2,4,6,7-TETRAHYDRO-PYRAZOLO[4,3-D]PYRIMIDIN-5-ONE DERIVATIVES AND RELATED COMPOUNDS AS C5A RECEPTOR MODULATORS FOR TREATING VASCULITIS AND INFLAMMATORY DISEASES

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## wherein Y represents CR.sup.6; one of X and Z represents NR.sup.7, O or S, and the other of X and Z represents N; or Y represents N; one of X and Z represents NR.sup.8, and the other of X and Z represents N or CH; ring A represents a saturated 4- to 7-membered mono-cyclic carbocyclic ring containing the ring nitrogen atom to which R.sup.1 is attached, wherein said ring A is optionally mono-substituted with R.sup.A; wherein R.sup.A represents (C.sub.1-4)alkyl; R.sup.1 represents phenyl; 5-membered heteroaryl, or 6-membered heteroaryl wherein said phenyl, 5-membered heteroaryl or 6-membered heteroaryl independently is mono-, di- or tri-substituted, wherein the substituents are independently selected from (C.sub.1-4)alkyl; (C.sub.1-4)alkoxy; (C.sub.1-3)fluoroalkyl; (C.sub.1-3)fluoroalkoxy; halogen; cyano; or (C.sub.3-6)cycloalkyl; R.sup.2 represents phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; wherein said phenyl, 5-membered heteroaryl, or 6-membered heteroaryl independently is mono-, or di-, or tri-substituted, wherein the substituents are independently selected from (C.sub.1-4)alkyl; (C.sub.1-4)alkoxy; (C.sub.1-3)fluoroalkyl; (C.sub.1-3)fluoroalkoxy; halogen; (C.sub.3-6)cycloalkyl-X.sup.21—, wherein X.sup.21 represents a direct bond, —O—, or —(C.sub.1-3)alkylene-O—, and wherein the (C.sub.3-6)cycloalkyl optionally contains one ring oxygen atom; or R.sup.21aR.sup.21bN—, wherein R.sup.21a and R.sup.21b independently represent hydrogen or (C.sub.1-4)alkyl; R.sup.3 represents hydrogen or (C.sub.1-3)alkyl; R.sup.4 represents hydrogen, or (C.sub.1-4)alkyl; wherein said ring.sup.B is optionally substituted by one or two substituents independently selected from oxo, hydroxy, fluoro, (C.sub.1-4)alkyl or (C.sub.1-4)alkoxy; and wherein R.sup.B independently represents hydrogen; (C.sub.1-4)alkyl; (C.sub.2-4)fluoroalkyl; (C.sub.1-4)alkyl-C(O)—; (C.sub.1-4)alkoxy-C(O)—; (C.sub.1-4)alkyl-SO.sub.2—; R.sup.N7R.sup.N8N—SO.sub.2— wherein R.sup.N7 and R.sup.N8 are independently hydrogen or (C.sub.1-4)alkyl; R.sup.N9R.sup.N10N—C(O)— wherein R.sup.N9 and R.sup.N10 are independently hydrogen or (C.sub.1-4)alkyl; Ring.sup.C-O—C(O)—, and wherein ring.sup.C is (C.sub.3-6)cycloalkyl optionally containing one ring oxygen atom, wherein ring.sup.C is optionally substituted with one R.sup.C, wherein R.sup.C is (C.sub.1-4)alkyl or (C.sub.1-4)fluoroalkyl; or Ring.sup.D, wherein ring.sup.D is a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from O, N or S, wherein ring.sup.D is unsubstituted or mono-substituted with R.sup.D, wherein R.sup.D is (C.sub.1-4)alkyl or (C.sub.1-4)fluoroalkyl; R.sup.6 represents hydrogen; (C.sub.1-4)alkyl; (C.sub.1-4)fluoroalkyl; or (C.sub.3-6)cycloalkyl-(C.sub.0-4)alkylene-, wherein the cycloalkyl is optionally substituted by one to three substituents independently selected from halogen or (C.sub.1-4)alkyl; R.sup.7 represents hydrogen; (C.sub.1-4)alkyl; or (CH.sub.3).sub.3Si—(CH.sub.2).sub.2—O—(C.sub.1-4)alkylene-; and R.sup.8 represents hydrogen; (C.sub.1-4)alkyl; (C.sub.2-4)fluoroalkyl; (C.sub.3-6)cycloalkyl-(C.sub.0-4)alkylene-, wherein the cycloalkyl is optionally substituted by one to three substituents independently selected from halogen or (C.sub.1-4)alkyl; (C.sub.1-4)alkoxy-C(O)—(C.sub.1-4)alkylene-; or (CH.sub.3).sub.3Si—(CH.sub.2).sub.2—O—(C.sub.1-4)alkylene-; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1; wherein ring A represents a fragment ##STR00024## wherein said ring A is selected from azetidin-1,3-diyl, pyrrolidin-1,3-diyl, piperidin-1,4-diyl, piperidin-1,3-yl, and azepan-1,4-diyl; and wherein said ring A is substituted with R.sup.1 on the ring nitrogen atom, and optionally substituted, on the ring carbon atom linked to the rest of the molecule, with R.sup.A, wherein R.sup.A is (C.sub.1-4)alkyl; or a pharmaceutically acceptable salt thereof.

3. (canceled)

4. The compound according to claim 1, wherein R.sup.1 represents phenyl which is mono- or di-substituted, wherein at least one substituent is attached in ortho position with regard to the point of attachment of the rest of the molecule, wherein the substituents are independently selected from (C.sub.1-4)alkyl; (C.sub.1-4)alkoxy; halogen; cyano; and (C.sub.1-3)fluoroalkyl; or pyridinyl which is di-substituted, wherein at least one substituent is attached in ortho position with regard to the point of attachment of the rest of the molecule, wherein the substituents are independently selected from (C.sub.1-4)alkyl; (C.sub.1-4)alkoxy; halogen; and (C.sub.1-3)fluoroalkyl; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein R.sup.1 represents phenyl which is mono-, or di-substituted; wherein at least one substituent is attached in ortho position with regard to the point of attachment of the rest of the molecule; wherein said ortho-substituent is (C.sub.1-4)alkyl); (C.sub.1-4)alkoxy; halogen; or (C.sub.1-3)fluoroalkyl; and, if present, the remaining substituent independently is methyl; methoxy; halogen; or cyano; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein R.sup.1 is 2-chloro-6-methyl-phenyl, 2-fluoro-6-methyl-phenyl, 2,6-dimethyl-phenyl, 2-methoxy-6-methyl-phenyl, 2-fluoro-6-cyano-phenyl, 2-fluoro-6-trifluoromethyl-phenyl, 2-fluoro-6-trifluoromethoxy-phenyl, 4-chloro-2,5-dimethyl-2H-pyrazol-3-yl, 2,5-dimethyl-4-cyano-pyrazol-3-yl, 3-fluoro-pyridin-2-yl, 3-methoxy-pyridin-2-yl, 2-methoxy-4-methyl-pyridin-3-yl, 2-fluoro-4-methyl-pyridin-3-yl, 2-methyl-4-fluoro-, 2-cyano-4-methyl-pyridin-3-yl, 2,4-dimethoxy-pyridin-3-yl, 4-methoxy-6-methyl-pyrimidin-5-yl, 4,6-dimethoxy-pyrimidin-5-yl, 2,6-difluorophenyl, 2-chloro-6-fluoro-phenyl, 2-bromo-6-fluoro-phenyl, 2-fluoro-6-difluoromethyl-phenyl, 2-fluoro-6-cyclopropyl-phenyl, 2-methoxy-4-chloro-pyridin-3-yl, 2-methoxy-4-difluoromethyl-pyridin-3-yl, or 2-methoxy-4-trifluoromethyl-pyridin-3-yl; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, wherein R.sup.2 represents phenyl, 5-membered heteroaryl; or 6-membered heteroaryl; wherein said phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, independently is mono-, or di-, or tri-substituted, wherein the substituents are independently selected from (C.sub.1-4)alkyl; (C.sub.1-4) alkoxy; (C.sub.1-3)fluoroalkyl; (C.sub.1-3)fluoroalkoxy; halogen; (C.sub.3-6)cycloalkyl-X.sup.21—, wherein X.sup.21 represents a direct bond, —O—, or —(C.sub.1-3)alkylene-O—, and wherein the (C.sub.3-6)cycloalkyl contains one optional ring oxygen atom; and R.sup.21aR.sup.21bN—, wherein R.sup.21a and R.sup.21b independently represent hydrogen or (C.sub.1-4)alkyl; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 5, wherein R.sup.2 represents phenyl; wherein said phenyl is mono-, or di-substituted, wherein the substituents are independently selected from (C.sub.1-4)alkyl; (C.sub.1-4)alkoxy; (C.sub.1-3)fluoroalkyl; (C.sub.1-3)fluoroalkoxy; halogen; and (C.sub.3-6)cycloalkyl-X.sup.21—, wherein X.sup.21 represents a direct bond, —O—, or —(C.sub.1-3)alkylene-O—, and wherein the (C.sub.3-6)cycloalkyl contains one optional ring oxygen atom; or 6-membered heteroaryl containing one or two nitrogen atoms; wherein said 6-membered heteroaryl independently is mono-, or di-substituted, wherein the substituents are independently selected from (C.sub.1-4)alkoxy; (C.sub.1-3)fluoroalkyl; halogen; and (C.sub.3-6)cycloalkyl-X.sup.21—, wherein X.sup.21 represents a direct bond, —O—, or —(C.sub.1-3)alkylene-O—, and wherein the (C.sub.3-6)cycloalkyl contains one optional ring oxygen atom; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 6, wherein R.sup.2 represents 2-chloro-phenyl, 2-cyclopropyl-phenyl, 2-isopropyl-phenyl, 2-ethoxy-phenyl, 2-trifluoromethyl-phenyl, 2-isopropoxy-phenyl, 2-cyclopropoxy-phenyl, 2-(oxetan-3-yloxy)-phenyl, 2-cyclopropylmethoxy-phenyl, 2-fluoro-6-trifluoromethyl-phenyl, 2-bromo-6-trifluoromethyl-phenyl, 2-trifluoromethoxy-phenyl, 2,4-difluoro-6-isopropoxy-phenyl, 4-isopropyl-pyramid-5-yl, 3-trifluoromethyl-pyrazin-2-yl, 3-trifluoromethyl-pyridin-2-yl, 6-methyl-3-trifluoromethyl-pyridin-2-yl, 6-chloro-3-trifluoromethyl-pyridin-2-yl, 6-fluoro-3-trifluoromethyl-pyridin-2-yl, 6-methylamino-3-trifluoromethyl-pyridin-2-yl, 6-methoxy-3-trifluoromethyl-pyridin-2-yl, 6-dimethylamino-3-trifluoromethyl-pyridin-2-yl, 4-trifluoromethyl-pyridin-3-yl or 2-methyl-4-trifluoromethyl-thiazol-5-yl; or a pharmaceutically acceptable salt thereof.

10. (canceled)

11. (canceled)

12. The compound according to claim 1, wherein R.sup.4 represents hydrogen or methyl; or a pharmaceutically acceptable salt thereof.

13. (canceled)

15. A pharmaceutical composition comprising, as active principle, a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

16. A medicament comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

17. A method for the prevention or treatment of a disease or disorder comprising administering the compound according to claim 1, or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease or disorder is selected from vasculitic diseases or disorders, inflammatory diseases or disorders involving intravascular microvesicle release, immune complex (IC) diseases or disorders, neurodegenerative diseases or disorders, complement related inflammatory diseases or disorders, bullous diseases or disorders, diseases or disorders related to ischemia and/or ischemic reperfusion injury, inflammatory bowel diseases or disorders, autoimmune diseases or disorders, or cancer.

18. A method for the prevention or treatment of a disease or disorder comprising administering the compound according to claim 1, or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease or disorder is selected from the prevention or treatment of deleterious consequences of contact sensitivity and inflammation caused by contact with artificial surfaces; the prevention or treatment of increased leukocyte and platelet activation (and infiltration to tissues thereof); the prevention or treatment of pathologic sequelae associated to an intoxication or an injury such as a trauma, an hemorrhage, a shock, or surgery including transplantation; the prevention or treatment of pathologic sequelae associated with insulin-dependent diabetes mellitus; the prevention of/the reduction of the risk of myocardial infarction or thrombosis; prevention or treatment of edema or increased capillary permeability; or the prevention of/the reduction of coronary endothelial dysfunction induced by cardiopulmonary bypass and/or cardioplegia.

19. (canceled)

20. A method of treatment of vasculitic diseases or disorders; inflammatory diseases or disorders involving intravascular microvesicle release, immune complex (IC) diseases or disorders; neurodegenerative diseases or disorders; complement related inflammatory diseases or disorders; bullous diseases or disorders; diseases or disorders related to ischemia and/or ischemic reperfusion injury; inflammatory bowel diseases or disorders; autoimmune diseases or disorders; cancer; deleterious consequences of contact sensitivity and inflammation caused by contact with artificial surfaces; increased leukocyte and platelet activation (and infiltration to tissues thereof); pathologic sequelae associated to an intoxication or an injury such as a trauma, an hemorrhage, a shock, or surgery including transplantation; pathologic sequelae associated with insulin-dependent diabetes mellitus; the risk of myocardial infarction or thrombosis; edema or increased capillary permeability; or coronary endothelial dysfunction induced by cardiopulmonary bypass and/or cardioplegia; comprising administering to a patient an effective amount of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof.

21. A method for the prevention or treatment of a disease or disorder comprising administering the compound according to claim 1, or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease or disorder is selected from vasculitic diseases or disorders, inflammatory diseases or disorders involving intravascular microvesicle release, immune complex (IC) diseases or disorders, neurodegenerative diseases or disorders, complement related inflammatory diseases or disorders, bullous diseases or disorders, diseases or disorders related to ischemia and/or ischemic reperfusion injury, inflammatory bowel diseases or disorders, autoimmune diseases or disorders, or cancer.

22. A pharmaceutical composition comprising, as active principle, a compound according to claim 12, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

23. A method for the prevention or treatment of a disease or disorder comprising administering the compound according to claim 1, or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease or disorder is selected from vasculitic diseases or disorders, inflammatory diseases or disorders involving intravascular microvesicle release, immune complex (IC) diseases or disorders, neurodegenerative diseases or disorders, complement related inflammatory diseases or disorders, bullous diseases or disorders, diseases or disorders related to ischemia and/or ischemic reperfusion injury, inflammatory bowel diseases or disorders, autoimmune diseases or disorders, or cancer.

Description

PREPARATION OF COMPOUNDS OF FORMULA (1)

[0954] A further aspect of the invention is a process for the preparation of compounds of Formula (I) as defined in any one of embodiments 1) to 50). Compounds of Formula (I) can be prepared from commercially available or well known starting materials according to the methods described in the experimental part, by analogous methods; or according to the general sequence of reactions outlined below, wherein R.sup.1, R.sup.A, R.sup.2, R.sup.3, R.sup.4, X, Y and Z are as defined for Formula (1).

[0955] Other abbreviations used herein are explicitly defined or are as defined in the experimental section. In some instances, the generic groups R.sup.1, R.sup.A, R.sup.2, R.sup.3, R.sup.4, X, Y and Z might be incompatible with the assembly illustrated in the schemes below and so will require the use of protecting groups (PG). The use of protecting groups is well known in the art (see for example “Protective Groups in Organic Synthesis”, T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place. The compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts thereof in a manner known per se.

[0956] Compounds of structure Ia which are compounds of Formula (I) wherein R.sup.4 represents hydrogen, can be prepared according to the synthetic routes given in scheme A1 below (wherein ring A may in addition be optionally substituted with R.sup.A as explicitly defined).

[0957] Compounds of structure A-1 can be prepared by reductive amination of suitable aldehydes of structure BB-4 with suitable amines of structure BB-7 using standard conditions such as treatment with NaBH(OAc).sub.3 in the optional presence of AcOH and a suitable solvent such as DCM, MeOH, THF or a mixture thereof at temperatures around RT.

[0958] Alternatively, NaBH.sub.4 can be used as reducing agent in the presence of TFE as solvent according to Synthesis, 2011, 3, 490-496. Optionally, a two-step procedure can be applied (i) condensation of a suitable aldehyde of structure BB-4 with amines of structure BB-7 in the presence of a suitable solvent such as MeOH at temperatures around 60° C. and (ii) subsequent reduction of the intermediate imine by treatment with NaBH.sub.4 at temperatures between 0° C. and RT (Scheme A1, step a).

[0959] Diamino compounds of structure A-2 can be prepared by reduction of the nitro group in compounds of structure A-1 using standard conditions such as catalytic hydrogenation with a suitable catalyst such as Pd/C in a suitable solvent such as EtOAc or EtOH or a mixture thereof (Scheme A1, step b).

[0960] Alternatively, diamino compounds of structure A-2 can be prepared by reductive alkylation of a suitable amine of structure BB-5 with ketones of structure BB-8 using standard conditions such as treatment with NaBH(OAc).sub.3 in the optional presence of AcOH and a suitable solvent such as DCM, MeOH, THF or a mixture thereof at temperatures around RT. Treatment of a suitable amine of structure BB-5 with tosylate of structure BB-33 in the presence of a suitable solvent such as MeCN at temperatures around 110° C. under microwave irradiation can be an alternative procedure to provide diamino compounds of structure A-2 (Scheme A1, step c).

[0961] An alternative preparation of compounds of structure A-2 may be a reductive amination of a suitable aldehyde of structure BB-6 (or BB-20, respectively) with amines of structure BB-7 using standard conditions such as treatment with NaBH(OAc).sub.3 in the optional presence of AcOH (or with NaBH.sub.4, respectively) and in the presence of a suitable solvent such as DCM, MeOH, THE or a mixture thereof (or TFE, respectively) at temperatures around RT (or around 35° C., respectively) (Scheme A1, step d (or step g, respectively)).

##STR00010##

[0962] Compounds of structure A-2 may alternatively be prepared by cleavage of the Boc protecting group in suitable compounds of structure A-4 (e.g. wherein R.sup.5 represents (C.sub.1-4)alkyl, (C.sub.2-3)fluoroalkyl, or (C.sub.3-6)cycloalkyl-(C.sub.0-4)alkylene, or the like) using a suitable acid such as HCl or TFA in the presence of a suitable solvent such as dioxane, MeOH or DCM at temperatures around RT (Scheme A1, step f).

[0963] The reductive alkylation of the amine of structure BB-24 with ketones of structure BB-8 using standard conditions such as treatment with NaBH(OAc).sub.3 in the optional presence of AcOH and a suitable solvent such as DCM, MeOH, THE or a mixture thereof at temperatures around RT can provide compounds of structure A-4 (Scheme A1, step e).

[0964] Cyclic ureas of structure A-3 can be prepared by cyclisation of diamines of structure A-2 by treatment with a suitable carbonyl transfer agent such as CDI in the presence of a suitable aprotic solvent such as MeCN or THE at temperatures between RT and 80° C. (Scheme A1, step h).

[0965] Alkylation of the nitrogen atom having a free valency in compounds of structure A-3 with a suitable halide of structure BB-9 wherein W represents chlorine or bromine, in the presence of a suitable base such as NaH or K.sub.2CO.sub.3 and in solvents such as THF, DMF or a mixture of both at temperatures between 0° C. and 50° C. may afford compounds of structure Ia.

[0966] Alternatively, alkylation of the nitrogen atom having a free valency in compounds of structure A-3 can be achieved using Mitsunobu conditions by treatment with a suitable alcohol of structure BB-9 wherein W represents hydroxy and for instance a (cyanomethylene)trialkylphosphorane reagent in the presence of a suitable solvent such as toluene at temperatures around 110° C. (Scheme A1, step i).

[0967] Compounds of structure Ib, Ic, Id, Ie, If and Ig can be prepared from suitable precursors of structure Ia according to the synthetic routes given in scheme A2 below, wherein said compounds of structure Ia may carry suitable protecting groups or functional groups as indicated.

[0968] Compounds of structure Ib wherein at least two of X, Y or Z represent N can be prepared from the corresponding N-SEM derivatives of compounds of structure Ia by cleavage of the SEM protecting group using for instance a suitable acid such as TFA in the presence of a suitable solvent such as DCM at temperatures around RT. An additional treatment with ethylenediamine in the presence of THE as solvent at temperatures around 60° C. might be necessary to achieve complete cleavage of the SEM protecting group (Scheme A2, step a). Subsequently to the TFA procedure, an additional treatment with an acid such as HCl in the presence of a suitable alcohol such as MeOH or EtOH at temperatures around 70° C. can afford the respective alkoxymethyl derivatives of structure Ic (Scheme A2, step g).

[0969] Alternatively, compounds of structure Ib wherein at least two of X, Y or Z represent N can be prepared from the corresponding Bn-protected derivatives by cleavage of the Bn protecting group in compounds of structure Ia by catalytic hydrogenation using a suitable catalyst such as Pd/C in the presence of a suitable solvent such as EtOH or MeOH and under a hydrogen atmosphere at temperatures around RT. Catalytic transfer hydrogenation conditions using for instance ammonium formate can be an alternative procedure (Scheme A2, step a).

[0970] Alternatively, compounds of structure Ib wherein at least two of X, Y or Z represent N can be prepared from the corresponding THP-protected derivatives by cleavage of the THP protecting group in compounds of structure Ia by treatment with a suitable acid such as TFA in the presence of a suitable solvent such as DCM at temperatures around RT (Scheme A2, step a).

[0971] Compounds of structure Ic (or Id or Ie, respectively) wherein R.sup.5 (or R.sup.8, respectively) represents methyl can be prepared by treatment with a methylating reagent such as Mel in the presence of a suitable base such as DBU and a suitable solvent such as DMF at temperatures around RT. Treatment with Mel in the presence of Ag.sub.2CO.sub.3 as base and heating in a suitable solvent such as toluene at temperatures around 85° C. can be an alternative procedure (Scheme A2, step b, c or d).

##STR00011##

[0972] In compounds of structure Ib, a free NH group corresponding to X, Y or Z can be alkylated by treatment with a suitable halide, aziridine, epoxide or tosylate of structure BB-10 in the presence of a suitable base such as NaH, K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3 and in solvents such as THF, DMF or DMA or a mixture thereof at temperatures between 0° C. and 150° C. under possible microwave irradiation can afford the corresponding compounds of structure Ic (Scheme A2, step b, c or d).

[0973] Alternatively, Mitsunobu conditions can be used by treatment with a suitable alcohol of structure BB-10 and for instance with a (cyanomethylene)trialkylphosphorane reagent in the presence of a suitable solvent such as toluene at temperatures around 110° C. (Scheme A2, step b, c or d).

[0974] Conditions for a 1,4-nucleophilic addition can alternatively be applied by treatment with a suitable ethyl or methyl 2-alkenoate or 2-nitroalkene of structure BB-10 in the presence of a suitable base such as CsF, TEA or K.sub.2CO.sub.3 and a suitable solvent such as THE or DMF at temperatures between 0° C. and 60° C. (Scheme A2, step b, c or d).

[0975] Alternatively, alkoxycarbonylation (or alkylcarbamylation, respectively) can be performed by treatment with a suitable alkylchloroformate (or alkylisocyanate, respectively) of structure BB-10 in the presence of a suitable base such as TEA or DIPEA and a suitable solvent such as DCM or DMF at temperatures between 0° C. and RT. Di-alkylcarbamylation can be achieved by treatment with a suitable carbonyl transfer reagent such as CDI and a suitable amine of structure BB-10 in the presence of a suitable base such as TEA or DIPEA and a suitable solvent such as THE or DCM at temperatures around RT (Scheme A2, step b, c or d).

[0976] Alternatively, Chan-Lam conditions can be applied by treatment with a suitable boronic acid or boronic ester of structure BB-10 in the presence of a suitable copper catalyst such as Cu(OAc).sub.2 and a suitable ligand such as 2,2′-bipyridyl, in the presence of a suitable base such as Na.sub.2CO.sub.3 and heating in a suitable solvent such as toluene or trifluoromethylbenzene at temperatures between 70° C. and 90° C. (Scheme A2, step b, c or d).

[0977] Where suitable for the remaining substituents or functional groups in the molecule, compounds of structure If can be prepared from compounds of structure Ic (and sub-sequently compounds of structure Ig from compounds of structure If) by conventional functional group transformation, e.g. within the substituent R.sup.5, as described below (Scheme A2, step e; sub-sequently step f): [0978] Carboxylic ester functions can be reduced by treatment with a suitable reducing reagent such as CaBH.sub.4 (formed in situ from NaBH.sub.4 and CaCl.sub.2) in the presence of a suitable solvent such as EtOH at temperatures between −10° C. and RT to give the corresponding primary alcohol. [0979] Nitrile functions can be reduced by treatment with a suitable reducing reagent such as CoBH.sub.4 (formed in situ from NaBH.sub.4 and CoCl.sub.2) in the presence of a suitable solvent such as MeOH at temperatures between 0° C. and RT; or by using a suitable catalyst such as Raney nickel in the presence of a suitable base such as ammonia and a suitable solvent such as MeOH at temperatures between 0° C. and RT to give the corresponding primary amine. [0980] Carboxylic ester functions can be hydrolysed by treatment with a suitable base such as LiOH, NaOH or KOH in the presence of water and a suitable solvent such as THF, MeOH or EtOH or a mixture thereof at temperatures between RT and 50° C. The resulting carboxylic acid can subsequently be coupled with a suitable amine by treatment with suitable activating reagents such as the combination EDC.Math.HCl and HOBt in the presence a suitable base such as DIPEA and stirring in a suitable solvent such as DCM or DMF or a mixture thereof at temperatures around RT. [0981] Acetal protected aldehydes can be deprotected by acidic treatment with aq. HCl in the presence of a suitable solvent such as THE at temperatures between RT and 70° C. Resulting aldehydes can subsequently react with a suitable Grignard reagent such as alkyl magnesium bromides in the presence of a suitable solvent such as THE at temperatures between 0° C. and RT. Alternatively, reductive amination with suitable amines using conditions such as treatment with NaBH(OAc).sub.3 in the presence of AcOH (or NaBH.sub.4 respectively) and in the presence of a suitable solvent such as DCM, MeOH, THE or a mixture thereof (or TFE respectively) at temperatures between RT and 40° C. can afford corresponding secondary or tertiary amines. [0982] A chlorine substituent can be substituted with suitable amines in the presence of a suitable solvent such as DMF at temperatures around 70° C. [0983] A primary amide can be dehydrated by treatment with a suitable dehydrating reagent such as Burgess reagent in the presence of a suitable solvent such as DCM at temperatures around RT to give the corresponding nitrile. [0984] A tertiary alcohol can be dehydrated by treatment with a suitable dehydrating reagent such as POCl.sub.3 in the presence of a suitable solvent such as pyridine and heating at temperatures around 50° C. to give the corresponding alkene. [0985] A Boc protected amine can be deprotected by treatment with a suitable acid such as HCl or TFA in the presence of a suitable solvent such as dioxane, MeOH or DCM at temperatures around RT to release the corresponding free amine. [0986] A trityl protected lactam can be deprotected by treatment with a suitable acid such as TFA in the presence of a suitable solvent such as H.sub.2O at temperatures around 0° C. to release the corresponding free lactam. [0987] A 2-nitrobenzenesulfonyl protected amine can be deprotected by treatment with a suitable solid-supported thiol such as QuadraPure® MPA in the presence of a suitable base such as Cs.sub.2CO.sub.3 and heating in a suitable solvent such as THE under microwave irradiation at temperatures around 130° C. to give the corresponding free amine. [0988] A carbon-carbon double bond can be reduced by catalytic hydrogenation using a suitable catalyst such as Pd/C in the presence of a suitable solvent such as EtOAc, MeOH or a mixture thereof at temperatures around RT to give the corresponding saturated bond. [0989] A primary or secondary amine can be acylated (or alkylsulfonylated or dialkylsulfamylated, respectively) by treatment with a suitable acyl chloride (or alkylsulfonyl chloride or di-alkylsulfamyl chlorides, respectively) in the presence of a suitable base such as TEA or DIPEA and a suitable solvent such as DCM or DMF at temperatures between 0° C. at RT. Alternatively, it can be alkoxycarbonylated by treatment with a suitable chloroformate or dialkyldicarbonate reagent (or pentafluorophenylcarbonate reagent, respectively) in the presence of a suitable base such as TEA or DIPEA and a suitable solvent such as DCM (or DMF, respectively) at temperatures between 0° C. at RT (or between RT and 110° C., respectively). Alternatively, it can be dialkylcarbamylated by treatment with a suitable carbonyl transfer reagent such as CDI and a suitable amine in the presence of a suitable base such as TEA or DIPEA and a suitable solvent such as THE or DCM at temperatures around RT. Alternatively, it can be alkylated by reductive alkylation with aldehydes using standard conditions such as treatment with NaBH(OAc).sub.3 in the presence of AcOH and in the presence of a suitable solvent such as DCM, MeOH, THE or a mixture thereof at temperatures between RT and 40° C. Alternatively, alkylation can be achieved by treatment with a suitable halide in the presence of a suitable base such as DIPEA, a catalytic amount of KI and heating in a suitable solvent such as DMF under possible microwave irradiation at temperature between 110° C. and 150° C. Alternatively, a primary or secondary amine can be engaged in an aromatic nuleophilic substitution with a suitable (hetero)aromatic halide in the presence of a suitable base such as DIPEA or K.sub.2CO.sub.3 and stirring in a suitable solvent such as DMSO at temperatures between RT and 110° C. Alternatively, aromatic nucleophilic substitution can be achieved by activation of a suitable (hetero)aromatic alcohol of structure with PyBOP in the presence of a suitable base such as DIPEA in solvents such as DMF at temperatures around RT. [0990] An alcohol can be transformed to a primary amine following the two-step procedure: (i) Mitsunobu conditions to form a phthalimide intermediate by treatment with phthalimide and e.g. a (cyanomethylene)trialkylphosphorane reagent and heating in a suitable solvent such as toluene at temperatures around 110° C. and (ii) cleavage of the phthalimide by treatment with hydrazine hydrate in the presence of a suitable solvent such as EtOH at temperature around 80° C. to release the corresponding primary amine.

[0991] Compounds of structure Ia and Ih can further be prepared according to the synthetic routes given in scheme B below.

##STR00012##

[0992] Compounds of structure B-1 wherein none of X, Y and Z represents NH and R.sup.1 does not represents Boc can be prepared by treatment of amines of structure A-2 wherein none of X, Y and Z represents NH and R.sup.1 does not represents Boc with Boc-anhydride in the presence of a suitable base such as TEA or DIPEA in a suitable solvent such as DCM or THE at temperatures between 0° C. and RT (Scheme B, step a).

[0993] Reductive alkylation of amines of structure B-1 with aldehydes or ketones of structure BB-12 using standard conditions such as treatment with NaBH(OAc).sub.3 in the presence of AcOH (or NaBH.sub.4, respectively) and in the presence of a suitable solvent such as DCM, MeOH, THE or a mixture thereof (or TFE, respectively) at temperatures between RT and 40° C. can afford compounds of structure B-2 (Scheme B, step b).

[0994] Cleavage of the Boc protecting group in compounds of structure B-2 wherein R.sup.1 does not represents Boc can be performed by treatment with a suitable acid such as HCl or TFA in the presence of a suitable solvent such as dioxane, MeOH or DCM at temperatures around RT to afford diamines of structure B-3 (Scheme B, step c).

[0995] Cyclic ureas of structure Ia can be prepared by cyclisation of compound of structure B-3 by treatment with a suitable carbonyl transfer agent such as CDI, DSC or phosgene in the presence of a suitable aprotic solvent such as MeCN at temperatures around 80° C. (Scheme B, step d).

[0996] Catalytic deuteration of (hetero)aryl groups which are substituted by one bromine or chlorine atom with a suitable catalyst such as Pd/C in the presence of a suitable solvent such as EtOAc, CD.sub.3OD or a mixture thereof under a deuterium atmosphere at temperatures around RT may afford the corresponding mono-deuterated (hetero)aryl groups (Scheme B, step e).

[0997] Heteroaryl groups which are substituted by one fluorine atom in ortho position to a ring nitrogen atom can be prepared by aromatic nucleophilic substitution of CsF on the corresponding chloro heteroaryl group in the presence of a suitable solvent such as DMSO under possible microwave irradiation at temperatures around 100° C. (Scheme B, step e).

[0998] Alkylated (hetero)aryl groups be prepared by Suzuki cross coupling of a suitable aromatic chloride with a (C.sub.1-C.sub.4)-alkyl boronic acid or boroxine in the presence of a suitable palladium catalyst such as Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 or PEPPSI-IPr, in the presence of a suitable base such as K.sub.2CO.sub.3 and heating in a suitable solvent such as dioxane at temperatures around 100° C. (Scheme B, step e).

[0999] Aromatic nucleophilic substitution of sodium alkoxides (or suitable amines) on suitable (hetero)aryl groups, e.g. heteroaryl groups which are substituted by one chlorine atom in ortho position of a nitrogen, in the presence of the corresponding alcohol as solvent (or in the presence of a suitable solvent such as MeOH, respectively) at temperatures around 80° C. (or at temperatures between 80° C. and 150° C. under microwave irradiation, respectively) may afford e.g. the compounds of structure Ih wherein R.sup.2 represents a mono-, di- or tri-substituted 5- or 6-membered heteroaryl which is substituted by one (C.sub.1-4)alkoxy substituent (or R.sup.21aR.sup.21bN—) (Scheme B, step e).

[1000] Alkylation of a free aromatic hydroxy group, e.g. in compounds of structure Ia wherein R.sup.2 represents a phenyl or 5- or 6-membered heteroaryl which is substituted by one hydroxy group, with a suitable alkyl halide, cycloalkyl halide (C.sub.3-6)cycloalkyl-(C.sub.0-3)alkyl halide wherein the (C.sub.3-6)cycloalkyl optionally contains one ring oxygen, in the presence of a suitable base such as NaH or K.sub.2CO.sub.3 and in solvents such as THF, DMF or a mixture thereof at temperatures between 0° C. and 150° C. and under possible microwave irradiation may alternatively afford the corresponding compounds of structure Ih. Alternatively, Mitsunobu conditions can be used by treatment for instance with a (cyanomethylene)trialkylphosphorane reagent in the presence of a suitable solvent such as toluene at temperatures around 110° C. (Scheme B, step e).

[1001] Compounds of structure Ia and Ii and Ij can be prepared according to the synthetic route given in scheme C below.

[1002] Compounds of structure C-1 can be prepared by reductive amination of suitable aldehydes of structure BB-14 (or ketones of structure BB-13, respectively) with suitable amines of structure BB-15 (or diamines of structure BB-5, respectively) using standard conditions as set out before. Alternatively, NaBH.sub.4 can be used as reducing agent in the presence of TFE as solvent at temperatures around 40° C. according to Synthesis, 2011, 3, 490-496 (Scheme C, step b (or step a, respectively).

[1003] Alternatively, compounds of structure C-1 can be prepared by a two step procedure (i) reductive amination of suitable aldehydes of structure BB-4 with suitable amines of structure BB-15 using standard conditions as set out before and (ii) subsequent reduction of the nitro group in intermediates of structure C-4 using standard conditions such as catalytic hydrogenation with a suitable catalyst such as Pd/C in a suitable solvent such as EtOAc or EtOH or a mixture thereof (Scheme C, steps g and h).

[1004] Cyclic ureas of structure C-2 can be prepared by cyclisation of compound of structure C-1 by treatment with a suitable carbonyl transfer agent such as CDI in the presence of a suitable aprotic solvent such as MeCN at temperatures around RT (Scheme C, step c).

[1005] Alkylation of the nitrogen atom having a free valency in compounds of structure C-2 with a suitable halide of structure BB-9 wherein W represents chlorine or bromine; or using Mitsunobu conditions as set out before (Scheme C, step d).

[1006] Cleavage of the Boc protecting group in compounds of structure Ii can be as set out before to afford amines of structure C-3 (Scheme C, step e).

##STR00013##

[1007] Compounds of structure Ij can be prepared by Buchwald-Hartwig cross coupling of halides of structure BB-16 wherein W represents iodine, bromine or chloride with amines of structure C-3 in the presence of a suitable palladium catalyst such as Pd.sub.2(dba).sub.3 and a suitable ligand such as BINAP, in the presence of a suitable base such as sodium tert-butoxide and heating in a suitable solvent such as toluene at temperatures between 100° C. and 110° C. (Scheme C, step f).

[1008] Aromatic nucleophilic substitution of amines of structure C-3 on suitable activated halogenides of structure BB-16 wherein W represents chlorine or fluorine in the presence of a suitable base such as K.sub.2CO.sub.3 or CsF and heating in a suitable solvent such as DMSO under possible microwave irradiation at temperatures between 100° C. and 130° C. may alternatively afford compounds of structure Ij (Scheme C, step f).

[1009] Compounds of structure Ij can alternatively be prepared following a three-step procedure: (i) aromatic nucleophilic substitution of amines of structure C-3 on activated halides of structure BB-16 wherein W represents fluorine or chlorine which is substituted for instance by one formyl group in ortho position of the halogen atom W in the presence of a suitable base such as CsF or K.sub.2CO.sub.3 and heating in a suitable solvent such as DMSO under microwave irradiation at temperatures between 60° C. and 150° C. and (ii) subsequent decarbonylation by treatment with a suitable acid such as toluene-4-sulfonic acid and in the presence of a suitable solvent such as MeOH under possible microwave irradiation at temperatures around 120° C. and (iii) subsequent chlorination by treatment with a chlorinating reagent such as NCS in the presence of a suitable solvent such as THE at temperatures around RT (Scheme C, step f).

[1010] Alternatively, compounds of structure Ia can be prepared according to scheme D below.

##STR00014##

[1011] Compounds of structure D-1 can be prepared by reductive amination of suitable aldehydes of structure BB-19 with suitable amines of structure BB-7 using standard conditions as set out before (Scheme D, step a).

[1012] Heating compounds of structure D-1 in a suitable solvent such as DMF under microwave irradiation at temperatures around 120° C. can alternatively afford compounds of structure A-3 (Scheme D, step b).

[1013] Alkylation of the nitrogen atom having a free valency in compounds of structure A-3 (Scheme D, step c) is described in Scheme A1 (step i).

[1014] Alternatively, compounds of structure Ia which are compounds of Formula (I) wherein R.sup.4 represents C.sub.1-4-alkyl can be prepared according to scheme E below.

[1015] Compounds of structure E-1 (or E-2, respectively) can be prepared by reductive amination of suitable ketones of structure BB-26 (or BB-27, respectively) with suitable amines of structure BB-7 using standard conditions as set out before. Alternatively, a two-step procedure can be applied (i) condensation of suitable ketones of structure BB-26 wherein R.sup.4 represents (C.sub.1-4)alkyl with amines of structure BB-7 in the presence of titanium (IV) isopropoxide at temperatures around RT and (ii) subsequent reduction of the intermediate by treatment with NaBH.sub.4 in the presence of a suitable solvent such as EtOH, THE or a mixture thereof at temperatures between −15° C. and RT (Scheme E, step a (or step e, respectively)).

[1016] The following sequence of reactions to provide compounds of structure Ia (Scheme E, steps b, c and d) is similar to the one already described in Scheme A1 (steps b, h and i).

[1017] Compounds of structure E-4 (or E-7, respectively) can be prepared following a two-step procedure (i) condensation of suitable aldehydes or ketones of structure BB-12 with amines of structure BB-28 (or BB-34, respectively) in the presence of AcOH and a suitable solvent such as THE or MeOH at temperatures between RT and 60° C. and (ii) subsequent reduction of the intermediate imine by treatment with NaBH.sub.4 at temperatures between 0° C. and RT (Scheme E, step f (or step j, respectively)).

##STR00015##

[1018] Addition of a suitable Grignard reagent of structure R.sup.4—MgBr, e.g. wherein R.sup.4 represents (C.sub.1-4)alkyl, on nitriles of structure E-4 in the presence of a suitable aprotic solvent such as THE at temperatures between 0° C. and RT followed by acidic hydrolysis may afford the corresponding ketones of structure E-5 (Scheme E, step g).

[1019] Alternatively, compounds of structure E-5 can be prepared by Heck cross coupling of halides of structure E-7 (or E-8, respectively) with butyl vinyl ether or ethyl 1-propenyl ether in the presence of a suitable palladium catalyst such as Pd(OAc).sub.2 in combination with 1,3-bis(diphenylphosphino)propane or 2-(di-tert-butylphosphino)biphenyl as ligand, in the presence of a suitable base such as K.sub.2CO.sub.3 and heating in a suitable solvent such as a mixture of DMF and H.sub.2O or MeCN at temperatures around 100° C. The consecutive treatment with an acid such as HCl can release the ketone (Scheme E, step m (or step n, respectively).

[1020] Compounds of structure E-6 can be prepared following a two-step procedure (i) condensation of suitable ketones of structure E-5 (or E-10, respectively), e.g. wherein R.sup.4 represents (C.sub.1-4)alkyl, with amines of structure BB-7 in the presence of titanium (IV) isopropoxide at temperatures around RT and (ii) subsequent reduction of the intermediate by treatment with NaBH.sub.4 as set out before (Scheme E, step h (or step q, respectively)).

[1021] Cyclisation of compounds of structure E-6 by treatment with a suitable carbonyl transfer agent such as DSC or CDT in the possible presence of a suitable base such as TEA and in a suitable aprotic solvent such as DCM or MeCN at temperatures between RT and 80° C. may alternatively afford compounds of structure Ia (Scheme E, step i).

[1022] Compounds of structure E-8 wherein Y represents N-THP can be prepared by treatment of compounds of structure E-7 wherein Y represents NH with 3,4-dihydro-2H-pyran in the presence of a catalytic amount of TsOH and a suitable solvent such as DCM at temperatures around 40° C. (Scheme E, step k).

[1023] The THP protecting group in compounds of structure E-5 wherein Y represents N-THP can be cleaved by treatment with a suitable acid such as TFA in the presence of a suitable solvent such as DCM at temperatures around RT to release compounds of structure E-9 wherein Y represents NH (Scheme E, step o).

[1024] Chan-Lam conditions can be applied to compounds of structure E-9 wherein Y represents NH by treatment with a suitable boronic acid or boronic ester of structure BB-10 in the presence of a suitable copper catalyst such as Cu(OAc).sub.2 and a suitable ligand such as 2,2′-bipyridyl, in the presence of a suitable base such as Na.sub.2CO.sub.3 and heating in a suitable solvent such as toluene at temperatures between 70° C. and 90° C. (Scheme E, step p).

[1025] If not commercially available, aldehydes of structure BB-4 can be prepared according to scheme F below.

[1026] Esters of structure BB-1 wherein R.sup.e represents methyl (or ethyl, respectively) can be prepared by esterification of carboxylic acids of structure A by treatment with a strong acid such as H.sub.2SO.sub.4 or HCl (which can be formed in situ from AcCl and MeOH (or EtOH, respectively)) and heating in a suitable alcohol such as MeOH (or EtOH, respectively) at temperatures around 80° C. (Scheme F, step a).

[1027] Protection of building blocks of structure BB-1 e.g. by treatment with SEM-Cl in the presence of a suitable base such as TEA or DIPEA and the presence of a suitable solvent such as DCM at temperatures between 0° C. and RT may afford the corresponding compounds of structure BB-2 wherein one of X, Y or Z represents N-SEM (Scheme F, step b).

##STR00016##

[1028] Reduction of carboxylic esters of structure BB-1 or BB-2 can be achieved for instance by treatment with a suitable reducing reagent such as NaBH.sub.4 or CaBH.sub.4 (formed in situ from NaBH.sub.4 and CaCl.sub.2) in the presence of a suitable solvent such as MeOH, EtOH or THE or a mixture thereof at temperatures between 0° C. and RT to give alcohols of structure BB-3 (Scheme F, step c and d).

[1029] Oxidation of primary alcohols of structure BB-3 by treatment with a suitable oxidizing reagent such as MnO.sub.2 in the presence of a suitable solvent such as DCM at temperatures between RT and 45° C. can afford aldehydes of structure BB-4 (Scheme F, step e).

[1030] Alternatively, aldehydes of structure BB-4 can be prepared by protection of building blocks of structure BB-11 wherein one of X, Y or Z represents NH with a suitable protecting group. The treatment for instance with SEM-Cl under standard conditions provides building blocks of structure BB-4 wherein one of X, Y or Z represents N-SEM (Scheme F, step f).

[1031] If not commercially available, aldehydes of structure BB-19 can be prepared according to scheme G below.

##STR00017##

[1032] Carbamates of structure BB-17 can be prepared by treatment of suitable amines of structure B (in case none of X, Y and Z represents NH) with methylchloroformate in the presence of a suitable base such as TEA or DIPEA, catalytic amounts of DMAP and in a suitable solvent such as MeCN, DCM or DMF at temperatures between 0° C. and RT (Scheme G, step a).

[1033] Reduction of the ester function in building blocks of structure BB-17 can be achieved for instance by treatment with a suitable reducing reagent as set out before to give alcohols of structure BB-18 (Scheme G, step b).

[1034] Oxidation of primary alcohols of structure BB-18 by treatment with a suitable oxidizing reagent such as MnO.sub.2 as set out before can afford aldehydes of structure BB-19 (Scheme G, step c).

[1035] If not commercially available, aldehydes of structure BB-20 can be prepared according to scheme H below.

##STR00018##

[1036] Aromatic nucleophilic substitution of sodium azide on suitable activated bromides of structure C in the presence of a suitable solvent such as DMSO at temperatures around RT can provide aldehydes of structure BB-20 (Scheme H, step a).

[1037] If not commercially available, amines of structure BB-24 can be prepared according to scheme I below.

[1038] Building blocks of structure BB-21 can be prepared by treatment of amines of structure D wherein one of X, Y or Z represents NH and the two others represent N with Boc.sub.2O in the presence of a suitable base such as TEA or DIPEA in a suitable solvent such as THE or DCM at temperatures between 0° C. and RT (Scheme I, step a). Alkylation of building blocks of structure BB-21 wherein one of X, Y or Z represents NH and the two others represent N with suitable halides of structure R.sup.5—W wherein W represents chlorine, bromine or iodine using conditions set out before may afford building blocks of structure BB-22 (Scheme I, step b). Dehydration of primary amides of structure BB-22 by treatment for instance with Burgess reagent in a suitable solvent such as DCM at temperatures around RT can provide nitriles of structure BB-23 (Scheme I, step c). Reduction of nitriles of structure BB-23 using standard Raney nickel conditions can afford amines of structure BB-24 (Scheme I, step d).

##STR00019##

[1039] If not commercially available, amines of structure BB-7 and ketones of structure BB-8 can be prepared according to the synthetic routes given in scheme J below.

##STR00020##

[1040] Building blocks of structure BB-29 can be prepared by standard Buchwald-Hartwig cross coupling of halides of structure R.sup.1—W wherein W represents iodine, bromine or chloride with amines of structure E (Scheme J, step a). Alternatively, building blocks of structure BB-29 wherein can be prepared by standard aromatic nucleophilic substitution of amines of structure E on activated halides of structure R.sup.1—W wherein W represents fluorine or chlorine (Scheme J, step a). Cleavage of the ketal protecting group in building blocks of structure BB-29 by acidic hydrolysis in the presence of a suitable acid such as aq. HCl and heating in a suitable solvent such as THE at temperatures around 70° C. may afford ketones of structure BB-8 (Scheme J, step b). Building blocks of structure BB-30 can be prepared by standard aromatic nucleophilic substitution of amines of structure F on activated halides of structure R.sup.1—W wherein W represents fluorine or chlorine (Scheme J, step c).

[1041] Alternatively, building blocks of structure BB-30 wherein R.sup.1 represents a mono-, di- or tri-substituted phenyl which is substituted by one methyl group at the ortho position to the connecting nitrogen can be prepared following a four-step procedure: (i) aromatic nucleophilic substitution of amines of structure F on halides of structure R.sup.1—W wherein W represents fluorine or chlorine and R.sup.1 represents a suitable mono-, or di-substituted phenyl which is substituted by one formyl group at the ortho position of the halogen atom W in the presence of a suitable base such as K.sub.2CO.sub.3 and heating in a suitable solvent such as DMSO at temperatures between 100° C. and 120° C. and (ii) subsequent reduction of the benzaldehyde derivative by treatment with a suitable reducing reagent such as NaBH.sub.4 in the presence of a suitable solvent such as MeOH at temperatures between 0° C. and RT and (iii) subsequent acetylation of the resulting benzyl alcohol by treatment with acetyl chloride in the presence of a suitable base such as TEA and in a suitable solvent such as DCM at temperatures between 0° C. and RT and (iv) final catalytic hydrogenation of the resulting benzyl ester with a suitable catalyst such as Pd/C in the presence of a suitable solvent such as EtOAc, MeOH or a mixture thereof at temperatures around RT (Scheme J, step c).

[1042] Alternatively, building blocks of structure BB-30 wherein R.sup.1 represents a mono- or di-substituted phenyl or pyridine which is substituted by one difluoromethyl group at the ortho position to the connecting nitrogen can be prepared following a two-step procedure: (i) aromatic nucleophilic substitution of amines of structure F on halides of structure R.sup.1—W wherein W represents fluorine or chlorine and R.sup.1 represents a suitable mono-, or di-substituted phenyl or pyridine which is substituted by one formyl group at the ortho position of the halogen atom W as set out before and (ii) subsequent defluorination of the benzaldehyde derivative by treatment with a suitable fluorinating reagent such as bis(2-methoxyethyl)aminosulfur trifluoride in the presence of a suitable solvent such as DCM at temperatures around RT (Scheme J, step c). An alternative sequence of reactions can provide compounds of structure BB-30 wherein R.sup.1 represents a mono- or di-substituted phenyl which is substituted by one halogen atom at the ortho position to the connecting nitrogen. A three-step procedure is followed (i) aromatic nucleophilic substitution of amines of structure F on halides of structure R.sup.1—W wherein W represents fluorine or chlorine and R.sup.1 represents a suitable mono-, or di-substituted phenyl which is substituted by one nitro group at the ortho position of the halogen atom W as set out before and (ii) subsequent reduction of the nitro group to an amino group as set out before and (iii) subsequent Sandmeyer rxn to introduce a halogen atom using standard conditions. An additional Suzuki or Kumada cross coupling reaction can be used to introduce an (C.sub.1-4)alkyl or (C.sub.3-6)cycloalkyl group at the place of the halogen atom (Scheme J, step c).

[1043] Cleavage of the Boc protecting group in building blocks of structure BB-30 can be performed to afford amines of structure BB-7 (Scheme J, step d).

[1044] Transformation of ketones of structure BB-8 to amines of structure BB-7 can be achieved by reductive amination with for instance aq. ammonia under catalytic hydrogenation conditions using a suitable catalyst such as Pd/C in the presence of a suitable solvent such as dioxane at temperatures around RT (Scheme J, step e).

[1045] Whenever the compounds of formula (I) are obtained in the form of mixtures of enantiomers, the enantiomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 μm) column, a Daicel ChiralCel OD-H (5-10 μm) column, or a Daicel ChiralPak IA (10 μm), IC (5 μm) or AD-H (5 μm) column. Typical conditions of chiral HPLC are as disclosed in the experimental part below.

[1046] The following examples are provided to illustrate the invention. These examples are illustrative only and should not be construed as limiting the invention in any way.

[1047] Experimental Part

[1048] 1. Chemistry

[1049] All temperatures are stated in ° C. Commercially available starting materials were used as received without further purification.

[1050] Characterization of Compounds

[1051] 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.

[1052] Analytical LC-MS:

[1053] LC-MS (Method I): Waters Acquity UPLC i-Class system with Waters i-Class BSM binary pump, Thermo MSQ Plus MS detector and Waters Acquity PDA detector.

[1054] 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

[1055] Column Agilent Zorbax RRHD SB-aq, 2.1×50 mm, 1.8 μm

[1056] LC-MS (Method II): Dionex Ultimate 3000 system with Dionex HPG-3200RS binary pump, Thermo MSQ Plus MS detector and Dionex DAD-3000RS PDA detector.

[1057] 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

[1058] Column Agilent Zorbax SB-aq, 4.6×50 mm, 3.5 μm

[1059] LC-MS (Method III): Dionex Ultimate 3000 system with Dionex HPG-3200SD binary pump, Thermo MSQ Plus MS detector and Dionex DAD-3000RS PDA detector.

[1060] 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

[1061] Column Waters BEH C.sub.18, 3.0×50 mm, 2.5 μm

[1062] LC-MS (Method IV): Waters Acquity UPLC i-Class system with Waters i-Class BSM binary pump, Thermo MSQ Plus MS detector and Waters Acquity PDA detector.

[1063] 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

[1064] Column Waters BEH C.sub.18, 2.1×50 mm, 2.5 μm

[1065] NMR Spectroscopy:

[1066] 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.

[1067] Purification of Compounds

[1068] The compounds were purified by either column chromatography on silica-gel and/or prep. LC-MS using the conditions described below.

[1069] Column Chromatography

[1070] 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.

[1071] Preparative LC-MS:

[1072] 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 mL/min. Detection: UV/Vis and/or MS.

[1073] Additional information for the purification is summarized in the table below with following definitions:

[1074] XBridge: column Waters XBridge C.sub.18, 10 μm, 30×75 mm

[1075] Zorbax: column Agilent Zorbax SB-aq, 5 μm, 30×75 mm

[1076] Atlantis: column Waters Atlantis T3, 10 μm, 30×75 mm

[1077] Acidic: eluant: A=H.sub.2O with 0.5% HCOOH, B=MeCN

[1078] Basic: eluant: A=H.sub.2O with 0.125% NH.sub.4OH, B=MeCN

[1079] Very lipophilic gradient: 50% B.fwdarw.95% B over 4 min then 95% B over 2 min

[1080] Lipophilic gradient: 30% B.fwdarw.95% B over 4 min then 95% B over 2 min

[1081] Normal gradient: 20% B.fwdarw.95% B over 4 min then 95% B over 2 min

[1082] Polar gradient: 10% B.fwdarw.95% B over 4 min then 95% B over 2 min

[1083] 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

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)

[1084] Ac acetyl

[1085] AcOH acetic acid

[1086] AIBN azobisisobutyronitrile

[1087] aq. aqueous

[1088] BINAP racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

[1089] Bn benzyl

[1090] Boc tert.-butyloxycarbonyl

[1091] Cbz benzyloxycarbonyl

[1092] CC column chromatography

[1093] CDI carbonyl diimidazole

[1094] CDT 1,1′-carbonyl-di-(1,2,4-triazole)

[1095] CPhos 2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)biphenyl

[1096] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[1097] DCM dichloromethane

[1098] dioxane 1,4-dioxane

[1099] DIPEA diisopropylethylamine

[1100] DMA dimethylacetamide

[1101] DMF dimethylformamide

[1102] DMSO dimethylsulfoxide

[1103] Dppf 1,1′-bis(diphenylphosphino)ferrocene

[1104] DSC N,N′-disuccinimidyl carbonate

[1105] EDC.Math.HCl N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

[1106] eq equivalent(s)

[1107] Et ethyl

[1108] EtOAc ethyl acetate

[1109] EtOH ethanol

[1110] Et.sub.2O diethylether

[1111] g gram(s)

[1112] h hour(s)

[1113] Hept heptane

[1114] HOBt 1-hydroxybenzotriazole

[1115] HPLC high performance liquid chromatography

[1116] io ionisation

[1117] LC-MS liquid chromatography-mass spectrometry

[1118] MeCN acetonitrile

[1119] MeOH methanol

[1120] mg milligram(s)

[1121] min minute(s)

[1122] mL milliliter(s)

[1123] mmol millimole(s)

[1124] MS mass spectroscopy

[1125] NaBH(OAc).sub.3 sodium triacetoxyborohydride

[1126] NBS N-bromosuccinimide

[1127] NCS N-chlorosuccinimide

[1128] NMR nuclear magnetic resonance spectroscopy

[1129] OAc acetate

[1130] org. organic

[1131] ON overnight

[1132] PEPPSI-IPr [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride

[1133] Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone)dipalladium(0)

[1134] prep. preparative

[1135] QuadraPure© MPA mercaptophenyl amino functionalized polystyrene beads

[1136] rac racemic

[1137] RT room temperature

[1138] rxn reaction

[1139] sat. saturated

[1140] SEM 2-(trimethylsilyl)ethoxymethyl

[1141] soln. solution

[1142] TEA triethylamine

[1143] TFA trifluoroacetic acid

[1144] TFE trifluoroethanol

[1145] THE tetrahydrofuran

[1146] THP tetrahydro-2H-pyranyl

[1147] Ts p-toluenesulfonyl

[1148] t.sub.R retention time

[1149] When not commercially available, the building blocks are prepared according to the procedures described below.

Synthesis of Building Blocks BB-1

[1150] 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.

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

[1151] 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.

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

[1152] To a soln. of methyl ester BB-1 or BB-2 (1 eq) in a mixture of THE (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.

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

Method A (Oxidation)

[1153] 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.

Method B (SEM Protection)

[1154] 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.

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)

Step A: Cyclocondensation (see Table 5)

[1155] 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 18 h. 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.

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

Step B: Nitrile Reduction (See Table 6)

[1156] 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.

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

[1157] Building Blocks BB-6

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

Method A: Boc Cleavage from BB-30

[1158] 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 1 h to 18 h 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.

Method B: Reductive Amination from BB-8

[1159] 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 48 h (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.

Method B2: Reductive Amination from BB-8

[1160] 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 2 h at RT, NaBH(OAc).sub.3 (2 eq) was added and the mixture was stirred at RT for 2 h. 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.

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

[1161] To a soln. of ketal intermediate BB-29 (1 eq) in anh. THE (3 mL/mmol) was added a 1M 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 24 h. 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.

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

Method A: Benzylic Bromination

[1162] 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 AIBN (0.1 eq) was added in one portion. The rxn mixture was heated to 80° C. and stirred for 6 h. 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.

Method B: Multi-Step

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

[1163] 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 110° C. and stirred for 2 h. 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.

TABLE-US-00011 TABLE 10 t.sub.R [min] MS-data Carboxylic Method/ (LC/MS m/z BB-9A Name acid 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

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

[1164] 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.

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

[1165] 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.4Cl 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.

Method C: Multi-Step

Step C1: Nucleophilic Aromatic Substitution (See Table 11)

[1166] 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 1 h 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.

TABLE-US-00012 TABLE 11 Halo- t.sub.R [min] MS-data 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

Step C2: Hydrogenation (See Table 12)

[1167] 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 1 h. 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.

TABLE-US-00013 TABLE 12 Halo- t.sub.R [min] MS-data 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

Final Step C3: Ester Reduction (See Table 13)

[1168] To a soln. of ester intermediate 11-91 (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 3.5 h 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.

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

Method A

Step A: Carboxylic Acid Reduction (See Table 14)

[1169] To a soln. of carboxylic acid (1 eq) in anh. THE (10 mL/mmol) was added 4-methylmorpholine (2 eq) and ethyl chloroformate (2 eq) at −10° C. The mixture was stirred for 1 h at −10° C. and NaBH.sub.4 (3 eq) was added in one portion. It was allowed to warm to 0° C. over 1 h, 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.

Step B: Appel Rxn (See Table 15)

[1170] 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 1 h. 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.

Method B

Step A: Sulfonylation (See Table 14)

[1171] 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 1 h. 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.

Step B: Aziridine Formation (See Table 15)

[1172] To a stirred soln. of amino alcohol derivative (1 eq) and TEA (2 eq) in DCM (3 mL/mmol) was added dropwise at 0° C. methanesulfonyl chloride (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 18 h and at 50° C. for 30 min 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 Hept/EtOAc.

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)

TABLE-US-00016 TABLE 15 Method t.sub.R [min] MS-data .sup.1H NMR Reactant (LC/MS m/z (500 MHz, BB-10 Name BB-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)

[1173] Building blocks BB-11, BB-12, BB-13, BB-14, BB-15 and BB-16

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

[1174] 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 3 h 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 1.5 h 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.

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

[1175] 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 5 h (see Table 18Error! Reference source not found.) 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.

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

[1176] 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. THE (2 mL/mmol) was added dropwise at −10° C. The rxn mixture was allowed to warm from −10° C. to 5° C. over 1 h 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.

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

[1177] 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 4 h. 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.

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

[1178] 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 18 h. 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.

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

[1179] 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 Mel (1.1 eq) was added at 0° C. The rxn mixture was stirred at 0° C. for 10 min and at RT for 48 h (see Table 21). When necessary to reach completion of the rxn, extra amounts of NaH (1 eq) and/or Mel (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.

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

[1180] 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 18 h (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.

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

[1181] 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 4 h (see Table 23) and filtered over a pad of Celite. The cake was washed with MeOH and the filtrate was concentrated in vacuo.

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

Method A (Pentafluorophenyl Ester)

[1182] 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 18 h (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.

Method B (Cyclisation)

[1183] 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 18 h. 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.

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

Method A (SEM Protection)

[1184] 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 h 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.

Method B (THP Protection)

[1185] 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 h 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.

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

[1186] Building Blocks BB-28

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

[1187] 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.

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

Step A: Aromatic Nucleophilic Substitution

[1188] 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 18 h (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.

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

Step B

Method A: Reduction

[1189] 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 1 h 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.

Method B: Hydrogenation

[1190] 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 3 h and filtered over a pad of Celite. The cake was washed with EtOAc and MeOH and the filtrate was concentrated in vacuo.

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

Step C

Method A: Acetylation

[1191] 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 1 h 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.

Method B: Sandmeyer Rxn (Bromination)

[1192] 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 18 h allowing the temperature to reach RT. It was partitioned between EtOAc and a sat. soln. of NHaCl. The org. phase was washed with a sat. soln. of NHaCl and brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

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

Final Step

[1193] Method A: hydrogenation (using BB-30C) Intermediate BB-300 (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 3 h 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.

Method B: Fluorination (Using BB-30A)

[1194] 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 18 h 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.

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

[1195] 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.

[1196] The rxn mixture was added dropwise at 0° C. to a suspension of copper(I) chloride (1.5 eq) and copper(II) chloride (3 eq) in H.sub.2O (3.1 mL/mmol). The resulting soln. was stirred for 18 h 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.

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

[1197] To a mixture of intermediate BB-30 (1 eq) and di-p-iodobis(tri-t-butylphosphino)dipalladium( ) 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.

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

[1198] 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 1 h. It was partitioned between water and DM 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.

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

[1199] To a soln. of intermediate BB-31 (1 eq) in THE (3 mL/mmol) was added dropwise at 0° C. a 1 M 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.

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

[1200] 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 2 h (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.

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

[1201] Building Blocks BB-34

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

Method A (NaBH(OAc).SUB.3./THF)

[1202] 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.

Method B (NaBH.SUB.4./TFE)

[1203] 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.

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

Method A (Nitro Reduction from A-1)

[1204] 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.

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

[1205] 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.

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

[1206] A soln. of amine BB-5 (1 eq) and ketone BB-8 (1.05 eq) in MeOH (4 mL/mmol) was stirred for 18 h 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.

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

[1207] 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.

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

[1208] 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. soln. of NaOH and extracted with DCM. The combined org. phases were dried over MgSO.sub.4 and concentrated in vacuo.

Method E (Boc cleavage from A-4)

[1209] To a Soln. Of Intermediate A-4 (1 Eq) in DCM (5 mL/Mmol) was Added TFA (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° C., 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.

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

[1210] 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.

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-yl)-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

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

[1211] 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) (1.2 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.

Method B (Cyclisation from D-1)

[1212] A soln. of intermediate D-1 (1 eq) in DMF (8 mL/mmol) was heated at 120° C. 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.

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

[1213] To a soln. of amine BB-24 (1 eq) and ketone B-8 (1.1 to 1.2 eq) in THE (10 m-8 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.

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

[1214] 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.

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

Method A (NaBH(OAc).SUB.4./AcOH/THF)

[1215] 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.

Method B (NaBH.SUB.4./TFE)

[1216] 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.

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

[1217] To a soln. of intermediate B-2 (1 eq) in DCM (4 to 16.5 mL/mmol) was added TFA (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.

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

Method A (NaBH(OAc).SUB.4./AcOH/THF)

[1218] 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.

Method B (NaBH.SUB.4./TFE)

[1219] 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.

Method C (Nitro Reduction from C-4)

[1220] 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.

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

[1221] 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.

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

[1222] To a soln. of intermediate Ii (1 eq) in DCM (4 to 10 mL/mmol) was added TFA (i 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.

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

[1223] 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.

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

[1224] 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.

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

Method A (NaBH(OAc).SUB.3./THF)

[1225] 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.

Method B (Ti(OiPr).SUB.4./NaBH.SUB.4.)

[1226] 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 18 h. 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 h and 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.

Method C (NaBH.SUB.4./TFE)

[1227] A soln. of ketone BB-26 (1 eq) and amine BB-7 (1.1 eq) in TEE (2 mL/mmol) was stirred for to 2.5 h 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.

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

Method A: Hydrogenation

[1228] 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.

Method B: Reduction

[1229] To a soln. of intermediate E-1 (1 eq) in MeOH (9 mL/mmol) was added CoCl.sub.2 (1.5 eq) and the n 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.

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

[1230] 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.

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

[1231] 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 18 h 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.

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

Method A (Grignard Addition Using Nitriles E-4)

[1232] 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.

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

[1233] 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 1 h at RT. It was neutralised 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.

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

Method A

[1234] 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 18 h. The rxn mixture was cooled to 0° C. and EtOH (i 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.

Method B

[1235] To a mixture of ketone E-5 or E-10 (1 eq) and amine [ ]-7 (1.1 to 1.2 eq) in THE (3 mL/mmol) was added titanium (IV) isopropoxide (3 to 4.4 eq) and the soln. was stirred at RT for 18 h. 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.

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

Method A

[1236] A soln. of amine BB-34 (1 eq) and aldehyde or ketone BB-12 (1.05 to 1.1 eq) in MCOH (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.

Method B

[1237] 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 1 h 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.

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

[1238] 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.

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

[1239] To a soln. of THP-protected intermediate E-5 (1 eq) in DCM (2 mL/mmol) was added dropwise TFA (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. 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.

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

[1240] 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 a 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.

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

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

[1241] 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.

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

[1242] 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.

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

[1243] 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.

Method C (Cyclisation from B-3)

[1244] 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.

Method D (Alkylations of A-3: K.SUB.2.CO.SUB.3./DMF)

[1245] To a stirred soln. of intermediate A-3 (1 eq) in DMF (3.9 to 4.7 mL/mmol) was added K.sub.2C.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.2O. 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.

Method E (Cyclisation from E-6)

[1246] 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.

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

Method A (Complete SEM Cleavage)

Step A (TFA Treatment)

[1247] 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.

Step B (Additional Treatment)

[1248] The crude was dissolved in THE (5 to 10 mL/mmol) and treated with ethylenediamine (3 eq) for 30 min to 1 h 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.

Method B (Partial SEM Cleavage with O-Alkylation)

Step A (TFA Treatment)

[1249] 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.

Step B (Treatment with Alcohol)

[1250] 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.

Method C (Bn Cleavage)

[1251] 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.

Method D (THP Cleavage)

[1252] To a soln. of THP-protected intermediate Ia (1 eq) in DM (4 to 5 mL/mmol) was added dropwise TFA (2 to 4 m/mmol). The soln. was stirred at RT for a given time (see Table), quenched at 0° C. with a 1 M 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.

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

Method A (Methylation Using Silver Carbonate)

[1253] To a suspension of intermediate Ib (1 eq) and silver carbonate (1.2 eq) in toluene (6 mL/mmol) was added Mel (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.

Method B (Alkylation Using NaH and Halide or Aziridine)

[1254] 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).

[1255] 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).

[1256] 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.

Method C (Alkylation Using Mitsunobu Conditions)

[1257] 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.

Method D (Methylation Using DBU)

[1258] To a soln. of intermediate Ib (1 eq) and DBU (1.2 eq) in anh. DMF (4 mL/mmol) was added Mel (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.

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

[1259] 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 2 h 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.

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

[1260] 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.

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

[1261] 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.

Method H (Alkoxycarbonylation/Alkylcarbamylation)

[1262] 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.

Method I (Urea Formation)

[1263] 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.

Method J1 (Chan-Lam Rxn 1)

[1264] 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.

Method J2 (Chan-Lam Rxn 2)

[1265] 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 mm. 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.

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

[1266] 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.

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- 110   (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- 110   (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- 18  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  [00021] 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  [00022] 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

Method A (Carboxylic Ester Reduction)

[1267] 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.

Method B (Nitrile Reduction)

[1268] 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.

Method C (Saponification/Amide Coupling)

Step A: Saponification

[1269] 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 1 h 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.

Step B: Amide Coupling

[1270] 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.Math.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.

Method D (Grignard Addition)

Step A: Acetal Cleavage

[1271] 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 3 h30 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.

Step B: Grignard Addition

[1272] 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.

Method E (Reductive Amination)

Step A: Acetal Cleavage

[1273] 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 3 h30 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.

Step B: Reductive Amination

[1274] 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.

Method F (Nucleophilic Substitution)

[1275] 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.

Method G (Dehydration of Primary Amide)

[1276] 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.

Method H (Boc Cleavage)

[1277] 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.

Method I (Sulfonamide Cleavage)

[1278] A soln. of intermediate Ic (1 eq) in THE (37 mL/mmol) was treated with Cs.sub.2CO.sub.3 (3.25 eq) and QuadraPureo 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.

Method J (Dehydration of Tertiary Alcohol)

[1279] 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.

Method K (Trityl Cleavage)

[1280] 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.

Method L (hydrogenation)

[1281] 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.

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

Method A (Carboxylic Ester Reduction)

[1282] 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.

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

[1283] 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.

Method C (Boc Protection)

[1284] 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.

Method D (Nitrile Reduction)

[1285] 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.

Method E

Step A: Mitsunobu

[1286] 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 18 h. 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.

Step B: Phtalimide Cleavage

[1287] 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.

Method F (Reductive Amination)

[1288] 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.

Method G (Alkylation)

[1289] 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.

Method H (Urea Formation)

[1290] 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.

Method I (PyBOP Activated SNAr)

[1291] 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.

Method J (SNAr)

[1292] 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.

Method K (Hydrogenation)

[1293] 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.

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

Method A (Deuteration)

[1294] 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.

Method B (Substitution with F)

[1295] 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.

Method C (Suzuki Coupling)

[1296] A mixture of compound Ia (1 eq), boron species (1.1 eq), Pd(dppf)Cl.sub.2.Math.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.

Method D (Substitution with OMe)

[1297] 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.

Method E (Substitution with Amine)

[1298] 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.

Method F (Phenol Alkylation Using NaH as Base)

[1299] 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.

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

[1300] 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.

Method H (Phenol Alkylation Using Mitsunobu Conditions)

[1301] To a soln. of compound Ia (1 eq) and alcohol (3 eq) in toluene (8 mL/mmol) was added a 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 D M. 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.

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

Method A (Alkylation Using NaH)

[1302] To a suspension or soln. of intermediate C-2 (1 eq) in a mixture of anh. THE (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.

Method B (Mitsunobu)

[1303] To a soln. or suspension of intermediate C-2 (1 eq) and alcohol BB-9 (1.1 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 NaHO.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 DM/MeOH. When necessary, an additional purification by prep. L-MS using methods 2, 3, 4 or 5 was performed.

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

Method A (Buchwald Coupling)

[1304] To a 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.

Method B (Aromatic Nucleophilic Substitution)

[1305] 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.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.

[1306] When necessary, an additional purification by prep. LC-MS using method 1 was performed.

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)

Method D (Multistep)

Step A: Aromatic Nucleophilic Substitution

[1307] To a soln. of amine 0-3 (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.

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

Step B: Decarbonylation

[1308] 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.

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

Step C: Chlorination

[1309] 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.

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)

[1310] Chiral Separation of Compounds of Formula Ia, Ic or Ij

[1311] 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).

[1312] 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).

[1313] 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.

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)

[1314] II. Biological Assays

[1315] In Vitro Assay

[1316] 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% CO2/24 h.

[1317] 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.

[1318] 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.

[1319] Antagonistic activities of exemplified compounds are displayed in Table.

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