Substituted piperidines for the treatment of cancer

Abstract

Compounds of formula (I): ##STR00001##
wherein R.sub.1, R.sub.2, R.sub.3, n and W are as defined in the description. Medicinal products containing the same which are useful in treating conditions requiring pro-apoptotic and/or anti-proliferative agents.

Claims

1. A compound of formula (I): ##STR00024## or a pharmaceutically acceptable addition salt, enantiomer, or diastereomer thereof, wherein: W represents ##STR00025## A represents a monocyclic aromatic ring or fused bicyclic ring comprising 5, 6, 7, 8, 9, or 10 ring members, wherein the monocyclic aromatic ring or fused bicyclic ring has 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the fused bicyclic ring has at least one aromatic moiety, and the monocyclic aromatic ring or fused bicyclic ring is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, nitro, cyano, oxo, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, Y.sub.1NR′R″, Y.sub.1NR′C(O)R″, Y.sub.1NR′C(O)OR″, Y.sub.1OR′, OC(O)R′, Y.sub.1S(O).sub.mR′, cyclopropyl, and pyridinyl, wherein the pyridinyl substituent is optionally substituted by a (C.sub.1-C.sub.6)alkyl substituent; X represents C or N; R.sub.1 represents: (i) phenyl, indanyl, or naphthyl, wherein the phenyl, indanyl, or naphthyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, nitro, cyano, oxo, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, Y.sub.1NR′R″, Y.sub.1NR′C(O)R″, Y.sub.1NR′C(O)OR″, Y.sub.1OR′, OC(O)R′, Y.sub.1S(O).sub.mR′, cyclopropyl, and pyridinyl, and further wherein the pyridinyl substituent is optionally substituted by a (C.sub.1-C.sub.6)alkyl substituent; or (ii) a monocyclic aromatic ring or fused bicyclic ring comprising 5, 6, 7, 8, 9, or 10 ring members, wherein the monocyclic aromatic ring or fused bicyclic ring has 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the fused bicyclic ring has at least one aromatic moiety, and the monocyclic aromatic ring or fused bicyclic ring is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, nitro, cyano, oxo, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, Y.sub.1NR′R″, Y.sub.1NR′C(O)R″, Y.sub.1NR′C(O)OR″, Y.sub.1OR′, OC(O)R′, Y.sub.1S(O).sub.mR′, cyclopropyl, and pyridinyl, wherein the pyridinyl substituent is optionally substituted by a (C.sub.1-C.sub.6)alkyl substituent; R.sub.2 represents hydrogen or halogen; R.sub.3 represents hydrogen, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, C(O)R.sub.8, or C(O)OR.sub.8; each R.sub.4 independently represents hydrogen, halogen, oxo, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, Y.sub.1NR.sub.6R.sub.7, Y.sub.1NR.sub.6C(O)R.sub.7, Y.sub.1OR.sub.6, Y.sub.1 Cy.sub.1, Cy.sub.1R.sub.7, or Cy.sub.1OR.sub.7; each R.sub.5 independently represents hydrogen, halogen, cyano, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, or hydroxy(C.sub.1-C.sub.6)alkyl; each R.sub.6 independently represents hydrogen, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, or Y.sub.2Si[(C.sub.1-C.sub.4)alkyl].sub.3; each R.sub.7 independently represents hydrogen, (C.sub.1-C.sub.6)alkyl, or Y.sub.2Cy.sub.2; R.sub.8 represents hydrogen or (C.sub.1-C.sub.6)alkyl; each Cy.sub.1 independently represents: (i) a monocyclic or fused bicyclic non-aromatic carbocyclic ring comprising 3, 4, 5, 6, or 7 ring members, wherein the monocyclic or fused bicyclic non-aromatic carbocyclic ring is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, nitro, cyano, oxo, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, Y.sub.1NR′R″, Y.sub.1NR′ C(O)R″, Y.sub.1NR′ C(O)OR″, Y.sub.1OR′, OC(O)R′, Y.sub.1S(O).sub.mR′, cyclopropyl, and pyridinyl, and further wherein the pyridinyl substituent is optionally substituted by a (C.sub.1-C.sub.6)alkyl substituent; (ii) a monocyclic or fused bicyclic non-aromatic ring comprising 3, 4, 5, 6, 7, 8, 9, or 10 ring members, wherein the monocyclic or fused bicyclic ring has 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the mono cyclic or fused bicyclic non-aromatic ring is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, nitro, cyano, oxo, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, Y.sub.1NR′R″, Y.sub.1NR′C(O)R″, Y.sub.1NR′C(O)OR″, Y.sub.1OR′, OC(O)R′, Y.sub.1S(O).sub.mR′, cyclopropyl, and pyridinyl, wherein the pyridinyl substituent is optionally substituted by a (C.sub.1-C.sub.6)alkyl substituent; (iii) phenyl, indanyl, or naphthyl, wherein the phenyl, indanyl, or naphthyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, nitro, cyano, oxo, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, Y.sub.1NR′R″, Y.sub.1 NR′ C(O)R″, Y.sub.1NR′ C(O)OR″, Y.sub.1OR′, OC(O)R′, Y.sub.1S(O).sub.mR′, cyclopropyl, and pyridinyl, and further wherein the pyridinyl substituent is optionally substituted by a (C.sub.1-C.sub.6)alkyl substituent; or (iv) a monocyclic aromatic ring or fused bicyclic ring comprising 5, 6, 7, 8, 9, or 10 ring members, wherein the monocyclic aromatic ring or fused bicyclic ring has 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the fused bicyclic ring has at least one aromatic moiety, and the monocyclic aromatic ring or fused bicyclic ring is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, nitro, cyano, oxo, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, Y.sub.1NR′R″, Y.sub.1NR′C(O)R″, Y.sub.1NR′C(O)OR″, Y.sub.1OR′, OC(O)R′, Y.sub.1S(O).sub.mR′, cyclopropyl, and pyridinyl, wherein the pyridinyl substituent is optionally substituted by a (C.sub.1-C.sub.6)alkyl substituent; each Cy.sub.2 independently represents: (i) a monocyclic or fused bicyclic non-aromatic carbocyclic ring comprising 3, 4, 5, 6, or 7 ring members, wherein the monocyclic or fused bicyclic non-aromatic carbocyclic ring is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, nitro, cyano, oxo, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, Y.sub.1 NR′R″, Y.sub.1NR′C(O)R″, Y.sub.1NR′C(O)OR″, Y.sub.1OR′, OC(O)R′, Y.sub.1S(O).sub.mR′, cyclopropyl, and pyridinyl, and further wherein the pyridinyl substituent is optionally substituted by a (C.sub.1-C.sub.6)alkyl substituent; (ii) a monocyclic or fused bicyclic non-aromatic ring comprising 3, 4, 5, 6, 7, 8, 9, or 10 ring members, wherein the monocyclic or fused bicyclic ring has 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the mono cyclic or fused bicyclic non-aromatic ring is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, nitro, cyano, oxo, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, Y.sub.1NR′R″, Y.sub.1NR′C(O)R″, Y.sub.1NR′C(O)OR″, Y.sub.1OR′, OC(O)R′, Y.sub.1S(O).sub.mR′, cyclopropyl, and pyridinyl, wherein the pyridinyl substituent is optionally substituted by a (C.sub.1-C.sub.6)alkyl substituent; (iii) phenyl, indanyl, or naphthyl, wherein the phenyl, indanyl, or naphthyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, nitro, cyano, oxo, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, Y.sub.1NR′R″, Y.sub.1NR′C(O)R″, Y.sub.1NR′C(O)OR″, Y.sub.1OR′, OC(O)R′, Y.sub.1S(O).sub.mR′, cyclopropyl, and pyridinyl, and further wherein the pyridinyl substituent is optionally substituted by a (C.sub.1-C.sub.6)alkyl substituent; or (iv) a monocyclic aromatic ring or fused bicyclic ring comprising 5, 6, 7, 8, 9, or 10 ring members, wherein the monocyclic aromatic ring or fused bicyclic ring has 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the fused bicyclic ring has at least one aromatic moiety, and the monocyclic aromatic ring or fused bicyclic ring is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, nitro, cyano, oxo, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, C(O)R′, C(O)NR′R″, C(O)OR′, Y.sub.1NR′R″, Y.sub.1NR′C(O)R″, Y.sub.1NR′C(O)OR″, Y.sub.1OR′, OC(O)R′, Y.sub.1S(O).sub.mR′, cyclopropyl, and pyridinyl, wherein the pyridinyl substituent is optionally substituted by a (C.sub.1-C.sub.6)alkyl substituent; each Y.sub.1 independently represents a bond or —(C.sub.1-C.sub.4)alkylene; each Y.sub.2 independently represents a bond or —(C.sub.1-C.sub.4)alkylene; each R′ independently represents hydrogen, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, hydroxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, cyclopropylmethyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy, tetrahydropyranyl, or phenyl; each R″ independently represents hydrogen, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, hydroxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, cyclopropylmethyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy, tetrahydropyranyl, or phenyl; or each R′ and R″, together with the nitrogen atom to which they are attached, independently represents a non-aromatic ring comprising 5, 6, or 7 ring members, wherein the non-aromatic ring optionally has 1 additional heteroatom selected from the group consisting of nitrogen and oxygen, and further wherein the optional additional nitrogen heteroatom is substituted by 1 or 2 substituents independently selected from the group consisting of hydrogen and (C.sub.1-C.sub.6)alkyl; m is 0, 1, or 2; and n is 0, 1, or 2.

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

3. The compound according to claim 1, or a pharmaceutically acceptable addition salt, enantiomer, or diastereomer thereof, wherein W represents: ##STR00027##

4. The compound according to claim 1, or a pharmaceutically acceptable addition salt, enantiomer, or diastereomer thereof, wherein R.sub.1 represents phenyl.

5. The compound according to claim 1, or a pharmaceutically acceptable addition salt, enantiomer, or diastereomer thereof, wherein R.sub.2 represents hydrogen.

6. The compound according to claim 1, or a pharmaceutically acceptable addition salt, enantiomer, or diastereomer thereof, wherein R.sub.3 represents hydrogen, CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, CH.sub.2CF.sub.3, C(O)CH.sub.3, C(O)CH(CH.sub.3).sub.2, C(O)CH.sub.2C(CH.sub.3).sub.3, or C(O)OC(CH.sub.3).sub.3.

7. The compound according to claim 1, or a pharmaceutically acceptable addition salt, enantiomer, or diastereomer thereof, wherein each R.sub.4 independently represents hydrogen, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, Y.sub.1NR.sub.6R.sub.7, Y.sub.1OR.sub.6, Y.sub.1Cy.sub.1, Cy.sub.1R.sub.7, or Cy.sub.1OR.sub.7.

8. The compound according to claim 1, or a pharmaceutically acceptable addition salt, enantiomer, or diastereomer thereof, wherein each R.sub.5 independently represents hydrogen, iodo, chloro, CH.sub.3, or CH.sub.2OH.

9. The compound according to claim 1, or a pharmaceutically acceptable addition salt, enantiomer, or diastereomer thereof, wherein each R.sub.6 independently represents hydrogen, CH.sub.3, or (CH.sub.2).sub.2Si(CH.sub.3).sub.3.

10. The compound according to claim 1, or a pharmaceutically acceptable addition salt, enantiomer, or diastereomer thereof, wherein each R.sub.7 independently represents hydrogen, CH.sub.3, or CH.sub.2Cy.sub.2.

11. The compound according to claim 1, or a pharmaceutically acceptable addition salt, enantiomer, or diastereomer thereof, wherein the compound, or pharmaceutically acceptable addition salt, enantiomer, or diastereomer thereof, is selected from the group consisting of: tert-butyl (3S,4S)-4-({4-hydroxy-4-[(4-oxothieno [2,3-d]pyrimidin-3 (4H)-yl)methyl]piperidin-1-yl}carbonyl)-3-phenylpiperidine-1-carboxylate; tert-butyl (3R,4R)-4-[(4-hydroxy-4-{[4-oxo-7-(pyridin-2-yl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-3-yl]methyl}piperidin-1-yl)carbonyl]-3-phenylpiperidine-1-carboxylate; tert-butyl (3R,4R)-4-[(4-hydroxy-4-{[7-(4-methoxyphenyl)-4-oxo-4,7-dihydro-3H-pyrrolo [2,3-d]pyrimidin-3-yl]methyl}piperidin-1-yl)carbonyl]-3-phenylpiperidine-1-carboxylate; tert-butyl (3R,4R)-4-[(4-hydroxy-4-{[1-(4-methoxyphenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidin-1-yl)carbonyl]-3-phenylpiperidine-1-carboxylate; tert-butyl (3R,4R)-4-[(4-{[7-(4-fluoro-3-methoxyphenyl)-4-oxo-4,7-dihydro-3H-pyrrolo [2,3-d]pyrimidin-3-yl]methyl}-4-hydroxypiperidin-1-yl)carbonyl]-3-phenylpiperidine-1-carboxylate; tert-butyl (3R,4R)-4-[(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-oxo-1,4-dihydro-5H-pyrazolo [3,4-d]pyrimidin-5-yl]methyl}-4-hydroxypiperidin-1-yl)carbonyl]-3-phenylpiperidine-1-carboxylate; 3-[(4-hydroxy-1-{[(3R,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-7-phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 5-[(4-hydroxy-1-{[(3R,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 3-[(4-hydroxy-1-{[(3R,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-7-(pyridin-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 3-[(4-hydroxy-1-{[(3R,4R)-3-phenyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 3-[(4-hydroxy-1-{[(3R,4R)-1-methyl-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-7-phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 7-(4-fluorophenyl)-3-[(4-hydroxy-1-{[(3R,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-4H-pyrrolo[2,3-4pyrimidin-4-one; 3-[(4-hydroxy-1-{[(3R,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-7-(4-methoxyphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 3-[(4-hydroxy-1-{[(3R,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-7-(3-methoxyphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 7-(4-fluorophenyl)-3-[(4-hydroxy-1-{[(3R,4R)-1-methyl-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 7-(3-chlorophenyl)-3-[(4-hydroxy-1-{[(3R,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 7-(4-chlorophenyl)-3-[(4-hydroxy-1-{[(3R,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 3-[(1-{[(3R,4R)-1-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4-yl)methyl]-7-phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 3-[(4-hydroxy-1-{[(3R,4R)-1-methyl-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-7-(4-methoxyphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 7-(3-chlorophenyl)-3-[(4-hydroxy-1-{[(3R,4R)-1-methyl-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 7-(4-chlorophenyl)-3-[(4-hydroxy-1-{[(3R,4R)-1-methyl-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 7-(4-fluoro-3-methoxyphenyl)-3-[(4-hydroxy-1-{[(3R,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 3-[(4-hydroxy-1-{[(3R,4R)-1-(2-methylpropyl)-3-phenylpiperidin-4-yl]carbonyl} piperidin-4-yl)methyl]-7-phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 1-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-[(4-hydroxy-1-{[(3R,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; 3-[(1-{[(3R,4R)-1-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4-yl)methyl]-7-(4-fluorophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; (3R,4R)-4-[(4-hydroxy-4-{[1-(4-methoxyphenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl]methyl}piperidin-1-yl)carbonyl]-1,1-dimethyl-3-phenylpiperidinium; 3-[(4-hydroxy-1-{[(3R,4R)-1-(2-methylpropanoyl)-3-phenylpiperidin-4-yl]carbonyl} piperidin-4-yl)methyl]-7-phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 3-[(1-{[(3R,4R)-1-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4-yl)methyl]-7-(4-methoxyphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 3-[(1-{[(3R,4R)-1-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4-yl)methyl]-7-(3-methoxyphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 3-[(1-{[(3R,4R)-1-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4-yl)methyl]-7-(3-chlorophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 3-[(1-{[(3R,4R)-1-acetyl-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4-yl)methyl]-7-(4-chlorophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; 3-[(1-{[(3R,4R)-1-(2,2-dimethylpropanoyl)-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4-yl)methyl]-7-phenyl-3,7-dihydro-4H-pyrrolo [2,3-d]pyrimidin-4-one; and 3-[(1-{[(3R,4R)-1-(3,3-dimethylbutanoyl)-3-phenylpiperidin-4-yl]carbonyl}-4-hydroxypiperidin-4-yl)methyl]-7-phenyl-3,7-dihydro-4H-pyrrolo [2,3-d]pyrimidin-4-one.

12. A combination consisting of the compound according to claim 1, or a pharmaceutically acceptable addition salt, enantiomer, or diastereomer thereof, and an a cancer agent selected from the group consisting of an anti-metabolite, an antibody, 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.

13. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable addition salt, enantiomer, or diastereomer thereof, and one or more pharmaceutically acceptable excipients.

14. A pharmaceutical composition comprising the combination according to claim 12 and one or more pharmaceutically acceptable excipients.

15. A method for treating acute myeloid leukemia, lymphoblastic leukemia, myeloma, bladder cancer, breast cancer, colon cancer, esophageal cancer, liver cancer, non-small-cell lung cancer, ovarian cancer, prostate cancer, or small-cell lung cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable addition salt, enantiomer, or diastereomer thereof, or the pharmaceutical composition according to claim 13.

16. The method according to claim 15, wherein the method further comprises administering radiotherapy to the subject.

17. A method for treating acute myeloid leukemia, lymphoblastic leukemia, myeloma, bladder cancer, breast cancer, colon cancer, esophageal cancer, liver cancer, non-small-cell lung cancer, ovarian cancer, prostate cancer, or small-cell lung cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the combination according to claim 12, or the pharmaceutical composition according to claim 14.

Description

EXAMPLES

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

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(7-methyl-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 1)

(2) Using General Procedure 5 starting from Preparation R2g and Preparation R1c as reagents, EXAMPLE 1 was obtained. HRMS calculated for C.sub.30H.sub.39N.sub.5O.sub.5: 549.2951; found 550.3021 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(4-oxothieno[2,3-d]pyrimidin-3-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 2)

(3) Using General Procedure 5 starting from 3H-thieno[2,3-d]pyrimidin-4-one and Preparation R1c as reagents, EXAMPLE 2 was obtained. HRMS calculated for C.sub.29H.sub.36N.sub.4O.sub.5S: 552.2406; found 553.2479 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[(7-ethyl-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl)methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 3)

(4) Using General Procedure 5 starting from Preparation R2h and Preparation R1c as reagents, EXAMPLE 3 was obtained. HRMS calculated for C.sub.31H.sub.41N.sub.5O.sub.5: 563.3108; found 564.319 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(4-oxo-7-prop-2-ynyl-pyrrolo[2,3-d]pyrimidin-3-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 4)

(5) Using General Procedure 5 starting from Preparation R2i and Preparation R1c as reagents, EXAMPLE 4 was obtained. HRMS calculated for C.sub.32H.sub.39N.sub.5O.sub.5: 573.2951; found 574.3024 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[(7-cyclopropyl-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl)methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 5)

(6) Using General Procedure 5 starting from Preparation R2j and Preparation R1c as reagents, EXAMPLE 5 was obtained. HRMS calculated for C.sub.32H.sub.41N.sub.5O.sub.5: 575.3108; found 576.3189 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[(7-chloro-4-oxo-thieno[3,4-d]pyrimidin-3-yl)methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 6)

(7) Using General Procedure 5 starting from 7-chloro-3H-thieno[3,4-d]pyrimidin-4-one and Preparation R1c as reagents, EXAMPLE 6 was obtained. HRMS calculated for C.sub.29H.sub.35ClN.sub.4O.sub.5S: 586.2017; found 609.1912 [(M+Na) form].

tert-butyl (3R,4R)-4-[4-[(7-buta-2,3-dienyl-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl)methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 7)

(8) Using General Procedure 5 starting from Preparation R2k and Preparation R1c as reagents, EXAMPLE 7 was obtained. HRMS calculated for C.sub.33H.sub.41N.sub.5O.sub.5: 587.3108; found 588.318 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(cyclopropylmethyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 8)

(9) Using General Procedure 5 starting from Preparation R21 and Preparation R1c as reagents, EXAMPLE 8 was obtained. HRMS calculated for C.sub.33H.sub.43N.sub.5O.sub.5: 589.3264; found 590.3342 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(7-isobutyl-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 9)

(10) Using General Procedure 5 starting from Preparation R2m and Preparation R1c as reagents, EXAMPLE 9 was obtained. HRMS calculated for C.sub.33H.sub.45N.sub.5O.sub.5: 591.342; found 592.3501 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(9-methyl-4-oxo-pyrimido[4,5-b]indol-3-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 10)

(11) Using General Procedure 5 starting from Preparation R2n and Preparation R1c as reagents, EXAMPLE 10 was obtained. HRMS calculated for C.sub.34H.sub.41N.sub.5O.sub.5: 599.3108; found 600.3181 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(cyclobutylmethyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 11)

(12) Using General Procedure 5 starting from Preparation R2o and Preparation R1c as reagents, EXAMPLE 11 was obtained. HRMS calculated for C.sub.34H.sub.45N.sub.5O.sub.5: 603.342; found 604.3502 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(2-dimethylaminoethyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 12)

(13) Using General Procedure 5 starting from Preparation R2p and Preparation R1c as reagents, EXAMPLE 12 was obtained. HRMS calculated for C.sub.33H.sub.46N.sub.6O.sub.5: 606.353; found 607.36 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(4-oxo-7-phenyl-pyrrolo[2,3-d]pyrimidin-3-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 13)

(14) Using General Procedure 5 starting from Preparation R2q and Preparation R1c as reagents, EXAMPLE 13 was obtained. HRMS calculated for C.sub.35H.sub.41N.sub.5O.sub.5: 611.3108; found 612.3192 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(4-oxo-7-phenyl-5H-pyrrolo[3,2-d]pyrimidin-3-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 14)

(15) Using General Procedure 5 starting from 7-phenyl-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one and Preparation R1c as reagents, EXAMPLE 14 was obtained. HRMS calculated for C.sub.35H.sub.41N.sub.5O.sub.5: 611.3108; found 612.3182 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-(2-pyridyl)pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 15)

(16) Using General Procedure 5 starting from Preparation R2b and Preparation R1c as reagents, EXAMPLE 15 was obtained. HRMS calculated for C.sub.34H.sub.40N.sub.6O.sub.5: 612.306; found 613.3132 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(4-oxo-1-phenyl-pyrazolo[3,4-d]pyrimidin-5-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 16)

(17) Using General Procedure 5 starting from 1-phenyl-5H-pyrazolo[3,4-d]pyrimidin-4-one and Preparation R1c as reagents, EXAMPLE 16 was obtained. HRMS calculated for C.sub.34H.sub.40N.sub.6O.sub.5: 612.306; found 613.312 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(6-oxo-9-phenyl-purin-1-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 17)

(18) Using General Procedure 5 starting from 9-phenyl-1H-purin-6-one and Preparation R1c as reagents, EXAMPLE 17 was obtained. HRMS calculated for C.sub.34H.sub.40N.sub.6O.sub.5: 612.306; found 613.3142 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[(7-bromo-4-oxo-pyrrolo[2,1-f][1,2,4]triazin-3-yl)methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 18)

(19) Using General Procedure 5 starting from 7-bromo-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one and Preparation R1c as reagents, EXAMPLE 18 was obtained. HRMS calculated for C.sub.29H.sub.36BrN.sub.5O.sub.5: 613.19; found 612.1851 [(M−H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(7-oxo-3-phenyl-isoxazolo[4,5-d]pyrimidin-6-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 19)

(20) Using General Procedure 5 starting from 3-phenyl-6H-isoxazolo[4,5-d]pyrimidin-7-one and Preparation R1c as reagents, EXAMPLE 19 was obtained. HRMS calculated for C.sub.34H.sub.39N.sub.5O.sub.6: 613.29; found 636.2782 [(M+Na) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(4-oxo-7-pyrimidin-2-yl-pyrrolo[2,3-d]pyrimidin-3-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 20)

(21) Using General Procedure 5 starting from Preparation R2s and Preparation R1c as reagents, EXAMPLE 20 was obtained. HRMS calculated for C.sub.33H.sub.39N.sub.7O.sub.5: 613.3013; found 614.3102 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(7-oxo-3-phenyl-triazolo[4,5-d]pyrimidin-6-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 21)

(22) Using General Procedure 5 starting from 3-phenyl-6H-triazolo[4,5-d]pyrimidin-7-one and Preparation R1c as reagents, EXAMPLE 21 was obtained. HRMS calculated for C.sub.33H.sub.39N.sub.7O.sub.5: 613.3013; found 614.3095 [(M+H) form].

tert-butyl (3R,4R)-4-({4-[(6,8-dimethyl-4-oxopyrimido[5,4-b]indolizin-3(4H)-yl)methyl]-4-hydroxypiperidin-1-yl}carbonyl)-3-phenylpiperidine-1-carboxylate (EXAMPLE 22)

(23) Using General Procedure 5 starting from Preparation R2t and Preparation R1c as reagents, EXAMPLE 22 was obtained. HRMS calculated for C.sub.34H.sub.42N.sub.6O.sub.5: 614.3217; found 615.3301 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(1-methylimidazol-4-yl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 23)

(24) Using General Procedure 5 starting from Preparation R2u and Preparation R1c as reagents, EXAMPLE 23 was obtained. HRMS calculated for C.sub.33H.sub.41N.sub.7O.sub.5: 615.3169; found 616.324 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-(3-thienyl)pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 24)

(25) Using General Procedure 5 starting from Preparation R2v and Preparation R1c as reagents, EXAMPLE 24 was obtained. HRMS calculated for C.sub.33H.sub.39N.sub.5O.sub.5S: 617.2672; found 618.2736 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-(2-thienyl)pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 25)

(26) Using General Procedure 5 starting from Preparation R2w and Preparation R1c as reagents, EXAMPLE 25 was obtained. HRMS calculated for C.sub.33H.sub.39N.sub.5O.sub.5S: 617.2672; found 618.2744 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-(2,2,2-trifluoroethyl)pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 26)

(27) Using General Procedure 5 starting from Preparation R2x and Preparation R1c as reagents, EXAMPLE 26 was obtained. HRMS calculated for C.sub.31H.sub.38F3N.sub.5O.sub.5: 617.2825; found 618.2912 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(4-oxo-7-thiazol-2-yl-pyrrolo[2,3-d]pyrimidin-3-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 27)

(28) Using General Procedure 5 starting from Preparation R2y and Preparation R1c as reagents, EXAMPLE 27 was obtained. HRMS calculated for C.sub.32H.sub.38N.sub.6O.sub.5S: 618.2625; found 641.251 [(M+Na) form].

tert-butyl (3R,4R)-4-[4-[[7-[3-(dimethylamino)propyl]-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 28)

(29) Using General Procedure 5 starting from Preparation R2z and Preparation R1c as reagents, EXAMPLE 28 was obtained. HRMS calculated for C.sub.34H.sub.48N.sub.6O.sub.5: 620.3686; found 621.3731 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(m-tolyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 29)

(30) Using General Procedure 5 starting from Preparation R2aa and Preparation R1c as reagents, EXAMPLE 29 was obtained. HRMS calculated for C.sub.36H.sub.43N.sub.5O.sub.5: 625.3264; found 626.3357 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-(p-tolyl)pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 30)

(31) Using General Procedure 5 starting from Preparation R2ab and Preparation R1c as reagents, EXAMPLE 30 was obtained. HRMS calculated for C.sub.36H.sub.43N.sub.5O.sub.5: 625.3264; found 626.3358 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[(7-benzyl-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl)methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 31)

(32) Using General Procedure 5 starting from Preparation R2ac and Preparation R1c as reagents, EXAMPLE 31 was obtained. HRMS calculated for C.sub.36H.sub.43N.sub.5O.sub.5: 625.3264; found 626.3343 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(6-methyl-4-oxo-7-phenyl-pyrrolo[2,3-d]pyrimidin-3-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 32)

(33) Using General Procedure 5 starting from Preparation R2ad and Preparation R1c as reagents, EXAMPLE 32 was obtained. HRMS calculated for C.sub.36H.sub.43N.sub.5O.sub.5: 625.3264; found 626.3335 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(7-oxo-3-phenyl-isothiazolo[4,5-d]pyrimidin-6-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 33)

(34) Using General Procedure 5 starting from 3-phenyl-6H-isothiazolo[4,5-d]pyrimidin-7-one and Preparation R1c as reagents, EXAMPLE 33 was obtained. HRMS calculated for C.sub.34H.sub.39N.sub.5O.sub.5S: 629.2672; found 652.2559 [(M+Na) form].

tert-butyl (3R,4R)-4-[4-[[7-(4-fluorophenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 34)

(35) Using General Procedure 5 starting from Preparation R2ae and Preparation R1c as reagents, EXAMPLE 34 was obtained. HRMS calculated for C.sub.35H.sub.40FN.sub.5O.sub.5: 629.3013; found 530.2568 [(M+H-Boc) form].

tert-butyl (3R,4R)-4-[4-[[7-(3-fluorophenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 35)

(36) Using General Procedure 5 starting from Preparation R2bl and Preparation R1c as reagents, EXAMPLE 35 was obtained. HRMS calculated for C.sub.35H.sub.40FN.sub.5O.sub.5: 629.3013; found 652.2909 [(M+Na) form].

tert-butyl (3R,4R)-4-[4-[(7-bromo-4-oxo-thieno[3,2-d]pyrimidin-3-yl)methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 36)

(37) Using General Procedure 5 starting from 7-bromo-3H-thieno[3,2-d]pyrimidin-4-one and Preparation R1c as reagents, EXAMPLE 36 was obtained. HRMS calculated for C.sub.29H.sub.35BrN.sub.4O.sub.5S: 630.1511; found 653.1419 [(M+Na) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(5-methyl-2-thienyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 37)

(38) Using General Procedure 5 starting from Preparation R2bc and Preparation R1c as reagents, EXAMPLE 37 was obtained. HRMS calculated for C.sub.34H.sub.41N.sub.5O.sub.5S: 631.2828; found 654.2719 [(M+Na) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(1-methyl-4-piperidyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 38)

(39) Using General Procedure 5 starting from Preparation R2cb and Preparation R1c as reagents, EXAMPLE 38 was obtained. HRMS calculated for C.sub.35H.sub.48N.sub.6O.sub.5: 632.3686; found 633.3766 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(4-cyanophenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 39)

(40) Using General Procedure 5 starting from Preparation R2au and Preparation R1c as reagents, EXAMPLE 39 was obtained. HRMS calculated for C.sub.36H.sub.40N.sub.6O.sub.5: 636.306; found 637.3127 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(4-methoxyphenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 40)

(41) Using General Procedure 5 starting from Preparation R2c and Preparation R1c as reagents, EXAMPLE 40 was obtained. HRMS calculated for C.sub.36H.sub.43N.sub.5O.sub.6: 641.3214; found 642.3297 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(3-methoxyphenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 41)

(42) Using General Procedure 5 starting from Preparation R2 bp and Preparation R1c as reagents, EXAMPLE 41 was obtained. HRMS calculated for C.sub.36H.sub.43N.sub.5O.sub.6: 641.3214; found 642.3313 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-[4-(hydroxymethyl)phenyl]-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 42)

(43) Using General Procedure 5 starting from Preparation R2ax and Preparation R1c as reagents, EXAMPLE 42 was obtained. HRMS calculated for C.sub.36H.sub.43N.sub.5O.sub.6: 641.3214; found 642.3288 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[6-(hydroxymethyl)-4-oxo-7-phenyl-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 43)

(44) Preparation R1b (10 g, 67.05 mmol, 1 eq.), iodobenzene (87.2 mmol, 1.3 eq.), CuI (1.28 g, 190.45, 6,705 mmol, 0.1 eq.), DMEDA (1.45 ml, 13.4 mmol, 1.18 g, 0.2 eq.), anhydrous K.sub.2CO.sub.3 (12.05 g, 87.16 mmol, 1.3 eq.) was suspended in dry acetonitrile (50 ml), flushed with N.sub.2 and stirred at 80° C. for 1.5 h. After the reaction completed, the mixture was diluted with water (200 ml) and cooled to r.t. The mixture was filtered, and washed with water (3×30 ml), aq. NH.sub.3 solution (40 ml, 25%), water (3×50 ml), heptane (50 then 30 ml) and dried in vacuum.

(45) A flame dried 3-necked round flask was charged with 5 ml dry THF under N.sub.2 atmosphere. 420 μl (1.5 eq.) iPr.sub.2NH was added via a syringe and the round flask was cooled to −78° C. 1.25 ml (1.5 eq.) n-BuLi was added via a syringe and stirred for 30 minutes. Then 4-methoxy-7-phenyl-pyrrolo[2,3-d]pyrimidine obtained in previous step (450 mg, 2 mmol, 1 eq.) dissolved in 20 ml dry THF was added dropwise and stirred for 1 hour. Then methyl formate (360 mg, 3 eq.) was added dissolved in 10 ml dry THF. After the reaction was completed 40 ml sat. NH.sub.4Cl was added and extracted with 3×40 ml EEO, dried, filtered and evaporated. Flash chromatography with Hexane:EEO gave (4-methoxy-7-phenyl-pyrrolo[2,3-d]pyrimidin-6-yl)methanol.

(46) A part of the crude product (127 mg, 0.5 mmol) was dissolved in 2.5 ml PDO and cc. HCl (82 μL, 1 mmol, 2 eq.) was added. The solution was heated, stirred at 100° C. for 2 hours, and it was evaporated to give 6-(hydroxymethyl)-7-phenyl-3H-pyrrolo[2,3-d]pyrimidin-4-one which was reacted according to General Procedure 5 with Preparation R1c as reagents to give EXAMPLE 43. HRMS calculated for C.sub.36H.sub.43N.sub.5O.sub.6: 641.3214; found 642.3295 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[1-(4-methoxyphenyl)-4-oxo-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 44)

(47) Using General Procedure 5 starting from 1-(4-methoxyphenyl)-5H-pyrazolo[3,4-d]pyrimidin-4-one and Preparation R1c as reagents, EXAMPLE 44 was obtained. HRMS calculated for C.sub.35H.sub.42N.sub.6O.sub.6: 642.3166; found 665.3057 [(M+Na) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(6-methoxy-2-pyridyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 45)

(48) Using General Procedure 5 starting from Preparation R2bs and Preparation R1c as reagents, EXAMPLE 45 was obtained. HRMS calculated for C.sub.35H.sub.42N.sub.6O.sub.6: 642.3166; found 643.3231 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(4-chlorophenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 46

(49) Using General Procedure 5 starting from Preparation R2ay and Preparation R1c as reagents, EXAMPLE 46 was obtained. HRMS calculated for C.sub.35H.sub.40ClN.sub.5O.sub.5: 645.2718; found 646.2787 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(3-chlorophenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 47)

(50) Using General Procedure 5 starting from Preparation R2bk and Preparation R1c as reagents, EXAMPLE 47 was obtained. HRMS calculated for C.sub.35H.sub.40ClN.sub.5O.sub.5: 645.2718; found 646.2821 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[(6-chloro-4-oxo-7-phenyl-pyrrolo[2,3-d]pyrimidin-3-yl)methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 48)

(51) Using General Procedure 5 starting from Preparation R2ai and Preparation R1c as reagents, EXAMPLE 48 was obtained. HRMS calculated for C.sub.35H.sub.40ClN.sub.5O.sub.5: 645.2718; found 646.2782 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(5-chloro-2-thienyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 49)

(52) Using General Procedure 5 starting from Preparation R2bd and Preparation R1c as reagents, EXAMPLE 49 was obtained. HRMS calculated for C.sub.33H.sub.38ClN.sub.5O.sub.5S: 651.2282; found 652.2348 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-[1-(difluoromethyl)pyrazol-4-yl]-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 50)

(53) Using General Procedure 5 starting from Preparation R2bw and Preparation R1c as reagents, EXAMPLE 50 was obtained. HRMS calculated for C.sub.33H.sub.39F2N.sub.7O.sub.5: 651.2981; found 674.2867 [(M+Na) form].

tert-butyl (3R,4R)-4-[4-[[7-(4-dimethylaminophenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 51)

(54) Using General Procedure 5 starting from Preparation R2az and Preparation R1c as reagents, EXAMPLE 51 was obtained. HRMS calculated for C.sub.37H.sub.46N.sub.6O.sub.5: 654.353; found 655.3589 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-[3-(dimethylamino)phenyl]-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 52)

(55) Using General Procedure 5 starting from Preparation R2bm and Preparation R1c as reagents, EXAMPLE 52 was obtained. HRMS calculated for C.sub.37H.sub.46N.sub.6O.sub.5: 654.353; found 655.3602 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(1,3-benzodioxol-5-yl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 53)

(56) Using General Procedure 5 starting from Preparation R2bf and Preparation R1c as reagents, EXAMPLE 53 was obtained. HRMS calculated for C.sub.36H.sub.41N.sub.5O.sub.7: 655.3006; found 655.3006 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-[(2-chlorophenyl)methyl]-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 54)

(57) Using General Procedure 5 starting from Preparation R2ci and Preparation R1c as reagents, EXAMPLE 54 was obtained. HRMS calculated for C.sub.36H.sub.42N.sub.5O.sub.5Cl: 659.2875; found 660.2949 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-[(3-chlorophenyl)methyl]-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 55)

(58) Using General Procedure 5 starting from Preparation R2ch and Preparation R1c as reagents, EXAMPLE 55 was obtained. HRMS calculated for C.sub.36H.sub.42ClN.sub.5O.sub.5: 659.2875; found 660.2933 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-[(4-chlorophenyl)methyl]-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 56)

(59) Using General Procedure 5 starting from Preparation R2cg and Preparation R1c as reagents, EXAMPLE 56 was obtained. HRMS calculated for C.sub.36H.sub.42ClN.sub.5O.sub.5: 659.2875; found 660.2949 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(4-fluoro-3-methoxy-phenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 57)

(60) Using General Procedure 5 starting from Preparation R2e and Preparation R1c as reagents, EXAMPLE 57 was obtained. HRMS calculated for C.sub.36H.sub.42FN.sub.5O.sub.6: 659.3119; found 660.3194 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-[4-(difluoromethyl)phenyl]-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 58)

(61) Using General Procedure 5 starting from Preparation R2aw and Preparation R1c as reagents, EXAMPLE 58 was obtained. HRMS calculated for C.sub.36H.sub.41F2N.sub.5O.sub.5: 661.3076; found 662.3141 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(1-naphthyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 59)

(62) Using General Procedure 5 starting from Preparation R2bt and Preparation R1c as reagents, EXAMPLE 59 was obtained. HRMS calculated for C.sub.39H.sub.43N.sub.5O.sub.5: 661.3264; found 662.3345 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(2-naphthyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 60)

(63) Using General Procedure 5 starting from Preparation R2bg and Preparation R1c as reagents, EXAMPLE 60 was obtained. HRMS calculated for C.sub.35H.sub.35N.sub.5O.sub.5: 661.3264; found 606.2715 [(M+H—C(CH3)3) form].

tert-butyl (3R,4R)-4-[4-[[7-(4-chloro-3-fluoro-phenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 61)

(64) Using General Procedure 5 starting from Preparation R2ar and Preparation R1c as reagents, EXAMPLE 61 was obtained. HRMS calculated for C.sub.35H.sub.39C.sub.1FN.sub.5O.sub.5: 663.2624; found 564.218 [(M+H-Boc) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 62)

(65) Using General Procedure 5 starting from 7-(2-trimethylsilylethoxymethyl)-3H-pyrrolo[2,3-d]pyrimidin-4-one and Preparation R1c as reagents, EXAMPLE 62 was obtained. HRMS calculated for C.sub.35H.sub.51N.sub.5O.sub.6Si: 665.3609; found 666.3696 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 63)

(66) Using General Procedure 5 starting from Preparation R2be and Preparation R1c as reagents, EXAMPLE 63 was obtained. HRMS calculated for C.sub.37H.sub.43N.sub.5O.sub.7: 669.3162; found 670.3238 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-oxo-pyrazolo[3,4-d]pyrimidin-5-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 64)

(67) Using General Procedure 5 starting from 1-(2,3-dihydro-1,4-benzodioxin-6-yl)-5H-pyrazolo[3,4-d]pyrimidin-4-one and Preparation R1c as reagents, EXAMPLE 64 was obtained. HRMS calculated for C.sub.36H.sub.42N.sub.6O.sub.7: 670.3115; found 693.3019 [(M+Na) form].

tert-butyl (3R,4R)-4-[4-[[7-(3,4-dimethoxyphenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 65)

(68) Using General Procedure 5 starting from Preparation R2at and Preparation R1c as reagents, EXAMPLE 65 was obtained. HRMS calculated for C.sub.37H.sub.45N.sub.5O.sub.7: 671.3319; found 672.3396 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(3,5-dimethoxyphenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 66)

(69) Using General Procedure 5 starting from Preparation R2ap and Preparation R1c as reagents, EXAMPLE 66 was obtained. HRMS calculated for C.sub.37H.sub.45N.sub.5O.sub.7: 671.3319; found 672.3401 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(6-iodo-7-methyl-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 67)

(70) Using General Procedure 5 starting from Preparation R2aj and Preparation R1c as reagents, EXAMPLE 67 was obtained. HRMS calculated for C.sub.30H.sub.381N.sub.5O.sub.5: 675.1918; found 676.1994 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(3-chloro-5-methoxy-phenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 68)

(71) Using General Procedure 5 starting from Preparation R2ao and Preparation R1c as reagents, EXAMPLE 68 was obtained. HRMS calculated for C.sub.36H.sub.42ClN.sub.5O.sub.6: 675.2823; found 676.2891 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(4-chloro-3-methoxy-phenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 69)

(72) Using General Procedure 5 starting from Preparation R2as and Preparation R1c as reagents, EXAMPLE 69 was obtained. HRMS calculated for C.sub.36H.sub.42ClN.sub.5O.sub.6: 675.2823; found 676.2885 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(3,4-dichlorophenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 70)

(73) Using General Procedure 5 starting from Preparation R2aq and Preparation R1c as reagents, EXAMPLE 70 was obtained. HRMS calculated for C.sub.35H.sub.39Cl.sub.2N.sub.5O.sub.5: 679.2328; found 680.2399 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(3,5-dichlorophenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 71)

(74) Using General Procedure 5 starting from Preparation R2an and Preparation R1c as reagents, EXAMPLE 71 was obtained. HRMS calculated for C.sub.35H.sub.39Cl.sub.2N.sub.5O.sub.5: 679.2328; found 680.2399 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-[4-(trifluoromethyl)phenyl]pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 72)

(75) Using General Procedure 5 starting from Preparation R2av and Preparation R1c as reagents, EXAMPLE 72 was obtained. HRMS calculated for C.sub.36H.sub.40F3N.sub.5O.sub.5: 679.2982; found 680.3068 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-[3-(trifluoromethyl)phenyl]pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 73)

(76) Using General Procedure 5 starting from Preparation R2bh and Preparation R1c as reagents, EXAMPLE 73 was obtained. HRMS calculated for C.sub.36H.sub.40F3N.sub.5O.sub.5: 679.2982; found 702.2875 [(M+Na) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[6-iodo-4-oxo-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 74)

(77) Using General Procedure 5 starting from Preparation R2al and Preparation R1c as reagents, EXAMPLE 74 was obtained. HRMS calculated for C.sub.35H.sub.50IN.sub.5O.sub.6Si: 791.2575; found 792.265 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-[3-(trifluoromethoxy)phenyl]pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 75)

(78) Using General Procedure 5 starting from Preparation R2bo and Preparation R1c as reagents, EXAMPLE 75 was obtained. HRMS calculated for C.sub.36H.sub.40F3N.sub.5O.sub.6: 695.2931; found 696.2997 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-[4-(trifluoromethoxy)phenyl]pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 76)

(79) Using General Procedure 5 starting from Preparation R2ba and Preparation R1c as reagents, EXAMPLE 76 was obtained. HRMS calculated for C.sub.36H.sub.40F3N.sub.5O.sub.6: 695.2931; found 696.3006 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-(3-morpholinophenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 77)

(80) Using General Procedure 5 starting from Preparation R2bn and Preparation R1c as reagents, EXAMPLE 77 was obtained. HRMS calculated for C.sub.39H.sub.48N.sub.6O.sub.6: 696.3635; found 697.3708 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[4-oxo-7-(3,4,5-trimethoxyphenyl)pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 78)

(81) Using General Procedure 5 starting from Preparation R2am and Preparation R1c as reagents, EXAMPLE 78 was obtained. HRMS calculated for C.sub.38H.sub.47N.sub.5O.sub.8: 701.3425; found 702.3487 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(4-benzyloxyphenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 79)

(82) Using General Procedure 5 starting from Preparation R2bb and Preparation R1c as reagents, EXAMPLE 79 was obtained. HRMS calculated for C.sub.42H.sub.47N.sub.5O.sub.6: 717.3527; found 718.3603 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[7-(3-benzyloxyphenyl)-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 80)

(83) Using General Procedure 5 starting from Preparation R2bq and Preparation R1c as reagents, EXAMPLE 80 was obtained. HRMS calculated for C.sub.42H.sub.47N.sub.5O.sub.6: 717.3527; found 740.3423 [(M+Na) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[[7-[3-[(4-methylpiperazin-1-yl)methyl]phenyl]-4-oxo-pyrrolo[2,3-d]pyrimidin-3-yl]methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 81)

(84) Using General Procedure 5 starting from Preparation R2bi and Preparation R1c as reagents, EXAMPLE 81 was obtained. HRMS calculated for C.sub.41H.sub.53N.sub.7O.sub.5: 723.4108; found 724.4175 [(M+H) form].

tert-butyl (3R,4R)-4-[4-[[6-cyano-4-oxo-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-3-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 82)

(85) EXAMPLE 74 was dissolved in PDO and copper cyanide (4.2 eq), tetraethylammonium cyanide (1.05 eq.), Pd.sub.2(dba).sub.3 (0.1 eq.), and 1,1′-bis(diphenylphosphino)ferrocene (0.4 eq.) were added. The mixture was heated and stirred at 110° C. till the reaction was completed. The residue was purified by flash chromatography in DCM-MeOH gradient to give EXAMPLE 82. HRMS calculated for C.sub.36H.sub.50N.sub.6O.sub.6Si: 690.3561; found 691.3637 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 83)

(86) Using General Procedure 5 starting from 3H,4H,7H-pyrrolo[2,3-d]pyrimidin-4-one and Preparation R1c as reagents, the resulted Boc-protected crude product was reacted using General Procedure 6, to give EXAMPLE 83 as HCl salt. HRMS calculated for C.sub.24H.sub.29N.sub.5O.sub.3: 435.2271; found 436.2345 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-methyl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 84)

(87) Using General Procedure 6 starting from EXAMPLE 1 as reagent, EXAMPLE 84 was obtained as HCl salt. HRMS calculated for C.sub.25H.sub.31N.sub.5O.sub.3: 449.2427; found 450.2517 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]thieno[2,3-d]pyrimidin-4-one (EXAMPLE 85)

(88) Using General Procedure 6 starting from EXAMPLE 2 as reagent, EXAMPLE 85 was obtained as HCl salt. HRMS calculated for C.sub.24H.sub.28N.sub.4O.sub.3S: 452.1882; found 453.1933 [(M+H) form].

7-ethyl-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 86)

(89) Using General Procedure 6 starting from EXAMPLE 3 as reagent, EXAMPLE 86 was obtained as HCl salt. HRMS calculated for C.sub.26H.sub.33N.sub.5O.sub.3: 463.2583; found 464.2654 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-prop-2-ynyl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 87)

(90) Using General Procedure 6 starting from EXAMPLE 4 as reagent, EXAMPLE 87 was obtained as HCl salt. HRMS calculated for C.sub.27H.sub.31N.sub.5O.sub.3: 473.2427; found 474.2502 [(M+H) form].

7-cyclopropyl-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 88)

(91) Using General Procedure 6 starting from EXAMPLE 5 as reagent, EXAMPLE 88 was obtained as HCl salt. HRMS calculated for C.sub.27H.sub.33N.sub.5O.sub.3: 475.2583; found 476.2668 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-isopropyl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 89)

(92) Using General Procedure 5 starting from Preparation R2by and Preparation R1c as reagents, the resulted Boc-protected crude product was reacted using General Procedure 6, to give EXAMPLE 89 as HCl salt. HRMS calculated for C.sub.27H.sub.35N.sub.5O.sub.3: 477.274; found 478.2819 [(M+H) form].

7-(2-hydroxyethyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 90)

(93) Using General Procedure 5 starting from Preparation R2ce and Preparation R1c as reagents, the resulted Boc-protected crude product was reacted using General Procedure 6, to give EXAMPLE 90 as HCl salt. HRMS calculated for C.sub.26H.sub.33N.sub.5O.sub.4: 479.2533; found (NMR available form].

7-(2-fluoroethyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 91)

(94) Using General Procedure 5 starting from Preparation R2cd and Preparation R1c as reagents, the resulted Boc-protected crude product was reacted using General Procedure 6, to give EXAMPLE 91 as HCl salt. HRMS calculated for C.sub.26H.sub.32N.sub.5O.sub.3F: 481.2489; found 482.2555 [(M+H) form].

7-chloro-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]thieno[3,4-d]pyrimidin-4-one (EXAMPLE 92)

(95) Using General Procedure 6 starting from EXAMPLE 6 as reagent, EXAMPLE 92 was obtained as HCl salt. HRMS calculated for C.sub.24H.sub.27ClN.sub.4O.sub.3S: 486.1492; found 487.1544 [(M+H) form].

7-buta-2,3-dienyl-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 93)

(96) Using General Procedure 6 starting from EXAMPLE 7 as reagents, EXAMPLE 93 was obtained as HCl salt. HRMS calculated for C.sub.28H.sub.33N.sub.5O.sub.3: 487.2583; found 488.2657 [(M+H) form].

7-cyclobutyl-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 94)

(97) Using General Procedure 5 starting from Preparation R2ca and Preparation R1c as reagents, the resulted Boc-protected crude product was reacted using General Procedure 6, to give EXAMPLE 94 as HCl salt. HRMS calculated for C.sub.28H.sub.35N.sub.5O.sub.3: 489.274; found 490.2796 [(M+H) form].

7-(cyclopropylmethyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 95)

(98) Using General Procedure 6 starting from EXAMPLE 8 as reagent, EXAMPLE 95 was obtained as HCl salt. HRMS calculated for C.sub.28H.sub.35N.sub.5O.sub.3: 489.274; found 490.2817 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-isobutyl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 96)

(99) Using General Procedure 6 starting from EXAMPLE 9 as reagent, EXAMPLE 96 was obtained as HCl salt. HRMS calculated for C.sub.28H.sub.37N.sub.5O.sub.3: 491.2896; found 492.2963 [(M+H) form].

7-(2,2-difluoroethyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 97)

(100) Using General Procedure 5 starting from Preparation R2cc and Preparation R1c as reagents, the resulted Boc-protected crude product was reacted using General Procedure 6, to give EXAMPLE 97 as HCl salt. HRMS calculated for C.sub.26H.sub.31N.sub.5O.sub.3F2: 499.2395; found 500.2485 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-9-methyl-pyrimido[4,5-b]indol-4-one (EXAMPLE 98)

(101) Using General Procedure 6 starting from EXAMPLE 10 as reagent, EXAMPLE 98 was obtained as HCl salt. HRMS calculated for C.sub.29H.sub.33N.sub.5O.sub.3: 499.2583; found 500.2677 [(M+H) form].

7-(cyclobutylmethyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 99)

(102) Using General Procedure 6 starting from EXAMPLE 11 as reagent, EXAMPLE 99 was obtained as HCl salt. HRMS calculated for C.sub.29H.sub.37N.sub.5O.sub.3: 503.2896; found 504.2957 [(M+H) form].

7-(2-dimethylaminoethyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 100)

(103) Using General Procedure 6 starting from EXAMPLE 12 as reagent, EXAMPLE 100 was obtained as HCl salt. HRMS calculated for C.sub.28H.sub.38N.sub.6O.sub.3: 506.3005; found 254.1581 [(M+2H)2+ form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 101)

(104) Using General Procedure 6 starting from EXAMPLE 13 as reagent, EXAMPLE 101 was obtained as HCl salt. HRMS calculated for C.sub.30H.sub.33N.sub.5O.sub.3: 511.2583; found 512.2648 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-one (EXAMPLE 102)

(105) Using General Procedure 6 starting from EXAMPLE 14 as reagents, EXAMPLE 102 was obtained as HCl salt. HRMS calculated for C.sub.30H.sub.33N.sub.5O.sub.3: 511.2583; found 512.2647 [(M+H) form].

5-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-1-phenyl-pyrazolo[3,4-d]pyrimidin-4-one (EXAMPLE 103)

(106) Using General Procedure 6 starting from EXAMPLE 16 as reagent, EXAMPLE 103 was obtained as HCl salt. HRMS calculated for C.sub.29H.sub.32N.sub.6O.sub.3: 512.2536; found 513.2623 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(2-pyridyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 104)

(107) Using General Procedure 6 starting from EXAMPLE 15 as reagent, EXAMPLE 104 was obtained as HCl salt. HRMS calculated for C.sub.29H.sub.32N.sub.6O.sub.3: 512.2536; found 257.134 [(M+2H)2+ form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(3-pyridyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 105)

(108) Using General Procedure 5 starting from Preparation R2bu and Preparation R1c as reagents, the resulted Boc-protected crude product was reacted using General Procedure 6, to give EXAMPLE 105 as HCl salt. HRMS calculated for C.sub.29H.sub.32N.sub.6O.sub.3: 512.2536; found 513.261 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(4-pyridyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 106)

(109) Using General Procedure 5 starting from Preparation R2bv and Preparation R1c as reagents, the resulted Boc-protected crude product was reacted using General Procedure 6, to give EXAMPLE 106 as HCl salt. HRMS calculated for C.sub.29H.sub.32N.sub.6O.sub.3: 512.2536; found 513.2609 [(M+H) form].

1-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-9-phenyl-purin-6-one (EXAMPLE 107)

(110) Using General Procedure 6 starting from EXAMPLE 17 as reagent, EXAMPLE 107 was obtained as HCl salt. HRMS calculated for C.sub.29H.sub.32N.sub.6O.sub.3: 512.2536; found 513.2616 [(M+H) form].

7-bromo-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,1-f][1,2,4]triazin-4-one (EXAMPLE 108)

(111) Using General Procedure 6 starting from EXAMPLE 18 as reagent, EXAMPLE 108 was obtained as HCl salt. HRMS calculated for C.sub.24H.sub.28BrN.sub.5O.sub.3: 513.1376; found 514.1462 [(M+H) form].

6-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-3-phenyl-isoxazolo[4,5-d]pyrimidin-7-one (EXAMPLE 109)

(112) Using General Procedure 6 starting from EXAMPLE 19 as reagent, EXAMPLE 109 was obtained as HCl salt. HRMS calculated for C.sub.29H.sub.31N.sub.5O.sub.4: 513.2376; found 514.2451 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-pyrimidin-2-yl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 110)

(113) Using General Procedure 6 starting from EXAMPLE 20 as reagent, EXAMPLE 110 was obtained as HCl salt. HRMS calculated for C.sub.28H.sub.31N.sub.7O.sub.3: 513.2488; found 257.6326 [(M+2H)2+ form].

6-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-3-phenyl-triazolo[4,5-d]pyrimidin-7-one (EXAMPLE 111)

(114) Using General Procedure 6 starting from EXAMPLE 21 as reagent, EXAMPLE 111 was obtained as HCl salt. HRMS calculated for C.sub.28H.sub.31N.sub.7O.sub.3: 513.2488; found 514.2576 [(M+H) form].

3-[(4-hydroxy-1-{[(3R,4R)-3-phenylpiperidin-4-yl]carbonyl}piperidin-4-yl)methyl]-6,8-dimethylpyrimido[5,4-b]indolizin-4(3H)-one (EXAMPLE 112)

(115) Using General Procedure 6 starting from EXAMPLE 22 as reagent, EXAMPLE 112 was obtained as HCl salt. HRMS calculated for C.sub.29H.sub.34N.sub.6O.sub.3: 514.2692; found 515.2757 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(1-methylimidazol-4-yl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 113)

(116) Using General Procedure 6 starting from EXAMPLE 23 as reagent, EXAMPLE 113 was obtained as HCl salt. HRMS calculated for C.sub.28H.sub.33N.sub.7O.sub.3: 515.2645; found 516.2728 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(1-methylpyrazol-4-yl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 114)

(117) Using General Procedure 5 starting from Preparation R2bx and Preparation R1c as reagents, the resulted Boc-protected crude product was reacted using General Procedure 6, to give EXAMPLE 114 as HCl salt. HRMS calculated for C.sub.28H.sub.33N.sub.7O.sub.3: 515.2645; found 516.2716 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(2-thienyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 115)

(118) Using General Procedure 6 starting from EXAMPLE 25 as reagent, EXAMPLE 115 was obtained as HCl salt. HRMS calculated for C.sub.28H.sub.31N.sub.5O.sub.3S: 517.2148; found 518.2231 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(3-thienyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 116)

(119) Using General Procedure 6 starting from EXAMPLE 24 as reagent, EXAMPLE 116 was obtained as HCl salt. HRMS calculated for C.sub.28H.sub.31N.sub.5O.sub.3S: 517.2148; found 518.2233 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenyl-1-(2,2,2-trifluoroethyl)piperidine-4-carbonyl]-4-piperidyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 117)

(120) EXAMPLE 62 (610 mg, 0.92 mmol) was dissolved in 12 ml DCM, then TFA (211 μl, 2.73 mmol, 3 eq.) and formic acid (399 μl, 10.6 mmol, 11.5 eq.) were added. The mixture was stirred at r.t. for 118 hours, then potassium carbonate (2.22g 16.1 mmol) was added. The solution was extrated with DCM (2×70 ml) and organic phase was dried (MgSO.sub.4) and evaporated.

(121) 112 mg (0.2 mmol) of crude 3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-one product was solved in 2 ml dry THF, then triethyl amine (42 μl, 0.3 mmol, 1.5 eq.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (32 μl, 0.22 mol, 1.2 eq.) were added. The mixture was stirred at r.t. for 141 hours, then 5 ml water was added. The solution was extracted with DCM (2×10 ml) and organic phase was dried (MgSO.sub.4) and evaporated

(122) The obtained 3-[[4-hydroxy-1-[(3R,4R)-3-phenyl-1-(2,2,2-trifluoroethyl)piperidine-4-carbonyl]-4-piperidyl]methyl]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-one was solved in 270 μl dry THF, and tetrabutylammonium fluoride (270 μl, 1M in THF, 0.27 mmol) and molecular sieves were added and stirred at 75° C. for 20 hours, then the molecular sieves was filtered off and the residue was purified by preparative HPLC in 25 mM NH.sub.4HCO.sub.3-acetonitrile gradient method, to give EXAMPLE 117. HRMS calculated for C.sub.26H.sub.30F3N.sub.5O.sub.3: 517.2301; found 518.2361 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(2,2,2-trifluoroethyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 118)

(123) Using General Procedure 6 starting from EXAMPLE 26 as reagent, EXAMPLE 118 was obtained as HCl salt. HRMS calculated for C.sub.26H.sub.30F3N.sub.5O.sub.3: 517.2301; found 518.2386 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-thiazol-2-yl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 119)

(124) Using General Procedure 6 starting from EXAMPLE 27 as reagent, EXAMPLE 119 was obtained as HCl salt. HRMS calculated for C.sub.27H.sub.30N.sub.6O.sub.3S: 518.21; found 519.2181 [(M+H) form].

7-[3-(dimethylamino)propyl]-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 120)

(125) Using General Procedure 6 starting from EXAMPLE 28 as reagent, EXAMPLE 120 was obtained as HCl salt. HRMS calculated for C.sub.29H.sub.40N.sub.6O.sub.3: 520.3162; found 261.1666 [(M+2H)2+ form].

3-[[4-hydroxy-1-[(3R,4R)-1-methyl-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 121)

(126) Using General Procedure 7 starting from EXAMPLE 101 and methyl iodide as reagents, EXAMPLE 121 was obtained as HCl salt. HRMS calculated for C.sub.31H.sub.35N.sub.5O.sub.3: 525.274; found 526.2802 [(M+H) form].

7-benzyl-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 122)

(127) Using General Procedure 6 starting from EXAMPLE 31 as reagent, EXAMPLE 122 was obtained as HCl salt. HRMS calculated for C.sub.31H.sub.35N.sub.5O.sub.3: 525.274; found 526.2822 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(p-tolyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 123)

(128) Using General Procedure 6 starting from EXAMPLE 30 as reagent, EXAMPLE 123 was obtained as HCl salt. HRMS calculated for C.sub.31H.sub.35N.sub.5O.sub.3: 525.274; found 526.2816 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(m-tolyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 124)

(129) Using General Procedure 6 starting from EXAMPLE 29 as reagent, EXAMPLE 124 was obtained as HCl salt. HRMS calculated for C.sub.31H.sub.35N.sub.5O.sub.3: 525.274; found 526.2825 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-methyl-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 125)

(130) Using General Procedure 6 starting from EXAMPLE 32 as reagent, EXAMPLE 125 was obtained as HCl salt. HRMS calculated for C.sub.31H.sub.35N.sub.5O.sub.3: 525.274; found 526.2827 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(6-methyl-2-pyridyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 126)

(131) Using General Procedure 5 starting from Preparation R2br and Preparation R1c as reagents, the resulted Boc-protected crude product was reacted using General Procedure 6, to give EXAMPLE 126 as HCl salt. HRMS calculated for C.sub.30H.sub.34N.sub.6O.sub.3: 526.2692; found 527.2764 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(4-oxo-7-phenyl-thieno[3,4-d]pyrimidin-3-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 127)

(132) EXAMPLE 6 (370 mg, 0.63 mmol) was dissolved in 2 ml THF and 2 ml water, then phenyl boronic acid (308 mg, 2.52 mmol, 4 eq.), AtaPhos*PdCl.sub.2 (8.6 mg, 0.012 mmol, 0.2 eq.), cesium carbonate (617 mg, 1.89 mmol, 3 eq.) were added. The mixture was heated and stirred in Anton Paar microwave reactor for 1 hour at 100° C. The residue was purified by preparative HPLC in 5 mM NH.sub.4HCO.sub.3-MeCN gradient method, to give EXAMPLE 127. HRMS calculated for C.sub.35H.sub.40N.sub.4O.sub.5S: 628.2719; found 629.2788 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(6-oxo-1H-pyridin-2-yl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 128)

(133) Using General Procedure 6 starting from EXAMPLE 45 as reagents, EXAMPLE 128 was obtained. HRMS calculated for C.sub.29H.sub.32N.sub.6O.sub.4: 528.2485; found 529.2567 [(M+H) form].

6-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-3-phenyl-isothiazolo[4,5-d]pyrimidin-7-one (EXAMPLE 129)

(134) Using General Procedure 6 starting from EXAMPLE 33 as reagent, EXAMPLE 129 was obtained. HRMS calculated for C.sub.29H.sub.31N.sub.5O.sub.3S: 529.2148; found 530.2223 [(M+H) form].

7-(4-fluorophenyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 130)

(135) Using General Procedure 6 starting from EXAMPLE 34 as reagent, EXAMPLE 130 was obtained. HRMS calculated for C.sub.30H.sub.30FN.sub.5O.sub.3: 529.2489; found 530.2584 [(M+H) form].

7-(3-fluorophenyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 131)

(136) Using General Procedure 6 starting from EXAMPLE 35 as reagents, EXAMPLE 131 was obtained. HRMS calculated for C.sub.30H.sub.32FN.sub.5O.sub.3: 529.2489; found 530.2571 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(5-methyl-2-thienyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 132)

(137) Using General Procedure 6 starting from EXAMPLE 37 as reagent, EXAMPLE 132 was obtained. HRMS calculated for C.sub.29H.sub.33N.sub.5O.sub.3S: 531.2304; found 532.2361 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(1-methyl-4-piperidyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 133)

(138) Using General Procedure 6 starting from EXAMPLE 38 as reagent, EXAMPLE 133 was obtained. HRMS calculated for C.sub.30H.sub.40N.sub.6O.sub.3: 532.3162; found 267.1658 [(M+2H)2+ form].

4-[3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-4-oxo-pyrrolo[2,3-d]pyrimidin-7-yl]benzonitrile (EXAMPLE 134)

(139) Using General Procedure 6 starting from EXAMPLE 39 as reagent, EXAMPLE 134 was obtained. HRMS calculated for C.sub.31H.sub.32N.sub.6O.sub.3: 536.2536; found 537.2599 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 135)

(140) Using General Procedure 6 starting from EXAMPLE 40 as reagents, EXAMPLE 135 was obtained. HRMS calculated for C.sub.31H.sub.35N.sub.5O.sub.4: 541.2689; found 542.2784 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(3-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 136)

(141) Using General Procedure 6 starting from EXAMPLE 41 as reagents, EXAMPLE 136 was obtained. HRMS calculated for C.sub.31H.sub.35N.sub.5O.sub.4: 541.2689; found 542.2777 [(M+H) form].

7-[4-(hydroxymethyl)phenyl]-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 137)

(142) Using General Procedure 6 starting from EXAMPLE 42 as reagents, EXAMPLE 137 was obtained. HRMS calculated for C.sub.31H.sub.35N.sub.5O.sub.4: 541.2689; found 542.2787 [(M+H) form].

7-[3-(hydroxymethyl)phenyl]-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 138)

(143) Using General Procedure 5 starting from Preparation R2bj and Preparation R1c as reagents, the resulted Boc-protected crude product was reacted using General Procedure 6, to give EXAMPLE 138. HRMS calculated for C.sub.31H.sub.35N.sub.5O.sub.4: 541.2689; found 542.2769 [(M+H) form].

6-(hydroxymethyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 139)

(144) Using General Procedure 6 starting from EXAMPLE 43 as reagent, EXAMPLE 139 was obtained. HRMS calculated for C.sub.31H.sub.35N.sub.5O.sub.4: 541.2689; found 542.2763 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(6-methoxy-2-pyridyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 140)

(145) Using General Procedure 6 starting from EXAMPLE 45 as reagent, EXAMPLE 140 was obtained. HRMS calculated for C.sub.30H.sub.34N.sub.6O.sub.4: 542.2642; found 543.2698 [(M+H) form].

7-(4-fluorophenyl)-3-[[4-hydroxy-1-[(3R,4R)-1-methyl-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 141)

(146) Using General Procedure 7 starting from EXAMPLE 130 and methyl iodide as reagents, EXAMPLE 141 was obtained. HRMS calculated for C.sub.31H.sub.34N.sub.5O.sub.3F: 543.2646; found 544.2721 [(M+H) form].

7-(3-chlorophenyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 142)

(147) Using General Procedure 6 starting from EXAMPLE 47 as reagent, EXAMPLE 142 was obtained. HRMS calculated for C.sub.30H.sub.32ClN.sub.5O.sub.3: 545.2194; found 546.2248 [(M+H) form].

7-(4-chlorophenyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 143)

(148) Using General Procedure 6 starting from EXAMPLE 46 as reagent, EXAMPLE 143 was obtained. HRMS calculated for C.sub.30H.sub.32ClN.sub.5O.sub.3: 545.2194; found 546.2262 [(M+H) form].

6-chloro-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 144)

(149) Using General Procedure 6 starting from EXAMPLE 48 as reagent, EXAMPLE 144 was obtained. HRMS calculated for C.sub.30H.sub.32ClN.sub.5O.sub.3: 545.2194; found 546.2277 [(M+H) form].

7-(5-chloro-2-thienyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 145)

(150) Using General Procedure 6 starting from EXAMPLE 49 as reagent, EXAMPLE 145 was obtained. HRMS calculated for C.sub.28H.sub.30ClN.sub.5O.sub.3S: 551.1758; found 552.1844 [(M+H) form].

7-[1-(difluoromethyl)pyrazol-4-yl]-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 146)

(151) Using General Procedure 6 starting from EXAMPLE 50 as reagent, EXAMPLE 146 was obtained. HRMS calculated for C.sub.28H.sub.31F2N.sub.7O.sub.3: 551.2457; found 552.254 [(M+H) form].

3-[[1-[(3R,4R)-1-acetyl-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 147)

(152) Using General Procedure 8 starting from EXAMPLE 101 and acetic acid as reagents, EXAMPLE 147 was obtained. HRMS calculated for C.sub.32H.sub.35N.sub.5O.sub.4: 553.2689; found 554.2757 [(M+H) form].

7-(4-dimethylaminophenyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 148)

(153) Using General Procedure 6 starting from EXAMPLE 51 as reagent, EXAMPLE 148 was obtained. HRMS calculated for C.sub.32H.sub.38N.sub.6O.sub.3: 554.3005; found 555.3076 [(M+H) form].

7-[3-(dimethylamino)phenyl]-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 149)

(154) Using General Procedure 6 starting from EXAMPLE 52 as reagent, EXAMPLE 149 was obtained. HRMS calculated for C.sub.32H.sub.38N.sub.6O.sub.3: 554.3005; found 555.3086 [(M+H) form].

7-(1,3-benzodioxol-5-yl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 150)

(155) Using General Procedure 6 starting from EXAMPLE 53 as reagent, EXAMPLE 150 was obtained. HRMS calculated for C.sub.31H.sub.33N.sub.5O.sub.5: 555.2482; found 556.2556 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-1-methyl-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 151)

(156) Using General Procedure 7 starting from EXAMPLE 135 and methyl iodide as reagents, EXAMPLE 151 was obtained. HRMS calculated for C.sub.32H.sub.37N.sub.5O.sub.4: 555.2845; found 556.2922 [(M+H) form].

7-(3-chlorophenyl)-3-[[4-hydroxy-1-[(3R,4R)-1-methyl-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 152)

(157) Using General Procedure 7 starting from EXAMPLE 142 and methyl iodide as reagents, EXAMPLE 152 was obtained. HRMS calculated for C.sub.31H.sub.34N.sub.5O.sub.3Cl: 559.235; found 560.2425 [(M+H) form].

7-(4-chlorophenyl)-3-[[4-hydroxy-1-[(3R,4R)-1-methyl-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 153)

(158) Using General Procedure 7 starting from EXAMPLE 143 and methyl iodide as reagents, EXAMPLE 153 was obtained. HRMS calculated for C.sub.31H.sub.34N.sub.5O.sub.3Cl: 559.235; found 560.2423 [(M+H) form].

7-[(4-chlorophenyl)methyl]-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 154)

(159) Using General Procedure 6 starting from EXAMPLE 56 as reagent, EXAMPLE 154 was obtained. HRMS calculated for C.sub.31H.sub.34ClN.sub.5O.sub.3: 559.235; found 560.2418 [(M+H) form].

7-[(3-chlorophenyl)methyl]-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 155)

(160) Using General Procedure 6 starting from EXAMPLE 55 as reagent, EXAMPLE 155 was obtained. HRMS calculated for C.sub.31H.sub.34ClN.sub.5O.sub.3: 559.235; found 560.2432 [(M+H) form].

7-[(2-chlorophenyl)methyl]-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 156)

(161) Using General Procedure 6 starting from EXAMPLE 54 as reagent, EXAMPLE 156 was obtained. HRMS calculated for C.sub.31H.sub.34ClN.sub.5O.sub.3: 559.235; found 560.2429 [(M+H) form].

7-(4-fluoro-3-methoxy-phenyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 157)

(162) Using General Procedure 6 starting from EXAMPLE 57 as reagent, EXAMPLE 157 was obtained. HRMS calculated for C.sub.31H.sub.34FN.sub.5O.sub.4: 559.2595; found 560.2638 [(M+H) form].

7-[4-(difluoromethyl)phenyl]-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 158)

(163) Using General Procedure 6 starting from EXAMPLE 58 as reagent, EXAMPLE 158 was obtained. HRMS calculated for C.sub.31H.sub.33F2N.sub.5O.sub.3: 561.2551; found 562.2636 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(2-naphthyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 159)

(164) Using General Procedure 6 starting from EXAMPLE 60 as reagent, EXAMPLE 159 was obtained. HRMS calculated for C.sub.34H.sub.35N.sub.5O.sub.3: 561.274; found 562.2831 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(1-naphthyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 160)

(165) Using General Procedure 6 starting from EXAMPLE 59 as reagent, EXAMPLE 160 was obtained. HRMS calculated for C.sub.34H.sub.35N.sub.5O.sub.3: 561.274; found 562.2827 [(M+H) form].

7-(4-chloro-3-fluoro-phenyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 161)

(166) Using General Procedure 6 starting from EXAMPLE 61 as reagent, EXAMPLE 161 was obtained. HRMS calculated for C.sub.30H.sub.31N.sub.5O.sub.3FCl: 563.21; found 564.2181 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 162)

(167) EXAMPLE 62 (1.6 g, 2.4 mmol) was dissolved in 30 ml DCM, then TFA (3 ml) and formic acid (550 μl, 7.2 mmol, 3 eq.) were added. The mixture was stirred at r.t. for 4 days, then potassium carbonate (15 g, 108 mmol) was added. The solution was extrated with DCM and organic phase was dried (MgSO.sub.4) and evaporated to give EXAMPLE 162. HRMS calculated for C.sub.30H.sub.43N.sub.5O.sub.4Si: 565.3084; found 566.3138 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-1-isobutyl-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 163)

(168) Using General Procedure 7 starting from EXAMPLE 101 and 1-bromo-2-methyl-propane as reagents, EXAMPLE 163 was obtained. HRMS calculated for C.sub.34H.sub.41N.sub.5O.sub.3: 567.3209; found 568.328 [(M+H) form].

7-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 164)

(169) Using General Procedure 6 starting from EXAMPLE 63 as reagent, EXAMPLE 164 was obtained. HRMS calculated for C.sub.32H.sub.35N.sub.5O.sub.5: 569.2638; found 570.2709 [(M+H) form].

1-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrazolo[3,4-d]pyrimidin-4-one (EXAMPLE 165)

(170) Using General Procedure 6 starting from EXAMPLE 64 as reagent, EXAMPLE 165 was obtained. HRMS calculated for C.sub.31H.sub.34N.sub.6O.sub.5: 570.2591; found 571.2663 [(M+H) form].

3-[[1-[(3R,4R)-1-acetyl-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-7-(4-fluorophenyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 166)

(171) Using General Procedure 8 starting from EXAMPLE 130 and acetic acid as reagents, EXAMPLE 166 was obtained. HRMS calculated for C.sub.32H.sub.34FN.sub.5O.sub.4: 571.2595; found 572.2679 [(M+H) form].

7-(3,5-dimethoxyphenyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 167)

(172) Using General Procedure 6 starting from EXAMPLE 66 as reagent, EXAMPLE 167 was obtained. HRMS calculated for C.sub.32H.sub.37N.sub.5O.sub.5: 571.2795; found 572.2881 [(M+H) form].

7-(3,4-dimethoxyphenyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 168)

(173) Using General Procedure 6 starting from EXAMPLE 65 as reagent, EXAMPLE 168 was obtained. HRMS calculated for C.sub.32H.sub.37N.sub.5O.sub.5: 571.2795; found 572.2892 [(M+H) form].

5-[[1-[(3R,4R)-1,1-dimethyl-3-phenyl-piperidin-1-ium-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-1-(4-methoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-one (EXAMPLE 169)

(174) Using General Procedure 7 starting from EXAMPLE 135 and methyl iodide as reagents, EXAMPLE 169 was obtained. HRMS calculated for C.sub.32H.sub.39N.sub.6O.sub.4: 571.3027; found 571.3038 [(M+) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-iodo-7-methyl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 170)

(175) Using General Procedure 6 starting from EXAMPLE 67 as reagent, EXAMPLE 170 was obtained. HRMS calculated for C.sub.25H.sub.301N.sub.5O.sub.3: 575.1393; found 576.1455 [(M+H) form].

7-(3-chloro-5-methoxy-phenyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 171)

(176) Using General Procedure 6 starting from EXAMPLE 68 as reagent, EXAMPLE 171 was obtained. HRMS calculated for C.sub.31H.sub.34ClN.sub.5O.sub.4: 575.2299; found 576.2382 [(M+H) form].

7-(4-chloro-3-methoxy-phenyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 172)

(177) Using General Procedure 6 starting from EXAMPLE 69 as reagents, EXAMPLE 172 was obtained. HRMS calculated for C.sub.31H.sub.34ClN.sub.5O.sub.4: 575.2299; found 576.2382 [(M+H) form].

7-(3,5-dichlorophenyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 173)

(178) Using General Procedure 6 starting from EXAMPLE 71 as reagent, EXAMPLE 173 was obtained. HRMS calculated for C.sub.30H.sub.31N.sub.5O.sub.3Cl.sub.2: 579.1804; found 580.1891 [(M+H) form].

7-(3,4-dichlorophenyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 174)

(179) Using General Procedure 6 starting from EXAMPLE 70 as reagent, EXAMPLE 174 was obtained. HRMS calculated for C.sub.30H.sub.31Cl.sub.2N.sub.5O.sub.3: 579.1804; found 580.187 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-[4-(trifluoromethyl)phenyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 175)

(180) Using General Procedure 6 starting from EXAMPLE 72 as reagent, EXAMPLE 175 was obtained. HRMS calculated for C.sub.31H.sub.32N.sub.5O.sub.3F3: 579.2457; found 580.2529 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-[3-(trifluoromethyl)phenyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 176)

(181) Using General Procedure 6 starting from EXAMPLE 73 as reagent, EXAMPLE 176 was obtained. HRMS calculated for C.sub.31H.sub.32F3N.sub.5O.sub.3: 579.2457; found 580.2509 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-1-(2-methylpropanoyl)-3-phenyl-piperidine-4-carbonyl]-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 177)

(182) Using General Procedure 8 starting from EXAMPLE 101 and 2-methylpropanoic acid as reagents, EXAMPLE 177 was obtained. HRMS calculated for C.sub.34H.sub.39N.sub.5O.sub.4: 581.3002; found 582.3072 [(M+H) form].

3-[[1-[(3R,4R)-1-acetyl-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-7-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 178)

(183) Using General Procedure 8 starting from EXAMPLE 135 and acetic acid as reagents, EXAMPLE 178 was obtained. HRMS calculated for C.sub.33H.sub.37N.sub.5O.sub.5: 583.2795; found 584.2868 [(M+H) form].

3-[[1-[(3R,4R)-1-acetyl-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-7-(3-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 179)

(184) Using General Procedure 8 starting from EXAMPLE 136 and acetic acid as reagents, EXAMPLE 179 was obtained. HRMS calculated for C.sub.33H.sub.37N.sub.5O.sub.5: 583.2795; found 584.2863 [(M+H) form].

3-[[1-[(3R,4R)-1-acetyl-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-7-(3-chlorophenyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 180)

(185) Using General Procedure 8 starting from EXAMPLE 142 and acetic acid as reagents, EXAMPLE 180 was obtained. HRMS calculated for C.sub.32H.sub.34ClN.sub.5O.sub.4: 587.2299; found 588.238 [(M+H) form].

3-[[1-[(3R,4R)-1-acetyl-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-7-(4-chlorophenyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 181)

(186) Using General Procedure 8 starting from EXAMPLE 143 and acetic acid as reagents, EXAMPLE 181 was obtained. HRMS calculated for C.sub.32H.sub.34ClN.sub.5O.sub.4: 587.2299; found 588.2366 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-[4-(trifluoromethoxy)phenyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 182)

(187) Using General Procedure 6 starting from EXAMPLE 76 as reagent, EXAMPLE 182 was obtained. HRMS calculated for C.sub.31H.sub.32N.sub.5O.sub.4F3: 595.2407; found 596.2494 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-[3-(trifluoromethoxy)phenyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 183)

(188) Using General Procedure 6 starting from EXAMPLE 75 as reagent, EXAMPLE 183 was obtained. HRMS calculated for C.sub.31H.sub.32N.sub.5O.sub.4F3: 595.2407; found 596.2491 [(M+H) form].

3-[[1-[(3R,4R)-1-(2,2-dimethylpropanoyl)-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 184)

(189) Using General Procedure 8 starting from EXAMPLE 101 and 2,2-dimethylpropanoic acid as reagents, EXAMPLE 184 was obtained. HRMS calculated for C.sub.35H.sub.41N.sub.5O.sub.4: 595.3159; found 596.3221 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(3-morpholinophenyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 185)

(190) Using General Procedure 6 starting from EXAMPLE 77 as reagent, EXAMPLE 185 was obtained. HRMS calculated for C.sub.34H.sub.40N.sub.6O.sub.4: 596.3111; found 597.3187 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-(3,4,5-trimethoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 186)

(191) Using General Procedure 6 starting from EXAMPLE 78 as reagent, EXAMPLE 186 was obtained. HRMS calculated for C.sub.33H.sub.39N.sub.5O.sub.6: 601.29; found 602.296 [(M+H) form].

3-[[1-[(3R,4R)-1-(3,3-dimethylbutanoyl)-3-phenyl-piperidine-4-carbonyl]-4-hydroxy-4-piperidyl]methyl]-7-phenyl-pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 187)

(192) Using General Procedure 8 starting from EXAMPLE 101 and 3,3-dimethylbutanoic acid as reagents, EXAMPLE 187 was obtained. HRMS calculated for C.sub.36H.sub.43N.sub.5O.sub.4: 609.3315; found 610.3384 [(M+H) form].

7-(4-benzyloxyphenyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 188)

(193) Using General Procedure 6 starting from EXAMPLE 79 as reagent, EXAMPLE 188 was obtained. HRMS calculated for C.sub.37H.sub.39N.sub.5O.sub.4: 617.3002; found 618.3083 [(M+H) form].

7-(3-benzyloxyphenyl)-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 189)

(194) Using General Procedure 6 starting from EXAMPLE 80 as reagent, EXAMPLE 189 was obtained. HRMS calculated for C.sub.37H.sub.39N.sub.5O.sub.4: 617.3002; found 618.3051 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-[3-[(4-methylpiperazin-1-yl)methyl]phenyl]pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 190)

(195) Using General Procedure 6 starting from EXAMPLE 81 as reagent, EXAMPLE 190 was obtained. HRMS calculated for C.sub.36H.sub.45N.sub.7O.sub.3: 623.3584; found 624.3656 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-7-phenyl-thieno[3,4-d]pyrimidin-4-one (EXAMPLE 191)

(196) Using General Procedure 6 starting from EXAMPLE 127 as reagent, EXAMPLE 191 was obtained. HRMS calculated for C.sub.30H.sub.32N.sub.4O.sub.3S: 528.2195; found 529.2265 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-iodo-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-one (EXAMPLE 192)

(197) EXAMPLE 74 (647 mg, 0.82 mmol) was dissolved in 13 ml DCM, then TFA (188 μl, 2.46 mmol, 3 eq.) and formic acid (356 μl, 9.43 mmol, 11.5 eq.) were added. The mixture was stirred at r.t. for 214 hours, then potassium carbonate (1.99 g, 14.3 mmol) was added. The solution was extrated with DCM (2×70 ml) and organic phase (MgSO.sub.4) was dried and evaporated to give EXAMPLE 192. HRMS calculated for C.sub.30H.sub.42IN.sub.5O.sub.4Si: 691.2051; found 692.2155 [(M+H) form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(4-oxopyrido[3,2-d]pyrimidin-3-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 193)

(198) Using General Procedure 5 starting from 3H-pyrido[3,2-d]pyrimidin-4-one and Preparation R1c as reagents, EXAMPLE 193 was obtained. HRMS calculated for C.sub.30H.sub.37N.sub.5O.sub.5: 547.2795; found 548.2870 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrido[3,2-d]pyrimidin-4-one (EXAMPLE 194)

(199) Using General Procedure 6 starting from EXAMPLE 193 as reagent, EXAMPLE 194 was obtained as HCl salt. HRMS calculated for C.sub.25H.sub.29N.sub.5O.sub.3: 447.227; found 448.2365 [(M+H).sup.+ form].

tert-butyl (3R,4R)-4-[4-[(6-chloro-4-oxo-pyrido[3,2-d]pyrimidin-3-yl)methyl]-4-hydroxy-piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 195)

(200) Using General Procedure 5 starting from 6-chloro-3H-pyrido[3,2-d]pyrimidin-4-one and Preparation R1c as reagents, EXAMPLE 195 was obtained. HRMS calculated for C.sub.30H.sub.36ClN.sub.5O.sub.5: 581.2405; found 604.2239 [(M+Na) form].

6-chloro-3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]pyrido[3,2-d]pyrimidin-4-one (EXAMPLE 196)

(201) Using General Procedure 6 starting from EXAMPLE 195 as reagent, EXAMPLE 196 was obtained as HCl salt. HRMS calculated for C.sub.25H.sub.28ClN.sub.5O.sub.3: 481.1881; found 482.1949 [(M+H).sup.+ form].

tert-butyl (3R,4R)-4-[4-hydroxy-4-[(6-methoxy-4-oxo-pyrido[3,2-d]pyrimidin-3-yl)methyl]piperidine-1-carbonyl]-3-phenyl-piperidine-1-carboxylate (EXAMPLE 197)

(202) Using General Procedure 5 starting from 6-methoxy-3H-pyrido[3,2-d]pyrimidin-4-one and Preparation R1c as reagents, EXAMPLE 197 was obtained. HRMS calculated for C.sub.31H.sub.39N.sub.5O.sub.6: 577.29; found 578.2976 [(M+H) form].

3-[[4-hydroxy-1-[(3R,4R)-3-phenylpiperidine-4-carbonyl]-4-piperidyl]methyl]-6-methoxy-pyrido[3,2-d]pyrimidin-4-one (EXAMPLE 198)

(203) Using General Procedure 6 starting from EXAMPLE 197 as reagent, EXAMPLE 198 was obtained as HCl salt. HRMS calculated for C.sub.26H.sub.31N.sub.5O.sub.4: 477.2376; found 478.2458 [(M+H).sup.+ form].

Pharmacological Study

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

(204) 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.

(205) 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% TritonX100, 1 mM TCEP, and 10% DMSO.

(206) 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-110 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).

(207) 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).

(208) The results presented in Table 1 below show that compounds of the invention inhibit interaction between USP7 protein and the fluorescent peptide described hereinbefore.

Example B: In Vitro Cytotoxicity

(209) The cytotoxicity studies were carried out on the MM1S multiple myeloma tumour cell line. 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 (Cancer Res., 1987, 47, 939-942).

(210) The results are expressed in IC.sub.50 (the concentration of compound that inhibits cell viability by 50%) and are presented in Table 1 below.

(211) The results show that the compounds of the invention are cytotoxic.

(212) TABLE-US-00002 TABLE 1 IC.sub.50 of USP7 inhibition and of cytotoxicity for MM1S cells EXAMPLE IC.sub.50 (M) USP7 FLINT IC.sub.50 (M) MTT MM1S 2 1.28E−07 ND 15 2.74E−07 ND 40 4.99E−08 3.15E−08 44 6.15E−08 ND 57 7.02E−08 ND 64 6.87E−08 ND 101 3.16E−08 2.72E−07 103 5.29E−08 ND 104 3.94E−07 ND 117 1.20E−06 ND 121 1.40E−07 ND 130 3.77E−08 ND 135 2.87E−08 1.35E−07 136 4.86E−08 ND 141 7.48E−08 ND 142 5.67E−08 ND 143 4.12E−08 ND 147 4.06E−07 ND 151 5.24E−08 ND 152 6.48E−08 ND 153 4.86E−08 7.47E−08 157 3.93E−08 ND 163 1.08E−07 ND 165 1.96E−08 3.00E−07 166 1.02E−07 ND 169 8.60E−07 ND 177 1.03E−07 ND 178 9.61E−08 ND 179 8.84E−08 ND 180 8.90E−08 ND 181 7.42E−08 ND 184 8.30E−08 ND 187 8.85E−08 ND ND: not determined

Example C: Anti-Tumor Activity In Vivo

(213) 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.

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

(215) 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.

(216) 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:

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

Example D: Pharmaceutical Composition: Tablets

(218) TABLE-US-00003 1000 tablets containing a dose of 5 mg of a 5 g compound selected from Examples 1 to 198 Wheat starch 20 g Maize starch 20 g Lactose 30 g Magnesium stearate 2 g Silica 1 g Hydroxypropylcellulose 2 g