INHIBITORS OF MLH1 AND/OR PMS2 FOR CANCER TREATMENT

Abstract

The present invention relates to compounds of Formula (I) that target the MLH1 and/or PMS2 proteins that are components of the DNA Mismatch Repair (MMR) process:

##STR00001##

wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6 and R.sup.10 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which MLH1 and/or PMS2 activity is implicated.

Claims

1. A compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural Formula (I), shown below: ##STR00203## wherein R.sup.1 and R.sup.3 are independently selected from the group consisting of hydrogen, hydroxy, halogen and (1-4C)alkoxy, with the proviso that at least one of R.sup.1 and R.sup.3 is hydroxy; R.sup.2 is hydrogen or fluoro; R.sup.4 is selected from the group consisting of hydrogen, halogen, (1-6C)alkyl, (3-6C)cycloalkyl and (3-6C)cycloalkyl(1-2C)alkyl, wherein the said (1-6C)alkyl is optionally substituted by one or more R.sup.5a and the said (3-6C)cycloalkyl and (3-6C)cycloalkyl(1-2C)alkyl groups are optionally substituted with one or more R.sup.5b; where each R.sup.5a is independently selected from halogen or (1-4C)alkoxy and each R.sup.5b is independently selected from the group consisting of halogen, (1-4C)alkyl and (1-4C)alkoxy; R.sup.6 is (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl or a 4- to 7-membered heterocyclyl ring comprising one heteroatom selected from N, O or S, or a group having a structure according to formula (A) shown below: ##STR00204## wherein R.sup.7 is hydrogen or (1-3C)alkyl; n is 1 or 2; R.sup.8 is aryl or heteroaryl, wherein the said aryl or heteroaryl is optionally substituted with one or more R.sup.9; where each R.sup.9 is independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (2-3C)alkenyl or (2-3C)alkynyl; R.sup.10 is —NR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are linked, such that, together with the nitrogen atom to which they are attached, they form a 5-7 membered monocyclic heterocyclic ring that is fused to either a 5-6 membered monocyclic heteroaromatic ring or a benzene ring, thereby forming a 8-11 membered bicyclic heteroaryl ring; wherein any one or more of the rings present in R.sup.10 is independently optionally substituted with one or more R.sup.13; each R.sup.13 is independently selected from the group consisting of halogen, cyano, oxo, epoxy and a group
-L.sup.1-X.sup.1-Q.sup.1 wherein: L.sup.1 is absent or (1-3C)alkylene; X.sup.1 is absent or is selected from the group consisting of —O—, —C(O)—, —C(O)—O—, —O—C(O)—, —S(O).sub.0-2—, —C(O)—N(R.sup.14)—, —N(R.sup.14)—C(O)—, —NR.sup.14—, —N(R.sup.14)—C(O)—NR.sup.14—, —SO.sub.2N(R.sup.1)—, or —N(R.sup.14)SO.sub.2—, where R.sup.14 is, at each occurrence, independently selected from the group consisting of hydrogen, hydroxy, cyano, (1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl, where any (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl in R.sup.14 is independently optionally substituted with one or more groups selected from the group consisting of halogen and hydroxy; Q.sup.1 is selected from the group consisting of hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-3C)alkyl, aryl, aryl(1-3C)alkyl, heterocyclyl, heterocyclyl(1-3C)alkyl, heteroaryl and heteroaryl(1-3C)alkyl, wherein any (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-3C)alkyl, aryl, aryl(1-3C)alkyl, heterocyclyl, heterocyclyl(1-3C)alkyl, heteroaryl or heteroaryl(1-3C)alkyl in Q.sup.1 is optionally substituted with one or more groups R.sup.15; and each R.sup.15 is independently selected from the group consisting of hydroxy, cyano, oxo, halogen, (1-3C)alkyl, (1-3C)alkoxy, —NR.sup.15aR.sup.15b, —C(O)—R.sup.15a, —C(O)—OR.sup.15a, —O—C(O)—R.sup.15a, —C(O)—NR.sup.15aR.sup.15b, —N(R.sup.15b)C(O)—R.sup.15a, —S(O).sub.0-2R.sup.15a, —S(O).sub.2NR.sup.15aR.sup.15b, and —N(R.sup.15b)—S(O).sub.2R.sup.15a, wherein R.sup.15a and R.sup.15b are each independently hydrogen or (1-3C)alkyl, and wherein any (1-3C)alkyl moiety present in a R.sup.15a or R.sup.15b group is optionally further substituted by one or more substituents independently selected from hydroxy, cyano, halogen, —OR.sup.15c, —NR.sup.15cR.sup.15d and —C(O)—R.sup.15c, wherein R.sup.15c and R.sup.15d are both independently selected from hydrogen and (1-2C)alkyl.

2. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to claim 1, wherein R.sup.1 and R.sup.3 are independently selected from the group consisting of hydrogen, hydroxy, fluoro and methoxy, with the proviso that at least one of R.sup.1 and R.sup.3 is hydroxy.

3. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to claim 1 or 2, wherein R.sup.1 and R.sup.3 are both hydroxy.

4. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to claim 1, 2 or 3, wherein R.sup.2 is hydrogen; and R.sup.4 is selected from the group consisting of hydrogen, fluoro, chloro (1-4C)alkyl, cyclopropyl and cyclobutyl, wherein the said (1-4C)alkyl is optionally substituted by one R.sup.5a and the said cyclopropyl and cyclobutyl groups are optionally substituted with one R.sup.5b.

5. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any preceding claim, wherein R.sup.7 is hydrogen or methyl; and n is 1.

6. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any preceding claim, wherein R.sup.8 is phenyl or 5-6 membered heteroaryl containing 1, 2 or 3 ring heteroatoms independently selected from N and O, wherein the said phenyl or 5-6 membered heteroaryl is optionally substituted with one, two or three R.sup.9.

7. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any preceding claim, wherein R.sup.8 has any one of the following structures: ##STR00205## wherein each m.sup.1 is independently 0, 1, 2 or 3; and each m.sup.2 is independently 0, 1 or 2.

8. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any preceding claim, wherein R.sup.3 has the following structure: ##STR00206## wherein m.sup.1 is 0, 1, 2 or 3.

9. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any preceding claim, wherein each R.sup.9 is independently selected from the group consisting of hydroxy, halogen, (1-3C)alkyl, (1-3C)alkoxy, (2-3C)alkenyl and (2-3C)alkynyl.

10. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any preceding claim, wherein R.sup.11 and R.sup.12 are linked, such that, together with the nitrogen atom to which they are attached, they form any one of the following ring systems: ##STR00207## wherein v.sup.2 and v.sup.3 are each independently 1 or 2; W.sup.1 is CH, N or O; each ring A is a benzene ring or a 5-6 membered heteroaromatic ring; and any ring is optionally substituted with one or two R.sup.13.

11. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any preceding claim, wherein R.sup.11 and R.sup.12 are linked, such that, together with the nitrogen atom to which they are attached, they form any one of the following ring systems: ##STR00208## wherein v.sup.1 is 1, 2 or 3; v.sup.2 and v.sup.3 are each independently 1 or 2; W.sup.1 is CH, N or O; each ring A is a benzene ring or a 5-6 membered heteroaromatic ring containing 1, 2 or 3 N atoms; each R.sup.13a is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy, wherein any (1-3C)alkyl and (1-3C)alkoxy in R.sup.13a is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo; each q.sup.2 is independently 0, 1 or 2; and each q.sup.3 is independently 0 or 1.

12. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any one of claims 1-10, wherein R.sup.11 and R.sup.12 are linked, such that, together with the nitrogen atom to which they are attached, they form any one of the following ring systems: ##STR00209## wherein each q.sup.2 is independently 0 or 1; each q.sup.3 is independently 0, 1 or 2; v.sup.2 and v.sup.3 are each independently 1 or 2; W.sup.3 and W.sup.4 are each independently OH, N or O, providing that only zero, one or two of W.sup.2, W.sup.3 and W.sup.4 are N or O; W.sup.5, W.sup.6, W.sup.7 and W.sup.8 are each independently CH, N or O, providing that only zero, one or two of W.sup.5, W.sup.6, W.sup.7 and W.sup.8 are N or O; W.sup.9 is N, O or CH.sub.2 W.sup.10 is C or N; W.sup.11, W.sup.12 and W.sup.13 are each independently CH, N or O, providing that only zero, one or two of W.sup.11, W.sup.12 and W.sup.13 are N or O; W.sup.14, W.sup.15, W.sup.16 and W.sup.17 are each independently CH, N or O, providing that only zero, one or two of W.sup.14, W.sup.15, W.sup.16 and W.sup.17 are N or O; W.sup.18 is N, O or CH.sub.2 W.sup.19 is C or N; and W.sup.20, W.sup.21, W.sup.22 and W.sup.23 are each independently CH, N or O, providing that only zero, one or two of W.sup.20, W.sup.21, W.sup.22 and W.sup.23 are N or O.

13. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to claim 12, wherein W.sup.2, W.sup.3 and W.sup.4 are each independently CH or N, providing that only zero, one or two of W.sup.2, W.sup.3 and W.sup.4 are N; W.sup.5, W.sup.6, W.sup.7 and W.sup.8 are each independently CH or N, providing that only zero, one or two of W.sup.5, W.sup.6, W.sup.7 and W.sup.8 are N; W.sup.11, W.sup.12 and W.sup.13 are each independently CH or N, providing that only zero, one or two of W.sup.11, W.sup.12 and W.sup.13 are N; W.sup.14, W.sup.15, W.sup.16 and W.sup.17 are each independently CH or N, providing that only zero, one or two of W.sup.14, W.sup.15, W.sup.16 and W.sup.17 are N; and W.sup.20, W.sup.21, W.sup.22 and W.sup.23 are each independently CH or N, providing that only zero, one or two of W.sup.20, W.sup.21, W.sup.22 and W.sup.23 are N.

14. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any preceding claim, wherein R.sup.11 and R.sup.12 are linked, such that, together with the nitrogen atom to which they are attached, they form any one of the following ring systems: ##STR00210## wherein each q.sup.2 is independently 0 or 1 and each q.sup.3 is independently 0, 1 or 2; and each R.sup.13a is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy, wherein any (1-3C)alkyl and (1-3C)alkoxy in R.sup.13a is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo.

15. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any one of claims 1-11, wherein R.sup.11 and R.sup.12 are linked, such that, together with the nitrogen atom to which they are attached, they form the following ring system: ##STR00211## wherein v.sup.2 is 1 or 2; ring A is a benzene ring or a 5-6 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from N and 0; each R.sup.13a is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy, wherein any (1-3C)alkyl and (1-3C)alkoxy in R.sup.13a is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo; each q.sup.2 is independently 0, 1 or 2; and each q.sup.3 is independently 0 or 1.

16. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any one of claims 1-11, wherein R.sup.11 and R.sup.12 are linked, such that, together with the nitrogen atom to which they are attached, they form any one of the following ring systems: ##STR00212## wherein each q.sup.2 is independently 0 or 1 and each q.sup.3 is independently 0, 1 or 2; and each R.sup.13a is independently selected from the group consisting of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy, wherein any (1-3C)alkyl and (1-3C)alkoxy in R.sup.13a is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and halo.

17. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any preceding claim, wherein each R.sup.13 is independently selected from the group consisting of halogen, oxo, epoxy and a group -L.sup.1-X.sup.1-Q.sup.1.

18. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any preceding claim, wherein L.sup.1 is absent or (1-2C)alkylene; X.sup.1 is absent or is selected from the group consisting of —O—, —C(O)—, —C(O)—O—, —O—C(O)—, —S(O).sub.0-2—, —C(O)—N(R.sup.14)—, —N(R.sup.14)—C(O)—, or —NR.sup.14—, where R.sup.14 is, at each occurrence, independently selected from the group consisting of hydrogen, hydroxy, cyano, (1-4C)alkyl and (2-4C)alkenyl, where any (1-4C)alkyl or (2-4C)alkenyl in R.sup.14 is independently optionally substituted with one or more groups selected from the group consisting of halogen and hydroxy; and Q.sup.1 is selected from the group consisting of hydrogen, (1-6C)alkyl, (2-6C)alkenyl, aryl, heterocyclyl and heteroaryl, wherein any (1-6C)alkyl, (2-6C)alkenyl, aryl, heterocyclyl or heteroaryl in Q.sup.1 is optionally substituted with one or more groups R.sup.15.

19. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any preceding claim, wherein L.sup.1 is absent or (1-2C)alkylene; X.sup.1 is absent or is selected from the group consisting of —O—, —C(O)—, —C(O)—O—, —N(R.sup.14)—C(O)—, or —NR.sup.14—, where R.sup.14 is, at each occurrence, independently selected from the group consisting of hydrogen, cyano, (1-4C)alkyl and (2-4C)alkenyl; and Q.sup.1 is selected from the group consisting of hydrogen, (1-4C)alkyl, (2-4C)alkenyl, phenyl, 5-6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N and O, and 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N and O, wherein any (1-4C)alkyl, (2-4C)alkenyl, phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl in Q.sup.1 is optionally substituted with one, two or three groups R.sup.15.

20. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any preceding claim, wherein each R.sup.15 is independently selected from the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, —NR.sup.15aR.sup.15b and —C(O)—NR.sup.15aR.sup.15b, wherein R.sup.15a and R.sup.15b are each independently hydrogen or (1-3C)alkyl.

21. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any preceding claim, wherein each R.sup.15 is independently selected from the group consisting of hydroxy, halogen, (1-3C)alkyl and —C(O)—NR.sup.15aR.sup.15b, wherein R.sup.15a and R.sup.15b are each independently hydrogen or methyl.

22. The compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, according to any preceding claim, wherein the compound is selected from any one of the following: [2,4-dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone; [2-(cyclopentoxy)-4,6-dihydroxy-phenyl]-pyrrolidin-1-yl-methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-pyrrolidin-1-yl-methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-isoindolin-2-yl-methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-(1-piperidyl)methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-[(3S)-3-hydroxypyrrolidin-1-yl]methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-[(3R)-3-hydroxypyrrolidin-1-yl]methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-[(3R)-3-hydroxy-1-piperidyl]methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-[(3S)-3-hydroxy-1-piperidyl]methanone; (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-pyrrolidin-1-yl-methanone; (2-benzyloxy-3-ethyl-4,6-dihydroxy-phenyl)-pyrrolidin-1-yl-methanone; [2,4-dihydroxy-6-(2-pyridylmethoxy)phenyl]-pyrrolidin-1-yl-methanone; [2,4-dihydroxy-6-[(1R)-1-phenylethoxy]phenyl]-pyrrolidin-1-yl-methanone; [2,4-dihydroxy-6-[(1R)-1-phenylethoxy]phenyl]-pyrrolidin-1-yl-methanone; [2-[(4-fluorophenyl)methoxy]-4,6-dihydroxy-phenyl]-pyrrolidin-1-yl-methanone; [2,4-dihydroxy-6-[(4-methoxyphenyl)methoxy]phenyl]-pyrrolidin-1-yl-methanone; [2,4-dihydroxy-6-(m-tolylmethoxy)phenyl]-pyrrolidin-1-yl-methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-(5,7-dihydropyrrolo[3,4-b]pyridin-6-yl)methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-(4-methoxyisoindolin-2-yl)methanone; [2,4-dihydroxy-6-(pyrimidin-4-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone; 2,4-dihydroxy-6-(1H-pyrazol-3-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone; [2,4-dihydroxy-6-(1H-triazol-4-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-(5-bromoisoindolin-2-yl)methanone; methyl 2-(2-benzyloxy-4,6-dihydroxy-benzoyl)isoindoline-5-carboxylate; (2-benzyloxy-4,6-dihydroxy-phenyl)-(5-methoxyisoindolin-2-yl)methanone; (2-benzyloxy-4,6-dihydroxy-phenyl)-(5,6-dimethoxyisoindolin-2-yl)methanone; [2,4-dihydroxy-6-(1-phenylethoxy)phenyl]-isoindolin-2-yl-methanone; [2,4-dihydroxy-6-(1-phenylethoxy)phenyl]-(5-methoxyisoindolin-2-yl)methanone; [2,4-dihydroxy-6-(1-phenylethoxy)phenyl]-(5,6-dimethoxyisoindolin-2-yl)methanone; (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(5,7-dihydropyrrolo[3,4-b]pyridin-6-yl)methanone; 5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[4,6-dihydroxy-3-methyl-2-(m-tolylmethoxy)phenyl]methanone; 5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[2,4-dihydroxy-6-(m-tolylmethoxy)phenyl]methanone; 5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]methanone; [4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]-isoindolin-2-yl-methanone; 5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[2,4-dihydroxy-6-(2-pyridylmethoxy)phenyl]methanone; (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(3,4-dihydro-1H-isoquinolin-2-yl)methanone; [2,4-dihydroxy-6-(2-pyridylmethoxy)phenyl]-isoindolin-2-yl-methanone; (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(4-bromoisoindolin-2-yl)methanone; (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-[4-(hydroxymethyl)isoindolin-2-yl]methanone; (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-[5-[(4-methylpiperazin-1-yl)methyl]isoindolin-2-yl]methanone; (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone; (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)methanone; (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(3,4-dihydro-1H-2,6-naphthyridin-2-yl)methanone; 3,4-dihydro-1H-isoquinolin-2-yl-[4,6-dihydroxy-3-methyl-2-(m-tolylmethoxy)phenyl]methanone; 3,4-dihydro-1H-isoquinolin-2-yl-[4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]methanone; [4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone; [4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone; 3,4-dihydro-1H-isoquinolin-2-yl-[2-[(4-fluorophenyl)methoxy]-4,6-dihydroxy-3-methyl-phenyl]methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; (4-aminoisoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-vinylisoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)methanone; (3,4-dihydroisoquinolin-2(1H)-yl)(4,6-dihydroxy-3-methyl-2-((1-methyl-1H-pyrazol-3-yl)methoxy)phenyl)methanone; (2-(benzyloxy)-4,6-dihydroxyphenyl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(isoindolin-2-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (S)-(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(1-(hydroxymethyl)isoindolin-2-yl)methanone; (R)-(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(1-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5-((dimethylamino)methyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5-(morpholinomethyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(indolin-1-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(indolin-1-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(3,4-dihydroquinolin-1(2H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxyphenyl)(3,4-dihydroquinolin-1(2H)-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(morpholinomethyl)isoindolin-2-yl)methanone; 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide; 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxamide; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(oxetan-3-ylamino)isoindolin-2-yl)methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(3-hydroxypiperidin-1-yl)isoindolin-2-yl)methanone; 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carbonitrile; 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-5-carboxamide; 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-methylisoindoline-5-carboxamide; 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-4-carboxamide; 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N-methylisoindoline-4-carboxamide; N-(2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)acetamide; ((2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone; (4-(Azetidin-3-yl methoxy) isoindolin-2-yl) (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl) methanone; (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone; 1-(2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)azetidine-3-carbonitrile; (4,6-Dihydroxy-2-methoxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; (2-Ethoxy-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; (2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; (2-(Cyclopropylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone; and (2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

23. A pharmaceutical composition comprising a compound as defined in any preceding claim, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

24. A method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined in any one of claims 1-22, or a pharmaceutical composition as defined in claim 23.

25. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined in any one of claims 1-22, or a pharmaceutical composition as defined in claim 23, for use in therapy.

26. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined in any one of claims 1-22, or a pharmaceutical composition as defined in claim 23, for use in: (i) the treatment of cancer; (ii) the treatment of cancer, wherein the compound or pharmaceutical composition is administered in combination with another anticancer agent (e.g. a chemotherapeutic agent, an immune checkpoint inhibitor, an immune stimulator or DNA damage repair modulator); (ii) the treatment of a triplet repeat disorder.

Description

EXAMPLES

[0798] While specific embodiments of the invention have been described herein for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims. Reference is made to the accompanying figures, in which:

[0799] FIG. 1 shows the reaction scheme for 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carbonitrile (Example 82);

[0800] FIG. 2 shows the reaction scheme for 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-5-carboxamide (Example 83);

[0801] FIG. 3 shows the reaction scheme for 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-4-carboxamide (Example 85);

[0802] FIG. 4 shows the reaction scheme for ((2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone (Example 88);

[0803] FIG. 5 shows the reaction scheme for (4-(Azetidin-3-yl methoxy) isoindolin-2-yl) (2-(benzyloxy) -4,6-dihydroxy-3-methylphenyl)methanone (Example 89);

[0804] FIG. 6 shows the reaction scheme for (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone (Example 90);

[0805] FIG. 7 shows the reaction scheme for (4,6-Dihydroxy-2-methoxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Example 92);

[0806] FIG. 8 shows the reaction scheme for (2-Ethoxy-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Example 93);

[0807] FIG. 9 shows the reaction scheme for (2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Example 94);

[0808] FIG. 10 shows the reaction scheme for (2-(Cyclopropylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Example 95);

[0809] FIG. 11 shows the reaction scheme for (2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino) methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Example 96);

[0810] FIG. 12 shows the reaction scheme for 4-formyl-5-(prop-2-yn-1-yloxy)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 37);

[0811] FIG. 13 shows the reaction scheme for N,N-Dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)methanamine (Intermediate 42);

[0812] FIG. 14 shows the reaction scheme for N,N-Dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)methanamine (Intermediate 43);

[0813] FIG. 15 shows the reaction scheme for 1-(isoindolin-5-yl)-N,N-dimethylmethanamine hydrochloride (Intermediate 46); and

[0814] FIG. 16 shows the reaction scheme for 4-((4-Methylpiperazin-1-yl)methyl) isoindoline hydrochloride (Intermediate 48).

ABBREVIATIONS

[0815] Boc for tert-butyloxycarbonyl
DAST for diethylaminosulfur trifluoride
DBU for 1,8-diazabicyclo(5.4.0)undec-7-ene
DCC for dicyclohexylcarbodiimide
DCE for 1,1-dichloroethane
DCM for dichloromethane
DEA for diethanolamine
DEAD for diethyl azodicarboxylate
DIAD for diisopropyl azodicarboxylate
DIBAL for Diisobutylaluminium hydride
DIPEA for N,N-diisopropylethylamine, Hünig's base

DMA for N,N-dimethylacetamide

[0816] DMAP for 4-(dimethylamino) pyridine

DMF for N,N-dimethylformamide

[0817] DMSO for dimethylsulfoxide.
EDC for 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
EtOAc for ethyl acetate
h for hours
HATU for N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide
HBTU for (1H-benzotriazol-1-yloxy)(dimethylamino)-N,N-dimethylmethaniminium hexafluorophosphate

HOBT for N-hydroxybenzotriazole

HPLC for High Pressure Liquid Chromatography.

[0818] LAH for lithium aluminium hydride
IPA for isopropyl alcohol

LCMS for Liquid Chromatography-Mass Spectrometry

[0819] LDA for Lithium diisopropylamide
LiHMDS for Lithium bis(trimethylsilyl)amide
mCPBA for meta-chloroperoxybenzoic acid

MI for Molecular Ion

[0820] Min for minutes
MgSO.sub.4 anhydrous magnesium sulfate
MW for microwave

NBS for N-bromosuccinamide

NCS for N-chlorosuccinamide

[0821] NFOBS for N-fluoro-o-benzenedisulfonimide

NFSI for N-fluorobenzenesulfonimide

NHS for N-hydroxysuccinimide

NIS for N-iodosuccinamide

NMM for N-methylmorpholine

[0822] NMP for 1-methyl-2-pyrrolidinone

NMR for Nuclear Magnetic Resonance.

[0823] PdCl.sub.2(PPh.sub.3).sub.2 for Bis(triphenylphosphine)palladium chloride
Pd(dppf).sub.2Cl.sub.2 for [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
Pd(dppf).sub.2Cl.sub.2.Math.DCM for [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM
(Pd(dba).sub.2) for bis(dibenzylideneacetone)palladium
Rbf for round bottomed flask

RT for Retention Time.

[0824] SCX-2 for a silica-based sorbent with a chemically bonded propylsulfonic acid functional group
SFC for supercritical fluid chromatography
TBAF for tetra-n-butylammonium fluoride
TBDMS for tert-butyldimethylsilyl
TFAA for trifluoroacetic anhydride
TFA for trifluoroacetic acid
THF for tetrahydrofuran
TPP for tripotassium phosphate
Ts for toluenesulfonyl
XPhos-Pd-G1 for 2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride
XPhos-Pd-G2 for Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

Analytical Methods

[0825] Commercially available starting materials, reagents and dry solvents were used as supplied. Flash column chromatography or glass column chromatography was performed using Merck silica gel 230-400 mesh size. Flash chromatography was also performed on combi-flash RF Teledyne Isco machine. Preparative TLC was performed on Merck plates.

Liquid Chromatography-Mass Spectrometry Methods

Method-A

[0826] Waters Acquity UPLC with binary solvent manager, PDA detector and Acquity QDA performance mass detector, column: X-Bridge BEH C18, 50×2.1 mm, 2.5 micron, column temperature: 35° C., auto sampler temperature: 5° C., mobile phase A: 0.1% (v/v) formic acid in water (pH=2.70), Mobile Phase B: 0.1% formic acid (v/v) in water: acetonitrile (10:90), mobile phase gradient details: t=0 min (97% A, 3% B) flow: 0.8 mL/min; t=0.75 min (97% A, 3% B) flow: 0.8 mL/min; gradient to t=2.7 min (2% A, 98% B) flow: 0.8 mL/min; gradient to t=3 min (0% A, 100% B) flow: 1 mL/min; t=3.5 min (0% A, 100% B) flow: 1 mL/min; gradient to t=3.51 min (97% A, 3% B) flow: 0.8 mL/min; end of run at t=4 min (97% A, 3% B), Flow rate: 0.8 mL/min, analysis time 4 min. Mass detector parameter: ionization mode was cycled through positive and negative modes with cone voltage 10 V and 30 V and 0.8 kV capillary voltage, temperature of source and probe were 120° C. and 600° C. respectively.

Method-B

[0827] Waters Acquity with PDA detector and SQ Detector, column: X-Bridge BEH C18, 50×2.1 mm, 2.5 micron, column temperature: 35° C., auto sampler temperature: 5° C., mobile phase A: 5 mM ammonium bicarbonate in water (pH=7.35), mobile phase B: acetonitrile; mobile phase gradient details: t=0 min (97% A, 3% B) flow: 0.5 mL/min; t=0.2 min (97% A, 3% B) flow: 0.5 mL/min; gradient to t=2.7 min (2% A, 98% B) flow: 0.5 mL/min; gradient to t=3 min (0% A, 100% B) flow: 0.7 mL/min; t=3.5 min (0% A, 100% B) flow: 0.7 mL/min; gradient to t=3.51 min (97% A, 3% B) flow: 0.5 mL/min; end of run at t=4 min (97% A, 3% B), flow rate: 0.5 mL/min, analysis time 4 min. Mass detection parameter: ionization mode was cycled through positive and negative mode with cone voltage 10 V and 30 V and 3.25 kV capillary voltage, temperature of source and probe were 120° C. and 400° C. respectively.

Method-C

[0828] Waters Acquity UPLC with binary solvent manager, PDA detector and Acquity QDA performance mass detector, column: YMC Tri-art C18, 50×2 mm, 1.9 micron, column temperature: 35° C., auto sampler temperature: 5° C., mobile phase A: 0.1% (v/v) formic acid in water (pH=2.70), Mobile Phase B: 0.1% formic acid (v/v) in water: acetonitrile (10:90), mobile phase gradient details: t=0 min (97% A, 3% B) flow: 0.8 mL/min; t=0.75 min (97% A, 3% B) flow: 0.8 mL/min; gradient to t=2.7 min (2% A, 98% B) flow: 0.8 mL/min; gradient to t=3 min (0% A, 100% B) flow: 1 mL/min; t=3.5 min (0% A, 100% B) flow: 1 mL/min; gradient to t=3.51 min (97% A, 3% B) flow: 0.8 mL/min; end of run at t=4 min (97% A, 3% B), Flow rate: 0.8 mL/min, analysis time 4 min. Mass detector parameter: ionization mode was cycled through positive and negative modes with cone voltage 10 V and 30 V and 0.8 kV capillary voltage, temperature of source and probe were 120° C. and 600° C. respectively.

Method-D

[0829] Waters Acquity UPLC with quaternary solvent manager, SQ detector and Acquity QDA mass detector, column: X-Bridge BEH C18, 50*2.1 mm, 2.5 micron, column temperature: 35° C., auto sampler temperature: 5° C., mobile phase A: 0.1% (v/v) Formic acid in water (pH=2.70), mobile phase B: 0.1% (v/v) formic acid in water: acetonitrile (10:90), mobile phase gradient details: t=0 min (97% A, 3% B) flow: 0.8 mL/min; t=0.75 min (97% A, 3% B) flow: 0.8 mL/min; gradient to t=2.7 min (2% A, 98% B) flow: 0.8 mL/min; gradient to t=3 min (0% A, 100% B) flow: 1 mL/min; t=3.5 min (0% A, 100% B) flow: 1 mL/min; gradient to t=3.51 min (97% A, 3% B) flow: 0.8 mL/min; end of run at t=4 min (97% A, 3% B), Flow rate: 0.8 mL/min, analysis time 4 min. Mass detector parameter: ESI capillary probe, ionization mode cycled through positive and negative modes with cone voltage 10 V and 30V and 0.8 kV capillary voltage, temperature of source and probe were 120° C. and 400° C. respectively.

Method-E

[0830] Waters Acquity UPLC with binary solvent manager, PDA detector and Acquity QDA performance mass detector, column: Welch Xtimate C18, 50*2.1 mm, 1.8 micron, column temperature: 35° C., auto sampler temperature: 5° C., mobile phase A: 0.1% (v/v) formic acid in water (pH=2.70), Mobile Phase B: 0.1% formic acid (v/v) in water: acetonitrile (10:90), mobile phase gradient details: t=0 min (97% A, 3% B) flow: 0.8 mL/min; t=0.75 min (97% A, 3% B) flow: 0.8 mL/min; gradient to t=2.7 min (2% A, 98% B) flow: 0.8 mL/min; gradient to t=3 min (0% A, 100% B) flow: 1 mL/min; t=3.5 min (0% A, 100% B) flow: 1 mL/min; gradient to t=3.51 min (97% A, 3% B) flow: 0.8 mL/min; end of run at t=4 min (97% A, 3% B), Flow rate: 0.8 mL/min, analysis time 4 min. Mass detector parameter: ionization mode was cycled through positive and negative modes with cone voltage 10 V and 30 V and 0.8 kV capillary voltage, temperature of source and probe were 120° C. and 600° C. respectively.

NMR

[0831] .sup.1H Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker Avance-400 instrument operating at 400 MHz using the stated solvent at room temperature unless otherwise stated. Samples were prepared as solutions in a suitable deuterated solvent and referenced to the appropriate internal non-deuterated solvent peak or tetramethylsilane. Chemical shifts were recorded in ppm (δ) downfield of tetramethylsilane. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad.

Purification Methods

Preparative Purification by Reverse Phase HPLC

Preparatory H PLC Method-A

[0832] Shimadzu Prep-20-AD with binary pump with UV/Visible wave-length detector, Column: C18, 250×20 mm, 5 micron, column temperature: room temp., mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitrile: Methanol:2-Propanol(65:25:10); mobile phase gradient details: t=0 min (55% A, 45% B); t=17 min (55% A, 45% B); gradient to t=17.01 min (2% A, 98% B); t=19 min (2% A, 98% B); gradient to t=19.01 min (55% A, 45% B); end of run at t=21 min (55% A, 45% B), flow rate: 27 mL/min, analysis time 21 min.

Preparatory HPLC Method-B

[0833] Shimadzu Prep-20-AD with binary pump with UV/Visible wave-length detector, Column: C18, 250*20 mm, 5 micron, column temperature: room temp., mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitrile; mobile phase gradient details: t=0 min (72% A, 28% B); t=19 min (72% A, 28% B); gradient to t=19.01 min (2% A, 98% B); t=21 min (2% A, 98% B); gradient to t=21.01 min (72% A, 28% B); end of run at t=24 min (72% A, 28% B), flow rate: 20 mL/min, analysis time 24 min.

Preparatory HPLC Method-C

[0834] Shimadzu LC20AP purification system with UV detector. Column: YMC-Actus Triart prep 250*20 mm, 5 micron, room temperature. Compounds eluted with: Mobile phase A: 0.1% Formic acid in Milli Q water, mobile phase B: Acetonitrile; mobile phase gradient details: t=0 min (65% A, 35% B); gradient to t=17 min (35% A, 65% B); t=17.01 min (2% A, 98% B); gradient to t=19 min (2% A, 98% B); t=19.01 min (65% A, 35% B) to t=21 min (65% A, 35% B); ); flow rate=20 ml/min; analysis time 21 min.

Chiral Prep HPLC Purification Methods

[0835] The enantiomeric separation of compounds was achieved by Chiral Prep HPLC purification methods.

[0836] Below is a list of Chiral Prep HPLC purification methods and conditions used to resolve enantiomers or to determine enantiomeric purity (ee).

TABLE-US-00001 Chiral Prep HPLC purification methods Conditions for chiral resolution or ee determination Method-A Waters binary gradient with 600-controller pump with Waters 2487-UV/Visible wave-length detector, Column: YMC-CHIRAL ART CELLULOSE-SC, 250*20 mm, 5 micron, column temperature: room temp., mobile phase A: n-Heptane, mobile phase B: 2-propanol; with isocratic flow A:B~70:30, flow rate: 17 mL/min, analysis time 55 min.

Synthesis

[0837] Several methods for the chemical synthesis of heterocyclic carboxamide compounds of the present application are described herein. These and/or other well-known methods may be modified and/or adapted in various ways to facilitate the synthesis of additional compounds within the scope of the present application and claims. Such alternative Methods and modifications should be understood as being within the spirit and scope of this application and claims. Accordingly, Methods set forth in the following descriptions, Schemes and Examples are intended for illustrative purposes and are not to be construed as limiting the scope of the disclosure.

[0838] In one approach (Scheme 1), compounds of formula [I] may be prepared by the reaction of a substituted aromatic carboxylic acid of formula [II] with oxalyl chloride or thionyl chloride in a solvent such as DCM, with an amine of general formula [III] in the presence of a tertiary amine base such as Et.sub.3N, DIPEA or NMM. The reaction is suitably conducted at RT. After reaction work up, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation (Method A). Compounds of compounds of formula [I] may also be prepared by the reaction of a substituted aromatic carboxylic acid of formula [II] with an amine of general formula [III] and a suitable coupling agent such as HBTU or HATU in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as Et.sub.3N, DIPEA or NMM. After reaction work up, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation (Method B). The bis-tosyl protected intermediate (from Method A or B) is then subject to base induced deprotection with a suitable base such as K.sub.2CO.sub.3 or KOH in a suitable protic solvent such as MeOH or EtOH. The reaction is suitably conducted at high temperature. After reaction work up, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation, to yield compounds of general the Formula [I]

##STR00059##

Example 1: [2,4-dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone

[0839] ##STR00060##

Method 1

Step-1: 5-(pyrimidin-2-ylmethoxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 40)

[0840] To a solution of 2-(pyrimidin-2-ylmethoxy)-4,6-bis(tosyloxy)benzoic acid (Intermediate 25) (0.3 g, 0.525 mmol, 1 eq) in DMF (3 mL) were added HATU (0.29 g, 0.788 mmol, 1.5 eq), DIPEA (0.135 g, 1.051 mmol, 2.0 eq) and pyrrolidine (0.041 g, 0.578 mmol, 1.0 eq) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 30 min. The resulting reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (4×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The crude material was purified by flash chromatography (product eluted with 15% MeOH in DCM) yielding 5-(pyrimidin-2-ylmethoxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 40) (0.19 g, 58% yield).

[0841] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.73-1.75 (m, 4H), 2.42 (s, 3H), 2.45 (s, 3H), 3.40-3.50 (m, 4H), 5.26 (d, J=3.2 Hz, 2H), 6.54 (d, J=1.6 Hz, 1H), 6.70 (d, J=2.0 Hz, 1H), 7.43-7.53 (m, 5H), 7.65-7.41 (m, 4H), 8.80 (d, J=4.8 Hz, 2H). LCMS (Method A): 2.204 min, MS: ES+624.20 (M+1)

Step-2: (2,4-dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl)(pyrrolidin-1-yl)methanone

[0842] To a solution of 5-(pyrimidin-2-ylmethoxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 40) (0.6 g, 0.481 mmol, 1 eq) in EtOH (0.6 mL) was added dropwise a solution of KOH (1.07 g, 19.24 mmol, 40 eq) in water (0.5 mL) at room temperature. The reaction mixture was heated at 80° C. for 2 h cooled, poured into ice-cold water (80 mL) and extracted with ethyl acetate (4×80 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The crude material was purified by flash chromatography (product eluted with 7% MeOH in DCM) yielding (2,4-dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl)(pyrrolidin-1-yl)methanone (0.045 g, 15% Yield).

[0843] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.75-1.81 (m, 4H), 3.21-3.23 (m, 2H), 3.31-3.33 (m, 2H), 5.16 (s, 2H), 5.79 (d, J=1.6 Hz, 1H), 5.92 (d, J=2.0 Hz, 1H), 7.45 (t, J=3.5 Hz, 1H), 8.82 (d, J=4.8 Hz, 2H), 9.36 (s, 1H), 9.41 (s, 1H). LCMS (Method A): 1.033 min, MS: ES+316.16 (M+1)

Example 2: (2-(cyclopentyloxy)-4,6-dihydroxyphenyl)(pyrrolidin-1-yl)methanone

[0844] ##STR00061##

Method 2

Step-1: Synthesis of 5-(cyclopentyloxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 41)

[0845] To a solution of 2-(cyclopentyloxy)-4,6-bis(tosyloxy)benzoic acid (Intermediate 20) (0.5 g, 0.91 mmol, 1 eq) in DCM (5 mL) was added dropwise oxalyl chloride (0.13 g, 1.02 mmol, 1.0 eq) at 0° C. under nitrogen atmosphere. A catalytic amount of DMF (0.5 mL) was added to the reaction mixture at 0° C., and the reaction mixture was slowly warmed to room temperature and stirred for 2 h. The resulting mixture was concentrated under reduce pressure to obtained crude acid chloride. In another Rbf, a solution of pyrrolidine in THF (0.130 g, 1.83 mmol, 2.0 eq) was treated with TEA (0.18 g, 1.78 mmol, 2.0 eq) at 0° C. Crude acid chloride in DCM (5 mL) was added dropwise to the amine solution at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture diluted with water (20 mL) and extracted in DCM (3×50 mL). The combined organic layer was washed with saturated NaHCO.sub.3 solution (2×20 mL), dried over Na.sub.2SO.sub.4 and concentrated under vacuum yielding 5-(cyclopentyloxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 41) as a brown oil (0.4 g, 72% yield). The crude material was used in the next step without purification.

[0846] .sup.1H NMR (DMSO-d6, 400 MHz): 1.37-1.44 (m, 2H), 1.53-1.55 (m, 4H), 1.65-1.80 (m, 6H), 2.43-2.45 (m, 6H), 2.50-2.51 (m, 1H), 2.83-2.94 (m, 1H), 3.24-3.40 (m, 2H), 4.60-4.70 (m, 1H), 6.57-6.60 (m, 2H), 7.48-7.54 (m, 4H), 7.73-7.77 (m, 4H). LCMS (Method A): 2.509 min, MS: ES+600.15 (M+1)

Step-2: (2-(cyclopentyloxy)-4,6-dihydroxyphenyl)(pyrrolidin-1-yl)methanone

[0847] To a solution of 5-(cyclopentyloxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 41) (0.2 g, 0.33 mmol, 1 eq) in MeOH (4 mL) was added KOH (0.74 g, 13.19 mmol, 40 eq) at room temperature. The reaction mixture was heated at 60° C. for 2 h. The resulting reaction mixture was poured into water (30 mL), acidified using saturated solution of KHSO.sub.4 and extracted with ethyl acetate (4×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The crude material was purified by flash chromatography (product eluted with 20% EtOAc in n-Hexane) yielding (2-(cyclopentyloxy)-4,6-dihydroxyphenyl)(pyrrolidin-1-yl)methanone (0.030 g, 30.9% Yield).

[0848] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.53-1.64 (m, 6H), 1.71-1.82 (m, 6H), 3.05 (t, J=6.4 Hz, 2H), 3.32-3.34 (m, 2H), 4.64-4.66 (m, 1H), 5.86-5.91 (m, 2H), 9.30-9.34 (m, 2H). LCMS (Method A): 1.434 min, MS: ES+292.06 (M+1).

[0849] The following compounds were prepared according to the Methods described above using the indicated intermediates

TABLE-US-00002 Ex. No. Name Structure Data  3 (2-benzyloxy- 4,6-dihydroxy- phenyl)- pyrrolidin-1-yl- methanone [00062] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.74-1.82 (m, 4H), 3.10-3.13 (m, 2H), 3.36-3.38 (m, 2H), 5.03 (s, 2H), 5.97 (s, 2H), 7.31-7.40 (m, 5H), 9.50 (s, 2H). LCMS (Method A): 1.515 min, MS: ES+ 314.11 (M + 1) Using Intermediate 21 and pyrrolidine according to Method 2  4 (2-benzyloxy- 4,6-dihydroxy- phenyl)- isoindolin-2-yl- methanone [00063] .sup.1H NMR (DMSO-d6, 400 MHz): δ 4.49 (s, 2H), 4.74 (s, 2H), 5.04 (s, 2H), 6.01 (s, 2H), 7.24-7.31 (m, 8H), 7.37-7.39 (m, 1H), 9.50 (s, 1H), 9.57 (s, 1H). LCMS (Method A): 1.719 min, MS: ES+ 362.17 (M + 1) Using Intermediate 21 and 2,3- dihydro-1H-isoindole according to Method 2  5 (2-benzyloxy- 4,6-dihydroxy- phenyl)-(1- piperidyl) methanone [00064] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.38-1.53 (m, 6H), 3.15-3.16 (m, 2H), 3.40-3.41 (m, 1H), 3.61-3.63 (m, 1H), 4.99 (s, 2H), 5.95 (s, 2H), 7.30-7.31 (m, 1H), 7.37-7.38 (m, 4H), 9.37 (s, 1H), 9.40 (s, 1H). LCMS (Method A): 1.632 min, MS: ES+ 328.17 (M + 1) Using Intermediate 21 and piperidine according to Method 2  6 (2-benzyloxy- 4,6-dihydroxy- phenyl)-[(3S)-3- hydroxypyrrolidin- 1-yl]methanone [00065] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.72-1.90 (m, 2H), 2.95-3.17 (m, 1H), 3.26-3.29 (m, 1H), 3.41-3.51 (m, 2H), 4.20-4.29 (m, 1H), 4.92- 4.95 (m, 1H), 5.01 (s, 2H), 5.95 (s, 2H) 7.29-7.37 (m, 5H), 9.41 (s, 2H). LCMS (Method A): 1.192 min, MS: ES+ 330.12 (M + 1) Using Intermediate 21 and (3S)-3- pyrrolidinol according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers.  7 (2-benzyloxy- 4,6-dihydroxy- phenyl)-[(3R)-3- hydroxypyrrolidin- 1-yl]methanone [00066] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.72-1.90 (m, 2H), 2.95-3.17 (m, 1H), 3.26-3.29 (m, 1H), 3.41-3.51 (m, 2H), 4.20-4.29 (m, 1H), 4.92- 4.95 (m, 1H), 5.01 (s, 2H), 5.95 (s, 2H) 7.29-7.37 (m, 5H), 9.41-9.44 (m, 2H). LCMS (Method A): 1.180 min, MS: ES+ 330.17 (M + 1) Using Intermediate 21 and (3R)-3- pyrrolidinol according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers.  8 (2-benzyloxy- 4,6-dihydroxy- phenyl)-[(3R)-3- hydroxy-1- piperidyl] methanone [00067] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.14-2.08 (m, 6H), 3.29-3.25 (m, 1H), 3.38-3.50 (m, 1H), 4.31-4.42 (m, 1H), 4.78-4.93 (m, 1H), 4.99 (d, J = 11.2 Hz, 2H), 5.93-5.96 (m, 2H) 7.29-7.38 (m, 5H), 9.39-9.42 (m, 2H). LCMS (Method A): 1.305 min, MS: ES+ 344.17 (M + 1) Using Intermediate 21 and (R)-3- hydroxypiperidine according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers.  9 (2-benzyloxy- 4,6-dihydroxy- phenyl)-[(3S)-3- hydroxy-1- piperidyl] methanone [00068] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.14-2.08 (m, 6H), 3.29-3.25 (m, 1H), 3.38-3.50 (m, 1H), 4.31-4.42 (m, 1H), 4.78-4.93 (m, 1H), 4.99 (d, J = 11.2 Hz, 2H), 5.93-5.96 (m, 2H) 7.29-7.38 (m, 5H), 9.39-9.42 (m, 2H). LCMS (Method A): 1.302 min, MS: ES+ 344.17 (M + 1) Using Intermediate 21 and (S)-3- hydroxypiperidine according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers. 10 (2-benzyloxy- 4,6-dihydroxy-3- methyl-phenyl)- pyrrolidin-1-yl- methanone [00069] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.73-1.75 (m, 4H), 1.94 (s, 3H), 3.01- 3.17 (m, 2H), 3.34-3.39 (m, 2H), 4.68-4.70 (m, 1H), 4.86-4.88 (m, 1H), 6.24 (s, 1H), 7.31-7.39 (m, 5H), 9.35 (s, 1H), 9.44 (s, 1H). LCMS (Method A): 1.638 min, MS: ES+ 328.17 (M + 1). Using Intermediate 22 and pyrrolidine according to Method 1 11 (2-benzyloxy-3- ethyl-4,6- dihydroxy- phenyl)- pyrrolidin-1-yl- methanone [00070] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.03 (t, J = 7.2 Hz, 3H), 1.73-1.75 (m, 4H), 3.13-3.16 (m, 2H), 3.34-3.40 (m, 2H), 4.68-4.70 (m, 1H), 4.90- 4.92 (m, 1H), 6.23 (s, 1H), 6.32 (s, 1H), 6.55 (s, 6H), 7.32-7.41 (m, 5H), 9.34 (s, 1H), 9.41 (s, 1H). LCMS (Method A): 1.776 min, MS: ES+ 342.17 (M + 1). Using Intermediate 23 and pyrrolidine according to Method 2 12 [2,4-dihydroxy- 6-(2- pyridylmethoxy) phenyl]- pyrrolidin-1-yl- methanone [00071] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.73-1.83 (m, 4H), 3.14 (t, J = 6.4 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 5.08 (s, 2H), 5.92 (d, J = 1.6 Hz, 1H), 5.96 (d, J = 1.6 Hz, 1H), 7.31 (dd, J = 6.8, 4.8 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.81-7.85 (m, 1H), 8.55 (d, J = 4.0 Hz, 1H), 9.44 (s, 1H), 9.47 (s, 1H). LCMS (Method A): 0.959 min, MS: ES+ 315.11 (M + 1) Using Intermediate 24 and pyrrolidine according to Method 1 13 [2,4-dihydroxy- 6-1- phenylethoxy] phenyl]-pyrrolidin- 1-yl-methanone ISOMER 1 [00072] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.42 (d, J = 7.6 Hz, 3H), 1.75-1.81 (m, 4H), 3.04-3.11 (m, 2H), 3.35- 3.40 (m, 2H), 5.28-5.33 (m, 1H), 5.77 (s, 1H), 5.87 (d, J = 1.6 Hz, 1H), 7.23-7.28 (m, 1H), 7.31-7.34 (m, 4H), 9.44 (s, 2H). LCMS (Method A): 1.660 min, MS: ES+ 328.20 (M + 1) Using Intermediate 26 and pyrrolidine according to Method 1 Separated by chiral Prep HPLC (Method A) 14 [2,4-dihydroxy- 6-1- phenylethoxy] phenyl]-pyrrolidin- 1-yl-methanone ISOMER 2 [00073] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.42 (d, J = 7.6 Hz, 3H), 1.75-1.81 (m, 4H), 3.04-3.11 (m, 2H), 3.35- 3.40 (m, 2H), 5.28-5.33 (m, 1H), 5.77 (s, 1H), 5.87 (d, J = 1.6 Hz, 1H), 7.23-7.28 (m, 1H), 7.31-7.34 (m, 4H), 9.44 (s, 2H). LCMS (Method A): 1.661 min, MS: ES+ 328.20 (M + 1) Using Intermediate 26 and pyrrolidine according to Method 1 Separated by chiral Prep HPLC (Method A) 15 [2-[(4- fluorophenyl) methoxy]-4,6- dihydroxy- phenyl]- pyrrolidin-1-yl- methanone [00074] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.72-1.81 (m, 4H), 3.09 (t, J = 6.0 Hz, 2H), 3.65 (t, J = 6.4 Hz, 2H), 5.00 (s, 2H), 5.96 (s, 2H), 7.19-7.22 (m, 2H), 7.38-7.42 (m, 2H), 9.42 (s, 2H). LCMS (Method A): 1.504 min, MS: ES+ 332.17 (M + 1) Using Intermediate 27 and pyrrolidine according to Method 2 16 [2,4-dihydroxy- 6-[(4- methoxyphenyl) methoxy]phenyl]- pyrrolidin-1-yl- methanone [00075] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.72-1.81 (m, 4H), 3.08 (t, J = 6.4 Hz, 2H), 3.34-3.36 (m, 2H), 3.74 (s, 3H), 4.92 (s, 2H), 5.94-5.96 (m, 2H), 6.92 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 9.40 (s, 2H). LCMS (Method A): 1.465 min, MS: ES+ 344.20 (M + 1) Using Intermediate 28 and pyrrolidine according to Method 2 17 [2,4-dihydroxy- 6-(m- tolylmethoxy) phenyl]-pyrrolidin- 1-yl-methanone [00076] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.74-1.82 (m, 4H), 2.30 (s, 3H), 3.09- 3.12 (t, J = 12.0 Hz, 2H), 3.36-3.39 (t, J = 12.0 Hz, 2H), 4.95 (s, 2H), 5.94- 5.95 (d, J = 3.6 Hz, 2H), 7.10-7.16 (m, 3H), 7.23-7.27 (t, J = 14.8 Hz, 1H), 9.41 (s, 1H). LCMS (Method A): 1.598 min, MS: ES.sup.+ 328.2 (M + 1) Using Intermediate 29 and pyrrolidine according to Method 2 18 (2-benzyloxy- 4,6-dihydroxy- phenyl)-(5,7- dihydropyrrolo[3,4- b]pyridin-6- yl)methanone [00077] .sup.1H NMR (DMSO-d6, 400 MHz): δ 4.44-4.52 (m, 2H), 4.70-4.78 (m, 2H), 5.04 (s, 2H), 6.02 (s, 2H), 7.23- 7.33 (m, 6H), 7.69-7.81 (m, 1H), 8.44-8.47 (dd, J = 12.4 Hz, 1H), 9.53- 9.54 (d, J = 5.2 Hz, 1H), 9.61-9.62 (d, J = 2.4 Hz, 1H). LCMS (Method A): 1.338 min, MS: ES.sup.+ 363.2 (M + 1) Using Intermediate 21 and 6,7- dihydro-5H-pyrrolo[3,4-b]pyridine according to Method 2 19 (2-benzyloxy- 4,6-dihydroxy- phenyl)-(4- methoxyisoindolin- 2-yl)methanone [00078] .sup.1H NMR (DMSO-d6, 400 MHz): δ 3.74-3.83 (m, 3H), 4.33-4.47 (m, 2H), 4.61-4.73 (m, 2H), 5.04 (s, 2H), 6.011-6.016 (d, J = 2.0 Hz, 2H), 6.83- 6.97 (m, 2H), 7.24-7.32 (m, 6H), 9.51-9.53 (d, J = 7.6 Hz, 1H), 9.58- 9.59 (d, J = 5.2 Hz, 1H). LCMS (Method A): 1.773 min, MS: ES.sup.+ 392.2 (M + 1) Using Intermediate 21 and 2,3- Dihydro-4-methoxy-1H-isoindole according to Method 1 20 [2,4-dihydroxy- 6-(pyrimidin-4- ylmethoxy)phenyl]- pyrrolidin-1- yl-methanone [00079] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.77-1.85 (m, 4H), 3.14-3.18 (t, J = 13.2 Hz, 2H), 3.42-3.44 (t, J = 6.0 Hz, 2H), 5.12 (s, 2H), 5.89-5.90 (d, J = 2.0 Hz, 2H), 6.020-6.024 (d, J = 1.6 Hz, 2H), 7.48-7.49 (d, J = 4.0 Hz, 1H), 8.83-8.85 (d, J = 5.2 Hz, 1H), 9.156-9.159 (d, J = 1.2 Hz, 2H), 9.52 (s, 1H), 9.60 (s, 1H). LCMS (Method A): 1.138 min, MS: ES.sup.+ 316.2 (M + 1) Using Intermediate 30 and pyrrolidine according to Method 1 21 (2-((1H-pyrazol- 3-yl)methoxy)- 4,6- dihydroxyphenyl) (pyrrolidin-1- yl)methanone [00080] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.71-1.79 (m, 4H), 3.05-3.08 (m, 2H), 3.08-3.31 (m, 2H), 4.94 (s, 2H), 5.94 (s, 1H), 6.03 (d, J = 1.6 Hz, 1H), 6.21 (d, J = 2.0 Hz, 1H), 7.70 (s, 1H), 9.39 (s, 1H), 9.42 (s, 1H), 12.78 (s, 1H). LCMS (Method A): 1.046 min, MS: ES+ 304.11 (M + 1) Using Intermediate 31 and pyrrolidine according to Method 1 (Boc- deprotection occurred in situ) 22 [2,4-dihydroxy- 6-(1H-triazol-4- ylmethoxy)phenyl]- pyrrolidin-1- yl-methanone [00081] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.70-1.78 (m, 4H), 3.03-3.06 (t, J = 12.8 Hz, 2H), 3.30-3.33 (t, J = 13.2 Hz, 2H), 5.08 (s, 2H), 5.95-5.96 (d, J = 2.0 Hz, 1H), 6.054-6.059 (d, J = 2.0 Hz, 2H), 7.82 (s, 1H), 9.44 (s, 2H), 14.99 (s, 1H). LCMS (Method B): 1.084 min, MS: ES.sup.+ 305.1 (M + 1) Using Intermediate 36 and pyrrolidine according to Method 1 23 (2-benzyloxy- 4,6-dihydroxy- phenyl)-(5- bromoisoindolin- 2-yl)methanone [00082] .sup.1H NMR (DMSO-d6, 400 MHz): δ 4.43-4.48 (m, 2H), 4.68-4.73 (m, 2H), 5.03 (s, 2H), 6.00 (s, 2H), 7.22- 7.53 (m, 6H), 7.45-7.61 (m, 2H), 9.51 (s, 1H), 9.59 (s, 1H). LCMS (Method A): 2.123 min, MS: ES.sup.+ 440 (M+) Using Intermediate 21 and 5-bromo- 2,3-dihydro-1H-isoindole according to Method 1 24 methyl 2-(2- benzyloxy-4,6- dihydroxy- benzoyl)isoindoline- 5-carboxylate [00083] .sup.1H NMR (DMSO-d6, 400 MHz): δ 3.83-3.86 (m, 3H), 4.54 (s, 2H), 4.79 (s, 2H), 5.03 (s, 2H), 6.01 (s, 2H), 7.22-7.29 (m, 5H), 7.39-7.53 (m, 1H), 9.86-7.98 (m, 2H), 9.516- 9.519 (d, J = 1.2 Hz, 1H), 9.59-9.60 (d, J = 2.4 Hz, 1H). LCMS (Method A): 1.699 min, MS: ES.sup.+ 420.2 (M + 1) Using Intermediate 21 and methyl isoindoline-5-carboxylate according to Method 1 25 (2-benzyloxy- 4,6-dihydroxy- phenyl)-(5- methoxyisoindolin- 2-yl)methanone [00084] .sup.1H NMR (DMSO-d6, 400 MHz): δ 3.70-3.75 (d, 3H), 4.40-4.44 (d, 2H), 4.65-4.69 (d, 2H), 5.03 (s, 2H), 6.00 (s, 2H), 6.82-6.96 (m, 2H), 7.14- 7.30 (m, 6H), 9.494-9.499 (d, J = 2.0 Hz, 1H), 9.565-9.576 (d, J = 4.4 Hz, 1H). LCMS (Method D): 1.980 min, MS: ES.sup.+ 392.5 (M + 1) Using Intermediate 21 and 5- methoxyisoindoline according to Method 1 26 (2-benzyloxy- 4,6-dihydroxy- phenyl)-(5,6- dimethoxyisoindolin- 2-yl)methanone [00085] .sup.1H NMR (DMSO-d6, 400 MHz): δ 3.68 (s, 3H), 3.75 (s, 3H), 4.39 (s, 2H), 4.65 (s, 2H), 5.03 (s, 2H), 6.004- 6.007 (d, J = 1.2 Hz, 2H), 6.86 (s, 1H), 6.98 (s, 1H), 7.23-7.31 (m, 5H), 9.49 (s, 1H), 9.56 (s, 1H). LCMS (Method D): 1.836 min, MS: ES.sup.+ 422.5 (M + 1) Using Intermediate 21 and 5,6- dimethoxyisoindoline according to Method 1 27 [2,4-dihydroxy- 6-(1- phenylethoxy) phenyl]-isoindolin- 2-yl-methanone [00086] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.375-1.391 (d, J = 6.4 Hz, 3H), 4.48 (s, 2H), 4.75-4.78 (d, J = 3.2 Hz, 2H), 5.33-5.35 (d, J = 6.4 Hz, 2H), 5.85 (s, 1H), 5.941-5.945 (d, J = 1.6 Hz, 2H), 7.20-7.40 (m, 9H), 9.389 (s, 1H), 9.525 (s, 1H). LCMS (Method A): 1.925 min, MS: ES.sup.+ 398.2 (M + 23) Using Intermediate 26 and isoindoline according to Method 1 28 [2,4-dihydroxy- 6-(1- phenylethoxy) phenyl]-(5- methoxyisoindolin- 2-yl)methanone [00087] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.374-1.388 (d, J = 5.6 Hz, 3H), 3.71- 3.76 (d, 3H), 4.42 (s, 2H), 4.46-4.77 (m, 2H), 5.33-5.34 (d, J = 5.6 Hz, 1H), 5.82 (s, 1H), 5.94 (s, 1H), 6.83- 7.29 (m, 8H), 9.380 (s, 1H), 9.507 (s, 1H). LCMS (Method D): 2.040 min, MS: ES.sup.+ 406.4 (M + 1) Using Intermediate 26 and 5- methoxyisoindoline according to Method 1 29 [2,4-dihydroxy- 6-(1- phenylethoxy) phenyl]-(5,6- dimethoxyisoindolin- 2-yl)methanone [00088] .sup.1H NMR (DMSO-d6, 400 MHz): δ 3.696 (s, 3H), 3.762 (s, 3H), 4.40 (s, 2H), 4.69 (s, 2H), 5.33-5.34 (d, J = 6.4 Hz, 1H), 5.844 (s, 1H), 5.937 (S, 1H), 6.86 (s, 1H), 7.00 (s, 1H), 7.21- 729 (m, 5H), 9.36 (s, 1H), 9.49 (s, 1H). LCMS (Method A): 1.738 min, MS: ES.sup.+ 436.1 (M + 1) Using Intermediate 26 and 5,6- dimethoxyisoindoline according to Method 1 30 (2-benzyloxy- 4,6-dihydroxy-3- methyl-phenyl)- (5,7- dihydropyrrolo[3,4- b]pyridin-6- yl)methanone [00089] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.96 (s, 3H), 4.34-4.60 (m, 2H), 4.67- 4.78 (m, 3H), 4.90-4.92 (d, J = 10.4 Hz, 1H), 6.30 (s, 1H), 7.21-7.35 (m, 6H), 7.66-7.81 (m, 1H), 8.41- 8.46 (dd, J = 14.0 Hz, 1H), 9.59 (s, 2H). LCMS (Method A): 1.492 min, MS: ES.sup.+ 477.3 (M + 1) Using Intermediate 22 and 6,7- dihydro-5H-pyrrolo[3,4-b]pyridine according to Method 1 31 5,7- dihydropyrrolo[3,4- b]pyridin-6-yl- [4,6-dihydroxy- 3-methyl-2-(m- tolylmethoxy) phenyl]methanone [00090] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.98 (s, 3H), 2.16 (s, 3H), 4.35-4.81 (m, 5H), 4.86-4.89 (d, J = 10.4 Hz, 1H), 6.30 (s, 1H), 7.018-7.035 (d, J = 6.8 Hz, 1H), 7.12-7.18 (m, 3H), 7.27-7.33 (m, 1H), 8.42-8.47 (dd, J = 18.4 Hz, 1H), 9.52-9.54 (d, J = 7.6 Hz, 1H), 9.58-9.59 (d, J = 4.8 Hz, 1H). LCMS (Method A): 1.584 min, MS: ES.sup.+ 391.1 (M + 1) Using Intermediate 33 and 6,7- dihydro-5H-pyrrolo[3,4-b]pyridine according to Method 1 32 5,7- dihydropyrrolo[3,4- b]pyridin-6-yl- [2,4-dihydroxy- 6-(m- tolylmethoxy) phenyl]methanone [00091] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.07-2.10 (m, 3H), 4.43-4.51 (d, 2H), 4.70-4.78 (d, 2H), 4.99 (s, 2H), 6.02 (s, 2H), 7.00-7.14 (m, 4H), 7.28- 7.34 (m, 1H), 7.69-7.83 (m, 1H), 8.43-8.48 (dd, J = 12.8 Hz, 1H), 9.55 (s, 1H), 9.62 (s, , 1H). LCMS (Method A): 1.454 min, MS: ES.sup.+ 377.2 (M + 1) Using Intermediate 29 and 6,7- dihydro-5H-pyrrolo[3,4-b]pyridine according to Method 1 33 5,7- dihydropyrrolo[3,4- b]pyridin-6-yl- [4,6-dihydroxy- 3-methyl-2-(2- pyridylmethoxy) phenyl]methanone [00092] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.97 (s, 3H), 4.40-4.69 (m, 4H), 4.80- 5.03 (m, 2H), 6.32 (s, 2H), 7.22- 7.33 (m, 2H), 7.46-7.49 (dd, , J = 7.6 Hz, 1H), 7.68-7.80 (m, 2H), 8.41- 8.46 (m, 2H), 9.58-9.63 (m, 2H). LCMS (Method A): 1.029 min, MS: ES.sup.+ 378.1 (M + 1) Using Intermediate 34 and 6,7- dihydro-5H-pyrrolo[3,4-b]pyridine according to Method 1 34 [4,6-dihydroxy- 3-methyl-2-(2- pyridylmethoxy) phenyl]- isoindolin-2-yl- methanone [00093] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.96 (s, 3H), 4.46-4.75 (m, 4H), 4.79- 5.03 (m, 2H), 6.31 (s, 2H), 7.23- 7.30 (m, 4H), 7.34-7.36 (d, J = 6.8 Hz, 1H), 7.46-7.48 (d, J = 7.6 Hz, 1H), 7.72-7.76 (m, 1H), 8.43-8.44 (d, J = 4.8 Hz, 1H), 9.54 (s, 1H), 9.58 (s, 1H). LCMS (Method A): 1.337 min, MS: ES.sup.+ 377.2 (M + 1) Using Intermediate 34 and isoindoline according to Method 1 35 5,7- dihydropyrrolo[3,4- b]pyridin-6-yl- [2,4-dihydroxy- 6-(2- pyridylmethoxy) phenyl]methanone [00094] .sup.1H NMR (DMSO-d6, 400 MHz): δ 4.52-4.59 (d, 2H), 4.73-4.81 (d, 2H), 5.10 (s, 2H), 6.03-6.05 (m, 2H), 7.22-7.28 (m, 2H), 7.35-7.37 (d, J = 8.0 Hz, 1H), 7.66-7.69 (t, J = 13.6 Hz, 2H), 8.45-8.46 (d, J = 4.4 Hz, 1H), 9.34 (s, 1H), 9.38 (s, 1H). LCMS (Method A): 0.926 min, MS: ES.sup.+ 364.1 (M + 1) Using Intermediate 24 and 6,7- dihydro-5H-pyrrolo[3,4-b]pyridine according to Method 1 36 (2-benzyloxy- 4,6-dihydroxy-3- methyl-phenyl)- (3,4-dihydro-1H- isoquinolin-2- yl)methanone [00095] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.92-1.95 (d, 3H), 2.70-2.83 (m, 2H), 3.38-4.01 (m, 2H), 4.40-4.69 (m, 2H), 4.76-4.85 (m, 2H), 6.26- 6.28 (m, 2H), 7.01-7.30 (m, 9H), 9.41 (s, 1H), 9.52 (s, 1H). LCMS (Method A): 1.977 min, MS: ES.sup.+ 390.2 (M + 1) Using Intermediate 22 and 1,2,3,4- tetrahydroisoquinoline according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers. 37 [2,4-dihydroxy- 6-(2- pyridylmethoxy) phenyl]- isoindolin-2-yl- methanone [00096] .sup.1H NMR (DMSO-d6, 400 MHz): δ 4.54 (s, 2H), 2.76 (s, 2H), 5.10 (s, 2H), 5.96-5.96 (d, J = 2.0 Hz, 1H), 6.014-6.018 (d, J = 1.6 Hz, 1H), 7.24- 7.39 (m, 6H), 7.67-7.72 (m, 1H), 8.48-8.49 (d, J = 4.0 Hz, 1H), 9.51 (s, 1H), 9.62 (s, 1H). LCMS (Method A): 1.278 min, MS: ES.sup.+ 363.1 (M + 1) Using Intermediate 24 and Isoindoline according to Method 1 38 (2-benzyloxy- 4,6-dihydroxy-3- methyl-phenyl)- (4- bromoisoindolin- 2-yl)methanone [00097] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.97-1.99 (d, 3H), 4.27-4.75 (m, 4H), 4.84-4.95 (m, 2H), 6.30-6.31 (d, J = 2.4 Hz, 1H), 7.25-7.41 (m, 7H), 7.47-7.52 (m, 1H), 9.52-9.60 (m, 2H). LCMS (Method D): 2.379 min, MS: ES.sup.+ 354.4 (M + 1) Using Intermediate 22 and 4- bromoisoindoline according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers. 39 (2-benzyloxy- 4,6-dihydroxy-3- methyl-phenyl)- [4- (hydroxymethyl) isoindolin-2- yl]methanone [00098] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.97-1.98 (d, 3H), 4.33-4.34 (d, 1H), 4.42-4.64 (m, 3H), 4.72-4.74 (d, 3H), 4.91-4.93 (d, 1H), 5.07- 5.21 (m, 1H), 6.30 (S, 1H), 7.13-7.37 (m, 8H), 9.49-9.55 (m, 2H). LCMS (Method A): 1.571 min, MS: ES.sup.+ 406.1 (M + 1) Using Intermediate 22 and 2,3- dihydro-1H-isoindole-4-methanol according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers. 40 (2-benzyloxy- 4,6-dihydroxy-3- methyl-phenyl)- [5-[(4- methylpiperazin- 1-yl)methyl] isoindolin-2- yl]methanone [00099] .sup.1H NMR (DMSO-d6, 400 MHz): 1.23 (s, 3H), 2.12 (d, J = 8.0 Hz, 3H), 2.20- 2.30 (m, 4H), 2.30-2.40 (m, 4H), 3.36-3.40 (m, 2H), 4.40-44 (m, 1H), 4.54-4.57 (m, 1H), 4.71-4.73 (m, 3H), 4.89-4.92 (m, 1H), 6.31 (s, 1H), 7.14-7.31 (m, 8H), 9.53-9.60 (m, 2H). LCMS (Method A): 1.250 min, MS: ES.sup.+ 488.3 (M + 1) Using Intermediate 22 and 2,3- dihydro-5-[(4-methyl-1- piperazinyl)methyl]-1H-isoindole according to Method 1 41 (2-benzyloxy- 4,6-dihydroxy-3- methyl-phenyl)- (6-methoxy-3,4- dihydro-1H- isoquinolin-2- yl)methanone [00100] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.92-1.95 (d, 3H), 2.68-2.73 (m, 2H), 3.70-3.71 (d, 3H), 3.96-4.85 (m, 6H), 6.26-6.28 (m, 1H), 6.68- 6.71 (m, 1H), 6.79-6.95 (m, 1H), 7.16-7.29 (m, 5H), 9.38-9.40 (d, 1H), 9.52 (s, 1H). LCMS (Method A): 1.888 min, MS: ES.sup.+ 420.2 (M + 1) Using Intermediate 22 and 6- methoxy-1,2,3,4- tetrahydroisoquinoline according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers. 42 (2-benzyloxy- 4,6-dihydroxy-3- methyl-phenyl)- (3,4-dihydro-1H- 2,7- naphthyridin-2- yl)methanone [00101] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.93-1.96 (d, 3H), 2.74-2.79 (m, 2H), 3.44-3.45 (m, 1H), 3.68-4.98 (m, 1H), 4.46 (s, 1H), 4.58-4.89 (m, 3H), 6.27-6.29 (m, 1H), 7.11-7.31 (m, 6H), 7.26-7.49 (m, 2H), 9.40- 9.46 (m, 1H), 9.56 (s, 1H). LCMS (Method A): 1.157 min, MS: ES.sup.+ 391.1 (M + 1) Using Intermediate 22 and 1,2,3,4- tetrahydro-2,7-naphthyridine according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers. 43 (2-benzyloxy- 4,6-dihydroxy-3- methyl-phenyl)- (3,4-dihydro-1H- 2,6- naphthyridin-2- yl)methanone [00102] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.92-1.96 (d, 3H), 2.74-2.75 (m, 2H), 3.41-3.47 (m, 1H), 3.73-4.00 (m, 1H), 4.43-4.84 (m, 4H), 6.26- 6.29 (m, 1H), 7.10-7.31 (m, 6H), 8.27-8.37 (m, 2H), 9.40-9.45 (d, 1H), 9.55 (s,1H). LCMS (Method A): 1.193 min, MS: ES.sup.+ 391.2 (M + 1) Using Intermediate 22 and 1,2,3,4- tetrahydro-2,6-naphthyridine according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers. 44 3,4-dihydro-1H- isoquinolin-2-yl- [4,6-dihydroxy- 3-methyl-2-(m- tolylmethoxy) phenyl]methanone [00103] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.93-1.96 (d, 3H), 2.12-2.16 (m, 3H), 2.75-2.84 (m, 2H), 3.42-3.45 (m, 1H), 3.62-4.04 (m, 1H), 4.41- 4.85 (m, 4H), 6.27-6.28 (m, 1H), 7.01-7.27 (m, 8H), 9.39-9.41 (d, 1H), 9.52 (s,1H). LCMS (Method A): 2.150 min, MS: ES.sup.+ 404.3 (M + 1) Using Intermediate 33 and 1,2,3,4- tetrahydroisoquinoline according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers. 45 3,4-dihydro-1H- isoquinolin-2-yl- [4,6-dihydroxy- 3-methyl-2-(2- pyridylmethoxy) phenyl]methanone [00104] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.93-1.96 (d, 3H), 2.67-2.75 (m, 2H), 3.43-3.48 (m, 1H), 3.62-3.92 (m, 1H), 4.43 (s, 1H), 4.71-4.95 (m, 3H), 6.29 (s, 1H), 7.04-7.31 (m, 6H), 7.51-7.74 (m, 1H), 8.45 (s, 1H), 9.40- 9.44 (d, 1H), 9.55 (s, 1H). LCMS (Method A): 1.362 min, MS: ES.sup.+ 391.2 (M + 1). Using Intermediate 34 and 1,2,3,4- tetrahydroisoquinoline according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers. 46 [4,6-dihydroxy- 3-methyl-2-(2- pyridylmethoxy) phenyl]-(7- methoxy-3,4- dihydro-1H- isoquinolin-2- yl)methanone [00105] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.93-1.95 (d, 3H), 2.67 (s, 2H), 3.42- 3.44 (m, 1H), 3.55-3.91 (m, 4H), 4.41 (s, 1H), 4.68-4.95 (m, 3H), 6.29 (s, 1H), 6.64-6.82 (m, 2H), 7.01- 7.03 (d, J = 8.0 Hz, 1H), 7.24-7.32 (m, 2H), 7.54-7.77 (m, 1H), 8.46 (s, 1H), 9.41-9.44 (d, 1H), 9.56 (s, 1H). LCMS (Method A): 1.381 min, MS: ES.sup.+ 421.2 (M + 1) Using Intermediate 34 and 7- methoxy-1,2,3,4- tetrahydroisoquinoline according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers. 47 [4,6-dihydroxy- 3-methyl-2-(2- pyridylmethoxy) phenyl]-(6- methoxy-3,4- dihydro-1H- isoquinolin-2- yl)methanone [00106] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.92-1.96 (d, 3H), 2.68-2.72 (m, 2H), 3.37-3.44 (m, 1H), 3.58-3.91 (m, 4H), 4.35 (s, 1H), 4.63-4.95 (m, 3H), 6.27-6.29 (m, 1H), 6.69 (s, 1H), 6.78-6.95 (m, 1H), 7.12-7.31 (m, 2H), 7.54-7.73 (m, 1H), 8.46 (s, 1H), 9.39-9.44 (m, 1H), 9.55 (s, 1H). LCMS (Method A): 1.329 min, MS: ES.sup.+ 421.1 (M + 1) Using Intermediate 34 and 6- methoxy-1,2,3,4- tetrahydroisoquinoline according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers. 48 3,4-dihydro-1H- isoquinolin-2-yl- [2-[(4- fluorophenyl) methoxy]-4,6- dihydroxy-3- methyl- phenyl]methanone [00107] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.92-1.95 (d, 3H), 2.74-2.75 (m, 2H), 3.38-3.48 (m, 1H), 3.63-4.00 (m, 1H), 4.40-4.82 (m, 4H), 6.27- 6.28 (d, 1H), 6.96-7.02 (m, 2H), 7.09- 7.19 (m, 3H), 7.21-7.27 (m, 3H), 9.40-9.42 (d, 1H), 9.53 (s,1H). LCMS (Method A): 2.008 min, MS: ES.sup.+ 408.2 (M + 1) Using Intermediate 32 and 1,2,3,4- tetrahydroisoquinoline according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers. 49 (2-(benzyloxy)- 4,6- dihydroxyphenyl) (5-((4- methylpiperazin- 1-yl)methyl) isoindolin-2- yl)methanone [00108] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.23 (s, 3H), 2.70-2.77 (m, 4H), 3.29- 3.59 (m, 4H), 4.50 (s, 2H), 4.75 (s, 2H), 5.04 (s, 2H), 6.03 (d, J = 11.6 Hz, 2H), 7.23-7.32 (m, 6H), 7.45-7.50 (m, 3H), 9.56-9.65 (m, 2H), 11.67 (brs, 2H). LCMS (Method E): 1.101 min, MS: ES+ 474.2 (M + 1) Using Intermediate 21 and 2,3- dihydro-5-[(4-methyl-1- piperazinyl)methyl]-1H-isoindole according to Method 1 50 (4- aminoisoindolin- 2-yl)(2- (benzyloxy)-4,6- dihydroxy-3- methylphenyl) methanone [00109] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.97 (s, 3H), 4.30-4.63 (m, 3H), 4.67- 4.72 (m, 2H), 4.90-4.93 (m, 1H), 5.58 (brs, 2H), 6.31 (d, J = 4.4 Hz, 1H), 6.43-6.60 (m, 2H), 6.96-7.00 (m, 1H), 7.30-7.36 (m, 5H), 9.48- 9.53 (m, 2H). LCMS (Method E): 1.750 min, MS: ES+ 391.3 (M + 1). Using Intermediate 22 and isoindolin- 4-amine according to Method 1 Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers 51 (2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(4- vinylisoindolin- 2-yl)methanone [00110] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.90 (d, J = 6.8 Hz, 3H), 4.44-4.66 (m, 2H), 4.72-4.91 (m, 4H), 5.27- 5.41 (dd, J = 10.8, 11.6 Hz, 1H), ), 5.64-5.80 (dd, J = 17.6, 17.6 Hz, 1H), 6.31 (s, 1H), 6.52-6.59 (m, 1H), 6.75-6.82 (m, 1H), 7.24-7.36 (m, 6H), 7.39-7.52 (m, 2H), 9.51-9.58 (s, 1H). LCMS (Method A): 2.127 min, MS: ES+ 402.2 (M + 1) Using Intermediate 22 and 4- vinylisoindoline according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers 52 (2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(7- methoxy-3,4- dihydroisoquinolin- 2(1H)- yl)methanone [00111] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.94 (d, J = 9.2 Hz, 3H), 2.68 (d, J = 6.4 Hz, 2H), 3.65 (s, 3H), 4.40 (s, 1H), 4.57-4.69 (m, 1H), 4.74-4.86 (m, 1H), 6.27 (s, 1H), 6.63-6.76 (m, 2H), 6.68 (s, 1H), 7.00-7.05 (m, 1H), 7.22- 7.31 (m, 5H), 9.40 (s, 1H), 9.51 (d, J = 4.8 Hz, 1H). LCMS (Method A): 1.951 min, MS: ES+ 420.22 (M + 1) Using Intermediate 22 and 7- methoxy-1,2,3,4- tetrahydroisoquinoline according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers 53 (2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(5,8- dihydro-1,7- naphthyridin- 7(6H)- yl)methanone [00112] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.94 (d, J = 17.6 Hz, 3H), 2.76 (s, 2H), 3.46-3.50 (m, 2H), 4.36-4.43 (m, 1H), 4.57-4.59 (m, 1H), 4.68-4.71 (m, 1H), 4.77-4.84 (m, 1H), 6.29 (d, J = 8.4 Hz, 1H), 7.16-7.31 (m, 6H), 7.51-7.56 (m, 1H), 8.30-8.43 (m, 1H), 9.45 (d, J = 11.6 Hz, 1H), 9.57 (d, J = 3.6 Hz, 1H). LCMS (Method A): 1.366 min, MS: ES+ 391.22 (M + 1) Using Intermediate 22 and 5,6,7,8- tetrahydro-1,7-naphthyridine according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers 54 (2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(7,8- dihydro-1,6- naphthyridin- 6(5H)- yl)methanone [00113] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.95 (d, J = 17.6 Hz, 3H), 2.83-2.84 (m, 2H), 3.48-3.55 (m, 2H), 4.46- 4.50 (m, 1H), 4.57-4.60 (m, 1H), 4.68-4.70 (m, 1H), 4.77-4.85 (m, 1H), 6.28 (d, J = 12.4 Hz, 1H), 7.20- 7.29 (m, 5H), 7.48-7.50 (m, 1H), 7.69-7.71 (m, 1H), 8.35-8.36 (m, 1H), 9.46 (s, 1H), 9.55 (s, 1H). LCMS (Method E): 1.098 min, MS: ES+ 391.27 (M + 1) Using Intermediate 22 and 5,6,7,8- tetrahydro-1,6-naphthyridine according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers 55 (2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(7,8- dihydropyrido[4,3- d]pyrimidin- 6(5H)- yl)methanone [00114] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.95 (d, J = 18.4 Hz, 3H), 2.78-2.88 (m, 2H), 3.48-3.55 (m, 2H), 4.68- 4.92 (m, 4H), 6.28 (d, J = 13.6 Hz, 1H), 7.16-7.31 (m, 5H), 8.72 (s, 1H), 8.92 (d, J = 10.4 Hz, 1H), 9.50 (s, 1H), 9.59 (s, 1H). LCMS (Method A): 1.378 min, MS: ES+ 392.12 (M + 1) Using Intermediate 22 and 5,6,7,8- tetrahydropyrido[4,3-d]pyrimidine according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers 56 (2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(5,8- dihydropyrido[3,4- d]pyrimidin- 7(6H)- yl)methanone [00115] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.95 (d, J = 20 Hz, 3H), 2.67-2.83 (m, 2H), 3.43-3.49 (m, 2H), 4.33- 4.46 (m, 1H), 4.60-4.86 (m, 3H), 6.28 (d, J = 14.8 Hz, 1H), 7.14-7.24 (m, 3H), 7.30-7.32 (m, 2H), 8.54 (d, J = 6.8 Hz, 1H), 8.90-9.00 (m, 1H), 9.44-9.50 (m, 1H), 9.60 (d, J = 6.8 Hz, 1H). LCMS (Method E): 1.414 min, MS: ES+ 392.20 (M + 1) Using Intermediate 22 and 5,6,7,8- tetrahydropyrido[3,4-d]pyrimidine according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers 57 (3,4- dihydroisoquinolin- 2(1H)-yl)(4,6- dihydroxy-3- methyl-2-((1- methyl-1H- pyrazol-3- yl)methoxy)phenyl) methanone [00116] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.92 (d, J = 10 Hz, 3H), 2.68-2.82 (m, 2H), 3.75 (d, J = 11.6 Hz, 5H), 4.39- 4.41 (m, 1H), 4.52-4.62 (m, 1H), 4.68-4.84 (m, 1H), 6.06-6.11 (m, 1H), 6.25 (d, J = 6.8 Hz, 1H), 7.00- 7.02 (m, 3H), 7.10-7.26 (m, 2H), 7.52-7.58 (m, 1H), 9.37 (d, J = 11.6 Hz, 1H), 9.50 (s, 1H). LCMS (Method A): 1.534 min, MS: ES+ 394.20 (M + 1) Using Intermediate 35 and 1,2,3,4- tetrahydroisoquinoline according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers 58 (2-(benzyloxy)- 4,6- dihydroxyphenyl) (3,4- dihydroisoquinolin- 2(1H)- yl)methanone [00117] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.67-2.75 (m, 2H), 3.44-3.56 (m, 2H), 4.74-5.00 (m, 4H), 5.95-5.99 (m, 2H), 7.03-7.23 (m, 9H), 9.48- 9.50 (m, 2H). LCMS (Method A): 1.900 min, MS: ES+ 376.20 (M + 1) Using Intermediate 21 and 1,2,3,4- tetrahydroisoquinoline according to Method 1. Note: Duplication of peaks observed in the .sup.1H NMR-material is a mixture of rotamers 59 (2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl) (isoindolin-2- yl)methanone [00118] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.97 (s, 3H), 4.43-4.58 (m, 2H), 4.71- 4.76 (m, 3H), 4.90-4.92 (m, 1H), 6.30 (s, 1H), 7.24-7.38 (m, 9H), 9.51 (s, 1H), 9.56 (s, 1H). LCMS (Method E): 1.911 min, MS: ES+ 376.22 (M + 1) Using Intermediate 22 and isoindoline according to Method 1. 60 (2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(7- ((dimethylamino) methyl)-3,4- dihydroisoquinolin- 2(1H)- yl)methanone [00119] .sup.1H NMR (DMSO-d6, 400 MHz, D.sub.2O exchange); Material is a mixture of rotamers: δ ppm 1.87 and 1.93 (singlets, 3H), 2.26 (3, 3H), 2.38 (s, 3H), 2.68-2.79 (m, 3H), 3.35-3.44 (m, 2H), 3.44-3.54 (m, 1H), 3.62 (bs, 1H), 3.75 (bs, 1H), 3.98-4.02 (m, 1H), 4.33-4.38 (m, 1H), 4.51-4.80 (m, 3H), 6.21 (s, br, 1H), 7.10-7.25 (m, 7H), 7.49-7.51 (m, 1H). LCMS (Method A): 1.220 min, MS ES+ 447.2 (M + 1). Prepared using Intermediate 22 and Intermediate 42 according to Method 1. 61 (2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(6- ((dimethylamino) methyl)-3,4- dihydroisoquinolin- 2(1H)- yl)methanone [00120] High temperature .sup.1H NMR (DMSO- d6, 400 MHz, 335.1 K); Material is a mixture of rotamers: δ 1.97 (s, 3H), 2.30 (s, 6H), 2.77-2.79 (m, 2H), 3.45- 3.46 (m, 2H), 3.49-3.51 (m, 2H), 3.53-3.58 (m, 2H), 4.74 (s, br, 2H), 6.28 (s, 1H), 7.09-7.25 (m, 8H), 9.15 (s, 1H, D.sub.2O exchangeable), 9.28 (s, 1H, D.sub.2O exchangeable). LCMS (Method A): 1.151 min, MS: ES+ 447.3 (M + 1). Prepared using Intermediate 22 and Intermediate 43 according to Method 1. 62 (S)-(2- (Benzyloxy)-4,6- dihydroxy-3- methylphenyl)(3- (hydroxymethyl)- 3,4- dihydroisoquinolin- 2(1H)- yl)methanone [00121] High temperature .sup.1H NMR (DMSO- d6, 400 MHz, 335 K); Material is a mixture of rotamers: δ 1.97 and 1.98 (singlets, 3H), 2.84-2.97 (m, 2H), 3.25-3.26 (m, 1H), 3.47-3.53 (m, 1H), 3.90-3.92 (m, 1H), 4.17-4.29 (m, 1H), 4.40-4.41 (m, 1H), 4.54- 5.03 (m, 3H), 5.22-5.27 (m, 1H), 6.23-6.30 (m, 1H), 7.01-7.33 (m, 6H), 7.38-7.43 (m, 2H), 9.03-9.19 (m, 1H, D.sub.2O exchangeable), 9.27 (m, 1H, D.sub.2O exchangeable). LCMS (Method A): 1.829 min, MS: ES+ 420.3 (M + 1). Prepared using Intermediate 22 and (S)-(1,2,3,4-tetrahydroisoquinolin-3- yl)methanol according to Method 1. 63 (2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(1- (hydroxymethyl) isoindolin-2- yl)methanone [00122] High temperature .sup.1H NMR (DMSO- d6, 400 MHz, 335 K); Material is a mixture of rotamers: δ 1.99 (2 singlets, 3H), 3.53-3.59 (m, 1H), 3.96-3.97 (m, 1H), 4.55-4.99 (m, 5H), 5.26-5.28 (m, 1H), 6.30 (s, br, 1H), 7.08 (s, 1H), 7.26-7.45 (m, 8H), 9.24 (s, 1H, D.sub.2O exchangeable), 9.32 (s, 1H, D.sub.2O exchangeable). LCMS (Method A): 1.800 min, MS: ES+ 406.27 (M + 1). Prepared using Intermediate 22 and (isoindolin-1-ylmethanol hydrochloride according to Method 1. 64 (R)-(2- (benzyloxy)-4,6- dihydroxy-3- methylphenyl)(3- (hydroxymethyl)-3,4- dihydroisoquinolin- 2(1H)-yl)methanone [00123] High temperature .sup.1H NMR (DMSO- d6, 400 MHz, 335 K); Material is a mixture of rotamers: δ 1.95-1.97 (2 singlets, 3H), 2.83-2.88 (m, 1H), 2.92-2.02 (m, 1H), 3.25-3.31 (m, 1H), 3.45-3.46 (m, 1H), 4.17-5.26 (m, 5H), 6.23-6.29 (m, 1H), 7.01- 7.21 (m, 7H), 7.29-7.43 (m, 2H), 9.01-9.26 (m, 2H, D.sub.2O exchangeable). LCMS (Method A): 1.805 min, MS ES+: 420.17 (M + 1). Prepared using Intermediate 22 and (R)-(1,2,3,4-tetrahydroisoquinolin-3- yl)methanol according to Method 1. 65 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(1- (hydroxymethyl)-3,4- dihydroisoquinolin- 2(1H)-yl)methanone [00124] High temperature .sup.1H NMR (DMSO- d6, 400 MHz, 340 K); material is a mixture of rotamers: δ 1.88-1.96 (m, 3H), 2.68-2.72 (m, 1H), 2.94-3.00 (m, 1H), 3.54-3.56 (m, 1H), 3.70- 3.71 (m, 1H), 3.82-3.83 (m, 1H), 4.56-4.57 (m, 1H), 4.65-4.66 (m, 1H), 4.81-4.84 (m, 1H), 5.06-5.09 (m, 1H), 5.54-5.61 (m, 1H), 6.27 and 6.30 (2 singlets, 1H), 6.93-7.17 (m, 6H), 7.31-7.40 (m, 2H), 7.48 (m, 1H), 9.10 (bs, 2H, D.sub.2O exchangeable). LCMS (Method A): 1.715 min, MS: ES+ 420.20 (M + 1). Prepared using Intermediate 22 and Intermediate 44 according to Method 1. 66 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(4- (hydroxymethyl)-3,4- dihydroisoquinolin- 2(1H)-yl)methanone [00125] High temperature .sup.1H NMR (DMSO- d6, 400 MHz, 340 K); material is a mixture of rotamers: δ 1.95 and 1.98 (singlets, 3H), 2.90-2.92 (m, 1H), 3.47-3.60 (m, 4H), 4.35-4.36 (m, 2H), 4.76-4.78 (m, 2H), 6.26 and 6.29 (singlets, 1H), 7.17-7.30 (m, 9H), 9.09-9.23 (m, 2H, D.sub.2O exchangeable). LCMS (Method A): 1.809 min, MS ES+: 420.27 (M + 1). Prepared using Intermediate 22 and Intermediate 45 according to Method 1. 67 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(2,3- dihydro-4H- benzo[b][1,4] oxazin-4- yl)methanone [00126] High temperature .sup.1H NMR (DMSO- d6, 400 MHz); material is a mixture of rotamers: δ 1.97 (s, 3H), 3.64 (m, 1H), 3.88 (m, br, 1H), 4.18-4.20 (m, 2H), 4.86 (m, 2H), 6.25 (s, 1H), 6.75- 6.87 (m, 2H), 6.99 (m, 2H), 7.30- 7.38 (m, 5H), 9.37 (s, 2H, D.sub.2O exchangeable). LCMS (Method A): 2.060 min, MS ES+ 392.22 (M + 1). Prepared using Intermediate 22 and 3,4-dihydro-2H-benzo[b][1,4]oxazine according to Method 2. 68 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(5- ((dimethylamino) methyl)isoindolin- 2-yl)methanone [00127] High temperature .sup.1H NMR (DMSO- d6, 400 MHz); material is a mixture of rotamers: δ 1.99 (s, 3H), 2.13 (s, 3H), 2.16 (s, 3H), 3.36-3.39 (m, 2H), 4.50- 4.51 (m, 2H), 4.73-4.74 (m, 2H), 4.90-4.91 (m, 2H), 6.31 (s, 1H), 7.17- 7.36 (m, 8H), 8.45 (s, br, 1H), 9.32 (s, br, 2H, D.sub.2O exchangeable). LCMS (Method A): 1.160 min, MS: ES+ 433.27 (M + 1). Using Intermediate 22 and Intermediate 46 according to Method 1. 69 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(5- (morpholinomethyl) isoindolin-2- yl)methanone [00128] .sup.1H NMR (DMSO-d6, 400 MHz); material is a mixture of rotamers: δ 1.97 (s, 3H), 2.33 (bs, 4H), 3.43-3.46 (m, 2H), 3.54-3.56 (m, 4H), 4.41- 4.43 (m, 2H), 4.72-4.92 (m, 4H), 6.31 (s, 1H), 7.17-7.36 (m, 8H), 9.51 (s, 1H, D.sub.2O exchangeable). 9.55 (s, 1H, D.sub.2O exchangeable). LCMS (Method A): 1.286 min, MS ES+: 475.17 (M + 1). Prepared using Intermediate 22 and Intermediate 47 according to Method 1. 70 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl) (indolin-1- yl)methanone [00129] High temperature .sup.1H NMR (DMSO- d6, 400 MHz, 350 K); material is a mixture of rotamers: δ 1.98 (s, 3H), 3.01-3.03 (m, 1H), 3.46-3.54 (m, 1H), 3.90-3.91 (m, 2H), 4.83-5.00 (m, 2H), 6.33 (s, 1H), 6.90-6.99 (m, 4H), 7.20-7.33 (m, 5H), 9.38 (s, br, 2H, D.sub.2O exchangeable). LCMS (Method A): 2.003 min, MS ES+ 376.22 (M + 1). Prepared using Intermediate 22 and indoline according to Method 1. 71 (2-(Benzyloxy)-4,6- dihydroxyphenyl) (indolin-1- yl)methanone [00130] High temperature .sup.1H NMR (DMSO- d6, 400 MHz, 330 K); material is a mixture of rotamers: δ 2.99-3.05 (m, 2H), 3.80-3.82 (m, br, 2H), 5.00- 5.03 (m, br, 2H), 6.04 (s, 2H), 7.16 7.27 (m, 8H), 8.15-8.17 (m, br 1H), 9.38-9.44 (m, 2H, D.sub.2O exchangeable). LCMS (Method A): 1.921 min, MS ES+ 362.2 (M + 1). Prepared using Intermediate 21 and indoline according to Method 1. 72 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl) (3,4- dihydroquinolin- 1(2H)- yl)methanone [00131] High temperature .sup.1H NMR (DMSO- d6, 400 MHz, 335 K); material is a mixture of rotamers: δ 1.84-1.90 (m, 2H), 1.94 (s, 3H), 2.65-2.67 (m, 2H), 3.53-3.69 (m, 2H), 4.84-4.85 (m, 2H), 6.20 (s, 1H), 6.95-6.97 (m, 2H), 7.09-7.10 (m, 1H), 7.30-7.39 (m, 6H), 9.90-9.24 (m, 2H, D.sub.2O exchangeable). LCMS (Method A): 2.222 min, MS ES+ 390.22 (M + 1). Prepared using Intermediate 22 and 1,2,3,4-tetrahydroquinoline according to Method 1. 73 (2-(Benzyloxy)- 4,6- dihydroxyphenyl) (3,4- dihydroquinolin- 1(2H)- yl)methanone [00132] High temperature .sup.1H NMR (DMSO- d6, 400 MHz, 335 K); material is a mixture of rotamers: δ 1.80-1.85 (m, 2H), 2.63-2.67 (m, 1H), 3.46-3.53 (m, 2H), 3.75-3.76 (m, 1H), 4.77- 4.95 (m, 2H), 5.87 (s, 1H) 5.94 (s, 1H), 6.90-6.99 (m, 2H), 7.07-7.09 (m, 1H), 7.25-7.34 (m, 6H), 9.25- 9.32 (m, 2H, D.sub.2O exchangeable). LCMS (Method A): 1.976 min, MS ES+ 376.30 (M + 1). Prepared using Intermediate 21 and 1,2,3,4-tetrahydroquinoline according to Method 1. 74 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(1,3- dihydro-2H- pyrrolo[3,4- c]pyridin-2- yl)methanone [00133] .sup.1H NMR (DMSO-d6, 400 MHz); material is a mixture of rotamers: δ 1.97 (s, 3H), 4.48-4.59 (m, 2H), 4.72- 4.93 (m, 4H), 6.31 (s, 1H), 7.24- 7.35 (m, 4H), 7.43-7.44 (m, 1H), 8.44-8.48 (m, 2H), 8.61 (s, 1H), 9.58- 9.61 (m, 2H, D.sub.2O exchangeable). LCMS (Method A): 1.103 min, MS ES+ 377.3 (M + 1). Prepared using Intermediate 22 and 2,3-dihydro-1H-pyrrolo[3,4- c]pyridine.2HCl according to Method 1. 75 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(4- ((4- methylpiperazin-1- yl)methyl)isoindolin- 2-yl)methanone [00134] High temperature .sup.1H NMR (DMSO- d6, 400 MHz, 340 K); material is a mixture of rotamers: δ 2.00 (s, 3H), 2.10-2.40 (m, 12H), 4.41-4.63 (m, 2H), 4.74-4.93 (m, 4H), 6.32 (s, 1H), 7.17-7.34 (m, 8H), 9.17 (bs, 2H, D.sub.2O exchangeable). LCMS (Method A): 1.467 min, MS ES+: 488.22 (M + 1). Prepared using Intermediate 22 and Intermediate 48 according to Method 1. 76 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(4- (morpholinomethyl) isoindolin-2- yl)methanone [00135] .sup.1H NMR (DMSO-d6, 400 MHz); material is a mixture of rotamers: δ 1.97 and 1.98 (singlets, 3H), 2.19 (s, 2H), 2.35 (s, 2H), 3.34 (s, 1H), 3.40- 3.49 (m, 3H), 3.57 (s, br, 2H), 4.44- 4.45 (m, 1H), 4.54-4.56 (m, 1H), 4.67-4.73 (m, 2H), 4.79-4.80 (m, 1H), 4.90-4.93 (m, 1H), 6.30 and 6.31 (singlets, 1H), 7.13-7.21 (m, 2H), 7.26-7.27 (m, 4H), 7.32-7.36 (m, 2H), 9.48-9.50 (m, 1H, D.sub.2O exchangeable), 9.54 (s, 1H, D.sub.2O exchangeable). LCMS (Method A): 1.326 min, MS ES+ 475.2 (M + 1). Prepared using Intermediate 22 and Intermediate 49 according to Method 1. 77 2-(2- (Benzyloxy)-4,6- dihydroxy-3- methylbenzoyl)- N,N-dimethyl- 1,2,3,4- tetrahydroisoquinoline- 7-carboxamide [00136] High temperature .sup.1H NMR (DMSO- d6, 400 MHz, 330 K); material is a mixture of rotamers: δ 1.96 (s, 3H), 2.97 (s, br, 6H), 3.50-3.52 (m, 2H), 3.71-4.00 (m, 2H), 4.74-4.88 (m, 4H), 6.28 (s, 1H), 7.17-7.24 (m, 8H), 9.20 (s, 1H, D.sub.2O exchangeable), 9.32 (s, 1H, D.sub.2O exchangeable). LCMS (Method A): 1.744 min, MS ES+ 461.2 (M + 1). Prepared using Intermediate 22 and N, N-dimethyl-1, 2,3,4- tetrahydroisoquinoline-7- carboxamide (Intermediate 42a) according to Method 1. 78 2-(2- (benzyloxy)-4,6- dihydroxy-3- methylbenzoyl)- N,N-dimethyl- 1,2,3,4- tetrahydroisoquinoline- 6-carboxamide [00137] High temperature .sup.1H NMR (DMSO- d6, 400 MHz, 335 K); material is a mixture of rotamers: δ 1.97 (s, 3H), 2.78-2.81 (m, 2H), 2.93-2.94 (s, br, 6H), 3.67-3.69 (m, 1H), 3.96-3.97 (m, 1H), 4.45-4.47 (m, 1H), 4.75- 4.76 (m, 3H), 6.28 (s, 1H), 7.15-7.25 (m, 8H), 9.17 (s, 1H, D.sub.2O exchangeable), 9.29 (s, 1H, D.sub.2O exchangeable). LCMS (Method A): 1.648 min, MS ES+ 461.27 (M + 1). Prepared using Intermediate 22 and N, N-dimethyl-1,2,3,4- tetrahydroisoquinoline-6- carboxamide (Intermediate 43a) according to Method 1. 79 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(4- ((tetrahydrofuran-3- yl)amino)isoindolin- 2-yl)methanone [00138] .sup.1H NMR (DMSO-d6, 400 MHz); material is a mixture of rotamers: δ 1.75-1.76 (m, 1H), 1.98 (s, 3H), 2.07- 2.33 (m, 1H), 3.50-3.55 (m, 2H), 3.60-3.69 (m, 2H), 4.32-4.35 (m, 2H), 4.59-4.63 (m, 1H), 4.67-4.74 (m, 2H), 4.90-4.92 (m, 1H), 5.33- 5.48 (m, 1H), 6.30 and 6.31 (singlets, 1H), 6.41 (m, 1H), 6.60-6.61 (m, 1H), 7.03-7.11 (m, 1H), 7.27-7.36 (m, 5H), 9.46-9.56 (m, 2H, D.sub.2O exchangeable). LCMS (Method A): 1.943 min, MS ES+ 461.2 (M + 1). Prepared using Intermediate 22 and Intermediate 50 according to Method 1. 80 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(4- (oxetan-3- ylamino)isoindolin- 2-yl)methanone [00139] .sup.1H NMR (DMSO-d6, 400 MHz); material is a mixture of rotamers: δ 1.98 and 1.99 (singlets, 3H), 4.35- 4.53 (m, 5H), 4.55-4.60 (m, 1H), 4.68-4.77 (m, 2H), 4.83-4.86 (m, 2H), 5.93-6.18 (m, 1H), 6.31 and 6.32 (singlets, 1H), 6.50-6.64 (m, 1H), 7.00-7.08 (m, 1H), 7.28-7.38 (m, 5H), 9.48-9.54 (m, 2H, D.sub.2O exchangeable). LCMS (Method A): 1.853 min, MS ES+ 447.20 (M + 1). Prepared using Intermediate 22 with Intermediate 51 according to Method 1. 81 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(4-(3- hydroxypiperidin- 1-yl)isoindolin- 2-yl)methanone [00140] .sup.1H NMR (DMSO-d6, 400 MHz); material is a mixture of rotamers: δ 1.27-1.40 (m, 1H), 1.57-1.60 (m, 2H), 1.82 (m, 1H), 1.96 and 1.99 (singlets, 3H), 2.92 (m, 1H), 3.25- 3.28 (m, 1H), 3.64 (m, br, 1H), 4.45- 4.52 (m, 3H), 4.65-4.75 (m, 3H), 4.86-4.93 (m, 2H), 6.30 (m, 1H), 6.83-7.01 (m, 2H), 7.19-7.36 (m, 6H), 9.19-9.23 (m, 1H, D.sub.2O exchangeable), 9.30 (s, 1H, D.sub.2O exchangeable). LCMS (Method A): 1.905 min, MS ES+ 475.2 (M + 1). Prepared using Intermediate 22 and Intermediate 52 according to Method 1.

Example 82: 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carbonitrile (Reaction Scheme Shown in FIG. 1)

4-Bromoisoindoline hydrochloride

[0850] To a stirred solution of tert-butyl 4-bromo-isoindoline-2-carboxylate (0.5 g, 1.67 mmol, 1.0 eq.) in 0CM at 000 (5 mL) was added dropwise 4N HCl in dioxane (5 mL) and the reaction stirred at room temperature for 2 h. Reaction completion was monitored by TLC (9:1; 0CM: methanol). The resulting reaction mixture was concentrated under reduced pressure and the crude material (0.48 g) was purified by trituration using n-pentane (3×25 mL) to give the title compound (0.47 g, 2.00 mmol, Yield: 100%).

[0851] .sup.1H NMR (DMSO-d6, D.sub.2O-exchange 400 MHz): δ 4.48 (s, 2H), 4.62 (s, 2H), 7.34 (t, J=7.6, 15.6 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 10.06 (s, 2H). LCMS (Method A): 0.766 min, MS: ES+198.03 (M+1).

5-(benzyloxy)-4-(4-bromoisoindoline-2-carbonyl)-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate)

[0852] Intermediate 22 (0.5 g, 0.86 mmol, 1.0 eq.) in DMF (5 mL) at 0° C. under nitrogen atmosphere was treated with HATU (0.48 g, 1.28 mmol, 1.5 eq.) and DIPEA (0.22 g, 1.71 mmol, 2.0 eq.) and stirred for 15 min. 4-Bromoisoindoline hydrochloride (0.17 g, 0.86 mmol, 1.0 eq.) was added and the resulting reaction mixture stirred at 0° C. for 1 h. Reaction completion was monitored by TLC (ethyl acetate: hexane 1:1). The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (4×50 mL). The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The obtained crude material (0.6 g) was purified by flash chromatography (product was eluted in 2% methanol in DCM) yielding the title compound (0.45 g, 0.591 mmol, Yield: 69%).

[0853] LCMS (Method A): 2.860 min, MS: ES+764 (M+1).

((2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-bromoisoindolin-2-yl)methanone

[0854] To a stirred solution 5-(benzyloxy)-4-(4-bromoisoindoline-2-carbonyl)-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (0.1 g, 0.13 mmol, 1.0 eq.) in EtOH: water (2 mL, 1:1) was added aqueous KOH (0.29 g, 0.52 mmol, 40 eq. in minimum water) at room temperature. The resulting reaction mixture was heated to 60° C. and stirred for 2 h. Reaction completion was monitored on TLC (DCM: Methanol 9:1). The resulting reaction mixture was allowed to cool to room temperature, diluted with water (10 mL), neutralized with diluted HCl and extracted with ethyl acetate (4×20 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (product eluted by 6% methanol in DCM) to give the title compound (0.030 g, 0.066 mmol, Yield: 50%).

[0855] .sup.1H NMR (DMSO-d6, 400 MHz): 1.98 (2 singlets, 3H), 4.27-4.57 (m, 2H), 4.63-4.75 (m, 2H), 4.84-4.95 (m, 2H), 6.30 (d, J=2.4 Hz, 1H), 7.22-7.41 (m, 7H), 7.47-7.52 (m, 1H), 9.52-9.60 (m, 2H). LCMS (Method A): 2.379 min, MS: ES+456.4 (M+1).

2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carbonitrile

[0856] (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-bromoisoindolin-2-yl)methanone (0.2 g, 0.44 mmol, 1.0 eq) in DMF (2 mL) at room temperature was treated with zinc cyanide (0.027 g, 0.23 mmol, 0.54 eq), zinc powder (0.005 g, 0.088 mmol, 0.2 eq) and BINAP (0.002 g, 0.044 mmol, 0.1 eq). The reaction mixture was degassed (N.sub.2 gas) for 10-15 mins. Pd(OAc).sub.2 (0.002 mg, 0.044 mmol, 0.1 eq) was added and the resulting reaction mixture heated to 100° C. and stirred for 1 h under microwave irradiation. The resulting reaction was allowed to cool to room temperature, poured into water (100 mL) and extracted with ethyl acetate (3×110 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography (product eluted in 35% EtOAc in hexane) to give the title compound (0.05 g, 0.12 mmol. Yield: 28.38%,).

[0857] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.99 (d, J=8.4 Hz, 3H), 4.48-4.52 (m, 1H), 4.62-4.93 (m, 5H), 6.31 (2 singlets, 1H), 7.18-7.28 (m, 5H), 7.45-7.61 (m, 1H), 7.73-7.79 (m, 2H), 9.57-9.65 (m, 2H). LCMS (Method A): 1.765 min, MS ES+401.2 (M+1).

Example 83: 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-5-carboxamide (Reaction scheme shown in FIG. 2)

Methyl 2-(2-(benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindoline-5-carboxylate

[0858] A stirred solution of Intermediate 22 (1.2 g, 2.06 mmol, 1.0 eq) in DMF (12 mL) at 0° C. under a nitrogen atmosphere was treated with HATU (1.17 g, 3.09 mmol, 1.5 eq.) and DIPEA (0.53 g, 4.12 mmol, 2.0 eq.) and stirred for 15 min. Methyl isoindoline-5-carboxylate hydrochloride (CAS:127168-93-8) (0.40 g, 0.22 mmol, 1.1 eq.) was added and the reaction mixture stirred for 1 h at 0° C. The reaction mixture was diluted with ethyl acetate (120 mL) and washed with cold brine solution (3×100 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (product eluted by 0.8% methanol in DCM) to give the title compound (0.95 g, 1.28 mmol, Yield: 62%).

[0859] .sup.1H NMR, compound is a mixture of rotamers. (DMSO-d6, 400 MHz): δ 1.87 (s, 3H), 2.13 (s, br, 3H), 2.46 (s, br, 3H), 3.75-3.87 (singlets, 3H), 4.40-4.79 (m, 4H), 6.88 (s, 1H), 7.19-7.32 (m, 8H), 7.51-7.56 (m, 3H), 7.67-7.80 (m, 5H), 7.86-7.93 (m, 1H). LCMS (Method A): 2.969 min, 254 nm, MS: ES+742.2 (M+1); 3.014 min, 210 nm, MS: ES+742.2 (M+1).

2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl) isoindoline-5-carboxylic acid (Intermediate 58)

[0860] To a stirred solution of methyl 2-(2-(benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindoline-5-carboxylate (0.95 g, 1.28 mmol, 1.0 eq.) in EtOH: Water (1: 1) (9.5 mL) at room temperature was added an aqueous solution of NaOH (0.51 g, 12.82 mmol, 10 eq. in 0.5 mL in water). The resulting reaction mixture was heated to 90° C. and stirred for 2 h. The reaction mixture was allowed to cool to room temperature, poured into water (125 mL) and neutralized with diluted HCl and extracted with ethyl acetate (4×100 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude material was triturated using n-pentane (3×30 mL) and dried using high vacuum to give the title compound (0.45 g, 1.07 mmol, Yield: 84%) which was used in the next step without purification.

[0861] LCMS (Method A): 1.555 min, MS: ES+420.20 (M+1).

2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-5-carboxamide

[0862] To a stirred solution of 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-5-carboxylic acid (0.2 g, 0.47 mmol, 1.0 eq.) and (CH.sub.3).sub.2NH (2M in THF) (0.52 g, 0.52 mmol, 1.1 eq.) in THF (2 mL, 10 v) at 0° C. were added T.sub.3P (50% in EtOAc) (0.22 g, 0.71 mmol, 1.5 eq.) and the reaction mixture stirred for 15 mins. TEA (0.096 g, 0.95 mmol, 2.0 eq.) was added and the reaction mixture stirred at 0° C. for 1 h. The resulting reaction mixture was poured into water (30 mL) and extracted by ethyl acetate (4×30 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by prep. TLC using 10% methanol in DCM yielding the title compound (0.03 g, 0.06 mmol, Yield: 14%).

[0863] .sup.1H NMR (DMSO-d6, 400 MHz), compound is a mixture of rotamers: δ 1.97 (s, 3H), 2.87 (d, J=14.4 Hz, 3H), 2.95 (m, 3H), 4.43-4.47 (m, 1H), 4.56-4.59 (m, 1H), 4.71-4.81 (m, 3H), 4.91 (d, J=10.8 Hz, 1H), 6.30 (s, 1H), 7.22-7.43 (m, 8H), 9.54 (d, J=16.4 Hz, 2H). LCMS (Method A): 1.563 min, MS: ES+447.1 (M+1).

Example 84: 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N-methylisoindoline-5-carboxamide

[0864] ##STR00141##

2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N-methylisoindoline-5-carboxamide

[0865] A stirred solution of 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl) isoindoline-5-carboxylic acid (0.1 g, 0.23 mmol, 1.0 eq.) (Intermediate 58) and MeNH.sub.2.Math.HCl (0.017 g, 0.26 mmol, 1.1 eq.) in THF (1 mL) at 0° C. under nitrogen atmosphere was treated with T.sub.3P (0.11 g, 0.35 mmol, 1.5 eq.) and stirred for 15 min. TEA (0.048 g, 0.47 mmol, 2.0 eq.) was added to the resulting reaction mixture at 0° C. and stirred for 1 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material (0.11 g) was purified by normal phase flash chromatography (silica gel: product eluted in 5.2% methanol in DCM) yielding the title compound (0.017 g, 0.039 mmol, Yield: 16%).

[0866] .sup.1H NMR (DMSO-d6, 400 MHz), compound is a mixture of rotamers: δ ppm 1.99 (s, 3H), 2.76-2.79 (m, 3H), 3.18 (m, 1H) 4.47-4.63 (m, 2H), 4.73-4.84 (m, 2H), 4.93 (d, J=10.4 Hz, 2H), 6.32 (s, 1H), 7.26-7.40 (m, 5H), 7.68-7.76 (m, 1H), 7.81-7.97 (m, 1H), 8.93-8.46 (m, 1H), 9.53-9.58 (m, 2H). LCMS (Method A): 1.515 min, MS: ES+433.2 (M+1).

Example 85: 2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-4-carboxamide (Reaction scheme shown in FIG. 3)

2-(t-Butyl) 4-methyl isoindoline-2,4-dicarboxylate

[0867] A stirred solution of t-butyl 4-bromoisoindoline-2-carboxylate (2.0 g, 6.73 mmol, 1.0 eq) (CAS: 1035235-27-8) in MeOH: DMF (10:1) (22 mL) in an autoclave at room temperature was treated with PdCl.sub.2(dppf) (0.98 g, 1.28 mmol, 1.34 eq), DPPF (0.37 g, 0.673 mmol, 0.1 eq) and TEA (2.0 g, 2.01 mmol, 3.0 eq). 22 kg/cm.sup.2 of CO (gas) was applied to reaction mixture which was heated to 110° C. and stirred for 24 h. The reaction mixture was allowed to cool to room temperature and filtered through a celite bed; water (60 mL) was added to filtrate which was extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography (product eluted in 5% ethyl acetate in hexane) yielding the title compound (1.5 g, 5.40 mmol. Yield: 80.6%).

[0868] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.46 (s, 9H), 3.86 (s, 3H), 4.62 (d, J=10.4 Hz, 2H), 4.82 (d, J=10.0 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.61 (t, br, 1H), 7.87 (d, J=7.2 Hz, 1H). LCMS (Method A): 2.172 min, MS: ES+222.2 (M−56).

Methyl isoindoline-4-carboxylate hydrochloride

[0869] A stirred solution of 2-(t-butyl) 4-methyl isoindoline-2,4-dicarboxylate (1.5 g, 5.41 mmol, 1.0 eq.) in DCM (15 mL) at room temperature was treated with 4M HCl in dioxane (7.5 mL) at 0° C. The reaction mixture was stirred for 1 h and then evaporated under reduced pressure and the resultant solid triturated using n-pentane (15 mL) to give the title compound (0.95 g, 5.36 mmol, Yield: 100%).

[0870] .sup.1H NMR (DMSO-d6, 400 MHz): δ 3.89 (s, br, 3H), 4.55 (s, br, 2H), 4.75 (s, br, 2H), 7.55 (t, J=7.6 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 10.0 (s, 2H). LCMS (Method A): 0.638 min, MS: ES+178.2 (M+1).

2-(2-(Benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindoline-4-carboxylate

[0871] Carried out on 4 parallel batches at 0.5 g scale. A stirred solution of Intermediate 22 (0.5 g, 0.858 mmol, 1.0 eq) in DMF (2 mL) at 0° C. was treated with HATU (0.489 g, 1.28 mmol, 1.5 eq) and DIPEA (0.553 g, 4.29 mmol, 5.0 eq) and stirred for 10 min. Methyl isoindoline-4-carboxylate hydrochloride (0.201 g, 0.944 mmol, 1.1 eq.) dissolved in DMF (1 mL) was added dropwise to reaction mixture at 0-5° C. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured onto ice-cold water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was dried through Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography (eluting product with 3% MeOH in DCM) yielding the title compound (2.0 g, 2.69 mmol Yield: 78.7%,) which was progressed to the next step without purification.

[0872] LCMS (Method A): 2.828 min, MS: ES+742.22.

2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carboxylic acid (Intermediate 59)

[0873] To a stirred solution of methyl 2-(2-(benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindoline-4-carboxylate (1.0 g, 1.34 mmol, 1.0 eq.) in EtOH: Water (1:1) (10 mL) at room temperature was added NaOH (2.15 g, 53.92 mmol, 40 eq.). The reaction mixture was heated to 70° C. and stirred for 16 h. The reaction was cooled to 0-5° C. and acidified using saturated solution of KHSO.sub.4 (pH 1-2). The aqueous layer was extracted with ethyl acetate (3×30 mL) and the combined organic layer dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude material was triturated using n-pentane (5 mL) and diethyl ether (5 mL) to give the title compound as a brown oil (0.5 g, 1.19 mmol. Yield: 88.5%).

[0874] .sup.1H NMR (DMSO-d6, 400 MHz) compound is a mixture of rotamers: δ 1.98 (s, br, 3H), 4.11-4.13 (m, 2H), 4.46-4.72 (m, 2H), 4.85-5.01 (m, 2H), 6.31 (s, 1H), 7.23-7.96 (m, 8H), 9.51-9.59 (m, 2H), 13.02 (s, br, 1H). LCMS (Method A): 1.728 min, MS: ES+420.17 (M+1).

2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-4-carboxamide

[0875] A stirred solution of 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carboxylic acid (0.250 g, 0.596 mmol, 1.0 eq) (Intermediate 59) in DMF (3 mL) at 0° C. was treated with T.sub.3P (50% in EtOAc) (0.568 mL, 0.894 mmol, 1.5 eq), TEA (0.300 g, 2.98 mmol, 5.0 eq) and stirred for 10 mins. Dimethylamine hydrochloride (0.058 g, 0.715 mmol, 1.2 eq) was added to the reaction mixture at 0-5° C. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured with ice-cold water (20 ml) and extracted with ethyl acetate (3×30 mL). The combined organic layer was dried through Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography (product eluted in 8% methanol in DCM), followed by prep TLC (5% MeOH: DCM system) yielding the title compound as an off white solid (0.034 g, 0.076 mmol. Yield: 12.8%).

[0876] High temperature .sup.1H NMR (DMSO-d6, 400 MHz, 335 K): compound is a mixture of rotamers δ 1.99 (s, 3H), 2.92 (singlets, br, 6H), 4.43-4.93 (m, 6H), 6.30 (s, 1H), 7.24-7.46 (m, 8H), 9.27-9.33 (m, 2H). LCMS (Method A): 1.640 min, MS: ES+447.27 (M+1).

Example 86: 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N-methylisoindoline-4-carboxamide

[0877] ##STR00142##

2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N-methylisoindoline-4-carboxamide

[0878] To a stirred solution of 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carboxylic acid (0.250 g, 0.596 mmol, 1.0 eq) (Intermediate 59) in THF (3 ml) at 0° C. were added T.sub.3P (50% in EtOAc) (0.284 g, 0.894 mmol, 1.5 eq) and TEA (0.180 g, 1.78 mmol, 3.0 eq). The resulting reaction was stirred at 0° C. for 10 mins. CH.sub.3NH.sub.2 (1M in THF) (0.22 g, 0.715 mmol, 1.2 eq.) was added dropwise into reaction mixture at 0° C. and the resulting reaction mixture stirred at room temperature for 16 h. The reaction mixture was poured into ice-cold water (20 mL) and extracted in ethyl acetate (3×30 mL). The combined organic layer was dried through Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography (product eluted using 8% methanol in DCM) followed by prep TLC yielding the title compound (0.017 g, 0.039 mmol. Yield: 6.6%).

[0879] High temperature .sup.1H NMR (DMSO-d6, 400 MHz, 335 K) compound is a mixture of rotamers: δ1.99 (s, br, 3H), 2.71-2.82 (singlets, br, 3H) 4.54-4.97 (m, 6H), 6.31 (s, 1H), 7.26-7.62 (m, br, 8H), 8.44 (s, br, 1H), 9.49-9.58 (m, 2H). LCMS (Method A): 1.561 min, MS: ES+433.22 (M+1).

Example 87: N-(2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)acetamide

[0880] ##STR00143##

N-(2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)acetamide

[0881] A stirred solution of (4-aminoisoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)methanone (0.06 g, 0.15 mmol, 1 eq.) in AcOH (0.5 mL) at 0° C. was treated with acetic anhydride (0.017 g, 0.17 mmol, 1.1 eq.). The resulting reaction mixture was stirred at room temperature for 30 min. Reaction completion was monitored by TLC (DCM: MeOH; 9.5:0.5). The reaction mixture was neutralized with sat. NaHCO.sub.3 solution (PH-6-7) and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude material was purified by preparative TLC (5% MeOH in DCM) yielding the title compound as a white solid (0.040 g, 0.092 mmol. Yield: 58.8%).

[0882] High temperature .sup.1H NMR (DMSO-d6, 400 MHz, 348K): compound is a mixture of rotamers: δ 1.99-2.11 (singlets, broad, 6H), 4.55-4.93 (m, 6H), 6.31 (s, 1H), 6.99-7.13 (m, 1H), 7.13 (s, br, 1H), 7.25-7.36 (m, 5H), 7.54-7.56 (m, 1H), 9.24-9.38 (m, 3H). LCMS (Method A): 1.616 min, MS: ES+433.2 (M+1).

Example 88: ((2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone (Reaction scheme shown in FIG. 4)

t-Butyl 4-bromoisoindoline-2-carboxylate

[0883] A stirred solution of 4-bromoisoindoline hydrochloride (CAS: 923590-95-8) (15 g, 64.38 mmol, 1.0 eq.) in DCM (150 mL) at room temperature was treated with TEA (19.50 g, 128.77 mmol, 2.0 eq.) and stirred for 15 min. Boc anhydride (28.10 g, 128.77 mmol, 2.0 eq.) was added and the reaction mixture stirred for 16 h. The resulting reaction mixture was poured into water (250 mL) and extracted with ethyl acetate (4×250 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure; the crude material was purified by flash chromatography (product was eluted with 2% ethyl acetate in hexane) yielding (15.4 g, 51.85 mmol, Yield: 81%).

[0884] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.46 (s, 9H), 4.51 (d, J=9.6 Hz, 2H), 4.68 (d, J=10.4 Hz, 2H), 7.23-7.27 (m, 1H), 7.33-7.36 (m, 1H), 7.49 (d, J=7.4 Hz, 1H).

t-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate

[0885] 8 Reactions at 1 g scale carried out in parallel and product combined. A stirred solution of t-butyl 4-bromoisoindoline-2-carboxylate (1.0 g, 33.67 mmol, 1 eq.) in 1.4-dioxane (10 mL) at room temperature was treated with bis(pinacolato)diborane (1.01 g, 40.06 mmol, 1.19 eq.) and potassium acetate (0.66 g, 67.34 mmol, 2.0 eq.) and degassed with nitrogen gas for 15 min. PdCl.sub.2(dppf) (0.49 g, 06.73 mmol, 0.2 eq.) was added and the resulting reaction mixture heated to 90° C. and stirred for 16 h. The resulting reaction mixture was allowed to cool to room temperature and filtered, the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography (product eluted with 7% ethyl acetate in hexane) yielding the title compound (9 g, 26.08 mmol, Yield: 97%).

[0886] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.30 (s, 12H), 1.46 (s, 9H), 4.55-4.58 (m, 2H), 4.65-4.67 (m, 2H), 7.28-7.31 (m, 1H), 7.45 (d, J=7.2 Hz, 1H), 7.58 (d, J=6.4 Hz, 1H). LCMS (Method A): 2.821 min, MS: ES+246.1 (M−100).

t-Butyl 4-hydroxyisoindoline-2-carboxylate

[0887] A stirred solution of t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate (2.3 g, 6.66 mmol, 1.0 eq.) in THF (23 mL) at 0° C. was treated with NaOH (0.53 g, 13.33 mmol, 2.0 eq.) and H.sub.2O.sub.2 solution (0.95 g, 27.99 mmol, 4.2 eq.) added dropwise. The resulting reaction mixture was stirred at 0° C. for 1 h. The resulting reaction mixture was poured into water (80 mL) and neutralized with dil. HCl and extracted with ethyl acetate (3×100 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (product eluted by 11% ethyl acetate in hexane) yielding the title compound (1.5 g, 6.37 mmol, Yield: 96%).

[0888] .sup.1H NMR (CDCl.sub.3-400 MHz): δ 1.54 (s, 9H), 4.65-4.70 (m, 3H), 4.81 (s, 1H), 6.71-6.85 (m, 2H), 7.14-7.19 (m, 1H). LCMS (Method A): 2.015 min, MS: ES+136.1 (M−100).

Isoindolin-4-ol hydrochloride

[0889] A stirred solution of t-butyl 4-hydroxyisoindoline-2-carboxylate (2.8 g, 11.91 mmol, 1.0 eq.) in DCM (28 mL) at 0° C. was treated with 4N HCl in dioxane (14 mL) added dropwise. The resulting reaction mixture was stirred for 1 h at room temperature. The resulting reaction mixture was concentrated under reduced pressure and the crude material triturated using n-pentane (3×50 mL) followed by drying under high vacuum yielding the title compound (1.8 g, 13.33 mmol, Yield: 87%).

[0890] .sup.1H NMR (DMSO-d6, 400 MHz): δ 4.37 (s, 2H), 4.45 (s, 2H), 6.78-6.83 (m, 2H), 7.16-7.20 (m, 1H), 9.86 (s, br, 1H), 10.06 (s, 1H). LCMS (Method A): 0.169 min, MS: ES+136.1 (M+1).

5-(Benzyloxy)-4-(4-hydroxyisoindoline-2-carbonyl)-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate)

[0891] A stirred solution of Intermediate 22 (5 g, 8.59 mmol, 1.0 eq.) in DMF (50 mL) at 0° C. was treated with HATU (4.89 g, 12.88 mmol, 1.5 eq), DIPEA (2.21 g, 17.18 mmol, 2.0 eq.) and stirred for 15 min. Isoindolin-4-ol hydrochloride (1.6 g, 9.45 mmol, and 1.1 eq) was added and the reaction mixture stirred at room temperature for 1 h. The resulting reaction mixture was diluted with ethyl acetate (180 mL) and washed with cold brine solution (4×150 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (product was eluted by 11% ethyl acetate in hexane) yielding the title compound (4 g, 5.72 mmol, Yield: 67%).

[0892] LCMS (Method A): 2.709 min, MS: ES+700.03 (M+1).

5-(Benzyloxy)-4-methyl-6-(4-((tetrahydrofuran-3-yl)oxy)isoindoline-2-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate)

[0893] 5-(Benzyloxy)-4-(4-hydroxyisoindoline-2-carbonyl)-6-methyl-1,3-phenylene-bis(4-methylbenzene sulfonate) (0.5 g, 0.71 mmol, 1 eq.), tetrahydrofuran-3-ol (CAS: 453-20-3) (0.062 g, 0.71 mmol, 1.0 eq.) and triphenyl phosphine (0.37 g, 1.43 mmol, 2.0 eq.) in THF (0.5 mL) were sonicated for 15 min at room temperature. DIAD (98%) (0.28 g, 1.43 mmol, 2.0 eq.) was added to the resulting reaction mixture dropwise under nitrogen atmosphere at 60° C. The resulting mixture was stirred at 60° C. for 30 min, allowed to cool to room temperature, poured into ice-water (70 mL) and extracted with ethyl acetate (3×75 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (product was eluted in DCM) to give the title compound (0.26 g, 3.38 mmol, Yield: 47%).

[0894] LCMS (Method A): 2.677 min, MS: ES+770.2 (M+1).

((2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone

[0895] A stirred solution of 5-(benzyloxy)-4-methyl-6-(4-((tetrahydrofuran-3-yl)oxy)isoindoline-2-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (0.25 g, 3.25 mmol, 1.0 eq.) in EtOH: water (2.5 mL, 1: 1) at room temperature was treated with aqueous KOH (0.72 g, 13.00 mmol, 40 eq. in minimum water). The resulting reaction mixture was heated to 60° C. and stirred for 2 h. The reaction mixture was allowed to cool to room temperature, poured into ice cooled water (50 mL) and neutralized with diluted HCl and extracted with ethyl acetate (4×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (product eluted in 5.7% methanol in DCM) yielding the title compound (0.022 g, 0.04 mmol, Yield: 15%).

[0896] .sup.1H NMR (DMSO-d6, 400 MHz), compound is a mixture of rotamers: δ 1.88-1.99 (M, 1H), 1.97 (2 singlets, 3H), 2.14-2.33 (m, 1H), 3.66-3.94 (m, 4H), 4.23-4.25 (m, 1H), 4.42-4.74 (m, 4H), 4.90-4.92 (m, 1H), 5.02-5.10 (m, 1H), 6.29 (2 singlets, 1H), 6.82-6.97 (m, 2H), 7.21-7.36 (m, 6H), 9.49-9.59 (m, 2H). LCMS (Method A): 1.869 min, MS: ES+462.2 (M+1).

Example 89: (4-(Azetidin-3-yl methoxy)isoindolin-2-yl) (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl) methanone (Reaction Scheme Shown in FIG. 5)

t-Butyl 3-(((2-(2-(benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindolin-4-yl)oxy)methyl)azetidine-1-carboxylate

[0897] A mixture of 5-(benzyloxy)-4-(4-hydroxyisoindoline-2-carbonyl)-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (0.7 g, 1.00 mmol, 1.0 eq), t-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (CAS: 142253-56-3) (0.18 g, 1.00 mmol, 1.0 eq) and triphenyl phosphine (0.52 g, 2.00 mmol, 2.0 eq) in THF (0.7 mL, minimum solvent to make a paste) was sonicated for 15 min at 35° C. The mixture was warmed to 60° C. and treated dropwise with DIAD (98%) (0.4 g, 2.00 mmol, 2.0 eq.), the resulting reaction mixture was stirred at 60° C. under a nitrogen atmosphere for 1 h. The reaction mixture was allowed to cool to room temperature, poured into ice-cold water (80 mL) and extracted with ethyl acetate (4×80 mL). The combined organic was dried over sodium sulphate, filtered, and concentrated under reduced pressure. The crude material (1.2 g) was purified by normal phase flash chromatography (230-400 mesh silica; product eluted in neat DCM) to give the title compound (0.5 g, 0.57 mmol, Yield: 57%).

[0898] LCMS (Method A): 2.860 min, MS ES+769.5 (M−100).

t-Butyl 3-(((2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)oxy)methyl)azetidine-1-carboxylate

[0899] A stirred solution of t-butyl 3-(((2-(2-(benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindolin-4-yl)oxy)methyl)azetidine-1-carboxylate (0.5 g, 0.57 mmol, 1.0 eq.) in EtOH (5 mL) at room temperature was treated with an aqueous solution of KOH (1.29 g, 23.00 mmol, 40 eq.) in water (5 mL). The reaction mixture was heated to 60° C. for 2 h then allowed to cool to room temperature, poured into water (80 mL) and neutralized with dil.HCl, extracted with ethyl acetate (3×80 mL) and the combined organic layer dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (product eluted with 6% methanol in DCM) followed by prep. TLC (5% methanol in DCM) yielding the title compound (0.09 g, 0.16 mmol, Yield: 28%).

[0900] .sup.1H NMR (DMSO-d6, 400 MHz), compound is a mixture of rotamers: δ 1.36-1.40 (2 singlets, 9H), 1.97-1.99 (2 singlets, 3H), 2.86-2.97 (m, 1H), 3.35-3.72 (m, 3H), 3.73-4.04 (m, 2H), 4.11-4.29 (m, 2H), 4.41-4.74 (m, 4H), 4.89-4.92 (m, 1H), 6.30 (s, 1H), 6.83-6.96 (m, 2H), 7.22-7.36 (m, 6H), 9.50-9.59 (m, 2H). LCMS (Method A): 2.188 min, purity: 100% MS ES+: 461.3 (M−100).

(4-(Azetidin-3-ylmethoxy)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl) methanone

[0901] A stirred solution of t-butyl 3-(((2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)oxy)methyl)azetidine-1-carboxylate (0.08 g, 0.14 mmol, 1.0 eq.) in DCM (2.4 mL) at 0° C. was treated with TFA (0.8 mL) added dropwise. The reaction mixture was stirred at room temperature for 1 h, concentrated under reduced pressure, poured into water (15 mL), neutralized with saturated sodium bicarbonate solution, and extracted with ethyl acetate (4×15 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by trituration [n-pentane (20 ml)] and dried under high vacuum to give the title compound as an off white solid (0.030 g, 0.06 mmol, Yield: 46%).

[0902] .sup.1H NMR (DMSO-d6, 400 MHz, 335K), compound is a mixture of rotamers: δ 1.99 (s, 3H), 3.41-3.43 (m, 1H), 3.72-3.73 (m, 1H), 3.95-4.20 (m, 4H), 4.40-4.92 (m, 7H), 6.30 (s, 1H), 6.86-7.02 (m, 2H), 7.24-7.35 (m, 6H), 9.53-9.62 (m, 2H). LCMS (Method A): 1.474 min, MS ES+: 461.3 (M+1).

Example 90: (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone (Reaction scheme shown in FIG. 6)

5-(Benzyloxy)-4-methyl-6-(4-(pyrimidin-5-ylmethoxy)isoindoline-2-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate)

[0903] A mixture of 5-(Benzyloxy)-4-(4-hydroxyisoindoline-2-carbonyl)-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (0.5 g, 0.71 mmol, 1.0 eq.), pyrimidin-5-ylmethanol (0.078 g, 0.71 mmol, 1.0 eq.) (CAS: 25193-95-7) and triphenyl phosphine (0.37 g, 1.43 mmol, 2.0 eq.) in THF (0.5 mL, minimum solvent to make a paste) was sonicated for 15 min at 35° C. The reaction mixture was warmed to 60° C. and treated dropwise with DIAD (98%) (0.28 g, 1.43 mmol, 2.0 eq.). The reaction mixture was stirred at 60° C. under a nitrogen atmosphere for 1 h then allowed to cool to room temperature, poured into water (130 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (3.4% methanol in DCM) to give the title compound (0.35 g, 0.45 mmol, Yield: 62%) which was carried forward to the next step without purification.

[0904] LCMS (Method A): 2.465 min, 2.586 min, MS: ES+778.1 (M+1).

(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone

[0905] A stirred solution of 5-(benzyloxy)-4-methyl-6-(4-(pyrimidin-5-ylmethoxy)isoindoline-2-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (0.2 g, 0.25 mmol, 1.0 eq.) in DCM: Methanol (9:1) (2 mL) at room temperature was treated with NaOH (0.05 g, 1.26 mmol, 5.0 eq.) and stirred for 1 h. The resulting reaction mixture was poured into water (25 mL), neutralized with dil. HCl and extracted with ethyl acetate (3×25 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by prep. TLC (10% MeOH in DCM) followed by prep. HPLC purification yielding (0.012 g, 0.024 mmol, Yield: 9%).

[0906] High temperature .sup.1H NMR (DMSO-d6, 400 MHz, 340K), compound is a mixture of rotamers: δ 1.96 (s, 3H), 4.50-4.51 (m, 2H), 4.66-4.75 (m, 4H), 5.18-5.28 (m, 2H), 6.27 (2 singlets, 1H), 6.84-7.02 (m, 2H), 7.22-7.32 (m, 6H), 8.78 (s, 1H), 8.90 (s, 1H), 9.08-9.14 (m, 1H). LCMS (Method A): 1.678 min, MS ES+484.27 (M+1).

Example 91: 1-(2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)azetidine-3-carbonitrile

[0907] ##STR00144##

1-(2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)azetidine-3-carbonitrile

[0908] A stirred solution of (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-bromoisoindolin-2-yl)methanone (0.3 g, 0.66 mmol, 1.0 eq.) in 1,4-dioxane (3 mL) at room temperature was treated with azetidine-3-carbonitrile (0.117 g, 0.99 mmol, 1.5 eq) (CAS: 345954-83-8) and K.sub.3PO.sub.4 (0.420 g, 1.90 mmol, 3 eq). The reaction mixture was degassed using N.sub.2 gas for 10 min. Pd.sub.2(dba).sub.3 (0.060 g, 0.06 mmol, 0.1 eq) and X-phos (0.063 g, 0.13 mmol, 0.2 eq) were added and the resulting reaction mixture heated to 100° C. and stirred for 1 h under microwave irradiation. The resulting reaction mixture was filtered through celite bed, poured into ice-cold water (100 mL) and extracted using ethyl acetate (3×100 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (product eluted in 3% MeOH: DCM) followed by prep. HPLC purification (MeCN: MeOH: IPA) yielding the title compound (0.005 g, 0.010 mmol, Yield: 1.61%).

[0909] .sup.1H NMR (DMSO-d6, 400 MHz), compound is a mixture of rotamers: δ 1.97 (2 singlets, 3H), 3.49-3.75 (m, 1H), 3.84-4.07 (m, 3H), 4.07-4.08 (m, 1H), 4.18-4.22 (m, 1H), 4.34-4.39 (m, 1H), 4.47-4.74 (m, 3H), 4.91 (m, 1H), 6.30-6.36 (m, 2H), 6.66-6.83 (m, 1H), 7.11-7.19 (m, 1H), 7.26-7.37 (m, 5H), 9.51-9.58 (m, 2H). LCMS (Method A): 1.862 min, MS ES+456.22 (M+1).

Example 92: (4,6-Dihydroxy-2-methoxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Reaction Scheme Shown in FIG. 7)

4-Formyl-5-methoxy-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 54)

[0910] A stirred solution of 4-formyl-5-hydroxy-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (2.0 g, 4.19 mmol, 1.0 eq) Intermediate 2 in DMF (20 mL) at room temperature was treated with K.sub.2CO.sub.3 (1.45 g, 10.49 mmol, 2.5 eq) and CH.sub.3I (0.89 g, 6.29 mmol, 1.5 eq). The resulting reaction mixture was heated to 65° C. and stirred for 4 h. The reaction mixture was poured into ice-cold water (100 mL) and extracted in ethyl acetate (3×100 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (product eluted in 12% ethyl acetate in hexane) yielding as an off-white solid (1.2 g, Yield: 58.29%, 2.44 mmol).

[0911] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.86 (s, 3H), 2.44 (s, 3H), 2.46 (s, 3H), 3.65 (s, 3H), 6.68 (s, 1H), 7.48-7.53 (m, 4H), 7.70-7.76 (m, 4H), 9.93 (s, 1H). LCMS (Method A): 2.588 min. MS: ES+491.12 (M+1).

2-Methoxy-3-methyl-4,6-bis(tosyloxy)benzoic acid (Intermediate 60)

[0912] A stirred solution of 4-formyl-5-methoxy-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (1.1 g, 2.24 mmol, 1.0 eq.) (Intermediate 54) in MeCN: Water (1:1) (20 mL) at room temperature was treated with NaH.sub.2PO.sub.4 (0.806 g, 6.72 mmol, 3.0 eq.) and NaClO.sub.2 (0.74 g, 8.2 mmol, 3.7 eq.) and the reaction mixture stirred at room temperature for 3 h. The resulting reaction mixture was evaporated, diluted with water (20 mL), acidified using 1N HCl solution and extracted with ethyl acetate (2×100 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduce pressure yielding the title compound as an off white solid (1.0 g, 1.97 mmol. Yield: 88.1%).

[0913] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.85 (s, 3H), 2.45 (s, 6H), 3.64 (s, 3H), 6.66 (s, 1H), 7.49-7.52 (m, 4H), 7.72-7.73 (m, 4H), 13.60 (bs, 1H). LCMS (Method A): 2.137 min, MS: ES+507.02

5-Methoxy-4-methyl-6-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate)

[0914] A stirred solution of 2-methoxy-3-methyl-4,6-bis(tosyloxy)benzoic acid (0.5 g, 0.987 mmol, 1.0 eq) (Intermediate 60) in DMF (5 mL) at 0° C. was treated with HATU (0.487 g, 1.28 mmol, 1.3 eq) and DIPEA (0.637 g, 4.93 mmol, 5.0 eq) and stirred for 10 mins. 5-((4-methylpiperazin-1-yl) methyl) isoindoline hydrochloride (0.290 g, 1.08 mmol, 1.1 eq.) was added and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into ice-cold water (50 mL) and extracted in ethyl acetate (3×100 mL). The combined organic layer was washed with brine solution (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The crude material was purified by flash chromatography (eluting product 3% methanol in DCM) yielding the title compound as an off white solid (0.350 g, Yield: 49.24%, 0.486 mmol) which was progressed to the next step.

(4,6-Dihydroxy-2-methoxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone

[0915] A stirred solution of 5-methoxy-4-methyl-6-(5-((4-methylpiperazin-1-yl) methyl) isoindoline-2-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (0.3 g, 0.416 mmol, 1.0 eq.) in EtOH: H.sub.2O (4 mL) (3:1) at room temperature was treated with KOH (0.933 g, 16.66 mmol, 40 eq.) and heated to 60° C. and stirred for 2 h. The resulting reaction mixture cooled to room temperature and concentrated under vacuum. The obtained crude material was acidified using saturated solution of KHSO.sub.4. The aqueous layer was concentrated under vacuum and extracted using 20% IPA: CHCl.sub.3 (3×30 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by prep HPLC (0.1% formic acid water in acetonitrile) yielding the title compound as an off-white solid (0.02 g, 0.048 mmol, Yield: 11.7%).

[0916] High temperature .sup.1H NMR (DMSO-d6, 400 MHz, 340K): δ 1.95 (s, 3H), 2.18 (s, 3H), 2.30-2.50 (m, 8H), 3.44-3.46 (m, 2H), 3.64 (s, 3H), 4.50 (s, 2H), 4.75 (s, 2H), 6.26 (s, 1H), 7.18-7.20 (m, 2H), 7.28-7.29 (m, 1H), 9.19 (bs, 2H). LCMS (Method A): 0.854 min, MS: ES+412.32 (M+1).

Example 93: (2-Ethoxy-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Reaction Scheme Shown in FIG. 8)

5-Ethoxy-4-formyl-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 55)

[0917] A stirred solution of 4-formyl-5-hydroxy-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (2.0 g, 4.19 mmol, 1.0 eq) Intermediate 2 in DMF (20 mL) at room temperature was treated with K.sub.2CO.sub.3 (2.89 g, 20.9 mmol, 5.0 eq) and ethyl bromide (2.89 g, 6.29 mmol, 1.5 eq) and the resulting reaction mixture stirred for 16 h. The reaction mixture was poured into ice-cold water (100 mL) and extracted in ethyl acetate (3×30 mL). The combined organic layer washed with cold water (2×50 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (product eluted with 13% ethyl acetate in hexane) yielding as off-white solid (1.5 g, 2.97 mmol. Yield: 71.0%).

[0918] .sup.1H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ 1.07-1.27 and 1.20-1.24 (m, 3H), 1.77 and 1.85 (singlets, 3H) 2.44-2.50 (singlets, 6H), 3.35-3.40 and 3.78-3.82 (m, 2H), 6.44 and 6.71 (singlets, 1H), 7.48-7.53 (m, 4H), 7.69-7.80 (m, 4H), 9.86 and 9.92 (singlets, 1H). LCMS (Method A): 2.721 min, MS: ES+505.7 (M+1).

2-Ethoxy-3-methyl-4,6-bis(tosyloxy)benzoic acid (Intermediate 61)

[0919] A solution of 5-ethoxy-4-formyl-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (1.4 g, 2.77 mmol, 1.0 eq.) (Intermediate 55) in MeCN:Water (1:1) (15 mL) at room temperature was treated with NaH.sub.2PO.sub.4 (1.16 g, 9.71 mmol, 3.5 eq.) and NaClO.sub.2 (1.25 g, 13.87 mmol, 5.0 eq.) and the reaction mixture stirred for 16 h. The reaction mixture was evaporated and the crude material diluted with water (30 mL), acidified using dil. HCl solution and extracted with ethyl acetate (3×30 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure; the crude material was purified by flash chromatography using silica gel eluting product with 10% ethyl acetate in hexane yielding the title compounds as an off white solid (0.6 g, 1.15 mmol. Yield: 41.7%).

[0920] .sup.1H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ 1.16-1.24 (m, 3H), 1.84 and 2.00 (singlets, 3H), 2.44-2.51 (s, br, 6H), 3.78-3.83 and 4.00-4.06 (m, 2H), 6.66 and 6.68 (singlets, 1H), 7.49-7.58 (m, 4H), 7.71-7.80 (m, 4H), 13.59 (s, 1H). LCMS (Method A): 2.455 min, MS: ES+521.12 (M+1).

5-Ethoxy-4-methyl-6-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate)

[0921] A stirred solution of 2-ethoxy-3-methyl-4,6-bis(tosyloxy)benzoic acid (0.4 g, 0.768 mmol, 1.0 eq) (Intermediate 61) in DMF (2 mL) at 0° C. was treated with HATU (0.438 g, 1.01 mmol, 1.5 eq) and DIPEA (0.495 g, 3.84 mmol, 5.0 eq) and stirred for 10 mins. 5-((4-methylpiperazin-1-yl) methyl) isoindoline hydrochloride (0.226 g, 0.845 mmol, 1.1 eq.) dissolved in DMF (1 mL) was added dropwise and the reaction mixture stirred at room temperature for 16 h. The reaction mixture was poured into ice-cold water (20 mL) and extracted in ethyl acetate (2×30 mL). The combined organic layer was washed with cold water (3×50 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The crude material was purified by flash chromatography (eluting product with 4% methanol in DCM) yielding the title compound as an off white solid (0.350 g, 0.476 mmol. Yield: 62%) which was progressed directly to the next step.

(2-Ethoxy-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone

[0922] A stirred solution of 5-ethoxy-4-methyl-6-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (0.320 g, 0.436 mmol, 1.0 eq.) in EtOH: H.sub.2O (3 mL) (2:1) at room temperature was treated with KOH (0.978 g, 17.44 mmol, 40 eq.) and heated to 60° C. for 3 h. The resulting reaction mixture was allowed to cool to room temperature, poured into water (10 mL) and acidified using saturated solution of KHSO.sub.4 and extracted using 20% IPA in CHCl.sub.3 (3×20 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by prep HPLC (0.1% formic acid/water in acetonitrile) yielding the title compound as an off-white solid (0.025 g, 0.058 mmol, Yield: 13.5%).

[0923] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.17 (t, J=6.8 Hz, 3H), 1.92 (s, 3H), 2.13-2.14 (m, 3H), 2.15-2.50 (m, 8H), 3.41-3.44 (m, 2H), 3.78-3.84 (m, 2H), 4.42-4.53 (m, 2H), 4.72 (s, br, 2H), 6.24 (s, 1H), 7.16-7.22 (m, 2H), 7.29-7.32 (m, 1H), 9.40 (s, 1H, D.sub.20 exchangeable), 9.48 (s, 1H, D.sub.20 exchangeable). LCMS (Method A): 1.021 min, MS: ES+426.32 (M+1).

Example 94: (2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Reaction Scheme Shown in FIG. 9)

5-(Cyclohexylmethoxy)-4-formyl-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 56)

[0924] A stirred solution of 4-formyl-5-hydroxy-6-methyl-1,3-phenylene-bis(4-methylbenzenesulfonate) (2.0 g, 4.19 mmol, 1.0 eq) in DMF (20 mL) at 0° C. was treated with K.sub.2CO.sub.3 (2.89 g, 20.9 mmol, 5.0 eq) and bromomethyl cyclohexane (1.11 g, 6.29 mmol, 1.5 eq) and stirred for 10 mins. The reaction mixture was gradually raised to room temperature and stirred for 16 h. The reaction mixture was poured into ice-cold water (20 mL) and extracted in ethyl acetate (3×30 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. Crude material was purified by flash chromatography (product eluted with 12% ethyl acetate in hexane) yielding the title compound (1.4 g, 2.44 mmol. Yield: 58.3%).

[0925] .sup.1H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ 0.97-1.00 (m, 2H), 1.11-1.26 (m, 3H), 1.67-1.73 (m, 5H), 1.77 and 1.83 (singlets, 3H), 2.33-2.45 (singlets, 6H), 3.49 and 3.70 (m, 2H), 5.77 (s, 1H), 6.44 and 6.70 (singlets, 1H), 7.48-7.53 (m, 4H), 7.71-7.81 (m, 4H), 9.86 and 9.90 (singlets, 1H). LCMS (Method A): 3.250 min, MS: ES+573.13 (M+1).

2-(Cyclohexylmethoxy)-3-methyl-4,6-bis(tosyloxy)benzoic acid (Intermediate 62)

[0926] A solution of 5-(cyclohexylmethoxy)-4-formyl-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (1.4 g, 2.44 mmol, 1.0 eq.) (Intermediate 56) in MeCN:Water (1:1) (15 mL) at room temperature was treated with NaH.sub.2PO.sub.4 (1.02 g, 8.55 mmol, 3.5 eq.) and NaClO.sub.2 (1.10 g, 12.22 mmol, 5.0 eq.) and stirred for 16 h. The mixture was evaporated and the crude material diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (eluting product using 15% ethyl acetate in hexane) yielding the title compound (0.950 g, 1.61 mmol. Yield: 66.4%).

[0927] .sup.1H NMR (DMSO-d6, 400 MHz): δ0.95-1.10 (m, 2H), 1.11-1.22 (m, 3H), 1.61-1.69 (m, 6H), 1.82 (s, br, 3H), 2.44 (s, br, 6H), 3.54 (m, br, 2H), 4.03 (q, J=6.8 Hz, 14.0 Hz, 2H), 6.69 (s, 1H), 7.49-7.52 (m, 4H), 7.70-7.73 (m, 4H), 13.59 (s, 1H). LCMS (Method A): 2.657 min, MS: ES+589.2 (M+1).

5-(Cyclohexylmethoxy)-4-methyl-6-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate)

[0928] A stirred solution of 2-(Cyclohexylmethoxy)-3-methyl-4,6-bis(tosyloxy)benzoic acid (0.4 g, 0.679 mmol, 1.0 eq) (Intermediate 62) in DMF (2 mL) at 0° C. was treated with HATU (0.387 g, 1.01 mmol, 1.5 eq) and DIPEA (0.438 g, 3.39 mmol, 5.0 eq) for 10 mins. 5-((4-methylpiperazin-1-yl) methyl) isoindoline hydrochloride (0.217 g, 0.815 mmol, 1.1 eq.) dissolved in DMF (1 mL) was added dropwise at 0-5° C. The resulting reaction mixture was gradually raised to room temperature and stirred for 16 h. The reaction mixture was poured onto ice-cold water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with cold water (3×100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The crude material was purified by flash chromatography (eluting product with 8% methanol in DCM) yielding the title compound as an off white solid (0.350 g, 0.436 mmol. Yield: 62.0%) which was used directly in the next step.

(2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone

[0929] A stirred solution of 5-(cyclohexylmethoxy)-4-methyl-6-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (0.330 g, 0.414 mmol, 1.0 eq.) in EtOH: H.sub.2O (2:1) was treated with KOH (0.923 g, 16.45 mmol, 40 eq.) at room temperature. The reaction mixture was heated to 60° C. and stirred for 3 h. The reaction mixture was allowed to cool to room temperature, poured into water (20 mL), acidified using KHSO.sub.4 solution) and extracted in 20% IPA in CHCl.sub.3 (3×30 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by prep HPLC (0.1% formic acid water in acetonitrile) yielding the title compound as an off-white solid (0.030 g, 0.060 mmol, Yield: 14.8%).

[0930] .sup.1H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ 0.88-0.94 (m, 2H), 1.02-1.24 (m, 3H), 1.56-1.60 (m, 6H), 1.91 (s, 3H), 2.18 and 2.19 (singlets, 3H), 2.29-2.50 (m, 6H), 3.63 (m, 2H), 4.49 (s, 2H), 4.70 (s, 2H), 6.24 (s, 1H), 7.10-7.22 (m, 2H), 7.30-7.33 (m, 1H), 9.37 (s, br, 1H), 9.47 (s, br, 1H). 4 protons obscured by solvent peaks. LCMS (Method A): 1.372 min, MS: ES+494.37 (M+1).

Example 95: (2-(Cyclopropylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (Reaction Scheme Shown in FIG. 10)

5-(Cyclopropylmethoxy)-4-formyl-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 57)

[0931] A stirred solution of 4-formyl-5-hydroxy-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) Intermediate 2 (1.0 g, 2.09 mmol, 1.0 eq) in DMF (10 mL) at room temperature was treated with K.sub.2CO.sub.3 (0.72 g, 5.24 mmol, 2.5 eq) and (bromomethyl)cyclopropane (0.420 g, 3.14 mmol, 1.5 eq). The reaction mixture was heated to 70° C. and stirred for 6 h. The reaction mixture was poured into ice-cold water (50 mL) and extracted in ethyl acetate (3×50 mL). The combined organic layer was washed with water (2×50 mL) and brine solution (2×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The crude material was purified by flash chromatography (product eluted in 13.1% ethyl acetate: hexane) yielding the title compound (0.86 g, 1.62 mmol. Yield: 77.2%).

[0932] .sup.1H NMR (DMSO-d6, 400 MHz): δ 0.075-0.18 (m, 2H), 0.40-0.49 (m, 2H), 0.96-1.01 (m, 1H), 1.82 (s, 3H), 2.42 and 2.44 (2 singlets, 6H), 3.53-3.61 (m, 2H), 6.74 (s, 1H), 7.46-7.51 (m, 4H), 7.68-7.75 (m, 4H), 9.95 (s, 1H). LCMS (Method A): 2.726 min. MS: ES+531.1 (M+1).

2-(Cyclopropylmethoxy)-3-methyl-4,6-bis(tosyloxy)benzoic acid (Intermediate 63)

[0933] A solution of 5-(cyclopropylmethoxy)-4-formyl-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (0.86 g, 1.62 mmol, 1.0 eq.) (Intermediate 57) in MeCN:Water (1:1) (10 mL) at room temperature was treated with NaH.sub.2PO.sub.4 (0.583 g, 4.86 mmol, 3.0 eq.) and NaClO.sub.2 (0.542 g, 5.99 mmol, 3.7 eq.). The reaction mixture was stirred at room temperature for 4 h, poured into ice-cold water (50 mL), acidified using dil. HCl and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was triturated using n-pentane (10 mL), diethyl ether (10 mL) and further dried using high vacuum yielding to give the title compound as an off white sticky solid (0.610 g, 1.11 mmol. Yield: 68.9%).

[0934] .sup.1H NMR (DMSO-d6, 400 MHz): δ 0.12-0.16 (m, 2H), 0.44-0.47 (m, 2H), 1.00-1.10 (m, 1H), 1.83 (s, 3H), 2.43 (s, 6H), 3.58-3.64 (m, 2H), 6.69 (s, 1H), 7.48-7.51 (m, 4H), 7.70-7.77 (m, 4H), 13.58 (bs, 1H). LCMS (Method A): 2.487 min, MS: ES+569.2 (M+23).

5-(Cyclopropylmethoxy)-4-methyl-6-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate)

[0935] A stirred solution of 2-(cyclopropylmethoxy)-3-methyl-4,6-bis(tosyloxy)benzoic acid (0.510 g, 0.933 mmol, 1.0 eq) (Intermediate 63) in DMF (5 mL) at 0° C. was treated with HATU (0.460 g, 1.21 mmol, 1.3 eq) and DIPEA (0.80 mL, 4.66 mmol, 5.0 eq). 5-((4-methylpiperazin-1-yl)methyl)isoindoline hydrochloride (0.274 g, 1.02 mmol, 1.1 eq.) was added and the reaction mixture raised to room temperature and stirred for 16 h. The reaction mixture was poured with ice-cold water (100 mL) and extracted in ethyl acetate (3×110 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The crude material was purified by column chromatography (eluting product with 20% EtOAc in Hexane) yielding the title compound (0.490 g, 0.64 mmol. Yield: 69.1%) which was progressed to the next step.

(2-(Cyclopropylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone

[0936] A stirred solution of 5-(cyclopropylmethoxy)-4-methyl-6-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)-1,3-phenylene bis(4-methylbenzenesulfonate) (0.47 g, 0.62 mmol, 1.0 eq.) in EtOH: H.sub.2O (1:1) at room temperature was treated with KOH (1.38 g, 24.59 mmol, 40 eq.). The reaction mixture was heated to 60° C. and stirred for 3 h. The resulting reaction mixture was allowed to cool to room temperature, poured into water (20 mL) and acidified using KHSO.sub.4 solution and extracted into EtOAc (3×30 mL). The aqueous layer was further extracted with 10% IPA in CHCl.sub.3(3×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material was purified by prep HPLC using 0.05% NH.sub.3 in water: acetonitrile. The pure fractions were lyophilized yielding the title compound as an off-white solid (0.050 g, 0.11 mmol. Yield: 17.9%).

[0937] .sup.1H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ 0.17 (m, 2H), 0.43 (m, 2H), 1.04-1.06 (m, 1H), 1.92 (s, 3H), 2.12 and 2.13 (singlets, 3H), 2.30-2.49 (m, 8H), 3.40-3.43 (m, 2H), 3.58 (m, 2H), 4.45-4.48 (m, 2H), 4.70-4.71 (m, br, 2H), 6.23 (s, 1H), 7.16-7.22 (m, 2H), 7.29-7.32 (m, 1H), 9.47 (bs, 2H, D.sub.20 exchangeable). LCMS (Method B): 4.732 min, MS: ES+452.4 (M+1).

Example 96: (2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino) methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Reaction Scheme Shown in FIG. 11)

5-(Cyclohexylmethoxy)-4-(6-((dimethyl amino) methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate)

[0938] To a stirred solution 2-(cyclohexylmethoxy)-3-methyl-4,6-bis(tosyloxy)benzoic acid (Intermediate 62) (0.3 g, 0.51 mmol, 1 eq) at 0° C. in DMF (3 mL) were added HATU (0.29 g, 0.76 mmol, 1.5 eq) and DIPEA (0.13 g, 1.02 mmol, 2 eq) and the mixture stirred for 15 min. N, N-dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)methanamine (Intermediate 43) (0.12 g, 0.66 mmol, 1.3 eq) was added and stirring continued at room temperature for 16 h. The reaction mixture was poured into ice cold water (60 mL) and extracted using ethyl acetate (3×60 mL). The combined organic layer was washed with ice cold water (3×80 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. Crude material was purified by flash chromatography (product eluted in 4% MeOH in DCM) to give the title compound as a yellow solid (0.3 g, Yield: 77.4%) which was used directly in the next step.

Example 96: (2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[0939] A stirred solution of 5-(cyclohexylmethoxy)-4-(6-((dimethyl amino) methyl)-1, 2, 3, 4-tetrahydro-isoquinoline-2-carbonyl)-6-methyl-1, 3-phenylene bis (4-methylbenzenesulfonate) (0.27 g, 0.35 mmol, 1 eq.) in EtOH: H.sub.2O (2:1) (3 mL) at room temperature was treated with KOH (0.790 g, 14.1 mmol, 40 eq.). The reaction mixture was heated to 60° C. and stirred for 2 h, poured into ice cold water (50 mL), neutralized using saturated solution of KHSO.sub.4 solution and extracted in ethyl acetate (3×60 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude material was purified by column chromatography followed by Prep HPLC purification (Method C) to give the title compound as an off white solid (0.012 g, Yield: 7.5%). .sup.1H NMR High temperature (DMSO-d6, 400 MHz, 351K): δ 0.85-0.87 (m, 2H), 1.01-1.12 (m, 3H), 1.51-1.53 (m, 6H), 1.92 (s, 3H), 2.15 (s, 6H), 2.66-2.81 (m, 2H), 3.33 (s, 2H), 3.45-3.48 (m, 2H), 4.42-4.66 (m, 2H), 6.21 (s, 1H), 7.06 (s, 3H), 9.37 (s, 2H). LCMS (Method D): 1.806 min, 97.60%, 254 nm, MS: ES+453.4 (M+1). HPLC (Method A): 4.639 min, 97.99%, 230 nm.

Synthesis of Intermediates

[0940] In one approach (Scheme 2), substituted aromatic carboxylic acid of formula [II] may be prepared by Pinnick oxidation of a substituted aromatic aldehyde of formula [IV] with an oxidising agent such as sodium chlorite (NaClO.sub.2), in monosodium phosphate buffered solution (NaH.sub.2PO.sub.4)aq in a polar solvent such as acetonitrile or THF. The reaction is suitably conducted at RT or by thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Intermediate substituted aromatic aldehyde compounds of general formula [IV] may be prepared by reaction of an intermediate bis-Ts protected phenol intermediate compound of general formula [V] with a halide of general formula [VI] in a polar solvent such as DMF or DMA with a base such as K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3. The reaction is suitably conducted under thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Intermediate bis-Ts protected phenol intermediate compounds of general formula [V] are prepared by reaction of a tri-phenol compound of general formula [VII] with tosyl chloride, in a polar solvent such as acetone or THF with a base such as K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3. The reaction is suitably conducted at 0° C. or RT. After reaction work up, typically by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation, to yield Intermediate bis-Ts protected phenol intermediate compounds of general formula [V].

##STR00145##

[0941] In one approach (Scheme 3), bis-tosyl protected phenol intermediate compounds of general formula [V] were prepared by reaction of a 1,3,5-triphenolbenzaldehyde derivative of general formula [VII] with para-toluenesulfonylchloride in a polar solvent such as acetonitrile or acetone, with a base such as K.sub.2CO.sub.3 or Na.sub.2CO.sub.3. The reaction is suitably conducted at RT or by thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation.

##STR00146##

Synthesis of 4-formyl-5-hydroxy-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 1)

[0942] ##STR00147##

[0943] To a solution of 2,4,6-trihydroxybenzaldehyde (CAS #487-70-7) (5 g, 32.2 mmol, 1.0 eq) in acetone (200 mL) was added K.sub.2CO.sub.3 (22.27 g, 161 mmol, 5.0 eq) and p-toluene sulphonyl chloride (12.90, 67.7 mmol, 2.1 eq) at room temperature. The reaction mixture was heated at 60° C. for 4 h. The resulting reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The crude material was diluted with water (300 mL) and extracted in EtOAc (3×400 mL). The combined organic layer was washed with brine solution (200 mL), dried over sodium sulphate and concentrated under reduced pressure to give crude material which was purified by column chromatography using silica gel (eluting product using 8.7% ethyl acetate in hexane) yielding 4-formyl-5-hydroxy-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 1) as a yellow solid (5.9 g, Yield: 39.3%).

[0944] .sup.1H NMR (DMSO-d.sup.6, 400 MHz): δ 2.44 (d, J=2.4 Hz, 6H), 6.38 (d, J=2.4 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 7.47-7.54 (m, 4H), 7.69 (d, J=8.0 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 9.89 (s, 1H), 11.52 (s, 1H). LCMS: 2.441 min, MS: ES+461.30 (M−1)

[0945] The following compounds were prepared according to the method described above using the indicated intermediates

TABLE-US-00003 Intermediate No. Name Structure Data 2 4-formyl-5-hydroxy-6- methyl-1,3-phenylene bis(4- methylbenzenesulfonate) [00148] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.77 (s, 1H), 2.45 (d, J = 8.0 Hz, 6H), 6.45 (s, 1H), 7.51-7.54 (m, 4H), 7.74-7.81 (m, 4H), 9.86 (s, 1H), 11.82 (s, 1H). LCMS (Method A): 2.582 min, MS: ES+ 477 (M + 1) Using 2,4,6-trihydroxy- 3-methylbenzaldehyde (CAS-55743-13-0) 3 4-ethyl-6-formyl-5- hydroxy-1,3-phenylene bis(4- methylbenzenesulfonate) [00149] .sup.1H NMR (DMSO-d6, 400 MHz): δ 0.89 (t, J = 7.6 Hz, 3H), 2.35-2.37 (m, 2H), 2.45 (d, 7.2 Hz, 6H), 6.46 (s, 1H), 7.51-7.55 (m, 4H), 7.77-7.82 (m, 4H), 9.86 (s, 1H), 11.88 (s, 1H). LCMS (Method A): 2.727 min, MS: ES+ 491 (M + 1) Using 3-ethyl-2,4,6- trihydroxybenzaldehyde (CAS 412021-94-4)

[0946] In one approach (Scheme 4), bis-tosyl protected alkoxy-phenol intermediate compounds of general formula [IV] were prepared by reaction of a bis-tosyl protected phenol intermediate of general formula [V] with a compound of general formula [VI] with a base such as Cs.sub.2CO.sub.3 or K.sub.2CO.sub.3 in a polar aprotic solvent such as DMF or DMA. The reaction is suitably conducted at RT or by thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation

##STR00150##

Synthesis of 5-(cyclopentyloxy)-4-formyl-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 4)

[0947] ##STR00151##

[0948] To a solution of 4-formyl-5-hydroxy-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 1) (3 g, 6.48 mmol, 1.0 eq) in DMF (20 mL) was added Cs.sub.2CO.sub.3 (2.10 g, 6.44 mmol, 1.0 eq) and bromocyclopentane (1.44 g, 9.66 mmol, 1.5 eq) at room temperature. The reaction mixture was heated to 80° C. and stirred for 3 h. The cooled reaction mixture was diluted with water (200 mL) and extracted in EtOAc (3×250 mL). The combined organic layer was washed with brine solution (200 mL), dried over sodium sulphate and concentrated under reduce pressure. The obtained crude material was purified by column chromatography using silica gel (eluting product using 10.2% ethyl acetate in hexane) yielding 5-(cyclopentyloxy)-4-formyl-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 4) as a yellow oil (2.1 g, Yield: 61.0%). .sup.1H NMR (DMSO-d.sup.6, 400 MHz): δ 1.53-1.62 (m, 8H), 2.42 (d, J=4.8 Hz, 6H), 4.60-4.80 (m, 1H), 6.45 (d, J=1.60 Hz, 1H), 6.75 (d, J=1.6 Hz, 1H), 7.46-7.52 (m, 4H), 7.66-7.76 (m, 4H), 9.92 (s, 1H). LCMS: 2.788 min, MS: ES+531.17 (M+1)

[0949] The following compounds were prepared according to the Method described above using the indicated intermediates

TABLE-US-00004 Int. No. Name Structure Data 5 5-(benzyloxy)-4- formyl-1,3- phenylene bis(4- methylbenzene- sulfonate) [00152] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.44 (d, J = 2.4 Hz, 6H), 5.15 (s, 2H), 6.46 (d, J = 2.8 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.40-7.41 (m, 4H), 7.46-7.51 (m, 4H), 7.65 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 9.99 (s, 1H). LCMS (Method A): 2.594 min, MS: ES+ 575.06 (M + 23) Using 4-formyl-5-hydroxy-1,3- phenylene bis(4- methylbenzenesulfonate) (Intermediate 1) and benzylbromide 6 5-(benzyloxy)-4- formyl-6-methyl-1,3- phenylene bis(4- methylbenzene- sulfonate) [00153] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.83 (d, J = 9.20 Hz, 3H), 2.44 (d, J = 8.0 Hz, 6H), 4.80 (s, 2H), 6.75 (s, 1H), 7.31- 7.37 (m, 5H), 7.49-7.54 (m, 4H), 7.71-7.77 (m, 4H), 9.87 (s, 1H). LCMS (Method A): 2.697 min, MS: ES+ 589.10 (M + 23) Using 4-formyl-5-hydroxy-6- methyl-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 2 and benzylbromide 7 5-(benzyloxy)-4- ethyl-6-formyl-1,3- phenylene bis(4- methylbenzene- sulfonate) [00154] .sup.1H NMR (DMSO-d6, 400 MHz): δ 0.89 (t, J = 7.6 Hz, 3H), 2.32-2.34 (q, 2H), 2.45 (d, J = 9.2 Hz, 6H), 4.82 (s, 2H), 6.79 (s, 1H), 7.35-7.40 (m, 5H), 7.51-7.55 (m, 4H), 7.73-7.80 (m, 4H), 9.91 (s, 1H). LCMS (Method A): 2.763 min, MS: ES+ 603.15 (M + 23) Using 4-ethyl-6-formyl-5- hydroxy-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 3 and benzylbromide 8 4-formyl-5-(pyridin- 2-ylmethoxy)-1,3- phenylene bis(4- methylbenzene- sulfonate) [00155] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.44 (d, J = 4.8 Hz, 6H), 5.19 (s, 2H), 6.50 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.36-7.39 (m, 4H), 7.48-7.54 (m, 1H), 7.67- 7.75 (m, 4H), 7.84-7.89 (m, 1H), 8.57 (d, J = 4.8, 1H), 10.05 (s, 1H). LCMS (Method A): 2.339 min, MS: ES+ 554.1 (M + 1) Using 4-formyl-5-hydroxy-1,3- phenylene bis(4- methylbenzenesulfonate) (Intermediate 1) and 2- (bromomethyl)pyridine hydrobromide 9 4-formyl-5- (pyrimidin-2- ylmethoxy)-1,3- phenylene bis(4- methylbenzene- sulfonate) [00156] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.42-2.44 (m, 6H), 5.38 (s, 2H), 6.49 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 7.44-7.51 (m, 5H), 7.66- 7.68 (m, 4H), 8.12 (d, J = 5.2 Hz, 2H), 10.83 (s, 1H). LCMS (Method A): 2.243 min, MS: ES+ 555.0 (M + 1) Using 4-formyl-5-hydroxy-1,3- phenylene bis(4- methylbenzenesulfonate) (Intermediate 1) and 2- (bromomethyl)-pyrimidine hydrochloride 10 4-formyl-5-(1- phenylethoxy)-1,3- phenylene bis(4- methylbenzene- sulfonate) [00157] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.48 (d, J = 6.0 Hz, 3H), 2.41-2.45 (m, 6H), 5.58- 5.68 (m, 1H), 6.40 (d, J = 1.60 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 7.31-7.38 (m, 5H), 7.39-7.42 (m, 4H), 7.50- 7.59 (m, 4H), 10.05 (s, 1H). LCMS (Method A): 2.800 min, MS: ES+ 589.1 (M + 23) Using 4-formyl-5-hydroxy-1,3- phenylene bis(4- methylbenzenesulfonate) (Intermediate 1) and (1- bromoethyl)benzene 11 5-((4- fluorobenzyl)oxy)-4- formy-1,3- phenylene bis(4- methylbenzene- sulfonate) [00158] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.44 (s, 6H), 5.14 (s, 2H), 6.46 (d, J = 2.0 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 7.21- 7.26 (m, 2H), 7.45-7.52 (m, 6H), 7.65-7.67 (m, 2H), 7.74- 7.76 (m, 2H), 9.99 (s, 1H). LCMS (Method A): 2.636 min, MS: ES+ 593.10 (M + 23) Using 4-formyl-5-hydroxy-1,3- phenylene bis(4- methylbenzenesulfonate) (Intermediate 1) and 4- fluorobenzylbromide 12 4-formyl-5-((4- methoxybenzyl)oxy)- 1,3-phenylene bis(4- methylbenzene- sulfonate) [00159] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.44 (s, 6H), 3.77 (s, 3H), 5.06 (s, 2H), 6.44 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 8.40 Hz, 2H), 7.08 (d, J = 2.0 Hz, 1H), 7.33-7.35 (m, 2H), 7.46- 7.52 (m, 4H), 7.65 (d, J = 9.2 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 9.95 (s, 1H). LCMS (Method A): 2.573 min, MS: ES+ 605.1 (M + 23) Using 4-formyl-5-hydroxy-1,3- phenylene bis(4- methylbenzenesulfonate) (Intermediate 1) and 4- methoxybenzylbromide 13 4-formyl-5-((3- methylbenzyl)oxy)- 1,3-phenylene bis(4- methylbenzene- sulfonate) [00160] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.32 (s, 3H), 2.44 (d, J = 2.4 Hz, 6H), 5.10 (s, 2H), 6.45 (d, J = 1.6 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 7.17-7.29 (m, 4H), 7.47-7.51 (m, 4H), 7.65 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 9.99 (s, 1H). LCMS (Method A): 2.691 min, MS: ES+ 589.20 (M + 23) Using 4-formyl-5-hydroxy-1,3- phenylene bis(4- methylbenzenesulfonate) (Intermediate 1) and 3- methylbenzylbromide 14 4-formyl-5- (pyrimidin-4- ylmethoxy)-1,3- phenylene bis(4- methylbenzene- sulfonate) [00161] LCMS (Method A): 2.508 min, MS: ES+ 555.1 (M + 1) Using 4-formyl-5-hydroxy-1,3- phenylene bis(4- methylbenzenesulfonate) (Intermediate 1) and 4- (Bromomethyl)pyrimidine 15 tert-butyl3-((2- formyl-3,5- bis(tosyloxy)phenox y)methyl)-1H- pyrazole-1- carboxylate [00162] 1H NMR (DMSO-d6, 400 MHz): δ 1.58 (s, 9H), 2.44 (s, 6H), 5.15 (s, 2H), 6.48 (d, 2.0 Hz, 1H), 6.58 (d, J = 2.8 Hz, 1H), 7.11 (d, 2.0 Hz, 1H), 7.47-7.52 (m, 4H), 7.66 (d, J = 8.4 Hz, 2H), 7.67 (d, 8.4 Hz, 2H), 8.29 (d, 2.8 Hz, 1H), 9.97 (s, 1H). LCMS (Method A): 2.672 min, MS: ES+ 665.00 (M + 23) Using 4-formyl-5-hydroxy-1,3- phenylene bis(4- methylbenzenesulfonate) (Intermediate 1) and tert-butyl 3-(bromomethyl)-1H- pyrazole-1-carboxylate 16 5-((4- fluorobenzyl)oxy)-4- formyl-6-methyl-1,3- phenylene bis(4- methylbenzene- sulfonate) [00163] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.81 (s, 3H), 2.44 (d, J = 7.6 Hz, 6H), 4.80 (s, 2H), 6.74 (s, 1H), 7.18-7.23 (m, 2H), 7.36-7.40 (m, 2H), 7.49- 7.54 (m, 4H), 7.71-7.77 (m, 4H), 9.86 (s, 1H). LCMS (Method A): 2.817 min, MS: ES+ 607.1 (M + 23) Using 4-formyl-5-hydroxy-6- methyl-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 2 and 4- fluorobenzylbromide 17 4-formyl-6-methyl-5- ((3- methylbenzyl)oxy)- 1,3-phenylene bis(4- methylbenzene- sulfonate) [00164] 1H NMR (DMSO-d6, 400 MHz): δ 1.82 (s, 3H), 2.30 (s, 3H), 2.45 (d, J = 8.0 Hz, 6H), 4.75 (s, 2H), 6.72 (s, 1H), 7.09 (d, J = 7.2 Hz, 1H), 7.17 (d, J = 7.6 Hz, 2H), 7.23-7.27 (m, 1H), 7.48-7.53 (m, 4H), 7.70- 7.76 (m, 4H), 9.87 (s, 1H). LCMS (Method A): 2.825 min, MS: ES+ 603.1 (M + 23) Using 4-formyl-5-hydroxy-6- methyl-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 2 and 3- methylbenzylbromide 18 4-formyl-6-methyl-5- (pyridin-2- ylmethoxy)-1,3- phenylene bis(4- methylbenzene- sulfonate) [00165] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.83 (s, 3H), 2.44 (d, J = 8.0 Hz, 6H), 4.87 (s, 2H), 6.74 (s, 1H), 7.36-7.39 (m, 1H), 7.47-7.53 (m, 5H0, 7.70- 7.76 (m, 4H), 7.81-7.86 (m, 1H), 8.54 (d, J = 4.0 Hz, 1H), 9.92 (s, 1H). LCMS (Method A): 2.420 min, MS: ES+ 568.1 (M + 1) Using 4-formyl-5-hydroxy-6- methyl-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 2 and 2- (bromomethyl)pyridine hydrobromide 19 4-formyl-6-methyl-5- ((1-methyl-1H- pyrazol-3- yl)methoxy)-1,3- phenylene bis(4- methylbenzene- sulfonate) [00166] 1H NMR (DMSO-d6, 400 MHz): δ 1.82 (s, 3H), 2.43 (s, 3H), 2.45 (s, 3H), 3.79 (s, 3H), 4.76 (s, 2H), 6.10 (s, 1H), 6.70 (s, 1H), 7.48-7.53 (m, 4H), 7.63-7.78 (m, 5H), 9.79 (s, 1H). LCMS (Method E): 2.395 min, MS: ES+ 571.11 (M + 1) Using 4-formyl-5-hydroxy-6- methyl-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 2 and 3- (chloromethyl)-1-methyl-1H- pyrazole hydrochloride 54 4-Formyl-5-methoxy- 6-methyl-1,3- phenylene bis(4- methylbenzene- sulfonate) [00167] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.86 (s, 3H), 2.44 (s, 3H), 2.46 (s, 3H), 3.65 (s, 3H), 6.68 (s, 1H), 7.48-7.53 (m, 4H), 7.70-7.76 (m, 4H), 9.93 (s, 1H). LCMS (Method A): 2.588 min. MS: ES+ 491.12 (M + 1). Using 4-formyl-5-hydroxy-6- methyl-1,3-phenylene bis(4- methylbenzenesulfonate) (Intermediate 2) 55 5-Ethoxy-4-formy 1-6- methyl-1,3- phenylene bis(4- methylbenzene- sulfonate) [00168] .sup.1H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ 1.07-1.27 and 1.20-1.24 (m, 3H), 1.77 and 1.85 (singlets, 3H) 2.44-2.50 (singlets, 6H), 3.35-3.40 and 3.78-3.82 (m, 2H), 6.44 and 6.71 (singlets, 1H), 7.48-7.53 (m, 4H), 7.69-7.80 (m, 4H), 9.86 and 9.92 (singlets, 1H). LCMS (Method A): 2.721 min, MS: ES+ 505.7 (M + 1). Using 4-formyl-5-hydroxy-6- methyl-1,3-phenylene bis(4- methylbenzenesulfonate) (Intermediate 2) 56 5- (Cyclohexylmethoxy)- 4-formyl-6-methyl- 1,3-phenylene bis(4- methylbenzene- sulfonate) [00169] .sup.1H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ 0.97-1.00 (m, 2H), 1.11-1.26 (m, 3H), 1.67- 1.73 (m, 5H), 1.77 and 1.83 (singlets, 3H), 2.33-2.45 (singlets, 6H), 3.49 and 3.70 (m, 2H), 5.77 (s, 1H), 6.44 and 6.70 (singlets, 1H), 7.48-7.53 (m, 4H), 7.71-7.81 (m, 4H), 9.86 and 9.90 (singlets, 1H). LCMS (Method A): 3.250 min, MS: ES+ 573.13 (M + 1). Using 4-formyl-5-hydroxy-6- methyl-1,3-phenylene-bis(4- methylbenzenesulfonate) 57 5- (Cyclopropylmethoxy)- 4-formyl-6-methyl- 1,3-phenylene bis(4- methylbenzene- sulfonate) [00170] .sup.1H NMR (DMSO-d6, 400 MHz): δ 0.075-0.18 (m, 2H), 0.40-0.49 (m, 2H), 0.96- 1.01 (m, 1H), 1.82 (s, 3H), 2.42 and 2.44 (2 singlets, 6H), 3.53-3.61 (m, 2H), 6.74 (s, 1H), 7.46-7.51 (m, 4H), 7.68- 7.75 (m, 4H), 9.95 (s, 1H). LCMS (Method A): 2.726 min, MS: ES+ 531.1 (M + 1). Using 4-formyl-5-hydroxy-6- methyl-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 2

[0950] In one approach (Scheme 5), substituted aromatic carboxylic acids of formula [II] were prepared by a Pinnick oxidation of a substituted aromatic aldehyde of formula [IV] with an oxidising agent such as sodium chlorite (NaClO.sub.2), in monosodium phosphate buffered solution (NaH.sub.2PO.sub.4)aq in a polar solvent such as acetonitrile or THF. The reaction is suitably conducted at RT or by thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation.

##STR00171##

Synthesis of 2-(cyclopentyloxy)-4,6-bis(tosyloxy)benzoic acid (Intermediate 20)

[0951] ##STR00172##

[0952] To a solution of 4 5-(cyclopentyloxy)-4-formyl-1,3-phenylene bis(4-methylbenzenesulfonate) (0.8 g, 1.51 mmol, 1 eq) in acetonitrile: water (1:1) (20 mL) was added NaH.sub.2PO.sub.4 (0.36 g, 3.00 mmol, 2 eq) and NaClO.sub.2 (0.496 g, 5.48 mmol, 3.6 eq) at room temperature. The reaction mixture was stirred at room temperature for 16 h. Solvent was removed under vacuum and the isolated crude material diluted with water (70 mL), acidified using formic acid, and extracted in EtOAc (3×150 mL). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure. The obtained crude material was purified by flash chromatography using silica gel (eluting product using 35.3% ethyl acetate in hexane) yielding 2-(cyclopentyloxy)-4,6-bis(tosyloxy)benzoic acid (Intermediate 20) as an oil (0.35 g, Yield: 42.5%). .sup.1H NMR (DMSO-d.sup.6, 400 MHz): δ 1.43-1.61 (m, 6H), 1.66-1.70 (m, 2H), 2.43 (d, J=9.2 Hz, 6H), 4.68-4.69 (m, 1H), 6.52 (d, J=2.0 Hz, 1H), 6.61 (d, J=1.6 Hz, 1H), 7.46-7.51 (m, 4H), 7.69-7.74 (m, 4H), 13.29 (s, 1H). LCMS: 2.395 min, MS: ES+569.11 (M+23).

[0953] The following compounds were prepared according to the Methods described above using the indicated intermediates

TABLE-US-00005 No Name Structure Data 21 2-(benzyloxy)-4,6- bis(tosyloxy)benzoic acid [00173] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.42 (s, 6H), 4.96 (s, 2H), 6.53 (d, J = 1.6 Hz, 1H), 6.68-6.70 (m, 1H), 7.33-7.36 (m, 5H), 7.41-7.48 (m, 4H), 7.67-7.75 (m, 4H), 13.70 (brs, 1H). LCMS (Method A): 2.293 min, MS: ES+ 591.1 (M + 23) Using 5-(benzyloxy)-4-formyl-1,3- phenylene bis(4- methylbenzenesulfonate) Intermediate 5 22 2-(benzyloxy)-3- methyl-4,6- bis(tosyloxy)benzoic acid [00174] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.84 (s, 3H), 2.45 (d, J = 1.20 Hz, 6H), 4.80 (s, 2H), 6.73 (s, 1H), 7.33-7.39 (m, 5H), 7.50-7.53 (m, 4H), 7.72-7.75 (m, 4H), 13.74 (s, 1H). LCMS (Method A): 2.464 min, MS: ES+ 605.20 (M + 23) Using 5-(benzyloxy)-4-formyl-6- methyl-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 6 23 2-(benzyloxy)-3- ethyl-4,6- bis(tosyloxy)benzoic acid [00175] .sup.1H NMR (DMSO-d6, 400 MHz): δ 0.92 (t, J = 7.6 Hz, 3H), 2.35-2.37 (m, 2H), 2.45 (d, J = 2.4 Hz, 6H), 4.86 (s, 2H), 6.76 (s, 1H), 7.35- 7.38 (m, 5H), 7.50-7.54 (m, 4H), 7.74-7.77 (m, 4H), 13.83 (s, 1H). LCMS (Method A): 2.510 min, MS: ES+ 619.10 (M + 23) Using 5-(benzyloxy)-4-ethyl-6- formyl-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 7 24 2-(pyridin-2- ylmethoxy)-4,6- bis(tosyloxy)benzoic acid [00176] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.44 (d, J = 7.2 Hz, 6H), 5.11 (s, 2H), 6.55 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 7.35-7.38 (m, 2H), 7.47-7.50 (m, 4H), 7.67- 7.73 (m, 4H), 7.82-7.86 (m, 1H), 8.56 (t, J = 1.6 Hz, 1H), 13.54 (s, 1H). LCMS (Method A): 2.069 min, MS: ES+ 570.1 (M + 1) Using 4-formyl-5-(pyridin-2- ylmethoxy)-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 8 25 2-(pyrimidin-2- ylmethoxy)-4,6- bis(tosyloxy)benzoic acid [00177] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.43 (d, J = 3.2 Hz, 6H), 5.22 (s, 2H), 6.54 (d, J = 2.0 Hz, 1H), 6.71 (d, J = 1.6 Hz, 1H), 7.44-7.51 (m, 5H), 7.65-7.70 (m, 4H), 8.81 (d, J = 4.8 Hz, 2H), 13.50 (s, 1H). LCMS (Method A): 2.087 min, MS: ES+ 571.1 (M + 1) Using 4-formyl-5-(pyrimidin-2- ylmethoxy)-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 9 26 2-(1-phenylethoxy)- 4,6- bis(tosyloxy)benzoic acid [00178] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.40 (d, J = 6.0 Hz, 3H), 2.42 (d, J = 4.8 Hz, 6H), 5.45-5.49 (m, 1H), 6.44 (d, J = 1.6 Hz, 1H), 6.68 (s, 1H), 7.27-7.33 (m, 5H), 7.35- 7.56 (m, 6H), 7.65 (d, J = 9.0 Hz, 2H), 13.48 (s, 1H). LCMS (Method A): 2.529 min, MS: ES+ 605.1 (M + 23) Using 4-formyl-5-(1- phenylethoxy)-1,3-phenylene bis(4-methylbenzenesulfonate) Intermediate 10 27 2-((4- fluorobenzyl)oxy)- 4,6- bis(tosyloxy)benzoic acid [00179] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.44 (d, J = 4.0 Hz, 6H), 5.05 (s, 2H), 6.50 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 7.22 (t, J = 8.8 Hz, 2H), 7.37-7.40 (m, 2H), 7.48- 7.51 (m, 4H), 7.67 (d, J = 7.6 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 13.42 (s, 1H). LCMS (Method A): 2.355 min, MS: ES+ 609.1 (M + 23) Using 5-((4-fluorobenzyl)oxy)-4- formyl-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 11 28 2-((4- methoxybenzyl)oxy)- 4,6- bis(tosyloxy)benzoic acid [00180] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.44 (d, J = 2.4 Hz, 6H), 3.76 (s, 3H), 4.95 (s, 2H), 6.50 (d, J = 2.0 Hz, 1H), 6.89-6.94 (m, 3H), 7.28 (t, J = 8.8 Hz, 2H), 7.41-7.56 (m, 24), 7.64-7.69 (m, 2H), 7.73- 7.78 (m, 2H), 13.38 (s, 1H). LCMS (Method A): 2.329 min, MS: ES+ 621.1 (M + 23) Using 4-formyl-5-((4- methoxybenzyl)oxy)-1,3- phenylene bis(4- methylbenzenesulfonate) Intermediate 12 29 2-((3- methylbenzyl)oxy)- 4,6- bis(tosyloxy)benzoic acid [00181] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.30 (s, 3H), 2.44 (d, J = 3.6 Hz, 6H), 5.00 (s, 2H), 6.50 (d, J = 1.2 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 7.10-7.15 (m, 3H), 7.25-7.28 (m, 1H), 7.48-7.51 (m, 4H), 7.67 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 13.42 (s, 1H). LCMS (Method A): 2.397 min, MS: ES+ 605.1 (M + 1) Using 4-formyl-5-((3- methylbenzyl)oxy)-1,3-phenylene bis(4-methylbenzenesulfonate) Intermediate 13 30 2-(pyrimidin-4- ylmethoxy)-4,6- bis(tosyloxy)benzoic acid [00182] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.43 (d, J = 5.6 Hz, 6H), 5.13 (s, 2H), 6.59 (d, J = 1.6 Hz, 1H), 7.43- 7.49 (m, 6H), 7.67-7.74 (m, 4H), 8.82 (d, J = 5.2 Hz, 1H), 9.16 (d, J = 0.8 Hz, 1H), 13.74 (s, 1H). LCMS (Method A): 2.312 min, MS: ES+ 571.1 (M + 1) Using 4-formyl-5-(pyrimidin-4- ylmethoxy)-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 14 31 2-((1-(tert- butoxycarbonyl)-1H- pyrazol-3- yl)methoxy)-4,6- bis(tosyloxy)benzoic acid [00183] 1H NMR (DMSO-d6, 400 MHz): δ 1.58 (s, 9H), 2.44 (s, 6H), 5.15 (s, 2H), 6.48 (d, 2.0 Hz, 1H), 6.58 (d, 2.8 Hz, 1H), 7.11 (d, 2.0 Hz, 1H), 7.47-7.52 (m, 4H), 7.66 (d, 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 8.29 (d, 2.8 Hz, 1H), 9.97 (s, 1H). LCMS (Method A): 2.672 min, MS: ES+ 665.00 (M + 23) Using tert-butyl 3-((2-formyl-3,5- bis(tosyloxy)phenoxy)methyl)-1H- pyrazole-1-carboxylate Intermediate 15 32 2-((4- fluorobenzyl)oxy)-3- methyl-4,6- bis(tosyloxy)benzoic acid [00184] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.84 (s, 3H), 2.45 (d, J = 1.2 Hz, 6H), 4.79 (s, 2H), 6.72 (s, 1H), 7.19-7.23 (m, 2H), 7.37-7.40 (m, 2H), 7.50-7.53 (m, 4H), 7.72- 7.74 (m, 4H), 13.75 (s, 1H). LCMS (Method A): 2.517 min, MS: ES+ 623.1 (M + 23) Using 5-((4-fluorobenzyl)oxy)-4- formyl-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) Intermediate 16 33 3-methyl-2-((3- methylbenzyl)oxy)- 4,6- bis(tosyloxy)benzoic acid [00185] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.84 (s, 3H), 2.30 (s, 3H), 2.44 (s, 6H), 4.75 (s, 2H), 6.71 (s, 1H), 7.13-7.16 (m, 3H), 7.23-7.25 (m, 1H), 7.49-7.52 (m, 4H), 7.73 (d, J = 8.4 Hz, 4H), 13.75 (s, 1H). LCMS (Method A): 2.583 min, MS: ES+ 619.1 (M + 23) Using 4-formyl-6-methyl-5-((3- methylbenzyl)oxy)-1,3-phenylene bis(4-methylbenzenesulfonate) Intermediate 17 34 3-methyl-2-(pyridin- 2-ylmethoxy)-4,6- bis(tosyloxy)benzoic acid [00186] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.85 (s, 3H), 2.44 (d, J = 1.6 Hz, 6H), 4.89 (s, 2H), 6.74 (s, 1H), 7.37-7.40 (m, 1H), 7.48-7.52 (m, 5H), 7.72-7.74 (m, 4H), 7.85- 7.89 (m, 1H), 8.54 (d, J = 4.4 Hz, 1H), 13.75 (s, 1H). LCMS (Method A): 2.112 min, MS: ES+ 584.1 (M + 1) Using 4-formyl-6-methyl-5- (pyridin-2-ylmethoxy)-1,3- phenylene bis(4- methylbenzenesulfonate) Intermediate 18 35 3-Methyl-2-((1- methyl-1H-pyrazol- 3-yl)methoxy)-4,6- bis(tosyloxy)benzoic acid [00187] 1H NMR (DMSO-d6, 400 MHz): δ 1.80 (s, 3H), 2.45 (s, 6H), 3.83 (s, 3H), 4.72 (s, 2H), 6.14 (d, 2.0 Hz, 1H), 6.71 (s, 1H), 7.49- 7.52 (m, 4H), 7.64 (d, 2.0 Hz, 1H), 7.63-7.78 (m, 4H). LCMS (Method E): 2.249 min, MS: ES+ 587.16 (M + 1) Using 4-formyl-6-methyl-5-((1- methyl-1H-pyrazol-3-yl)methoxy)- 1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 19 36 2-((1-tosyl-1H-1,2,3- triazol-4- yl)methoxy)-4,6- bis(tosyloxy)benzoic acid [00188] LCMS (Method A): 2.228 min, MS: ES+ 560.10 (M − 155, tosyl) Using 4-formyl-5-((1-tosyl-1H- 1,2,3-triazol-4-yl)methoxy)-1,3- phenylene bis(4- methylbenzenesulfonate) Intermediate 38 58 2-(2-(Benzyloxy)- 4,6-dihydroxy-3- methylbenzoyl) isoindoline-5- carboxylic acid [00189] LCMS (Method A): 1.555 min, MS: ES+ 420.20 (M + 1). Using methyl 2-(2-(benzyloxy)-3- methyl-4,6- bis(tosyloxy)benzoyl)isoindoline- 5-carboxylate 59 2-(2-(Benzyloxy)- 4,6-dihydroxy-3- methylbenzoyl) isoindoline-4- carboxylic acid [00190] .sup.1H NMR (DMSO-d6, 400 MHz) compound is a mixture of rotamers: δ 1.98 (s, br, 3H), 4.11- 4.13 (m, 2H), 4.46-4.72 (m, 2H), 4.85-5.01 (m, 2H), 6.31 (s, 1H), 7.23-7.96 (m, 8H), 9.51-9.59 (m, 2H), 13.02 (s, br, 1H). LCMS (Method A): 1.728 min, MS: ES+ 420.17 (M + 1). Using methyl 2-(2-(benzyloxy)-3- methyl-4,6- bis(tosyloxy)benzoyl)isoindoline- 4-carboxylate 60 2-Methoxy-3-methyl- 4,6- bis(tosyloxy)benzoic acid [00191] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.85 (s, 3H), 2.45 (s, 6H), 3.64 (s, 3H), 6.66 (s, 1H), 7.49-7.52 (m, 4H), 7.72-7.73 (m, 4H), 13.60 (bs, 1H). LCMS (Method A): 2.137 min, MS: ES+ 507.02 Using 4-formyl-5-methoxy-6- methyl-1,3-phenylene bis(4- methylbenzenesulfonate) (Intermediate 54) 61 2-Ethoxy-3-methyl- 4,6- bis(tosyloxy)benzoic acid [00192] .sup.1H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ 1.16-1.24 (m, 3H), 1.84 and 2.00 (singlets, 3H), 2.44- 2.51 (s, br, 6H), 3.78-3.83 and 4.00-4.06 (m, 2H), 6.66 and 6.68 (singlets, 1H), 7.49-7.58 (m, 4H), 7.71-7.80 (m, 4H), 13.59 (s, 1H). LCMS (Method A): 2.455 min, MS: ES+ 521.12 (M + 1). Using 5-ethoxy-4-formyl-6-methyl- 1,3-phenylene bis(4- methylbenzenesulfonate) (Intermediate 55) 62 2- (Cyclohexylmethoxy)- 3-methyl-4,6- bis(tosyloxy)benzoic acid [00193] .sup.1H NMR (DMSO-d6, 400 MHz): δ 0.95-1.10 (m, 2H), 1.11-1.22 (m, 3H), 1.61-1.69 (m, 6H), 1.82 (s, br, 3H), 2.44 (s, br, 6H), 3.54 (m, br, 2H), 4.03 (q, J = 6.8 Hz, 14.0 Hz, 2H), 6.69 (s, 1H), 7.49- 7.52 (m, 4H), 7.70-7.73 (m, 4H), 13.59 (s, 1H). LCMS (Method A): 2.657 min, MS: ES+ 589.2 (M + 1). Using 5-(cyclohexylmethoxy)-4- formyl-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 56) 63 2- (Cyclopropylmethoxy)- 3-methyl-4,6- bis(tosyloxy)benzoic acid [00194] .sup.1H NMR (DMSO-d6, 400 MHz): δ 0.12-0.16 (m, 2H), 0.44-0.47 (m, 2H), 1.00-1.10 (m, 1H), 1.83 (s, 3H), 2.43 (s, 6H), 3.58-3.64 (m, 2H), 6.69 (s, 1H), 7.48-7.51 (m, 4H), 7.70-7.77 (m, 4H), 13.58 (bs, 1H). LCMS (Method A): 2.487 min, MS: ES+ 569.2 (M + 23). Using 5-(cyclopropylmethoxy)-4- formyl-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 57)

Additional Procedures

Synthesis of 4-formyl-5-(prop-2-yn-1-yloxy)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 37) (Reaction Scheme Shown in FIG. 12)

[0954] To a solution of 4-formyl-5-hydroxy-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 1) (2.0 g, 4.32 mmol, 1.0 eq) in DMF (20 mL) was added K.sub.2CO.sub.3 (1.8 g, 13.0 mmol, 2.0 eq) at 000 under a nitrogen atmosphere. 3-Bromoprop-1-yne (CAS #106-96-7) (0.613 g, 5.2 mmol, 1.5 eq) was added dropwise to the reaction mixture at 0° C. The reaction was stirred at room temperature overnight. The resulting reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×30 mL) yielding 4-formyl-5-(prop-2-yn-1-yloxy)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 37) (3.0 g, 74% yield). This material was progressed to the next step without further purification.

[0955] .sup.1H NMR (CDCl3-d6, 400 MHz): δ 2.48 (s, 3H), 2.49 (s, 3H), 3.51 (s, 1H), 4.73-4.75 (m, 2H), 6.60 (d, J=2.0 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H), 7.35-7.40 (m, 4H), 7.75-7.78 (m, 4H), 10.09 (s, 1H). LCMS (Method B): 2.820 min, MS: ES+502.01 (M+1)

Synthesis of 4-formyl-5-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 38)

[0956] To a solution of 4-formyl-5-(prop-2-yn-1-yloxy)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 37) (2.0 g, 4.00 mmol, 1.0 eq) in toluene (20 mL) was added copper(I) thiophene-2-carboxylate (0.030, 0.16 mmol, 0.04 eq) at 0° C. under nitrogen atmosphere. p-Toluenesulfonyl azide (0.0.945 g, 4.8 mmol, 1.2 eq) was added to the reaction mixture at 0° C. The reaction was stirred at room temperature for 2 h and the resulting reaction mixture diluted with water (100 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layer was dried under reduced pressure. The obtained crude material was purified by column chromatography (product eluted with 1% MeOH in DCM) yielding 4-formyl-5-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 38) (2.8 g, 19% yield).

[0957] .sup.1H NMR (CDCl3, 400 MHz): δ 2.47 (s, 3H), 2.49 (s, 6H), 5.17 (s, 2H), 6.59 (d, J=2.0 Hz, 1H), 6.80 (d, J=2.0 Hz, 1H), 7.33-7.43 (m, 6H), 7.71-7.75 (m, 4H), 8.03-8.06 (m, 2H), 8.31 (s, 1H), 10.05 (s, 1H). LCMS (Method B): 3.02 min, MS: ES+699.52 (M+1)

Synthesis of N,N-Dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)methanamine (Intermediate 42) (Reaction Scheme Shown in FIG. 13)

2-(t-Butyl) 7-methyl 3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate

[0958] To a stirred solution of t-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (5.0 g, 16.0 mmol, 1.0 eq) in MeOH (66 mL) and MeCN (16 mL) in an autoclave was added TEA (3.23 g, 3.20 mmol, 2.0 eq) at room temperature. The reaction mixture was degassed (N.sub.2 gas) for 15 min. PdCl.sub.2(dppf) (0.93 g, 1.28 mmol, 0.08 eq) was added and 22 kg/cm.sup.2 CO.sub.(gas) pressure was applied with heat (100° C.) for 16 h. The reaction mixture was concentrated under vacuum and the crude material purified by flash column chromatography (220-400 silica; product eluted by 2.5% ethyl acetate in hexane) to give the title compound (3.5 g, 12.02 mmol, Yield: 75%).

[0959] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.43 (s, 9H), 2.84 (t, J=6 Hz, 2H), 3.56 (t, J=5.6 Hz, 2H), 3.81 (s, 3H), 4.56 (m, 2H), 7.31 (d, J=8 Hz, 1H), 7.74-7.78 (m, 2H). LCMS (Method A): 2.111 min, MS: ES+192.18 (M+1-100).

2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid

[0960] To a stirred solution of 2-(t-butyl) 7-methyl 3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate (3.5 g, 12.02 mmol, 1.0 eq.) in MeOH: water (9:1) (50 mL) was added NaOH (2.40 g, 60.1 mmol, 5.0 eq.) at room temperature and the mixture stirred for 3 h. The resulting mixture was poured into water (60 mL) and neutralized (dil. HCl), extracted with ethyl acetate (3×90 mL) and the combined organic layer dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Crude material was purified by trituration using n-pentane (250 mL) yielding the title compounds as a brown oil (3.5 g, 12.63 mmol. Yield: 100%).

[0961] .sup.1H NMR (DMSO-d6, 400 MHz): δ ppm 1.42 (s, 9H), 2.75 (t, J=5.6 Hz, 2H), 3.52-3.55 (m, 2H), 4.48 (brs, 2H), 7.05 (d, J=7.6 Hz, 1H), 7.66-7.694 (m, 2H). —COOH proton not observed. LCMS (Method A): 1.783 min, MS: ES+178.17 (M−100)

t-Butyl 7-(dimethylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0962] A stirred solution of 2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (2.5 g, 9.2 mmol, 1.0 eq) in DMF (25 mL) at 0° C. was treated with HATU (5.14 g, 13.53 mmol, 1.5 eq), DIPEA (2.32 g, 18.04 mmol, 2.0 eq) and dimethyl amine (2M in THF) (0.44 g, 99.23 mmol, 1.1 eq.) added dropwise. The reaction was allowed to warm to room temperature and stirred for 1 h. Reaction completion was monitored by TLC (DCM: MeOH; 9:1). The reaction mixture was diluted with ethyl acetate (45 mL), washed with chilled brine solution (4×50 mL); the organic layer dried Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography (product eluted with 4% methanol in DCM) yielding the title compound as an off white solid (2.1 g, 11.49 mmol. Yield: 76%).

[0963] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.44 (s, 9H), 2.80 (t, J=6 Hz, 2H), 2.92-2.97 (2 singlets, 6H), 3.57 (t, J=6 Hz, 2H), 4.52 (s, 2H), 7.21-7.22 (m, 3H). LCMS (Method A): 1.687 min, MS: ES+249.05 (M−56).

N,N-Dimethyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide (Intermediate 42a)

[0964] tert-Butyl 7-(dimethylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.1 g, 6.90 mmol, 1.0 eq.) in DCM (21 mL) at 0° C. was treated dropwise with TFA (2.1 mL) and the reaction mixture stirred at room temperature for 1 h. The resulting reaction mixture was concentrated under reduced pressure, poured into water (60 mL) and neutralized with 1M NaOH solution and extracted using DCM (5×60 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound as an oil (1.8 g, 8.81 mmol. Yield: 78%).

[0965] .sup.1H NMR (DMSO-d6, 400 MHz): 2.74-2.85 (t, br, 2H), 2.92-2.94 (singlets, broad, 6H), 2.93-3.03 (t, br, 2H), 3.91 (s, br, 2H), 7.08-7.30 (m, 3H). LCMS (Method B): 0.463 min, MS: ES+205.25 (M+1).

N,N-Dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)methanamine (Intermediate 42)

[0966] N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide (Intermediate 42a) (0.2 g, 0.97 mmol, 1.0 eq.) in THF (2 ml) at 0° C. was treated dropwise with LiAlH.sub.4 (1M in THF) (2.84 mL, 2.9 eq). The resulting reaction mixture was heated to 80° C. and stirred for 3 h. Reaction completion was monitored by TLC (methanol: DCM 8:2). The reaction mixture was allowed to cool to 0° C. and basified (1M NaOH), extracted with ethyl acetate (3×25 mL) and the combined organic layer dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure yielding the title compound as yellow oil (0.18 g, 0.94 mmol, Yield: 97%).

[0967] .sup.1H NMR (DMSO-d6, 400 MHz): 2.64-2.67 (t, br, 2H), 2.92-2.94 (t, br, 2H), 3.23-3.34 (2 singlets, br, 6H), 3.81 (s, br, 2H), 6.90-7.04 (m, 3H). LCMS (Method B): 1.52 min, MS: ES+191.28 (M+1).

Synthesis of N,N-Dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)methanamine (Intermediate 43) (Reaction Scheme Shown in FIG. 14)

2-(t-Butyl) 6-methyl 3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate

[0968] A stirred solution of t-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (5.0 g, 16.0 mmol, 1.0 eq.) in methanol (45 mL) and acetonitrile (10 mL) was treated with PdCl.sub.2(dppf) (0.95 g, 1.28 mmol, 0.08 eq) and TEA (3.23 g, 3.20 mmol, 2.0 eq) in an autoclave. The resulting reaction mixture was taken 22 kg/cm.sup.2 CO(g) pressure and heated to 100° C. for 24 h. The cooled reaction mixture was filtered through a celite bed, washed with ethyl acetate (50 mL) and the combined filtrate concentrated under vacuum. The obtained crude material was purified by flash chromatography (product eluted by 5% ethyl acetate in hexane) yielding the title compound (3.8 g, 13.04 mmol. Yield: 81.4%).

[0969] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.43 (s, 9H), 2.85 (t, J=6.0 Hz, 2H), 3.57 (t, J=6.0 Hz, 2H), 3.84 (s, 3H), 4.57 (s, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.76-7.77 (m, 2H). LCMS (Method A): 2.233 min, MS: ES+192.18 (M+1-100).

2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid

[0970] To a stirred solution of 2-(tert-butyl) 6-methyl 3,4-dihydroisoquinoline-2,6(1/H)-dicarboxylate (3.8 g, 13.0 mmol, 1.0 eq.) in methanol:water (1:1) (20 mL) at room temperature was added NaOH (2.6 g, 65.0 mmol, 5.0 eq.). The resulting reaction mixture was heated to 70° C. and stirred for 2 h. The resulting mixture was allowed to cool to 0-5° C., acidified using 1 N HCl solution and extracted with ethyl acetate (3×30 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and distilled under vacuum yielding the title compound as a brown oil (3.5 g, 13.7 mmol, Yield: 97.2%).

[0971] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.43 (s, 9H), 2.84 (t, J=5.6 Hz, 2H), 3.57 (t, J=5.6 Hz, 2H), 4.56 (s, 2H), 7.29 (d, J=8.0 Hz, 1H), 7.74-7.75 (m, 2H), 12.90 (s, 1H). LCMS (Method A): 1.837 min, MS: ES, 178.17 (M+1-100).

tert-butyl 6-(dimethylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0972] To a stirred solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (3.5 g, 12.6 mmol, 1.0 eq) in DMF (10 ml) at 0° C.-5° C. were added HATU (7.19 g, 18.9 mmol, 1.5 eq) and DIPEA (3.25 g, 25.4 mmol, 2.0 eq). The reaction mixture was stirred for 30 mins at 0° C.-5° C. Dimethyl amine (2M in THF) (6.94 mL, 13.88 mmol, 1.1 eq.) was added dropwise at 0-5° C. The resulting reaction was gradually raised to room temperature and stirred for 16 h. Reaction completion was monitored by TLC (ethyl acetate: hexane 1:1). The reaction mixture was poured onto ice-cold water (100 mL), extracted into ethyl acetate (2×50 mL) and the combined organic layer washed with cold water (50 mL), dried with Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography (eluting product with 4% methanol in DCM) to give the title compound (3.5 g, 11.49 mmol. Yield: 91.14%).

[0973] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.43 (s, 9H), 2.79 (t, J=6.0 Hz, 2H), 2.96-2.99 (singlets, br, 6H), 3.56 (t, J=6.0 Hz, 2H), 4.52 (s, 2H), 7.20-7.24 (m, 3H). LCMS (Method A): 1.775 min, MS: ES+249.05 (M−56).

N,N-Dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (Intermediate 43a)

[0974] To a stirred solution of t-butyl 6-(dimethyl carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.5 g, 11.50 mmol, 1.0 eq.) in DCM (4 mL) at 0-5° C. was treated dropwise with TFA (17.5 mL). The resulting reaction mixture was stirred at room temperature for 2 h. Reaction completion was monitored by TLC (methanol: DCM 9:1). The resulting reaction was concentrated, and remaining TFA was removed by co-distillation with DCM (2×10 mL) followed by n-pentane (10 mL); the crude material was dried over high vacuum to give crude material as the TFA salt (3.6 g). Of this material, 1.6 g was taken into DCM (30 mL), cooled to 0-5° C., basified using 1N NaOH solution and extracted with dichloromethane (3×30 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give the title compound (0.9 g, 4.40 mmol. Yield: 88.53%).

[0975] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.70 (t, J=5.2 Hz, 2H), 2.91-2.96 (m, 8H), 3.87 (s, 2H), 7.04-7.13 (m, 3H). LCMS (Method B): 1.40 min, MS: ES+205.25 (M+1).

N,N-Dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)methanamine (Intermediate 43)

[0976] A stirred solution of N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (Intermediate 43a) (0.5 g, 2.44 mmol, 1.0 eq.) in THF (5 mL) at 0-5° C. was treated dropwise with LiAlH.sub.4 (2M in THF) (3.54 mL, 2.9 eq) and stirred for 10 mins. The resulting reaction mixture was heated to 75° C. and stirred for 3 h. Reaction completion was monitored by TLC (DCM: MeOH 4:1). The reaction mixture was allowed to cool to 0-5° C., basified using 1N NaOH solution and extracted with dichloromethane (2×20 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound as yellow oil (0.350 g, 1.84 mmol, Yield: 75.43%).

[0977] .sup.1H NMR (DMSO-d6, 400 MHz): δ 2.09-2.11 (m, 6H), 2.64-2.65 (m, 2H), 2.90-2.91 (m, 2H), 3.27-3.29 (m, 2H), 3.78-3.80 (m, 2H), 6.93-6.99 (m, 3H). LCMS (Method B): 1.39 min, MS: ES+191.28 (M+1).

Synthesis of 1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (Intermediate 44)

[0978] ##STR00195##

Methyl isoquinoline-1-carboxylate

[0979] A stirred solution of isoquinoline-1-carboxylic acid (7.0 g, 40.46 mmol, 1.0 eq) (CAS: 486-73-7) in MeOH (350 mL) at room temperature was treated dropwise with cH.sub.2SO.sub.4 (15 mL). The reaction mixture was heated to 65° C. and stirred for 5 h. The reaction mixture was carefully poured into saturated NaHCO.sub.3 (50 mL) and extracted with DCM (500 mL). The aq. layer was extracted with DCM (200 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure yielding the title compound (4.7 g, 25.10 mmol. Yield: 62.16%).

[0980] LCMS (Method A): 1.484 min, MS: ES+188.13 (M+1).

Isoquinolin-1-ylmethanol

[0981] A stirred solution of methyl isoquinoline-1-carboxylate (4.5 g, 24.03 mmol, 1.0 eq) in THF (350 mL) and EtOH (40 mL) at room temperature were treated with NaBH.sub.4 (1.8 g, 48.07 mmol, 2.0 eq) and LiCl (2.03 g, 48.07, 2.0 eq). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was quenched into ice cold water (200 mL) and extracted with DCM (2×200 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography (product eluted in 2% MeOH in DCM) yielding the title compound (1.2 g, 7.53 mmol. Yield: 39.16%).

[0982] .sup.1H NMR (DMSO-d6, 400 MHz): δ 5.05 (d, J=5.2 Hz, 2H), 5.42 (t, J=5.2 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.76-7.80 (m, 2H), 7.98 (d, J=8 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.42 (d, J=5.6 Hz, 1H). LCMS (Method A): 0.376 min, MS: ES+160.12 (M+1).

1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (Intermediate 44)

[0983] A stirred solution of isoquinolin-1-ylmethanol (1.0 g, 6.28 mmol, 1.0 eq) in MeOH (100 mL) at room temperature in autoclave was treated with PtO.sub.2 monohydrate (0.129 g, 0.56 mmol, 0.09 eq). The resulting reaction mixture was stirred at room temperature for 16 h under 60 psi pressure of H.sub.2 (gas). Reaction completion was monitored by TLC (DCM: MeOH; 9:1). The reaction mixture was filtered through celite bed and concentrated under reduced pressure yielding the title compound (0.85 g, 5.20 mmol. Yield: 85.0%,).

[0984] LCMS (Method B): 1.46 min, MS: ES+164.16 (M+1). The crude material was used in next step without purification.

Synthesis of (1,2,3,4-tetrahydroisoquinolin-4-yl)methanol (Intermediate 45)

[0985] ##STR00196##

Isoquinoline-4-carbaldehyde

[0986] A stirred solution of 4-bromoisoquinoline (4.0 g, 19.4 mmol, 1.0 eq) (CAS: 532-97-4) in THF (40 ml) at −78° C. was treated dropwise with n-BuLi (8.5 mL, 21.3 mmol, 1.1 eq), then DMF (2.8 mL, 38.8 mmol, 2.0 eq) was added dropwise; the resulting reaction mixture was stirred at -780C for 30 min. The reaction mixture was poured into saturated solution of NH.sub.4Cl (50 mL) and extracted with diethyl ether (4×25 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude was purified by flash chromatography using neutral alumina; (product eluted in 5% EtOAc in hexane) yielding the title compound (1.8 g, 11.46 mmol. Yield: 37.07%).

[0987] .sup.1H NMR (DMSO-d6, 400 MHz): δ 7.85 (t, J=7.2 Hz, 1H), 8.01-8.05 (m, 1H), 8.32 (d, J=8 Hz, 1H), 9.07-9.10 (m, 2H), 9.61 (s, 1H), 10.42 (s, 1H). LCMS (Method A): 1.369 min, MS: ES+158.0 (M+1).

Isoquinolin-4-ylmethanol

[0988] A stirred solution of isoquinoline-4-carbaldehyde (1.8 g, 11.4 mmol, 1.0 eq) in EtOH (260 mL at room temperature) was treated with NaBH.sub.4 (0.43 g, 11.4 mmol, 1.0 eq) added portionwise. The reaction mixture was stirred at room temperature for 40 min. Water (100 mL) was added to the reaction mixture and stirred for 20 minutes. AcOH (4.1 mL, 68.4 mmol, 6.0 eq) was added drop wise to the reaction mixture at room temperature. The reaction mixture was extracted with DCM (200 mL) and washed with saturated solution of NaHCO.sub.3 (50 mL). The combined organic layer was dried by Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The crude was purified by flash chromatography (product eluted in 30% EtOAc in hexane) yielding the title compound (0.7 g, 4.39 mmol. Yield: 38.4%).

[0989] .sup.1H NMR (DMSO-d6, 400 MHz): δ 4.94 (d, J=5.0 Hz, 2H), 5.40 (t, J=5.2 Hz 1H), 7.70 (t, J=7.6 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 8.14 (d, J=8.4 Hz, 2H), 8.48 (s, 1H), 9.24 (s, 1H). LCMS (Method A): 0.264 min, MS: ES+160.2 (M+1).

(1,2,3,4-tetrahydroisoquinolin-4-yl)methanol (Intermediate 45)

[0990] A stirred solution of isoquinolin-4-ylmethanol (0.5 g, 3.14 mmol, 1.0 eq) in MeOH (20 mL) in an autoclave at room temperature was treated with PtO.sub.2 monohydrate (0.064 g, 0.28 mmol, 0.09 eq); 60 psi of H.sub.2(gas) was applied and the mixture stirred for 16 h at room temperature. The reaction mixture was filtered through a small Millipore filter, washed with MeOH (3×25 mL) and the combined filtrate concentrated under vacuum yielding the tile compound (0.19 g, 1.16 mmol. Yield: 19.7%).

[0991] LCMS (Method A): 1.67 min, MS: ES+164.16 (M+1).

Synthesis of 1-(isoindolin-5-yl)N,N-dimethylmethanamine hydrochloride (Intermediate 46) (Reaction Scheme Shown in FIG. 15)

t-Butyl-5-(bromomethyl)isoindoline-2-carboxylate

[0992] To a stirred solution of t-butyl 5-(hydroxymethyl) isoindoline-2-carboxylate (3.0 g, 12.0 mmol, 1.0 eq) in DCM (30 mL) at 0° C. were added PPh.sub.3 (4.73 g, 18.04 mmol, 1.5 eq) and CBr.sub.4 (2.99 g, 18.04 mmol, 1.5 eq). The resulting reaction mixture was stirred at room temperature for 3 h and then evaporated under reduced pressure. The crude material was purified by flash chromatography (product eluted in 20% EtOAc/hexane) yielding the title compound (2.7 g, 8.64 mmol. Yield: 71.05%).

[0993] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.45 (s, 9H), 4.57 (d, J=8.4 Hz, 4H), 4.72 (s, 2H), 7.30-7.41 (m, 3H). LCMS (Method A): 2.278 min. MS: ES+212.1 (M−100).

t-Butyl 5-((dimethylamino)methyl)isoindoline-2-carboxylate

[0994] A stirred solution of t-butyl 5-(bromomethyl) isoindoline-2-carboxylate (1.5 g, 4.80 mmol, 1.0 eq) in DMF (10 mL) at room temperature was treated with K.sub.2CO.sub.3 (4.65 g, 33.6 mmol, 7.0 eq) and stirred for 20 min. Dimethylamine. HCl (0.980 g, 12.0 mmol, 2.5 eq) was added to the reaction mixture at room temperature and stirred for 16 h. The resulting reaction mixture was poured onto ice-cold water (100 mL) and extracted into ethyl acetate (3×30 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography (product eluted in 8% ethyl acetate in hexane) to give the title compound (0.550 g, 1.99 mmol. Yield: 41.41%).

[0995] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.53 (s, 9H), 2.90 (s, 3H), 2.98 (s, 3H), 4.66-4.70 (m, 4H), 7.21-7.33 (m, 3H). LCMS (Method A): 1.074 min, MS: ES+277.21 (M+1).

1-(isoindolin-5-yl)N,N-dimethylmethanamine hydrochloride (Intermediate 46)

[0996] A stirred solution of t-butyl 5-((dimethylamino)methyl)isoindoline-2-carboxylate (0.55 g, 1.98 mmol, 1.0 eq.) in DCM (5 mL) at 0-5° C. was treated with 4M HCl in dioxane (5 mL). The resulting reaction mixture stirred at room temperature for 16 h. Reaction completion was monitored by TLC (methanol: DCM 9:1). The resulting reaction mixture was evaporated under reduced pressure and the crude material was triturating using diethyl ether (5 mL) yielding the title compound (0.350 g, 1.98 mmol, Yield: 100%) which was used in next step without purification.

[0997] LCMS (Method B): 1.28 min, MS: ES+177.13 (M+1).

Synthesis of 4-(isoindolin-5-ylmethyl) morpholine hydrochloride (Intermediate 47)

[0998] ##STR00197##

t-Butyl 5-(morpholinomethyl)isoindoline-2-carboxylate

[0999] Conducted as two parallel batches of 0.35 g. A stirred solution of t-butyl 5-formylisoindoline-2-carboxylate (0.35 g, 1.41 mmol, 1.0 eq) in MeOH (5 mL) at room temperature was treated with morpholine (0.12 g, 1.41 mmol, 1.0 eq) and ZnCl.sub.2 (0.09 g, 0.70 mmol, 0.5 eq). The resulting reaction mixture was heated to 70° C. and stirred for 6 h. NaCNBH.sub.3 (0.17 g, 2.82 mmol, 2.0 eq) was added portionwise to the reaction mixture at 0° C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum, the crude material was poured into water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer washed with brine solution (2×50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography (product eluted in 3% MeOH in DCM) yielding the title compound (0.61 g, 1.91 mmol. Yield: 67.6%).

[1000] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.45 (s, 9H), 2.33-2.34 (m, 4H), 3.45 (s, 2H), 3.55-3.57 (m, 4H), 4.48-4.56 (m, 4H), 7.20-7.28 (m, 3H). LCMS (Method A): 1.192 min, MS: ES+319.26 (M+1).

4-(isoindolin-5-ylmethyl) morpholine hydrochloride (Intermediate 47)

[1001] To a stirred solution of t-butyl 5-(morpholinomethyl)isoindoline-2-carboxylate (0.25 g, 0.78 mmol, 1.0 eq) in DCM (2 mL) was added 4M HCl in 1,4-dioxane (2.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the crude material triturated using diethyl ether (2×20 mL) to give the title compound (0.26 g, 1.19 mmol, Yield 100%).

[1002] .sup.1H NMR (DMSO-d6, 400 MHz): δ 3.06-3.09 (m, 2H), 3.18-3.21 (m, 2H), 3.80-3.93 (m, 4H), 4.34-4.35 (m, 2H), 4.52 (s, br, 4H), 7.48 (d, J=8 Hz, 1H), 7.63-7.65 (m, 2H), 10.20 (s, 2H)._LCMS (Method A): 1.54 min, MS: ES+219.33 (M+1).

Synthesis of 4-((4-Methylpiperazin-1-yl)methyl) isoindoline hydrochloride (Intermediate 48) (Reaction Scheme Shown in FIG. 16)

t-Butyl-4-(hydroxymethyl)isoindoline-2-carboxylate

[1003] A stirred solution of 2-(t-butyl)-4-methyl isoindoline-2, 4-dicarboxylate (4.0 g, 14.4 mmol, 1.0 eq) in THF (80 mL) at 0° C. was treated dropwise with LiAlH.sub.4 solution (1.0 M in THF) (14.4 mL, 14.4 mmol, 1.0 eq). The resulting reaction mixture was stirred at 0° C. for 1 h and carefully poured onto ice cold saturated NH.sub.4Cl in water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum yielding the title compound (3.5 g, 14.05 mmol. Yield: 97.34%).

[1004] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.46 (s, 9H), 4.46-4.48 (m, 2H), 4.56-4.59 (m, 4H), 5.16-5.20 (m, 1H), 7.21-7.28 (m, 3H). LCMS (Method A): 1.609 min, MS: ES+150.1 (M−100).

t-Butyl 4-formylisoindoline-2-carboxylate

[1005] To a stirred solution of t-butyl 4-(hydroxymethyl) isoindoline-2-carboxylate (3.5 g, 14.04 mmol, 1.0 eq) in DCM (70 mL) was added MnO.sub.2 (35 g, 10% w/w) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h, filtered through a celite bed, washed with 10% MeOH in DCM (3×100 mL) and the combined filtrate concentrated under vacuum. The crude material was purified by flash chromatography (product eluted with 8% ethyl acetate in n-hexane) to give the title compound (2.0 g, 8.08 mmol. Yield: 57.6%).

[1006] .sup.1H NMR (DMSO-d6, 400 MHz): 1.46-1.47 (m, 9H), 4.61 (d, J=10.4 Hz, 2H), 4.83 (d, J=8 Hz, 2H), 7.58 (t, J=6.4 Hz, 1H), 7.67 (t, J=5.6 Hz, 1H), 7.90 (d, J=6.0 Hz, 1H), 10.06 (d, J=5.6 Hz, 1H). LCMS (Method A): 1.993 min, MS: ES+192.1 (M−56).

t-Butyl-4-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate

[1007] Three batches of 0.3 g scale progressed in parallel. A stirred solution of t-butyl 4-formylisoindoline-2-carboxylate (0.3 g, 1.21 mmol, 1.0 eq) in MeOH (10 mL) at room temperature was treated with N-methyl piperazine (0.121 g, 1.21 mmol, 1.0 eq) and ZnCl.sub.2 (0.078 g, 0.60 mmol, 0.5 eq). The reaction mixture was heated to 70° C. and stirred for 16 h. NaCNBH.sub.3 (0.152 g, 2.42 mmol, 2.0 eq) was added portionwise to the reaction mixture at 0° C. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum, poured into water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed by brine solution (30 mL), dried with Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography (product eluted with 4% MeOH in DCM) to give the title compound (0.6 g, 1.80 mmol. Yield 49.7%).

[1008] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.46 (s, 9H), 2.61-2.63 (m, 5H), 2.95-2.97 (m, br, 4H), 3.34-3.35 (m, br, 4H), 4.57-4.63 (m, 4H), 7.19-7.25 (m, 3H). LCMS (Method A): 1.212 min, MS: ES+332.37 (M+1).

4-((4-Methylpiperazin-1-yl)methyl) isoindoline hydrochloride (Intermediate 48)

[1009] To a stirred solution of t-butyl 4-((4-methylpiperazin-1-yl) methyl)isoindoline-2-carboxylate (0.3 g, 0.9 mmol, 1.0 eq) in DCM (2 mL) was added 4M HCl in dioxane (1 mL) at 0° C. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum yielding the title compound which was used directly in the next step (0.3 g, Yield: quantitative, 1.29 mmol).

[1010] LCMS (Method A): 0.165 min, MS: ES+232.19 (M+1).

Synthesis of 4-(isoindolin-4-ylmethyl)morpholine hydrochloride (Intermediate 49)

[1011] ##STR00198##

t-Butyl 4-(morpholinomethyl)isoindoline-2-carboxylate

[1012] 2 Batches of 0.4 g scale were progressed in parallel. A stirred solution of t-butyl 4-formylisoindoline-2-carboxylate (0.4 g, 1.62 mmol, 1.0 eq) in MeOH (5 mL) at room temperature were treated with morpholine (0.169 g, 1.94 mmol, 1.2 eq) and ZnCl.sub.2 (0.110 g, 0.810 mmol, 0.5 eq). The reaction mixture was heated to 70° C. and stirred for 16 h. NaCNBH.sub.3 (0.203 g, 3.23 mmol, 2.0 eq) was added portion wise to the reaction mixture at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum and the crude material purified by flash chromatography (product eluted with 30% ethyl acetate in hexane) to give the title compound (0.6 g, 1.89 mmol. Yield: 58.25%).

[1013] .sup.1H NMR (DMSO-d6, 400 MHz): δ ppm 1.45-1.46 (m, 9H), 2.33 (m, br, 4H), 3.43 (s, 2H), 3.55-3.56 (m, 4H), 4.56-4.64 (m, 4H), 7.18-7.24 (m, 3H). LCMS (Method A): 1.221 min, MS: ES+319.2 (M+1).

4-(isoindolin-4-ylmethyl)morpholine hydrochloride (Intermediate 49)

[1014] A stirred solution of t-butyl 4-(morpholinomethyl)isoindoline-2-carboxylate (0.6 g, 1.89 mmol, 1.0 eq) in DCM (5 mL) was cooled to 0° C. and 4M HCl in dioxane (6 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and the crude material triturated using n-pentane (3×10 mL) followed by diethyl ether (10 mL) and dried under high vacuum yielding to give the title compound as a pink solid (0.6 g, 2.36 mmol. Yield 100%).

[1015] .sup.1H NMR (DMSO-d6, 400 MHz): δ 3.16-3.27 (m, 4H), 3.85-3.93 (m, 4H), 4.34-4.35 (m, 2H), 4.51-4.54 (m, 2H), 4.81-4.84 (m, 2H), 7.44-7.51 (m, 2H), 7.68-7.70 (m, 1H), 10.2 (s, 2H). LCMS (Method B): 1.65 min, MS: ES+219.03 (M+1).

Synthesis of N-(tetrahydrofuran-3-yl)isoindolin-4-amine hydrochloride salt (Intermediate 50)

[1016] ##STR00199##

t-Butyl 4-((tetrahydrofuran-3-yl) amino) isoindoline-2-carboxylate

[1017] t-Butyl 4-bromoisoindoline-2-carboxylate (1.00 g, 3.36 mmol, 1 eq), tetrahydrofuran-3-amine hydrochloride (0.624 g, 5 mmol, 1.5 eq) and 1, 4-dioxane (5 mL) were placed in a 35 mL microwave glass tube and the mixture degassed at room temperature using N.sub.2 gas for 30 min. NaOtBu (0.805 g, 8.38 mmol, 2.5 eq) and Brettphos (0.108 g, 0.20 mmol, 0.06 eq) were added to reaction mixture and again purged with N.sub.2 for 10 min. Pd.sub.2(dba).sub.3 (0.092 g, 0.10 mmol, 0.03 eq) was added and the reaction heated to 110° C. under microwave irradiation for 1.5 h. The reaction mixture was filtered through celite and washed with ethyl acetate (2×50 mL). The combined filtrate was poured to ice-cold water (100 mL) and extracted in ethyl acetate (3×100 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The crude material was purified by flash chromatography (product eluted in 20% EtOAc in hexane) to give the title compound as a yellow solid (0.6 g, Yield: 58.82%, 1.97 mmol).

[1018] .sup.1H NMR (DMSO-d6, 400 MHz): δ ppm 1.47 (s, 9H), 1.83-1.86 (m, 1H), 2.13-2.19 (m, 1H), 3.55-3.59 (m, 1H), 3.69-3.74 (m, 1H), 3.79-3.85 (m, 1H), 3.88-3.92 (m, 1H), 4.01-4.02 (m, 1H), 4.42 (d, J=4.4 Hz, 2H), 4.49-4.52 (m, 2H), 5.34-5.39 (m, 1H, D.sub.2O exchangeable), 6.42-6.45 (m, 1H), 6.53-6.57 (m, 1H), 7.06-7.10 (m, 1H). LCMS (Method A): 2.038 min, MS: ES+249.15 (M−56).

N-(tetrahydrofuran-3-yl)isoindolin-4-amine hydrochloride salt (Intermediate 50)

[1019] A stirred solution of t-butyl 4-((tetrahydrofuran-3-yl) amino) isoindoline-2-carboxylate (0.550 g, 1.81 mmol, 1.0 eq) in DCM (5 mL) at 0° C. was treated dropwise with 4M HCl in dioxane (0.5 mL). The reaction mixture was stirred for 1 h at RT. The reaction mixture was concentrated under vacuum and crude material triturated using n-pentane (3×10 mL) followed by diethyl ether (10 mL) to give solid that was dried under high vacuum to give the title compound (0.50 g, 2.08 mmol. Yield 100%).

[1020] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.82-1.84 (m, 1H), 2.15-2.24 (m, 1H), 3.57-3.60 (m, 2H), 3.69-3.74 (m, 1H), 3.81-3.92 (m, 2H), 4.30-4.33 (m, 2H), 4.35-4.40 (m, 2H), 6.54 (d, J=8.0 Hz, 1H), 6.64 (d, J=7.6 Hz, 1H), 7.16 (t, J=8 Hz, 15.6 Hz, 1H). LCMS (Method A): 0.702 min. MS: ES+205.18 (M+1).

Synthesis of N-(Oxetan-3-yl)isoindolin-4-amine.Math.TFA salt (Intermediate 51)

[1021] ##STR00200##

t-Butyl 4-(oxetan-3-ylamino) isoindoline-2-carboxylate

[1022] A mixture of tert-butyl 4-bromoisoindoline-2-carboxylate (1.00 g, 3.36 mmol, 1 eq) and oxetan-3-amine (0.735 g, 6.71 mmol, 2 eq) in 1, 4-dioxane (5 mL) at room temperature in a 35 mL microwave glass vial was treated with NaOtBu (0.451 g, 4.70 mmol, 1.4 eq) and the mixture degassed using N.sub.2 gas for 10 min. BINAP (0.125 g, 0.20 mmol, 0.06 eq) and Pd.sub.2(dba).sub.3 (0.120 g, 0.13 mmol, 0.04 eq) were added and again purged with N.sub.2 for 10 min. The reaction resulting reaction mixture was heated to 130° C. under microwave irradiation for 1.5 h. The reaction mixture was filtered through celite, washed with ethyl acetate (2×50 mL) and the combined filtrate poured onto ice-cold water (100 mL) and extracted in ethyl acetate (3×100 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The crude material was purified by flash chromatography (product eluted in 20% EtOAc in hexane) yielding the title compound as a yellow solid (0.8 g, 2.76 mmol. Yield: 78.16%).

[1023] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.47 (2 singlets, 9H), 4.44-4.58 (m, 7H), 4.83 (t, J=6 Hz, 12 Hz, 2H), 5.99-6.02 (m, 1H), 6.16-6.18 (m, 1H), 6.59 (t, J=7.6 Hz, 14.8 Hz, 1H), 7.05 (t, J=7.6 Hz, 1H). LCMS (Method A): 2.051 min, MS: ES+235.1 (M−56).

N-(Oxetan-3-yl)isoindolin-4-amine.Math.TFA salt (Intermediate 51)

[1024] A stirred solution of t-butyl 4-((tetrahydrofuran-3-yl) amino) isoindoline-2-carboxylate (0.4 g, 1.32 mmol, 1.0 eq) in DCM (5 mL) at 0° C. was treated dropwise with 4M HCl in dioxane (1.5 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and the crude material triturated using n-pentane (3×10 mL) followed by diethyl ether (10 mL) and dried under high vacuum to give the title compound (0.4 g, 1.2 mmol. Yield: 91%).

[1025] .sup.1H NMR (DMSO-d6, 400 MHz): δ 4.30-4.47 (m, 6H), 4.52-4.61 (m, 1H), 4.83 (t, J=6.4 Hz, 2H), 6.26 (d, J=8 Hz, 1H), 6.66 (d, J=8 Hz, 1H), 7.16 (t, J=8 Hz, 1H). 9.42 (m, 3H) LCMS (Method A): 0.735 min, MS: ES+191.2 (M+1).

Synthesis of 1-(isoindolin-4-yl)piperidin-3-ol hydrochloride (Intermediate 52)

[1026] ##STR00201##

t-butyl 4-(3-hydroxypiperidin-1-yl)isoindoline-2-carboxylate

[1027] t-Butyl 4-bromoisoindoline-2-carboxylate (1.00 g, 3.36 mmol, 1 eq), piperidin-3-ol (0.670 g, 6.63 mmol, 2 eq) and NaOtBu (0.451 g, 4.70 mmol, 1.4 eq) in 1,4-dioxane (5 mL) were added to a 35 mL microwave glass tube. The reaction mixture was degassed using N.sub.2 gas for 10 min. BINAP (0.125 g, 0.20 mmol, 0.06 eq) and Pd.sub.2(dba).sub.3 (0.120 g, 0.13 mmol, 0.04 eq) were added to the reaction mixture which was again purged with N.sub.2 for 10 min. The reaction was heated to 130° C. under microwave irradiation for 1.5 h. The reaction mixture was filtered through a celite bed and washed with ethyl acetate (2×50 mL). The combined filtrate was poured to ice cold water (100 mL) and extracted in ethyl acetate (3×100 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The crude material was purified by flash chromatography (product eluted in 20% EtOAc in hexane) yielding the title compound as a yellow solid (0.6 g, Yield: 56.23%, 1.89 mmol).

[1028] .sup.1H NMR (DMSO-d6, 400 MHz): δ ppm 1.24 (m, 1H), 1.46 (s, 9H), 1.5 (m, 1H), 1.74 (m, 1H), 1.99 (m, 1H), 3.06 (m, 2H), 3.17-3.23 (m, 2H), 3.59 (m, 1H), 4.52-4.56 (m, 3H), 4.81-4.84 (m, 1H), 6.84 (t, J=7.6 Hz, 15.6 Hz, 1H), 6.93 (t, J=8 Hz, 16.8 Hz, 1H), 7.20-7.22 (m, 1H). LCMS (Method A): 1.929 min, MS: ES+319.3 (M+1).

1-(isoindolin-4-yl)piperidin-3-ol hydrochloride (Intermediate 52)

[1029] A stirred solution of t-butyl 4-(3-hydroxypiperidin-1-yl)isoindoline-2-carboxylate (0.5 g, 1.57 mmol, 1.0 eq) in DCM (5 mL) at 0° C. was treated dropwise with 4M HCl in dioxane (5 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and the crude material triturated using n-pentane (3×10 mL) followed by diethyl ether (10 mL) and dried under high vacuum yielding the title compound as brown solid (0.500 g, 1.97 mmol, Yield 100%).

[1030] .sup.1H NMR (DMSO-d6, 400 MHz): δ 1.24-1.35 (m, 1H), 1.60-1.63 (m, 1H), 1.80-1.90 (m, 2H), 2.55-2.60 (m, 1H), 2.68-2.74 (m, 1H), 3.09-3.12 (m, 1H), 3.18-3.21 (m, 1H), 3.71 (bs, 1H), 4.46 (s, br, 4H), 6.99-7.01 (m, 1H), 7.05-7.07 (m, 1H), 7.33 (t, J=7.6 Hz, 15.6 Hz, 1H), 9.98 (s, 2H). LCMS (Method A): 0.555 min, MS ES+219.2 (M+1).

Synthesis of 5-((4-methylpiperazin-1-yl) methyl) isoindoline. HCl salt (Intermediate 53)

[1031] ##STR00202##

t-Butyl 5-((4-methylpiperazin-1-yl) methyl) isoindoline-2-carboxylate

[1032] A stirred solution of t-butyl 5-formylisoindoline-2-carboxylate (4.0 g, 16.17 mmol, 1.0 eq) in MeOH (100 mL) at room temperature was treated with N-methyl piperazine (1.61 g, 16.17 mmol, 1.0 eq) and ZnCl.sub.2 (1.04 g, 8.05 mmol, 0.5 eq). The reaction mixture was heated to 70° C. and stirred for 16 h. The resulting reaction mixture was allowed to cool to 0° C. and treated with NaCNBH.sub.3 (2.02 g, 32.2 mmol, 2.0 eq). The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum, water (100 mL) was added and extracted using ethyl acetate (3×150 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The crude material was purified by flash chromatography (product was eluted at 6% MeOH in DCM) yielding the title compound (4.3 g, Yield: 80.21%, 12.98 mmol).

[1033] .sup.1H NMR (DMSO-d6) (400 MHz): 1.45 (s, 9H), 2.23 (s, 3H), 2.40-2.50 (m, 8H) (piperazine proton merged), 2.45 (s, 2H), 4.54-4.56 (m, 4H), 7.19-7.26 (m, 3H). LCMS (Method A): 0.945 min, MS: ES+332.32 (M+1).

5-((4-methylpiperazin-1-yl) methyl) isoindoline. HCl salt (Intermediate 53)

[1034] A stirred solution of t-butyl 5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate (1.3 g, 3.92 mmol, 1.0 eq) in DCM (5 mL) at 0° C. was treated dropwise with 4M HCl in dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum yielding the title compound (1.3 g, Yield: quantitative, 5.62 mmol).

[1035] .sup.1H NMR (DMSO-d6, 400 MHz): 2.78 (s, 3H), 3.20-3.59 (m, br, 4H), 3.82-3.84 (m, br, 4H), 4.32-4.35 (m, 2H), 4.51 (s, br, 4H), 7.48 (d, J=7.6 Hz, 1H), 7.64 (s, 2H), 10.15 (s, 1H). LCMS (Method B): 1.33 min, MS: ES+232.37 (M+1).

Biological Assays

Fluorescence Polarisation Assay for MLH1 (Protocol for all Examples Except Examples 64, 76, 90 and 95)

[1036] Test compounds, as 10 mM DMSO stocks, were dispensed into a Black Fluotrac 200 384 well medium binding plate (Greiner Bio-One, item number 781076) using a Labcyte Echo acoustic liquid handler. For single point screening, test compounds were added to wells in columns 1-22 whilst DMSO was added to wells in columns 23 and 24 in order to normalise the plate. For potency determination, serial dilutions of test compounds were added to wells in columns 3-22 and DMSO volume was normalised across the plate.

[1037] 20 μL of a 2× solution (200 nM) of recombinant N-terminal MLH1 (residues 15-340) in assay buffer (25 mM HEPES, pH 7.5, 250 mM NaCl, 10 mM MgCl.sub.2, 0.01% Triton X-100, 5 mM Dithiothreitol) was added to all wells in columns 2-23 for potency determination or columns 1-23 for single point screening. 20 μL assay buffer was added to all wells in columns 1 and 24 (column 24 only for single point screening) using a MultiDrop Combi (ThermoFisher). Plates were centrifuged for 1 minute at 250×g and were incubated at room temperature for 30 minutes prior to the addition of 20 μL of 2×(10 nM) of 5-((5-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentyl)carbamoyl)-2-(6-(dimethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)benzoate (referred to hereinafter as “probe compound”) in assay buffer (prepared from a 100 μM DMSO stock) with a MultiDrop Combi (ThermoFisher). The final concentration of N-terminal MLH1 was 100 nM and the final concentration of probe compound was 5 nM.

[1038] Compound plates were centrifuged for 1 minute at 250×g for 1 minute and were incubated at room temperature for 15 minutes before being read on a PheraStar FSX (fitted with 384-well aperture spoon and 540 590 590 FP optic module). The gain and focus were adjusted before each plate was read so that the polarisation of a no enzyme control (column 24) was equal to 35 mP. Data were normalised against the no inhibitor controls (column 23) and no enzyme controls (column 24).

Fluorescence Polarisation Assay for MLH1 (Protocol for Examples 64, 76, 90 and 95)

[1039] Test compounds, as 10 mM DMSO stocks, were dispensed into a 384-well Low Flange Black Flat Bottom Polystyrene Non-binding Surface plate (Corning®, item number 3575) using a Labcyte Echo acoustic liquid handler. Test compounds were added to wells in columns 1-22 whilst DMSO was added to wells in columns 23 and 24 in order to normalise the plate. 20 μL of a 2× solution (200 nM) of recombinant N-terminal MLH1 (residues 15-340) in assay buffer (25 mM HEPES, pH 7.5, 250 mM NaCl, 10 mM MgCl.sub.2, 0.01% Triton X-100, 5 mM dithiothreitol) was added to all wells in columns 1-23 and 20 μL assay buffer was added to all wells in column 24 using an E1-ClipTip pipette (ThermoFisher). Plates were centrifuged for 1 minute at 250×g and were incubated at room temperature for 30 minutes prior to the addition of 20 μL of 2×(10 nM) 5-((5-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentyl)carbamoyl)-2-(6-(dimethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)benzoate in assay buffer (prepared from a 1 mM DMSO stock) with an E1-ClipTip pipette (ThermoFisher). The final concentration of N-terminal MLH1 was 100 nM and the final concentration of the probe compound was 5 nM. Compound plates were centrifuged for 1 minute at 250 xg for 1 minute and immediately read on a PheraStar FSX (fitted with 384-well aperture spoon and 590 675 675 FP optic module). The gain and focus were adjusted before each plate was read so that the polarisation of a no enzyme control (column 24) was equal to 35 mP. Data were normalised against the no inhibitor controls (column 23) and no enzyme controls (column 24).

[1040] Data obtained in this assay is shown in Table B1 below.

Fluorescence Polarisation Assay for PMS2

[1041] Test compounds, as 10 mM DMSO stocks, were dispensed into a Black Fluotrac 200 384 well medium binding plate (Greiner Bio-One, item number 781076) using a Labcyte Echo acoustic liquid handler. For single point screening, test compounds were added to wells in columns 1-22 whilst DMSO was added to wells in columns 23 and 24 in order to normalise the plate. For potency determination, serial dilutions of test compounds were added to wells in columns 3-22 and DMSO volume was normalised across the plate.

[1042] 20 μL of a 2× solution (20 nM) of recombinant N-terminal PMS2 (residues 1-365) in assay buffer (25 mM HEPES, pH 7.5, 250 mM NaCl, 10 mM MgCl.sub.2, 0.01% Triton X-100, 5 mM Dithiothreitol) was added to all wells in columns 2-23 for potency determination or columns 1-23 for single point screening. 20 μL assay buffer was added to all wells in columns 1 and 24 (column 24 only for single point screening) using a MultiDrop Combi (ThermoFisher). Plates were centrifuged for 1 minute at 250×g and were incubated at room temperature for 30 minutes prior to the addition of 20 μL of 2×(20 nM) of 5-((5-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentyl)carbamoyl)-2-(6-(dimethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)benzoate (referred to hereinafter as “probe compound”) in assay buffer (prepared from a 100 μM DMSO stock) with a MultiDrop Combi (ThermoFisher). The final concentration of N-terminal PMS2 was 10 nM and the final concentration of probe compound was 5 nM.

[1043] Compound plates were centrifuged for 1 minute at 250×g for 1 minute and were incubated at room temperature for 1 hour before being read on a PheraStar FSX (fitted with 384-well aperture spoon and 540 590 590 FP optic module). The gain and focus were adjusted before each plate was read so that the polarisation of a no enzyme control (column 24) was equal to 35 mP. Data were normalised against the no inhibitor controls (column 23) and no enzyme controls (column 24).

[1044] Data obtained in this assay is shown in Table B1 below.

TABLE-US-00006 TABLE B1 *>10 μM **1-10 μM ***less than 1 μM Example Name MLH1 IC.sub.50 PMS2 IC.sub.50 1 [2,4-dihydroxy-6-(pyrimidin-2- * * ylmethoxy)phenyl]-pyrrolidin-1-yl- methanone 2 [2-(cyclopentoxy)-4,6-dihydroxy- * * phenyl]-pyrrolidin-1-yl-methanone 3 (2-benzyloxy-4,6-dihydroxy-phenyl)- * * pyrrolidin-1-yl-methanone 4 (2-benzyloxy-4,6-dihydroxy-phenyl)- *** *** isoindolin-2-yl-methanone 5 (2-benzyloxy-4,6-dihydroxy-phenyl)- * * (1-piperidyl)methanone 6 (2-benzyloxy-4,6-dihydroxy-phenyl)- * * [(3S)-3-hydroxypyrrolidin-1- yl]methanone 7 (2-benzyloxy-4,6-dihydroxy-phenyl)- * * [(3R)-3-hydroxypyrrolidin-1- yl]methanone 8 (2-benzyloxy-4,6-dihydroxy-phenyl)- * * [(3R)-3-hydroxy-1- piperidyl]methanone 9 (2-benzyloxy-4,6-dihydroxy-phenyl)- * * [(3S)-3-hydroxy-1- piperidyl]methanone 10 (2-benzyloxy-4,6-dihydroxy-3-methyl- * ** phenyl)-pyrrolidin-1-yl-methanone 11 (2-benzyloxy-3-ethyl-4,6-dihydroxy- * * phenyl)-pyrrolidin-1-yl-methanone 12 [2,4-dihydroxy-6-(2- * * pyridylmethoxy)phenyl]-pyrrolidin-1- yl-methanone 13 [2,4-dihydroxy-6-[(1R)-1- * * phenylethoxy]phenyl]-pyrrolidin-1-yl- methanone 14 [2,4-dihydroxy-6-[(1R)-1- * * phenylethoxy]phenyl]-pyrrolidin-1-yl- methanone 15 [2-[(4-fluorophenyl)methoxy]-4,6- * * dihydroxy-phenyl]-pyrrolidin-1-yl- 16 [2,4-dihydroxy-6-[(4- * * methoxyphenyl)methoxy]phenyl]- pyrrolidin-1-yl-methanone 17 [2,4-dihydroxy-6-(m- * * tolylmethoxy)phenyl]-pyrrolidin-1-yl- methanone 18 (2-benzyloxy-4,6-dihydroxy-phenyl)- ** ** (5,7-dihydropyrrolo[3,4-b]pyridin-6- yl)methanone 19 (2-benzyloxy-4,6-dihydroxy-phenyl)- *** *** (4-methoxyisoindolin-2-yl)methanone 20 [2,4-dihydroxy-6-(pyrimidin-4- * * ylmethoxy)phenyl]-pyrrolidin-1-yl- methanone 21 2,4-dihydroxy-6-(1H-pyrazol-3- * * ylmethoxy)phenyl]-pyrrolidin-1-yl- methanone 22 [2,4-dihydroxy-6-(1H-triazol-4- * * ylmethoxy)phenyl]-pyrrolidin-1-yl- methanone 23 (2-benzyloxy-4,6-dihydroxy-phenyl)- *** *** (5-bromoisoindolin-2-yl)methanone 24 methyl 2-(2-benzyloxy-4,6-dihydroxy- *** *** benzoyl)isoindoline-5-carboxylate 25 (2-benzyloxy-4,6-dihydroxy-phenyl)- *** *** (5-methoxyisoindolin-2-yl)methanone 26 (2-benzyloxy-4,6-dihydroxy-phenyl)- ** *** (5,6-dimethoxyisoindolin-2- yl)methanone 27 [2,4-dihydroxy-6-(1- ** *** phenylethoxy)phenyl]-isoindolin-2-yl- methanone 28 [2,4-dihydroxy-6-(1- ** *** phenylethoxy)phenyl]-(5- methoxyisoindolin-2-yl)methanone 29 [2,4-dihydroxy-6-(1- ** *** phenylethoxy)phenyl]-(5,6- dimethoxyisoindolin-2-yl)methanone 30 (2-benzyloxy-4,6-dihydroxy-3-methyl- * *** phenyl)-(5,7-dihydropyrrolo[3,4- b]pyridin-6-yl)methanone 31 5,7-dihydropyrrolo[3,4-b]pyridin-6-yl- * *** [4,6-dihydroxy-3-methyl-2-(m- tolylmethoxy)phenyl]methanone 32 5,7-dihydropyrrolo[3,4-b]pyridin-6-yl- ** *** [2,4-dihydroxy-6-(m- tolylmethoxy)phenyl]methanone 33 5,7-dihydropyrrolo[3,4-b]pyridin-6-yl- * ** [4,6-dihydroxy-3-methyl-2-(2- pyridylmethoxy)phenyl] methanone 34 [4,6-dihydroxy-3-methyl-2-(2- * ** pyridylmethoxy)phenyl]-isoindolin-2- yl-methanone 35 5,7-dihydropyrrolo[3,4-b]pyridin-6-yl- ** ** [2,4-dihydroxy-6-(2- pyridylmethoxy)phenyl]methanone 36 (2-benzyloxy-4,6-dihydroxy-3-methyl- * *** phenyl)-(3,4-dihydro-1H-isoquinolin- 2-yl)methanone 37 [2,4-dihydroxy-6-(2- ** ** pyridylmethoxy)phenyl]-isoindolin-2- yl-methanone 38 (2-benzyloxy-4,6-dihydroxy-3-methyl- * *** phenyl)-(4-bromoisoindolin-2- yl)methanone 39 (2-benzyloxy-4,6-dihydroxy-3-methyl- * *** phenyl)-[4-(hydroxymethyl)isoindolin- 2-yl]methanone 40 (2-benzyloxy-4,6-dihydroxy-3-methyl- * *** phenyl)-[5-[(4-methylpiperazin-1- yl)methyl]isoindolin-2-yl]methanone 41 (2-benzyloxy-4,6-dihydroxy-3-methyl- * *** phenyl)-(6-methoxy-3,4-dihydro-1H- isoquinolin-2-yl)methanone 42 (2-benzyloxy-4,6-dihydroxy-3-methyl- * ** phenyl)-(3,4-dihydro-1H-2,7- naphthyridin-2-yl)methanone 43 (2-benzyloxy-4,6-dihydroxy-3-methyl- * ** phenyl)-(3,4-dihydro-1H-2,6- naphthyridin-2-yl)methanone 44 3,4-dihydro-1H-isoquinolin-2-yl-[4,6- * *** dihydroxy-3-methyl-2-(m- tolylmethoxy)phenyl]methanone 45 3,4-dihydro-1H-isoquinolin-2-yl-[4,6- * * dihydroxy-3-methyl-2-(2- pyridylmethoxy)phenyl] methanone 46 [4,6-dihydroxy-3-methyl-2-(2- * * pyridylmethoxy)phenyl]-(7-methoxy- 3,4-dihydro-1H-isoquinolin-2- yl)methanone 47 [4,6-dihydroxy-3-methyl-2-(2- * * pyridylmethoxy)phenyl]-(6-methoxy- 3,4-dihydro-1H-isoquinolin-2- yl)methanone 48 3,4-dihydro-1H-isoquinolin-2-yl-[2-[(4- * *** fluorophenyl)methoxy]-4,6-dihydroxy- 3-methyl-phenyl]methanone 49 (2-(benzyloxy)-4,6- ** *** dihydroxyphenyl)(5-((4- methylpiperazin-1- yl)methyl)isoindolin-2-yl)methanone 50 (4-aminoisoindolin-2-yl)(2- * *** (benzyloxy)-4,6-dihydroxy-3- methylphenyl)methanone 51 (2-(benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(4-vinylisoindolin-2- yl)methanone 52 (2-(benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(7-methoxy-3,4- dihydroisoquinolin-2(1H)- yl)methanone 53 (2-(benzyloxy)-4,6-dihydroxy-3- * ** methylphenyl)(5,8-dihydro-1,7- naphthyridin-7(6H)-yl)methanone 54 (2-(benzyloxy)-4,6-dihydroxy-3- * ** methylphenyl)(7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone 55 (2-(benzyloxy)-4,6-dihydroxy-3- * ** methylphenyl)(7,8-dihydropyrido[4,3- d]pyrimidin-6(5H)-yl)methanone 56 (2-(benzyloxy)-4,6-dihydroxy-3- * ** methylphenyl)(5,8-dihydropyrido[3,4- d]pyrimidin-7(6H)-yl)methanone 57 (3,4-dihydroisoquinolin-2(1H)-yl)(4,6- * * dihydroxy-3-methyl-2-((1-methyl-1H- pyrazol-3- yl)methoxy)phenyl) methanone 58 (2-(benzyloxy)-4,6- ** ** dihydroxyphenyl)(3,4- dihydroisoquinolin-2(1H)- yl)methanone 59 (2-(benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(isoindolin-2- yl)methanone 60 (2-(benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(7- ((dimethylamino)methyl)-3,4- dihydroisoquinolin-2(1H)- yl)methanone 61 (2-(benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(6- ((dimethylamino)methyl)-3,4- dihydroisoquinolin-2(1H)- yl)methanone 62 (S)-(2-(Benzyloxy)-4,6-dihydroxy-3- * ** methylphenyl)(3-(hydroxymethyl)-3,4- dihydroisoquinolin-2(1H)- yl)methanone 63 (2-(benzyloxy)-4,6-dihydroxy-3- * ** methylphenyl)(1- (hydroxymethyl)isoindolin-2- yl)methanone 64 (R)-(2-(benzyloxy)-4,6-dihydroxy-3- * ** methylphenyl)(3-(hydroxymethyl)-3,4- dihydroisoquinolin-2(1H)- yl)methanone 65 (2-(Benzyloxy)-4,6-dihydroxy-3- * * methylphenyl)(1-(hydroxymethyl)-3,4- dihydroisoquinolin-2(1H)- yl)methanone 66 (2-(Benzyloxy)-4,6-dihydroxy-3- * ** methylphenyl)(4-(hydroxymethyl)-3,4- dihydroisoquinolin-2(1H)- yl)methanone 67 (2-(Benzyloxy)-4,6-dihydroxy-3- * * methylphenyl)(2,3-dihydro-4/7- benzo[b][1,4]oxazin-4-yl)methanone 68 (2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(5- ((dimethylamino)methyl)isoindolin-2- yl)methanone 69 (2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(5- (morpholinomethyl)isoindolin-2- yl)methanone 70 (2-(Benzyloxy)-4,6-dihydroxy-3- * ** methylphenyl)(indolin-1-yl)methanone 71 (2-(Benzyloxy)-4,6- ** ** dihydroxyphenyl)(indolin-1- yl)methanone 72 (2-(Benzyloxy)-4,6-dihydroxy-3- * ** methylphenyl)(3,4-dihydroquinolin- 1(2H)-yl)methanone 73 (2-(Benzyloxy)-4,6- ** ** dihydroxyphenyl)(3,4-dihydroquinolin- 1(2H)-yl)methanone 74 (2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(1,3-dihydro-2H- pyrrolo[3,4-c]pyridin-2-yl)methanone 75 (2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(4-((4-methylpiperazin- 1-yl)methyl)isoindolin-2-yl)methanone 76 (2-(Benzyloxy)-4,6-dihydroxy-3- * ** methylphenyl)(4- (morpholinomethyl)isoindolin-2- yl)methanone 77 2-(2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylbenzoyl)-N,N-dimethyl-1,2,3,4- tetrahydroisoquinoline-7-carboxamide 78 2-(2-(benzyloxy)-4,6-dihydroxy-3- * *** methylbenzoyl)-N,N-dimethyl-1,2,3,4- tetrahydroisoquinoline-6-carboxamide 79 (2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(4-((tetrahydrofuran-3- yl)amino)isoindolin-2-yl)methanone 80 (2-(Benzyloxy)-4,6-dihydroxy-3- ** *** methylphenyl)(4-(oxetan-3- ylamino)isoindolin-2-yl)methanone 81 (2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(4-(3-hydroxypiperidin- 1-yl)isoindolin-2-yl)methanone 82 2-(2-(benzyloxy)-4,6-dihydroxy-3- * *** methylbenzoyl)isoindoline-4- carbonitrile 83 2-(2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylbenzoyl)-N,N- dimethylisoindoline-5-carboxamide 84 2-(2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylbenzoyl)-N-methylisoindoline- 5-carboxamide 85 2-(2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylbenzoyl)-N,N- dimethylisoindoline-4-carboxamide 86 2-(2-(Benzyloxy)-4,6-dihydroxy-3- * ** methylbenzoyl)-N-methylisoindoline- 4-carboxamide 87 N-(2-(2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylbenzoyl)isoindolin-4- yl)acetamide 88 ((2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(4-((tetrahydrofuran-3- yl)oxy)isoindolin-2-yl)methanone 89 (4-(Azetidin-3-yl methoxy) isoindolin- * *** 2-yl) (2-(benzyloxy)-4,6-dihydroxy- 3-methylphenyl)methanone 90 (2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(4-(pyrimidin-5- ylmethoxy)isoindolin-2-yl)methanone 91 1-(2-(2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylbenzoyl)isoindolin-4- yl)azetidine-3-carbonitrile 92 (4,6-Dihydroxy-2-methoxy-3- * *** methylphenyl)(5-((4-methylpiperazin- 1-yl)methyl)isoindolin-2-yl)methanone 93 (2-Ethoxy-4,6-dihydroxy-3- * *** methylphenyl)(5-((4-methylpiperazin- 1-yl)methyl)isoindolin-2-yl)methanone 94 (2-(Cyclohexylmethoxy)-4,6- * *** dihydroxy-3-methylphenyl)(5-((4- methylpiperazin-1- yl)methyl)isoindolin-2-yl)methanone 95 (2-(Cyclopropylmethoxy)-4,6- * *** dihydroxy-3-methylphenyl)(5-((4- methylpiperazin-1- yl)methyl)isoindolin-2-yl)methanone