Substituted piperidines as inhibitors of ubiquitin specific protease 7

Abstract

Compounds of formula (I): ##STR00001##
wherein R.sub.1, R.sub.2, R.sub.3, B, W, Z, m and n are as defined in the description.

Claims

1. A compound of formula (I): ##STR00022## or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W represents: ##STR00023## wherein: ring A represents heteroaryl, wherein the heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, N-oxide, oxo, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) haloalkyl, (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, OC(O)R′, Y.sub.1—NR′R″, Y.sub.1—NR′—C(O)—R″, Y.sub.1—NR′—C(O)—OR″, Y.sub.1—OR′, Y.sub.1—S(O).sub.m—R′, cyclopropyl, and pyridinyl, and further wherein the pyridinyl substituent is optionally substituted with a (C.sub.1-C.sub.6) alkyl substituent; R.sub.4 represents hydrogen, halogen, oxo, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) haloalkyl, (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl, Y.sub.1—NR.sub.6R.sub.7, Y.sub.1—NR.sub.6—C(O)—R.sub.7, Y.sub.1—OR.sub.6, Y.sub.1-Cy.sub.1, Cy.sub.1—R.sub.7, or Cy.sub.1—ORS; R.sub.5 represents hydrogen, halogen, cyano, (C.sub.1-C.sub.6) alkyl, or (C.sub.1-C.sub.6) hydroxyalkyl; R.sub.6 represents hydrogen or (C.sub.1-C.sub.6) alkyl; R.sub.7 represents hydrogen, (C.sub.1-C.sub.6) alkyl, Y.sub.2—SR.sub.8, or Y.sub.2-Cy.sub.2; R.sub.8 represents hydrogen or (C.sub.1-C.sub.6) alkyl; X represents C, CH, or N; Y.sub.1 represents a bond or (C.sub.1-C.sub.4) alkylene; Y.sub.2 represents a bond or (C.sub.1-C.sub.4) alkylene; Cy.sub.1 represents cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, N-oxide, oxo, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) haloalkyl, (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl, C(O)R′, C(O)NR′R″, C(O)OR', OC(O)R′, Y.sub.1—NR′R″, Y.sub.1—NR′—C(O)—R″, Y.sub.1—NR′—C(O)—OR″, Y.sub.1—OR′, Y.sub.1—S(O).sub.m—R′, cyclopropyl, and pyridinyl, and further wherein the pyridinyl substituent is optionally substituted with a (C.sub.1-C.sub.6) alkyl substituent; and Cy.sub.2 represents cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, N-oxide, oxo, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) haloalkyl, (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, OC(O)R′, Y.sub.1—NR′R″, Y.sub.1—NR′—C(O)—R″, Y.sub.1—NR′—C(O)—OR″, Y.sub.1—OR′, Y.sub.1—S(O).sub.m —R′, cyclopropyl, and pyridinyl, and further wherein the pyridinyl substituent is optionally substituted with a (C.sub.1-C.sub.6) alkyl substituent; ##STR00024## represents: ##STR00025## wherein: R.sub.1 represents cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, N-oxide, oxo, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) haloalkyl, (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, OC(O)R′, Y.sub.1—NR′R″, Y.sub.1—NR′—C(O)—R″, Y.sub.1—NR′—C(O)—OR″, Y.sub.1—OR', Y.sub.1—S(O).sub.m—R′, cyclopropyl, and pyridinyl, and further wherein the pyridinyl substituent is optionally substituted with a (C.sub.1-C.sub.6) alkyl substituent; each R.sub.3 independently represents hydrogen, halogen, oxo, (C.sub.1-C.sub.6) alkyl, or OH; and m represents 0, 1, or 2; each R.sub.2 independently represents hydrogen or halogen; each R′ independently represents hydrogen, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) hydroxyalkyl, (C.sub.1-C.sub.6) alkyl—O(C.sub.1-C.sub.6) alkyl, CH.sub.2-cyclopropyl, (C.sub.2-C.sub.6) alkenyl, O(Ci-C.sub.6) alkyl, tetrahydropyranyl, or phenyl; each R″ independently represents hydrogen, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) hydroxyalkyl, (C.sub.1-C.sub.6) alkyl—O(C.sub.1-C.sub.6) alkyl, CH.sub.2-cyclopropyl, (C.sub.2-C.sub.6) alkenyl, O(C.sub.1-C.sub.6) alkyl, tetrahydropyranyl, or phenyl; or each R′ and R″, together with the nitrogen atom to which they are attached, independently forms a non-aromatic ring having 5, 6, or 7 ring members, wherein each non-aromatic ring optionally and independently contains one additional heteroatom or heteroatomic group selected from the group consisting of N, NH, N(C.sub.1-C.sub.6) alkyl, N.sup.+[(C.sub.1-C.sub.6) alkyl].sub.2, and O; and n represents 0, 1, or 2; wherein cycloalkyl represents a non-aromatic, monocyclic, or fused bicyclic carbocyclic ring having 3, 4, 5, 6, or 7 ring members; wherein heterocycloalkyl represents a non-aromatic, monocyclic, or fused bicyclic ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring members, and further having 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from the group consisting of N, NH, O, and S; wherein aryl represents phenyl, naphthyl, or indanyl; and wherein heteroaryl represents a monocyclic or fused bicyclic ring having at least one aromatic moiety and further having 5, 6, 7, 8, 9, or 10 ring members and 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein W represents: ##STR00026##

3. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R.sub.1 represents pyrrolidinyl, phenyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, or pyridinyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R.sub.2 independently represents hydrogen or fluoro.

5. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R.sub.3 independently represents hydrogen, fluoro, oxo, CH.sub.3, or OH.

6. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R.sub.4 represents hydrogen, halogen, (C.sub.1-C.sub.6) alkyl, Y.sub.1—NR.sub.6R.sub.7, Y.sub.1—NR.sub.6—C(O)—R.sub.7, or Y.sub.1-Cy.sub.1.

7. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R.sub.5 represents hydrogen; and R.sub.6 represents hydrogen.

8. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R.sub.7 represents hydrogen, Y.sub.2—SR.sub.8, or Y.sub.2-Cy.sub.2.

9. The compound according to claim 1, wherein the compound, or stereoisomer thereof, is selected from the group consisting of: ##STR00027## ##STR00028## or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients together with the compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

11. A combination comprising the compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, and an anticancer agent; wherein the anticancer agent is selected from the group consisting of an antibody, an anti-metabolite, a chimeric antigen receptor T-cell therapy, an E3 ligase inhibitor, a genotoxic agent, an immunomodulator, a kinase inhibitor, a mitotic poison, a proteasome inhibitor, and a protein-protein interaction inhibitor.

12. A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients together with the combination according to claim 11.

Description

EXAMPLES

(1) The following Examples illustrate the invention but do not limit it in any way.

3-[[4-hydroxy-1-[trans-2-(3-thienyl)cyclohexanecarbonyl]-4-piperidyl]methyl]pyrido[3,2-d]pyrimidin-4-one (Example 1)

(2) Using Step 3 of General Procedure 3 and starting from Preparation R3f and 2-(3-thienyl)cyclohexanecarboxylic acid as reagents. EXAMPLE 1 was obtained. HRMS calculated for C.sub.24H.sub.28N.sub.4O.sub.3S: 452.182: found 453.1974 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[trans-2-(3-thienyl)cyclohexanecarbonyl]-4-piperidyl]methyl]-7-methyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 2)

(3) Using Step 3 of General Procedure 3 and starting from Preparation R3d and 2-(3-thienyl)cyclohexanecarboxylic acid as reagents. EXAMPLE 2 was obtained. HRMS calculated for C.sub.24H.sub.30N.sub.4O.sub.3S: 454.2039: found 455.2123 [(M+H).sup.+ form].

3-[[1-[trans-2-(3-furyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-methyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 3)

(4) Using Step 3 of General Procedure 3 and starting from Preparation R3d and 2-(3-furyl)cyclohexanecarboxylic acid as reagents. EXAMPLE 3 was obtained. HRMS calculated for C.sub.24H.sub.30N.sub.4O.sub.4: 438.2267: found 439.2348 [(M+H).sup.+ form].

3-[[1-[trans-2-(3-furyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]pyrido[3,2-d]pyrimidin-4-one (Example 4)

(5) Using Step 3 of General Procedure 3 and starting from Preparation R3f and 2-(3-furyl)cyclohexanecarboxylic acid as reagents EXAMPLE 4 was obtained. HRMS calculated for C.sub.24H.sub.28N.sub.4O.sub.4: 436.2111: found 437.2185 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[cis-3-phenyl-1,4-dioxane-2-carbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 5)

(6) and

3-[[4-hydroxy-1-[cis-3-phenyl-1,4-dioxane-2-carbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 6)

(7) Using Step 3 of General Procedure 3 and starting from Preparation R3e and cis-3-phenyl-1,4-dioxane-2-carboxylic acid as reagents, EXAMPLE 5 and EXAMPLE 6 were obtained separately by chiral chromatography.

(8) EXAMPLE 5: HRMS calculated for C.sub.29H.sub.30N.sub.4O.sub.5: 514.2216: found 515.2289 [(M+H).sup.+ form].

(9) EXAMPLE 6: HRMS calculated for C.sub.29H.sub.30N.sub.4O.sub.5: 514.2216: found 515.2302 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[cis-3-phenyl-1,4-dioxane-2-carbonyl]-4-piperidyl]methyl]-7-(4 methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 7)

(10) and

3-[[4-hydroxy-1-[cis-3-phenyl-1,4-dioxane-2-carbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 8)

(11) Using Step 3 of General Procedure 3 and starting from Preparation R3b and cis-3-phenyl-1,4-dioxane-2-carboxylic acid as reagents. EXAMPLE 7 and EXAMPLE 8 were obtained separately by chiral chromatography.

(12) EXAMPLE 7: HRMS calculated for C.sub.30H.sub.32N.sub.4O.sub.6: 544.2322: found 545.2403 [(M+H).sup.+ form].

(13) EXAMPLE 8: HRMS calculated for C.sub.30H.sub.32N.sub.4O.sub.6: 544.2322: found 545.239 [(M+H).sup.+ form].

3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 9)

(14) Using Step 3 of General Procedure 3 and starting from Preparation R3e and trans-2-phenylcyclohexanecarboxylic acid as reagents. EXAMPLE 9 was obtained. HRMS calculated for C.sub.31H.sub.34N.sub.4O.sub.3: 510.2631: found 511.2718 [(M+H).sup.+ form].

3-[[4-hydroxy-1-(1-phenylpiperidine-2-carbonyl)-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 10)

(15) Using Step 3 of General Procedure 3 and starting from Preparation R3b and 1-phenylpiperidine-2-carboxylic acid as reagents. EXAMPLE 10 was obtained. HRMS calculated for C.sub.31H.sub.35N.sub.5O.sub.4: 541.2689: found 542.2757 [(M+H).sup.+ form].

3-[[4-hydroxy-1-(1-phenylpyrrolidine-2-carbonyl)-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,9-d]pyrimidin-4-one (Example 11)

(16) Using Step 3 of General Procedure 3 and starting from Preparation R3b and 1-phenylpyrrolidine-2-carboxylic acid as reagents, EXAMPLE 11 was obtained. HRMS calculated for C.sub.30H.sub.33N.sub.5O.sub.4: 527.2532: found 52.2598 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[trans-2-pyrrol-1-ylcyclohexanecarbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, racemic (Example 12)

(17) and

3-[[4-hydroxy-1-[trans-2-pyrrol-1-ylcyclohexanecarbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 13)

(18) and

3-[[4-hydroxy-1-[trans-2-pyrrol-1-ylcyclohexanecarbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 14)

(19) Using Step 3 of General Procedure 3 and starting from Preparation R3e and 2-pyrrol-1-ylcyclohexanecarboxylic acid as reagents, EXAMPLE 12 was obtained. EXAMPLE 13 and EXAMPLE 14 were obtained separately by chiral chromatography.

(20) EXAMPLE 12: HRMS calculated for C.sub.29H.sub.33N.sub.5O.sub.3: 499.253: found 522.2478 [(M+Na).sup.+ form].

(21) EXAMPLE 13: HRMS calculated for C.sub.29H.sub.33N.sub.5O.sub.3: 499.2583: found 500.2667 [(M+H).sup.+ form].

(22) EXAMPLE 14: HRMS calculated for C.sub.29H.sub.33N.sub.5O.sub.3: 499.2583: found 500.2665 [(M+H).sup.+ form.

3-[[4-hydroxy-1-trans-2-pyrrol-1-ylcyclohexanecarbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, racemic (Example 15)

(23) and

3-[[4-hydroxy-1-[trans-2-pyrrol-1-ylcyclohexanecarbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 16)

(24) and

3-[[4-hydroxy-1-[trans-2-pyrrol-1-ylcyclohexanecarbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 17)

(25) Using Step 3 or General Procedure 3 and starting from Preparation R3b and 2-pyrrol-1-ylcyclohexanecarboxylic acid as reagents, EXAMPLE 15 was obtained. EXAMPLE 16 and EXAMPLE 17 were obtained separately by chiral chromatography.

(26) EXAMPLE 15: HRMS calculated for C.sub.30H.sub.35N.sub.5O.sub.4: 529.26H.sub.9: found 530.2759 [(M+H).sup.+ form].

(27) EXAMPLE 16: HRMS calculated for C.sub.30H.sub.35N.sub.5O.sub.4: 529.2689: found 530.2766 [(M+H).sup.+ form].

(28) EXAMPLE 17: HRMS calculated for C.sub.30H.sub.35N.sub.5O.sub.4: 529.2689: found 530.277 [(M+H).sup.+ form].

6-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-3-phenyl-triazolo[4,5-d]pyrimidin-7-one (Example 18)

(29) Using General Procedure 4 starting from 3-phenyl-6H-triazolo[4,5-d]pyrimidin-7-one and Preparation R1c as reagents. EXAMPLE 18 was obtained. HRMS calculated for C.sub.29H.sub.32N.sub.6O.sub.3: 512.2536: found 513.2606 [(M+H).sup.+ form].

5-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-1-phenyl-pyrazolo[3,4-d]pyrimidin-4-one (Example 19)

(30) Using General Procedure 4 starting from 1-phenyl-H-pyrazolo[3,4-d]pyrimidin-4-one and Preparation R1c as reagents. EXAMPLE 19 was obtained. HRMS calculated for C.sub.30H.sub.33N.sub.5O.sub.3: 512.253: found 512.2652 [(M+H).sup.+ form].

1-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-9-phenyl-purin-6-one (Example 20)

(31) Using General Procedure 4 starting from 9-phenyl-1H-purin-6-one and Preparation R1c as reagents. EXAMPLE 20 was obtained. HRMS calculated for C.sub.30H.sub.33N.sub.5O.sub.3: 511.2583: found 512.2651 [(M+H).sup.+ form].

3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl) 4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 21)

(32) Using General Procedure 4 starting from Preparation R2d and Preparation R1c as reagents. EXAMPLE 21 was obtained. HRMS calculated for C.sub.32H.sub.36N.sub.4O.sub.4: 540.2737: found 541.2806 [(M+H).sup.+ form].

7-(4-chlorophenyl)-3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (Example 22)

(33) Using General Procedure 4 starting from Preparation R2c and Preparation R1c as reagents. EXAMPLE 22 was obtained. HRMS calculated for C.sub.31H.sub.33N.sub.4O.sub.3Cl: 544.2241: found 545.2307 [(M+H).sup.+ form].

3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-7-(3-thienyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 23)

(34) Using General Procedure 4 starting from Preparation R2f and Preparation R1c as reagents. EXAMPLE 23 was obtained. HRMS calculated for C.sub.29H.sub.32N.sub.4O.sub.3S: 516.2195: found 517.2267 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[trans-2-phenyltetrahydropyran-3-carbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 24)

(35) Using Step 3 of General Procedure 3 starting from Preparation R3b and 2-phenyltetrahydropyran-3-carboxylic acid as reagents. EXAMPLE 24 was obtained. HRMS calculated for C.sub.31H.sub.34N.sub.4O.sub.5: 542.2529: found 543.26 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[(trans-2-phenyltetrahydropyran-3-carbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 25)

(36) and

3-[[4-hydroxy-1-[trans-2-phenyltetrahydropyran-3-carbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 26)

(37) Using Step 3 of General Procedure 3 starting from Preparation R3e and 2-phenyltetrahydropyran-3-carboxylic acid as reagents. EXAMPLE 25 and EXAMPLE 26 were obtained separately by chiral chromatography.

(38) EXAMPLE 25: HRMS calculated for C.sub.30H.sub.32N.sub.4O.sub.4: 512.2424: found 513.249 [(M+H).sup.+ form

(39) EXAMPLE 26: HRMS calculated for C.sub.30H.sub.32N.sub.4O.sub.4: 512.2424: found 513.2501 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[trans-1-methyl-6-oxo-2-phenyl-piperidine-3-carbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 27)

(40) and

3-[[4-hydroxy-1-[trans-1-methyl-6-oxo-2-phenyl-piperidine-3-carbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 28)

(41) Using Step 3 of General Procedure 3 starting from Preparation R3e and trans-1-methyl-6-oxo-2-phenyl-piperidine-3-carboxylic acid a reagents, EXAMPLE 27 and EXAMPLE 28 were obtained separately by chiral chromatography.

(42) EXAMPLE 27: HRMS calculated for C.sub.31H.sub.33N.sub.5O.sub.4: 339.2532: found 540.2606 [(M+H).sup.+ form].

(43) EXAMPLE 28: HRMS calculated for C.sub.31H.sub.33N.sub.5O.sub.4: 539.2532: found 540.2607 [(M+H).sup.+ form].

3-[[1-[trans-5,5-difluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 29)

(44) and

3-[[1-[trans-5,5-difluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 30)

(45) Using Step 3 of General Procedure 3 starting from Preparation R3b and Preparation R4ak as reagents. EXAMPLE 29 and EXAMPLE 36 were obtained separately by chiral chromatography.

(46) EXAMPLE 29: HRMS calculated for C.sub.32H.sub.34N.sub.4O.sub.4F.sub.2: 576.2548: found 577.2624 [(M+H)+ form].

(47) EXAMPLE 30: HRMS calculated for C.sub.32H.sub.34N.sub.4O.sub.4F.sub.2: 576.2548: round 5771619 [(M+H).sup.+ form].

3-[[1-[trans-5,5-difluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 31)

(48) and

3-[[1-[trans-5,5-difluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 32)

(49) Using Step 3 of General Procedure 3 starting from Preparation R3e and Preparation R4ak as reagents, EXAMPLE 31 and EXAMPLE 32 were obtained separately by chiral chromatography.

(50) EXAMPLE 31: HRMS calculated for C.sub.31H.sub.32N.sub.4O.sub.3F.sub.2: 546.2443: found 547.2516 [(M+H).sup.+ form].

(51) EXAMPLE 32: HRMS calculated for C.sub.31H.sub.32N.sub.4O.sub.3F.sub.2: 546.2443: found 547.2519 [(M+H).sup.+ form].

3-[[1-(trans-4,4-difluoro-2-phenyl-cyclohexanecarbonyl)-4-hydroxy-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 33)

(52) and

3-[[1-[trans-4,4-difluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 34)

(53) Using Step 3 of General Procedure 3 starting from Preparation R3b and Preparation R4ah as reagents. EXAMPLE 33 and EXAMPLE 34 were obtained separately by chiral chromatography.

(54) EXAMPLE 33: HRMS calculated for C.sub.32H.sub.34N.sub.4O.sub.4F.sub.2: 576.2548: found 577.2619 [(M+H).sup.+ form].

(55) EXAMPLE 34: HRMS calculated for C.sub.32H.sub.34N.sub.4O.sub.4F.sub.2: 576.2548: found 577.2623 [(M+H).sup.+ form].

3-[[1-[trans-4,4-difluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 35)

(56) and

3-[[1-[trans-4,4-difluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 36)

(57) Using Step 3 of General Procedure 3 starting from Preparation R3e and Preparation R4ah as reagents EXAMPLE 35 and EXAMPLE 36 were obtained separately by chiral chromatography.

(58) EXAMPLE 35: HRMS calculated for C.sub.31H.sub.32N.sub.5O.sub.3F.sub.2: 546.2443: found 547.2519 [(M+H).sup.+ form].

(59) EXAMPLE 36: HRMS calculated for C.sub.31H.sub.32N.sub.4O.sub.3F.sub.2: 546.2443: found 547.2518 [(M+H).sup.+ form].

3-[[1-[5-fluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 37)

(60) Using Step 3 of General Procedure 3 starting from Preparation R3e and Preparation R4h as reagents. EXAMPLE 37 was obtained. HRMS calculated for C.sub.31H.sub.33N.sub.4O.sub.3F: 528.2537: found 329.2602 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[trans-1-methyl-6-oxo-2-phenyl-piperidine-3-carbonyl]-4-piperidyl]methyl]-7-methyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 38)

(61) and

3-[[4-hydroxy-1-[trans-1-methyl-6-oxo-2-phenyl-piperidine-3-carbonyl]-4-piperidyl]methyl]-7-methyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 39)

(62) Using Step 3 of General Procedure 3 starting from Preparation R3d and trans-1-methyl-6-oxo-2-phenyl-piperidine-3-carboxylic acid as reagents. EXAMPLE 3 and EXAMPLE 39 were obtained separately by chiral separation.

(63) EXAMPLE 38: HRMS calculated for C.sub.26H.sub.31N.sub.5O.sub.4: 477.2376: found 478.2456 [(M+H).sup.+ form].

(64) EXAMPLE 39: HRMS calculated for C.sub.26H.sub.31N.sub.5O.sub.4: 477.2376: found 478.2447 [(M+H).sup.+ form].

3-[[1-[trans-2-(4-fluorophenyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 40)

(65) and

3-[[1-[trans-2-(4-fluorophenyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 41)

(66) Using Step 3 of General Procedure 3 starting from Preparation R3b and 2-(4-fluorophenyl)cyclohexanecarboxylic acid as reagents. EXAMPLE 40 and EXAMPLE 41 were obtained separately by chiral chromatography.

(67) EXAMPLE 40: HRMS calculated for C.sub.32H.sub.35N.sub.4O.sub.4F: 558.2642: found 559.2722 [(M+H).sup.+ form].

(68) EXAMPLE 41: HRMS calculated for C.sub.32H.sub.35N.sub.4O.sub.4F: 559.2642: found 559.2722 [(M+H).sup.+ form].

3-[[1-[(trans-2-(4-fluorophenyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 42)

(69) and

3-[[1-[trans-2-(4-fluorophenyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 43)

(70) Using Step 3 of General Procedure 3 starting from Preparation R3e and 2-(4-fluorophenyl)cyclohexanecarboxylic acid as reagents. EXAMPLE 42 and EXAMPLE 43 were obtained separately by chiral chromatography.

(71) EXAMPLE 42: HRMS calculated for C.sub.31H.sub.33N.sub.4O.sub.3F: 528.2537: found 529.2625 [(M+H).sup.+ form].

(72) EXAMPLE 43: HRMS calculated for C.sub.31H.sub.33N.sub.4O.sub.3F: 528.2537: found 529.2615 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[trans-2-phenyltetrahydropyran-3-carbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 44)

(73) and

3-[[4-hydroxy-1-[trans-2-phenyltetrahydropyran-3-carbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 45)

(74) Using Step 3 of General Procedure 3 starting from Preparation R3b and 2-phenyltetrahydropyran-3-carboxylic acid as reagents, EXAMPLE 44 and EXAMPLE 45 were obtained separately by chiral chromatography.

(75) EXAMPLE 44: HRMS calculated for C.sub.31H.sub.34N.sub.4O.sub.5: 542.2529: found 543.2614 [(M+H).sup.+ form].

(76) EXAMPLE 45: HRMS calculated for C.sub.31H.sub.34N.sub.4O.sub.5: 542.2529: found 543.2589 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[trans-2-phenyltetrahydrofuran-3-carbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 46)

(77) Using Step 3 of General Procedure 3 starting from Preparation Re and trans-2-phenyltetrahydrofuran-3-carboxylic acid as reagents. EXAMPLE 46 was obtained. HRMS calculated for C.sub.29H.sub.30N.sub.4O.sub.4: 49.2267: found 499.2336 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[trans-2-imidazol-1-ylcyclohexanecarbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 47)

(78) and

3-[[4-hydroxy-1-[trans-2-imidazol-1-ylcyclohexanecarbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 48)

(79) Using Step 3 of General Procedure 3 starting from Preparation R3b and trans-2-imidazol-1-ylcyclohexanecarboxylic acid as reagents. EXAMPLE 47 and EXAMPLE 48 were obtained separately by chiral chromatography.

(80) EXAMPLE 47: HRMS calculated for C.sub.29H.sub.34N.sub.6O.sub.4: 530.2642: found 531.2708 [(M+H).sup.+ form].

(81) EXAMPLE 48: HRMS calculated for C.sub.29H.sub.34N.sub.6O.sub.4: 530.2642: found 531.2718 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[trans-2-imidazol-1-ylcyclohexanecarbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one enantiomer 1 (Example 49)

(82) and

3-[[4-hydroxy-1-[trans-2-imidazol-1-ylcyclohexanecarbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 50)

(83) Using Step 3 of General Procedure 3 starting from Preparation R3e and trans-2-imidazol-1-ylcyclohexanecarbonylic acid as reagents EXAMPLE 49 and EXAMPLE 50 were obtained separately by chiral chromatography.

(84) EXAMPLE 49: HRMS calculated for C.sub.28H.sub.32N.sub.6O.sub.3: 500.2536: found 501.2612 [(M+H).sup.+ form].

(85) EXAMPLE 50: HRMS calculated for C.sub.28H.sub.32N.sub.6O.sub.3: 500.2536: found 501.262 [(M+H).sup.+ form].

3-[[1-[trans-3,3-difluo-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 51)

(86) Using Step 3 of General Procedure 3 starting from Preparation Re and Preparation R4x as reagents. EXAMPLE 51 was obtained. HRMS calculated for C.sub.31H.sub.32N.sub.4O.sub.3F.sub.2: 546.2443; found 547.2507 [(M+H).sup.+ form].

3-[[1-[trans-3,3-difluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enanatiomer 2 (Example 52)

(87) Using Step 3 of General Procedure 3 starting from Preparation Re and Preparation R4y as reagents, EXAMPLE 52 was obtained. HRMS calculated for C.sub.31H.sub.32N.sub.4O.sub.3F.sub.2: 546.2443: found 547.2505 [(M+H).sup.+ form].

(1S,2S,3R or 1R,2R,3S)-3-[[4-hydroxy-1-[3-hydroxy-2-phenyl-cyclohexanecarbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 53)

(88) Using Step 3 of General Procedure 3 starting from Preparation R3e and Preparation R4d as reagents. EXAMPLE 53 was obtained. HRMS calculated for C.sub.31H.sub.34N.sub.4O.sub.4: 526.258: found 527.2657 [(M+H).sup.+ form].

(1S,2S,3S or 1R,2R,3R)-3-[[4-hydroxy-1-[3-hydroxy-2-phenyl-cyclohexanecarbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 54)

(89) Using Step 3 of General Procedure 3 starting from Preparation Re and Preparation R4e as reagents. EXAMPLE 54 was obtained. HRMS calculated for C.sub.31H.sub.34N.sub.4O.sub.4: 526.258: found 527.2672 [(M+H).sup.+ form].

(1S,2S,3R or 1R,2R,3S)-3-[[4-hydroxy-1-[3-hydroxy-2-phenyl-cyclohexanecarbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 55)

(90) Using Step 3 of General Procedure 3 starting from Preparation R3e and Preparation R4f 3 as reagents. EXAMPLE 55 was obtained. HRMS calculated for C.sub.31H.sub.34N.sub.4O.sub.4: 26.258: found 527.2668 [(M+H).sup.+ form].

(1S,2S,3S or 1R,2R,3R)-3-[[4-hydroxy-1-[3-hydroxy-2-phenyl-cyclohexanecarbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 56)

(91) Using Step 3 of General Procedure 3 starting from Preparation R3e and Preparation R4g as reagents. EXAMPLE 56 was obtained. HRMS calculated for C.sub.31H.sub.34N.sub.4O.sub.4: 526.258: found 527.2659 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[trans-2-(1-methylimidazol-2-yl)cyclohexanecarbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 57)

(92) and

3-[[4-hydroxy-1-[trans-2-(1-methylimidazol-2-yl)cyclohexanecarbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 58)

(93) Using Step 3 of General Procedure 3 starting from Preparation R3e and trans-2-(1-methylimidazol-2-yl)cyclohexanecarboxylic acid as reagents. EXAMPLE 57 and

(94) EXAMPLE 58 were obtained separately by chiral chromatography.

(95) EXAMPLE 57: HRMS calculated for C.sub.29H.sub.34N.sub.6O.sub.3: 514.2692: found 515.2768 [(M+H).sup.+ form].

(96) EXAMPLE 58: HRMS calculated for C.sub.29H.sub.34N.sub.6O.sub.3: 514.2692: found 515.2771 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[trans-2-methyl-6-(2-thienyl)cyclohex-2-ene-1-carbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 59)

(97) and

3-[[4-hydroxy-1-[trans-2-methy-6-(2-thienyl)cyclohex-2-ene-1-carbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 60)

(98) Using Step 3 of General Procedure 3 starting from Preparation Rb and Preparation R4s as reagents. EXAMPLE 59 and EXAMPLE 60 were obtained separately by chiral chromatography.

(99) EXAMPLE 9: HRMS calculated for C.sub.31H.sub.34N.sub.4O.sub.4S: 55.2301: found 559.2314 [(M+H).sup.− form].

(100) EXAMPLE 60: HRMS calculated for C.sub.31H.sub.34N.sub.4O.sub.4S: 558.2301: found 559.2379 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[trans-2-methyl-6-(3-thienyl)cyclohex-2-ene-1-carbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 61)

(101) and

3-[[4-hydroxy-1-[trans-2-methyl-6-(3-thienyl)cyclohex-2-ene-1-carbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 62)

(102) Using Step 3 of General Procedure 3 starting from Preparation R3b and Preparation R4 as reagents. EXAMPLE 61 and EXAMPLE 62 were obtained separately by chiral chromatography.

(103) EXAMPLE 61: HRMS calculated for C.sub.31H.sub.34N.sub.4O.sub.4S: 558.2301: found 559.2379 [(M+H).sup.+ form].

(104) EXAMPLE 62: HRMS calculated for C.sub.31H.sub.34N.sub.4O.sub.4S: 558.2301: found 559.2371 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[trans-2-(2-oxopyrrolidin-1-yl)cyclohexanecarbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 63)

(105) and

3-[[4-hydroxy-1-[trans-2-(2-oxopyrrolidin-1-yl)cyclohexanecarbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 64)

(106) Using Step 3 of General Procedure 3 starting from Preparation R3b and trans-2-(2-oxopyrrolidin-1-yl)cyclohexanecarboxylic acid as reagents. EXAMPLE 63 and EXAMPLE 64 were obtained separately by chiral chromatography.

(107) EXAMPLE 63: HRMS calculated for C.sub.30H.sub.37N.sub.5O.sub.5: 547.2795: found 548.2867 [(M+H).sup.+ form].

(108) EXAMPLE 64: HRMS calculated for C.sub.30H.sub.37N.sub.5O.sub.5: 547.2795: found 548.287 [(M+H).sup.+ form].

3-[[4-hydroxy-1-trans-2-(2-oxopyrrolidin-1-yl)cyclohexanecarbonyl-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 65)

(109) and

3-[[4-hydroxy-1-[trans-2-oxopyrrolidin-1-yl)cyclohexanecarbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 66)

(110) Using Step 3 of General Procedure 3 starting from Preparation R3e and trans-2-(2-oxopyrrolidin-1-yl)cyclohexanecarboxylic acid as reagents. EXAMPLE 65 and EXAMPLE 66 were obtained separately by chiral chromatography.

(111) EXAMPLE 65: HRMS calculated for C.sub.29H.sub.35N.sub.5O.sub.4: 517.269: found 518.2767 [(M+H).sup.+ form].

(112) EXAMPLE 66: HRMS calculated for C.sub.29H.sub.35N.sub.5O.sub.4: 517.2689: found 518.2755 [(M+H).sup.+ form].

7-[4-(hydroxymethyl)phenyl]-3-[[4-hydroxy-1-[trans-2-(2-oxopyrrolidin-1-yl)cyclohexanecarbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 67)

(113) and

7-[4-(hydroxymethyl)phenyl]-3-[[4-hydroxy-1-[trans-2-(2-oxopyrrolidin-1-yl)cyclohexanecarbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 68)

(114) Using Step 3 of General Procedure 3 starting from Preparation R3g and trans-2-(2-oxopyrrolidin-1-yl)cyclohexanecarboxylic acid as reagents. EXAMPLE 67 and EXAMPLE 68 were obtained separately by chiral chromatography.

(115) EXAMPLE 67: HRMS calculated for C.sub.30H.sub.37N.sub.5O.sub.5: 547.2795: found 54.2872 [(M+H).sup.+ form].

(116) EXAMPLE 68: HRMS calculated for C.sub.30H.sub.37N.sub.5O.sub.5: 547.2795: found 54.2864 [(M+H).sup.+ form].

3-[[4-hydroxy-1-trans-2-(1-methylimidazol-2-yl)cyclohexanecarbonyl]-4-piperidyl]methyl-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 69)

(117) and

3-[[4-hydroxy-1-[trans-2-(1-methylimidazol-2-yl)cyclohexanecarbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 70)

(118) Using Step 3 of General Procedure 3 starting from Preparation R3b and trans-2-(1-methylimidazol-2-yl)cyclohexanecarboxylic acid as reagents, EXAMPLE 69 and

(119) EXAMPLE 70 were obtained separately by chiral chromatography.

(120) EXAMPLE 69: HRMS calculated for C.sub.30H.sub.36N.sub.6O.sub.4: 544.2798: found 545.2878 [(M+H).sup.+ form].

(121) EXAMPLE 70: HRMS calculated for C.sub.30H.sub.36N.sub.6O.sub.4: 544.2798: found 545.2874 [(M+H).sup.+ form].

3-[[1-[trans-4,4-difluoro-2-(2-thienyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (Example 71)

(122) Using Step 3 of General Procedure 3 starting from Preparation R3e and Preparation R4aj as reagents. EXAMPLE 71 was obtained. HRMS calculated for C.sub.29H.sub.30N.sub.4O.sub.3F.sub.2S: 552.2007: found 553.2077 [(M+H).sup.+ form].

3-[[1-[trans-4,4-difluoro-2-(2-thienyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 72)

(123) and

3-[[1-[trans-4,4-difluoro-2-(2-thienyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 73)

(124) Using Step 3 of General Procedure 3 starting from Preparation R3b and Preparation R4aj as reagents. EXAMPLE 72 and EXAMPLE 73 were obtained separately by chiral chromatography.

(125) EXAMPLE 72: HRMS calculated for C.sub.30H.sub.32F.sub.2N.sub.4O.sub.4S: 582.2112: found 583.2204 [(M+H).sup.+ form].

(126) EXAMPLE 73: HRMS calculated for C.sub.30H.sub.32N.sub.4O.sub.4F.sub.2S: 582.2112: found 583.2184 [(M+H).sup.+ form].

3-[[1-[trans-4,4-difluoro-2-(3-fury)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 74)

(127) and

3-[[1-[trans-4,4-difluoro-2-(3-furyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 75)

(128) Using Step 3 of General Procedure 3 starting from Preparation R3b and Preparation R4aa as reagents. EXAMPLE 74 and EXAMPLE 75 were obtained separately by chiral chromatography.

(129) EXAMPLE 74: HRMS calculated for C.sub.30H.sub.32F.sub.2N.sub.4O.sub.5: 566.2341: found 567.2413 [(M+H).sup.+ form].

(130) EXAMPLE 75: HRMS calculated for C.sub.30H.sub.32F.sub.2N.sub.4O.sub.5: 566.2341: found 567.2429 [(M+H).sup.+ form].

7-chloro-3-[[1-[trans-4,4-difluoro-2-oxazol-5-yl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]thieno[3,4-d]pyrimidin-4-one (Example 76)

(131) Using Step 3 of General Procedure 3 starting from Preparation R3 and Preparation R4ag as reagents. EXAMPLE 76 was obtained. HRMS calculated for C.sub.22H.sub.23ClF.sub.2N.sub.4O.sub.4S: 512.1097: found 513.1172 [(M+H).sup.+ form].

3-[[1-[trans-4,4-difluoro-2-oxazol-4-yl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-[4-(hydroxymethyl)phenyl]thieno[3,4-d]pyrimidin-4-one (Example 77)

(132) Using Step 3 of General Procedure 3 starting from Preparation R3h and Preparation R4af as reagents, the corresponding halogenated compound was obtained which, using General Procedure 5, was reacted with 4-(hydroxymethyl)phenylboronic acid to give EXAMPLE 77. HRMS calculated for C.sub.29H.sub.30F.sub.2N.sub.4O.sub.5S: 584.1905: found 585.1992 [(M+H).sup.+ form].

3-[[1-[trans-5,5-difluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one, enantiomer 1 (Example 73)

(133) and

3-[[1-[trans-5,5-difluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one, enantiomer 2 (Example 79)

(134) Using Step 3 of: General Procedure 3 starting from Preparation R3h and Preparation R4ak as reagents, the corresponding halogenated compound was obtained which, using General Procedure 5, was reacted with phenylboronic acid to give EXAMPLE 78 and EXAMPLE 79 separately by chiral chromatography.

(135) EXAMPLE 78: HRMS calculated for C.sub.31H.sub.31F.sub.2N.sub.3O.sub.3S: 563.2054: found 564.212 [(M+H).sup.+ form].

(136) EXAMPLE 79: HRMS calculated for C.sub.31H.sub.31F.sub.2N.sub.3O.sub.3S: 563.2054: found 564.2118 [(M+H).sup.+ form].

3-[[1-[trans-2-(1-ethylpyrazol-4-yl)-4,4-difluoro-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one, enantiomer 1 (Example 80)

(137) and

3-[[1-[trans-2-(1-ethylpyrazol-4-yl)-4,4-difluoro-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one, enantiomer 2 (Example 81)

(138) Using Step 3 of General Procedure 3 starting from Preparation R3h and Preparation R4l as reagents, the corresponding halogenated compound was obtained which, using General Procedure 5, was reacted with phenylboronic acid to give EXAMPLE 80 and EXAMPLE 81 separately by chiral chromatography.

(139) EXAMPLE 80: HRMS calculated for C.sub.30H.sub.33F.sub.2N.sub.5O.sub.3: 581.2272: found 582.2336 [(M+H).sup.+ form].

(140) EXAMPLE 81: HRMS calculated for C.sub.30H.sub.33F.sub.2N.sub.5O.sub.3S: 581.2272: found 582.2346 [(M+H).sup.+ form].

3-[[1-[trans-4,4-difluoro-2-thiazol-4-yl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one, enantiomer 1 (Example 82)

(141) and

3-[[1-[trans-4,4-difluoro-2-thiazol-4-yl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one, enantiomer 2 (Example 83)

(142) Using Step 3 of General Procedure 3 starting from Preparation R3h and Preparation R4ai as reagents, the corresponding halogenated compound was obtained which, using General Procedure 5, was reacted with phenylboronic acid to give EXAMPLE 82 and EXAMPLE 83 separately by chiral chromatography.

(143) EXAMPLE 82: HRMS calculated for C.sub.28H.sub.28F.sub.2N.sub.4O.sub.3S.sub.2: 570.1571: found 571.1638 [(M+H).sup.+ form].

(144) EXAMPLE 83: HRMS calculated for C.sub.28H.sub.28F.sub.2N.sub.4O.sub.3S.sub.2: 570.1571: found 571.163 [(M+H).sup.+ form].

3-[[1-[trans-4,4-difluoro-2-(4-pyridyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one (Example 34)

(145) Using Step 3 of General Procedure 3 starting from Preparation R3b and Preparation R4ac as reagents, the corresponding halogenated compound was obtained which, using General Procedure 5, was reacted with phenylboronic acid to give EXAMPLE 84. HRMS calculated for C.sub.30H.sub.30F.sub.2N.sub.4O.sub.3S: 564.2007: found 565.2084 [(M+H).sup.+ form].

3-[[1-[trans-4,4-difluoro-2-(2-furyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4d]pyrimidin-4-one, enantiomer 1 (Example 85)

(146) and

3-[[1-[trans-4,4-difluoro-2-(2-furyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one, enantiomer 2 (Example 86)

(147) Using Step 3 of General Procedure 3 starting from Preparation R3 and Preparation R4z as reagents, the corresponding halogenated compound was obtained which, using General Procedure 5, was reacted with phenylboronic acid to give EXAMPLE 85 and EXAMPLE 86 separately by chiral chromatography.

(148) EXAMPLE 35: HRMS calculated for C.sub.29H.sub.29F.sub.2N.sub.3O.sub.4S: 553.1947: found 554.1923 [(M+H).sup.+ form].

(149) EXAMPLE 86: HRMS calculated for C.sub.29H.sub.29F.sub.2N.sub.3O.sub.4S: 553.1147: found 554.1921 [(M+H).sup.+ form].

3-[[1-[trans-4,4-difluoro-2-(3-thienyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one, enantiomer 1 (Example 87)

(150) and

3-[[1-[trans-4,4-difluoro-2-(3-thienyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one, enantiomer 2 (Example 88)

(151) Using Step 3 of General Procedure 3 starting from Preparation R3h and Preparation R4ab as reagents, the corresponding halogenated compound was obtained which, using General Procedure 5, was reacted with phenylboronic acid to give EXAMPLE 87 and EXAMPLE 88 separately by chiral chromatography.

(152) EXAMPLE 87: HRMS calculated for C.sub.29H.sub.29F.sub.2N.sub.3O.sub.3S.sub.3: 569.1619: found 570.1693 [(M+H).sup.+ form].

(153) EXAMPLE 88: HRMS calculated for C.sub.29H.sub.29F.sub.2N.sub.3O.sub.3S.sub.2: 569.1619: found 570.1695 [(M+H).sup.+ form].

3-[[1-[trans-4,4-difluoro-2-(5-methyl-3-thienyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one, enantiomer 1 (Example 89)

(154) and

3-[[1-[trans-4,4-difluoro-2-(S-methyl-3-thienyl)cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one, enantiomer 2 (Example 90)

(155) Using Step 3 of General Procedure 3 starting from Preparation R3h and Preparation R4ad as reagents, the corresponding halogenated compound was obtained which, using General Procedure 5, was reacted with phenylboronic acid to give EXAMPLE 89 and EXAMPLE 90 separately by chiral chromatography.

(156) EXAMPLE 89: HRMS calculated for C.sub.30H.sub.31F.sub.2N.sub.3O.sub.3S.sub.2: 583.1775: found 584.1847 [(M+H).sup.+ form].

(157) EXAMPLE 90: HRMS calculated for C.sub.30H.sub.31F.sub.2N.sub.3O.sub.3S.sub.2: 583.1775: found 584.15 [(M+H).sup.+ form].

3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]thieno[2,3-d]pyrimidin-4-one (Example 91)

(158) Using General Procedure 4 starting from 3H-thieno[2,3-d]pyrimidin-4-one and Preparation R1c as reagents. EXAMPLE 91 was obtained. HRMS calculated for C.sub.25H.sub.29N.sub.3O.sub.3S: 451.193: found 452.1996 [(M+H).sup.+ form].

3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-one (Example 92)

(159) Using Step 3 of General Procedure 3 starting from Preparation R3c and trans-2-phenylcyclohexanecarboxylic acid as reagents. EXAMPLE 92 was obtained. HRMS calculated for C.sub.25H.sub.30N.sub.4O.sub.3:434.2318: found 435.2403 [(M+H).sup.+ form].

3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]pyrido[3,2-d]pyrimidin-4-one (Example 93)

(160) Using Step 3 of General Procedure 3 starting from Preparation R3f and trans-2-phenylcyclohexanecarboxylic acid as reagents. EXAMPLE 93 was obtained. HRMS calculated for C.sub.26H.sub.30N.sub.4O.sub.3: 446.2311: found 447.2397 [(M+H).sup.+ form].

3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-6-[(4-methoxyphenyl)methylamino]pyrido[3,2-d]pyrimidin-4-one (Example 94)

(161) Using Step 3 of General Procedure 3 starting from Preparation R3a and trans-2-phenylcyclohexanecarboxylic acid as reagents, EXAMPLE 94 was obtained. HRMS calculated for C.sub.34H.sub.39N.sub.5O.sub.4: 581.3002: found 582.3049 [(M+H).sup.+ form].

3-[[1-[trans-4,4-difluoro-2-[5-(trifluoromethyl)-3-thienyl]cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one (Example 95)

(162) Using Step 3 of General Procedure 3 starting from Preparation R3h and Preparation R4ae as reagents, the corresponding halogenated compound was obtained which, using General Procedure 5, was reacted with phenylboronic acid to give EXAMPLE 95. HRMS calculated for C.sub.30H.sub.28F.sub.5N.sub.3O.sub.3S.sub.2: 637.1492: found 638.1559 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[trans-2-(1,2,4-triazol-1-yl)cyclohexanecarbonyl]-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one (Example 96)

(163) Using Step 3 of General Procedure 3 starting from Preparation R3h and trans-2-(1,2,4-triazol-1-yl)cyclohexanecarboxylic acid as reagents, the corresponding halogenated compound was obtained which, using General Procedure 5, was reacted with phenylboronic acid to give EXAMPLE 96. HRMS calculated for C.sub.27H.sub.30N.sub.6O.sub.3S: 518.21: found 519.2173 [(M+H).sup.+ form].

3-[[4-hydroxy-1-[cis-2-(1,2,4-triazol-1-yl)cyclohexanecarbonyl]-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one (Example 97)

(164) Using Step 3 of General Procedure 3 starting from Preparation R3 and cis-2-0,2,4-triazol-1-yl)cyclohexanecarboxylic acid as reagents, the corresponding halogenated compound was obtained which, using General Procedure 5, was reacted with phenylboronic acid to give EXAMPLE 97. HRMS calculated for C.sub.27H.sub.30N.sub.6O.sub.3S: 518.21: found 519.2170 [(M+H).sup.+ form].

3-[[1-(trans-4,4-dimethyl-2-phenyl-cyclohexanecarbonyl)-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one, enantiomer 1 (Example 9g)

(165) and

3-[[1-(trans-4,4-dimethyl-2-phenyl-cyclohexanecarbonyl)-4-hydroxy-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one, enantiomer 2 (Example 99)

(166) Using Step 3 of General Procedure 3 starting from Preparation R3h and trans-4,4-dimethyl-2-phenyl-cyclohexanecarboxylic acid as reagents, the corresponding halogenated compound was obtained which, using General Procedure 5, was reacted with phenylboronic acid to give EXAMPLE 98 and EXAMPLE 99 separately by chiral chromatography.

(167) EXAMPLE 9g: HRMS calculated for C.sub.33H.sub.37N.sub.3O.sub.3S: 555.2556: found 556.2628 [(M+H).sup.+ form].

(168) EXAMPLE 99: HRMS calculated for C.sub.33H.sub.37N.sub.3O.sub.3S: 555.2556: found 556.26149 [(M+H).sup.+ form].

6-amino-3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]pyrido[3,2-d]pyrimidin-4-one (Example 100)

(169) EXAMPLE 94 was dissolved in TFA and heated and stirred at 70° C. for 2 hours, then it was evaporated. The residue was purified by preparative HPLC (on C-18 Gemini-NX 5 μm column, 5 mM aqueous NH.sub.4HCO.sub.3-MeCN, gradient) to give EXAMPLE 100. HRMS calculated for C.sub.26H.sub.31N.sub.5O.sub.3: 461.2427: found 462.2513 [(M+H).sup.+ form].

N-[3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-4-oxo-pyrido[3,2-d]pyrimidin-6-yl]tetrahydrofuran-3-carboxamide (Example 101)

(170) Using General Procedure 6 and starting from EXAMPLE 100 and tetrahydrofuran-3-carboxylic acid as reagents. EXAMPLE 101 was obtained. HRMS calculated for C.sub.31H.sub.37N.sub.5O.sub.5: 559.2795: found 560.2874 [(M+H).sup.+ form].

N-[3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-4-oxo-pyrido[3,2-d]pyrimidin-6-yl]-2-(2-oxoindolin-6-yl)acetamide (Example 102)

(171) Using General Procedure 6 and starting from EXAMPLE 100 and 2-(2-oxoindolin-6-yl)acetic acid as reagents. EXAMPLE 102 was obtained. HRMS calculated for C.sub.36H.sub.38N6O5: 634.2903: found 635.299 (M+H).sup.+ form.

2-hydroxy-N-[3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]4-oxo-pyrido[3,2-d]pyrimidin-6-yl]cyclopentanecarboxamide (Example 103)

(172) Using General Procedure 6 and starting from EXAMPLE 100 and 2-hydroxycyclopentane-1-carboxylic acid as reagents EXAMPLE 103 was obtained as mixture of diastereomers. HRMS calculated for C.sub.32H.sub.39N.sub.5O.sub.5: 573.2951: found 574.3039 and 574.3043 [(M+H).sup.+ form].

2-(3-hydroxyphenyl)-N-[3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-4-oxo-pyrido[3,2-d]pyrimidin-6-yl]acetamide (Example 104)

(173) Using General Procedure 6 and starting from EXAMPLE 100 and 3-hydroxyphenylacetic acid as reagents, EXAMPLE 104 was obtained. HRMS calculated for C.sub.34H.sub.37N.sub.5O.sub.5: 595.2795: found 96.2873 [(M+H).sup.+ form].

2-(5-hydroxy-1H-idol-3-yl)-N-[3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-4-oxo-pyrido[3,2-d]pyrimidin-6-yl]acetamide (Example 105)

(174) Using General Procedure 6 and starting from EXAMPLE 100 and 5-hydroxyindole-3-acetic acid as reagents. EXAMPLE 145 was obtained. HRMS calculated for C.sub.36H.sub.38N.sub.6O.sub.5: 634.2903: found 635.2982 [(M+H).sup.+ form].

N-[3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-4-oxo-pyrido[3,2-d]pyrimidin-6-yl]-2-tetrahydrofuran-2-yl-acetamide (Example 106)

(175) Using General Procedure 6 and starting from EXAMPLE 100 and 2-(oxolan-2-yl)acetic acid as reagents. EXAMPLE 106 was obtained. HRMS calculated for C.sub.32H.sub.39N.sub.5O.sub.5: 573.2951: found 574.302 [(M+H).sup.+ form].

N-[3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-4-oxo-pyrido[3,2-d]pyrimidin-6-yl]-4-methoxy-benzamide (Example 107)

(176) Using General Procedure 6 and starting from EXAMPLE 100 and p-anisic acid as reagents, EXAMPLE 107 was obtained. HRMS calculated for C.sub.34H.sub.37N.sub.5O5: 595.2795: found 596.2875 [(M+H).sup.+ form].

3-(2-amino-2-oxo-ethyl)sulfanyl-N-[3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-4-oxo-pyrido[3,2-d]pyrimidin-6-yl]propanamide (Example 108)

(177) Using General Procedure 6 and starting from EXAMPLE 100 and 3-[(2-amino-2-oxoethyl)thio]propanoic acid as reagents, EXAMPLE 100 was obtained. HRMS calculated for C.sub.31H.sub.38N.sub.5O.sub.5S: 606.2625: found 607.2704 [(M+H).sup.+ form].

3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-7-(3-pyridylmethyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 109)

(178) EXAMPLE 92 was dissolved in abs. DMF and 3-(bromomethyl)pyridine (1.5eq.) and Cs.sub.2CO.sub.3 (3 eq.) were added. The solution was heated and stirred for 116 hours, then it was purified by preparative HPLC (on C-18 Gemini-NX 5 μm column, 0.2% HCOOH aqueous solution-MeCN, gradient) to give EXAMPLE 109. HRMS calculated for C.sub.31H.sub.35N.sub.5O.sub.3: 525.274: found 526.2919 [(M+H).sup.+ form].

3-[[4-hydroxy-1-(trans-2-phenylcyclohexanecarbonyl)-4-piperidyl]methyl]-7-(3-thienylmethyl)pyrrolo[2,3-d]pyrimidin-4-one (Example 110)

(179) EXAMPLE 92 was dissolved in abs. DMF and 3-(bromomethyl)thiophene (1.5 eq.) and Cs.sub.2CO.sub.3 (3 eq.) were added. The solution was heated and stirred for 116 hours, then it was purified by preparative HPLC (on C-18 Gemini-NX 5 μm column, 5 mM aqueous NH.sub.4HCO.sub.3-MeCN, gradient) to give EXAMPLE 110. HRMS calculated for C.sub.30H.sub.34N.sub.4O.sub.3S: 530.2352: found 531.2433 [(M+H).sup.+ form].

3-[[1-[trans-4,4-difluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-methyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 111)

(180) and

3-[[1-[trans-4,4-difluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-methyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 112)

(181) Using General Procedure 3 and starting from 7-methyl-3H-pyrrolo[2,3-d]pyrimidin-4-one and Preparation R1d as reagents. EXAMPLE 111 and EXAMPLE 112 were obtained separately by chiral chromatography.

(182) EXAMPLE 111: HRMS calculated for C.sub.26H.sub.30F.sub.2N.sub.4O.sub.3: 494.2296: found 485.2352 [(M+H).sup.+ form].

(183) EXAMPLE 112: HRMS calculated for C.sub.26H.sub.30F.sub.2N.sub.4O.sub.3: 494.2286: found 485.2354 [(M+H).sup.+ form].

3-[[1-[trans-4,4-difluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]-7-isopropyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 113)

(184) and

3-[[1-[trans-4,4-difluoro-2-phenyl-cyclohexanecarbonyl]4-hydroxy-4-piperidyl]methyl]-7-isopropyl-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 114)

(185) Using General Procedure 8 and starting from Preparation R2o and Preparation R1d as reagents. EXAMPLE 113 and EXAMPLE 114 were obtained separately by chiral chromatography.

(186) EXAMPLE 113: HRMS calculated for C.sub.28H.sub.34F.sub.2N.sub.4O.sub.3: 512.2599: found 513.2683 [(M+H).sup.+ form].

(187) EXAMPLE 114: HRMS calculated for C.sub.28H.sub.34F.sub.2N.sub.4O.sub.3: 512.2599; round 513.2658 [(M+H).sup.+ form].

7-cyclopropyl-3-[[1-[trans-4,4-difluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 115)

(188) and

7-cyclopropyl-3-[[1-[trans-4,4-difluoro-2-phenyl-cyclohexanecarbonyl]-4-hydroxy-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 116)

(189) Using General Procedure 8 starting from Preparation R2p and Preparation R1d as reagents. EXAMPLE 115 and EXAMPLE 116 were obtained separately by chiral chromatography.

(190) EXAMPLE 115: HRMS calculated for C.sub.28H.sub.32F.sub.2N.sub.4O.sub.3: 510.2442: found 51.2514 [(M+H).sup.+ form].

(191) EXAMPLE 116: HRMS calculated for C.sub.28H.sub.32F.sub.2N.sub.4O.sub.3: 510.2442: found 511.2509 [(M+H).sup.+ form].

3-{[4-hydroxy-1-trans-1-methyl-6-oxo-2-phenylpiperidine-3-carbonyl)piperidin-4-yl]methyl}-7-(4-methoxyphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 1 (Example 117)

(192) and

3-{[4-hydroxy-1-(trans-1-methyl-6-oxo-2-phenylpiperidine-3-carbonyl)piperidin-4-yl]methyl}-7-(4-methoxyphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, enantiomer 2 (Example 318)

(193) Using General Procedure 6 starting from Preparation R3b and trans-1-methyl-6-oxo-2-phenyl-piperidine-3-carboxylic acid as reagents. EXAMPLE 117 and EXAMPLE 118 were obtained separately by chiral chromatography.

(194) EXAMPLE 117: HRMS calculated for C.sub.31H.sub.33N.sub.5O.sub.4: 569.2638: found 570.2717 [(M+H).sup.+ form].

(195) EXAMPLE 118: HRMS calculated for C.sub.31H.sub.33N.sub.5O.sub.4: 569.2639: found 570.2721 [(M+H).sup.+ form].

Pharmacological Study

Example A: Evaluation of the Inhibition of USP7 by the Fluorescence Intensity (FLINT) Readings

(196) USP7 activity was measured using Rhodamine-110 c-terminal labelled Ubiquitin as a substrate (Viva Biosciences). Incubation with USP7 results in the release of Rhodamine-110 leading to an increase in fluorescence which can be used in the continuous measurement of USP7 activity.

(197) The USP7 reactions were performed in a 50 μL volume, in 384 well black solid low binding plates (Corning #3575). The reaction buffer consisted of 100 mM Bicine pH 8.0, 0.01% TritonX 100, 1 mM TCEP, and 10% DMSO.

(198) 0.25 nM His-His-USP7 (aa208-560, [C315A]) was incubated with compound (final concentration 10% DMSO) for 60 minutes at 30° C. The reaction was then initiated by the addition of 500 nM Ubiquitin-Rhodamine-10 substrate and the plate read every 3 minutes for 21 minutes to measure the release of Rhodamine-110. Fluorescence Intensity (FLINT) readings were measured using a Biomek Neo plate reader (Ex. 485 nm. Em. 535 nm).

(199) The inhibition of increasing doses of compound was expressed as a percentage reduction in kinetic rate compared to the kinetic rates established between ‘DMSO only’ and ‘total inhibition’ controls (no USP7). The inhibitory concentrations that gave a 50% reduction in kinetic rate (IC.sub.50) were determined, from 11-point dose response curves, in XL-Fit using a 4-Parameter Logistic Model (Sigmoidal Dose-Response Model).

(200) The results presented in Table I below show that compounds of the invention inhibit interaction between USP7 protein and the fluorescent peptide described hereinbefore.

Example B: In Vitro Cytotoxicity

(201) The cytotoxicity studies were evaluated by MTT assay and carried out on MM 1S multiple myeloma or Z138 mantle cell lymphoma tumour cell lines. The cells are distributed onto microplates and exposed to the test compounds for 96 hours. The cell viability is then quantified by a colorimetric assay, the Microculture Tetrazolium Assay (Carmichael et. al., Cancer Res. 1997, 47, 936-942). The results are expressed in IC.sub.50 (the concentration of compound that inhibits cell viability by 50%) and are presented in Table I below. The results show that the compounds of the invention are cytotoxic.

(202) TABLE-US-00002 TABLE 1 IC.sub.50 of USP7 inhibition and of cytotoxicity for MM1S cells EXAMPLE IC.sub.50 (M) USP7 FLINT IC50 (M) MTT 1 9.16E−07 NT 2 4.39E−07 NT 3 5.30E−07 NT 4 4.58E−06 NT 5 1.94E−05 NT 6 2.80E−05 NT 7 6.50E−06 NT 8 1.33E−05 NT 9 3.59E−08 1.39E−08 10 4.25E−07 NT 11 2.57E−06 NT 12 7.11E−08 3.45E−08 13 1.11E−05 NT 14 2.71E−08 6.42E−09/1.47E−08 15 2.61E−08 8.76E−09 16 2.97E−06 NT 17 3.35E−08 4.21E−09 18 5.06E−08 6.36E−07 19 1.43E−08 1.95E−07 20 2.93E−08 2.10E−07 21 2.69E−08 3.40E−09 22 3.16E−08 9.88E−09 23 1.72E−08 7.01E−08 24 2.17E−07 1.46E−07 26 6.70E−08 NT 27 3.15E−08 4.65E−08 29 6.12E−07 NT 30 1.59E−08 1.08E−08 31 2.76E−06 NT 32 3.53E−08 1.58E−08 33 4.67E−06 NT 34 2.31E−08 2.45E−08/5.66E−09 35 1.35E−05 NT 36 7.53E−08 1.26E−07 37 4.63E−08 8.41E−08 38 3.99E−07 NT 40 8.83E−07 NT 41 1.30E−08 7.22E−09 42 1.59E−06 NT 43 9.81E−09 3.23E−08 44 2.75E−06 NT 45 8.60E−08 NT 46 6.85E−07 NT 48 4.13E−07 NT 50 5.70E−07 NT 51 1.01E−05 NT 52 7.18E−08 1.00E−07 55 1.13E−07 NT 56 2.55E−06 NT 57 2.84E−05 NT 58 2.03E−05 NT 59 6.52E−08 NT 60 7.25E−07 NT 61 7.23E−08 NT 62 6.82E−07 NT 69 1.05E−05 NT 70 9.23E−06 NT 71 1.62E−07 NT 73 8.38E−08 NT 74 2.90E−06 NT 75 5.91E−08 3.29E−09 76 6.64E−06 NT 77 5.91E−07 NT 78 1.03E−05 NT 79 6.01E−08 NT 81 7.63E−05 NT 82 1.01E−05 NT 83 6.32E−07 NT 84 6.11E−07 NT 86 1.25E−07 NT 88 3.10E−07 NT 90 2.92E−06 NT 91 1.37E−07 NT 92 1.24E−07 5.23E−07 93 1.71E−07 NT 94 3.51E−07 NT 99 2.68E−07 NT 100 2.26E−07 NT 101 9.96E−08 NT 102 1.58E−08 5.39E−06 103 1.25E−07 NT 104 2.17E−08 NT 105 1.53E−08 NT 106 1.00E−07 NT 107 1.02E−07 NT 108 7.65E−08 NT 109 1.01E−06 NT 110 4.50E−07 NT 112 4.71E−07 NT 113 4.56E−07 NT 116 2.05E−07 NT 117 3.09E−08 2.64E−08 118 4.64E−06 NT Note: IC.sub.50 of cytotoxicity for Z138 tumour cell line are underlined. NT: not tested

Example C: Anti-Tumor Activity In Vivo

(203) The anti-tumour activity of the compounds of the invention is evaluated in a xenograft model of multiple myeloma and/or acute lymphoblastic leukaemia cells.

(204) Human tumour cells are grafted subcutaneously into immunosuppressed mice.

(205) When the tumour volume (TV) reaches about 200 mm.sup.3, the mice are treated per os with the various compounds once a day for 5 days on/2 days off during 3 weeks. The tumour mass is measured twice weekly from the start of treatment.

(206) The compounds of the invention display anti-tumour activities represented by the TGI (tumor growth inhibition) at the end of the treatment period. The TGI is defined as follows:

(207) $\mathrm{TGI}=\left(1-\frac{\mathrm{Median}\left(\mathrm{DTV}\mathrm{at}\mathrm{Dx}\mathrm{in}\mathrm{treated}\mathrm{group}\right)}{\mathrm{Median}\left(\mathrm{DTV}\mathrm{at}\mathrm{Dx}\mathrm{in}\mathrm{control}\mathrm{group}\right)}\right)\times 100.$
with:
DTV (delta tumoral volume) at Dx=(TV at Dx)−(TV at randomization for each animal).

Example D: Pharmaceutical Composition: Tablets

(208) TABLE-US-00003 1000 tablets containing a dose of 5 mg of 5 g a compound selected from Examples 1 to 118 Wheat starch 20 g Maize starch 20 g Lactose 30 8 Magnesium stearate 2 g Silica 1 g Hydroxypropylcellulose 2 g