The present invention relates to derivatives of formula (I) ##STR00001##
wherein Ring A, X, Y, Z, R.sup.A, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as described in the description, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as C5a receptor modulators.

Claims

1. A compound of Formula (I): ##STR00023## or a pharmaceutically acceptable salt or deuterium labelled form thereof, wherein: (i) X represents N; Y represents NR.sup.5; and Z represents CH; or (ii) X represents CH; Y represents NR.sup.5; and Z represents N; ring A represents piperidin-1,4-diyl, wherein ring A is optionally substituted in position 4 with one R.sup.A substituent; R.sup.A represents CH.sub.3; R.sup.1 represents phenyl; wherein the phenyl is substituted with one or two substituents; wherein the phenyl is substituted in the ortho position with one substituent selected from the group consisting of F, CH.sub.3, CHF.sub.2, and OCH.sub.3; and wherein the phenyl is optionally substituted in the other ortho position with one substituent selected from the group consisting of F, CH.sub.3, and OCH.sub.3; R.sup.2 represents phenyl, wherein the phenyl is substituted in the ortho position with one substituent selected from the group consisting of F, Cl, CH(CH.sub.3).sub.2, CF.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2, OCF.sub.3, OCH.sub.2-cyclopropyl, O(cyclopropyl), and O(oxetan-3-yl); R.sup.3 represents hydrogen; R.sup.4 represents hydrogen; and R.sup.5 represents CH.sub.2CHF.sub.2, CH(CH.sub.3)CHF.sub.2, CH.sub.2CH(F)CH.sub.3, CH.sub.2CF.sub.2CH.sub.3, or CH.sub.2C(F)(CH.sub.3)CH.sub.3.

2. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound according to claim 1, or a pharmaceutically acceptable salt or deuterium labelled form thereof.

3. A method for modulating C5a receptor activity in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or deuterium labelled form thereof.

4. The method of claim 3, wherein the patient has a disease or disorder selected from the group consisting of cancer, an autoimmune disease or disorder, a bullous disease or disorder, an immune complex disease or disorder, an inflammatory bowel disease or disorder, a complement related inflammatory disease or disorder, an inflammatory disease or disorder involving intravascular microvesicle release, an ischemia related disease or disorder, an ischemic reperfusion injury related disease or disorder, a neurodegenerative disease or disorder, and a vasculitic disease or disorder.

5. The method of claim 3, wherein the patient has a disease or disorder selected from the group consisting of coronary endothelial dysfunction induced by cardioplegia, coronary endothelial dysfunction induced by cardiopulmonary bypass, edema, increased capillary permeability, myocardial infarction, thrombosis, a deleterious consequence of contact sensitivity and inflammation caused by contact with an artificial surface, an increase in leukocyte and platelet activation, a pathologic sequelae associated with insulin-dependent diabetes mellitus, a pathologic sequelae associated with an injury, and a pathologic sequelae associated with intoxication.

6. The method of claim 5, wherein the pathologic sequelae associated with an injury or the pathologic sequelae associated with intoxication is selected from the group consisting of a hemorrhage, a shock, a surgery, and a trauma.

7. The method of claim 6, wherein the surgery is a surgery including transplantation.

8. The compound: ##STR00024## or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and the compound according to claim 8, or a pharmaceutically acceptable salt thereof.

10. A method for modulating C5a receptor activity in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a compound according to claim 8, or a pharmaceutically acceptable salt thereof.

11. The method of claim 10, wherein the patient has a disease or disorder selected from the group consisting of cancer, an autoimmune disease or disorder, a bullous disease or disorder, an immune complex disease or disorder, an inflammatory bowel disease or disorder, a complement related inflammatory disease or disorder, an inflammatory disease or disorder involving intravascular microvesicle release, an ischemia related disease or disorder, an ischemic reperfusion injury related disease or disorder, a neurodegenerative disease or disorder, and a vasculitic disease or disorder.

12. The method of claim 10, wherein the patient has a disease or disorder selected from the group consisting of coronary endothelial dysfunction induced by cardioplegia, coronary endothelial dysfunction induced by cardiopulmonary bypass, edema, increased capillary permeability, myocardial infarction, thrombosis, a deleterious consequence of contact sensitivity and inflammation caused by contact with an artificial surface, an increase in leukocyte and platelet activation, a pathologic sequelae associated with insulin-dependent diabetes mellitus, a pathologic sequelae associated with an injury, and a pathologic sequelae associated with intoxication.

13. The method of claim 12, wherein the pathologic sequelae associated with an injury or the pathologic sequelae associated with intoxication is selected from the group consisting of a hemorrhage, a shock, a surgery, and a trauma.

14. The method of claim 13, wherein the surgery is a surgery including transplantation.

15. The compound: ##STR00025## or a deuterium labelled form thereof.

16. The compound: ##STR00026##

17. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and the compound according to claim 16.

18. A method for modulating C5a receptor activity in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a compound according to claim 16.

19. The method of claim 18, wherein the patient has a disease or disorder selected from the group consisting of cancer, an autoimmune disease or disorder, a bullous disease or disorder, an immune complex disease or disorder, an inflammatory bowel disease or disorder, a complement related inflammatory disease or disorder, an inflammatory disease or disorder involving intravascular microvesicle release, an ischemia related disease or disorder, an ischemic reperfusion injury related disease or disorder, a neurodegenerative disease or disorder, and a vasculitic disease or disorder.

20. The method of claim 18, wherein the patient has a disease or disorder selected from the group consisting of coronary endothelial dysfunction induced by cardioplegia, coronary endothelial dysfunction induced by cardiopulmonary bypass, edema, increased capillary permeability, myocardial infarction, thrombosis, a deleterious consequence of contact sensitivity and inflammation caused by contact with an artificial surface, an increase in leukocyte and platelet activation, a pathologic sequelae associated with insulin-dependent diabetes mellitus, a pathologic sequelae associated with an injury, and a pathologic sequelae associated with intoxication.

21. The method of claim 20, wherein the pathologic sequelae associated with an injury or the pathologic sequelae associated with intoxication is selected from the group consisting of a hemorrhage, a shock, a surgery, and a trauma.

22. The method of claim 21, wherein the surgery is a surgery including transplantation.

Description

EXPERIMENTAL PART

(1) I. Chemistry

(2) All temperatures are stated in ° C. Commercially available starting materials were used as received without further purification.

(3) Characterization of Compounds

(4) Compounds described in the invention are characterized by LC-MS data (retention time t.sub.R is given in min) and/or NMR using the conditions described below.

(5) Analytical LC-MS:

(6) LC-MS (Method 1):

(7) Waters Acquity UPLC i-Class system with Waters i-Class BSM binary pump, Thermo MSQ Plus MS detector and Waters Acquity PDA detector.

(8) Eluents (acidic conditions): A: H.sub.2O+0.04% TFA; B: MeCN; gradient: 5% B.fwdarw.95% B; runtime: 1.2 min; flow: 0.8 mL/min; detection: UV/Vis+MS

(9) Column Agilent Zorbax RRHD SB-aq, 2.1×50 mm, 1.8 μm

(10) LC-MS (Method II):

(11) Dionex Ultimate 3000 system with Dionex HPG-3200RS binary pump, Thermo MSQ Plus MS detector and Dionex DAD-3000RS PDA detector.

(12) Eluents (acidic conditions): A: H.sub.2O+0.04% TFA; B: MeCN; gradient: 5% B.fwdarw.95% B; runtime: 1.5 min; flow: 4.5 mL/min; detection: UV/Vis+MS

(13) Column Agilent Zorbax SB-aq, 4.6×50 mm, 3.5 μm

(14) LC-MS (Method III):

(15) Dionex Ultimate 3000 system with Dionex HPG-3200SD binary pump, Thermo MSQ Plus MS detector and Dionex DAD-3000RS PDA detector.

(16) Eluents (basic conditions): A: H.sub.2O+13 mmol/L NH.sub.4OH; B: MeCN; gradient: 5% B.fwdarw.95% B; runtime: 1.9 min; flow: 1.6 mL/min; detection: UV/Vis+MS

(17) Column Waters BEH C.sub.18, 3.0×50 mm, 2.5 μm

(18) LC-MS (Method IV):

(19) Waters Acquity UPLC i-Class system with Waters i-Class BSM binary pump, Thermo MSQ Plus MS detector and Waters Acquity PDA detector.

(20) Eluents (basic conditions): A: H.sub.2O+13 mmol/L NH.sub.4OH; B: MeCN; gradient: 5% B.fwdarw.95% B; runtime: 1.9 min; flow: 0.8 mL/min; detection: UV/Vis+MS

(21) Column Waters BEH C.sub.18,2.1×50 mm, 2.5 μm

(22) NMR Spectroscopy:

(23) Bruker Avance HD spectrometer equipped with a 500 MHz Ultrashield™ Magnet and a 5 mm DCH cryoprobe or Bruker Avance II spectrometer equipped with a 400 MHz Ultrashield™ Magnet and a BBO 5 mm probehead. Chemical shifts (S) are reported in parts per million (ppm) relative to proton resonances resulting from incomplete deuteration of the NMR solvent, e.g. for dimethylsulfoxide δ(H) 2.49 ppm, for chloroform δ(H) 7.24 ppm. The abbreviations s, d, t, q and m refer to singlet, doublet, triplet, quartet, multiplet, respectively and br to broad. Coupling constants J are reported in Hz.

(24) Purification of Compounds

(25) The compounds were purified by either column chromatography on silica-gel and/or prep. LC-MS using the conditions described below.

(26) Column Chromatography

(27) Column chromatography (CC) was performed using prepacked cartridges (SNAP Ultra™, SNAP KP-SIL™, SNAP KP-NH™, Isolute™ Silica II or Isolute™ NH.sub.2) from Biotage.

(28) Preparative LC-MS:

(29) Gilson 333/334 Prep-Scale HPLC pump equipped with Gilson LH215 autosampler, Dionex SRD-3200 degasser, Dionex ISO-3100A make-up pump, Dionex DAD-3000 DAD detector and Thermo MSQ Plus Single Quadrupole MS detector. Flow: 75 mLmin. Detection: UV/Vis and/or MS.

(30) Additional information for the purification is summarized in the table below with following definitions:

(31) XBridge: column Waters XBridge C18, 10 μm, 30×75 mm

(32) Zorbax: column Agilent Zorbax SB-aq, 5 μm, 30×75 mm

(33) Atlantis: column Waters Atlantis T3, 10 μm, 30×75 mm

(34) Acidic: eluant: A=H.sub.2O with 0.5% HCOOH, B=MeCN

(35) Basic: eluant: A=H.sub.2O with 0.125% NH.sub.4OH, B=MeCN

(36) Very lipophilic gradient: 50% B.fwdarw.95% B over 4 min then 95% B over 2 min

(37) Lipophilic gradient: 30% B.fwdarw.95% B over 4 min then 95% B over 2 min

(38) Normal gradient: 20% B.fwdarw.95% B over 4 min then 95% B over 2 min

(39) Polar gradient: 10% B.fwdarw.95% B over 4 min then 95% B over 2 min

(40) Very polar gradient: 5% B.fwdarw.50% B over 3 min then 50% B.fwdarw.95% B over 1 min and finally 95% B over 2 min

(41) TABLE-US-00001 XBridge Zorbax Atlantis acidic basic acidic basic Very lipophilic gradient Method 10 Method 8 Method 9 Method 6 Lipophilic gradient Method 4 Method 5 Method 2 Normal gradient Method 3 Method 1 Method 11 Polar gradient Method 7 Very polar gradient Method 12

Abbreviations (as Used Hereinbefore or Hereinafter)

(42) Ac acetyl AcOH acetic acid AlBN azobisisobutyronitrile aq. aqueous BINAP racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl Bn benzyl Boc tert.-butyloxycarbonyl Cbz benzyloxycarbonyl CC column chromatography CDI carbonyl diimidazole CDT 1,1′-carbonyl-di-(1,2,4-triazole) CPhos 2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)biphenyl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane dioxane 1,4-dioxane DIPEA diisopropylethylamine DMA dimethylacetamide DMF dimethylformamide DMSO dimethylsulfoxide Dppf 1,1′-bis(diphenylphosphino)ferrocene DSC N,N′-disuccinimidyl carbonate EDC.HCl N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride eq equivalent(s) Et ethyl EtOAc ethyl acetate EtOH ethanol Et.sub.2O diethylether g gram(s) h hour(s) Hept heptane HOBt 1-hydroxybenzotriazole HPLC high performance liquid chromatography io ionisation LC-MS liquid chromatography—mass spectrometry MeCN acetonitrile MeOH methanol mg milligram(s) min minute(s) mL milliliter(s) mmol millimole(s) MS mass spectroscopy NaBH(OAc).sub.3 sodium triacetoxyborohydride NBS N-bromosuccinimide NCS N-chlorosuccinimide NMR nuclear magnetic resonance spectroscopy OAc acetate org. organic ON overnight PEPPSI-IPr [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone)dipalladium(0) prep. preparative QuadraPure® MPA mercaptophenyl amino functionalized polystyrene beads rac racemic RT room temperature rxn reaction sat. saturated SEM 2-(trimethylsilyl)ethoxymethyl soln. solution TEA triethylamine TFA trifluoroacetic acid TFE trifluoroethanol THE tetrahydrofuran THP tetrahydro-2H-pyranyl Ts p-toluenesulfonyl t.sub.R retention time

(43) When not commercially available, the building blocks are prepared according to the procedures described below.

Synthesis of Building Blocks BB-1

(44) To a soln. of carboxylic acid A (1 eq) in anh. MeOH (4 mL/mmol) was added AcCl (3 eq) and the rxn mixture was stirred for 2.5 h at 80° C. (see Table 1). MeOH was evaporated off and the residue was partitioned between a sat. aq. soln. of NaHCO.sub.3 and EtOAc. The org. phase was washed with a 10% aq. soln. of Na.sub.2CO.sub.3 and with brine, dried over MgSO.sub.4 and concentrated in vacuo.

(45) TABLE-US-00002 TABLE 1 t.sub.R [min] MS-data .sup.1H NMR Acid (LC/MS m/z (500 MHz, BB-1 Name reactant A method) [M + H].sup.+ DMSO-d6) δ: BB-1-1 4-Nitro-2H-pyrazole-3- commercially available carboxylic acid methyl ester BB-1-2 5-Nitro-1H-pyrazole-4- 3-Nitro-1H- 0.55 (I) no io 14.34 (s, 1 H), carboxylic acid methyl pyrazole-4- 8.60 (s, 1 H), ester carboxylic 3.79 (s, 3 H) or acid 3-Nitro-1H-pyrazole-4- carboxylic acid methyl ester BB-1-3 1-Methyl-4-nitro-1H- commercially available pyrazole-3-carboxylic acid methyl ester

Synthesis of Building Blocks BB-2

(46) To a suspension of BB-1 (1 eq) and SEM-Cl (1.3 eq) in DCM (3.5 mL/mmol) was added dropwise DIPEA (1.5 eq) at 0° C. The rxn mixture was stirred at 0° C. for a given time (see Table 2) and quenched with a sat. aq. soln. of NaHCO.sub.3. It was extracted with DCM, the org. phase was washed with a sat. aq. soln. of NaHCO.sub.3, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(47) TABLE-US-00003 TABLE 2 t.sub.R [min] MS-data .sup.1H NMR Reactant time (LC/MS m/z (500 MHz, BB-2 Name BB-1 [h] method) [M + H].sup.+ DMSO-d6) δ: BB-2-1A 4-Nitro-2-(2- BB-1-1 0.25 1.06 (I) no io 8.48 (s, 1 H), 5.61 (s, 2 trimethylsilanyl- H), 3.98 (s, 3 H), 3.56 ethoxymethyl)-2H- (m, 2 H), 0.84 (m, 2 H), −0.04 pyrazole-3-carboxylic (m, 9 H) acid methyl ester BB-2-1B 4-Nitro-1-(2- 1.02 (I) 302.27 9.19 (s, 1 H), 5.52 (s, 2 trimethylsilanyl- H), 3.91 (s, 3 H), 3.61 ethoxymethyl)-1H- (m, 2 H), 0.87 (m, 2 H), −0.03 pyrazole-3-carboxylic (s, 9 H) acid methyl ester BB-2-2A 5-Nitro-1-(2- BB-1-2 0.5 1.03 (I) no io 8.19 (s, 1 H), 5.69 (s, 2 trimethylsilanyl- H), 3.82 (s, 3 H), 3.57 (m, ethoxymethyl)-1H- 2 H), 0.82 (m, 2 H), −0.06 pyrazole-4-carboxylic (m, 9 H) acid methyl ester BB-2-2B 3-Nitro-1-(2- 1.00 (I) 302.15 8.80 (s, 1 H), 5.54 (s, 2 trimethylsilanyl- H), 3.81 (s, 3 H), 3.61 (m, ethoxymethyl)-1H- 2 H), 0.87 (m, 2 H), −0.03 pyrazole-4-carboxylic (s, 9 H) acid methyl ester

Synthesis of Building Blocks BB-3

(48) To a soln. of methyl ester BB-1 or BB-2 (1 eq) in a mixture of THF (6.3 mL/mmol) and MeOH (0.8 mL/mmol) was added portionwise NaBH.sub.4 (4 to 8 eq) at 0° C. The rxn mixture was stirred at 0° C. for a given time (see Table 3), poured into an aq. sat. soln. of NH.sub.4Cl and extracted with EtOAc. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(49) TABLE-US-00004 TABLE 3 Reactant t.sub.R [min] MS-data .sup.1H NMR BB-1 or time (LC/MS m/z (500 MHz, BB-3 Name BB-2 [h] method) [M + H].sup.+ DMSO-d6) δ: BB-3-1A [4-Nitro-2-(2- BB-2-1A 2.5 0.92 (I) 273.91 trimethylsilanyl- ethoxymethyl)-2H- pyrazol-3-yl]-methanol BB-3-1B [4-Nitro-1-(2- BB-2-1B 2.5 0.87 (I) 273.97 trimethylsilanyl- ethoxymethyl)-1H- pyrazol-3-yl]-methanol BB-3-2 [3-Nitro-1-(2- BB-2-2B 3.5 0.89 (I) no io 8.06 (s, 1 H), 5.51 (s, trimethylsilanyl- 2 H), 5.39 (t, J = 5.4 ethoxymethyl)-1H- Hz, 1 H), 4.66 (dd, J = pyrazol-4-yl]-methanol 5.4 Hz, 2 H), 3.59 (m, 2 H), 0.87 (m, 2 H), −0.03- 0.01 (m, 9 H) BB-3-3 (1-Methyl-4-nitro-1H- BB-1-3 0.5  0.37 (II) no io 8.80 (s, 1 H), 5.22 (t, pyrazol-3-yl)-methanol J = 5.9 Hz, 1 H), 4.66 (d, J = 5.8 Hz, 2 H), 3.88 (s, 3 H)

Synthesis of Building Blocks BB-4

(50) Method A (Oxidation)

(51) To a soln. of alcohol BB-3 (1 eq) in anh. DCM (10 mL/mmol) was added portionwise MnO.sub.2 (9 to 10 eq) at RT and the rxn mixture was stirred at a given temperature for a given time (see Table 4). It was filtered over a pad of celite and the filtrate was concentrated in vacuo.

(52) Method B (SEM Protection)

(53) To a soln. of BB-11 (1 eq) in anh. DMF (9 mL/mmol) was added portionwise NaH (1.1 eq, as a 60% dispersion in mineral oil) at 0° C. The rxn mixture was stirred for 10 min at 0° C. and SEM-Cl (1.4 eq) was added dropwise. It was allowed to reach RT, stirred for a given time (see Table 4) at RT and partitioned between EtOAc and water. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(54) TABLE-US-00005 TABLE 4 Method Reactant T [° C.] t.sub.R [min] MS-data .sup.1H NMR BB-3 or time (LC/MS m/z (500 MHz, BB-4 Name BB-11 [h] method) [M + H].sup.+ DMSO-d6) δ: BB-4-1A 4-Nitro-2-(2- BB-3-1A A 1.04 (I) no io 10.28 (s, 1 H), 8.52 (s, trimethylsilanyl- 45 1 H), 5.74 (s, 2 H), ethoxymethyl)-2H- 18 3.60 (m, 2 H), 0.85 pyrazole-3-carbaldehyde (m, 2 H), −0.05 (s, 9 H) BB-4-1B 4-Nitro-1-(2- BB-3-1B A 0.79/0.99 (I)   no io 10.25 (s, 1 H), 9.20 (s, trimethylsilanyl- RT 1 H), 5.57 (s, 2 H), ethoxymethyl)-1H- 24 3.62 (m, 2 H), 0.88 pyrazole-3-carbaldehyde (m, 2 H), −0.02 (m, 9 H) BB-4-2 3-Nitro-1-(2- BB-3-2 A 1.00 (I) no io 10.14 (s, 1 H), 8.82 (s, trimethylsilanyl- RT 1 H), 5.58 (s, 2 H), ethoxymethyl)-1H- 18 3.62 (m, 2 H), 0.88 pyrazole-4-carbaldehyde (m, 2 H), −0.02 (m, 9 H) BB-4-3 1-Methyl-4-nitro-1H- BB-3-3 A  .sup. 0.35 (III) no io 10.23 (s, 1 H), 8.98 (s, pyrazole-3-carbaldehyde 45 1 H), 4.00 (s, 3 H) 3.5 BB-4-4 5-Nitro-3-(2- BB-11-1 B 0.89 289.99 10.28 (s, 1 H), 8.39 (s, trimethylsilanyl- RT (hydrate) 1 H), 5.70 (s, 2 H), ethoxymethyl)-3H- 0.5 3.58 (m, 2 H), 0.88 imidazole-4- (m, 2 H), −0.03-0.02 carbaldehyde (m, 9 H) BB-4-5 1-Methyl-3-nitro-1H- commercially available pyrazole-4-carbaldehyde

Synthesis of Building Blocks BB-5

Synthesis of 5-aminomethyl-3-benzyl-3H-[1,2,3]triazol-4-ylamine (BB-5-2)

(55) Step A: Cyclocondensation (see Table 5)

(56) A suspension of benzyl azide (1 eq), malononitrile (1.4 eq) and K.sub.2CO.sub.3(4 eq) in DMSO (1.4 mL/mmol) was stirred at RT for 18h. The rxn mixture was partitioned between EtOAc and H.sub.2O. The org. phase was washed with H.sub.2O and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(57) TABLE-US-00006 TABLE 5 t.sub.R [min] MS-data (LC/MS m/z BB-5A Name method) [M + H].sup.+ BB-5-2A 5-Amino-1-benzyl-1H- 0.67 (II) 200.19 [1,2,3]triazole-4-carbonitrile

(58) Step B: Nitrile Reduction (see Table 6)

(59) Nitrile BB-5A (1 eq) was dissolved in a 7M soln. of NH.sub.3 in MeOH (7 mL/mmol). The flask was evacuated three times and refilled with nitrogen. Raney nickel (0.1 eq) was added at 0° C. and the temperature was allowed to reach RT. The flask was evacuated and refilled three times with hydrogen. The suspension was stirred under a hydrogen atmosphere for 11 h and filtered over a pad of Celite. The cake was washed with EtOAc and MeOH and the filtrate was concentrated in vacuo.

(60) TABLE-US-00007 TABLE 6 t.sub.R [min] MS-data Reactant (LC/MS m/z BB-5 Name BB-5A method) [M + H].sup.+ BB-5-1 4-Aminomethyl-1-methyl- commercially available 1H-pyrazol-3-amine BB-5-2 5-Aminomethyl-3-benzyl- BB-5-2A 0.41 (II) 204.20 3H-[1,2,3]triazol-4-ylamine

(61) Building Blocks BB-6

(62) TABLE-US-00008 TABLE 7 BB-6 Name BB-6-1 3-Amino-1-methyl-1H- commercially available pyrazole-4-carbaldehyde

Synthesis of Building Blocks BB-7

(63) Method A: Boc Cleavage from BB-30

(64) To a soln. of intermediate BB-30 (1 eq) in DCM (4 mL/mmol) was added dropwise TFA (1 mL/mmol) and the rxn mixture was stirred for 1h to 18h at RT (see Table 8). It was basified with a 1M aq. soln. of NaOH until pH 12-13 and extracted with DCM. The combined org. phases were dried over MgSO.sub.4 and concentrated in vacuo.

(65) Method B: Reductive Amination from BB-8

(66) To a soln. of ketone intermediate BB-8 (1 eq) in dioxane (9.1 mL/mmol) was added a 25% aq. soln. of NH.sub.4OH (36 to 38 eq) and H.sub.2O (0.35 mL/mmol). The flask was evacuated three times and refilled with nitrogen. Wet Pd/C (0.03 to 0.06 eq) was added and the flask was evacuated and refilled three times with hydrogen. The suspension was stirred under a hydrogen atmosphere for 24 to 48h (see Table 8) and filtered over a pad of Celite. The cake was washed with dioxane and MeOH and the filtrate was concentrated in vacuo. The crude was purified by CC using DCM/MeOH or Hept/EtOAc.

(67) Method B2: Reductive Amination from BB-8

(68) To a soln. of ketone intermediate BB-8 (1 eq) and ammonium acetate (10 eq) in MeOH (5 mL/mmol) was added AcOH (2 eq). The rxn mixture was stirred for 2h at RT, NaBH(OAc).sub.3 (2 eq) was added and the mixture was stirred at RT for 2h. MeOH was evaporated and the residue was partitioned between a 1M aq. soln. of NaOH and DCM. The org. phase was dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc/MeOH.

(69) TABLE-US-00009 TABLE 8 Reactant t.sub.R [min] MS-data BB-30 or (LC/MS m/z BB-7 Name BB-8 Method method) [M + H].sup.+ BB-7-1 1-(2-Fluoro-6-methyl-phenyl)- BB-30-1 A 0.62 (I) 209.21 piperidin-4-ylamine BB-7-2 2′-Methoxy-4′-methyl-3,4,5,6- BB-8-2 B 0.51 (I) 222.27 tetrahydro-2H-[1,3′]bipyridinyl- 4-ylamine BB-7-3 1-(2-Fluoro-6-methyl-phenyl)- BB-30-2 A 0.65 (I) 223.19 4-methyl-piperidin-4-ylamine BB-7-4 1-(2-Fluoro-6-methyl-phenyl)- BB-30-3 A 0.65 (I) 209.28 3-methyl-pyrrolidin-3-ylamine BB-7-5 (R)-1-(2-Fluoro-6-methyl- BB-30-4 A 0.60 (I) 195.22 phenyl)-pyrrolidin-3-ylamine BB-7-7 1-(2-Difluoromethyl-6-fluoro- BB-30-6 A 0.65 (I) 245.39 phenyl)-piperidin-4-ylamine BB-7-8 1-(2-Chloro-6-fluoro-phenyl)- BB-30-7 A 0.61 (I) 229.11 piperidin-4-ylamine BB-7-9 1-(2-Cyclopropyl-6-fluoro- BB-30-8 A 0.70 (I) 235.18 phenyl)-piperidin-4-ylamine BB-7-10 4′-Difluoromethyl-2′-methoxy- BB-30-9 A 0.61 (I) 258.01 3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-ylamine BB-7-11 1-(2-Bromo-6-fluoro-phenyl)- BB-30-6C A 0.65 (I) 273.20 piperidin-4-ylamine BB-7-12 2′-Methoxy-4′-trifluoromethyl- BB-8-6  B1 0.65 (I) 276.21 3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-ylamine BB-7-13 4′-Chloro-2′-methoxy-3,4,5,6- BB-8-7  B2 0.58 (I) 241.92 tetrahydro-2H-[1,3′]bipyridinyl- 4-ylamine

Synthesis of Building Blocks BB-8

(70) To a soln. of ketal intermediate BB-29(1 eq) in anh. THF (3 mL/mmol) was added a 1 aq. soln. of HCl (2 to 2.5 mL/mmol) at RT (see Table 9). The rxn mixture was heated to 70° C. and stirred for 3 to 24h. It was quenched with a sat. aq. soln. of NaHCO.sub.3 or a 1M aq. soln. of NaOH and extracted with EtOAc or DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by CC using Hept/EtOAc.

(71) TABLE-US-00010 TABLE 9 t.sub.R [min] MS-data Reactant (LC/MS m/z BB-8 Name BB-29 method) [M + H].sup.+ BB-8-1 1-(2-Fluoro-6-methyl-phenyl)- BB-29-1 0.94 (I) 208.19 piperidin-4-one BB-8-2 2′-Methoxy-4′-methyl-2,3,5,6- BB-29-2 0.78 (I) 221.24 tetrahydro-[1,3′]bipyridinyl- 4-one BB-8-3 1-(2-Fluoro-6-methyl-phenyl)- BB-29-3 0.96 (I) 222.25 azepan-4-one BB-8-4 1-(2-Fluoro-6-methyl-phenyl)- BB-29-4 0.95 (I) 208.26 piperidin-3-one BB-8-6 2′-Methoxy-4′-trifluoromethyl- BB-29-5 0.96 (I) 275.15 2,3,5,6-tetrahydro- [1,3′]bipyridinyl-4-one BB-8-7 4′-Chloro-2′-methoxy-2,3,5,6- BB-29-6 0.87 (I) 241.11 tetrahydro-[1,3′]bipyridinyl- 4-one

Synthesis of Building Blocks BB-9

(72) Method A: Benzylic Bromination

(73) A suspension of methyl-heteroarene (1 eq) in chlorobenzene (4 mL/mmol) was heated to 50° C. and NBS (1.3 eq) was added portionwise at 50° C. (see Table 13). The flask was purged with argon and AlBN (0.1 eq) was added in one portion. Then mixture was heated to 80° C. and stirred for 6h. After cooling to RT, the mixture was diluted with Et.sub.2O and washed with a 1 M aq. soln. of HCl. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(74) Method B: Multi-Step

(75) Step B1: O-Alkylation Via Mitsunobu (see Table 10)

(76) To a soln. of methyl ester (1 eq) and 2-propanol (1.5 eq) in toluene (1.5 mL/mmol) was added a 1M soln. of (tributylphosphoranylidene)acetonitrile in toluene (2 eq) under argon. The rxn mixture was heated to 11000 and stirred for 2h. It was quenched with water and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(77) TABLE-US-00011 TABLE 10 t.sub.R [min] MS-data Carboxylic acid Method/ (LC/MS m/z BB-9A Name reactant Step method) [M + H].sup.+ BB-9-13A 2,4-Difluoro-6-isopropoxy- 2,4-Difluoro-6- B1 0.89 (II) 231.10 benzoic acid methyl ester hydroxybenzoic acid methyl ester

(78) Step B2: Methyl/Ethyl Ester Reduction Using CaCl.sub.2/NaBH.sub.4 (See Table 13)

(79) To a soln. of methyl or ethyl ester (1 eq) in anh. EtOH (15 mL/mmol) was added CaCl.sub.2 (0.3 eq) and the rxn mixture was cooled to −10° C. NaBH.sub.4 (2.5 eq) was added portionwise and the mixture was stirred for 30 min at −10° C. and for 1.5 h at 70° C. It was quenched at 0° C. with water and EtOH was evaporated off. The residue was partitioned between EtOAc and water and the aq. phase was further extracted with EtOAc. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. When necessary the crude was purified by CC using DCM/MeOH.

(80) Step B3: Methyl/Ethyl Ester Reduction Using LiAlH.sub.4 (See Table 13)

(81) To a soln. of methyl or ethyl ester (1 eq) in anh. THE (4.5 to 7 mL/mmol) was added dropwise at 0° C. a 2.4 M soln. of LiAlH.sub.4 in THE (1 eq). The rxn mixture was stirred for 1.5 h at 0° C., quenched with a sat. aq. soln. of NH.sub.4C and extracted with EtOAc. The combined org. phases were dried over MgSO.sub.4 and concentrated in vacuo. When necessary the crude was purified by CC using EtOAc.

(82) Method C: Multi-Step

(83) Step C1: Nucleophilic Aromatic Substitution (See Table 11)

(84) To a soln. of halo-heteroarene (1 eq) in anh. THE (5 mL/mmol) was added dropwise at 0° C. a 2M soln. of lithium isopropoxide in THE (1.05 eq). The rxn mixture was stirred for 1h at 0° C. and poured into a 1M aq. soln. of HCl. The aq. soln. was neutralized with a sat. aq. soln. of NaHCO.sub.3 and extracted with EtOAc. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(85) TABLE-US-00012 TABLE 11 t.sub.R [min] MS-data Halo-heteroarene Method/ (LC/MS m/z BB-9A Name reactant Step method) [M + H].sup.+ BB-9-19A 6-Chloro-4-isopropoxy- 4,6-dichloropyridazine- C1 0.88 (I) 259.17 pyridazine-3-carboxylic 3-carboxylic acid methyl acid isopropyl ester ester

(86) Step C2: Hydrogenation (see Table 12)

(87) To a soln. of intermediate BB-9A (1 eq) in EtOH (4 mL/mmol) was added ammonium formate (2 eq) and the rxn mixture was flushed with nitrogen. Wet Pd/C (0.05 eq) was added and after inertising with nitrogen the rxn mixture was heated to 60° C. and stirred for 1h. It was filtered over a pad of Celite, the cake was washed with MeOH and the filtrate was concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(88) TABLE-US-00013 TABLE 12 t.sub.R [min] MS-data Halo-heteroarene Method/ (LC/MS m/z BB-9B Name reactant Step method) [M + H].sup.+ BB-9-19B 4-Isopropoxy-pyridazine- BB-9-19A C2 0.74 (I) 225.05 3-carboxylic acid isopropyl ester

(89) Final Step C3: Ester Reduction (see Table 13)

(90) To a soln. of ester intermediate BB-9B (1 eq) in anh. EtOH (15.8 mL/mmol) was added CaCl.sub.2 (0.3 eq) and the rxn mixture was cooled to −10° C. NaBH.sub.4 (2.5 eq) was added portionwise and the mixture was stirred for 30 min at −10° C. and for 3.5h at RT. It was quenched at 0° C. with water and EtOH was evaporated off. The residue was partitioned between EtOAc and water and the aq. phase was further extracted with EtOAc. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo.

(91) TABLE-US-00014 TABLE 13 t.sub.R [min] MS-data .sup.1H NMR (LC/MS m/z (500 MHz, BB-9 Name Reactant Method/Step method) [M + H].sup.+ DMSO-d6) δ: BB-9-1 2-(Trifluoromethyl) commercially available benzyl bromide BB-9-2 2-Bromomethyl-3- 2-Methyl-3- A 0.76 (II) no io 9.03 (d, J = 2.2 trifluoromethyl-pyrazine trifluoromethyl Hz, 1 H), 8.84 pyrazine (d, J = 2.3 Hz, 1 H), 4.84 (d, J = 0.9 Hz, 2 H) BB-9-3 (4-Trifluoromethyl- commercially available pyridin-3-yl)-methanol BB-9-4 [3-(Trifluoromethyl) pyridin-2-yl]methanol BB-9-5 1-(Bromomethyl)-2- cyclopropyloxybenzene BB-9-6 2-(Trifluoromethyl) benzyl alcohol BB-9-7 2-(Chloromethyl)-3- (trifluoromethyl)pyridine BB-9-8 2-Bromo-6- (trifluoromethyl) benzylbromide BB-9-9 (2-Cyclopropylphenyl) methanol BB-9-10 1-(Bromomethyl)-2- isopropylbenzene BB-9-11 2-(Trifluoromethoxy) benzyl bromide BB-9-12 2-Chlorobenzyl bromide BB-9-13 (2,4-Difluoro-6- BB-9-13A B3 0.78 (II) no io 6.41-6.47 (m, 2 isopropoxy-phenyl)- H), 4.70 (d, J = methanol 1.5 Hz, 2 H), 4.58 (m, 1 H), 1.40-1.45 (m, 6 H) BB-9-14 [2-Methyl-4- commercially available (trifluoromethyl)-1,3- thiazol-5-yl]methanol hydrochloride BB-9-15 1-(2-Trifluoromethyl- phenyl)-ethanol BB-9-16 2-(Bromomethyl)phenyl acetate BB-9-17 (4-Isopropyl-pyrimidin- 4-Isopropyl B2 0.47 (II) 153.46 5-yl)-methanol pyrimidine-5- carboxylic acid ethyl ester BB-9-18 (2-Ethoxy commercially available phenyl)methanol BB-9-19 (4-Isopropoxy-pyridazin BB-9-19B C3 0.34 (I)  169.08 -3-yl)-methanol

Synthesis of Building Blocks BB-10

(92) Method A

(93) Step A: Carboxylic Acid Reduction (See Table 14)

(94) To a soln. of carboxylic acid (1 eq) in anh. THF (10 mL/mmol) was added 4-methylmorpholine (2 eq) and ethyl chloroformate (2 eq) at −10° C. The mixture was stirred for 1h at −10° C. and NaBH.sub.4 (3 eq) was added in one portion. It was allowed to warm to 0° C. over 1h, quenched with water and extracted with DCM. The org. phase was washed with H.sub.2O and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using DCM/MeOH.

(95) Step B: Appel rxn (see Table 15)

(96) To a soln. of intermediate BB-10A (1 eq) in DCM (5.2 mL/mmol) was added CBr.sub.4 (1.5 eq) and diphenyl-2-pyridylphosphine (1.5 eq) at 0° C. The rxn mixture was stirred at 0° C. for 10 min and at RT for 1h. It was partitioned between DCM and a 5% aq. soln. of citric acid and the org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(97) Method B

(98) Step A: Sulfonylation (see Table 14)

(99) A soln. of amino alcohol (1 eq) and TEA (3 eq) in DCM (5 mL/mmol) was cooled to 0° C. and 2-nitro benzenesulfonyl chloride (1.2 eq) was added dropwise at 0° C. The rxn mixture was allowed to slowly reach RT and stirred for 1h. It was diluted with DCM and washed with a sat. aq. soln. of NaHCO.sub.3 and with brine. The org. phase was dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(100) Step B: Aziridine Formation (see Table 15)

(101) To a stirred soln. of amino alcohol derivative (1 eq) and TEA (2 eq) in DCM (mL/mmol) was added dropwise at 0° C. methanesulfonylchloride (1.05 eq). The rxn mixture was allowed to warm to RT and stirred for 45 min. It was partitioned between DCM and H.sub.2O and the org. phase was dried over MgSO.sub.4 and concentrated in vacuo. The crude was dissolved in THE (4.2 mL/mmol) and TEA (2 eq) was added. The rxn mixture was stirred at RT for 18h and at 500 for 30 min and partitioned between DCM and H.sub.2. The org. phase was dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(102) TABLE-US-00015 TABLE 14 t.sub.R [min] MS-data .sup.1H NMR Method (LC/MS m/z (500 MHz, BB-10A Name Reactant method) [M + H].sup.+ DMSO-d6) δ: BB-10-1A (2,2,2-Trifluoro-1- A (step A) 7.43 (d, J = 9.2 Hz, hydroxymethyl- 2-{[(tert-Butoxy) 1 H), 5.07 (t, J = 5.9 ethyl)-carbamic acid carbonyl]amino}- Hz, 1 H), 4.11-4.19 tert-butyl ester 3,3,3-trifluoro (m, 1 H), 3.64 (m, 1 H), propanoic acid 3.51 (m, 1 H), 1.41 (s, 9 H) BB-10-2A 4-Chloro-N-(2- commercially available hydroxy-1,1- dimethylethyl) benzene sulfonamide BB-10-3A N-(2-Hydroxy-1,1- B (step A) 0.68 (II) 275.04 8.11-8.13 (m, 1 H), dimethyl-ethyl)-2- 2-Amino-2-methyl- 7.92-7.95 (m, 1 H), nitro-benzene 1-propanol 7.81-7.87 (m, 2 H), sulfonamide 7.59 (s, 1 H), 4.94 (t, J = 5.7 Hz, 1 H), 3.24 (d, J = 5.7 Hz, 2 H), 1.06 (s, 6 H)

(103) TABLE-US-00016 TABLE 15 Method t.sub.R [min] MS-data .sup.1H NMR Reactant BB- (LC/MS m/z (500 MHz, BB-10 Name 10A method) [M + H].sup.+ DMSO-d6) δ: BB-10-1 (3-Bromo-1,1,1- A (step B) 7.79 (d, J = 9.4 Hz, trifluoropropan- BB-10-1A 1 H), 4.41-4.48 (m, 1 H), 2-yl)-carbamic acid 3.78 (dd, J.sub.1 = 10.6 Hz, tert-butyl ester J.sub.2 = 3.5 Hz, 1 H), 3.46 (dd, J.sub.1 = J.sub.2 = 10.6 Hz, 1 H), 1.42 (s, 9 H) BB-10-2 1-(4-Chloro-benzene B (step B) 0.84 (II) 246.11 7.90 (d, J = 8.8 Hz, sulfonyl)-2,2- BB-10-2A 2 H), 7.71 (d, J = 8.6 dimethyl-aziridine Hz, 2 H), 2.53 (s, 2 H), 1.47 (s, 6 H) BB-10-3 2,2-Dimethyl-1-(2-nitro- B (step B) 0.87 (I) 257.07 benzenesulfonyl)- BB-10-3A aziridine BB-10-4 (R)-3-Chloro-1-trityl- Prepared 1.09 (I) 348.06 7.12-7.40 (m, 15 H), azetidin-2-one according to 5.13 (dd, J.sub.1 = 5.1 J. Heterocyclic Hz, J.sub.2 = 2.0 Hz, 1 H), Chem., 2006, 3.78 (dd, J.sub.1 = 6.4 Hz, 43, 11-19. J.sub.2 = 5.1 Hz, 1 H), 3.32 (m, 1 H)

(104) Building Blocks BB-11, BB-12, BB-13, BB-14, BB-15 and BB-16

(105) TABLE-US-00017 TABLE 16 Name BB-11 BB-11-1 5-Nitro-1H-imidazole-4-carbaldehyde commercially BB-12 BB-12-1 3-Trifluoromethyl-2-formylpyridine available BB-12-2 6-Chloro-3-(trifluoromethyl)picolinaldehyde BB-12-3 2-Fluoro-6-(trifluoromethyl)benzaldehyde BB-12-4 2-(Trifluoromethyl)benzaldehyde BB-12-5 2-Cyclopropylbenzaldehyde BB-13 BB-13-1 N-Boc-3-pyrrolidinone BB-13-2 N-Boc-4-piperidone BB-14 BB-14-1 3-Amino-1-methyl-1H-pyrazole-4-carbaldehyde BB-15 BB-15-1 tert-Butyl-4-aminoazepane-1-carboxylate BB-15-2 tert-Butyl 4-aminopiperidine-1-carboxylate BB-16 BB-16-1 2-Bromo-3-fluorotoluene BB-16-2 2-Bromo-1,3-dimethylbenzene BB-16-3 2-Bromo-1-methoxy-3-methylbenzene BB-16-4 Isopropyl chloroformate BB-16-5 2,3-Difluorobenzonitrile BB-16-6 3-Bromo-2-fluoro-4-methylpyridine BB-16-7 3-Bromo-2-methoxy-4-methylpyridine BB-16-8 2-Bromo-3-fluoropyridine BB-16-9 2-Bromo-3-methylpyridine BB-16-10 2-Bromo-3-methoxypyridine BB-16-11 3-Bromo-4-methylpicolinonitrile BB-16-12 3-Bromo-4-fluoro-2-methylpyridine BB-16-13 3-Bromo-2,4-dimethoxypyridine BB-16-14 5-Bromo-4-methoxy-6-methylpyrimidine BB-16-15 5-Bromo-4,6-dimethoxypyrimidine BB-16-16 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbonitrile BB-16-17 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde BB-16-18 Cyclopropyl chloroformate BB-16-19 2-Bromo-3-fluorobenzotrifluoride BB-16-20 2-Bromo-1-fluoro-3-(trifluoromethoxy)benzene BB-16-21 2-Bromo-3-chlorotoluene BB-16-22 1-Bromo-2-isopropylbenzene BB-16-23 1-Bromo-2-cyclopropylbenzene BB-16-24 2-Bromo-1-chloro-3-fluorobenzene BB-16-25 1-Bromo-2,6-difluorobenzene BB-16-26 2-Bromo-1-ethyl-3-fluorobenzene BB-16-27 2-Bromo-1-(difluoromethyl)-3-fluorobenzene BB-16-28 2-Bromo-1-cyclopropyl-3-fluorobenzene

Synthesis of Building Blocks BB-17

(106) To a soln. of amines B (1 eq, see Table 17) and DIPEA (2.5 eq) in MeCN (5 mL/mmol) was added DMAP (0.2 eq) and methylchloroformate (2.5 eq) at 0° C. The rxn mixture was stirred for 5 min at 0° C. and for 3h at RT. MeOH (3 mL/mmol) was added followed by a 1 M aq. soln. of NaOH (1.7 eq). The rxn mixture was stirred for 1.5h at RT and the volatiles were evaporated. The residue was diluted with EtOAc and washed successively with a 10% aq. soln. of citric acid, a sat. aq. soln. of NaHCO.sub.3 and brine. The org. phase was dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(107) TABLE-US-00018 TABLE 17 Amino- t.sub.R [min] MS-data .sup.1H NMR (hetero)arene (LC/MS m/z (500 MHz, BB-17 Name reactant B method) [M + H].sup.+ DMSO-d6) δ: BB-17-1 5-Methoxycarbonylamino- 5-Amino-2-methyl-1,3- 0.56 (II) 229.13 10.12 (s, 1 H), 4.20 2-methyl-oxazole-4- oxazole-4-carboxylic (q, J = 7.1 Hz, carboxylic acid ethyl ester acid ethyl ester 2 H), 3.67 (s, 3 H), 2.39 (s, 3 H), 1.24 (t, J = 7.1 Hz, 3 H)

Synthesis of Building Blocks BB-20

(108) To a soln. of bromides C (1 eq) in DMSO (2.5 mL/mmol) was added NaN.sub.3 (1.5 eq) at RT. The rxn mixture was stirred at RT for 5h (see Table 18) and quenched with H.sub.2O. It was extracted with EtOAc and the combined org. phases were dried over MgSO.sub.4 and concentrated in vacuo.

(109) TABLE-US-00019 TABLE 18 Bromo- t.sub.R [min] MS-data (hetero)arene (LC/MS m/z BB-20 Name reactant C method) [M + H].sup.+ BB-20-1 5-Azido-2-methyl- 5-Bromo-2- 0.56 (II) 169.04 thiazole-4- methylthiazole-4- carbaldehyde carbaldehyde

Synthesis of Building Blocks BB-18

(110) A 2.4 M soln. of LiAlH.sub.4 in THE (1 eq) was diluted with anh. THE (2 mL/mmol) and cooled to −10° C. A soln. of ethyl ester BB-17 (1 eq, see Table) in anh. THF (2 mL/mmol) was added dropwise at −10° C. The rxn mixture was allowed to warm from −10° C. to 5° C. over 1h and quenched successively at 0° C. with ice water, with a 2M aq. soln. of NaOH and with ice water. The suspension was diluted with THE, stirred for 30 min at RT, filtered over a pad of celite and the filtrate was concentrated in vacuo. The crude was purified by CC using DCM/MeOH.

(111) TABLE-US-00020 TABLE 19 t.sub.R [min] MS-data .sup.1H NMR Reactant (LC/MS m/z (500 MHz, BB-18 Name BB-17 method) [M + H].sup.+ DMSO-d6) δ: BB-18-1 (4-Hydroxymethyl-2- BB-17-1 0.37 (II) 187.14 9.47 (s, 1 H), 4.92 methyl-oxazol-5-yl)- (t, J = 5.6 Hz, carbamic acid 1 H), 4.16 (d, methyl ester J = 5.7 Hz, 2 H), 3.65 (s, 3 H), 2.32 (s, 3 H)

Synthesis of Building Blocks BB-19

(112) To a soln. of alcohol BB-18 (1 eq, see Table) in anh. DCM (10 mL/mmol) was added portionwise MnO.sub.2 (9 eq) at RT and the rxn mixture was stirred at 45° C. for 4h. It was filtered over a pad of celite and the filtrate was washed with a sat. aq. soln. of NaHCO.sub.3 and brine, dried over MgSO.sub.4 and concentrated in vacuo.

(113) TABLE-US-00021 TABLE 20 t.sub.R [min] MS-data .sup.1H NMR Reactant (LC/MS m/z (500 MHz, BB-19 Name BB-18 method) [M + H].sup.+ DMSO-d6) δ: BB-19-1 (4-Formyl-2-methyl- BB-18-1 0.44 (II) 185.17 11.10 (s, 1 H), 9.81 oxazol-5-yl)-carbamic (s, 1 H), 3.74 (s, 3 acid methyl ester H), 2.39 (s, 3 H)

Synthesis of Building Blocks BB-21

(114) To a soln. of amines D (1 eq, see Table 20) and TEA (3 eq) in THE (10 mL/mmol) was added Boc.sub.2O (1.1 eq) at 0° C. The rxn mixture was stirred at 0° C. for 10 min and at RT for 18h. It was partitioned between DCM and H.sub.2O and the aq. phase was extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo.

(115) TABLE-US-00022 TABLE 20 Amino- t.sub.R [min] MS-data .sup.1H NMR (hetero)arene (LC/MS m/z (500 MHz, BB-21 Name reactant D method) [M + H].sup.+ DMSO-d6) δ: BB-21-1 (5-Carbamoyl-1H- 4-Amino-1H-1,2,3- 0.59 (II) no 14.70 (s br, 1 H), 9.03 [1,2,3]triazol-4-yl)- triazole-5- (s, 1 H), 7.88 (s, 1 H), carbamic acid tert- carboxamide 7.56 (s, 1 H), 1.48 (s, 9 H) butyl ester

Synthesis of Building Blocks BB-22

(116) NaH (3 eq, as a 60% dispersion in mineral oil) was added portionwise at 0° C. to a soln. or suspension of intermediate BB-21 (1 eq) in THE (10 mL/mmol). The suspension was stirred at RT for 20 min and MeI (1.1 eq) was added at 0° C. The rxn mixture was stirred at 0° C. for 10 min and at RT for 48h (see Table 21). When necessary to reach completion of the rxn, extra amounts of NaH (1 eq) and/or MeI (0.3 eq) were needed. The rxn mixture was quenched with half sat. aq. soln. of NaHCO.sub.3 at 0° C. and extracted with EtOAc. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by precipitation of the impurities from a soln. of the crude in DCM/MeOH and addition of Et.sub.2O.

(117) TABLE-US-00023 TABLE 21 t.sub.R [min] MS-data .sup.1H NMR Reactant (LC/MS m/z (500 MHz, BB-22 Name BB-21 method) [M + H].sup.+ DMSO-d6) δ: BB-22-1 (5-Carbamoyl-2-methyl- BB-21-1 0.61 (II) 242.19 8.89 (s, 1 H), 2H-[1,2,3]triazol- 7.84 (s, 1 H), 4-yl)-carbamic acid 7.60 (s, 1 H), 4.10 tert-butyl ester (s, 3 H), 1.44 (s, 9 H)

Synthesis of Building Blocks BB-23

(118) To a stirred soln. of amide intermediate BB-22 (1 eq) in DCM (10 mL/mmol) was added portionwise Burgess' reagent (3 eq) under argon. The rxn mixture was stirred at RT for 18h (see Table 22) and partitioned between DCM and H.sub.2O. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(119) TABLE-US-00024 TABLE 22 t.sub.R [min] MS-data .sup.1H NMR Reactant (LC/MS m/z (500 MHz, BB-23 Name BB-22 method) [M + H].sup.+ DMSO-d6) δ: BB-23-1 (5-Cyano-2-methyl-2H- BB-22-1 0.74 (II) 224.12 10.38 (s, 1 H), [1,2,3]triazol-4- 4.16 (s, 3 H), yl)-carbamic acid tert- 1.48 (s, 9 H) butyl ester

Synthesis of Building Blocks BB-24

(120) Nitrile BB-23 (1 eq) was dissolved in a 7M soln. of NH.sub.3 in MeOH (7 mL/mmol). The flask was evacuated and refilled with nitrogen. Raney nickel (0.1 eq) was added at 0° C. and the temperature was allowed to reach RT. The flask was evacuated and refilled with hydrogen. The suspension was stirred under a hydrogen atmosphere at RT for 4h (see Table 23) and filtered over a pad of Celite. The cake was washed with MeOH and the filtrate was concentrated in vacuo.

(121) TABLE-US-00025 TABLE 23 t.sub.R [min] MS-data .sup.1H NMR Reactant (LC/MS m/z (500 MHz, BB-24 Name BB-23 method) [M + H].sup.+ DMSO-d6) δ: BB-24-1 (5-Aminomethyl-2-methyl- BB-23-1 0.45 (II) 228.17 9.07 (s br, 1 H), 2H-[1,2,3]triazol- 3.99 (s, 3 H), 4-yl)-carbamic acid 3.58 (s, 2 H), tert-butyl ester 1.43 (s, 9 H)

Synthesis of Building Blocks BB-25

(122) Method A (Pentafluorophenyl Ester)

(123) A soln. of the appropriate alcohol (1 eq) and bis(pentafluorophenyl)carbonate (1.2 eq) in MeCN (0.55 mL/mmol) was cooled to 0° C. and Et.sub.3N (3.2 eq) was added dropwise. The rxn mixture was allowed to reach RT and stirred for 18h (see Table 24). The mixture was concentrated in vacuo and the residue was purified by CC using DCM/MeOH and/or by prep. LC-MS using method 3.

(124) Method B (Cyclisation)

(125) A soln. of the appropriate hydrazide (1 eq) and CDI (1.5 eq) in anh. Dioxane (4.2 mL/mmol) was heated to 85° C. and stirred for 18h. The solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc and H.sub.2O. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(126) TABLE-US-00026 TABLE 24 t.sub.R [min] MS-data .sup.1H NMR Method Reactant (LC/MS m/z (500 MHz, BB-25 Name alcohol/hydrazide method) [M + H].sup.+ DMSO-d6) δ: BB-25-1 Carbonic acid A 0.86 (II) no io 5.65 (m, 1 H), 4.87 oxetan-3-yl ester 3-Hydroxy oxetane (m, 2 H), 4.65 (ddd, pentafluorophenyl J.sub.1 = 0.9 Hz, J.sub.2 = ester 4.7 Hz, J.sub.3 = 8.1 Hz, 2 H) BB-25-2 Carbonic acid Prepared according 0.95 (II) no io 5.18 (d, J = 8.7 pentafluorophenyl ester to Med. Chem. Hz, 2 H), 4.87 (d, 3-trifluoromethyl-oxetan- Commun., 2013, 4, J = 9.6 Hz, 2 H) 3-yl ester 95-100 BB-25-3 Carbonic acid 3-methyl- A 0.90 (II) no io 4.77 (d, J = 7.7 Hz, oxetan-3-yl ester 3-Methyloxetan-3-ol 2 H), 4.54 (d, pentafluorophenyl ester J = 8.2 Hz, 2 H), 1.76 (s, 3 H) BB-25-4 5-Isopropyl-3H- B 0.49 (II) 130.49 12.05 (s br, 1 H), [1,3,4]oxadiazol-2-one Isobutyric acid 2.81-2.91 (m, 1 H), hydrazide 1.19 (d, J = 6.9 Hz, 6 H)

Synthesis of Building Blocks BB-26

(127) Method A (SEM Protection)

(128) To a suspension of the appropriate ketone (1 eq) and SEM-Cl (1.3 eq) in DCM (3.5 mL/mmol) was added dropwise DIPEA (1.5 eq) at 0° C. The rxn mixture was stirred at 0° C. for 1.5 hand quenched with a sat. aq. soln. of NaHCO.sub.3. It was extracted with DCM, the org. phase was washed with a sat. aq. sol. of NaHCO.sub.3, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(129) Method B (THP Protection)

(130) To a suspension of the appropriate ketone (1 eq) in DCM (1.6 mL/mmol) was added TsOH (0.1 eq) and 3,4-dihydro-2H-pyran (1.3 eq). The rxn mixture was stirred at RT for 1.5 hand quenched with a sat. aq. soln. of NaHCO.sub.3. It was extracted with DCM, the org. phase was washed with a sat. aq. soln. of NaHCO.sub.3 and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(131) TABLE-US-00027 TABLE 25 Method t.sub.R [min] MS-data .sup.1H NMR Reactant (LC/MS m/z (500 MHz, BB-26 Name ketone method) [M + H].sup.+ DMSO-d6) δ: BB-26-1 1-(1-Methyl-4-nitro-1H- commercially available pyrazol-3-yl)-ethanone BB-26-2 1-[4-Nitro-2-(2- A 1.05 (I) no io 8.41 (s, 1 H), 5.48 trimethylsilanyl- 1-(4-Nitro-1H- (s, 2 H), 3.55 (m, 2 H), ethoxymethyl)-2H- pyrazol-5- 2.65 (s, 3 H), 0.85 pyrazol-3-yl]-ethanone yl)ethanone (m, 2 H), −0.03 (m, 9 H) BB-26-3 1-[4-Nitro-1-(2- 1.01 (I) 286.25 trimethylsilanyl- ethoxymethyl)-1H- pyrazol-3-yl]-ethanone BB-26-4 1-[4-Nitro-1-(tetrahydro- B 0.80 (I) 240.22 pyran-2-yl)-1H-pyrazol- 1-(4-Nitro-1H- 3-yl]-ethanone pyrazol-5- yl)ethanone

(132) Building Blocks BB-28

(133) TABLE-US-00028 TABLE 26 BB-28 Name BB-28-1 3-Amino-1-methyl-1H- commercially pyrazole-4-carbonitrile available

Synthesis of Building Blocks BB-29

(134) To a mixture of the appropriate amine E (1 eq), the appropriate halide (1.05 to 1.2 eq) and sodium tert-butoxide (2 eq) in toluene (3 mL/mmol) under N.sub.2, was added BINAP (0.2 eq) and Pd.sub.2(dba).sub.3 (0.1 eq). The rxn mixture was flushed with N.sub.2, heated to a given temperature in a sealed vial and stirred for a given time (see Table 27). It was partitioned between water and EtOAc and the org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(135) TABLE-US-00029 TABLE 27 T [° C.] t.sub.R [min] MS-data Reactant Reactant time (LC/MS m/z BB-29 Name amine E halide [h] method) [M + H].sup.+ BB-29-1 8-(2-Fluoro-6-methyl- 1,4-Dioxa-8- 2-Bromo-3- 100 1.01 (I) 252.19 phenyl)-1,4-dioxa-8- azaspiro[4.5]decane fluorotoluene 18 aza-spiro[4.5]decane BB-29-2 8-(2-Methoxy-4-methyl- 1,4-Dioxa-8- 3-Bromo-2- 100 0.81 (I) 265.19 pyridin-3-yl)-1,4-dioxa- azaspiro[4.5]decane methoxy-4- 20 8-aza-spiro[4.5]decane methylpyridine BB-29-3 8-(2-Fluoro-6-methyl- 1,4-Dioxa-8- 2-Bromo-3- 100 1.03 (I) 266.30 phenyl)-1,4-dioxa-8- azaspiro[4.6]undecane fluorotoluene 2.5 aza-spiro[4.6]undecane BB-29-4 7-(2-Fluoro-6-methyl- 1,4-Dioxa-7- 2-Bromo-3- 100 1.00 (I) 252.29 phenyl)-1,4-dioxa-7- azaspiro[4.5]decane fluorotoluene 6 aza-spiro[4.5]decane BB-29-5 8-(2-Methoxy-4- 1,4-Dioxa-8- 3-Bromo-2- 100 1.03 (I) 319.16 trifluoromethyl-pyridin- azaspiro[4.5]decane methoxy-4- 18 3-yl)-1,4-dioxa-8-aza- trifluoromethyl- spiro[4.5]decane pyridine BB-29-6 8-(4-Chloro-2-methoxy- 1,4-Dioxa-8- 3-Bromo-4- 80 0.96 (I) 285.12 pyridin-3-yl)-1,4-dioxa- azaspiro[4.5]decane chloro-2- 6 8-aza-spiro[4.5]decane methoxy- pyridine

Synthesis of Building Blocks BB-30

(136) Step A: Aromatic Nucleophilic Substitution

(137) To a soln. of the appropriate amine F (1 eq) and the appropriate halide (1.1 eq) in a given solvent (0.9 to 1.5 mL/mmol) was added K.sub.2CO.sub.3(2 eq) and the mixture was heated to a given temperature and stirred for 18h (see Table 28). It was quenched with water and extracted with DCM or EtOAc. The org. phase was washed with water and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH.

(138) TABLE-US-00030 TABLE 28 t.sub.R [min] MS-data Reactant Reactant Solvent (LC/MS m/z BB-30A Name amine F halide T [° C.] method) [M + H].sup.+ BB-30-1A [1-(2-Fluoro-6-formyl- 4-(Boc-amino) 2,3-Difluoro- DMSO  0.93 (II) 323.20 phenyl)-piperidin-4-yl]- piperidine benzaldehyde 100 carbamic acid tert-butyl ester BB-30-2A [1-(2-Fluoro-6-formyl- 4-(Boc- 2,3-Difluoro- DMA 1.05 (I) 337.15 phenyl)-4-methyl-piperidin-4- amino)-4- benzaldehyde 120 yl]-carbamic acid methyl- tert-butyl ester piperidine BB-30-3A [1-(2-Fluoro-6-formyl- 3-(Boc- 2,3-Difluoro- DMA 1.03 (I) 323.17 phenyl)-3-methyl-pyrrolidin- amino)-3- benzaldehyde 120 3-yl]-carbamic acid tert-butyl methyl- ester pyrrolidine BB-30-4A [(R)-1-(2-Fluoro-6-formyl- (R)-3-(Boc- 2,3-Difluoro- DMSO 0.98 (I) 309.19 phenyl)-pyrrolidin-3-yl]- amino)pyrrolidine benzaldehyde 100 carbamic acid tert-butyl ester BB-30-6A [1-(2-Fluoro-6-nitro-phenyl)- 4-(Boc-amino) 2,3-Difluoro- DMA 1.05 (I) 340.22 piperidin-4-yl]-carbamic acid piperidine nitrobenzene 80 tert-butyl ester BB-30-7A (4′-Formyl-2′-methoxy- 4-(Boc-amino) 3-fluoro-2- DMA 0.95 (I) 336.21 3,4,5,6-tetrahydro-2H- piperidine methoxypyridine- 120 [1,3′]bipyridinyl-4-yl)- 4-carbaldehyde carbamic acid tert-butyl ester

(139) Step B:

(140) Method A: Reduction

(141) A suspension of intermediate BB-30A (1 eq) in anh. MeOH (2 mL/mmol) was cooled to 0° C. and NaBH.sub.4 (1.2 to 1.3 eq) was added portionwise at 0° C. (see Table 29). The rxn mixture was stirred for 1h at 0° C. to reach completion. It was carefully quenched by dropwise addition of water at 0° C. and extracted with EtOAc. The org. phase was washed with water and brine, dried over MgSO.sub.4 and concentrated in vacuo.

(142) Method B: Hydrogenation

(143) Intermediate BB-30A (1 eq) was dissolved in EtOH (5 mL/mmol). The flask was evacuated three times and refilled with nitrogen. Wet Pd/C (0.05 eq) was added and the flask was evacuated three times and refilled with hydrogen. The suspension was stirred under an atmospheric pressure of hydrogen for 3h and filtered over a pad of Celite. The cake was washed with EtOAc and MeOH and the filtrate was concentrated in vacuo.

(144) TABLE-US-00031 TABLE 29 Method t.sub.R [min] MS-data Reactant (LC/MS m/z BB-30B Name BB-32A method) [M + H].sup.+ BB-30-1B [1-(2-Fluoro-6-hydroxymethyl- A  0.82 (II) 325.24 phenyl)-piperidin-4-yl]- BB-30-1A carbamic acid tert-butyl ester BB-30-2B [1-(2-Fluoro-6- A 0.86 (I) 339.23 hydroxymethyl-phenyl)-4-methyl- BB-30-2A piperidin-4-yl]-carbamic acid tert-butyl ester BB-30-3B [1-(2-Fluoro-6-hydroxymethyl- A 0.82 (I) 325.22 phenyl)-3-methyl-pyrrolidin-3- BB-30-3A yl]-carbamic acid tert- butyl ester BB-30-4B [(R)-1-(2-Fluoro-6- A 0.82 (I) 311.23 hydroxymethyl-phenyl)- BB-30-4A pyrrolidin-3-yl]-carbamic acid tert-butyl ester BB-30-6B [1-(2-Amino-6-fluoro-phenyl)- B 0.88 (I) 310.28 piperidin-4-yl]-carbamic BB-30-6A acid tert-butyl ester

(145) Step C:

(146) Method A: Acetylation

(147) A soln. of intermediate BB-30B (1 eq) and TEA (1.5 eq) in DCM (0.5 to 5 mL/mmol) was cooled to 0° C. and AcCl (1.5 eq) was added dropwise at 0° C. (see Table 30). The rxn mixture was stirred for 1h at 0° C. to reach completion. It was diluted with DCM and washed with a 10% aq. soln. of citric acid, with a sat. aq. soln. of NaHCO.sub.3 and with brine. The org. phase was dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(148) Method B: Sandmeyer rxn (Bromination)

(149) To a soln. of intermediate BB-30B (1 eq) in MeCN (5 mL/mmol) was added dropwise at 0° C. tetrafluoroboric acid as diethyl ether complex (1.2 eq). The soln. was stirred for 5 min at 0° C. and tert-butyl nitrite (1.2 eq) was added dropwise. The rxn mixture was added dropwise at 0° C. to a suspension of copper(I) bromide (1.5 eq) and copper(II) bromide (3 eq) in H.sub.2O (3.1 mL/mmol). The resulting soln. was stirred for 18h allowing the temperature to reach RT. It was partitioned between EtOAc and a sat soln. of NH.sub.4Cl. The org. phase was washed with a sat. soln. of NH.sub.4Cl and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(150) TABLE-US-00032 TABLE 30 Method t.sub.R [min] MS-data Reactant (LC/MS m/z BB-30C Name BB-30B method) [M + H].sup.+ BB-30-1C Acetic acid 2-(4-tert- A  0.97 (II) 367.25 butoxycarbonylamino- BB-30-1B piperidin-1-yl)-3- fluoro-benzyl ester BB-30-2C Acetic acid 2-(4-tert- A 1.09 (I) 381.22 butoxycarbonylamino-4- BB-30-2B methyl-piperidin-1-yl)- 3-fluoro-benzyl ester BB-30-3C Acetic acid 2-(3-tert- A 1.06 (I) 367.22 butoxycarbonylamino-3- BB-30-3B methyl-pyrrolidin-1-yl)- 3-fluoro-benzyl ester BB-30-4C Acetic acid 2-((R)-3-tert- A 1.02 (I) 353.14 butoxycarbonylamino- BB-30-4B pyrrolidin-1-yl)-3- fluoro-benzyl ester BB-30-6C [1-(2-Bromo-6-fluoro- B 1.13 (I) 373.15 phenyl)-piperidin-4-yl]- BB-30-6B carbamic acid tert- butyl ester

(151) Final Step:

(152) Method A: hydrogenation (using BB-30C) Intermediate BB-30 (1 eq) was dissolved in a mixture of MeOH (6 mL/mmol) and EtOAc (2 mL/mmol) and the flask was evacuated three times and refilled with nitrogen (see Table 31). Wet Pd/C (0.08 eq) was added and the flask was evacuated three times and refilled with hydrogen. The suspension was hydrogenated under atmospheric pressure for 3h and filtered over a pad of Celite. The cake was washed with EtOAc and MeOH and the filtrate was concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(153) Method B: Fluorination (Using BB-30A)

(154) To a soln. of intermediate BB-30A (1 eq) in DCM (6 to 58 mL/mmol) was added dropwise a 50% soln. of bis(2-methoxyethyl)aminosulfur trifluoride (2 to 2.75 eq). The soln. was stirred for 4 to 18h at RT (see Table 31), quenched at 0° C. with a sat. aq. soln. of NaHCO.sub.3 and extracted with DCM. The org. phase was dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(155) Method C: Sandmeyer Rxn (Chlorination Using BB-30B)

(156) To a soln. of intermediate BB-30B (1 eq) in MeCN (5 mL/mmol) was added dropwise at 0° C. tetrafluoroboric acid as diethyl ether complex (1.2 eq). The soln. was stirred for 5 min at 0° C. and tert-butyl nitrite (1.2 eq) was added dropwise. The rxn mixture was added dropwise at 0° C. to a suspension of copper(I) chloride (1.5 eq) and copper(I) chloride (3 eq) in H.sub.2O (3.1 mL/mmol). The resulting soln. was stirred for 18h allowing the temperature to reach RT. It was partitioned between EtOAc and a sat. soln. of NH.sub.4Cl. The org. phase was washed with a sat. soln. of NH.sub.4Cl and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(157) Method D: Kumada Rxn (Using BB-30C)

(158) To a mixture of intermediate BB-30(1 eq) and di-μ-iodobis(tri-t-butylphosphino)dipalladium(I) in toluene (3.8 mL/mmol) was added dropwise under argon a 1 M soln. of cyclopropylmagnesium bromide in 2-methyl tetrahydrofuran (4 eq). The rxn mixture was stirred at RT for a given time (see Table 31). When necessary, an extra amount of a 1M soln. of cyclopropylmagnesium bromide in 2-methyltetrahydrofuran (2 eq) was added. The rxn mixture was quenched with H.sub.2O and extracted with EtOAc. The org. phase was washed with H.sub.2O and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc and when necessary, an additional purification by prep. LC-MS using method 1 was performed.

(159) TABLE-US-00033 TABLE 31 Method Reactant t.sub.R [min] MS-data BB-30C, BB-30- (LC/MS m/z BB-30 Name B or BB-30A method) [M + H].sup.+ BB-30-1 [1-(2-Fluoro-6-methyl- A  1.00 (II) 309.16 phenyl)-piperidin-4-yl]- BB-30-1C carbamic acid tert-butyl ester BB-30-2 [1-(2-Fluoro-6-methyl- A 1.12 (I) 323.24 phenyl)-4-methyl- BB-30-2C piperidin-4-yl]- carbamic acid tert-butyl ester BB-30-3 [1-(2-Fluoro-6-methyl- A 1.02 (I) 309.24 phenyl)-3-methyl- BB-30-3C pyrrolidin-3-yl]- carbamic acid tert-butyl ester BB-30-4 [(R)-1-(2-Fluoro-6-methyl- A 0.99 (I) 295.29 phenyl)-pyrrolidin-3-yl]- BB-30-4C carbamic acid tert-butyl ester BB-30-6 [1-(2-Difluoromethyl-6- B 1.09 (I) 345.43 fluoro-phenyl)-piperidin-4-yl]- BB-30-1A carbamic acid tert-butyl ester BB-30-7 [1-(2-Chloro-6-fluoro- C 1.10 (I) 329.16 phenyl)-piperidin-4-yl]- BB-30-6B carbamic acid tert-butyl ester BB-30-8 [1-(2-Cyclopropyl-6-fluoro- D 1.14 (I) 335.26 phenyl)-piperidin-4-yl]- BB-30-6C carbamic acid tert-butyl ester BB-30-9 (4′-Difluoromethyl-2′- B 1.09 (I) 358.21 methoxy-3,4,5,6-tetrahydro- BB-30-7A 2H-[1,3′]bipyridinyl-4-yl)- carbamic acid tert-butyl ester

Synthesis of Building Blocks BB-31

(160) To a mixture of the appropriate amine G (1 eq), the appropriate halide (1.5 eq) and sodium tert-butoxide (2 eq) in toluene (3.5 mL/mmol) under N.sub.2, was added BINAP (0.2 eq) and Pd.sub.2(dba).sub.3 (0.1 eq) (see Table 32). The rxn mixture was flushed with N.sub.2, heated to 110° C. in a sealed vial and stirred for 1h. It was partitioned between water and DCM and the org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(161) TABLE-US-00034 TABLE 32 t.sub.R [min] MS-data Reactant Reactant (LC/MS m/z BB-31 Name amine G halide method) [M + H].sup.+ BB-31-1 3-(tert-Butyl-dimethyl- 3-[(tert-Butyl 2-Bromo-3- 1.21 (I) 296.28 silanyloxy)-1-(2-fluoro- dimethylsilanyl)oxy] fluorotoluene 6-methyl-phenyl)-azetidine azetidine

Synthesis of Building Blocks BB-32

(162) To a soln. of intermediate BB-31 (1 eq) in THE (3 mL/mmol) was added dropwise at 0° C. a 1M soln. of TBAF (2 eq) in THF. The rxn mixture was stirred for 30 min at 0° C. (see Table 33) and partitioned between DCM and water. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using DCM/MeOH.

(163) TABLE-US-00035 TABLE 33 t.sub.R [min] MS-data Reactant (LC/MS m/z BB-32 Name BB-31 method) [M + H].sup.+ BB-32-1 1-(2-Fluoro-6- BB-31-1 0.60 (I) 182.35 methyl-phenyl)- azetidin-3-ol

Synthesis of Building Blocks BB-33

(164) To a soln. of intermediate BB-32 (1 eq), TEA (2 eq) and catalytic amount of DMAP (0.25 eq) in DCM (5 mL/mmol) was added at 0° C. p-toluenesulfonyl chloride (1.3 eq). The rxn mixture was allowed to warm to RT and stirred for 2h (see Table 34). When necessary to reach completion of the rxn, an extra amount of p-toluenesulfonyl chloride (0.3 eq) was added. It was partitioned between water and DCM and the org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using DCM.

(165) TABLE-US-00036 TABLE 34 t.sub.R [min] MS-data Reactant (LC/MS m/z BB-33 Name BB-32 method) [M + H].sup.+ BB-33-1 Toluene-4-sulfonic acid BB-32-2 1.08 (I) 336.15 1-(2-fluoro-6-methyl- phenyl)-azetidin-3-yl ester

(166) Building Blocks BB-34

(167) TABLE-US-00037 BB-34 Name BB-34-1 3-amino-4-bromopyrazole commercially BB-34-2 4-Bromo-1-methyl-1H-pyrazol-3-ylamine available

Synthesis of Intermediates of Formula A-1

(168) Method A (NaBH(OAc).sub.3/THF)

(169) To a soln. of aldehyde BB-4 (1 eq) and amine BB-7 (1 to 1.15 eq) in THE (4 to 8 mL/mmol) were added AcOH (1.5 eq) and the rxn mixture was stirred for 20 min at RT. NaBH(OAc).sub.3 (1.5 eq) was added portionwise and the rxn mixture was stirred at RT for a given time (see Table 35). When necessary to reach completion of the rxn, an extra portion of NaBH(OAc).sub.3 (1 eq) was added at RT. It was partitioned between EtOAc and a sat. aq. soln. of NaHCO.sub.3. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc/MeOH.

(170) Method B (NaBH.sub.4/TFE)

(171) A soln. of aldehyde BB-4 (1 eq) and amine BB-7 (1 to 1.1 eq) in TFE (2 mL/mmol) was stirred for 10 min at 40° C. and cooled to 0° C. NaBH.sub.4 (1.2 eq) was added portionwise and the rxn mixture was stirred at 40° C. for a given time (see Table 35). It was quenched with a sat. aq. soln. of NaHCO.sub.3 and extracted with EtOAc. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(172) TABLE-US-00038 TABLE 35 t.sub.R [min] MS-data Reactant Reactant Method (LC/MS m/z A-1 Name BB-4 BB-7 time [h] method) [M + H].sup.+ A-1-1A [1-(2-Fluoro-6-methyl-phenyl)- BB-4-1A BB-7-1 A 0.95 (I) 464.26 piperidin-4-yl]-[4-nitro-2-(2- 18 trimethylsilanyl-ethoxymethyl)- 2H-pyrazol-3-ylmethyl]-amine A-1-1B [1-(2-Fluoro-6-methyl-phenyl)- BB-4-1B BB-7-1 A 0.93 (I) 464.29 piperidin-4-yl]-[4-nitro-1-(2- 18 trimethylsilanyl-ethoxymethyl)- 1H-pyrazol-3-ylmethyl]-amine A-1-2 [1-(2-Fluoro-6-methyl-phenyl)- BB-4-2 BB-7-1 A 0.94 (I) 464.25 piperidin-4-yl]-[3-nitro-1-(2- 2 trimethylsilanyl-ethoxymethyl)- 1H-pyrazol-4-ylmethyl]-amine A-1-3 [1-(2-Fluoro-6-methyl-phenyl)- BB-4-3 BB-7-1 A  0.69 (II) 348.21 piperidin-4-yl]-(1-methyl-4-nitro- 1 1H-pyrazol-3-ylmethyl)-amine A-1-4 [1-(2-Fluoro-6-methyl-phenyl)- BB-4-4 BB-7-1 B  0.85 (II) 464.22 piperidin-4-yl]-[5-nitro-3-(2- 1 trimethylsilanyl-ethoxymethyl)- 3H-imidazol-4-ylmethyl]-amine A-1-5 (2′-Methoxy-4′-methyl-3,4,5,6- BB-4-2 BB-7-2 A 0.93 (I) 477.23 tetrahydro-2H-[1,3′]bipyridinyl-4- 24 yl)-[3-nitro-1-(2-trimethylsilanyl- ethoxymethyl)-1H-pyrazol-4- ylmethyl]-amine A-1-6 (2′-Methoxy-4′-methyl-3,4,5,6- BB-4-1A BB-7-2 A 0.93 (I) 477.25 tetrahydro-2H-[1,3′]bipyridinyl-4- 24 yl)-[4-nitro-2-(2-trimethylsilanyl- ethoxymethyl)-2H-pyrazol-3- ylmethyl]-amine A-1-7 [1-(2-Fluoro-6-methyl-phenyl)-4- BB-4-5 BB-7-3 A 0.76 (I) 362.21 methyl-piperidin-4-yl]-(1-methyl- 18 3-nitro-1H-pyrazol-4-ylmethyl)- amine A-1-8 [1-(2-Fluoro-6-methyl-phenyl)-3- BB-4-5 BB-7-4 A 0.77 (I) 348.21 methyl-pyrrolidin-3-yl]-(1-methyl- 18 3-nitro-1H-pyrazol-4-ylmethyl)- amine

Synthesis of Intermediates of Formula A-2

(173) Method a (Nitro Reduction from A-1)

(174) To a soln. of intermediate A-1 (1 eq) in EtOH (3.5 to 7.4 mL/mmol) was added 10% Pd/C moistened with ˜50% water (0.02 eq) and the rxn mixture was hydrogenated under atmospheric pressure for a given time (see Table 36). It was filtered over a pad of celite and the filtrate was concentrated in vacuo. When necessary, the crude was purified by CC using Hept/EtOAc or DCM/MeOH.

(175) Method B1 (Reductive Amination from BB-5 and BB-8 Using NaBH(OAc).sub.3)

(176) To a soln. of amine BB-5 (1 eq) and ketone BB-8 (1.05 to 1.2 eq) in THE (4 mL/mmol) was added AcOH (1.5 eq) and the rxn mixture was stirred for 5 min at RT. NaBH(OAc).sub.3 (1.5 eq) was added portionwise and the rxn mixture was stirred at RT for a given time (see Table 36). It was acidified with a 1M aq. soln. of HCl until pH-3-4 and extracted with DCM. The aq. phase was basified with a sat. aq. soln. of NaHCO.sub.3 and extracted with DCM. The combined org. phases were dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by CC using Hept/EtOAc/MeOH.

(177) Method B2 (Reductive Amination from BB-5 and BB-8 Using NaBH.sub.4)

(178) A soln. of amine BB-5 (1 eq) and ketone BB-8 (1.05 eq) in MeOH (4 mL/mmol) was stirred for 18h at RT. NaBH.sub.4 (1.6 eq) was added portionwise at 0° C. and the rxn mixture was stirred at RT for a given time (see Table 36). It was quenched with H.sub.2O at 0° C., basified with a 1M aq. soln. of NaOH and extracted with DCM. The combined org. phases were dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by CC using EtOAc/MeOH.

(179) Method C (Reductive Amination from BB-6 and BB-7)

(180) To a soln. of aldehyde BB-6 (1 eq) and amine BB-7 (1.1 eq) in THE (4 mL/mmol) was added AcOH (1.5 eq) and the rxn mixture was stirred for 5 min at RT. NaBH(OAc).sub.3 (1.5 eq) was added portionwise and the rxn mixture was stirred at RT for a given time (see Table 36). It was acidified with a 10% aq. soln. of citric acid and extracted with DCM. The aq. phase was basified with a 1M aq. soln. of NaOH and extracted with DCM. The combined org. phases were dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by prep. LC-MS using method 7.

(181) Method D (Reductive Amination from BB-7 and BB-20)

(182) A soln. of aldehyde BB-20 (1 eq) in TFE (2 mL/mmol) was stirred at 35° C. for 5 min. Amine BB-7 (1 eq) was added and the rxn mixture stirred at 35° C. for 5 min. NaBH.sub.4 (1.2 eq) was added portionwise and the rxn mixture was stirred at 3500 for a given time (see Table 36). It was quenched with H.sub.2O, basified with a 1 M aq. sol. of NaOH and extracted with DCM. The combined org. phases were dried over MgSO.sub.4 and concentrated in vacuo.

(183) Method E (Boc Cleavage from A-4)

(184) To a soln. of intermediate A-4 (1 eq) in DCM (5 mL/mmol) was added TEA (1.5 to 2 mL/mmol) at 0° C. and the rxn mixture was stirred at RT for a given time (see Table 36). It was cooled to 0°, quenched with a 1M aq. soln. of NaOH until pH reached 12 to 13 and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo.

(185) Method F (Nucleophilic Substitution of BB-5 on BB-33)

(186) A soln. of intermediate BB-33 (1 eq) and amine BB-5 (3 eq) in MeCN (5.7 mL/mmol) was heated at 110° C. under microwave irradiation for a given time (see Table 36) and filtered. The filtrate was purified by prep. LC-MS using method 12.

(187) TABLE-US-00039 TABLE 36 Reactant Reactant Method A-1, BB-5, BB-8, T [° C.] t.sub.R [min] MS-data BB-6, BB-20 BB-7 or time (LC/MS m/z A-2 Name or A-4 BB-33 [h] method) [M + H].sup.+ A-2-1A [4-Amino-2-(2-trimethylsilanyl- A-1-1A — A 0.85 (I) 433.86 ethoxymethyl)-2H-pyrazol-3- RT ylmethyl]-[1-(2-fluoro-6-methyl- 3 phenyl)-piperidin-4-yl]-amine A-2-1B [4-Amino-1-(2-trimethylsilanyl- A-1-1B — A 0.81 (I) 433.80 ethoxymethyl)-1H-pyrazol-3- RT ylmethyl]-[1-(2-fluoro-6-methyl- 2 phenyl)-piperidin-4-yl]-amine A-2-2 [3-Amino-1-(2-trimethylsilanyl- A-1-2 — A 0.85 (I) 434.10 ethoxymethyl)-1H-pyrazol-4- RT ylmethyl]-[1-(2-fluoro-6-methyl- 18 phenyl)-piperidin-4-yl]-amine A-2-3 (4-Amino-1-methyl-1H-pyrazol- A-1-3 — A  0.56 (II) 318.13 3-ylmethyl)-[1-(2-fluoro-6- RT methyl-phenyl)-piperidin-4-yl]- 2 amine A-2-4 [5-Amino-3-(2-trimethylsilanyl- A-1-4 — A  0.72 (II) 434.23 ethoxymethyl)-3H-imidazol-4- (EtOAc ylmethyl]-[1-(2-fluoro-6-methyl- replacing phenyl)-piperidin-4-yl]-amine EtOH) RT 1.5 A-2-5 (3-Amino-1-methyl-1H-pyrazol- BB-5-1 BB-8-1 B  0.61 (II) 318.13 4-ylmethyl)-[1-(2-fluoro-6- RT methyl-phenyl)-piperidin-4-yl]- 0.5 amine A-2-6 4-{[(R)-1-(2-Fluoro-6-methyl- BB-6-1 BB-7-5 C  0.60 (II) 304.12 phenyl)-pyrrolidin-3-ylamino]- RT methyl}-1-methyl-1H-pyrazol- 2.5 3-ylamine A-2-7 (5-Amino-1-benzyl-1H- BB-5-2 BB-8-1 B  0.71 (II) 395.21 [1,2,3]triazol-4-ylmethyl)-[1- RT (2-fluoro-6-methyl-phenyl)- 18 piperidin-4-yl]-amine A-2-8 (5-Amino-2-methyl-thiazol-4- BB-20-1 BB-7-1 D  0.67 (II) 335.11 ylmethyl)-[1-(2-fluoro-6-methyl- 35 phenyl)-piperidin-4-yl]-amine 18 A-2-9 (5-Amino-2-methyl-2H- A-4-1 — E  0.65 (II) 319.17 [1,2,3]triazol-4-ylmethyl)-[1-(2- RT fluoro-6-methyl-phenyl)- 3 piperidin-4-yl]-amine A-2-10 (3-Amino-1-methyl-1H-pyrazol- BB-5-1 BB-8-2 B 0.53 (I) 331.24 4-ylmethyl)-(2′-methoxy-4′- RT methyl-3,4,5,6-tetrahydro-2H- 1 [1,3′]bipyridinyl-4-y l)-amine A-2-11 (5-Amino-2-methyl-2H- A-4-2 — E 0.57 (I) 332.17 [1,2,3]triazol-4-ylmethyl)-(2′- RT methoxy-4′-methyl-3,4,5,6- 4 tetrahydro-2H-[1,3′]bipyridinyl- 4-yl)-amine A-2-12 [3-Amino-1-(2-trimethylsilanyl- A-1-5 — A 0.79 (I) 447.31 ethoxymethyl)-1H-pyrazol-4- RT ylmethyl]-(2′-methoxy-4′- 5 methyl-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-amine A-2-13 [4-Amino-2-(2-trimethylsilanyl- A-1-6 — A 0.80 (I) 447.30 ethoxymethyl)-2H-pyrazol-3- RT ylmethyl]-(2′-methoxy-4′- 2.5 methyl-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-amine A-2-14 (3-Amino-1-methyl-1H-pyrazol- A-1-7 — A 0.67 (I) 332.27 4-ylmethyl)-[1-(2-fluoro-6- RT methyl-phenyl)-4-methyl- 4 piperidin-4-yl]-amine A-2-15 (3-Amino-1-methyl-1H-pyrazol- BB-5-1 BB-8-3 B 0.69 (I) 332.25 4-ylmethyl)-[1-(2-fluoro-6- RT methyl-phenyl)-azepan-4-yl]- 18 amine A-2-16 4-{[1-(2-Fluoro-6-methyl- A-1-8 — A 0.66 (I) 318.22 phenyl)-3-methyl-pyrrolidin-3- RT ylamino]-methyl}-1-methyl-1H- 2 pyrazol-3-ylamine A-2-17 (3-Amino-1-methyl-1H-pyrazol- BB-5-1 BB-8-4 B 0.64 (I) 318.22 4-ylmethyl)-[1-(2-fluoro-6- RT methyl-phenyl)-piperidin-3-yl]- 20 amine A-2-18 4-{[1-(2-Fluoro-6-methyl- BB-5- BB-33-1 F 0.57 (I) 290.04 phenyl)-azetidin-3-ylamino]- 110 methyl}-1-methyl-1H-pyrazol- 1 3-ylamine

Synthesis of Intermediates of Formula A-3

(188) Method A1 (or A2, Respectively) (Cyclisation from A-2)

(189) To a soln. of intermediate A-2 (1 eq) in MeCN (or DCM, respectively) (3.7 to 10 mL/mmol) was added CDI (or DSC, respectively) (0.2 to 2 eq) and the rxn mixture was stirred at a given temperature for a given time (see Table 37). When necessary to reach completion of the rxn an extra amount of CDI (0.5 to 1 eq) was added. The solvent was evaporated off and the residue was partitioned between EtOAc or DCM and water. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by CC using Hept/EtOAc or DCM/MeOH, by precipitation from DCM/MeOH/Et.sub.2O or MeCN or by prep. LC-MS using method 12.

(190) Method B (Cyclisation from D-1)

(191) A soln. of intermediate D-1 (1 eq) in DMF (8 mL/mmol) was heated at 1200 under microwave irradiation for a given time (see Table 37) and partitioned between EtOAc and H.sub.2O. The org. phase was washed with H.sub.2O and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(192) TABLE-US-00040 TABLE 37 Method t.sub.R [min] MS-data Reactant T [° C.] (LC/MS m/z A-3 Name A-2 or D-1 time [h] method) [M + H].sup.+ A-3-1A 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-1A A1 1.15 (I) 460.16 yl]-1-(2-trimethylsilanyl-ethoxymethyl)- RT 1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin- 0.5 5-one A-3-1B 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-1B A1 1.13 (I) 460.28 yl]-2-(2-trimethylsilanyl-ethoxymethyl)- RT 2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin- 0.8 5-one A-3-2 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-2 A1 1.16 (I) 460.26 yl]-2-(2-trimethylsilanyl-ethoxymethyl)- RT 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 1.5 6-one A-3-3 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-3 A1  0.85 (II) 344.10 yl]-2-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3- RT d]pyrimidin-5-one 18 A-3-4 1-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-4 A1  1.07 (II) 460.24 yl]-7-(2-trimethylsilanyl-ethoxymethyl)- RT 1,3,6,7-tetrahydro-purin-2-one 18 A-3-5 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-5 A1  0.93 (II) 344.18 yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- RT d]pyrimidin-6-one 1.5 A-3-6 5-[(R)-1-(2-Fluoro-6-methyl-phenyl)- A-2-6 A1  0.70 (II) 330.09 pyrrolidin-3-yl]-2-methyl-2,4,5,7-tetrahydro- RT pyrazolo[3,4-d]pyrimidin-6-one 2 A-3-7 3-Benzyl-6-[1-(2-fluoro-6-methyl-phenyl)- A-2-7 A1 (THF  0.93 (II) 421.13 piperidin-4-yl]-3,4,6,7-tetrahydro- replacing [1,2,3]triazolo[4,5-d]pyrimidin-5-one MeCN) 80 24 A-3-8 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- D-1-1 B  0.89 (II) 345.19 yl]-2-methyl-6,7-dihydro-4H-oxazolo[5,4- 120 d]pyrimidin-5-one 0.13 A-3-9 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-8 A1  0.90 (II) 361.07 yl]-2-methyl-6,7-dihydro-4H-thiazolo[5,4- RT d]pyrimidin-5-one 24 A-3-10 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-2-9 A1  0.89 (II) 345.20 yl]-2-methyl-2,4,6,7-tetrahydro- RT [1,2,3]triazolo[4,5-d]pyrimidin-5-one 3.5 A-3-11 5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-2-10 A1 0.83 (I) 357.21 2H-[1,3′]bipyridinyl-4-yl)-2-methyl-2,4,5,7- RT tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 0.25 A-3-12 6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-2-11 A1 0.81 (I) 358.21 2H-[1,3′]bipyridinyl-4-yl)-2-methyl-2,4,6,7- RT tetrahydro-[1,2,3]triazolo[4,5-d]pyrimidin-5- 18 one A-3-13 5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-2-12 A1 1.06 (I) 473.29 2H-[1,3′]bipyridinyl-4-yl)-2-(2-trimethylsilanyl- RT ethoxymethyl)-2,4,5,7-tetrahydro- 2 pyrazolo[3,4-d]pyrimidin-6-one A-3-14 6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-2-13 A1 1.06 (I) 473.27 2H-[1,3′]bipyridinyl-4-yl)-1-(2-trimethylsilanyl- RT ethoxymethyl)-1,4,6,7-tetrahydro- 1 pyrazolo[4,3-d]pyrimidin-5-one A-3-15 5-[1-(2-Fluoro-6-methyl-phenyl)-4-methyl- A-2-14 A1 1.02 (I) 358.22 piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro- RT pyrazolo[3,4-d]pyrimidin-6-one 18 A-3-16 5-[1-(2-Fluoro-6-methyl-phenyl)-azepan-4- A-2-15 A1 1.03 (I) 358.21 yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- RT d]pyrimidin-6-one 2 A-3-17 5-[1-(2-Fluoro-6-methyl-phenyl)-3-methyl- A-2-16 A1 0.94 (I) 344.18 pyrrolidin-3-yl]-2-methyl-2,4,5,7-tetrahydro- RT pyrazolo[3,4-d]pyrimidin-6-one 0.5 A-3-18 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-3- A-2-17 A1 0.99 (I) 344.16 yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- RT d]pyrimidin-6-one 1 A-3-19 5-[1-(2-Fluoro-6-methyl-phenyl)-azetidin-3- A-2-18 A2 0.61 (I) 316.17 yl]-2-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- 45 d]pyrimidin-6-one 18

Synthesis of Intermediates of Formula A-4

(193) To a soln. of amine BB-24 (1 eq) and ketone BB-8 (1.1 to 1.2 eq) in THF (10 mL/mmol) was added AcOH (1.5 eq) and the rxn mixture was stirred for 5 min at RT. NaBH(OAc).sub.3 (1.5 eq) was added portionwise and the rxn mixture was stirred at RT for a given time (see Table 38). It was quenched with a sat. aq. soln. of NaHCO.sub.3 and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc/MeOH.

(194) TABLE-US-00041 TABLE 38 t.sub.R [min] MS-data Reactant Reactant time (LC/MS m/z A-4 Name BB-24 BB-8 [h] method) [M + H].sup.+ A-4-1 (5-{[1-(2-Fluoro-6-methyl-phenyl)-piperidin- BB-24-1 BB-8-1 2 0.80 (II) 419.19 4-ylamino]-methyl]-2-methyl-2H- [1,2,3]triazol-4-yl)-carbamic acid tert-butyl ester A-4-2 {5-[(2′-Methoxy-4′-methyl-3,4,5,6- BB-24-1 BB-8-2 1.5 0.78 (I) 432.29 tetrahydro-2H-[1,3′]bipyridinyl-4-ylamino)- methyl]-2-methyl-2H-[1,2,3]triazol-4-yl}- carbamic acid tert-butyl ester

Synthesis of Intermediates of Formula B-1

(195) To a suspension of intermediate A-2 (1 eq) in anh. THE (3 mL/mmol) was added TEA (3 eq). The rxn mixture was cooled to 0° C. and Boc.sub.2O (1.1 eq) was added. It was stirred for 10 min at 0° C. and at RT for a given time (see Table 39) and was partitioned between EtOAc and water. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by CC using DCM/MeOH or Hept/EtOAc.

(196) TABLE-US-00042 TABLE 39 T [° C.] t.sub.R [min] MS-data Reactant time (LC/MS m/z B-1 Name A-2 [h] method) [M + H].sup.+ B-1-1 (3-Amino-1-methyl-1H-pyrazol- A-2-5 RT 0.91 (II) 418.08 4-ylmethyl)-[1-(2-fluoro- 18 6-methyl-phenyl)-piperidin-4-yl]- carbamic acid tert-butyl ester

Synthesis of Intermediates of Formula B-2

(197) Method A (NaBH(OAc).sub.4/AcOH/THF)

(198) To a soln. of amine B-1 (1 eq) and aldehyde BB-12 (1.2 eq) in THE (4 to 5 mL/mmol) was added AcOH (1.5 eq) and the rxn mixture was stirred for 5 min at RT. NaBH(OAc).sub.3 (1.5 to 2 eq) was added portionwise and the rxn mixture was stirred at RT for a given time (see Table 40). When necessary to reach completion of the rxn an extra amount of NaBH(OAc).sub.3 (0.2 to 1 eq) was added. The rxn mixture was quenched with a sat. aq. soln. of NaHCO.sub.3 and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by CC using Hept/EtOAc/MeOH.

(199) Method B (NaBH.sub.4/TFE)

(200) A soln. of amine B-1 (1 eq) and aldehyde BB-12 (1 eq) in TFE (2 mL/mmol) was stirred for 10 min at 35° C. and cooled to 0° C. NaBH.sub.4 (1.2 eq) was added portionwise and the rxn mixture was stirred for a given time at a given temperature (see Table 40). When necessary to reach completion of the rxn an extra amount of aldehyde BB-12 (1 eq) was added. It was quenched with a sat. aq. soln. of NaHCO.sub.3 and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(201) TABLE-US-00043 TABLE 40 Method T [° C.] t.sub.R [min] MS-data Reactant Reactant time (LC/MS m/z B-2 Name B-1 BB-12 [h] method) [M + H].sup.+ B-2-1 [1-(2-Fluoro-6-methyl-phenyl)- B-1-1 BB-12-1 A 1.03 (II) 577.03 piperidin-4-yl]-{1-methyl-3-[(3- RT trifluoromethyl-pyridin-2- 48 ylmethyl)-amino]-1H-pyrazol-4- ylmethyl}-carbamic acid tert- butyl ester B-2-2 {3-[(6-Chloro-3-trifluoromethyl- B-1-1 BB-12-2 A 1.08 (II) 611.06 pyridin-2-ylmethyl)-amino]-1- RT methyl-1H-pyrazol-4-ylmethyl}- 48 [1-(2-fluoro-6-methyl-phenyl)- piperidin-4-yl]-carbamic acid tert-butyl ester B-2-3 [1-(2-Fluoro-6-methyl-phenyl)- B-1-1 BB-12-3 B 1.09 (II) 594.02 piperidin-4-yl]-[3-(2-fluoro-6- 35 trifluoromethyl-benzylamino)-1- 4 methyl-1H-pyrazol-4-ylmethyl]- carbamic acid tert-butyl ester

Synthesis of Intermediates of Formula B-3

(202) To a soln. of intermediate B-2 (1 eq) in DCM (4 to 16.5 mL/mmol) was added TEA (1 to 3.2 mL/mmol) and the rxn mixture was stirred at RT for a given time (see Table 41). It was quenched with a 2M aq. soln. of NaOH until pH 12-13 and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by CC using DCM/MeOH.

(203) TABLE-US-00044 TABLE 41 T [° C.] t.sub.R [min] MS-data Reactant time (LC/MS m/z B-3 Name B-2 [h] method) [M + H].sup.+ B-3-1 [1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]- B-2-1 RT 0.77 (II) 477.10 {1-methyl-3-[(3-trifluoromethyl-pyridin-2- 4 ylmethyl)-amino]-1H-pyrazol-4-ylmethyl}-amine B-3-2 {3-[(6-Chloro-3-trifluoromethyl-pyridin-2- B-2-2 RT 0.82 (II) 511.08 ylmethyl)-amino]-1-methyl-1H-pyrazol-4- 3.5 ylmethyl}-[1-(2-fluoro-6-methyl-phenyl)- piperidin-4-yl]-amine B-3-3 [1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]- B-2-3 RT 0.82 (II) 494.10 [3-(2-fluoro-6-trifluoromethyl-benzylamino)-1- 1 methyl-1H-pyrazol-4-ylmethyl]-amine

Synthesis of Intermediates of Formula C-1

(204) Method A (NaBH(OAc).sub.4/AcOH/THF)

(205) To a soln. of amine BB-5 (1 eq) and ketone BB-13 (1.1 to 1.2 eq) in THE (4 mL/mmol) was added AcOH (1.5 eq) and the rxn mixture was stirred for 5 min at RT. NaBH(OAc).sub.3 (1.5 eq) was added portionwise and the rxn mixture was stirred at RT for a given time (see Table 42). It was quenched with a 1M aq. soln. of NaOH until pH 10 and extracted with DCM. The combined org. phases were dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by CC using EtOAc/MeOH.

(206) Method B (NaBH.sub.4/TFE)

(207) A soln. of aldehyde BB-14 (1 eq) and amine BB-15 (1.1 eq) in TFE (2 mL/mmol) was stirred for 5 min at 40° C. and cooled to 0° C. NaBH.sub.4 (1.2 eq) was added portionwise and the rxn mixture was stirred for a given time at a given temperature (see Table 42). It was quenched with a sat. aq. soln. of NaHCO.sub.3 and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by CC using Hept/EtOAc.

(208) Method C (Nitro Reduction from C-4)

(209) To a soln. of intermediate C-4 (1 eq) in EtOH (4.5 mL/mmol) was added 10% Pd/C moistened with ˜50% water (0.02 eq) and the rxn mixture was hydrogenated under atmospheric pressure for a given time (see Table 42). It was filtered over a pad of celite and the filtrate was concentrated in vacuo.

(210) TABLE-US-00045 TABLE 42 Method Reactant Reactant T [° C.] t.sub.R [min] MS-data BB-5 or BB-13 or time (LC/MS m/z C-1 Name BB-14 BB-15 [h] method) [M + H].sup.+ C-1-1 3-[(3-Amino-1-methyl-1H- BB-5-1 BB-13-1 A 0.49 (II) 296.16 pyrazol-4-ylmethyl)-amino]- RT pyrrolidine-1-carboxylic acid tert- 18 butyl ester C-1-2 4-[(3-Amino-1-methyl-1H- BB-5-1 BB-13-2 A 0.51 (II) 310.13 pyrazol-4-ylmethyl)-amino]- RT piperidine-1-carboxylic acid tert- 1 butyl ester C-1-3 4-[(3-Amino-1-methyl-1H- BB-14-1 BB-15-1 B 0.53 (II) 324.19 pyrazol-4-ylmethyl)-amino]- 40 azepane-1-carboxylic acid tert- 1 butyl ester C-1-4 4-[(4-Amino-1-methyl-1H- C-4-1 C 0.48 (I)  310.28 pyrazol-3-ylmethyl)-amino]- RT piperidine-1-carboxylic acid tert- 4.5 butyl ester

Synthesis of Intermediates of Formula C-2

(211) To a soln. of intermediate C-1(1 eq) in MeCN (3.7 mL/mmol) was added CDI (1.2 to 2 eq) and the rxn mixture was stirred at a given temperature for a given time (see Table 43). The solvent was evaporated off and the residue was partitioned between DCM and water. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by CC using Hept/EtOAc or triturated in MeCN and the solid was filtered.

(212) TABLE-US-00046 TABLE 43 T [° C.] t.sub.R [min] MS-data Reactant time (LC/MS m/z C-2 Name C-1 [h] method) [M + H].sup.+ C-2-1 3-(2-Methyl-6-oxo-2,4,6,7-tetrahydro- C-1-1 RT 0.73 (II) 321.98 pyrazolo[3,4-d]pyrimidin-5-yl)-pyrrolidine-1- 0.5 carboxylic acid tert-butyl ester C-2-2 4-(2-Methyl-6-oxo-2,4,6,7-tetrahydro- C-1-2 RT 0.75 (II) 336.14 pyrazolo[3,4-d]pyrimidin-5-yl)-piperidine-1- 0.7 carboxylic acid tert-butyl ester C-2-3 4-(2-Methyl-6-oxo-2,4,6,7-tetrahydro- C-1-3 RT 0.77 (II) 350.24 pyrazolo[3,4-d]pyrimidin-5-yl)-azepane-1- 18 carboxylic acid tert-butyl ester C-2-4 4-(2-Methyl-5-oxo-2,4,5,7-tetrahydro- C-1-4 RT 0.75 (I)  336.38 pyrazolo[4,3-d]pyrimidin-6-yl)-piperidine-1- 0.5 carboxylic acid tert-butyl ester

Synthesis of Intermediates of Formula C-3

(213) To a soln. of intermediate Ii (1 eq) in DCM (4 to 10 mL/mmol) was added TEA (1 to 1.6 mL/mmol) at 0° C. and the rxn mixture was stirred at RT for a given time (see Table 44). It was cooled to 0° C., quenched with a 32% aq. soln. of NaOH until pH reached 12 to 13 and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo.

(214) TABLE-US-00047 TABLE 44 T [° C.] t.sub.R [min] MS-data Reactant time (LC/MS m/z C-3 Name Ii [h] method) [M + H].sup.+ C-3-1 2-Methyl-5-pyrrolidin-3-yl-7-(2-trifluoromethyl- Ii-1 RT 0.64 (II) 380.17 benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 18 d]pyrimidin-6-one C-3-2 2-Methyl-5-piperidin-4-yl-7-(2-trifluoromethyl- Ii-2 RT 0.62 (II) 394.08 benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 0.75 d]pyrimidin-6-one C-3-3 5-Azepan-4-yl-2-methyl-7-(2-trifluoromethyl- Ii-3 RT 0.64 (II) 408.22 benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 0.5 d]pyrimidin-6-one C-3-4 2-Methyl-6-piperidin-4-yl-4-(2-trifluoromethyl- Ii-4 RT 0.67 (I)  394.22 benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3- 1.5 d]pyrimidin-5-one C-3-5 2-Methyl-5-piperidin-4-yl-7-[1-(2-trifluoromethyl- Ii-5 RT 0.69 (I)  408.29 phenyl)-ethyl]-2,4,5,7-tetrahydro-pyrazolo[3,4- 1 d]pyrimidin-6-one C-3-6 7-(2-Cyclopropyl-benzyl)-2-methyl-5-piperidin-4-yl- Ii-6 RT 0.67 (I)  366.28 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 1

Synthesis of Intermediates of Formula C-4

(215) A soln. of aldehyde BB-4 (1 eq) and amine BB-15 (1.1 eq) in MeOH (4 mL/mmol) was stirred for 1.5 h at RT and cooled to 0° C. NaBH.sub.4 (1.6 eq) was added portionwise and the rxn mixture was stirred at RT for a given time (see Table 45). It was quenched with a 1M aq. soln. of NaOH and extracted with EtOAc. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(216) TABLE-US-00048 TABLE 45 t.sub.R [min] MS-data Reactant Reactant time (LC/MS m/z C-4 Name BB-4 BB-15 [h] method) [M + H].sup.+ C-4-1 4-[(1-Methyl-4-nitro-1H-pyrazol- BB-4-3 BB-15-2 0.5 0.61 (I) 340.39 3-ylmethyl)-amino]-piperidine-1- carboxylic acid tert-butyl ester

Synthesis of Intermediates of Formula D-1

(217) To a soln. of aldehyde BB-19 (1 eq) and amine BB-7 (1.4 eq) in THE (10 mL/mmol) was added AcOH (1.5 eq) followed by NaBH(OAc).sub.3 (1.5 eq). The rxn mixture was stirred at RT for a given time (see Table). It was quenched with a sat. aq. soln. of NaHCO.sub.3 and extracted with DCM. The combined org. phases were dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using DCM/MeOH.

(218) TABLE-US-00049 TABLE 46 t.sub.R [min] MS-data Aldehyde Amine time (LC/MS m/z D-1 Name BB-19 BB-7 [h] method) [M + H].sup.+ D-1-1 (4-{[1-(2-Fluoro-6-methyl- BB-19-1 BB-7-1 18 0.70 (II) 377.27 phenyl)-piperidin-4-ylamino]- methyl]-2-methyl-oxazol-5-yl)- carbamic acid methyl ester

Synthesis of Intermediates of Formula E-1

(219) Method A (NaBH(OAc).sub.3/THF)

(220) To a soln. of ketone BB-26 (1 eq) and amine BB-7 (1 eq) in THE (8 mL/mmol) were added AcOH (1.5 eq) and the rxn mixture was stirred for 20 min at RT. NaBH(OAc).sub.3 (1.5 eq) was added portionwise and the rxn mixture was stirred at RT for a given time (see Table). When necessary to reach completion of the rxn, an extra amount of NaBH(OAc).sub.3 (1 eq) was added at RT. It was partitioned between EtOAc and a sat. aq. soln. of NaHCO.sub.3. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(221) Method B (Ti(OiPr).sub.4/NaBH.sub.4)

(222) A suspension of ketone BB-26 (1 eq) and amine BB-7(1.05 eq) in titanium (IV) isopropoxide (3 eq) was stirred at RT for 18h. The rxn mixture was cooled to −10° C. and EtOH (1 mL/mmol), THE (1 mL/mmol) and NaBH.sub.4 (3 eq) were sequentially added. The mixture was allowed to reach RT for 1 hand further stirred at RT for a given time (see Table). It was quenched with water at 0° C. and filtered. The filtrate was extracted with EtOAc and the combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo.

(223) Method C (NaBH.sub.4/TFE)

(224) A soln. of ketone BB-26(1 eq) and amine BB-7 (1.1 eq) in TFE (2 mL/mmol) was stirred for 1 to 2.5h at RT and cooled to 0° C. NaBH.sub.4 (1.5 to 2 eq) was added portionwise and the rxn mixture was stirred for 20 min at 0° C. and for a given time at RT (see Table). It was quenched at 0° C. with a sat. aq. soln. of NaHCO.sub.3 and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(225) TABLE-US-00050 TABLE 47 Method t.sub.R [min] MS-data Reactant Reactant time (LC/MS m/z E-1 Name BB-26 BB-7 [h] method) [M + H].sup.+ E-1-1 [1-(2-Fluoro-6-methyl-phenyl)- BB-26-1 BB-7-1 A 0.77 (I) 362.23 piperidin-4-yl]-[1-(1-methyl-4- 144 nitro-1H-pyrazol-3-yl)-ethyl]- amine E-1-2 [1-(2-Fluoro-6-methyl-phenyl)- BB-26-2 BB-7-1 B 1.01 (I) 478.18 piperidin-4-yl]-{1-[4-nitro-2-(2- 2 trimethylsilanyl-ethoxymethyl)- 2H-pyrazol-3-yl]-ethyl}-amine E-1-3 [1-(2-Fluoro-6-methyl-phenyl)- BB-26-4 BB-7-1 C 0.87 (I) 432.24 piperidin-4-yl]-{1-[4-nitro-1- 0.5 (tetrahydro-pyran-2-yl)-1H- pyrazol-3-yl]-ethyl}-amine E-1-4 (2′-Methoxy-4′-methyl-3,4,5,6- BB-26-4 BB-7-2 C 0.80 (I) 445.23 tetrahydro-2H-[1,3′]bipyridinyl-4- 2.5 yl)-{1-[4-nitro-1-(tetrahydro- pyran-2-yl)-1H-pyrazol-3-yl]- ethyl}-amine E-1-5 [1-(2-Chloro-6-fluoro-phenyl)- BB-26-4 BB-7-8 C 0.85 (I) 452.22 piperidin-4-yl]-{1-[4-nitro-1- 0 (tetrahydro-pyran-2-yl)-1H- pyrazol-3-yl]-ethyl}-amine E-1-6 [1-(2-Difluoromethyl-6-fluoro- BB-26-4 BB-7-7 C 0.86 (I) 468.25 phenyl)-piperidin-4-yl]-{1-[4- 0 nitro-1-(tetrahydro-pyran-2-yl)- 1H-pyrazol-3-yl]-ethyl}-amine

Synthesis of Intermediates of Formula E-2

(226) Method A: Hydrogenation

(227) To a soln. of intermediate E-1 (1 eq) in EtOH (7 to 7.5 mL/mmol) was added 10% Pd/C moistened with ˜50% water (0.02 eq) and the rxn mixture was hydrogenated under atmospheric pressure for a given time (see Table). It was filtered over a pad of celite and the filtrate was concentrated in vacuo. When necessary, the crude was purified by prep. LC-MS using method 5.

(228) Method B: Reduction

(229) To a soln. of intermediate E-1 (1 eq) in MeOH (9 mL/mmol) was added CoCl.sub.2(1.5 eq) and the rxn mixture was stirred for 5 min at RT and cooled to 0° C. NaBH.sub.4 (5 eq) was added portionwise and the mixture was stirred for 15 min at 0° C. (see Table). It was quenched at 0° C. with water and MeOH was evaporated off. The residue was partitioned between EtOAc and water and the aq. phase was further extracted with EtOAc. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo.

(230) TABLE-US-00051 TABLE 48 t.sub.R [min] MS-data Reactant time (LC/MS m/z E-2 Name E-1 [h] method) [M + H].sup.+ E-2-1 [1-(4-Amino-1-methyl-1H-pyrazol-3-yl)-ethyl]-[1-(2- E-1-1  4 0.59 (I) 332.28 fluoro-6-methyl-phenyl)-piperidin-4-yl]-amine E-2-2 {1-[4-Amino-2-(2-trimethylsilanyl-ethoxymethyl)-2H- E-1-2 24 0.92 (I) 448.25 pyrazol-3-yl]-ethyl}-[1-(2-fluoro-6-methyl-phenyl)- piperidin-4-yl]-amine E-2-3 {1-[4-Amino-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3- E-1-3 A 0.71 (I) 402.09 yl]-ethyl}-[1-(2-fluoro-6-methyl-phenyl)-piperidin-4-yl]- 2 amine E-2-4 {1-[4-Amino-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3- E-1-4 A 0.62 (I) 415.32 yl]-ethyl}-(2′-methoxy-4′-methyl-3,4,5,6-tetrahydro-2H- 2 [1,3′]bipyridinyl-4-yl)-amine E-2-5 {1-[4-Amino-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3- E-1-5 B 0.68 (I) 422.24 yl]-ethyl}-[1-(2-chloro-6-fluoro-phenyl)-piperidin-4-yl]- 0.25 amine E-2-6 {1-[4-Amino-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3- E-1-6 A 0.70 (I) 438.30 yl]-ethyl}-[1-(2-difluoromethyl-6-fluoro-phenyl)- 2 piperidin-4-yl]-amine

Synthesis of Intermediates of Formula E-3

(231) To a soln. of intermediate E-2 (1 eq) in MeCN (8.5 to 14.3 mL/mmol) was added CDI (1.2 to 1.5 eq) and the rxn mixture was stirred at a given temperature for a given time (see Table 50). The solvent was evaporated off and the residue was partitioned between DCM and water or a sat. aq. soln. of NaHCO.sub.3. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. When necessary the crude was purified by CC using Hept/EtOAc.

(232) TABLE-US-00052 TABLE 50 T [° C.] t.sub.R [min] MS-data Reactant time (LC/MS m/z E-3 Name E-2 [h] method) [M + H].sup.+ E-3-1 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]- E-2-1 RT 0.94 (I) 358.44 2,7-dimethyl-2,4,6,7-tetrahydro-pyrazolo[4,3- 18 d]pyrimidin-5-one E-3-2 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- E-2-2 RT 1.17 (I) 474.19 methyl-1-(2-trimethylsilanyl-ethoxymethyl)- 1.5 1,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5- one E-3-3 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- E-2-3 RT 1.00 (I) 428.25 methyl-2-(tetrahydro-pyran-2-yl)-2,4,6,7- 0.5 tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one E-3-4 6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H- E-2-4 RT 0.84 (I) 441.23 [1,3′]bipyridinyl-4-yl)-7-methyl-2-(tetrahydro- 0.5 pyran-2-yl)-2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one E-3-5 6-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-7- E-2-5 RT 1.02 (I) 448.22 methyl-2-(tetrahydro-pyran-2-yl)-2,4,6,7- 1.5 tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one E-3-6 6-[1-(2-Difluoromethyl-6-fluoro-phenyl)-piperidin- E-2-6 RT 1.02 (I) 464.27 4-yl]-7-methyl-2-(tetrahydro-pyran-2-yl)-2,4,6,7- 1.5 tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one

Synthesis of Intermediates of Formula E-4

(233) To a soln. of amine BB-28 (1 eq) and aldehyde or ketone BB-12 (2 eq) in THE (2.6 mL/mmol) were added AcOH (1.5 eq) and the rxn mixture was stirred for 18h at RT. NaBH.sub.4 (1.5 eq) was added portionwise and the rxn mixture was stirred at RT for a given time (see Table). It was partitioned between EtOAc and a sat. aq. soln. of NaHCO.sub.3. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(234) TABLE-US-00053 TABLE 49 t.sub.R [min] MS-data Reactant Reactant time (LC/MS m/z E-4 Name BB-28 BB-12 [h] method) [M + H].sup.+ E-4-1 1-Methyl-3-(2-trifluoromethyl- BB-28-1 BB-12-4 2 0.90 (I) 281.20 benzylamino)-1H-pyrazole-4- carbonitrile

Synthesis of Intermediates of Formula E-5

(235) Method a (Grignard Addition Using Nitriles E-4)

(236) To a stirred soln. of nitrile E-4 (1 eq) in THE (6 mL/mmol) under argon was added dropwise at 0° C. a 3M soln. of R.sup.4MgBr in Et.sub.2O (6 eq). The rxn mixture was allowed to reach RT and stirred at a given temperature for a given time (see Table). When necessary to reach completion of the rxn, extra amounts of a 3M soln. of R.sup.4MgBr in Et.sub.2O (2 eq) were added. The mixture was cooled to 0° C., quenched with a sat. aq. soln. of NH.sub.4Cl and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(237) Method B (Heck rxn Using Bromides E-7 or E-8)

(238) A mixture of bromide E-7 or E-8 (1 eq), K.sub.2CO.sub.3 (1.2 eq), Pd(OAc).sub.2 (0.03 eq) and 1,3-bis(diphenylphosphino)propane (0.06 eq) in a mixture of DMF (2.5 mL/mmol) and H.sub.2O (0.6 mL/mmol) was flushed with Ar and butyl vinyl ether (5 eq) was added dropwise at RT. The rxn mixture was heated at a given temperature for a given time (see Table). After cooling to RT, a 1M aq. solution of HCl (2 mL/mmol) was added and the mixture was stirred for 1h at RT. It was neutralised with a sat. aq. sol. of NaHCO.sub.3 and extracted with EtOAc. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(239) TABLE-US-00054 TABLE 50 Reactant Reactant MethodT t.sub.R [min] MS-data E-4, E-7 R.sup.4MgBr or [° C.] (LC/MS m/z E-5 Name or E-8 vinyl ether time [h] method) [M + H].sup.+ E-5-1 1-[1-Methyl-3-(2- E-4-1 MeMgBr, as A 0.91 (I) 298.22 trifluoromethyl- a 3M soln. in 80 benzylamino)-1H- Et.sub.2O 3 pyrazol-4-yl]-ethanone E-5-2 1-[1-(Tetrahydro-pyran-2- E-8-1 Butyl vinyl B 1.01 (I) 368.24 yl)-3-(2-trifluoromethyl- ether 105 benzylamino)-1H- 18 pyrazol-4-yl]-ethanone E-5-3 1-[3-(2-Cyclopropyl- E-7-2 Butyl vinyl B 0.89 (I) 270.35 benzylamino)-1-methyl- ether 100 1H-pyrazol-4-yl]- 3 ethanone E-5-4 1-[3-(2-Cyclopropyl- E-8-2 Butyl vinyl B 1.00 (I) 340.24 benzylamino)-1- ether 100 (tetrahydro-pyran-2-yl)- 2 1H-pyrazol-4-yl]- ethanone E-5-5 1-{1-Methyl-3-[(3- E-7-4 Butyl vinyl B 0.76 (I) 299.22 trifluoromethyl-pyridin-2- ether 100 ylmethyl)-amino]-1H- 18 pyrazol-4-yl}-ethanone

Synthesis of Intermediates of Formula E-6

(240) Method A

(241) A suspension of ketone E-5 or E-10 (1 eq) and amine BB-7 (1.1 to 1.2 eq) in titanium (IV) isopropoxide (3 to 5 eq) was stirred at RT for 18h. The rxn mixture was cooled to 0° C. and EtOH (to 2.5 mL/mmol), THE (1 mL/mmol) and NaBH.sub.4 (3 eq) were sequentially added. The mixture was stirred at RT for a given time (see Table), quenched with water at 0° C. and when necessary filtered over a pad of celite. It was extracted with EtOAc and the combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(242) Method B

(243) To a mixture of ketone E-5 or E-10 (1 eq) and amine BB-7 (1.1 to 1.2 eq) in THF (3 mL/mmol) was added titanium (IV) isopropoxide (3 to 4.4 eq) and the soln. was stirred at RT for 18h. It was cooled to 0° C. and MeOH (6 mL/mmol) and NaBH.sub.4 (1.3 to 2 eq) were sequentially added. After stirring for a given time at RT (see Table), it was quenched with water and a 1M soln. of NaOH and extracted with EtOAc. When necessary a filtration over a pad of celite was performed. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or by prep. LC-MS using method 5 or 8.

(244) TABLE-US-00055 TABLE 51 Reactant t.sub.R [min] MS-data E-5 or Reactant Method (LC/MS m/z E-6 Name E-10 BB-7 time [h] method) [M + H].sup.+ E-6-1 [1-(2-Fluoro-6-methyl- E-5-1 BB-7-1 1 0.89 (I) 490.28 phenyl)-piperidin-4-yl]-{1-[1- methyl-3-(2-trifluoromethyl- benzylamino)-1H-pyrazol-4- yl]-ethyl}-amine E-6-2 [1-(2-Fluoro-6-methyl- E-5-2 BB-7-1 A 0.96 (I) 560.38 phenyl)-piperidin-4-yl]-{1-[1- 18 (tetrahydro-pyran-2-yl)-3-(2- trifluoromethyl-benzylamino)- 1H-pyrazol-4-yl]-ethyl}-amine E-6-3 {1-[1-Cyclopropyl-3-(2- E-10-1 BB-7-1 A 0.98 (I) 516.39 trifluoromethyl-benzylamino)- 1 1H-pyrazol-4-yl]-ethyl}-[1-(2- fluoro-6-methyl-phenyl)- piperidin-4-yl]-amine E-6-4 {1-[1-Cyclopropyl-3-(2- E-10-1 BB-7-7 A 0.93 (I) 552.33 trifluoromethyl-benzylamino)- 0.5 1H-pyrazol-4-yl]-ethyl}-[1-(2- difluoromethyl-6-fluoro- phenyl)-piperidin-4-yl]-amine E-6-5 [1-(2-Difluoromethyl-6-fluoro- E-5-1 BB-7-7 A 0.92 (I) 526.38 phenyl)-piperidin-4-yl]-{1-[1- 0.5 methyl-3-(2-trifluoromethyl- benzylamino)-1H-pyrazol-4- yl]-ethyl}-amine E-6-6 {1-[3-(2-Cyclopropyl- E-5-3 BB-7-1 B 0.91 (I) 462.36 benzylamino)-1-methyl-1H- 1 pyrazol-4-yl]-ethyl}-[1-(2- fluoro-6-methyl-phenyl)- piperidin-4-yl]-amine E-6-7 [1-(2-Chloro-6-fluoro- E-5-1 BB-7-8 A 0.89 (I) 510.26 phenyl)-piperidin-4-yl]-{1-[1- 0.5 methyl-3-(2-trifluoromethyl- benzylamino)-1H-pyrazol-4- yl]-ethyl}-amine E-6-8 [1-(2-Chloro-6-fluoro- E-5-3 BB-7-8 B 0.91 (I) 482.08 phenyl)-piperidin-4-yl]-{1-[3- 18 (2-cyclopropyl-benzylamino)- 1-methyl-1H-pyrazol-4-yl]- ethyl}-amine E-6-9 {1-[3-(2-Cyclopropyl- E-5-3 BB-7-7 B 0.92 (I) 498.15 benzylamino)-1-methyl-1H- 0.5 pyrazol-4-yl]-ethyl}-[1-(2- difluoromethyl-6-fluoro- phenyl)-piperidin-4-yl]-amine E-6-10 {1-[3-(2-Cyclopropyl- E-5-3 BB-7-9 B 0.92 (I) 488.37 benzylamino)-1-methyl-1H- 0.5 pyrazol-4-yl]-ethyl}-[1-(2- cyclopropyl-6-fluoro-phenyl)- piperidin-4-yl]-amine E-6-11 (2′-Methoxy-4′-methyl- E-5-1 BB-7-2 B 0.86 (I) 503.33 3,4,5,6-tetrahydro-2H- 2 [1,3′]bipyridinyl-4-yl)-{1-[1- methyl-3-(2-trifluoromethyl- benzylamino)-1H-pyrazol-4- yl]-ethyl}-amine E-6-12 [1-(2-Cyclopropyl-6-fluoro- E-5-1 BB-7-9 B 0.93 (I) 516.24 phenyl)-piperidin-4-yl]-{1-[1- 0.5 methyl-3-(2-trifluoromethyl- benzylamino)-1H-pyrazol-4- yl]-ethyl}-amine E-6-13 [1-(2-Chloro-6-fluoro- E-10-1 BB-7-8 A 0.93 (I) 536.22 phenyl)-piperidin-4-yl]-{1-[1- 0.5 cyclopropyl-3-(2- trifluoromethyl-benzylamino)- 1H-pyrazol-4-yl]-ethyl}-amine E-6-14 {1-[1-Cyclopropyl-3-(2- E-10-2 BB-7-1 B 0.95 (I) 488.34 cyclopropyl-benzylamino)- 3 1H-pyrazol-4-yl]-ethyl}-[1-(2- fluoro-6-methyl-phenyl)- piperidin-4-yl]-amine E-6-15 [1-(2-Chloro-6-fluoro- E-10-2 BB-7-8 B 0.94 (I) 508.32 phenyl)-piperidin-4-yl]-{1-[1- 3 cyclopropyl-3-(2-cyclopropyl- benzylamino)-1H-pyrazol-4- yl]-ethyl}-amine E-6-16 {1-[1-Cyclopropyl-3-(2- E-10-1 BB-7-2 A 0.91 (I) 529.18 trifluoromethyl-benzylamino)- 0.5 1H-pyrazol-4-yl]-ethyl}-(2′- methoxy-4′-methyl-3,4,5,6- tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-amine E-6-17 (4′-Difluoromethyl-2′- E-5-1 BB-7-10 A 0.88 (I) 539.26 methoxy-3,4,5,6-tetrahydro- 1 2H-[1,3′]bipyridinyl-4-yl)-{1- [1-methyl-3-(2- trifluoromethyl-benzylamino)- 1H-pyrazol-4-yl]-ethyl}-amine E-6-18 [1-(2-Difluoromethyl-6-fluoro- E-5-2 BB-7-7 A 0.97 (I) 596.33 phenyl)-piperidin-4-yl]-{1-[1- 0.5 (tetrahydro-pyran-2-yl)-3-(2- trifluoromethyl-benzylamino)- 1H-pyrazol-4-yl]-ethyl}-amine E-6-19 [1-(2-Chloro-6-fluoro- E-5-2 BB-7-8 A 0.98 (I) 580.31 phenyl)-piperidin-4-yl]-{1-[1- 1 (tetrahydro-pyran-2-yl)-3-(2- trifluoromethyl-benzylamino)- 1H-pyrazol-4-yl]-ethyl}-amine E-6-20 (4′-Difluoromethyl-2′- E-5-2 BB-7-10 A 0.98 (I) 609.09 methoxy-3,4,5,6-tetrahydro- 0.5 2H-[1,3′]bipyridinyl-4-yl)-{1- [1-(tetrahydro-pyran-2-yl)-3- (2-trifluoromethyl- benzylamino)-1H-pyrazol-4- yl]-ethyl}-amine E-6-21 [1-(2-Fluoro-6-methyl- E-5-5 BB-7-1 B 0.83 (I) 491.26 phenyl)-piperidin-4-yl]-(1-{1- 0.5 methyl-3-[(3-trifluoromethyl- pyridin-2-ylmethyl)-amino]- 1H-pyrazol-4-yl}-ethyl)- amine E-6-22 (2′-Methoxy-4′-methyl- E-5-5 BB-7-2 B 0.77 (I) 504.26 3,4,5,6-tetrahydro-2H- 0.5 [1,3′]bipyridinyl-4-yl)-(1-{1- methyl-3-[(3-trifluoromethyl- pyridin-2-ylmethyl)-amino]- 1H-pyrazol-4-yl}-ethyl)- amine E-6-23 {1-[1-Cyclopropyl-3-(2- E-10-1 BB-7-10 B 0.92 (I) 565.27 trifluoromethyl-benzylamino)- 1 1H-pyrazol-4-yl]-ethyl}-(4′- difluoromethyl-2′-methoxy- 3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-amine E-6-24 [1-(2-Bromo-6-fluoro- E-10-1 BB-7-11 B 0.93 (I) 580.20 phenyl)-piperidin-4-yl]-{1-[1- 1.5 cyclopropyl-3-(2- trifluoromethyl-benzylamino)- 1H-pyrazol-4-yl]-ethyl}-amine E-6-25 (2′-Methoxy-4′- E-5-1 BB-7-12 A 0.93 (I) 557.32 trifluoromethyl-3,4,5,6- 1.5 tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-{1-[1- methyl-3-(2-trifluoromethyl- benzylamino)-1H-pyrazol-4- yl]-ethyl}-amine E-6-26 {1-[3-(2-Cyclopropyl- E-5-3 BB-7-2 B 0.86 (I) 475.31 benzylamino)-1-methyl-1H- 1.5 pyrazol-4-yl]-ethyl}-(2′- methoxy-4′-methyl-3,4,5,6- tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-amine E-6-27 {1-[3-(2-Cyclopropyl- E-5-3 BB-7-10 B 0.91 (I) 511.31 benzylamino)-1-methyl-1H- 1.5 pyrazol-4-yl]-ethyl}-(4′- difluoromethyl-2′-methoxy- 3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-amine E-6-28 {1-[3-(2-Cyclopropyl- E-5-4 BB-7-10 B 0.98 (I) 581.38 benzylamino)-1-(tetrahydro- 1 pyran-2-yl)-1H-pyrazol-4-yl]- ethyl}-(4′-difluoromethyl-2′- methoxy-3,4,5,6-tetrahydro- 2H-[1,3′]bipyridinyl-4-yl)- amine E-6-29 [1-(2-Chloro-6-fluoro- E-5-4 BB-7-8 B 0.98 (I) 552.36 phenyl)-piperidin-4-yl]-{1-[3- 1 (2-cyclopropyl-benzylamino)- 1-(tetrahydro-pyran-2-yl)-1H- pyrazol-4-yl]-ethyl}-amine E-6-30 {1-[3-(2-Cyclopropyl- E-5-3 BB-7-12 A 0.91 (I) 529.14 benzylamino)-1-methyl-1H- 1 pyrazol-4-yl]-ethyl}-(2′- methoxy-4′-trifluoromethyl- 3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-amine E-6-31 (4′-Chloro-2′-methoxy- E-5-1 BB-7-13 A 0.87 (I) 523.21 3,4,5,6-tetrahydro-2H- 0.5 [1,3′]bipyridinyl-4-yl)-{1-[1- methyl-3-(2-trifluoromethyl- benzylamino)-1H-pyrazol-4- yl]-ethyl}-amine E-6-32 (4′-Chloro-2′-methoxy- E-5-3 BB-7-13 A 0.87 (I) 495.26 3,4,5,6-tetrahydro-2H- 0.5 [1,3′]bipyridinyl-4-yl)-{1-[3-(2- cyclopropyl-benzylamino)-1- methyl-1H-pyrazol-4-yl]- ethyl}-amine E-6-33 {1-[1-Cyclopropyl-3-(2- E-10-2 BB-7-2 B 0.90 (I) 501.37 cyclopropyl-benzylamino)- 0.5 1H-pyrazol-4-yl]-ethyl}-(2′- methoxy-4′-methyl-3,4,5,6- tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-amine E-6-34 {1-[1-Cyclopropyl-3-(2- E-10-2 BB-7-10 B 0.95 (I) 537.38 cyclopropyl-benzylamino)- 0.5 1H-pyrazol-4-yl]-ethyl}-(4′- difluoromethyl-2′-methoxy- 3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-amine E-6-35 [1-(2-Bromo-6-fluoro- E-5-3 BB-7-11 B 0.93 (I) 526.28 phenyl)-piperidin-4-yl]-{1-[3- 1 (2-cyclopropyl-benzylamino)- 1-methyl-1H-pyrazol-4-yl]- ethyl}-amine

Synthesis of Intermediates of Formula E-7

(245) Method A

(246) A soln. of amine BB-34(1 eq) and aldehyde or ketone BB-12 (1.05 to 1.1 eq) in MeOH (2 to 4 mL/mmol) was stirred for 1 h at RT. NaBH.sub.4 (1.6 to 2 eq) was added portionwise at 0° C. and the rxn mixture was stirred at a given temperature for a given time (see Table 52). It was quenched with H.sub.2O at 0° C. and extracted with EtOAc. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by CC using EtOAc/MeOH.

(247) Method B

(248) A soln. of amine BB-34(1 eq), aldehyde or ketone BB-12 (1.1 eq) and AcOH (1.1 eq) in MeOH (1.5 mL/mmol) was stirred under Ar for 1h at RT. Molybdenum(VI) dichloride dioxide (0.05 eq) in MeOH (1.5 mL/mmol) was added at RT followed by phenylsilane (1.5 eq). The rxn mixture was stirred at a given temperature for a given time (see Table 52) and quenched with a sat. soln. of NaHCO.sub.3. It was extracted with DCM and the combined org. phases were dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using EtOAc/MeOH.

(249) TABLE-US-00056 TABLE 52 Method t.sub.R [min] MS-data Reactant Reactant T [° C.] (LC/MS m/z E-7 Name BB-34 BB-12 time [h] method) [M + H].sup.+ E-7-1 (4-Bromo-1H-pyrazol-3-yl)- BB-34-1 BB-12-4 A 0.91 (I) 320.02 (2-trifluoromethyl-benzyl)- 0 amine 1.5 E-7-2 (4-Bromo-1-methyl-1H- BB-34-2 BB-12-5 A 0.97 (I) 305.85 pyrazol-3-yl)-(2-cydopropyl- RT benzyl)-amine 2.5 E-7-3 (4-Bromo-1H-pyrazol-3-yl)- BB-34-1 BB-12-5 A 0.89 (I) 292.18 (2-cyclopropyl-benzyl)-amine RT 1 E-7-4 (4-Bromo-1-methyl-1H- BB-34-2 BB-12-1 B 0.87 (I) 335.08 pyrazol-3-yl)-(3- RT trifluoromethyl-pyridin-2- 18 ylmethyl)-amine

Synthesis of Intermediates of Formula E-8

(250) To a suspension or solution of the intermediate E-7 (1 eq) in DCM (2 to 4 mL/mmol) was added TsOH (0.1 eq) and 3,4-dihydro-2H-pyran (1.3 eq). The rxn mixture was stirred at a given temperature for a given time (see Table 53) and quenched with a sat. aq. soln. of NaHCO.sub.3. It was extracted with DCM, the org. phase was washed with a sat. aq. soln. of NaHCO.sub.3 and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(251) TABLE-US-00057 TABLE 53 T [° C.] t.sub.R [min] MS-data Reactant time (LC/MS m/z E-8 Name E-7 [h] method) [M + H].sup.+ E-8-1 [4-Bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3- E-7-1 50 1.08 (I) 404.09 yl]-(2-trifluoromethyl-benzyl)-amine 20 E-8-2 [4-Bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3- E-7-3 45 1.06 (I) 376.17 yl]-(2-cydopropyl-benzyl)-amine 18

Synthesis of Intermediates of Formula E-9

(252) To a sol. of THP-protected intermediate E-5 (1 eq) in DCM (2 mL/mmol) was added dropwise TA (1.5 mL/mmol). The soln. was stirred at RT for a given time (see Table 54), quenched at 0° C. with a 1 M aq. sol. of NaOH until pH 10-11 and extracted with DCM. The combined org. phases were dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(253) TABLE-US-00058 TABLE 54 T [° C.] t.sub.R [min] MS-data Reactant time (LC/MS m/z E-9 Name E-5 [h] method) [M + H].sup.+ E-9-1 1-[3-(2-Trifluoromethyl-benzylamino)- E-5-2 RT 0.82 (I) 284.16 1H-pyrazol-4-yl]-ethanone 1 E-9-2 1-[3-(2-Cyclopropyl-benzylamino)-1H- E-5-4 RT 0.82 (I) 256.33 pyrazol-4-yl]-ethanone 72

Synthesis of Intermediates of Formula E-10

(254) A mixture of intermediates E-9(1 eq), boron species BB-10(2 eq), Na.sub.2CO.sub.3 (2 eq), 2,2-bipyridyl (1 eq) and Cu(OAc).sub.2 (1 eq) in toluene (10 to 12 mL/mmol) was flushed with N.sub.2 and heated at a given temperature for given time (see Table 55). It was partitioned between EtOAc or DCM and a sat. aq. soln. of NaHCO.sub.3 and the org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(255) TABLE-US-00059 TABLE 55 t.sub.R [min] MS-data Reactant Reactant T [° C.] (LC/MS- m/z E-10 Name E-9 BB-10 time [h] method) [M + H].sup.+ E-10-1 1-[1-Cyclopropyl-3-(2- E-9-1 Cyclopropyl 70 0.97 (I) 324.22 trifluoromethyl-benzylamino)-1H- boronic acid 2.5 pyrazol-4-yl]-ethanone E-10-2 1-[1-Cyclopropyl-3-(2-cyclopropyl- E-9-2 Cyclopropyl 80 0.95 (I) 296.33 benzylamino)-1H-pyrazol-4-yl]- boronic acid 2 ethanone

Synthesis of Compounds of Formula Ia

(256) Method A1 (Alkylation of A-3 or E-3: NaH/THF)

(257) To a soln. of intermediate A-3 or E-3 (1 eq) in a mixture of anh. THE (3 to 7.3 mL/mmol) and anh. DMF (0 to 0.7 mL/mmol) was added NaH (1.5 to 10 eq, as a 60% dispersion in mineral oil) at 0° C. The suspension was stirred for 10 min and halide BB-9 (1.1 to 1.5 eq) was added at 0° C. The rxn mixture was stirred at a given temperature for a given time under possible microwave irradiation (see Table). When necessary to reach completion of the rxn an extra amount of NaH (0.5 eq, as a 60% dispersion in mineral oil) and/or halide BB-9 (0.5 eq) was added. The mixture was quenched with water or a sat. aq. soln. of NaHCO.sub.3 and extracted with EtOAc. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or by prep. LC-MS using method 1, 2 or 5.

(258) Method A2 (Alkylation of A-3 or E-3 Using NaH/THF Followed by Saponification)

(259) Similar to method A1 except that the rxn mixture was quenched with a 2M aq. soln. of NaOH and stirred ON at RT before the extraction with EtOAc.

(260) Method B (Mitsunobu with A-3 or E-3)

(261) To a soln. or suspension of intermediate A-3 or E-3 (1 eq) and alcohol BB-9 (1.1 to 6 eq) in toluene (3.4 to 24 mL/mmol) was added a 1M soln. of (tributylphosphoranylidene)acetonitrile in toluene (1.1 to 2 eq) under argon. The rxn mixture was heated to a given temperature and stirred for a given time (see Table). When necessary to reach completion of the rxn, extra amounts of a 1M soln. of (tributylphosphoranylidene)acetonitrile in toluene (0.2 eq) were sequentially added under argon. It was quenched with water or a sat. aq. soln. of NaHCO.sub.3 and extracted with EtOAc or DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH. When necessary, an additional purification by prep. LC-MS using methods 2, 3, 4 or 5 was performed.

(262) Method C (Cyclisation from B-3)

(263) To a suspension of intermediate B-3 (1 eq) in MeCN (5.1 to 11.2 mL/mmol) was added CDI (5 to 7 eq) and the rxn mixture was stirred at a given temperature for a given time (see Table). The solvent was evaporated off and the residue was partitioned between EtOAc and water. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by CC using Hept/EtOAc/MeOH.

(264) Method D (Alkylation of A-3: K.sub.2CO.sub.3/DMF)

(265) To a stirred soln. of intermediate A-3 (1 eq) in DMF (3.9 to 4.7 mL/mmol) was added K.sub.2CO.sub.3 (1.5 to 3 eq) followed by the appropriate halide BB-9 (1.3 to 1.5 eq). The rxn mixture was stirred at a given temperature for a given time (see Table). When necessary to reach completion of the rxn, extra amounts of halide BB-9 (1 eq) were added at RT. It was partitioned between EtOAc and H.sub.2. The org. phase was washed with water and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc and/or DCM/MeOH.

(266) Method E (Cyclisation from E-6)

(267) To a suspension of diamine E-6 (1 eq) in MeCN (or DCM, respectively) (8 to 12.7 mL/mmol) was added DSC (or CDT, respectively) (1.2 to 1.3 eq) and optionally Et.sub.3N (3 eq) at RT. The rxn mixture was stirred at a given temperature for a given time (see Table) and partitioned between EtOAc or DCM and a 1 M soln. of NaOH or a sat. soln. of NaHCO.sub.3. The org. phase was washed with water and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or by prep. LC-MS using method 4, 5, 8 or 10.

(268) TABLE-US-00060 TABLE 56 Reactant Method t.sub.R [min] MS-data A-3, B-3, Reactant T [° C.] (LC/MS- m/z Ia Name E-3 or E-6 BB-9 time [h] method) [M + H].sup.+ Ia-1A 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-1A BB-9-1 A1 1.30 (I) 618.26 yl]-4-(2-trifluoromethyl-benzyl)-1-(2- RT trimethylsilanyl-ethoxymethyl)-1,4,6,7- 66 tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 1) Ia-1B 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-1B BB-9-1 A1 1.29 (I) 618.28 yl]-4-(2-trifluoromethyl-benzyl)-2-(2- RT trimethylsilanyl-ethoxymethyl)-2,4,6,7- 2 tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 195) Ia-2 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-2 BB-9-1 A1 1.31 (I) 618.38 yl]-7-(2-trifluoromethyl-benzyl)-2-(2- RT trimethylsilanyl-ethoxymethyl)-2,4,5,7- 24 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 5) Ia-3 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-3 BB-9-2 A1  1.00 (II) 504.17 yl]-2-methyl-4-(3-trifluoromethyl-pyrazin-2- RT ylmethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3- 18 d]pyrimidin-5-one (Example 11) Ia-4 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-3 BB-9-3 B  1.04 (II) 503.19 yl]-2-methyl-4-(4-trifluoromethyl-pyridin-3- 110 ylmethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3- 3 d]pyrimidin-5-one (Example 12) Ia-5 1-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-4 BB-9-1 A1  1.12 (II) 618.17 yl]-3-(2-trifluoromethyl-benzyl)-7-(2- RT trimethylsilanyl-ethoxymethyl)-1,3,6,7- 18 tetrahydro-purin-2-one (Example 13) Ia-6 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-3 BB-9-4 B  1.01 (II) 503.16 yl]-2-methyl-4-(3-trifluoromethyl-pyridin-2- 110 ylmethyl)-2,4,6,7-tetrahydro-pyrazolo[4,3- 18 d]pyrimidin-5-one (Example 15) Ia-7 7-(2-Cyclopropoxy-benzyl)-5-[1-(2-fluoro-6- A-3-5 BB-9-5 A1  1.06 (II) 490.15 methyl-phenyl)-piperidin-4-yl]-2-methyl- RT 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 18 6-one (Example 21) Ia-8 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- B-3-1 — C  1.00 (II) 503.09 yl]-2-methyl-7-(3-trifluoromethyl-pyridin-2- 80 ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 2 d]pyrimidin-6-one (Example 22) Ia-9 7-(6-Chloro-3-trifluoromethyl-pyridin-2- B-3-2 — C  1.05 (II) 537.07 ylmethyl)-5-[1-(2-fluoro-6-methyl-phenyl)- 80 piperidin-4-yl]-2-methyl-2,4,5,7-tetrahydro- 2 pyrazolo[3,4-d]pyrimidin-6-one (Example 35) Ia-10 5-[(R)-1-(2-Fluoro-6-methyl-phenyl)- A-3-6 BB-9-1 A1  0.91 (II) 488.09 pyrrolidin-3-yl]-2-methyl-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one (Example 55) Ia-11 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- B-3-3 — C  1.06 (II) 520.07 yl]-7-(2-fluoro-6-trifluoromethyl-benzyl)-2- 80 methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- 72 d]pyrimidin-6-one (Example 61) Ia-12 3-Benzyl-6-[1-(2-fluoro-6-methyl-phenyl)- A-3-7 BB-9-1 D  1.10 (II) 579.16 piperidin-4-yl]-4-(2-trifluoromethyl-benzyl)- 45 and 80 3,4,6,7-tetrahydro-[1,2,3]triazolo[4,5- 18 and 5 d]pyrimidin-5-one Ia-13 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-8 BB-9-6 B  1.12 (II) 503.15 yl]-2-methyl-4-(2-trifluoromethyl-benzyl)- 110 6,7-dihydro-4H-oxazolo[5,4-d]pyrimidin-5- 0.25 one (Example 89) Ia-14 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-9 BB-9-6 B  1.12 (II) 519.04 yl]-2-methyl-4-(2-trifluoromethyl-benzyl)- 110 6,7-dihydro-4H-thiazolo[5,4-d]pyrimidin-5- 0.5 one (Example 90) Ia-15 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-10 BB-9-4 B 1.17 (I) 504.17 yl]-2-methyl-4-(3-trifluoromethyl-pyridin-2- 110 ylmethyl)-2,4,6,7-tetrahydro- 2 [1,2,3]triazolo[4,5-d]pyrimidin-5-one (Example 128) Ia-16 5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-3-11 BB-9-7 A1 1.01 (I) 516.14 2H-[1,3′]bipyridinyl-4-yl)-2-methyl-7-(3- microwave trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7- 100 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 0.75 (Example 138) Ia-17 6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-3-12 BB-9-6 B 1.17 (I) 516.02 2H-[1,3′]bipyridinyl-4-yl)-2-methyl-4-(2- 110 trifluoromethyl-benzyl)-2,4,6,7-tetrahydro- 1 [1,2,3]triazolo[4,5-d]pyrimidin-5-one (Example 145) Ia-18 6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-3-12 BB-9-4 B 1.07 (I) 517.11 2H-[1,3′]bipyridinyl-4-yl)-2-methyl-4-(3- 110 trifluoromethyl-pyridin-2-ylmethyl)-2,4,6,7- 18 tetrahydro-[1,2,3]triazolo[4,5-d]pyrimidin-5- one (Example 146) Ia-19 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-2 BB-9-7 D 1.26 (I) 619.39 yl]-7-(3-trifluoromethyl-pyridin-2-ylmethyl)- 140 2-(2-trimethylsilanyl-ethoxymethyl)-2,4,5,7- 4 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one microwave Ia-20 5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-3-13 BB-9-1 A1 1.27 (I) 631.22 2H-[1,3′]bipyridinyl-4-yl)-7-(2- RT trifluoromethyl-benzyl)-2-(2-trimethylsilanyl- 18 ethoxymethyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 196) Ia-21 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-1B BB-9-7 A1 1.24 (I) 619.25 yl]-4-(3-trifluoromethyl-pyridin-2-ylmethyl)- RT 2-(2-trimethylsilanyl-ethoxymethyl)-2,4,6,7- 18 tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 199) Ia-22 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- E-3-1 BB-9-1 A1 1.22 (I) 516.07 yl]-2,7-dimethyl-4-(2-trifluoromethyl- RT benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3- 3 d]pyrimidin-5-one Ia-23 7-(2-Bromo-6-trifluoromethyl-benzyl)-5-[1- A-3-2 BB-9-8 A1 1.35 (I) 696.27 (2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2- RT (2-trimethylsilanyl-ethoxymethyl)-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one Ia-24 6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- A-3-14 BB-9-1 A1 1.25 (I) 631.40 2H-[1,3′]bipyridinyl-4-yl)-4-(2- RT trifluoromethyl-benzyl)-1-(2-trimethylsilanyl- 18 ethoxymethyl)-1,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Example 216) Ia-25 5-[1-(2-Fluoro-6-methyl-phenyl)-4-methyl- A-3-15 BB-9-1 A1 1.20 (I) 516.26 piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl- RT benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 24 d]pyrimidin-6-one (Example 217) Ia-26 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- E-6-1 — E 1.21 (I) 516.22 yl]-2,4-dimethyl-7-(2-trifluoromethyl- 40 benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 3.5 d]pyrimidin-6-one Ia-27 5-[1-(2-Fluoro-6-methyl-phenyl)-azepan-4- A-3-16 BB-9-1 A1 1.22 (I) 516.17 yl]-2-methyl-7-(2-trifluoromethyl-benzyl)- RT 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 5 6-one Ia-28 7-(2-Cyclopropyl-benzyl)-5-[1-(2-fluoro-6- A-3-5 BB-9-9 B 1.19 (I) 474.23 methyl-phenyl)-piperidin-4-yl]-2-methyl- 110 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 1 6-one (Example 228) Ia-29 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-1A BB-9-7 A1 1.24 (I) 619.22 yl]-4-(3-trifluoromethyl-pyridin-2-ylmethyl)- RT 1-(2-trimethylsilanyl-ethoxymethyl)-1,4,6,7- 48 tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 230) Ia-30 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-5 BB-9-10 A1 1.22 (I) 476.21 yl]-7-(2-isopropyl-benzyl)-2-methyl-2,4,5,7- RT tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 18 (Example 231) Ia-31 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-5 BB-9-11 A1 1.20 (I) 518.19 yl]-2-methyl-7-(2-trifluoromethoxy-benzyl)- RT 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 18 6-one (Example 232) Ia-32 7-(2-Chloro-benzyl)-5-[1-(2-fluoro-6-methyl- A-3-5 BB-9-12 A1 1.17 (I) 468.13 phenyl)-piperidin-4-yl]-2-methyl-2,4,5,7- RT tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 18 (Example 233) Ia-33 5-[1-(2-Fluoro-6-methyl-phenyl)-3-methyl- A-3-17 BB-9-1 A1 1.15 (I) 502.16 pyrrolidin-3-yl]-2-methyl-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one Ia-34 7-(2,4-Difluoro-6-isopropoxy-benzyl)-5-[1- A-3-5 BB-9-13 B 1.18 (I) 528.23 (2-fluoro-6-methyl-phenyl)-piperidin-4-yl]-2- 110 methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- 2 d]pyrimidin-6-one (Example 236) Ia-35 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- E-3-2 BB-9-1 A1 1.31 (I) 632.19 yl]-7-methyl-4-(2-trifluoromethyl-benzyl)-1- RT (2-trimethylsilanyl-ethoxymethyl)-1,4,6,7- 18 tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one (Example 237) Ia-36 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-5 BB-9-14 B 1.16 (I) 523.16 yl]-2-methyl-7-(2-methyl-4-trifluoromethyl- 110 thiazol-5-ylmethyl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one (Example 240) Ia-37 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-3- A-3-18 BB-9-1 A1 1.17 (I) 502.18 yl]-2-methyl-7-(2-trifluoromethyl-benzyl)- RT 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 18 6-one Ia-38 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-5 BB-9-15 B 1.21 (I) 516.21 yl]-2-methyl-7-[1-(2-trifluoromethyl-phenyl)- 110 ethyl]-2,4,5,7-tetrahydropyrazolo[3,4- 1 d]pyrimidin-6-one Ia-39 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-5 BB-9-16 A2 1.15 (I) 449.95 yl]-7-(2-hydroxy-benzyl)-2-methyl-2,4,5,7- RT tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 5 Ia-40 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-5 BB-9-17 B 1.19 (I) 478.22 yl]-7-(4-isopropyl-pyrimidin-5-ylmethyl)-2- 110 methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- 5.5 d]pyrimidin-6-one (Example 249) Ia-41 7-(2-Ethoxy-benzyl)-5-[1-(2-fluoro-6- A-3-5 BB-9-18 B 1.16 (I) 478.19 methyl-phenyl)-piperidin-4-yl]-2-methyl- 110 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 1 6-one (Example 252) Ia-42 4-(2-Cyclopropyl-benzyl)-6-[1-(2-fluoro-6- A-3-3 BB-9-9 B 1.20 (I) 474.20 methyl-phenyl)-piperidin-4-yl]-2-methyl- 110 2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin- 1 5-one (Example 259) Ia-43 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-3 BB-9-10 A1 1.22 (I) 476.20 yl]-4-(2-isopropyl-benzyl)-2-methyl-2,4,6,7- RT tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one 18 (Example 260) Ia-44 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-3 BB-9-15 B 1.18 (I) 516.21 yl]-2-methyl-4-[1-(2-trifluoromethyl-phenyl)- 110 ethyl]-2,4,6,7-tetrahydro-pyrazolo[4,3- 2 d]pyrimidin-5-one Ia-45 5-[1-(2-Fluoro-6-methyl-phenyl)-azetidin-3- A-3-19 BB-9-6 B .sup. 1.17 (IV) 474.01 yl]-2-methyl-7-(2-trifluoromethyl-benzyl)- 100 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 1 6-one (Example 264) Ia-46 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- A-3-5 BB-9-19 B 0.89 (I) 494.21 yl]-7-(4-isopropoxy-pyridazin-3-ylmethyl)-2- 100 methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- 18 d]pyrimidin-6-one (Example 267) Ia-47 4-(2-Cyclopropyl-benzyl)-6-[1-(2-fluoro-6- E-3-3 BB-9-9 B 1.22 (I) 558.34 methyl-phenyl)-piperidin-4-yl]-7-methyl-2- 110 (tetrahydro-pyran-2-yl)-2,4,6,7-tetrahydro- 3.5 pyrazolo[4,3-d]pyrimidin-5-one (mixture of diastereoisomers) (Example 268) Ia-48 4-(2-Cyclopropyl-benzyl)-6-(2′-methoxy-4′- E-3-4 BB-9-9 B 1.14 (I) 571.34 methyl-3,4,5,6-tetrahydro-2H- 110 [1,3′]bipyridinyl-4-yl)-7-methyl-2- 18 (tetrahydro-pyran-2-yl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (mixture of diastereoisomers) (Example 269) Ia-51 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- E-6-2 — E 1.25 (I) 586.40 yl]-4-methyl-2-(tetrahydro-pyran-2-yl)-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 1.5 pyrazolo[3,4-d]pyrimidin-6-one (mixture of +50 diastereoisomers) (Example 313) 0.25 Ia-53 6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- E-3-4 BB-9-6 B 1.14 (I) 599.35 2H-[1,3′]bipyridinyl-4-yl)-7-methyl-2- 110 (tetrahydro-pyran-2-yl)-4-(2-trifluoromethyl- 18 benzyl)-2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (mixture of diastereoisomers) Ia-54 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- E-3-3 BB-9-1 A1 1.21 (I) 586.35 yl]-7-methyl-2-(tetrahydro-pyran-2-yl)-4-(2- RT trifluoromethyl-benzyl)-2,4,6,7-tetrahydro- 18 pyrazolo[4,3-d]pyrimidin-5-one (mixture of diastereoisomers) (Example 294) Ia-55 2-Cyclopropyl-5-[1-(2-fluoro-6-methyl- E-6-3 — E 1.24 (I) 542.28 phenyl)-piperidin-4-yl]-4-methyl-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 72 pyrazolo[3,4-d]pyrimidin-6-one Ia-56 2-Cyclopropyl-5-[1-(2-difluoromethyl-6- E-6-4 — E 1.24 (I) 578.15 fluoro-phenyl)-piperidin-4-yl]-4-methyl-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 5 pyrazolo[3,4-d]pyrimidin-6-one Ia-57 5-[1-(2-Difluoromethyl-6-fluoro-phenyl)- E-6-5 — E 1.22 (I) 552.30 piperidin-4-yl]-2,4-dimethyl-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one Ia-58 7-(2-Cyclopropyl-benzyl)-5-[1-(2-fluoro-6- E-6-6 — E 1.22 (I) 488.34 methyl-phenyl)-piperidin-4-yl]-2,4-dimethyl- RT 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 20 6-one Ia-59 5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4- E-6-7 — E 1.23 (I) 536.23 yl]-2,4-dimethyl-7-(2-trifluoromethyl- RT benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 20 d]pyrimidin-6-one Ia-60 5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4- E-6-8 — E 1.20 (I) 508.32 yl]-7-(2-cyclopropyl-benzyl)-2,4-dimethyl- RT 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 5 6-one Ia-61 7-(2-Cyclopropyl-benzyl)-5-[1-(2- E-6-9 — E 1.18 (I) 524.31 difluoromethyl-6-fluoro-phenyl)-piperidin-4- RT yl]-2,4-dimethyl-2,4,5,7-tetrahydro- 4 pyrazolo[3,4-d]pyrimidin-6-one Ia-62 7-(2-Cyclopropyl-benzyl)-5-[1-(2- E-6-10 — E 1.22 (I) 514.05 cyclopropyl-6-fluoro-phenyl)-piperidin-4-yl]- RT 2,4-dimethyl-2,4,5,7-tetrahydro- 3 pyrazolo[3,4-d]pyrimidin-6-one Ia-63 6-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4- E-3-5 BB-9-1 A1 1.25 (I) 606.32 yl]-7-methyl-2-(tetrahydro-pyran-2-yl)-4-(2- RT trifluoromethyl-benzyl)-2,4,6,7-tetrahydro- 18 pyrazolo[4,3-d]pyrimidin-5-one (mixture of diastereoisomers) Ia-64 6-[1-(2-Difluoromethyl-6-fluoro-phenyl)- E-3-6 BB-9-1 A1 1.24 (I) 622.34 piperidin-4-yl]-7-methyl-2-(tetrahydro- RT pyran-2-yl)-4-(2-trifluoromethyl-benzyl)- 18 2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (mixture of diastereoisomers) Ia-65 5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- E-6-11 — E 1.13 (I) 529.13 2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one Ia-66 5-[1-(2-Cyclopropyl-6-fluoro-phenyl)- E-6-12 — E 1.22 (I) 542.33 piperidin-4-yl]-2,4-dimethyl-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 2 pyrazolo[3,4-d]pyrimidin-6-one Ia-67 5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4- E-6-13 — E 1.26 (I) 562.05 yl]-2-cyclopropyl-4-methyl-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one Ia-68 2-Cyclopropyl-7-(2-cyclopropyl-benzyl)-5- E-6-14 — E 1.23 (I) 514.16 [1-(2-fluoro-6-methyl-phenyl)-piperidin-4- RT yl]-4-methyl-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one Ia-69 5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4- E-6-15 — E 1.24 (I) 534.32 yl]-2-cyclopropyl-7-(2-cyclopropyl-benzyl)- RT 4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- 18 d]pyrimidin-6-one Ia-70 2-Cyclopropyl-5-(2′-methoxy-4′-methyl- E-6-16 — E 1.16 (I) 555.35 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- RT 4-methyl-7-(2-trifluoromethyl-benzyl)- 18 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one Ia-71 5-(4′-Difluoromethyl-2′-methoxy-3,4,5,6- E-6-17 — E 1.21 (I) 565.26 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4- RT dimethyl-7-(2-trifluoromethyl-benzyl)- 16 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one Ia-72 5-[1-(2-Difluoromethyl-6-fluoro-phenyl)- E-6-18 — E 1.25 (I) 622.35 piperidin-4-yl]-4-methyl-2-(tetrahydro- RT pyran-2-yl)-7-(2-trifluoromethyl-benzyl)- 18 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (mixture of diastereoisomers) (Example 341) Ia-73 5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4- E-6-19 — E 1.27 (I) 606.26 yl]-4-methyl-2-(tetrahydro-pyran-2-yl)-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 72 pyrazolo[3,4-d]pyrimidin-6-one (mixture of diastereoisomers) (Example 342) Ia-74 5-(4′-Difluoromethyl-2′-methoxy-3,4,5,6- E-6-20 — E 1.26 (I) 635.34 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4- RT methyl-2-(tetrahydro-pyran-2-yl)-7-(2- 72 trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (mixture of diastereoisomers) (Example 343) Ia-75 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- E-6-21 — E 1.12 (I) 517.27 yl]-2,4-dimethyl-7-(3-trifluoromethyl-pyridin- RT 2-ylmethyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 18 d]pyrimidin-6-one Ia-76 5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro- E-6-22 — E 1.01 (I) 530.12 2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(3- RT trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one Ia-77 2-Cyclopropyl-5-(4′-difluoromethyl-2′- E-6-23 — E 1.23 (I) 591.28 methoxy-3,4,5,6-tetrahydro-2H- RT [1,3′]bipyridinyl-4-yl)-4-methyl-7-(2- 18 trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one Ia-78 5-[1-(2-Bromo-6-fluoro-phenyl)-piperidin-4- E-6-24 — E 1.26 (I) 606.19 yl]-2-cydopropyl-4-methyl-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one Ia-79 5-(2′-Methoxy-4′-trifluoromethyl-3,4,5,6- E-6-25 — E 1.24 (I) 583.25 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4- RT dimethyl-7-(2-trifluoromethyl-benzyl)- 18 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one Ia-80 7-(2-Cyclopropyl-benzyl)-5-(2′-methoxy-4′- E-6-26 — E 1.11 (I) 501.29 methyl-3,4,5,6-tetrahydro-2H- RT [1,3′]bipyridinyl-4-yl)-2,4-dimethyl-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one Ia-81 7-(2-Cyclopropyl-benzyl)-5-(4′- E-6-27 — E 1.19 (I) 537.25 difluoromethyl-2′-methoxy-3,4,5,6- RT tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-2,4- 72 dimethyl-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one Ia-82 7-(2-Cydopropyl-benzyl)-5-(4′- E-6-28 — E 1.24 (I) 607.35 difluoromethyl-2′-methoxy-3,4,5,6- RT tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4- 18 methyl-2-(tetrahydro-pyran-2-yl)-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (mixture of diastereoisomers) (Example 364) Ia-83 5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4- E-6-29 — E 1.25 (I) 578.16 yl]-7-(2-cyclopropyl-benzyl)-4-methyl-2- RT (tetrahydro-pyran-2-yl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one (mixture of diastereoisomers) (Example 365) Ia-84 7-(2-Cyclopropyl-benzyl)-5-(2′-methoxy-4′- E-6-30 — E 1.23 (I) 555.33 trifluoromethyl-3,4,5,6-tetrahydro-2H- RT [1,3′]bipyridinyl-4-yl)-2,4-dimethyl-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one Ia-85 5-(4′-Chloro-2′-methoxy-3,4,5,6-tetrahydro- E-6-31 — E 1.19 (I) 549.26 2H-[1,3′]bipyridinyl-4-yl)-2,4-dimethyl-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one Ia-86 5-(4′-Chloro-2′-methoxy-3,4,5,6-tetrahydro- E-6-32 — E 1.19 (I) 521.29 2H-[1,3′]bipyridinyl-4-yl)-7-(2-cyclopropyl- RT benzyl)-2,4-dimethyl-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one Ia-87 2-Cydopropyl-7-(2-cyclopropyl-benzyl)-5- E-6-33 — E 1.15 (I) 527.37 (2′-methoxy-4′-methyl-3,4,5,6-tetrahydro- RT 2H-[1,3′]bipyridinyl-4-yl)-4-methyl-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one Ia-88 2-Cydopropyl-7-(2-cyclopropyl-benzyl)-5- E-6-34 — E 1.22 (I) 563.37 (4′-difluoromethyl-2′-methoxy-3,4,5,6- RT tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4- 18 methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one Ia-89 5-[1-(2-Bromo-6-fluoro-phenyl)-piperidin-4- E-6-35 — E 1.22 (I) 552.28 yl]-7-(2-cyclopropyl-benzyl)-2,4-dimethyl- RT 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin- 1.5 6-one

Synthesis of Compounds of Formula Ib and Ic

(269) Method A (Complete SEM Cleavage)

(270) Step A (TFA Treatment):

(271) To a soln. of SEM-protected intermediate Ia (1 eq) in DCM (2 to 4 mL/mmol) was added dropwise TFA (4 to 6 mL/mmol). The soln. was stirred at RT for a given time (see Table), quenched at 0° C. with a 32% or 1M aq. soln. of NaOH until pH 7-8 and extracted with DCM. The combined org. phases were dried over MgSO.sub.4 and concentrated in vacuo.

(272) Step B (Additional Treatment):

(273) The crude was dissolved in THE (5 to 10 mL/mmol) and treated with ethylenediamine (3 eq) for 30 min to 1h at 60° C. The rxn mixture was partitioned between DCM and water and the org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by CC using Hept/EtOAc.

(274) Method B (Partial SEM Cleavage with O-Alkylation)

(275) Step a (TFA Treatment):

(276) To a soln. of SEM-protected intermediate Ia (1 eq) in DCM (2 mL/mmol) was added dropwise TFA (4 mL/mmol). The soln. was stirred at RT for a given time (see Table), quenched at 0° C. with a 32% aq. soln. of NaOH until pH 7-8 and extracted with DCM. The combined org. phases were dried over MgSO.sub.4 and concentrated in vacuo.

(277) Step B (Treatment with Alcohol):

(278) The crude was dissolved in EtOH or MeOH (5 mL/mmol) and treated with a 4M soln. of HCl in dioxane (5 mL/mmol) for 30 min at 70° C. The rxn mixture was basified with a 1M aq. soln. of NaOH until pH 8-9 and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(279) Method C (Bn Cleavage)

(280) To a soln. of Bn-protected intermediate Ia (1 eq) in EtOH (9.8 mL/mmol) was added ammonium formate (4 eq). The flask was evacuated three times and refilled with nitrogen. 10% Pd/C moistened with ˜50% water (0.1 eq) was added and the flask was evacuated and refilled with hydrogen. The rxn mixture was hydrogenated under atmospheric pressure at a given temperature for a given time (see Table). When necessary to reach completion of the rxn, extra amounts of ammonium formate (4 eq) and/or 10% Pd/C moistened with ˜50% water (0.1 eq) were added. The rxn mixture was filtered over a pad of celite and the filtrate was concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(281) Method D (THP Cleavage)

(282) To soln. of THP-protected intermediate Ia (1 eq) in DM (4 to 5 mL/mmol) was added dropwise TA (2 to 4 mL/mmol). The soln. was stirred at RT for a given time (see Table), quenched at 0° C. with a 1M aq. soln. of NaOH until pH 10-11 and extracted with DCM. The combined org. phases were dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or by prep. LC-MS using method 2, 5 or 11.

(283) TABLE-US-00061 TABLE 57 Method t.sub.R [min] MS-data Reactant T [° C.] (LC/MS m/z Ib or Ic Name Ia time [h] method) [M + H].sup.+ Ib-1 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4- Ia-1A A 1.15 (I) 488.22 (2-trifluoromethyl-benzyl)-1,4,6,7-tetrahydro- or RT pyrazolo[4,3-d]pyrimidin-5-one Ia-1B 2 or 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4- (2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Example 2) Ib-2 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- Ia-2 A 1.14 (I) 488.24 (2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- RT pyrazolo[3,4-d]pyrimidin-6-one 2.5 (Example 6) Ic-1 2-Ethoxymethyl-5-[1-(2-fluoro-6-methyl-phenyl)- Ia-2 B (EtOH)  1.08 (II) 546.02 piperidin-4-yl]-7-(2-trifluoromethyl-benzyl)- RT 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6- 1 one (Example 7) Ib-3 1-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-3- Ia-5 A (only  0.91 (II) 488.11 (2-trifluoromethyl-benzyl)-1,3,6,9-tetrahydro- step A) purin-2-one RT (Example 14) 4.5 Ib-4 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4- Ia-12 C  1.02 (II) 489.10 (2-trifluoromethyl-benzyl)-3,4,6,7-tetrahydro- 60 [1,2,3]triazolo[4,5-d]pyrimidin-5-one 48 or 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4- (2-trifluoromethyl-benzyl)-2,4,6,7-tetrahydro- [1,2,3]triazolo[4,5-d]pyrimidin-5-one (Example 76) Ib-5 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- Ia-19 A 1.04 (I) 489.22 (3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,5,7- RT tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 0.7 (Example 193) Ib-6 5-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H- Ia-20 A 1.03 (I) 501.24 [1,3′]bipyridinyl-4-yl)-7-(2-trifluoromethyl-benzyl)- RT 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6- 1 one (Example 197) Ib-7 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4- Ia-21 A 1.04 (I) 489.22 (3-trifluoromethyl-pyridin-2-ylmethyl)-2,4,6,7- RT tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one 2 (Example 204) Ib-8 7-(2-Bromo-6-trifluoromethyl-benzyl)-5-[1-(2- Ia-23 A 1.16 (I) 566.11 fluoro-6-methyl-phenyl)-piperidin-4-yl]-2,4,5,7- RT tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 0.5 (Example 211) Ib-9 6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H- Ia-24 A 1.03 (I) 501.22 [1,3′]bipyridinyl-4-yl)-4-(2-trifluoromethyl-benzyl)- RT 2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5- 2 one (Example 218) Ic-92 2-Methoxymethyl-5-(2′-methoxy-4′-methyl- Ia-20 B .sup. 1.21 (IV) 544.80 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-7-(2- (MeOH) trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- RT pyrazolo[3,4-d]pyrimidin-6-one (Example 227) 1 Ib-10 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- Ia-35 A 1.16 (I) 502.18 methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7- RT tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one 1 Ib-11 4-(2-Cyclopropyl-benzyl)-6-(2′-methoxy-4′- Ia-48 D 1.02 (I) 487.25 methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4- RT yl)-7-methyl-2,4,6,7-tetrahydro-pyrazolo[4,3- 20 d]pyrimidin-5-one Ib-12 4-(2-Cyclopropyl-benzyl)-6-[1-(2-fluoro-6-methyl- Ia-47 D 1.13 (I) 474.29 phenyl)-piperidin-4-yl]-7-methyl-2,4,6,7- RT tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one 20 Ib-13 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4-yl]-4- Ia-51 D 1.14 (I) 502.33 methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7- RT tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 20 Ib-14 6-(2′-Methoxy-4′-methyl-3,4,5,6-tetrahydro-2H- Ia-53 D 1.03 (I) 515.31 [1,3′]bipyridinyl-4-yl)-7-methyl-4-(2- RT trifluoromethyl-benzyl)-2,4,6,7-tetrahydro- 2 pyrazolo[4,3-d]pyrimidin-5-one Ib-15 6-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-7- Ia-63 D 1.17 (I) 522.19 methyl-4-(2-trifluoromethyl-benzyl)-2,4,6,7- RT tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one 1.5 Ib-16 6-[1-(2-Difluoromethyl-6-fluoro-phenyl)-piperidin- Ia-64 D 1.16 (I) 538.21 4-yl]-7-methyl-4-(2-trifluoromethyl-benzyl)- RT 2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5- 1.5 one Ib-17 5-[1-(2-Difluoromethyl-6-fluoro-phenyl)-piperidin- Ia-72 D 1.15 (I) 538.19 4-yl]-4-methyl-7-(2-trifluoromethyl-benzyl)- RT 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6- 18 one Ib-18 5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-4- Ia-73 D 1.16 (I) 522.17 methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7- RT tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 18 Ib-19 5-(4′-Difluoromethyl-2′-methoxy-3,4,5,6- Ia-74 D 1.14 (I) 551.23 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-4-methyl-7- RT (2-trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one Ib-20 7-(2-Cyclopropyl-benzyl)-5-(4′-difluoromethyl-2′- Ia-82 D 1.12 (I) 523.30 methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl- RT 4-yl)-4-methyl-2,4,5,7-tetrahydro-pyrazolo[3,4- 3 d]pyrimidin-6-one Ib-21 5-[1-(2-Chloro-6-fluoro-phenyl)-piperidin-4-yl]-7- Ia-83 D 1.15 (I) 494.22 (2-cyclopropyl-benzyl)-4-methyl-2,4,5,7- RT tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one 6

Synthesis of Compounds of Formula Ic, Id and Ie

(284) Method a (Methylation Using Silver Carbonate)

(285) To a suspension of intermediate Ib (1 eq) and silver carbonate (1.2 eq) in toluene (6 mL/mmol) was added MeI (5 eq) and the rxn mixture was stirred at 85° C. for a given time (see Table). It was filtered and the filtrate was concentrated in vacuo. The crude was purified by CC using DCM/MeOH. When necessary, an additional purification by prep. LC-MS using methods 1, 3 or 4 was performed.

(286) Method B (Alkylation Using NaH and Halide or Aziridine)

(287) Method B1: A soln. or suspension of intermediate Ib (1 eq) in anh. THE (6 to 10 mL/mmol) was added dropwise at 0° C. to a suspension of NaH (2.2 to 4 eq, as a 60% dispersion in mineral oil) in anh. THE (4 to 6 mL/mmol).

(288) Method B2: NaH (4 eq, as a 60% dispersion in mineral oil) was added portionwise at 0° C. to a soln. or suspension of intermediate Ib (1 eq) in THE (10 to 13 mL/mmol).

(289) Common following procedure: The suspension was stirred for 10 to 30 min at RT, cooled to 0° C. and halide or aziridine BB-10 (1.2 to 3 eq) was added. The rxn mixture was stirred at a given temperature for a given time (see Table). When necessary to reach completion of the rxn, extra amounts of NaH (1 to 2 eq) and/or halide or aziridine BB-10 (1 eq) were added. The rxn mixture was quenched with H.sub.2O at 0° C. and extracted with EtOAc or DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc and/or DCM/MeOH.

(290) Method C (Alkylation Using Mitsunobu Conditions)

(291) To a soln. or suspension of intermediate Ib (1 eq) and alcohol BB-10 (1.5 to 2 eq) in toluene (6 to 12 mL/mmol) was added a 1M soln. of (tributylphosphoranylidene)acetonitrile in toluene (2 eq) under argon. The rxn mixture was heated to a given temperature and stirred for a given time (see Table). It was quenched with water and extracted with EtOAc or DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH. When necessary, an additional purification by prep. LC-MS using methods 2, 4, 5, 8 or 10 was performed.

(292) Method D (Methylation Using DBU)

(293) To a soln. of intermediate Ib (1 eq) and DBU (1.2 eq) in anh. DMF (4 mL/mmol) was added MeI (1.3 eq). The rxn mixture was stirred at RT for a given time (see Table) and evaporated under reduced pressure. The residue was purified by prep. LC-MS using methods 2, 4 and/or 5.

(294) Method E (Alkylation Using K.sub.2CO.sub.3 and Halide or Epoxide)

(295) A mixture of compound Ib (1 eq), K.sub.2CO.sub.3 (1.5 to 5 eq) and epoxide or halide BB-10 (2 to 5 eq) in DMF (5 to 8.5 mL/mmol) was heated to a given temperature and stirred for a given time (see Table). When necessary to reach completion of the rxn an extra amount of epoxide or halide BB-10 (1 eq) was added and the rxn mixture was further stirred for 2h at 120° C. It was partitioned between EtOAc and H.sub.2O and the org. phase was washed with H.sub.2O and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(296) Method F (1,4-Nucleophilic Addition Using K.sub.2CO.sub.3)

(297) A mixture of compound Ib (1 eq), α,β-unsaturated carbonyl reagent BB-10 (2 eq), K.sub.2CO.sub.3 (1.5 eq) and TEA (3 eq) in THE (10 mL/mmol) was heated to 60° C. and stirred for a given time (see Table). It was partitioned between DCM and H.sub.2O and the org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(298) Method G (1,4-Nucleophilic Addition Using CsF)

(299) To a soln. of compound Ib (1 eq) in DMF (10 mL/mmol) was added nitroalkene BB-10 (1 eq) and CsF (1.2 eq) at 0° C. The rxn mixture was stirred for 30 min at 0° C. and at RT for a given time (see Table). Consecutive additions of BB-10 (1 eq) and CsF (1 eq) at 0° C. were necessary to allow the rxn to proceed. It was partitioned between EtOAc and H.sub.2O and the org. phase was washed with H.sub.2O and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by prep LC-MS using method 4.

(300) Method H (Alkoxycarbonylation/Alkylcarbamylation)

(301) A soln. of compound Ib (1 eq) and TEA (3 eq) in DCM (8.1 mL/mmol) was cooled to 0° C. and chloroformate or isocyanate BB-10 (2 eq) was added dropwise at 0° C. The rxn mixture was allowed to slowly reach RT and stirred for a given time (see Table). It was diluted with DCM and washed with a sat. aq. soln. of NaHCO.sub.3 and with brine. The org. phase was dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(302) Method I (Urea Formation)

(303) A soln. of compound Ib (1 eq) and TEA (3 eq) in THE (10 mL/mmol) was treated with CDI (1.2 eq) and the rxn mixture was stirred at RT for 15 min. Amine BB-10 (3 to 5 eq) was added at RT and the mixture was stirred at a given temperature for a given time (see Table). The rxn mixture was partitioned between DCM and a half sat. aq. soln. of NaHCO.sub.3 and the org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(304) Method J1 (Chan-Lam rxn 1)

(305) A mixture of compound Ib (1 eq), boron species BB-10 (2 eq), Na.sub.2CO.sub.3 (2 eq), 2,2′-bipyridyl (1 eq) and Cu(OAc).sub.2 (1 eq) in toluene (10 to 12 mL/mmol) was flushed with N.sub.2 and heated at a given temperature for a given time (see Table). When necessary to reach completion of the rxn an extra amount of boron species BB-10 (2 eq) was added. It was partitioned between EtOAc or DCM and a sat. aq. soln. of NaHCO.sub.3 and the org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH and/or by prep. HPLC using method 3 or 5.

(306) Method J2 (Chan-Lam rxn 2)

(307) A suspension of 2,2-bipyridyl(1 eq) and Cu(OAc).sub.2(1 eq) in trifluorobenzene (3 mL/mmol) was heated to 70° C. and stirred for 30 min. It was added at RT to a mixture of compound Ib (1 eq), boron species BB-10 (2 eq) and Na.sub.2CO.sub.3 (2 eq) in trifluoromethylbenzene (1.5 mL/mmol). The rxn mixture was heated to 110° C. and stirred for a given time (see Table). It was diluted with EtOAc and washed with a 10% soln. of citric acid. The org. phase was washed with brine dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by prep. LC-MS using method 4.

(308) Method K (Alkylation Using Cs.sub.2CO.sub.3 and Tosylate)

(309) A mixture of compound Ib (1 eq), tosylate BB-10 (1.05 to 1.5 eq) and Cs.sub.2CO.sub.3 (2 to 2.3 eq) in DMA (5 to 7 mL/mmol) was heated at a given temperature for a given time (see Table). It was partitioned between EtOAc and water and the org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or/and by prep. LC-MS using method 4 or 5.

(310) TABLE-US-00062 TABLE 60 Method t.sub.R [min] MS-data Reactant Reactant T [° C.] (LC/MS- m/z Ic/Id/Ie Name Ib BB-10 time [h] method) [M + H].sup.+ Ic-2 6-[1-(2-Fluoro-6-methyl-phenyl)- Ib-1  MeI A 1.08 502.27 piperidin-4-yl]-2-methyl-4-(2- 85  (II) trifluoromethyl-benzyl)-2,4,6,7-  0.25 tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 3) Id-1 6-[1-(2-Fluoro-6-methyl-phenyl)- 1.07 502.70 piperidin-4-yl]-1-methyl-4-(2- (II) trifluoromethyl-benzyl)-1,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 4) Ic-3 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  MeI B1 1.22 502.16 piperidin-4-yl]-2-methyl-7-(2- RT (I) trifluoromethyl-benzyl)-2,4,5,7- 1.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 8) Ic-4 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  CD.sub.3OD C 1.20 505.27 piperidin-4-yl]-2-[.sup.2H.sub.3]methyl-7-(2- 110   (I) trifluoromethyl-benzyl)-2,4,5,7- 1  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 9) Ie-1 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  MeI A 1.11 502.10 piperidin-4-yl]-1-methyl-7-(2- 85  (II) trifluoromethyl-benzyl)-1,4,5,7- 3  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 10) Id-2 1-[1-(2-Fluoro-6-methyl-phenyl)- Ib-3  MeI D 0.99 502.11 piperidin-4-yl]-7-methyl-3-(2- RT (II) trifluoromethyl-benzyl)-1,3,6,7- 18  tetrahydro-purin-2-one (Example 16) Ic-5 [5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  Bromoacetic acid B1 1.05 560.09 piperidin-4-yl]-6-oxo-7-(2- methyl ester RT (II) trifluoromethyl-benzyl)-4,5,6,7- 1.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-acetic acid methyl ester (Example 17) Ic-6 [6-[1-(2-Fluoro-6-methyl-phenyl)- Ib-1  Bromoacetic acid B1 1.04 560.19 piperidin-4-yl]-5-oxo-4-(2- methyl ester RT (II) trifluoromethyl-benzyl)-4,5,6,7- 4  tetrahydro-pyrazolo[4,3-d]pyrimidin- 2-yl]-acetic acid methyl ester (Example 18) Id-3 [6-[1-(2-Fluoro-6-methyl-phenyl)- 1.04 560.19 piperidin-4-yl]-5-oxo-4-(2- (II) trifluoromethyl-benzyl)-4,5,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin- 1-yl]-acetic acid methyl ester (Example 19) Ic-8 [5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  Bromo B1 1.04 527.12 piperidin-4-yl]-6-oxo-7-(2- acetonitrile RT (II) trifluoromethyl-benzyl)-4,5,6,7-  0.25 tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-acetonitrile (Example 24) Ic-9 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2,2-Dimethyl E 1.18 560.16 piperidin-4-yl]-2-(2-hydroxy-2- oxirane 100   (I) methyl-propyl)-7-(2-trifluoromethyl- 18  benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 25) Ic-10 2-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-Bromo-2-methyl B1 1.10 588.08 piperidin-4-yl]-6-oxo-7-(2- propanoic acid 60  (II) trifluoromethyl-benzyl)-4,5,6,7- methyl ester 18  tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-2-methyl-propionic acid methyl ester (Example 27) Ic-11 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- 1.09 588.12 piperidin-4-yl]-6-oxo-7-(2- (II) trifluoromethyl-benzyl)-4,5,6,7- tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-2-methyl-propionic acid methyl ester (Example 31) Ic-12 2-(2,2-Diethoxy-ethyl)-5-[1-(2-fluoro- Ib-2  Bromo B1 1.11 604.06 6-methyl-phenyl)-piperidin-4-yl]-7- acetaldehyde 70  (II) (2-trifluoromethyl-benzyl)-2,4,5,7- diethyl acetal 192   tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 28) Ic-13 2-(2,3-Dihydroxy-propyl)-5-[1-(2- Ib-2  Oxiran-2-yl E 0.95 561.98 fluoro-6-methyl-phenyl)-piperidin-4- methanol 100   (II) yl]-7-(2-trifluoromethyl-benzyl)- 1  2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 40) Ic-14 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  (S)-2-(Methoxy E 1.02 576.10 piperidin-4-yl]-2-((R)-2-hydroxy-3- methyl)oxirane 100   (II) methoxy-propyl)-7-(2- 5  trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 41) Ic-15 2-Chloro-3-[5-[1-(2-fluoro-6-methyl- Ib-2  2-Chloro acrylic F 1.09 608.01 phenyl)-piperidin-4-yl]-6-oxo-7-(2- acid methyl ester 60  (II) trifluoromethyl-benzyl)-4,5,6,7- 24  tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-propionic acid methyl ester (Example 42) Ic-16 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-Chloro-2-methyl E 1.07 555.12 piperidin-4-yl]-6-oxo-7-(2- propanenitrile 100   (II) trifluoromethyl-benzyl)-4,5,6,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-2-methyl-propionitrile (Example 43) Ic-17 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  (R)-2-(methoxy E 1.02 576.11 piperidin-4-yl]-2-((S)-2-hydroxy-3- methyl)oxirane 100 (II) methoxy-propyl)-7-(2- 4  trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 46) Ic-18 2-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-Bromo B1 1.01 559.19 piperidin-4-yl]-6-oxo-7-(2- propionamide RT (II) trifluoromethyl-benzyl)-4,5,6,7- 2  tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-propionamide (Example 75) Ic-19 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  Oxetan-3-ol C 1.08 544.18 piperidin-4-yl]-2-oxetan-3-yl-7-(2- 110   (II) trifluoromethyl-benzyl)-2,4,5,7- 1.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 77) Ic-20 6-[1-(2-Fluoro-6-methyl-phenyl)- Ib-4  MeI B2 1.10 503.15 piperidin-4-yl]-2-methyl-4-(2- RT (II) trifluoromethyl-benzyl)-2,4,6,7- 2  tetrahydro-[1,2,3]triazolo[4,5- d]pyrimidin-5-one (Example 81) Ic-21 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  1-Nitro-1- G 1.12 615.13 piperidin-4-yl]-2-(2-nitro-cyclohexyl)- cyclohexane RT (II) 7-(2-trifluoromethyl-benzyl)-2,4,5,7- 72  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 82) Ic-22 {2,2,2-Trifluoro-1-[5-[1-(2-fluoro-6- Ib-2  BB-10-1 E 1.14 699.20 methyl-phenyl)-piperidin-4-yl]-6-oxo- 80  (II) 7-(2-trifluoromethyl-benzyl)-4,5,6,7- 24  tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-1-methyl-ethyl}-carbamic acid tert-butyl ester (Example 83) Ic-23 2-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2 2-Bromo-2-methyl B2 1.04 573.09 piperidin-4-yl]-6-oxo-7-(2- propionamide RT (II) trifluoromethyl-benzyl)-4,5,6,7- 168   tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-isobutyramide (Example 84) Ic-24 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  3-Hydroxy C 1.12 643.17 piperidin-4-yl]-6-oxo-7-(2- azetidine-1- 100   (II) trifluoromethyl-benzyl)-4,5,6,7- carboxylic acid tert- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin- butyl ester 2-yl]-azetidine-1-carboxylic acid tert- butyl ester (Example 91) Ic-25 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  3-Hydroxy- C 1.13 657.20 piperidin-4-yl]-6-oxo-7-(2- pyrrolidine-1- 110   (II) trifluoromethyl-benzyl)-4,5,6,7- carboxylic acid tert- 1  tetrahydro-pyrazolo[3,4-d]pyrimidin- butyl ester 2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (Example 93) Ic-26 2-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-Hydroxy methyl- C 1.13 657.18 piperidin-4-yl]-6-oxo-7-(2- azetidine-1- 100   (II) trifluoromethyl-benzyl)-4,5,6,7- carboxylic acid tert- 0.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- butyl ester 2-ylmethyl]-azetidine-1-carboxylic acid tert-butyl ester Ic-27 2-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-Hydroxy methyl- C 1.14 671.17 piperidin-4-yl]-6-oxo-7-(2- pyrrolidine-1- 110   (II) trifluoromethyl-benzyl)-4,5,6,7- carboxylic acid tert- 1  tetrahydro-pyrazolo[3,4-d]pyrimidin- butyl ester 2-ylmethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (Example 97) Ic-28 {2-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  (2-Hydroxy- C 1.14 671.21 piperidin-4-yl]-6-oxo-7-(2- cyclopentyl)- 110   (II) trifluoromethyl-benzyl-)-4,5,6,7- carbamic acid tert- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin- butyl ester 2-yl]-cyclopentyl}-carbamic acid tert- butyl ester (Example 98) Ic-29 4-Chloro-N-{2-[5-[1-(2-fluoro-6- Ib-2  BB-10-2 B2 1.13 733.18 methyl-phenyl)-piperidin-4-yl]-6-oxo- 70  (II) 7-(2-trifluoromethyl-benzyl)-4,5,6,7- 3.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-1,1-dimethyl-ethyl}- benzenesulfonamide (Example 101) Ic-30 (R)-4,4-Difluoro-2-[5-[1-(2-fluoro-6- Ib-2  (R)-4,4-Difluoro-2- C 1.30 707.14 methyl-phenyl)-piperidin-4-yl]-6-oxo- hydroxy methyl- 110   (I) 7-(2-trifluoromethyl-benzyl)-4,5,6,7- pyrrolidine-1- 1 tetrahydro-pyrazolo[3,4-d]pyrimidin- carboxylic acid tert- 2-ylmethyl]-pyrrolidine-1-carboxylic butyl ester acid tert-butyl ester (Example 108) Ic-31 (S)-4,4-Difluoro-2-[5-[1-(2-fluoro-6- Ib-2  (S)-4,4-Difluoro-2- C 1.30 707.16 methyl-phenyl)-piperidin-4-yl]-6-oxo- hydroxy methyl- 110   (I) 7-(2-trifluoromethyl-benzyl)-4,5,6,7- pyrrolidine-1- 1 tetrahydro-pyrazolo[3,4-d]pyrimidin- carboxylic acid tert- 2-ylmethyl]-pyrrolidine-1-carboxylic butyl ester acid tert-butyl ester (Example 109) Ic-32 N-{2-[5-[1-(2-Fluoro-6-methyl- Ib-2  BB-10-3 B2 1.26 744.23 phenyl)-piperidin-4-yl]-6-oxo-7-(2- RT (I) trifluoromethyl-benzyl)-4,5,6,7- 24  tetrahydro-pyrazolo[3,4-d]pyrimidin- 2-yl]-1,1-dimethyl-ethyl}-2-nitro- benzenesulfonamide (Example 110) Ic-33 (S)-2-[5-(1-(2-Fluoro-6-methyl- Ib-2  (S)-2-Hydroxy- C 1.28 657.21 phenyl)-piperidin-4-yl]-6-oxo-7-(2- methyl-azetidine-1- 110   (I) trifluoromethyl-benzyl)-4,5,6,7- carboxylic acid tert-  1.25 tetrahydro-pyrazolo[3,4-d]pyrimidin- butyl ester 2-ylmethyl]-azetidine-1-carboxylic acid tert-butyl ester (Example 121) Ic-34 (R)-2-[5-[1-(2-Fluoro-6-methyl- Ib-2  (R)-2-Hydroxy C 1.30 657.22 phenyl)-piperidin-4-yl]-6-oxo-7-(2- methyl-azetidine-1- 110   (I) trifluoromethyl-benzyl)-4,5,6,7- carboxylic acid tert- 1.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- butyl ester 2-ylmethyl]-azetidine-1-carboxylic acid tert-butyl ester (Example 129) Ic-35 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  Isopropyl H 1.27 574.10 piperidin-4-yl]-6-oxo-7-(2- chloroformate (1M RT (I) trifluoromethyl-benzyl)-4,5,6,7- soln. In toluene) 1  tetrahydro-pyrazolo[3,4- d]pyrimidine-2-carboxylic acid isopropyl ester (Example 147) Ic-36 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  Isobutyl H 1.30 588.12 piperidin-4-yl]-6-oxo-7-(2- chloroformate RT (I) trifluoromethyl-benzyl)-4,5,6,7- 1.5 tetrahydro-pyrazolo[3,4- d]pyrimidine-2-carboxylic acid isobutyl ester (Example 148) Ic-37 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  Dimethylamine (2M I 1.25 559.11 piperidin-4-yl]-6-oxo-7-(2- soln. in THF) RT (I) trifluoromethyl-benzyl)-4,5,6,7- 18  tetrahydro-pyrazolo[3,4- d]pyrimidine-2-carboxylic acid dimethylamide (Example 149) Ic-38 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  Isobutyl-methyl- I 1.32 601.11 piperidin-4-yl]-6-oxo-7-(2- amine RT (I) trifluoromethyl-benzyl)-4,5,6,7- tetrahydro-pyrazolo[3,4- d]pyrimidine-2-carboxylic acid isobutyl-methyl-amide (Example 150) Ic-39 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  3-Bromo-1- B2 1.17 585.20 piperidin-4-yl]-2-(1-methyl-2-oxo- methylpyrrolidin-2- RT (I) pyrrolidin-3-yl)-7-(2-trifluoromethyl- one 0.5 benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 151) Ic-40 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  3-Bromo-1-(propan- B2 1.22 613.24 piperidin-4-yl]-2-(1-isopropyl-2-oxo- 2-yl)pyrrolidin-2- RT (I) pyrrolidin-3-yl)-7-(2-trifluoromethyl- one 0.5 benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 152) Ic-41 5-[1-(2-Fluoro-6-methyl-phenyl)- piperidin-4-yl]-2-[2- ([.sup.2H.sub.3]methyl)[1,1,2,3,3,3-.sup.2H.sub.6]propyl]- 7-(2-trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 156) Ib-2  C 110   2.5 1.27 (I) 553.24 Ic-42 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  BB-10-4 E 1.35 799.16 piperidin-4-yl]-2-(2-oxo-1-trityl- 150   (I) azetidin-3-yl)-7-(2-trifluoromethyl- 1.5 benzyl)-2,4,5,7-tetrahydro- (microwave) pyrazolo[3,4-d]pyrimidin-6-one Ic-43 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  (1-Methyl- C 1.28 556.14 piperidin-4-yl]-2-(1-methyl- cyclopropyl)- 110   (I) cyclopropylmethyl)-7-(2- methanol 1 trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 158) Ic-44 2-(2,2-Difluoro-ethyl)-5-[1-(2-fluoro- Ib-2  2,2-Difluoroethanol C 1.21 552.07 6-methyl-phenyl)-piperidin-4-yl]-7- 110   (I) (2-trifluoromethyl-benzyl)-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 159) Ic-45 2-(1,1-Dimethyl-prop-2-ynyl)-5-[1- Ib-2  2-Methyl-3-butyn-2- C 1.28 554.13 (2-fluoro-6-methyl-phenyl)-piperidin- ol 110   (I) 4-yl]-7-(2-trifluoromethyl-benzyl)- 18  2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 160) Ic-46 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-Propanol C 1.26 530.12 piperidin-4-yl]-2-isopropyl-7-(2- 110   (I) trifluoromethyl-benzyl)-2,4,5,7- 1  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 161) Ic-47 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-[1,1,1,2,3,3,3- C 1.26 537.31 piperidin-4-yl]-2-([1,1,1,2,3,3,3- .sup.2H.sub.7]Propan[.sup.2H]ol 110   (I) .sup.2H.sub.7]propan-2-yl)-7-(2- 1.5 trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 162) Ic-48 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-[1,1,1,3,3,3- C 1.26 536.30 piperidin-4-yl]-2-([1,1,1,3,3,3- .sup.2H.sub.6]Propanol 110   (I) .sup.2H.sub.6]propan-2-yl)-7-(2- 1.5 trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 163) Ic-49 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  (3-Fluoro-oxetan-3- C 1.20 576.12 piperidin-4-yl]-2-(3-fluoro-oxetan-3- yl)-methanol 110   (I) ylmethyl)-7-(2-trifluoromethyl- 1.5 benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 164) Ic-50 2-Cyclopropylmethyl-5-[1-(2-fluoro- Ib-2  Cyclopropyl- C 1.26 542.09 6-methyl-phenyl)-piperidin-4-yl]-7- methanol 110   (I) (2-trifluoromethyl-benzyl)-2,4,5,7- 1  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 165) Ie-2 1-Cyclopropylmethyl-5-[1-(2-fluoro- 1.24 542.30 6-methyl-phenyl)-piperidin-4-yl]-7- (I) (2-trifluoromethyl-benzyl)-1,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 210) Ic-52 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  (3-Methyl-oxetan-3- C 1.23 572.12 piperidin-4-yl]-2-(3-methyl-oxetan-3- yl)-methanol 110   (I) ylmethyl)-7-(2-trifluoromethyl- 1  benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 166) Ic-53 2-(1-Fluoro-cyclopropylmethyl)-5-[1- Ib-2  (1-Fluoro- C 1.25 560.22 (2-fluoro-6-methyl-phenyl)-piperidin- cyclopropyl)- 110   (I) 4-yl]-7-(2-trifluoromethyl-benzyl)- methanol 2  2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 167) Ic-54 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-Fluoro-2- C 1.27 562.23 piperidin-4-yl]-2-(2-fluoro-2-methyl- methylpropan-1-ol 110   (I) propyl)-7-(2-trifluoromethyl-benzyl)- 2  2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 168) Ic-55 2-Ethyl-5-[1-(2-fluoro-6-methyl- Ib-2  Ethanol C 1.23 516.03 phenyl)-piperidin-4-yl]-7-(2- 110   (I) trifluoromethyl-benzyl)-2,4,5,7- 1  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 169) Ic-56 2-[1,1,2,2,2-.sup.2H.sub.5]Ethyl-5-[1-(2-fluoro- 6-methyl-phenyl)-piperidin-4-yl]-7- (2-trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 170) Ib-2  C 110   2  1.24 (I) 521.27 Ic-57 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  3-Hydroxy methyl- C 1.12 574.22 piperidin-4-yl]-2-(3-hydroxy-oxetan- oxetan-3-ol 110   (I) 3-ylmethyl)-7-(2-trifluoromethyl- 1  benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 171) Ic-58 2-(2,2-Difluoro-propyl)-5-[1-(2- Ib-2  2,2-Difluoro C 1.24 566.14 fluoro-6-methyl-phenyl)-piperidin-4- propanol 110   (I) yl]-7-(2-trifluoromethyl-benzyl)- 5  2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 172) Ic-59 2-tert-Butyl-5-[1-(2-fluoro-6-methyl- Ib-2  tert-Butanol C 1.30 544.29 phenyl)-piperidin-4-yl]-7-(2- 110   (I) trifluoromethyl-benzyl)-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 173) Ic-60 2-Cyclopropyl-5-[1-(2-fluoro-6- Ib-2  Cyclopropyl boronic J 1.22 528.26 methyl-phenyl)-piperidin-4-yl]-7-(2- acid 70  (I) trifluoromethyl-benzyl)-2,4,5,7- 18  tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 174) Ic-61 2-Cyclopropyl-6-[1-(2-fluoro-6- Ib-1  Cyclopropyl boronic J 1.22 528.17 methyl-phenyl)-piperidin-4-yl]-4-(2- acid 90  (I) trifluoromethyl-benzyl)-2,4,6,7- 18  tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 175) Ic-62 6-[1-(2-Fluoro-6-methyl-phenyl)- Ib-1  2-Fluoro-2- C 1.22 562.14 piperidin-4-yl]-2-(2-fluoro-2-methyl- methylpropan-1-ol 100   (I) propyl)-4-(2-trifluoromethyl-benzyl)- 2  2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Example 176) Id-4 6-[1-(2-Fluoro-6-methyl-phenyl)- 1.22 562.13 piperidin-4-yl]-1-(2-fluoro-2-methyl- (I) propyl)-4-(2-trifluoromethyl-benzyl)- 1,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Example 177) Ic-64 2-Cyclopropylmethyl-6-[1-(2-fluoro- Ib-1  Cyclopropyl C 1.24 542.28 6-methyl-phenyl)-piperidin-4-yl]-4- methanol 100   (I) (2-trifluoromethyl-benzyl)-2,4,6,7- 1  tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 178) Id-5 1-Cyclopropylmethyl-6-[1-(2-fluoro- 1.23 542.27 6-methyl-phenyl)-piperidin-4-yl]-4- (I) (2-trifluoromethyl-benzyl)-1,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 179) Ic-66 6-[1-(2-Fluoro-6-methyl-phenyl)- Ib-1  (1-Methyl- C 1.25 556.20 piperidin-4-yl]-2-(1-methyl- cyclopropyl)- 100   (I) cyclopropylmethyl)-4-(2- methanol 1  trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 180) Id-6 6-[1-(2-Fluoro-6-methyl-phenyl)- 1.24 556.20 piperidin-4-yl]-1-(1-methyl- (I) cyclopropylmethyl)-4-(2- trifluoromethyl-benzyl)-1,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 181) Ic-68 2-Ethyl-6-[1-(2-fluoro-6-methyl- Ib-1  Ethanol C 1.22 516.26 phenyl)-piperidin-4-yl]-4-(2- 100   (I) trifluoromethyl-benzyl)-2,4,6,7- 1  tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 182) Ic-69 2-tert-Butyl-6-[1-(2-fluoro-6-methyl- Ib-1  tert-Butanol C 1.26 544.30 phenyl)-piperidin-4-yl]-4-(2- 100   (I) trifluoromethyl-benzyl)-2,4,6,7- 48  tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 183) Ic-70 2-(1-Fluoro-cyclopropylmethyl)-6-[1- Ib-1  (1-Fluoro- C 1.21 560.26 (2-fluoro-6-methyl-phenyl)-piperidin- cyclopropyl)- 100   (I) 4-yl]-4-(2-trifluoromethyl-benzyl)- methanol 1  2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Example 184) Ic-71 5-[1-(2-Fluoro-6-methyl-phenyl)- Ib-2  2-Fluoro C 1.22 548.15 piperidin-4-yl]-2-(2-fluoro-propyl)-7- propan-1-ol 100   (I) (2-trifluoromethyl-benzyl)-2,4,5,7- 2.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one Ic-72 2-(2,2-Difluoro-1-methyl-ethyl)-5-[1- Ib-2  1,1-Difluoro C 1.23 566.13 (2-fluoro-6-methyl-phenyl)-piperidin- propan-2-ol 100   (I) 4-yl]-7-(2-trifluoromethyl-benzyl)- 18  2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one Ic-73 2-(2,2-Difluoro-cyclopropylmethyl)- Ib-2  (2,2-Difluoro- C 1.24 578.23 5-[1-(2-fluoro-6-methyl-phenyl)- cyclopropyl)- 100   (I) piperidin-4-yl]-7-(2-trifluoromethyl- methanol 2.5 benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one Ic-74 6-[1-(2-Fluoro-6-methyl-phenyl)- Ib-1  2-Isopropenyl- J 1.26 528.23 piperidin-4-yl]-2-isopropenyl-4-(2- 4,4,5,5-tetramethyl- 70  (I) trifluoromethyl-benzyl)-2,4,6,7- [1,3,2]dioxaborolane 18  tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 192) Ic-75 2-(2,2-Difluoro-propyl)-5-[1-(2- Ib-5  2,2-Difluoro C 1.17 567.25 fluoro-6-methyl-phenyl)-piperidin-4- propanol 110   (I) yl]-7-(3-trifluoromethyl-pyridin-2- 4  ylmethyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 194) Ic-76 2-(2,2-Difluoro-propyl)-6-[1-(2- Ib-1  2,2-Difluoro C 1.20 566.02 fluoro-6-methyl-phenyl)-piperidin-4- propanol 110   (I) yl]-4-(2-trifluoromethyl-benzyl)- 20  2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Example 198) Ic-77 2-(1-Fluoro-cyclopropylmethyl)-5-[1- Ib-5  (1-Fluoro- C 1.16 561.12 (2-fluoro-6-methyl-phenyl)-piperidin- cyclopropyl)- 110   (I) 4-yl]-7-(3-trifluoromethyl-pyridin-2- methanol 2  ylmethyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 200) Ic-78 2-(1-Fluoro-cyclopropylmethyl)-5- Ib-6  (1-Fluoro- C 1.16 573.27 (2′-methoxy-4′-methyl-3,4,5,6- cyclopropyl)- 110   (I) tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- methanol 2.5 7-(2-trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 201) Ic-79 2-(2,2-Difluoro-propyl)-5-(2′- Ib-6  2,2-Difluoro C 1.17 579.29 methoxy-4′-methyl-3,4,5,6- propanol 110   (I) tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- 18  7-(2-trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 205) Ic-80 2-Cyclopropyl-5-[1-(2-fluoro-6- Ib-5  Cyclopropyl boronic J 1.17 529.17 methyl-phenyl)-piperidin-4-yl]-7-(3- acid 70  (I) trifluoromethyl-pyridin-2-ylmethyl)- 18  2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-5-one (Example 206) Ic-81 2-(2,2-Difluoro-propyl)-6-[1-(2- Ib-7  2,2-Difluoro C 1.13 567.23 fluoro-6-methyl-phenyl)-piperidin-4- propanol 100   (I) yl]-4-(3-trifluoromethyl-pyridin-2- 18  ylmethyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Example 207) Ic-82 2-(1-Fluoro-cyclopropylmethyl)-6-[1- Ib-7  (1-Fluoro- C 1.14 561.21 (2-fluoro-6-methyl-phenyl)-piperidin- cyclopropyl)- 100   (I) 4-yl]-4-(3-trifluoromethyl-pyridin-2- methanol 1  ylmethyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Example 208) Ic-83 2-Cyclopropyl-5-(2′-methoxy-4′- Ib-6  Cyclopropyl boronic J 1.17 541.22 methyl-3,4,5,6-tetrahydro-2H- acid 70  (I) [1,3′]bipyridinyl-4-yl)-7-(2- 18  trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 209) Ic-84 2-Cyclopropyl-6-[1-(2-fluoro-6- Ib-7  Cyclopropyl boronic J 1.13 529.13 methyl-phenyl)-piperidin-4-yl]-4-(3- acid 70  (I) trifluoromethyl-pyridin-2-ylmethyl)- 3.5 2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Example 212) Id-7 1-Cyclopropyl-6-[1-(2-fluoro-6 1.13 529.08 methyl-phenyl)-piperidin-4-yl]-4-(3- (I) trifluoromethyl-pyridin-2-ylmethyl)- 1,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Example 215) Ic-86 7-(2-Bromo-6-trifluoromethyl- Ib-8  Cyclopropyl boronic J 1.24 606.10 benzyl)-2-cyclopropyl-5-[1-(2-fluoro- acid 70  (I) 6-methyl-phenyl)-piperidin-4-yl]- 2  2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 213) Ic-87 7-(2-Bromo-6-trifluoromethyl- Ib-8  2,2-Difluoro C 1.23 643.87 benzyl)-2-(2,2-difluoro-propyl)-5-[1- propanol 100   (I) (2-fluoro-6-methyl-phenyl)-piperidin- 3  4-yl]-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 214) Ic-88 2-(2,2-Difluoro-propyl)-6-(2′- Ib-9  2,2-Difluoro C 1.13 579.24 methoxy-4′-methyl-3,4,5,6- propanol 100   (I) tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- 48  4-(2-trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 219) Ic-89 2-(1-Fluoro-cyclopropylmethyl)-6- Ib-9  (1-Fluoro- C 1.13 573.27 (2′-methoxy-4′-methyl-3,4,5,6- cyclopropyl)- 110   (I) tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- methanol 2.5 4-(2-trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 222) Ic-90 2-Cyclopropyl-6-(2′-methoxy-4′- Ib-9  Cyclopropyl boronic J 1.14 541.28 methyl-3,4,5,6-tetrahydro-2H- acid 70  (I) [1,3′]bipyridinyl-4-yl)-4-(2- 4  trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 223) Ic-91 6-(2′-Methoxy-4′-methyl-3,4,5,6- Ib-9  Methyl 4- K 1.11 515.26 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- toluenesulfonate 100   (I) 2-methyl-4-(2-trifluoromethyl- 3  benzyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Example 224) Id-8 2-(2,2-Difluoro-propyl)-6-[1-(2- Ib-7  2,2-Difluoropropyl K 1.14 567.20 fluoro-6-methyl-phenyl)-piperidin-4- 4-methyl benzene 60  (I) yl]-4-(3-trifluoromethyl-pyridin-2- sulfonate 18  ylmethyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Example 239) Ic-93 2-(2,2-Difluoro-propyl)-6-[1-(2- Ib-10 2,2-Difluoropropyl K 1.21 580.23 fluoro-6-methyl-phenyl)-piperidin-4- 4-methyl benzene 100   (I) yl]-7-methyl-4-(2-trifluoromethyl- sulfonate 2  benzyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one Id-9 1-(2,2-Difluoro-propyl)-6-[1-(2- 1.20 580.22 fluoro-6-methyl-phenyl)-piperidin-4- (I) yl]-7-methyl-4-(2-trifluoromethyl- benzyl)-1,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one Ic-94 2-Cyclopropyl-6-[1-(2-fluoro-6- Ib-10 Cyclopropyl boronic J 1.22 542.26 methyl-phenyl)-piperidin-4-yl]-7- acid 70  (I) methyl-4-(2-trifluoromethyl-benzyl)- 72  2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one Ic-95 4-(2-Cyclopropyl-benzyl)-2-(2,2- Ib-12 2,2-Difluoropropyl K 1.20 552.31 difluoro-propyl)-6-[1-(2-fluoro-6- 4-methyl benzene 100   (I) methyl-phenyl)-piperidin-4-yl]-7- sulfonate 72  methyl-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one Id-10 4-(2-Cyclopropyl-benzyl)-1-(2,2- 1.19 552.34 difluoro-propyl)-6-[1-(2-fluoro-6- (I) methyl-phenyl)-piperidin-4-yl]-7- methyl-1,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one Ic-96 2-Cyclopropyl-4-(2-cyclopropyl- Ib-12 Cyclopropyl boronic J1 1.21 514.09 benzyl)-6-[1-(2-fluoro-6-methyl- acid 70  (I) phenyl)-piperidin-4-yl]-7-methyl- 48  2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one Id-11 1-Cyclopropyl-4-(2-cyclopropyl- 1.21 514.12 benzyl)-6-[1-(2-fluoro-6-methyl- (I) phenyl)-piperidin-4-yl]-7-methyl- 1,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one Ic-97 2-Cyclopropyl-4-(2-cyclopropyl- Ib-11 Cyclopropyl boronic J1 1.11 527.40 benzyl)-6-(2′-methoxy-4′-methyl- acid 100   (I) 3,4,5,6-tetrahydro-2H- 5  [1,3′]bipyridinyl-4-yl)-7-methyl- 2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one Id-12 1-Cyclopropyl-4-(2-cyclopropyl- 1.13 527.40 benzyl)-6-(2′-methoxy-4′-methyl- (I) 3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-7-methyl- 1,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one Ic-98 2-Cyclopropyl-6-(2′-methoxy-4′- Ib-14 Cyclopropyl boronic J1 1.15 555.37 methyl-3,4,5,6-tetrahydro-2H- acid 100   (I) [1,3′]bipyridinyl-4-yl)-7-methyl-4-(2- 18  trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one Id-13 1-Cyclopropyl-6-(2′-methoxy-4′- 1.16 555.36 methyl-3,4,5,6-tetrahydro-2H- (I) [1,3′]bipyridinyl-4-yl)-7-methyl-4-(2- trifluoromethyl-benzyl)-1,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one Ic-99 6-(2′-Methoxy-4′-methyl-3,4,5,6- Ib-14 Methyl 4-methyl K 1.13 529.22 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- benzene sulfonate 100   (I) 2,7-dimethyl-4-(2-trifluoromethyl- 1  benzyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one Id-14 6-(2′-Methoxy-4′-methyl-3,4,5,6- 1.14 529.19 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- (I) 1,7-dimethyl-4-(2-trifluoromethyl- benzyl)-1,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one Ic-100 2-(2,2-Difluoro-propyl)-5-[1-(2- Ib-13 2,2-Difluoropropyl K 1.24 580.34 fluoro-6-methyl-phenyl)-piperidin-4- 4-methyl benzene 80  (I) yl]-4-methyl-7-(2-trifluoromethyl- sulfonate 18  benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one Ic-101 6-[1-(2-Chloro-6-fluoro-phenyl)- Ib-15 Potassium J2 1.36 562.06 piperidin-4-yl]-2-cyclopropyl-7- cyclopropyl 110   (I) methyl-4-(2-trifluoromethyl-benzyl)- trifluoroborate 18  2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one Ic-102 2-Cyclopropyl-6-[1-(2- Ib-16 Potassium J2 1.23 578.15 difluoromethyl-6-fluoro-phenyl)- cyclopropyl 110   (I) piperidin-4-yl]-7-methyl-4-(2- trifluoroborate 18  trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one

Synthesis of Compounds of Formula if

(311) Method a (Carboxylic Ester Reduction)

(312) To a soln. of methyl ester Ic (1 eq) in anh. EtOH (12 to 22 mL/mmol) was added CaCl.sub.2) (0.3 eq) and the rxn mixture was cooled to −10° C. NaBH.sub.4 (2.5 eq) was added portionwise and the mixture was stirred for 30 min at −10° C. and at a given temperature for a given time (see Table 61). It was quenched at 0° C. with water and EtOH was evaporated off. The residue was partitioned between EtOAc (or DCM respectively) and water and the aq. phase was further extracted with EtOAc (or DCM respectively). The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by CC using Hept/EtOAc.

(313) Method B (Nitrile Reduction)

(314) To a suspension of nitrile Ic (1 eq) in anh. MeOH (28 mL/mmol) was added CoCl.sub.2 (1.5 eq). The rxn mixture was stirred for 5 min at RT, cooled to 0° C. and NaBH.sub.4 (5 eq) was added portionwise. The rxn mixture was stirred for 5 min at 0° C. and at RT for a given time (see Table 61). It was quenched with a 10% aq. soln. of citric acid, stirred for 30 min at RT and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using DCM/MeOH or EtOAc/MeOH.

(315) Method C (Saponification/Amide Coupling)

(316) Step A: Saponification

(317) To a soln. of carboxylic ester Ic (1 eq) in THE (8 mL/mmol) was added a 2M aq. soln. of NaOH (7 eq) and the rxn mixture was stirred for 1h at RT. It was acidified with a 1M aq. soln. of HCl until pH-3-4 and extracted with EtOAc. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo.

(318) Step B: Amide Coupling

(319) To a soln. of the crude carboxylic acid (1 eq) in DCM (10 to 23 mL/mmol) were sequentially added DIPEA (3 eq), HOBt (1.5 eq) and EDC.HCl (1.5 eq). The rxn mixture was stirred for 5 min at RT and the appropriate amine (1.2 to 1.5 eq) pure or as soln. was added. The rxn mixture was further stirred at a given temperature for a given time and partitioned between DCM and a sat. aq. soln. of NaHCO.sub.3. The org. phase was washed with water and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc/MeOH.

(320) Method D (Grignard Addition)

(321) Step A: Acetal Cleavage

(322) To a soln. of acetal Ic (1 eq) in THE (7.2 mL/mmol) was added a 1M aq. soln. of HCl (2 eq) and the rxn mixture was stirred for 3h30 at 70° C. It was quenched with a sat. aq. soln. of NaHCO.sub.3 and extracted with EtOAc. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo.

(323) Step B: Grignard Addition

(324) To a soln. of the crude aldehyde (1 eq) in anh. THE (10.6 mL/mmol) was added dropwise at 0° C. a 3M soln. of methylmagnesium bromide in Et.sub.2O (2 eq). The rxn mixture was stirred at a given temperature for a given time (see Table 61), quenched at 0° C. with a sat. aq. soln. of NH.sub.4Cl and extracted with EtOAc. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc/MeOH.

(325) Method E (Reductive Amination)

(326) Step A: Acetal Cleavage

(327) To a soln. of acetal Ic (1 eq) in THE (7.2 mL/mmol) was added a 1M aq. soln. of HCl (2 eq) and the rxn mixture was stirred for 3h30 at 70° C. It was quenched with a sat. aq. soln. of NaHCO.sub.3 and extracted with EtOAc. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo.

(328) Step B: Reductive Amination

(329) To a mixture of aldehyde Ic (1 eq) and the appropriate amine (1.2 to 2 eq) (when the amine was used as HCl salt, TEA (1.2 eq) was additionally added) in THE (12 to 16 mL/mmol) was added AcOH (1.5 eq) and the rxn mixture was stirred for 5 min at RT. NaBH(OAc).sub.3 (1.5 eq) was added portionwise and the rxn mixture was stirred at RT for a given time (see Table 61). It was quenched with a sat. aq. soln. of NaHCO.sub.3 and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using DCM/MeOH or Hept/EtOAc/MeOH and/or by prep. LC-MS using method 3.

(330) Method F (Nucleophilic Substitution)

(331) To a soln. of Ic (1 eq) in DMF (10 mL/mmol) was added the appropriate amine (10 eq pure or as soln.). The rxn mixture was heated to a given temperature and stirred for a given time (see Table 61). It was partitioned between DCM and H.sub.2O and the org. phase was washed brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(332) Method G (Dehydration of Primary Amide)

(333) To a stirred soln. of amide intermediate Ic (1 eq) in DCM (11 mL/mmol) was added portionwise Burgess' reagent (3 eq) under argon. The rxn mixture was stirred at RT for a given time (see Table 61) and partitioned between DCM and H.sub.2O. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(334) Method H (Boc Cleavage)

(335) To a soln. of intermediate Ic (1 eq) in DCM (10 mL/mmol) was added TFA (2 mL/mmol) at 0° C. and the rxn mixture was stirred at RT for a given time (see Table 61). It was cooled to 0° C., quenched with a 32% or 1M aq. soln. of NaOH until pH reached 12 to 13 and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc/MeOH or DCM/MeOH.

(336) Method I (Sulfonamide Cleavage)

(337) A soln. of intermediate Ic (1 eq) in THE (37 mL/mmol) was treated with Cs.sub.2CO.sub.3 (3.25 eq) and QuadraPure® MPA (3 eq). The rxn mixture was heated at 130° C. under microwave irradiation for a given time (see Table 61). It was diluted with EtOAc and filtered. The filtrate was washed with a 0.5M aq. soln. of NaOH and with brine and the org. phase was dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc and/or by prep. LC-MS using method 5.

(338) Method J (Dehydration of Tertiary Alcohol)

(339) POCl.sub.3 (2 eq) was added dropwise at 0° C. to a soln. of compound Ic (1 eq) in pyridine (8 mL/mmol). The rxn mixture was heated to 50° C. and stirred for a given time (see Table 61). The rxn mixture was diluted with EtOAc and washed with a 1M aq. soln. of HCl and brine. The org. phase was dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using DCM/MeOH.

(340) Method K (Trityl Cleavage)

(341) Compound Ic (1 eq) was treated with TFA (9 mL/mmol) and H.sub.2O (1 mL/mmol) at 0° C. The rxn mixture was stirred at 0° C. for a given time (see Table 61), poured into a 1M aq. soln. of NaOH and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by prep. LC-MS using method 9.

(342) Method L (Hydrogenation)

(343) Compound of formula Ic (1 eq) was dissolved in EtOAc (27 mL/mmol). The flask was evacuated three times and refilled with nitrogen. Wet Pd/C (0.05 eq) was added and the flask was evacuated three times and refilled with hydrogen. The suspension was stirred under an atmospheric pressure of hydrogen for a given time (see Table 61) and filtered over a pad of Celite. The cake was washed with MeOH and the filtrate was concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(344) TABLE-US-00063 TABLE 61 Method t.sub.R [min] MS-data Reactant T [° C.] (LC/MS m/z If Name Ic Amine time [h] method) [M + H].sup.+ If-1 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-5 — A 1.01 (II) 532.26 yl]-2-(2-hydroxy-ethyl)-7-(2-trifluoromethyl- 0 benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 1 d]pyrimidin-6-one (Example 20) If-2 2-(2-Amino-ethyl)-5-[1-(2-fluoro-6-methyl- Ic-8 — B 0.83 (II) 531.12 phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl- RT benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 2 d]pyrimidin-6-one (Example 26) If-3 2-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ic-5 25% aq. C 0.97 (II) 545.15 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- soln. of 40 benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- NH.sub.4OH 24 d]pyrimidin-2-yl]-acetamide (Example 29) If-4 2-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ic-5 2M soln. of C 1.02 (II) 573.24 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- dimethylamine in 40 benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- THF 5 d]pyrimidin-2-yl]-N,N-dimethyl-acetamide (Example 30) If-5 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-10 — A 1.07 (II) 560.05 yl]-2-(2-hydroxy-1,1-dimethyl-ethyl)-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 3 pyrazolo[3,4-d]pyrimidin-6-one (Example 32) If-6 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 — D 1.02 (II) 546.18 yl]-2-(2-hydroxy-propyl)-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 3 pyrazolo[3,4-d]pyrimidin-6-one (Example 33) If-7 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 3-Methoxyazetidine E 0.85 (II) 601.11 yl]-2-[2-(3-methoxy-azetidin-1-yl)-ethyl]-7- hydrochloride RT (2-trifluoromethyl-benzyl)-2,4,5,7- 4.5 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 34) If-8 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-11 — A 1.04 (II) 560.13 yl]-2-(3-hydroxy-2-methyl-propyl)-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 1.5 pyrazolo[3,4-d]pyrimidin-6-one (Example 39) If-9 2-(3-Amino-2-methyl-propyl)-5-[1-(2-fluoro- Ic-16 — B 0.84 (II) 559.15 6-methyl-phenyl)-piperidin-4-yl]-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 0.25 pyrazolo[3,4-d]pyrimidin-6-one (Example 45) If-10 2-Dimethylamino-3-[5-[1-(2-fluoro-6- Ic-15 2M soln. of F 0.88 (II) 617.09 methyl-phenyl)-piperidin-4-yl]-6-oxo-7-(2- dimethylamine in 70 trifluoromethyl-benzyl)-4,5,6,7-tetrahydro- THF 3 pyrazolo[3,4-d]pyrimidin-2-yl]-propionic acid methyl ester (Example 53) If-11 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 2M soln. of E 0.85 (II) 545.08 yl]-2-(2-methylamino-ethyl)-7-(2- methylamine in RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- THF 18 pyrazolo[3,4-d]pyrimidin-6-one (Example 59) If-12 2-(2-Dimethylamino-ethyl)-5-[1-(2-fluoro-6- Ic-12 2M soln. of E 0.86 (II) 559.17 methyl-phenyl)-piperidin-4-yl]-7-(2- dimethylamine in RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- THF 18 pyrazolo[3,4-d]pyrimidin-6-one (Example 60) If-13 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 Pyrrolidine E 0.88 (II) 585.14 yl]-2-(2-pyrrolidin-1-yl-ethyl)-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one (Example 62) If-14 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 Piperidine E 0.90 (II) 599.14 yl]-2-(2-piperidin-1-yl-ethyl)-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one (Example 63) If-15 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 Morpholine E 0.86 (II) 601.14 yl]-2-(2-morpholin-4-yl-ethyl)-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one (Example 64) If-16 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 1-Methyl- E 0.84 (II) 614.15 yl]-2-[2-(4-methyl-piperazin-1-yl)-ethyl]-7- piperazine RT (2-trifluoromethyl-benzyl)-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 65) If-17 2-(2-Cyclopropylamino-ethyl)-5-[1-(2- Ic-12 Cyclopropylamine E 0.86 (II) 571.20 fluoro-6-methyl-phenyl)-piperidin-4-yl]-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one (Example 71) If-18 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 N-Iso- E 0.88 (II) 587.21 yl]-2-[2-(isopropyl-methyl-amino)-ethyl]-7- propylmethylamine RT (2-trifluoromethyl-benzyl)-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 72) If-19 2-[2-(Cyclopropyl-methyl-amino)-ethyl]-5- Ic-12 N-methyl- E 0.87 (II) 585.20 [1-(2-fluoro-6-methyl-phenyl)-piperidin-4- cyclopropanamine RT yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 73) If-20 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-12 N-(2- E 0.87 (II) 603.19 yl]-2-{2-[(2-methoxy-ethyl)-methyl-amino]- Methoxyethyl) RT ethyl}-7-(2-trifluoromethyl-benzyl)-2,4,5,7- methylamine 18 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 74) If-21 2-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ic-18 — G 1.07 (II) 541.10 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 18 d]pyrimidin-2-yl]-propionitrile (Example 78) If-22 2-[5-[1-(2-Fluoro-6-methyl-phenyl)- Ic-23 — G 1.09 (II) 555.07 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 18 d]pyrimidin-2-yl]-2-methyl-propionitrile (Example 87) If-23 2-Azetidin-3-yl-5-[1-(2-fluoro-6-methyl- Ic-24 — H 0.89 (I)  543.16 phenyl)-piperidin-4-yl]-7-(2-trifluoromethyl- RT benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 0.4 d]pyrimidin-6-one (Example 92) If-24 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-25 — H 0.86 (II) 557.20 yl]-2-pyrrolidin-3-yl-7-(2-trifluoromethyl- RT benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 1 d]pyrimidin-6-one (Example 94) If-25 2-Azetidin-2-ylmethyl-5-[1-(2-fluoro-6- Ic-26 — H 0.86 (II) 557.21 methyl-phenyl)-piperidin-4-yl]-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one If-26 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-27 — H 0.87 (II) 571.21 yl]-2-pyrrolidin-2-ylmethyl-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 1.5 pyrazolo[3,4-d]pyrimidin-6-one (Example 89) If-27 2-((R)-4,4-Difluoro-pyrrolidin-2-ylmethyl)-5- Ic-30 — H 0.94 (I)  607.19 [1-(2-fluoro-6-methyl-phenyl)-piperidin-4- RT yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7- 1.5 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 111) If-28 2-((S)-4,4-Difluoro-pyrrolidin-2-ylmethyl)-5- Ic-31 — H 0.94 (I)  607.16 [1-(2-fluoro-6-methyl-phenyl)-piperidin-4- RT yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7- 1.5 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 112) If-29 2-(2-Amino-2-methyl-propyl)-5-[1-(2-fluoro- Ic-32 — I 0.93 (I)  559.29 6-methyl-phenyl)-piperidin-4-yl]-7-(2- 130 trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 0.5 pyrazolo[3,4-d]pyrimidin-6-one (Example 118) If-30 (S)-2-(Azetidin-2-ylmethyl)-5-[1-(2-fluoro-6- Ic-33 — H 0.91 (I)  557.19 methyl-phenyl)-piperidin-4-yl]-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 5 pyrazolo[3,4-d]pyrimidin-6-one (Example 122) If-31 (R)-2-(Azetidin-2-ylmethyl)-5-[1-(2-fluoro-6- Ic-34 — H 0.91 (I)  557.14 methyl-phenyl)-piperidin-4-yl]-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 4 pyrazolo[3,4-d]pyrimidin-6-one (Example 130) If-32 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-9 — J 1.32 (I)  542.18 yl]-2-(2-methyl-propenyl)-7-(2- 50 trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 0.5 pyrazolo[3,4-d]pyrimidin-6-one (Example 153) If-33 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- 1.28 (I)  542.17 yl]-2-(2-methyl-allyl)-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 154) If-34 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-42 — K 1.11 (I)  557.13 yl]-2-(2-oxo-azetidin-3-yl)-7-(2- 0 trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 72 pyrazolo[3,4-d]pyrimidin-6-one (Example 157) If-35 6-[1-(2-Fluoro-6-methyl-phenyl)-piperidin-4- Ic-74 — L 1.22 (I)  530.05 yl]-2-isopropyl-4-(2-trifluoromethyl-benzyl)- RT 2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin- 18 5-one (Example 191)

Synthesis of Compounds of Formula Ig

(345) Method a (Carboxylic Ester Reduction)

(346) To a soln. of methyl ester If (1 eq) in anh. EtOH (23 mL/mmol) was added CaCl.sub.2 (0.3 eq) and the rxn mixture was cooled to −10° C. NaBH.sub.4 (4 eq) was added portionwise and the mixture was stirred for 15 min at −10° C. and at a given temperature for a given time (see Table). When necessary to reach completion of the rxn, a further amount of NaBH.sub.4 (4 eq) was added. It was quenched at 0° C. with water and EtOH was evaporated off. The residue was partitioned between DCM and water and the aq. phase was further extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(347) Method B (Acylation/Alkoxycarbonylation/Dialkylcarbamylation/Alkylsulfonylation/Dialkylsulfamylation)

(348) A soln. of amine If (1 eq) and TEA (1.5 to 6 eq) in DCM (0.5 to 36 mL/mmol) (or DMF, respectively) was cooled to 0° C. and halide BB-25 (1.1 to 2 eq) (or pentafluorophenylcarbonate BB-25, respectively) was added dropwise at 0° C. (or at RT, respectively). The rxn mixture was allowed to slowly reach RT and stirred for a given time (or stirred at a given temperature for a given time, respectively) (see Table). It was diluted with DCM and washed with a 10% aq. soln. of citric acid when suitable, with a sat. aq. soln. of NaHCO.sub.3 and with brine. The org. phase was dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH and/or by prep. LC-MS using methods 3 or 8.

(349) Method C (Boc Protection)

(350) To a soln. of amine If (1 eq) in anh. THE (2 mL/mmol) was added TEA (3 eq). The rxn mixture was cooled to 0° C. and Boc.sub.2O (1.5 eq) was added. It was stirred for 5 min at 0° C. and at RT for a given time (see Table) and was partitioned between DCM and water. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. When necessary, the crude was purified by CC using Hept/EtOAc.

(351) Method D (Nitrile Reduction)

(352) Nitrile If (1 eq) was suspended in a 7M soln. of NH.sub.3 in MeOH (40 mL/mmol). The flask was evacuated and refilled with nitrogen. Raney nickel (0.1 eq) was added at 0° C. and the temperature was allowed to reach RT. The flask was evacuated and refilled with hydrogen. The suspension was stirred under a hydrogen atmosphere at RT for a given time (see Table) and filtered over a pad of Celite. The cake was washed with MeOH and the filtrate was concentrated in vacuo.

(353) Method E

(354) Step A: Mitsunobu

(355) To a suspension of alcohol If (1 eq) and phtalimide (1.5 eq) in toluene (16 mL/mmol) was added a 1M soln. of (tributylphosphoranylidene)acetonitrile in toluene (2 eq) under argon. The rxn mixture was heated to 110° C. and stirred for 18h. It was quenched with water and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc and/or DCM/MeOH.

(356) Step B: Phtalimide Cleavage

(357) A soln. of the crude from previous step (1 eq) was dissolved in EtOH (35 mL/mmol) and treated with hydrazine hydrate (20 eq). The rxn mixture was heated to 80° C. and stirred for a given time (see Table). It was basified with a 1M aq. soln. of NaOH and partitioned between DCM and H.sub.2O. The org. phase was dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using DCM/MeOH.

(358) Method F (Reductive Amination)

(359) To a stirred soln. of amine If (1 eq) in a mixture of DCM (10 mL/mmol) and MeOH (15 mL/mmol) or in THE (7 to 8.5 mL/mmol) was added successively AcOH (1.2 to 1.5 eq), the appropriate aldehyde BB-25 (1.3 to 2 eq) and NaBH(OAc).sub.3 (1.5 to 2 eq). The rxn mixture was stirred at RT for a given time (see Table) and the volatiles were evaporated in vacuo. The residue was partitioned between DCM and a sat. aq. soln. of NaHCO.sub.3. The org. phase was dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(360) Method G (Alkylation)

(361) To a soln. of amine If (1 eq) in DMF (10 mL/mmol) was added the appropriate halide BB-25 (3 eq), DIPEA (2 eq) and KI (0.05 eq). The rxn mixture was heated at 150° C. under microwave irradiation for a given time (see Table) and partitioned between EtOAc and H.sub.2O. The org. phase was washed with H.sub.2O and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(362) Method H (Urea Formation)

(363) A soln. of amine If (1 eq) and TEA (4 eq) in THE (12 mL/mmol) was treated with CDI (1.5 eq) and the rxn mixture was stirred at RT for 15 min. Amine BB-25 (1.5 eq) was added at RT and the mixture was stirred at a given temperature for a given time (see Table). When necessary to reach completion of the rxn, extra amounts of amine (1 to 10 eq) were added. The rxn mixture was partitioned between DCM and H.sub.2O and the org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using DCM/MeOH and/or by prep. LC-MS using method 4.

(364) Method I (PyBOP Activated SNAr)

(365) Compound If (1 eq), heteroarene BB-25 (1.5 eq) and DIPEA (2 eq) were dissolved in anh. DMF (5 mL/mmol) and the mixture was stirred for 5 min at RT. PyBOP (1.6 eq) was added portionwise and the rxn mixture was further stirred at RT for a given time (see Table). It was partitioned between EtOAc and a 5% aq. soln. of KHSO.sub.4 and the org. phase was washed with a sat. aq. soln. of NaHCO.sub.3 and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(366) Method J (SNAr)

(367) To a soln. of compound If (1 eq) in DMSO (5 mL/mmol) was added DIPEA (3 eq) and halo-heteroarene BB-25 (1.2 eq). The rxn mixture was stirred at RT for a given time (see Table) and partitioned between EtOAc and a 5% aq. soln. of KHSO.sub.4. The org. phase was washed with a 5% aq. soln. of KHSO.sub.4 and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(368) Method K (Hydrogenation)

(369) Compound of formula If (1 eq) was dissolved in EtOH (10 mL/mmol). The flask was evacuated three times and refilled with nitrogen. Wet Pd/C (0.02 eq) was added and the flask was evacuated three times and refilled with hydrogen. The suspension was stirred under an atmospheric pressure of hydrogen for a given time (see Table) and filtered over a pad of Celite. The cake was washed with MeOH and the filtrate was concentrated in vacuo.

(370) TABLE-US-00064 TABLE 62 Method t.sub.R [min] MS-data Reactant Reactant T [° C.] (LC/MS m/z Ig Name If BB-25 time [h] method) [M + H].sup.+ Ig-1 2-(2-Dimethylamino-3-hydroxy-propyl)-5- If-10 — A  0.85 (II) 589.12 [1-(2-fluoro-6-methyl-phenyl)-piperidin-4- RT yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 56) Ig-2 N-{2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-2 Acetyl B  1.02 (II) 573.15 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloride RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 2 d]pyrimidin-2-yl]-ethyl]-acetamide (Example 66) Ig-3 {2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-2 — C  1.09 (II) 631.15 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 18 d]pyrimidin-2-yl]-ethyl}-carbamic acid tert- butyl ester (Example 67) Ig-4 2-(2-Amino-1-methyl-ethyl)-5-[1-(2-fluoro- If-21 — D  0.86 (II) 545.23 6-methyl-phenyl)-piperidin-4-yl]-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 2 pyrazolo[3,4-d]pyrimidin-6-one (Example 79) Ig-5 2-(2-Amino-propyl)-5-[1-(2-fluoro-6- If-6 — E  0.81 (II) 545.13 methyl-phenyl)-piperidin-4-yl]-7-(2- 80 trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 2 pyrazolo[3,4-d]pyrimidin-6-one (Example 80) Ig-6 2-(2-Amino-1,1-dimethyl-ethyl)-5-[1-(2- If-22 — D  0.88 (II) 559.25 fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- RT (2-trifluoromethyl-benzyl)-2,4,5,7- 3.5 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 88) Ig-7 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-23 Formaldehyde F 0.91 (I) 557.16 4-yl]-2-(1-methyl-azetidin-3-yl)-7-(2- (as a 37% soln. RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- in H.sub.2O) 1.5 pyrazolo[3,4-d]pyrimidin-6-one (Example 102) Ig-8 2-(1-Ethyl-azetidin-3-yl)-5-[1-(2-fluoro-6- If-23 Acetaldehyde F 0.93 (I) 571.19 methyl-phenyl)-piperidin-4-yl]-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 1.5 pyrazolo[3,4-d]pyrimidin-6-one (Example 103) Ig-9 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-23 Isobutyraldehyde F 0.98 (I) 599.23 4-yl]-2-(1-isobutyl-azetidin-3-yl)-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 1.5 pyrazolo[3,4-d]pyrimidin-6-one (Example 104) Ig-10 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-23 Acetone F 0.95 (I) 585.18 4-yl]-2-(1-isopropyl-azetidin-3-yl)-7-(2- RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 0.5 pyrazolo[3,4-d]pyrimidin-6-one (Example 105) Ig-11 2-[1-(2,2-Difluoro-ethyl)-azetidin-3-yl]-5- If-23 2-Bromo-1,1- G 0.95 (I) 607.18 [1-(2-fluoro-6-methyl-phenyl)-piperidin-4- difluoroethane 150 yl]-7-(2-trifluoromethyl-benzyl)-2,4,5,7- 0.25 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 106) Ig-12 2-[1-(2-Fluoro-ethyl)-azetidin-3-yl]-5-[1- If-23 1-Chloro-2- G 0.93 (I) 589.20 (2-fluoro-6-methyl-phenyl)-piperidin-4-yl]- fluoroethane 150 7-(2-trifluoromethyl-benzyl)-2,4,5,7- 0.25 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 107) Ig-13 2-(1-Acetyl-pyrrolidin-3-yl)-5-[1-(2-fluoro- If-24 Acetyl B 1.24 (I) 599.21 6-methyl-phenyl)-piperidin-4-yl]-7-(2- chloride RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 0.5 pyrazolo[3,4-d]pyrimidin-6-one (Example 113) Ig-14 2-(1-Acetyl-azetidin-2-ylmethyl)-5-[1-(2- If-25 Acetyl B 1.20 (I) 599.26 fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- chloride RT (2-trifluoromethyl-benzyl)-2,4,5,7- 0.5 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 114) Ig-15 2-(1-Acetyl-pyrrolidin-2-ylmethyl)-5-[1-(2- If-26 Acetyl B 1.21 (I) 613.25 fluoro-6-methyl-phenyl)-piperidin-4-yl]-7- chloride RT (2-trifluoromethyl-benzyl)-2,4,5,7- 0.5 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 115) Ig-16 2-(1-Acetyl-azetidin-3-yl)-5-[1-(2-fluoro-6- If-23 Acetyl B 1.22 (I) 585.21 methyl-phenyl)-piperidin-4-yl]-7-(2- chloride RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 1 pyrazolo[3,4-d]pyrimidin-6-one (Example 116) Ig-17 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 Methyl B 1.21 (I) 601.18 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloroformate RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 1 d]pyrimidin-2-yl]-azetidine-1-carboxylic acid methyl ester (Example 117) Ig-18 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 Dimethylamine H 1.24 (I) 614.25 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- (as 2M soln. in 45 benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- THF) 18 d]pyrimidin-2-yl]-azetidine-1-carboxylic acid dimethylamide (Example 119) Ig-19 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 Methylamine H 1.17 (I) 600.19 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- (as 2M soln. in 45 benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- THF) 18 d]pyrimidin-2-yl]-azetidine-1-carboxylic acid methylamide (Example 120) Ig-20 (S)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-30 Methyl B 1.21 (I) 615.16 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloroformate RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 0.25 d]pyrimidin-2-ylmethyl]-azetidine-1- carboxylic acid methyl ester (Example 123) Ig-21 (S)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-30 Ethyl B 1.23 (I) 629.18 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloroformate RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 0.25 d]pyrimidin-2-ylmethyl]-azetidine-1- carboxylic acid ethyl ester (Example 124) Ig-22 (S)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-30 Isopropyl B 1.26 (I) 643.11 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloroformate RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 0.25 d]pyrimidin-2-ylmethyl]-azetidine-1- carboxylic acid isopropyl ester (Example 125) Ig-23 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 Ethyl B 1.25 (I) 615.21 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloroformate RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 2 d]pyrimidin-2-yl]-azetidine-1-carboxylic acid ethyl ester (Example 126) Ig-24 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 Isopropyl B 1.27 (I) 629.21 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloroformate RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 2 d]pyrimidin-2-yl]-azetidine-1-carboxylic acid isopropyl ester (Example 127) Ig-25 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-23 Isobutyryl B 1.24 (I) 613.29 4-yl]-2-(1-isobutyryl-azetidin-3-yl)-7-(2- chloride RT trifluoromethyl-benzyl)-2,4,5,7-tetrahydro- 1.5 pyrazolo[3,4-d]pyrimidin-6-one (Example 131) Ig-26 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 Isobutyl B 1.29 (I) 643.23 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloroformate RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 1.5 d]pyrimidin-2-yl]-azetidine-1-carboxylic acid isobutyl ester (Example 132) Ig-27 (R)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-31 Methyl B 1.22 (I) 615.15 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloroformate RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 0.5 d]pyrimidin-2-ylmethyl]-azetidine-1- carboxylic acid methyl ester (Example 133) Ig-28 (R)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-31 Ethyl B 1.24 (I) 629.16 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloroformate RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 0.5 d]pyrimidin-2-ylmethyl]-azetidine-1- carboxylic acid ethyl ester (Example 134) Ig-29 (R)-2-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-31 Isopropyl B 1.26 (I) 643.11 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- chloroformate RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 0.5 d]pyrimidin-2-ylmethyl]-azetidine-1- carboxylic acid isopropyl ester (Example 135) Ig-30 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-23 Methanesulfonyl B 1.20 (I) 621.21 4-yl]-2-(1-methanesulfonyl-azetidin-3-yl)- chloride RT 7-(2-trifluoromethyl-benzyl)-2,4,5,7- 3 tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 136) Ig-31 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 N,N- B 1.23 (I) 650.14 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- Dimethylsulfamoyl RT benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- chloride 3 d]pyrimidin-2-yl]-azetidine-1-sulfonic acid dimethylamide (Example 137) Ig-32 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 BB-25-1 B 1.19 (I) 643.12 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- 110 benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 1 d]pyrimidin-2-yl]-azetidine-1-carboxylic acid oxetan-3-yl ester (Example 139) Ig-33 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 BB-25-2 B 1.27 (I) 711.15 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- 110 benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 1 d]pyrimidin-2-yl]-azetidine-1-carboxylic acid 3-trifluoromethyl-oxetan-3-yl ester (Example 140) Ig-34 3-[5-[1-(2-Fluoro-6-methyl-phenyl)- If-23 BB-25-3 B 1.24 (I) 657.11 piperidin-4-yl]-6-oxo-7-(2-trifluoromethyl- 110 benzyl)-4,5,6,7-tetrahydro-pyrazolo[3,4- 1 d]pyrimidin-2-yl]-azetidine-1-carboxylic acid 3-methyl-oxetan-3-yl ester (Example 141) Ig-35 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-23 5-Methyl-3H- I 1.24 (I) 625.04 4-yl]-2-[1-(5-methyl-[1,3,4]oxadiazol-2-yl)- [1,3,4]oxadiazol- RT azetidin-3-yl]-7-(2-trifluoromethyl-benzyl)- 2-one 1.5 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 142) Ig-36 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-23 BB-25-4 I 1.28 (I) 653.15 4-yl]-2-[1-(5-isopropyl-[1,3,4]oxadiazol-2- RT yl)-azetidin-3-yl]-7-(2-trifluoromethyl- 1.5 benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 143) Ig-37 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-23 2-Iodo-5- J 1.26 (I) 679.11 4-yl]-7-(2-trifluoromethyl-benzyl)-2-[1-(5- (trifluoromethyl)- RT trifluoromethyl-[1,3,4]oxadiazol-2-yl)- 1,3,4-oxadiazole 1 azetidin-3-yl]-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 144) Ig-38 5-[1-(2-Fluoro-6-methyl-phenyl)-piperidin- If-33 — K 1.28 (I) 544.11 4-yl]-2-isobutyl-7-(2-trifluoromethyl- RT benzyl)-2,4,5,7-tetrahydro-pyrazolo[3,4- 5 d]pyrimidin-6-one (Example 155)

Synthesis of Compounds of Formula Ih

(371) Method a (Deuteration)

(372) Compound of formula Ia (1 eq) was dissolved in a mixture of CD.sub.3OD (12 mL/mmol) and EtOAc (4 mL/mmol). The flask was evacuated three times and refilled with nitrogen. Wet Pd/C (0.1 eq) was added and the flask was evacuated three times and refilled with deuterium. The suspension was stirred under an atmospheric pressure of deuterium for a given time (see Table) and filtered over a pad of Celite. The cake was washed with EtOAc and the filtrate was concentrated in vacuo. The crude was purified by prep. LC-MS using method 4.

(373) Method B (Substitution with F)

(374) A suspension of compound Ia (1 eq) and dry CsF (6 eq) in anh. DMSO (5.4 mL/mmol) was heated to a given temperature under argon and stirred for a given time (see Table). The rxn mixture was partitioned between EtOAc and H.sub.2O and the org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(375) Method C (Suzuki Coupling)

(376) A mixture of compound Ia (1 eq), boron species (1.1 eq), Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (0.03 eq) and K.sub.2CO.sub.3 (2 eq) in dioxane (13.6 mL/mmol) was flushed with N.sub.2 and heated at a given temperature for a given time (see Table). It was partitioned between EtOAc and a sat. aq. soln. of NaHCO.sub.3 and the org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc/MeOH.

(377) Method D (Substitution with OMe)

(378) A suspension of compound Ia (1 eq) in MeOH (6 mL) was treated with a 25% soln. of NaOMe in MeOH (6 eq). The rxn mixture was heated to a given temperature for a given time (see Table) and partitioned between DCM and water. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(379) Method E (Substitution with Amine)

(380) A soln. of compound Ia (1 eq) in MeOH (9 mL/mmol) was treated with the appropriate amine (21 eq, pure or as soln.). The rxn mixture was heated at 150° C. under microwave irradiation for a given time (see Table) and partitioned between DCM and H.sub.2O. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(381) Method F (Phenol Alkylation Using NaH as Base)

(382) To a soln. of compound Ia (1 eq) in anh. THE (9.7 mL/mmol) was added NaH (5 eq, as a 60% dispersion in mineral oil) at 0° C. The suspension was stirred for 10 min and the appropriate halide (1.1 to 1.5 eq) was added at 0° C. The rxn mixture was stirred at a given temperature for a given time (see Table). When necessary to reach completion of the rxn, extra amounts of NaH (5 eq, as a 60% dispersion in mineral oil) and/or halide BB-9 (3 eq) were added. The mixture was quenched with water at 0° C. and extracted with EtOAc. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or by prep. LC-MS using method 11.

(383) Method G (Phenol Alkylation Using K.sub.2CO.sub.3 as Base)

(384) To a stirred suspension of compound Ia (1 eq) in DMF (8.5 mL/mmol) was added K.sub.2CO.sub.3(3 eq) followed by the appropriate halide (5 eq). The rxn mixture was stirred at a given temperature under microwave irradiation for a given time (see Table). It was partitioned between EtOAc and H.sub.2O and the org. phase was washed with water and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(385) Method H (Phenol Alkylation Using Mitsunobu Conditions)

(386) To a soln. of compound Ia (1 eq) and alcohol (3 eq) in toluene (8 mL/mmol) was added 1M soln. of (tributylphosphoranylidene)acetonitrile in toluene (1.5 eq) under argon. The rxn mixture was heated to 110° C. and stirred for a given time (see Table). It was quenched with water and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc and/or by prep. LC-MS using method 11.

(387) TABLE-US-00065 TABLE 63 Amine/ halide/ alcohol/ Method t.sub.R [min] MS-data Reactant boron T [° C.] (LC/MS m/z Ih Name Ia reagent time [h] method) [M + H].sup.+ Ih-1 5-(1-(2-fluoro-6- Ia-9 — A 1.00 (II) 504.12 methylphenyl)piperidin-4-yl)-2- RT methyl-7-(3-trifluoromethyl-[6- 48 .sup.2H]pyridine-2-yl-methyl)-2,4,5,7- tetrahydro-6H-pyrazolo[3,4- d]pyrimidin-6-one (Example 23) Ih-2 5-[1-(2-Fluoro-6-methyl-phenyl)- Ia-9 — B 1.03 521.11 piperidin-4-yl]-7-(6-fluoro-3- 100 trifluoromethyl-pyridin-2-ylmethyl)-2- 3 methyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 36) Ih-3 5-[1-(2-Fluoro-6-methyl-phenyl)- Ia-9 Trimethyl C 1.03 (I)  517.13 piperidin-4-yl]-2-methyl-7-(6-methyl- boroxine 100 3-trifluoromethyl-pyridin-2-ylmethyl)- 2 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Example 37) Ih-4 5-[1-(2-Fluoro-6-methyl-phenyl)- Ia-9 25% soln. of D 1.05 (II) 533.13 piperidin-4-yl]-7-(6-methoxy-3- NaOMe in MeOH 70 trifluoromethyl-pyridin-2-ylmethyl)-2- 2 methyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 38) Ih-5 7-(6-Dimethylamino-3- Ia-9 2M soln. of E 1.05 (II) 546.06 trifluoromethyl-pyridin-2-ylmethyl)-5- dimethylamine in 150 [1-(2-fluoro-6-methyl-phenyl)- THF 1 piperidin-4-yl]-2-methyl-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 50) Ih-6 5-[1-(2-Fluoro-6-methyl-phenyl)- Ia-9 2M soln. of E 0.99 (II) 532.13 piperidin-4-yl]-2-methyl-7-(6- methylamine in 150 methylamino-3-trifluoromethyl- THF 4 pyridin-2-ylmethyl)-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 51) Ih-7 7-(2-Cyclopropylmethoxy-benzyl)-5- Ia-39 (Bromomethyl) F 1.20 (I)  504.25 [1-(2-fluoro-6-methyl-phenyl)- cyclopropane RT piperidin-4-yl]-2-methyl-2,4,5,7- to tetrahydro-pyrazolo[3,4-d]pyrimidin- 70120 6-one (Example 248) Ih-8 5-[1-(2-Fluoro-6-methyl-phenyl)- Ia-39 3-Bromooxetane G 1.10 (I)  506.20 piperidin-4-yl]-2-methyl-7-[2-(oxetan- 150 3-yloxy)-benzyl]-2,4,5,7-tetrahydro- 7 pyrazolo[3,4-d]pyrimidin-6-one (Example 250) Ih-9 5-[1-(2-Fluoro-6-methyl-phenyl)- Ia-39 2-Propanol H 1.19 (I)  492.20 piperidin-4-yl]-7-(2-isopropoxy- 110 benzyl)-2-methyl-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one (Example 251)

Synthesis of Compounds of Formula Ii

(388) Method A (Alkylation Using NaH)

(389) To suspension or soln. of intermediate C-2 (1 eq) in mixture of anh. THF (3 to 3.6 mL/mmol) and anh. DMF (0.1 to 0.25 mL/mmol) was added NaH (2 eq, as a 60% dispersion in mineral oil) at 0° C. The suspension was stirred for 10 min at 0° C. and BB-9 (1.2 to 1.5 eq) was added at 0° C. The rxn mixture was stirred at a given temperature for a given time (see Table), quenched at 0° C. with a sat. aq. soln. of NaHCO.sub.3 and extracted with EtOAc or DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(390) Method B (Mitsunobu)

(391) To a soln. or suspension of intermediate-2(1 eq) and alcohol B-9(1 to 1.3 eq) in toluene (7 mL/mmol) was added a 1M soln. of (tributylphosphoranylidene)acetonitrile in toluene (2 eq) under argon. The rxn mixture was heated to a given temperature and stirred for a given time (see Table). When necessary to reach completion of the rxn, extra amounts of a 1M soln. of (tributylphosphoranylidene)acetonitrile in toluene (0.2 eq) were sequentially added under argon. It was quenched with water or a sat. aq. soln. of NaHCO.sub.3 and extracted with EtOAc or DCM. The combined org. phases were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH. When necessary, an additional purification by prep. LC-MS using methods 2,3,4 or 5 was performed.

(392) TABLE-US-00066 TABLE 64 Method t.sub.R [min] MS-data Reactant Reactant T [° C.] (LC/MS- m/z Ii Name C-2 BB-9 time [h] method) [M + H].sup.+ Ii-1 3-[2-Methyl-6-oxo-7-(2-trifluoromethyl- C-2-1 BB-9-1 A 0.94 (II) 480.08 benzyl)-2,4,6,7-tetrahydro- RT pyrazolo[3,4-d]pyrimidin-5-yl]- 18 pyrrolidine-1-carboxylic acid tert-butyl ester Ii-2 4-[2-Methyl-6-oxo-7-(2-trifluoromethyl- C-2-2 BB-9-1 A 0.97 (II) 494.09 benzyl)-2,4,6,7-tetrahydro- RT pyrazolo[3,4-d]pyrimidin-5-yl]- 18 piperidine-1-carboxylic acid tert-butyl ester Ii-3 4-[2-Methyl-6-oxo-7-(2-trifluoromethyl- C-2-3 BB-9-1 A 0.98 (II) 508.19 benzyl)-2,4,6,7-tetrahydro- RT pyrazolo[3,4-d]pyrimidin-5-yl]- 18 azepane-1-carboxylic acid tert-butyl ester Ii-4 4-[2-Methyl-5-oxo-4-(2-trifluoromethyl- C-2-4 BB-9-1 A 1.07 (I)  494.21 benzyl)-2,4,5,7-tetrahydro- RT pyrazolo[4,3-d]pyrimidin-6-yl]- 2 piperidine-1-carboxylic acid tert-butyl ester Ii-5 4-{2-Methyl-6-oxo-7-[1-(2- C-2-2 BB-9-15 B 1.07 (I)  508.26 trifluoromethyl-phenyl)-ethyl]-2,4,6,7- 110 tetrahydro-pyrazolo[3,4-d]pyrimidin-5- 24 yl}-piperidine-1-carboxylic acid tert- butyl ester Ii-6 4-[7-(2-Cyclopropyl-benzyl)-2-methyl- C-2-2 BB-9-9 B 1.05 (I)  466.03 6-oxo-2,4,6,7-tetrahydro-pyrazolo[3,4- 110 d]pyrimidin-5-yl]-piperidine-1- 1.5 carboxylic acid tert-butyl ester

Synthesis of Compounds of Formula Ij

(393) Method A (Buchwald Coupling)

(394) To mixture of intermediate C-3 (1 eq), halo-(hetero)arene BB-16(1.1 to 2 eq) and sodium tert-butoxide (2 to 2.3 eq) in toluene (3 to 7.8 mL/mmol) under N.sub.2, was added BINAP (0.2 to 0.3 eq) and Pd.sub.2(dba).sub.3(0.1 to 0.15 eq). The rxn mixture was flushed with N.sub.2, heated under stirring at a given temperature for a given time (see Table). It was partitioned between water and EtOAc or DCM and the org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH. When necessary, an additional purification by prep. LC-MS using methods 1, 3, 4, 5, 6 or 10 was performed.

(395) Method B (Aromatic Nucleophilic Substitution)

(396) To a soln. of intermediate C-3(1 eq) and halo-(hetero)arene BB-16 (1.2 to 2 eq) in DMSO (1.5 to 4.5 mL/mmol) was added K.sub.2CO.sub.3 or CsF (2 eq) and the mixture was heated to a given temperature and stirred for a given time under possible microwave irradiation (see Table). It was partitioned between EtOAc and H.sub.2. The org. phase was washed with H.sub.2O and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc. When necessary, an additional purification by prep. LC-MS using method 1 was performed.

(397) TABLE-US-00067 TABLE 58 Method t.sub.R [min] MS-data Reactant Reactant T [° C.] (LC/MS- m/z Ij Name C-3 BB-16 time [h] method) [M + H].sup.+ Ij-1 5-[1-(2-Fluoro-6-methyl-phenyl)- C-3-1 BB-16-1 A  0.92 (II) 488.06 pyrrolidin-3-yl]-2-methyl-7-(2- 110 trifluoromethyl-benzyl)-2,4,5,7- 2.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 44) Ij-2 5-[1-(2,6-Dimethyl-phenyl)-piperidin- C-3-2 BB-16-2 A  1.08 (II) 498.01 4-yl]-2-methyl-7-(2-trifluoromethyl- 110 benzyl)-2,4,5,7-tetrahydro- 18 pyrazolo[3,4-d]pyrimidin-6-one (Example 47) Ij-3 5-[1-(2-Methoxy-6-methyl-phenyl)- C-3-2 BB-16-3 A  0.91 (II) 514.01 piperidin-4-yl]-2-methyl-7-(2- 110 trifluoromethyl-benzyl)-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 48) Ij-4 3-Fluoro-2-{4-[2-methyl-6-oxo-7-(2- C-3-2 BB-16-5 B  1.02 (II) 513.00 trifluoromethyl-benzyl)-2,4,6,7- 100 tetrahydro-pyrazolo[3,4-d]pyrimidin- 3.5 5-yl]-piperidin-1-yl}-benzonitrile (Example 49) Ij-5 5-[1-(2,6-Dimethyl-phenyl)- C-3-1 BB-16-2 A  0.95 (II) 484.10 pyrrolidin-3-yl]-2-methyl-7-(2- 110 trifluoromethyl-benzyl)-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one Ij-6 5-(2′-Fluoro-4′-methyl-3,4,5,6- C-3-2 BB-16-6 A  1.01 (II) 503.10 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- 110 2-methyl-7-(2-trifluoromethyl- 18 benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 52) Ij-7 5-(2′-Methoxy-4′-methyl-3,4,5,6- C-3-2 BB-16-7 A  1.01 (II) 515.11 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- 110 2-methyl-7-(2-trifluoromethyl- 18 benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 54) Ij-8 5-(3′-Fluoro-3,4,5,6-tetrahydro-2H- C-3-2 BB-16-8 A  0.90 (II) 489.12 [1,2′]bipyridinyl-4-yl)-2-methyl-7-(2- 110 trifluoromethyl-benzyl)-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 68) Ij-9 2-Methyl-5-(3′-methyl-3,4,5,6- C-3-2 BB-16-9 A  0.73 (II) 485.12 tetrahydro-2H-[1,2′]bipyridinyl-4-yl)- 110 7-(2-trifluoromethyl-benzyl)-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 69) Ij-10 5-(3′-Methoxy-3,4,5,6-tetrahydro-2H- C-3-2 BB-16-10 A  0.74 (II) 501.11 [1,2′]bipyridinyl-4-yl)-2-methyl-7-(2- 110 trifluoromethyl-benzyl)-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 70) Ij-11 4′-Methyl-4-[2-methyl-6-oxo-7-(2- C-3-2 BB-16-11 A  0.98 (II) 510.11 trifluoromethyl-benzyl)-2,4,6,7- 110 tetrahydro-pyrazolo[3,4-d]pyrimidin- 18 5-yl]-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-2′-carbonitrile (Example 85) Ij-12 5-(4′-Fluoro-2′-methyl-3,4,5,6- C-3-2 BB-16-12 A  0.74 (II) 503.10 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- 110 2-methyl-7-(2-trifluoromethyl- 18 benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 86) Ij-13 5-(2′,4′-Dimethoxy-3,4,5,6- C-3-2 BB-16-13 A  0.76 (II) 531.09 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- 110 2-methyl-7-(2-trifluoromethyl- 18 benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 95) Ij-14 5-[1-(4-Methoxy-6-methyl-pyrimidin- C-3-2 BB-16-14 A  0.84 (II) 516.11 5-yl)-piperidin-4-yl]-2-methyl-7-(2- 110 trifluoromethyl-benzyl)-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 96) Ij-15 5-[1-(4,6-Dimethoxy-pyrimidin-5-yl)- C-3-2 BB-16-15 A  0.93 (II) 532.09 piperidin-4-yl]-2-methyl-7-(2- 110 trifluoromethyl-benzyl)-2,4,5,7- 18 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 100) Ij-16 1,3-Dimethyl-5-{4-[2-methyl-6-oxo-7- C-3-2 BB-16-16 B 1.04 (I) 513.01 (2-trifluoromethyl-benzyl)-2,4,6,7- 130 tetrahydro-pyrazolo[3,4-d]pyrimidin- 2.5 5-yl]-piperidin-1-yl}-1H-pyrazole-4- microwave carbonitrile (Example 229) Ij-18 5-[1-(2-Fluoro-6-trifluoromethyl- C-3-2 BB-16-19 A 1.22 (I) 556.19 phenyl)-piperidin-4-yl]-2-methyl-7-(2- 110 trifluoromethyl-benzyl)-2,4,5,7- 2.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 243) Ij-19 5-[1-(2-Fluoro-6-trifluoromethoxy- C-3-2 BB-16-20 A 1.22 (I) 572.17 phenyl)-piperidin-4-yl]-2-methyl-7-(2- 110 trifluoromethyl-benzyl)-2,4,5,7- 2.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 244) Ij-20 5-[1-(2-Chloro-6-methyl-phenyl)- C-3-2 BB-16-21 A 1.22 (I) 518.17 piperidin-4-yl]-2-methyl-7-(2- 110 trifluoromethyl-benzyl)-2,4,5,7- 2.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 245) Ij-21 5-[1-(2-Isopropyl-phenyl)-piperidin-4- C-3-2 BB-16-22 A 1.06 (I) 512.24 yl]-2-methyl-7-(2-trifluoromethyl- 110 benzyl)-2,4,5,7-tetrahydro- 2 pyrazolo[3,4-d]pyrimidin-6-one (Example 257) Ij-22 5-[1-(2-Cyclopropyl-phenyl)- C-3-2 BB-16-23 A 1.02 (I) 510.24 piperidin-4-yl]-2-methyl-7-(2- 110 trifluoromethyl-benzyl)-2,4,5,7- 2 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 258) Ij-23 6-[1-(2-Fluoro-6-trifluoromethoxy- C-3-4 BB-16-20 A 1.25 (I) 572.23 phenyl)-piperidin-4-yl]-2-methyl-4-(2- 110 trifluoromethyl-benzyl)-2,4,6,7- 18 tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 270) Ij-24 6-[1-(2-Fluoro-6-trifluoromethyl- C-3-4 BB-16-19 A 1.24 (I) 556.23 phenyl)-piperidin-4-yl]-2-methyl-4-(2- 100 trifluoromethyl-benzyl)-2,4,6,7- 18 tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 271) Ij-25 5-[1-(2-Chloro-6-fluoro-phenyl)- C-3-2 BB-16-24 A 1.19 (I) 522.18 piperidin-4-yl]-2-methyl-7-(2- 100 trifluoromethyl-benzyl)-2,4,5,7- 2.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 272) Ij-26 5-[1-(2,6-Difluoro-phenyl)-piperidin- C-3-2 BB-16-25 A 1.15 (I) 506.18 4-yl]-2-methyl-7-(2-trifluoromethyl- 100 benzyl)-2,4,5,7-tetrahydro- 2.5 pyrazolo[3,4-d]pyrimidin-6-one (Example 273) Ij-27 5-(2′-Methoxy-4′-methyl-3,4,5,6- C-3-5 BB-16-7 A 1.11 (I) 529.16 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- 100 2-methyl-7-[1-(2-trifluoromethyl- 2 phenyl)-ethyl]-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one Ij-28 3-Fluoro-2-(4-{2-methyl-6-oxo-7-[1- C-3-5 BB-16-5 B 1.13 (I) 527.27 (2-trifluoromethyl-phenyl)-ethyl]- 100 2,4,6,7-tetrahydro-pyrazolo[3,4- 5 d]pyrimidin-5-yl}-piperidin-1-yl)- benzonitrile Ij-29 5-[1-(2,6-Difluoro-phenyl)-piperidin- C-3-5 BB-16-25 A 1.16 (I) 520.27 4-yl]-2-methyl-7-[1-(2-trifluoromethyl- 100 phenyl)-ethyl]-2,4,5,7-tetrahydro- 2 pyrazolo[3,4-d]pyrimidin-6-one Ij-30 7-(2-Cyclopropyl-benzyl)-5-[1-(2- C-3-6 BB-16-19 A 1.22 (I) 528.31 fluoro-6-trifluoromethyl-phenyl)- 100 piperidin-4-yl]-2-methyl-2,4,5,7- 4 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 280) Ij-31 7-(2-Cyclopropyl-benzyl)-5-[1-(2- C-3-6 BB-16-20 A 1.22 (I) 544.31 fluoro-6-trifluoromethoxy-phenyl)- 100 piperidin-4-yl]-2-methyl-2,4,5,7- 1.5 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 281) Ij-32 2-{4-[7-(2-Cydopropyl-benzyl)-2- C-3-6 BB-16-5 B 1.13 (I) 485.25 methyl-6-oxo-2,4,6,7-tetrahydro- 100 pyrazolo[3,4-d]pyrimidin-5-yl]- 4 piperidin-1-yl}-3-fluoro-benzonitrile (Example 282) Ij-33 7-(2-Cyclopropyl-benzyl)-5-(2′- C-3-6 BB-16-7 A 1.10 (I) 487.28 methoxy-4′-methyl-3,4,5,6- 100 tetrahydro-2H-[1,3′]bipyridinyl-4-yl)- 2 2-methyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Example 283) Ij-34 5-[1-(2-Chloro-6-fluoro-phenyl)- C-3-6 BB-16-24 A 1.19 (I) 494.27 piperidin-4-yl]-7-(2-cyclopropyl- 100 benzyl)-2-methyl-2,4,5,7-tetrahydro- 2 pyrazolo[3,4-d]pyrimidin-6-one (Example 284) Ij-35 7-(2-Cyclopropyl-benzyl)-5-[1-(2,6- C-3-6 BB-16-25 A 1.14 (I) 478.31 difluoro-phenyl)-piperidin-4-yl]-2- 100 methyl-2,4,5,7-tetrahydro- 5 pyrazolo[3,4-d]pyrimidin-6-one (Example 285) Ij-36 5-[1-(2-Ethyl-6-fluoro-phenyl)- C-3-2 BB-16-26 A 1.12 (I) 516.35 piperidin-4-yl]-2-methyl-7-(2- 100 trifluoromethyl-benzyl)-2,4,5,7- 1 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 299) Ij-37 5-[1-(2-Difluoromethyl-6-fluoro- C-3-2 BB-16-27 A 1.18 (I) 538.35 phenyl)-piperidin-4-yl]-2-methyl-7-(2- 100 trifluoromethyl-benzyl)-2,4,5,7- 1 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 300) Ij-38 6-[1-(2-Difluoromethyl-6-fluoro- C-3-4 BB-16-27 A 1.18 (I) 538.29 phenyl)-piperidin-4-yl]-2-methyl-4-(2- 100 trifluoromethyl-benzyl)-2,4,6,7- 4 tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 301) Ij-40 6-[1-(2-Chloro-6-fluoro-phenyl)- C-3-4 BB-16-24 A 1.21 (I) 522.27 piperidin-4-yl]-2-methyl-4-(2- 100 trifluoromethyl-benzyl)-2,4,6,7- 4 tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 302) Ij-41 5-[1-(2-Cyclopropyl-6-fluoro-phenyl)- C-3-2 BB-16-28 A 1.21 (I) 528.35 piperidin-4-yl]-2-methyl-7-(2- 100 trifluoromethyl-benzyl)-2,4,5,7- 4 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 303) Ij-42 6-[1-(2-Cyclopropyl-6-fluoro-phenyl)- C-3-4 BB-16-28 A 1.22 (I) 528.32 piperidin-4-yl]-2-methyl-4-(2- 100 trifluoromethyl-benzyl)-2,4,6,7- 2.5 tetrahydro-pyrazolo[4,3-d]pyrimidin- 5-one (Example 304) Ij-43 7-(2-Cyclopropyl-benzyl)-5-[1-(2- C-3-6 BB-16-28 A 1.21 (I) 500.36 cyclopropyl-6-fluoro-phenyl)- 100 piperidin-4-yl]-2-methyl-2,4,5,7- 3 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 307) Ij-44 7-(2-Cyclopropyl-benzyl)-5-[1-(2- C-3-6 BB-16-27 A 1.17 (I) 510.36 difluoromethyl-6-fluoro-phenyl)- 100 piperidin-4-yl]-2-methyl-2,4,5,7- 3 tetrahydro-pyrazolo[3,4-d]pyrimidin- 6-one (Example 308)

(398) Method D (Multistep)

(399) Step A: Aromatic Nucleophilic Substitution

(400) To a soln. of amine C-3(1 eq) and halide BB-16 (2 eq) in DMSO (3.4 mL/mmol) was added CsF (2 eq). The rxn mixture was heated at a given temperature for a given time under possible microwave irradiation (see Table) and was partitioned between EtOAc and water. The org. phase was washed with water and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

(401) TABLE-US-00068 TABLE 59 t.sub.R [min] MS-data Reactant Reactant T [° C.] (LC/MS m/z Ij-A Name C-3 BB-16 time [h] method) [M + H].sup.+ Ij-17A 1,3-Dimethyl-5-{4-[2-methyl-6-oxo-7-(2- C-3-2 BB-16-17 150 1.01 (I) 516.21 trifluoromethyl-benzyl)-2,4,6,7- 3 tetrahydro-pyrazolo[3,4-d]pyrimidin-5- microwave yl]-piperidin-1-yl}-1H-pyrazole-4- carbaldehyde

(402) Step B: Decarbonylation

(403) To a soln. of Ij-A (1 eq) in MeOH (8 mL/mmol) was added toluene-4-sulfonic acid monohydrate (0.25 eq) and the rxn mixture was heated at 120° C. under microwave condition for a given time (see Table). It was concentrated in vacuo and partitioned between EtOAc and a sat. aq. soln. of NaHCO.sub.3. The org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc/MeOH.

(404) TABLE-US-00069 TABLE 60 t.sub.R [min] MS-data Reactant time (LC/MS- m/z Ij-B Name Ij-A [h] method) [M + H].sup.+ Ij-17B 5-[1-(2,5-Dimethyl-2H-pyrazol-3-yl)-piperidin-4-yl]- Ij-17A 9 0.86 (I) 488.21 2-methyl-7-(2-trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one

(405) Step C: Chlorination

(406) To a soln. of Ij-B (1 eq) in THE (5 mL/mmol) was added NCS (1.4 eq) and the rxn mixture was stirred at RT for a given time (see Table). It was partitioned between EtOAc and water and the org. phase was washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc. When necessary an additional purification by prep. LC-MS using method 5 was performed.

(407) TABLE-US-00070 TABLE 61 t.sub.R [min] MS-data Reactant time (LC/MS m/z Ij Name Ij-B [h] method) [M + H].sup.+ Ij-17 5-[1-(4-Chloro-2,5-dimethyl-2H-pyrazol-3-yl)- Ij-17B 0.5 1.11 (I) 522.17 piperidin-4-yl]-2-methyl-7-(2-trifluoromethyl-benzyl)- 2,4,5,7-tetrahydro-pyrazolo[3,4-d]pyrimidin-6-one (Example 238)

(408) Chiral Separation of Compounds of Formula Ia, Ic or Ii

(409) Racemates of formula Ia, Ic or Ij were separated into the respective enantiomers using preparative chiral HPLC or SFC (equipped with a given column and eluting with given parameters (see Table), detection: UV 210 nm).

(410) Both enantiomers were characterized by analytical chiral HPLC or SFC (equipped with a given Daicel column and eluting with given parameters (see Table), detection: UV 210 to 280 nm).

(411) The absolute configuration for the molecule Ik-70 (Example 324, enantiomer B) was assessed by single crystal X-ray diffraction (suitable crystal obtained from iPrOH) and proved to be in absolute (R)-configuration. Consequently, the absolute configuration for the molecule Ik-69 (Example 323, enantiomer A) was assigned (S). In analogy, for all example compounds wherein R.sup.4 represents methyl listed in Table 69 below, the enantiomer showing higher activity in the in vitro biological assay disclosed below may be assumed to have the absolute (S)-configuration.

(412) TABLE-US-00071 TABLE 62 Column Column t.sub.R Racemate Eluent Flow Eluent Flow [min] Ik Name Ia, Ic or Ij (preparative) (analytical) chiral HPLC Ik-1 5-[(R)- or (S)-1-(2,6-Dimethyl- Ij-5 ChiralCel OD-H ChiralCel OD-H 5.97 phenyl)-pyrrolidin-3-yl]-2-methyl- 20 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm 7-(2-trifluoromethyl-benzyl)- Hept/(EtOH + 0.1% (Hept + 0.05% 2,4,5,7-tetrahydro-pyrazolo[3,4- DEA) 70/30 DEA)/(EtOH + 0.05% d]pyrimidin-6-one (Enantiomer A) 16 mL/min DEA) 70/30 (Example 57) 0.8 mL/min Ik-2 5-[(S)- or (R)-1-(2,6-Dimethyl- 8.36 phenyl)-pyrrolidin-3-yl]-2-methyl- 7-(2-trifluoromethyl-benzyl)- 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 58) Ik-3 5-[1-(2-Fluoro-6-methyl-phenyl)- Ic-71 ChiralPak ID ChiralPak ID 12.8 piperidin-4-yl]-2-((S)- or (R)-2- 20 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm fluoro-propyl)-7-(2-trifluoromethyl- Hept/(EtOH + 0.1% (Hept + 0.02% benzyl)-2,4,5,7-tetrahydro- DEA) 90/10 DEA)/(EtOH + 0.02% pyrazolo[3,4-d]pyrimidin-6-one 16 mL/min DEA) 90/10 (Enantiomer B) (Example 185) Ik-4 5-[1-(2-Fluoro-6-methyl-phenyl)- 0.8 mL/min 10.0 piperidin-4-yl]-2-((R)- or (S)-2- fluoro-propyl)-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer A) (Example 186) Ik-5 2-((S)-or (R)-2,2-Difluoro-1- Ic-72 ChiralPak IC ChiralPak IC 10.29 methyl-ethyl)-5-[1-(2-fluoro-6- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm methyl-phenyl)-piperidin-4-yl]-7- Hept/(EtOH + 0.1% (Hept + 0.02% (2-trifluoromethyl-benzyl)-2,4,5,7- DEA) 90/10 DEA)/(EtOH + 0.02% tetrahydro-pyrazolo[3,4- 34 mL/min DEA) 90/10 d]pyrimidin-6-one (Enantiomer B) 0.8 mL/min (Example 187) Ik-6 2-((R)- or (S)-2,2-Difluoro-1- 8.49 methyl-ethyl)-5-[1-(2-fluoro-6- methyl-phenyl)-piperidin-4-yl]-7- (2-trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer A) (Example 188) Ik-7 2-((R)- or (S)-2,2-Difluoro- Ic-73 ChiralPak IG ChiralPak IG 8.12 cyclopropylmethyl)-5-[1-(2-fluoro- 20 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm 6-methyl-phenyl)-piperidin-4-yl]-7- Hept/(EtOH + 0.1% (Hept + 0.02% (2-trifluoromethyl-benzyl)-2,4,5,7- DEA) 70/30 DEA)/(EtOH + 0.02% tetrahydro-pyrazolo[3,4- 16 mL/min DEA) 70/30 d]pyrimidin-6-one (Enantiomer A) 0.8 mL/min (Example 189) Ik-8 2-((S)- or (R)-2,2-Difluoro- 9.87 cyclopropylmethyl)-5-[1-(2-fluoro- 6-methyl-phenyl)-piperidin-4-yl]-7- (2-trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 190) Ik-9 (R)- or (S)-6-[1-(2-Fluoro-6- Ia-22 Chiralpak IA Chiralpak IA 1.73 methyl-phenyl)-piperidin-4-yl]-2,7- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm dimethyl-4-(2-trifluoromethyl- CO.sub.2/(2-propanol + CO.sub.2/EtOH 85/15 benzyl)-2,4,6,7-tetrahydro- 0.1% DEA) 90/10 4 mL/min pyrazolo[4,3-d]pyrimidin-5-one 160 mL/min 150 bars, 40° C. (Enantiomer A) (Example 202) 100 bars, 40° C. Ik-10 (S)- or (R)-6-[1-(2-Fluoro-6- 2.02 methyl-phenyl)-piperidin-4-yl]-2,7- dimethyl-4-(2-trifluoromethyl- benzyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer B) (Example 203) Ik-11 (R)- or (S)-5-[1-(2-Fluoro-6- Ia-26 Chiralpak IC Chiralpak IC 1.81 methyl-phenyl)-piperidin-4-yl]-2,4- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm dimethyl-7-(2-trifluoromethyl- CO.sub.2/EtOH 80/20 CO.sub.2/EtOH 80/20 benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/min pyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C. (Enantiomer A) (Example 220) Ik-12 (S)- or (R)-5-[1-(2-Fluoro-6- 2.82 methyl-phenyl)-piperidin-4-yl]-2,4- dimethyl-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 221) Ik-13 5-[(S)- or (R)-1-(2-Fluoro-6- Ia-27 Chiralpak AD-H Chiralpak AD-H 3.69 methyl-phenyl)-azepan-4-yl]-2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm methyl-7-(2-trifluoromethyl- CO.sub.2/EtOH 85/15 CO.sub.2/EtOH 85/15 benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/min pyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C. (Enantiomer A) (Example 225) Ik-14 5-[(R)- or (S)-1-(2-Fluoro-6- 2.77 methyl-phenyl)-azepan-4-yl]-2- methyl-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 226) Ik-15 5-[(R)- or (S)-1-(2-Fluoro-6- Ia-33 Chiralpak AD-H Chiralpak AD-H 1.40 methyl-phenyl)-3-methyl- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm pyrrolidin-3-yl]-2-methyl-7-(2- CO.sub.2/EtOH 80/20 CO.sub.2/(EtOH + trifluoromethyl-benzyl)-2,4,5,7- 160 mL/min 1% DEA) 85/15 tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 4 mL/min d]pyrimidin-6-one (Enantiomer A) 150 bars, 40° C. (Example 234) Ik-16 5-[(S)- or (R)-1-(2-Fluoro-6- 1.82 methyl-phenyl)-3-methyl- pyrrolidin-3-yl]-2-methyl-7-(2- trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 235) Ik-17 5-[(R)- or (S)-1-(2-Fluoro-6- Ia-37 Chiralpak IF Chiralpak IF 2.07 methyl-phenyl)-piperidin-3-yl]-2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm methyl-7-(2-trifluoromethyl- CO.sub.2/EtOH 75/25 CO.sub.2/EtOH 75/25 benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/min pyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C. (Enantiomer A) (Example 241) Ik-18 5-[(S)- or (R)-1-(2-Fluoro-6- 2.70 methyl-phenyl)-piperidin-3-yl]-2- methyl-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 242) Ik-19 5-[1-(2-Fluoro-6-methyl-phenyl)- Ia-38 Chiralpak AZ-H Chiralpak AZ-H 1.88 piperidin-4-yl]-2-methyl-7-[(R)- or 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm (S)-1-(2-trifluoromethyl-phenyl)- CO.sub.2/EtOH 75/25 CO.sub.2/EtOH 75/25 ethyl]-2,4,5,7-tetrahydro- 160 mL/min 4 mL/min pyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C. (Enantiomer A) (Example 246) Ik-20 5-[1-(2-Fluoro-6-methyl-phenyl)- 2.63 piperidin-4-yl]-2-methyl-7-[(S)- or (R)-1-(2-trifluoromethyl-phenyl)- ethyl]-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 247) Ik-21 (R)- or (S)-2-(2,2-Difluoro-propyl)- Ic-93 Regis (R,R) Regis (R,R) 1.57 6-[1-(2-fluoro-6-methyl-phenyl)- Whelk-O1 Whelk-O1 piperidin-4-yl]-7-methyl-4-(2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm trifluoromethyl-benzyl)-2,4,6,7- CO.sub.2/(MeCN/EtOH CO.sub.2/(MeCN/EtOH tetrahydro-pyrazolo[4,3- 1/1) 70/30 1/1) 70/30 d]pyrimidin-5-one (Enantiomer A) 160 mL/min 4 mL/min (Example 253) 100 bars, 40° C. 150 bars, 40° C. Ik-22 (S)- or (R)-2-(2,2-Difluoro-propyl)- 2.09 6-[1-(2-fluoro-6-methyl-phenyl)- piperidin-4-yl]-7-methyl-4-(2- trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Enantiomer B) (Example 254) Ik-23 (R)- or (S)-1-(2,2-Difluoro-propyl)- Id-9 Regis (R,R) Regis (R,R) 1.69 6-[1-(2-fluoro-6-methyl-phenyl)- Whelk-O1 Whelk-O1 piperidin-4-yl]-7-methyl-4-(2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm trifluoromethyl-benzyl)-1,4,6,7- CO.sub.2/(MeCN/EtOH CO.sub.2/(MeCN/EtOH tetrahydro-pyrazolo[4,3- 1/1) 70/30 1/1) 70/30 d]pyrimidin-5-one (Enantiomer A) 160 mL/min 4 mL/min (Example 255) 100 bars, 40° C. 150 bars, 40° C. Ik-24 (S)- or (R)-1-(2,2-Difluoro-propyl)- 2.21 6-[1-(2-fluoro-6-methyl-phenyl)- piperidin-4-yl]-7-methyl-4-(2- trifluoromethyl-benzyl)-1,4,6,7- tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Enantiomer B) (Example 256) Ik-25 6-[1-(2-Fluoro-6-methyl-phenyl)- Ia-44 Chiralpak IG Chiralpak IG 1.88 piperidin-4-yl]-2-methyl-4-[(R)- or 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm (S)-1-(2-trifluoromethyl-phenyl)- CO.sub.2/EtOH 70/30 CO.sub.2/EtOH 70/30 ethyl]-2,4,6,7-tetrahydro- 160 mL/min 4 mL/min pyrazolo[4,3-d]pyrimidin-5-one 100 bars, 40° C. 150 bars, 40° C. (Enantiomer A) (Example 261) Ik-26 6-[1-(2-Fluoro-6-methyl-phenyl)- 2.42 piperidin-4-yl]-2-methyl-4-[(S)- or (R)-1-(2-trifluoromethyl-phenyl)- ethyl]-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer B) (Example 262) Ik-27 (R)- or (S)-6-[1-(2-Fluoro-6- Ib-10 Regis (R,R) Regis (R,R) 1.74 methyl-phenyl)-piperidin-4-yl]-7- Whelk-O1 Whelk-O1 methyl-4-(2-trifluoromethyl- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm benzyl)-2,4,6,7-tetrahydro- CO.sub.2/EtOH 60/40 CO.sub.2/EtOH 60/40 pyrazolo[4,3-d]pyrimidin-5-one 160 mL/min 4 mL/min (Enantiomer A) (Example 263) 100 bars, 40° C. 150 bars, 40° C. Ik-28 (S)- or (R)-6-[1-(2-Fluoro-6- 2.30 methyl-phenyl)-piperidin-4-yl]-7- methyl-4-(2-trifluoromethyl- benzyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer B) Ik-29 (R)- or (S)-2-Cyclopropyl-6-[1-(2- Ic-94 Regis (R,R) Regis (R,R) 1.90 fluoro-6-methyl-phenyl)-piperidin- Whelk-O1 Whelk-O1 4-yl]-7-methyl-4-(2-trifluoromethyl- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm benzyl)-2,4,6,7-tetrahydro- CO.sub.2/(MeCN/EtOH CO.sub.2/(MeCN/EtOH pyrazolo[4,3-d]pyrimidin-5-one 1/1) 70/30 1/1) 70/30 (Enantiomer A) (Example 265) 160 mL/min 4 mL/min 100 bars, 40° C. 150 bars, 40° C. Ik-30 (S)- or (R)-2-Cyclopropyl-6-[1-(2- 2.48 fluoro-6-methyl-phenyl)-piperidin- 4-yl]-7-methyl-4-(2-trifluoromethyl- benzyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer B) (Example 266) Ik-31 (R)- or (S)-4-(2-Cyclopropyl- Ib-11 Chiralpak IB Chiralpak IB 2.16 benzyl)-6-(2′-methoxy-4′-methyl- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm 3,4,5,6-tetrahydro-2H- CO.sub.2/EtOH 75/25 CO.sub.2/EtOH 75/25 [1,3′]bipyridinyl-4-yl)-7-methyl- 160 mL/min 4 mL/min 2,4,6,7-tetrahydro-pyrazolo[4,3- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-5-one (Enantiomer A) Ik-32 (S)- or (R)-4-(2-Cyclopropyl- 2.80 benzyl)-6-(2′-methoxy-4′-methyl- 3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-7-methyl- 2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Enantiomer B) (Example 274) Ik-33 (R)- or (S)-4-(2-Cyclopropyl- Ib-12 Chiralpak IB Chiralpak IB 2.16 benzyl)-6-[1-(2-fluoro-6-methyl- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm phenyl)-piperidin-4-yl]-7-methyl- CO.sub.2/EtOH 70/30 CO.sub.2/EtOH 75/25 2,4,6,7-tetrahydro-pyrazolo[4,3- 160 mL/min 4 mL/min d]pyrimidin-5-one (Enantiomer A) 100 bars, 40° C. 150 bars, 40° C. Ik-34 (S)- or (R)-4-(2-Cyclopropyl- 3.06 benzyl)-6-[1-(2-fluoro-6-methyl- phenyl)-piperidin-4-yl]-7-methyl- 2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Enantiomer B) (Example 275) Ik-35 (R)- or (S)-4-(2-Cyclopropyl- Ic-95 Chiralpak IB Chiralpak IB 1.56 benzyl)-2-(2,2-difluoro-propyl)-6- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm [1-(2-fluoro-6-methyl-phenyl)- CO.sub.2/EtOH 80/20 CO.sub.2/EtOH 80/20 piperidin-4-yl]-7-methyl-2,4,6,7- 160 mL/min 4 mL/min tetrahydro-pyrazolo[4,3- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-5-one (Enantiomer A) (Example 276) Ik-36 (S)- or (R)-4-(2-Cyclopropyl- 2.32 benzyl)-2-(2,2-difluoro-propyl)-6- [1-(2-fluoro-6-methyl-phenyl)- piperidin-4-yl]-7-methyl-2,4,6,7- tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Enantiomer B) (Example 277) Ik-37 (R)- or (S)-2-Cyclopropyl-4-(2- Ic-96 Chiralpak IB Chiralpak IB 1.74 cyclopropyl-benzyl)-6-[1-(2-fluoro- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm 6-methyl-phenyl)-piperidin-4-yl]-7- CO.sub.2/EtOH 75/25 CO.sub.2/EtOH 75/25 methyl-2,4,6,7-tetrahydro- 160 mL/min 4 mL/min pyrazolo[4,3-d]pyrimidin-5-one 100 bars, 40° C. 150 bars, 40° C. (Enantiomer A) (Example 278) Ik-38 (S)- or (R)-2-Cyclopropyl-4-(2- 2.42 cyclopropyl-benzyl)-6-[1-(2-fluoro- 6-methyl-phenyl)-piperidin-4-yl]-7- methyl-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer B) (Example 279) Ik-39 5-(2′-Methoxy-4′-methyl-3,4,5,6- Ij-27 Regis (R,R) Regis (R,R) 2.12 tetrahydro-2H-[1,3′]bipyridinyl-4- Whelk-O1 Whelk-O1 yl)-2-methyl-7-[(R)- or (S)-1-(2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm trifluoromethyl-phenyl)-ethyl]- CO.sub.2/EtOH 70/30 CO.sub.2/EtOH 70/30 2,4,5,7-tetrahydro-pyrazolo[3,4- 160 mL/min 4 mL/min d]pyrimidin-6-one (Enantiomer A) 100 bars, 40° C. 150 bars, 40° C. (Example 286) Ik-40 5-(2′-Methoxy-4′-methyl-3,4,5,6- 2.66 tetrahydro-2H-[1,3′]bipyridinyl-4- yl)-2-methyl-7-[(S)- or (R)-1-(2- trifluoromethyl-phenyl)-ethyl]- 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 287) Ik-41 3-Fluoro-2-(4-{2-methyl-6-oxo-7- Ij-28 Regis (R,R) Regis (R,R) 2.81 [(R)- or (S)-1-(2-trifluoromethyl- Whelk-O1 Whelk-O1 phenyl)-ethyl]-2,4,6,7-tetrahydro- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm pyrazolo[3,4-d]pyrimidin-5-yl}- CO.sub.2/EtOH 75/25 CO.sub.2/EtOH 75/25 piperidin-1-yl)-benzonitrile 160 mL/min 4 mL/min (Enantiomer A) (Example 288) 100 bars, 40° C. 150 bars, 40° C. Ik-42 3-Fluoro-2-(4-{2-methyl-6-oxo-7- 3.32 [(S)- or (R)-1-(2-trifluoromethyl- phenyl)-ethyl]-2,4,6,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-5-yl}- piperidin-1-yl)-benzonitrile (Enantiomer B) (Example 289) Ik-43 5-[1-(2,6-Difluoro-phenyl)- Ij-29 Regis (R,R) Regis (R,R) 2.61 piperidin-4-yl]-2-methyl-7-[(R)- or Whelk-O1 Whelk-O1 (S)-1-(2-trifluoromethyl-phenyl)- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm ethyl]-2,4,5,7-tetrahydro- CO.sub.2/EtOH 80/20 CO.sub.2/EtOH 80/20 pyrazolo[3,4-d]pyrimidin-6-one 160 mL/min 4 mL/min (Enantiomer A) (Example 290) 100 bars, 40° C. 150 bars, 40° C. Ik-44 5-[1-(2,6-Difluoro-phenyl)- 3.11 piperidin-4-yl]-2-methyl-7-[(S)- or (R)-1-(2-trifluoromethyl-phenyl)- ethyl]-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 291) Ik-45 (R)- or (S)-2-Cyclopropyl-4-(2- Ic-97 Chiralpak AD-H Chiralpak AD-H 1.42 cyclopropyl-benzyl)-6-(2′- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm methoxy-4′-methyl-3,4,5,6- CO.sub.2/EtOH 70/30 CO.sub.2/EtOH 70/30 tetrahydro-2H-[1,3′]bipyridinyl-4- 160 mL/min 4 mL/min yl)-7-methyl-2,4,6,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C. pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer A) (Example 293) Ik-46 (S)- or (R)-2-Cyclopropyl-4-(2- 1.97 cyclopropyl-benzyl)-6-(2′- methoxy-4′-methyl-3,4,5,6- tetrahydro-2H-[1,3′]bipyridinyl-4- yl)-7-methyl-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer B) (Example 292) Ik-47 (R)- or (S)-6-(2′-Methoxy-4′- Ib-14 Regis (R,R) Regis (R,R) 1.80 methyl-3,4,5,6-tetrahydro-2H- Whelk-O1 Whelk-O1 [1,3′]bipyridinyl-4-yl)-7-methyl-4- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm (2-trifluoromethyl-benzyl)-2,4,6,7- CO.sub.2/(MeCN/EtOH CO.sub.2/(MeCN/EtOH tetrahydro-pyrazolo[4,3- 1/1) 65/35 1/1) 65/35 d]pyrimidin-5-one (Enantiomer A) 160 mL/min 4 mL/min (Example 295) 100 bars, 40° C. 150 bars, 40° C. Ik-48 (S)- or (R)-6-(2′-Methoxy-4′- 2.50 methyl-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-7-methyl-4- (2-trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Enantiomer B) Ik-49 (R)- or (S)-2-Cyclopropyl-6-(2′- Ic-98 Chiralpak IE Chiralpak IE 1.89 methoxy-4′-methyl-3,4,5,6- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm tetrahydro-2H-[1,3′]bipyridinyl-4- CO.sub.2/EtOH 65/35 CO.sub.2/EtOH 65/35 yl)-7-methyl-4-(2-trifluoromethyl- 160 mL/min 4 mL/min benzyl)-2,4,6,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C. pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer A) (Example 296) Ik-50 (S)- or (R)-2-Cyclopropy l-6-(2′- 2.39 methoxy-4′-methyl-3,4,5,6- tetrahydro-2H-[1,3′]bipyridinyl-4- yl)-7-methyl-4-(2-trifluoromethyl- benzyl)-2,4,6,7-tetrahydro- pyrazolo[4,3-d]pyrimidin-5-one (Enantiomer B) (Example 297) Ik-51 (R)- or (S)-6-(2′-Methoxy-4′- Ic-99 Chiralpak IE Chiralpak IE 2.56 methyl-3,4,5,6-tetrahydro-2H- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm [1,3′]bipyridinyl-4-yl)-2,7-dimethyl- CO.sub.2/EtOH 75/25 CO.sub.2/EtOH 75/25 4-(2-trifluoromethyl-benzyl)- 160 mL/min 4 mL/min 2,4,6,7-tetrahydro-pyrazolo[4,3- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-5-one (Enantiomer A) (Example 298) Ik-52 (S)- or (R)-6-(2′-Methoxy-4′- 3.19 methyl-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-2,7-dimethyl- 4-(2-trifluoromethyl-benzyl)- 2,4,6,7-tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Enantiomer B) Ik-53 (R)- or (S)-2-(2,2-Difluoro-propyl)- Ic-100 Regis (R,R) Regis (R,R) 2.24 5-[1-(2-fluoro-6-methyl-phenyl)- Whelk-O1 Whelk-O1 piperidin-4-yl]-4-methyl-7-(2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm trifluoromethyl-benzyl)-2,4,5,7- CO.sub.2/EtOH 70/30 CO.sub.2/EtOH 70/30 tetrahydro-pyrazolo[3,4- 160 mL/min 4 mL/min d]pyrimidin-6-one (Enantiomer A) 100 bars, 40° C. 150 bars, 40° C. (Example 305) Ik-54 (S)- or (R)-2-(2,2-Difluoro-propyl)- 2.76 5-[1-(2-fluoro-6-methyl-phenyl)- piperidin-4-yl]-4-methyl-7-(2- trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 306) Ik-55 (R)- or (S)-2-Cyclopropyl-5-[1-(2- Ia-55 Chiralpak IC Chiralpak IC 1.19 fluoro-6-methyl-phenyl)-piperidin- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm 4-yl]-4-methyl-7-(2-trifluoromethyl- CO.sub.2/EtOH 65/35 CO.sub.2/EtOH 65/35 benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/min pyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C. (Enantiomer A) (Example 309) Ik-56 (S)- or (R)-2-Cyclopropyl-5-[1-(2- 1.59 fluoro-6-methyl-phenyl)-piperidin- 4-yl]-4-methyl-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 310) Ik-57 (R)- or (S)-2-Cyclopropyl-5-[1-(2- Ia-56 Chiralpak IC Chiralpak IC 1.22 difluoromethyl-6-fluoro-phenyl)- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm piperidin-4-yl]-4-methyl-7-(2- CO.sub.2/EtOH 75/25 CO.sub.2/EtOH 75/25 trifluoromethyl-benzyl)-2,4,5,7- 160 mL/min 4 mL/min tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-6-one (Enantiomer A) (Example 311) Ik-58 (S)- or (R)-2-Cyclopropyl-5-[1-(2- 1.62 difluoromethyl-6-fluoro-phenyl)- piperidin-4-yl]-4-methyl-7-(2- trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 312) Ik-59 (R)- or (S)-5-[1-(2-Difluoromethyl- Ia-57 Chiralpak IC Chiralpak IC 1.33 6-fluoro-phenyl)-piperidin-4-yl]- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm 2,4-dimethyl-7-(2-trifluoromethyl- CO.sub.2/EtOH 80/20 CO.sub.2/EtOH 80/20 benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/min pyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C. (Enantiomer A) (Example 314) Ik-60 (S)- or (R)-5-[1-(2-Difluoromethyl- 1.80 6-fluoro-phenyl)-piperidin-4-yl]- 2,4-dimethyl-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 315) Ik-61 (R)- or (S)-5-[1-(2-Fluoro-6- Ib-13 Chiralpak AD-H Chiralpak AD-H 0.86 methyl-phenyl)-piperidin-4-yl]-4- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm methyl-7-(2-trifluoromethyl- CO.sub.2/EtOH 55/45 CO.sub.2/EtOH 55/45 benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/min pyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C. (Enantiomer A) Ik-62 (S)- or (R)-5-[1-(2-Fluoro-6- 1.20 methyl-phenyl)-piperidin-4-yl]-4- methyl-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 316) Ik-63 (R)- or (S)-7-(2-Cyclopropyl- Ia-58 Chiralpak AD-H Chiralpak AD-H 1.75 benzyl)-5-[1-(2-fluoro-6-methyl- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm phenyl)-piperidin-4-yl]-2,4- CO.sub.2/EtOH 70/30 CO.sub.2/EtOH 70/30 dimethyl-2,4,5,7-tetrahydro- 160 mL/min 4 mL/min pyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C. (Enantiomer A) (Example 317) Ik-64 (S)- or (R)-7-(2-Cyclopropyl- 2.32 benzyl)-5-[1-(2-fluoro-6-methyl- phenyl)-piperidin-4-yl]-2,4- dimethyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 318) Ik-65 (R)- or (S)-5-[1-(2-Chloro-6-fluoro- Ia-59 Chiralpak IC Chiralpak IC 1.32 phenyl)-piperidin-4-yl]-2,4- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm dimethyl-7-(2-trifluoromethyl- CO.sub.2/EtOH 70/30 CO.sub.2/EtOH 70/30 benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/min pyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C. (Enantiomer A) (Example 319) Ik-66 (S)- or (R)-5-[1-(2-Chloro-6-fluoro- 1.78 phenyl)-piperidin-4-yl]-2,4- dimethyl-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 320) Ik-67 (R)- or (S)-5-[1-(2-Chloro-6-fluoro- Ia-60 Chiralpak IB Chiralpak IB 1.97 phenyl)-piperidin-4-yl]-7-(2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm cyclopropyl-benzyl)-2,4-dimethyl- CO.sub.2/EtOH 70/30 CO.sub.2/EtOH 70/30 2,4,5,7-tetrahydro-pyrazolo[3,4- 160 mL/min 4 mL/min d]pyrimidin-6-one (Enantiomer A) 100 bars, 40° C. 150 bars, 40° C. (Example 321) Ik-68 (S)- or (R)-5-[1-(2-Chloro-6-fluoro- 2.46 phenyl)-piperidin-4-yl]-7-(2- cyclopropyl-benzyl)-2,4-dimethyl- 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 322) Ik-69 (S)-7-(2-Cyclopropyl-benzyl)-5-[1- Ia-61 Chiralpak AD-H Chiralpak AD-H 1.34 (2-difluoromethyl-6-fluoro-phenyl)- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm piperidin-4-yl]-2,4-dimethyl- CO.sub.2/EtOH 75/25 CO.sub.2/EtOH 70/30 2,4,5,7-tetrahydro-pyrazolo[3,4- 160 mL/min 4 mL/min d]pyrimidin-6-one (Enantiomer A) 100 bars, 40° C. 150 bars, 40° C. (Example 323) Ik-70 (R)-7-(2-Cyclopropyl-benzyl)-5-[1- 1.70 (2-difluoromethyl-6-fluoro-phenyl)- piperidin-4-yl]-2,4-dimethyl- 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 324) Ik-71 (R)- or (S)-7-(2-Cyclopropyl- Ia-62 Chiralpak AD-H Chiralpak AD-H 1.59 benzyl)-5-[1-(2-cyclopropyl-6- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm fluoro-phenyl)-piperidin-4-yl]-2,4- CO.sub.2/EtOH 70/30 CO.sub.2/EtOH 70/30 dimethyl-2,4,5,7-tetrahydro- 160 mL/min 4 mL/min pyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C. (Enantiomer A) (Example 325) Ik-72 (S)- or (R)-7-(2-Cyclopropyl- 2.16 benzyl)-5-[1-(2-cyclopropyl-6- fluoro-phenyl)-piperidin-4-yl]-2,4- dimethyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 326) Ik-73 (R)- or (S)-6-[1-(2-Chloro-6-fluoro- Ic-101 Chiralpak AD-H Chiralpak AD-H 1.93 phenyl)-piperidin-4-yl]-2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm cyclopropyl-7-methyl-4-(2- CO.sub.2/EtOH 85/15 CO.sub.2/EtOH 85/15 trifluoromethyl-benzyl)-2,4,6,7- 160 mL/min 4 mL/min tetrahydro-pyrazolo[4,3- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-5-one (Enantiomer A) (Example 327) Ik-74 (S)- or (R)-6-[1-(2-Chloro-6-fluoro- 2.51 phenyl)-piperidin-4-yl]-2- cyclopropyl-7-methyl-4-(2- trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Enantiomer B) (Example 328) Ik-75 (R)- or (S)-2-Cyclopropyl-6-[1-(2- Ic-102 Regis (R,R) Regis (R,R) 1.82 difluoromethyl-6-fluoro-phenyl)- Whelk-O1 Whelk-O1 piperidin-4-yl]-7-methyl-4-(2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm trifluoromethyl-benzyl)-2,4,6,7- CO.sub.2/EtOH 65/35 CO.sub.2/EtOH 65/35 tetrahydro-pyrazolo[4,3- 160 mL/min 4 mL/min d]pyrimidin-5-one (Enantiomer A) 100 bars, 40° C. 150 bars, 40° C. (Example 329) Ik-76 (S)- or (R)-2-Cyclopropyl-6-[1-(2- 2.47 difluoromethyl-6-fluoro-phenyl)- piperidin-4-yl]-7-methyl-4-(2- trifluoromethyl-benzyl)-2,4,6,7- tetrahydro-pyrazolo[4,3- d]pyrimidin-5-one (Enantiomer B) (Example 330) Ik-77 (R)- or (S)-5-(2′-Methoxy-4′- Ia-65 Chiralpak IC Chiralpak IC 1.22 methyl-3,4,5,6-tetrahydro-2H- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm [1,3′]bipyridinyl-4-yl)-2,4-dimethyl- CO.sub.2/EtOH 60/40 CO.sub.2/EtOH 60/40 7-(2-trifluoromethyl-benzyl)- 160 mL/min 4 mL/min 2,4,5,7-tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-6-one (Enantiomer A) (Example 331) Ik-78 (S)- or (R)-5-(2′-Methoxy-4′- 1.78 methyl-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-2,4-dimethyl- 7-(2-trifluoromethyl-benzyl)- 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 332) Ik-79 (R)- or (S)-5-[1-(2-Cydopropyl-6- Ia-66 Chiralpak IC Chiralpak IC 1.55 fluoro-phenyl)-piperidin-4-yl]-2,4- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm dimethyl-7-(2-trifluoromethyl- CO.sub.2/EtOH 75/25 CO.sub.2/EtOH 75/25 benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/min pyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C. (Enantiomer A) (Example 333) Ik-80 (S)- or (R)-5-[1-(2-Cyclopropyl-6- 2.18 fluoro-phenyl)-piperidin-4-yl]-2,4- dimethyl-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 334) Ik-81 (R)- or (S)-5-[1-(2-Chloro-6-fluoro- Ia-67 Chiralpak IC Chiralpak IC 1.41 phenyl)-piperidin-4-yl]-2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm cyclopropyl-4-methyl-7-(2- CO.sub.2/EtOH 70/30 CO.sub.2/EtOH 70/30 trifluoromethyl-benzyl)-2,4,5,7- 160 mL/min 4 mL/min tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-6-one (Enantiomer A) (Example 335) Ik-82 (S)- or (R)-5-[1-(2-Chloro-6-fluoro- 2.01 phenyl)-piperidin-4-yl]-2- cyclopropyl-4-methyl-7-(2- trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 336) Ik-83 (R)- or (S)-5-[1-(2-Chloro-6-fluoro- Ia-69 Chiralpak AD-H Chiralpak AD-H 1.24 phenyl)-piperidin-4-yl]-2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm cydopropyl-7-(2-cyclopropyl- CO.sub.2/EtOH 50/50 CO.sub.2/EtOH 50/50 benzyl)-4-methyl-2,4,5,7- 160 mL/min 4 mL/min tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-6-one (Enantiomer A) (Example 337) Ik-84 (S)- or (R)-5-[1-(2-Chloro-6-fluoro- 1.81 phenyl)-piperidin-4-yl]-2- cyclopropyl-7-(2-cyclopropyl- benzyl)-4-methyl-2,4,5,7- tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 338) Ik-85 (R)- or (S)-2-Cyclopropyl-7-(2- Ia-68 Chiralpak AD-H Chiralpak AD-H 1.07 cyclopropyl-benzyl)-5-[1-(2-fluoro- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm 6-methyl-phenyl)-piperidin-4-yl]-4- CO.sub.2/EtOH 50/50 CO.sub.2/EtOH 50/50 methyl-2,4,5,7-tetrahydro- 160 mL/min 4 mL/min pyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C. (Enantiomer A) (Example 339) Ik-86 (S)- or (R)-2-Cyclopropyl-7-(2- 1.55 cyclopropyl-benzyl)-5-[1-(2-fluoro- 6-methyl-phenyl)-piperidin-4-yl]-4- methyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 340) Ik-87 (R)- or (S)-2-Cyclopropyl-5-(2′- Ia-70 Chiralpak IC Chiralpak IC 1.47 methoxy-4′-methyl-3,4,5,6- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm tetrahydro-2H-[1,3′]bipyridinyl-4- CO.sub.2/EtOH 65/35 CO.sub.2/EtOH 65/35 yl)-4-methyl-7-(2-trifluoromethyl- 160 mL/min 4 mL/min benzyl)-2,4,5,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C. pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer A) (Example 344) Ik-88 (S)- or (R)-2-Cyclopropyl-5-(2′- 2.42 methoxy-4′-methyl-3,4,5,6- tetrahydro-2H-[1,3′]bipyridinyl-4- yl)-4-methyl-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 345) Ik-89 (R)- or (S)-5-(4′-Difluoromethyl-2′- Ia-71 Chiralpak IC Chiralpak IC 1.45 methoxy-3,4,5,6-tetrahydro-2H- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm [1,3′]bipyridinyl-4-yl)-2,4-dimethyl- CO.sub.2/EtOH 80/20 CO.sub.2/EtOH 80/20 7-(2-trifluoromethyl-benzyl)- 160 mL/min 4 mL/min 2,4,5,7-tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-6-one (Enantiomer A) (Example 346) Ik-90 (S)- or (R)-5-(4′-Difluoromethyl-2′- 2.28 methoxy-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-2,4-dimethyl- 7-(2-trifluoromethyl-benzyl)- 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 347) Ik-91 (R)- or (S)-5-[1-(2-Difluoromethyl- Ib-17 ChiralCel OZ-H ChiralCel OZ-H 0.91 6-fluoro-phenyl)-piperidin-4-yl]-4- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm methyl-7-(2-trifluoromethyl- CO.sub.2/EtOH 60/40 CO.sub.2/EtOH 60/40 benzyl)-2,4,5,7-tetrahydro- 160 mL/min 4 mL/min pyrazolo[3,4-d]pyrimidin-6-one 100 bars, 40° C. 150 bars, 40° C. (Enantiomer A) (Example 348) Ik-92 (S)- or (R)-5-[1-(2-Difluoromethyl- 1.37 6-fluoro-phenyl)-piperidin-4-yl]-4- methyl-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 349) Ik-93 (R)- or (S)-5-[1-(2-Chloro-6-fluoro- Ib-18 ChiralCel OZ-H ChiralCel OZ-H 0.93 phenyl)-piperidin-4-yl]-4-methyl-7- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm (2-trifluoromethyl-benzyl)-2,4,5,7- CO.sub.2/EtOH 50/50 CO.sub.2/EtOH 50/50 tetrahydro-pyrazolo[3,4- 160 mL/min 4 mL/min d]pyrimidin-6-one (Enantiomer A) 100 bars, 40° C. 150 bars, 40° C. (Example 350) Ik-94 (S)- or (R)-5-[1-(2-Chloro-6-fluoro- 1.53 phenyl)-piperidin-4-yl]-4-methyl-7- (2-trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 351) Ik-95 (R)- or (S)-5-(4′-Difluoromethyl-2′- Ib-19 ChiralCel OZ-H ChiralCel OZ-H 0.93 methoxy-3,4,5,6-tetrahydro-2H- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm [1,3′]bipyridinyl-4-yl)-4-methyl-7- CO.sub.2/EtOH 60/40 CO.sub.2/EtOH 60/40 (2-trifluoromethyl-benzyl)-2,4,5,7- 160 mL/min 4 mL/min tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-6-one (Enantiomer A) (Example 352) Ik-96 (S)- or (R)-5-(4′-Difluoromethyl-2′- 1.42 methoxy-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-4-methyl-7- (2-trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 353) Ik-97 (R)- or (S)-5-[1-(2-Fluoro-6- Ia-75 Chiralpak IC Chiralpak IC 0.98 methyl-phenyl)-piperidin-4-yl]-2,4- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm dimethyl-7-(3-trifluoromethyl- CO.sub.2/EtOH 50/50 CO.sub.2/EtOH 50/50 pyridin-2-ylmethyl)-2,4,5,7- 160 mL/min 4 mL/min tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-6-one (Enantiomer A) (Example 354) Ik-98 (S)-or (R)-5-[1-(2-Fluoro-6- 1.37 methyl-phenyl)-piperidin-4-yl]-2,4- dimethyl-7-(3-trifluoromethyl- pyridin-2-ylmethyl)-2,4,5,7- tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 355) Ik-99 (R)- or (S)-5-(2′-Methoxy-4′- Ia-76 Chiralpak IC Chiralpak IC 1.11 methyl-3,4,5,6-tetrahydro-2H- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm [1,3′]bipyridinyl-4-yl)-2,4-dimethyl- CO.sub.2/EtOH 50/50 CO.sub.2/EtOH 50/50 7-(3-trifluoromethyl-pyridin-2- 160 mL/min 4 mL/min ylmethyl)-2,4,5,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C. pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer A) (Example 356) Ik-100 (S)- or (R)-5-(2′-Methoxy-4′- 2.02 methyl-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-2,4-dimethyl- 7-(3-trifluoromethyl-pyridin-2- ylmethyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 357) Ik-101 (R)- or (S)-2-Cyclopropyl-5-(4′- Ia-77 Chiralpak IC Chiralpak IC 1.19 difluoromethyl-2′-methoxy-3,4,5,6- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm tetrahydro-2H-[1,3′]bipyridinyl-4- CO.sub.2/EtOH 70/30 CO.sub.2/EtOH 70/30 yl)-4-methyl-7-(2-trifluoromethyl- 160 mL/min 4 mL/min benzyl)-2,4,5,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C. pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer A) (Example 358) Ik-102 (S)- or (R)-2-Cyclopropyl-5-(4′- 1.66 difluoromethyl-2′-methoxy-3,4,5,6- tetrahydro-2H-[1,3′]bipyridinyl-4- yl)-4-methyl-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 359) Ik-103 (R)- or (S)-5-[1-(2-Bromo-6-fluoro- Ia-78 Chiralpak IC Chiralpak IC 1.34 phenyl)-piperidin-4-yl]-2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm cyclopropyl-4-methyl-7-(2- CO.sub.2/EtOH 65/35 CO.sub.2/EtOH 65/35 trifluoromethyl-benzyl)-2,4,5,7- 160 mL/min 4 mL/min tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-6-one (Enantiomer A) (Example 360) Ik-104 (S)- or (R)-5-[1-(2-Bromo-6-fluoro- 1.86 phenyl)-piperidin-4-yl]-2- cyclopropyl-4-methyl-7-(2- trifluoromethyl-benzyl)-2,4,5,7- tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 361) Ik-105 (R)- or (S)-5-(2′-Methoxy-4′- Ia-79 Chiralpak IC Chiralpak IC 1.03 trifluoromethyl-3,4,5,6-tetrahydro- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm 2H-[1,3′]bipyridinyl-4-yl)-2,4- CO.sub.2/EtOH 70/30 CO.sub.2/EtOH 70/30 dimethyl-7-(2-trifluoromethyl- 160 mL/min 4 mL/min benzyl)-2,4,5,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C. pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer A) (Example 362) Ik-106 (S)- or (R)-5-(2′-Methoxy-4′- 1.37 trifluoromethyl-3,4,5,6-tetrahydro- 2H-[1,3′]bipyridinyl-4-yl)-2,4- dimethyl-7-(2-trifluoromethyl- benzyl)-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 363) Ik-107 (R)- or (S)-7-(2-Cydopropyl- Ia-81 Chiralpak AD-H Chiralpak AD-H 0.99 benzyl)-5-(4′-difluoromethyl-2′- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm methoxy-3,4,5,6-tetrahydro-2H- CO.sub.2/EtOH 60/40 CO.sub.2/EtOH 60/40 [1,3′]bipyridinyl-4-yl)-2,4-dimethyl- 160 mL/min 4 mL/min 2,4,5,7-tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-6-one (Enantiomer A) (Example 366) Ik-108 (S)- or (R)-7-(2-Cyclopropyl- 1.33 benzyl)-5-(4′-difluoromethyl-2′- methoxy-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-2,4-dimethyl- 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 367) Ik-109 (R)- or (S)-7-(2-Cydopropyl- Ia-80 Chiralpak AD-H Chiralpak AD-H 0.99 benzyl)-5-(2′-methoxy-4′-methyl- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm 3,4,5,6-tetrahydro-2H- CO.sub.2/EtOH 50/50 CO.sub.2/EtOH 50/50 [1,3′]bipyridinyl-4-yl)-2,4-dimethyl- 160 mL/min 4 mL/min 2,4,5,7-tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-6-one (Enantiomer A) (Example 368) Ik-110 (S)- or (R)-7-(2-Cyclopropyl- 1.39 benzyl)-5-(2′-methoxy-4′-methyl- 3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-2,4-dimethyl- 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 369) Ik-111 (R)- or (S)-7-(2-Cyclopropyl- Ib-20 Chiralpak IF Chiralpak IF 1.52 benzyl)-5-(4′-difluoromethyl-2′- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm methoxy-3,4,5,6-tetrahydro-2H- CO.sub.2/EtOH 65/35 CO.sub.2/EtOH 65/35 [1,3′]bipyridinyl-4-yl)-4-methyl- 160 mL/min 4 mL/min 2,4,5,7-tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-6-one (Enantiomer A) (Example 370) Ik-112 (S)- or (R)-7-(2-Cyclopropyl- 1.94 benzyl)-5-(4′-difluoromethyl-2′- methoxy-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-4-methyl- 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 371) Ik-113 (R)- or (S)-5-[1-(2-Chloro-6-fluoro- Ib-21 Chiralpak IF Chiralpak IF 1.54 phenyl)-piperidin-4-yl]-7-(2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm cyclopropyl-benzyl)-4-methyl- CO.sub.2/EtOH 55/45 CO.sub.2/EtOH 55/45 2,4,5,7-tetrahydro-pyrazolo[3,4- 160 mL/min 4 mL/min d]pyrimidin-6-one (Enantiomer A) 100 bars, 40° C. 150 bars, 40° C. (Example 372) Ik-114 (S)- or (R)-5-[1-(2-Chloro-6-fluoro- 2.05 phenyl)-piperidin-4-yl]-7-(2- cyclopropyl-benzyl)-4-methyl- 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 373) Ik-115 (R)- or (S)-7-(2-Cyclopropyl- Ia-84 Chiralpak AD-H Chiralpak AD-H 0.90 benzyl)-5-(2′-methoxy-4′- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm trifluoromethyl-3,4,5,6-tetrahydro- CO.sub.2/EtOH 60/40 CO.sub.2/EtOH 60/40 2H-[1,3′]bipyridinyl-4-yl)-2,4- 160 mL/min 4 mL/min dimethyl-2,4,5,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C. pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer A) (Example 374) Ik-116 (S)- or (R)-7-(2-Cyclopropyl- 1.26 benzyl)-5-(2′-methoxy-4′- trifluoromethyl-3,4,5,6-tetrahydro- 2H-[1,3′]bipyridinyl-4-yl)-2,4- dimethyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 375) Ik-117 (R)- or (S)-5-(4′-Chloro-2′- Ia-85 Chiralpak IC Chiralpak IC 1.10 methoxy-3,4,5,6-tetrahydro-2H- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm [1,3′]bipyridinyl-4-yl)-2,4-dimethyl- CO.sub.2/EtOH 55/45 CO.sub.2/EtOH 55/45 7-(2-trifluoromethyl-benzyl)- 160 mL/min 4 mL/min 2,4,5,7-tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-6-one (Enantiomer A) (Example 376) Ik-118 (S)- or (R)-5-(4′-Chloro-2′- 1.48 methoxy-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-2,4-dimethyl- 7-(2-trifluoromethyl-benzyl)- 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 377) Ik-119 (R)- or (S)-5-(4′-Chloro-2′- Ia-86 Chiralpak AD-H Chiralpak AD-H 1.23 methoxy-3,4,5,6-tetrahydro-2H- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm [1,3′]bipyridinyl-4-yl)-7-(2- CO.sub.2/EtOH 55/45 CO.sub.2/EtOH 55/45 cyclopropyl-benzyl)-2,4-dimethyl- 150 mL/min 4 mL/min 2,4,5,7-tetrahydro-pyrazolo[3,4- 100 bars, 40° C. 150 bars, 40° C. d]pyrimidin-6-one (Enantiomer A) (Example 378) Ik-120 (S)- or (R)-5-(4′-Chloro-2′- 1.71 methoxy-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-4-yl)-7-(2- cyclopropyl-benzyl)-2,4-dimethyl- 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 379) Ik-121 (R)- or (S)-2-Cyclopropyl-7-(2- Ia-87 Chiralpak AD-H Chiralpak AD-H 1.00 cyclopropyl-benzyl)-5-(2′- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm methoxy-4′-methyl-3,4,5,6- CO.sub.2/EtOH 50/50 CO.sub.2/EtOH 50/50 tetrahydro-2H-[1,3′]bipyridinyl-4- 160 mL/min 4 mL/min yl)-4-methyl-2,4,5,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C. pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer A) (Example 380) Ik-122 (S)- or (R)-2-Cyclopropyl-7-(2- 1.57 cyclopropyl-benzyl)-5-(2′- methoxy-4′-methyl-3,4,5,6- tetrahydro-2H-[1,3′]bipyridinyl-4- yl)-4-methyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 381) Ik-123 (R)- or (S)-2-Cyclopropyl-7-(2- Ia-88 Chiralpak AD-H Chiralpak AD-H 0.94 cyclopropyl-benzyl)-5-(4′- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm difluoromethyl-2′-methoxy-3,4,5,6- CO.sub.2/EtOH 55/45 CO.sub.2/EtOH 55/45 tetrahydro-2H-[1,3′]bipyridinyl-4- 160 mL/min 4 mL/min yl)-4-methyl-2,4,5,7-tetrahydro- 100 bars, 40° C. 150 bars, 40° C. pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer A) (Example 382) Ik-124 (S)- or (R)-2-Cyclopropyl-7-(2- 1.33 cyclopropyl-benzyl)-5-(4′- difluoromethyl-2′-methoxy-3,4,5,6- tetrahydro-2H-[1,3′]bipyridinyl-4- yl)-4-methyl-2,4,5,7-tetrahydro- pyrazolo[3,4-d]pyrimidin-6-one (Enantiomer B) (Example 383) Ik-125 (R)- or (S)-5-[1-(2-Bromo-6-fluoro- Ia-89 Chiralpak IF Chiralpak IF 1.96 phenyl)-piperidin-4-yl]-7-(2- 30 × 250 mm, 5 μm 4.6 × 250 mm, 5 μm cyclopropyl-benzyl)-2,4-dimethyl- CO.sub.2/EtOH 50/50 CO.sub.2/EtOH 55/45 2,4,5,7-tetrahydro-pyrazolo[3,4- 160 mL/min 4 mL/min d]pyrimidin-6-one (Enantiomer A) 100 bars, 40° C. 150 bars, 40° C. (Example 384) Ik-126 (S)- or (R)-5-[1-(2-Bromo-6-fluoro- 2.77 phenyl)-piperidin-4-yl]-7-(2- cyclopropyl-benzyl)-2,4-dimethyl- 2,4,5,7-tetrahydro-pyrazolo[3,4- d]pyrimidin-6-one (Enantiomer B) (Example 385)

(413) II. Biological Assays

(414) In Vitro Assay

(415) Adherent cells (CHO-K1 C5AR1 beta-arrestin cell line, DiscoverX, CA USA) are washed with PBS, detached by incubation with Dissociation Buffer (Gibco Cat #13151-014, 2 ml per 165 cm2 dish) for 3 minutes, then washed with 10 ml PBS (without Mg++ and Ca++) and counted. 7500 cells/384-well are seeded out in 384-well plates (Cell culture plate MTP384 white Polystyrene, Corning, Cat #3570) in 20 μl/well Cell plating medium (F12 HAMs/10% FCS/1% P/S) and incubated at 37° C./5% CO2/24h.

(416) 5 μl Antagonist at 6-fold end concentration or DMSO control is added to assay medium and subsequently 5 μl 1-10 nM C5a agonist at 6 fold end concentration. Cells are centrifuged for 1 min at 1000 rpm and incubated for 1.5 hour in at 37° C. Plates are equilibrated at room temperature for several minutes before adding 12 μl/well Detection Reagent (PathHunter Detection Kit, DiscoverX, Cat #93-0001). Plates are centrifuged for 1 min at 1000 rpm and incubated for 45 minutes at RT before being measured on a Fluostar Optima, BMG Labtech. IC.sub.50 values are calculated from a serial dilution range of antagonist using inhouse software and given in nmol/l.

(417) The calculated IC.sub.50 values may fluctuate depending on the daily cellular assay performance. Fluctuations of this kind are known to those skilled in the art. Average IC.sub.50 values from several measurements are given as geometric mean values.

(418) Antagonistic activities of exemplified compounds are displayed in Table.

(419) TABLE-US-00072 TABLE 70 list of examples and their antagonistic activities C5aR Example Compound IC.sub.50 Number No (nM) 1 Ia-1A 85 2 Ib-1 10 3 Ic-2 36 4 Id-1 293 5 Ia-2 16 6 Ib-2 9 7 Ic-1 16 8 Ic-3 14 9 Ic-4 8 10 Ie-1 341 11 Ia-3 603 12 Ia-4 226 13 Ia-5 28 14 Ib-3 466 15 Ia-6 45 16 Id-2 74 17 Ic-5 13 18 Ic-6 132 19 Ic-7 637 20 If-1 12 21 Ia-7 13 22 Ia-8 10 23 Ih-1 16 24 Ic-8 15 25 Ic-9 18 26 If-2 173 27 Ic-10 17 28 Ic-12 83 29 If-3 103 30 If-4 95 31 Ic-11 13 32 If-5 14 33 If-6 12 34 If-7 22 35 Ia-9 9 36 Ih-2 7 37 Ih-3 53 38 Ih-4 12 39 If-8 16 40 Ic-13 27 41 Ic-14 17 42 Ic-15 24 43 Ic-16 18 44 Ij-1 35 45 If-9 203 46 Ic-17 21 47 Ij-2 19 48 Ij-3 18 49 Ij-4 12 50 Ih-5 85 51 Ih-6 46 52 Ij-6 72 53 If-10 46 54 Ij-7 14 55 Ia-10 11 56 Ig-1 91 57 Ik-1 19 58 Ik-2 238 59 If-11 196 60 If-12 56 61 Ia-11 16 62 If-13 105 63 If-14 91 64 If-15 21 65 If-16 120 66 Ig-2 152 67 Ig-3 15 68 Ij-8 318 69 Ij-9 38 70 Ij-10 512 71 If-17 24 72 If-18 43 73 If-19 17 74 If-20 26 75 Ic-18 171 76 Ib-4 20 77 Ic-19 10 78 If-21 14 79 Ig-4 676 80 Ig-5 350 81 Ic-20 21 82 Ic-21 119 83 Ic-22 75 84 Ic-23 74 85 Ij-11 34 86 Ij-12 230 87 If-22 12 88 Ig-6 156 89 Ia-13 54 90 Ia-14 153 91 Ic-24 26 92 If-23 428 93 Ic-25 17 94 If-24 727 95 Ij-13 125 96 Ij-14 492 97 Ic-27 30 98 Ic-28 24 99 If-26 354 100 Ij-15 339 101 Ic-29 22 102 Ig-7 278 103 Ig-8 351 104 Ig-9 146 105 Ig-10 330 106 Ig-11 24 107 Ig-12 52 108 Ic-30 21 109 Ic-31 27 110 Ic-32 28 111 If-27 29 112 If-28 18 113 Ig-13 110 114 Ig-14 107 115 Ig-15 137 116 Ig-16 844 117 Ig-17 33 118 If-29 578 119 Ig-18 296 120 Ig-19 1354 121 Ic-33 17 122 If-30 342 123 Ig-20 19 124 Ig-21 13 125 Ig-22 14 126 Ig-23 15 127 Ig-24 14 128 Ia-15 15 129 Ic-34 20 130 If-31 390 131 Ig-25 100 132 Ig-26 8 133 Ig-27 22 134 Ig-28 13 135 Ig-29 17 136 Ig-30 163 137 Ig-31 81 138 Ia-16 11 139 Ig-32 18 140 Ig-33 18 141 Ig-34 21 142 Ig-35 32 143 Ig-36 17 144 Ig-37 14 145 Ia-17 13 146 Ia-18 32 147 Ic-35 152 148 Ic-36 341 149 Ic-37 70 150 Ic-38 767 151 Ic-39 517 152 Ic-40 322 153 If-32 40 154 If-33 26 155 Ig-38 25 156 Ic-41 10 157 If-34 17 158 Ic-43 11 159 Ic-44 8 160 Ic-45 147 161 Ic-46 7 162 Ic-47 9 163 Ic-48 10 164 Ic-49 13 165 Ic-50 8 166 Ic-52 12 167 Ic-53 10 168 Ic-54 6 169 Ic-55 8 170 Ic-56 6 171 Ic-57 17 172 Ic-58 11 173 Ic-59 15 174 Ic-60 7 175 Ic-61 14 176 Ic-62 16 177 Id-4 48 178 Ic-64 16 179 Id-5 152 180 Ic-66 11 181 Id-6 50 182 Ic-68 30 183 Ic-69 22 184 Ic-70 9 185 Ik-3 10 186 Ik-4 8 187 Ik-5 13 188 Ik-6 10 189 Ik-7 10 190 Ik-8 11 191 If-35 4 192 Ic-74 4 193 Ib-5 14 194 Ic-75 5 195 Ia-1B 45 196 Ia-20 11 197 Ib-6 17 198 Ic-76 13 199 Ia-21 32 200 Ic-77 4 201 Ic-78 6 202 Ik-9 919 203 Ik-10 74 204 Ib-7 23 205 Ic-79 8 206 Ic-80 3 207 Ic-81 15 208 Ic-82 3 209 Ic-83 5 210 Ie-2 46 211 Ib-8 275 212 Ic-84 10 213 Ic-86 53 214 Ic-87 87 215 Id-7 146 216 Ia-24 41 217 Ia-25 11 218 Ib-9 12 219 Ic-88 38 220 Ik-11 8 221 Ik-12 77 222 Ic-89 19 223 Ic-90 32 224 Ic-91 76 225 Ik-13 34 226 Ik-14 24 227 Ic-92 10 228 Ia-28 10 229 Ij-16 550 230 Ia-29 37 231 Ia-30 17 232 Ia-31 16 233 Ia-32 10 234 Ik-15 109 235 Ik-16 169 236 Ia-34 312 237 Ia-35 80 238 Ij-17 166 239 Id-8 59 240 Ia-36 630 241 Ik-17 112 242 Ik-18 628 243 Ij-18 28 244 Ij-19 16 245 Ij-20 16 246 Ik-19 21 247 Ik-20 21 248 Ih-7 16 249 Ia-40 69 250 Ih-8 10 251 Ih-9 9 252 Ia-41 9 253 Ik-21 16 254 Ik-22 192 255 Ik-23 87 256 Ik-24 570 257 Ij-21 9 258 Ij-22 14 259 Ia-42 49 260 Ia-43 40 261 Ik-25 580 262 Ik-26 472 263 Ik-27 21 264 Ia-45 216 265 Ik-29 12 266 Ik-30 356 267 Ia-46 201 268 Ia-47 72 269 Ia-48 193 270 Ij-23 54 271 Ij-24 51 272 Ij-25 18 273 Ij-26 13 274 Ik-32 37 275 Ik-34 20 276 Ik-35 491 277 Ik-36 56 278 Ik-37 492 279 Ik-38 28 280 Ij-30 12 281 Ij-31 17 282 Ij-32 18 283 Ij-33 8 284 Ij-34 9 285 Ij-35 9 286 Ik-39 33 287 Ik-40 37 288 Ik-41 75 289 Ik-42 55 290 Ik-43 351 291 Ik-44 116 292 Ik-46 515 293 Ik-45 20 294 Ia-54 56 295 Ik-47 25 296 Ik-49 15 297 Ik-50 326 298 Ik-51 29 299 Ij-36 402 300 Ij-37 29 301 Ij-38 69 302 Ij-40 48 303 Ij-41 10 304 Ij-42 35 305 Ik-53 16 306 Ik-54 285 307 Ij-43 30 308 Ij-44 22 309 Ik-55 11 310 Ik-56 30 311 Ik-57 13 312 Ik-58 72 313 Ia-51 13 314 Ik-59 8 315 Ik-60 362 316 Ik-62 9 317 Ik-63 11 318 Ik-64 131 319 Ik-65 2 320 Ik-66 325 321 Ik-67 196 322 Ik-68 3 323 Ik-69 9 324 Ik-70 182 325 Ik-71 14 326 Ik-72 355 327 Ik-73 520 328 Ik-74 10 329 Ik-75 18 330 Ik-76 1424 331 Ik-77 6 332 Ik-78 184 333 Ik-79 14 334 Ik-80 210 335 Ik-81 12 336 Ik-82 89 337 Ik-83 15 338 Ik-84 110 339 Ik-85 12 340 Ik-86 67 341 Ia-72 31 342 Ia-73 24 343 Ia-74 57 344 Ik-87 8 345 Ik-88 35 346 Ik-89 7 347 Ik-90 201 348 Ik-91 11 349 Ik-92 918 350 Ik-93 4 351 Ik-94 784 352 Ik-95 11 353 Ik-96 997 354 Ik-97 5 355 Ik-98 298 356 Ik-99 5 357 Ik-100 572 358 Ik-101 12 359 Ik-102 185 360 Ik-103 3 361 Ik-104 13 362 Ik-105 9 363 Ik-106 97 364 Ia-82 84 365 Ia-83 45 366 Ik-107 10 367 Ik-108 286 368 Ik-109 8 369 Ik-110 256 370 Ik-111 19 371 Ik-112 1332 372 Ik-113 11 373 Ik-114 1006 374 Ik-115 8 375 Ik-116 146 376 Ik-117 5 377 Ik-118 552 378 Ik-119 6 379 Ik-120 412 380 Ik-121 21 381 Ik-122 190 382 Ik-123 21 383 Ik-124 204 384 Ik-125 12 385 Ik-126 491