BENZOLACTAM COMPOUNDS AS PROTEIN KINASE INHIBITORS

Abstract

The invention provides a compound of formula (0):

##STR00001## or a pharmaceutically acceptable salt, N-oxide or tautomer thereof; wherein: n is 1 or 2; X is CH or N; Y is selected from CH and C—F; Z is selected from C—R.sup.z and N; R.sup.1 is selected from: -(Alk.sup.1).sub.t-Cyc.sup.1; wherein t is 0 or 1; Optionally substituted C.sub.1-6 acyclic hydrocarbon groups R.sup.2 is selected from hydrogen; halogen; and C.sub.1-3 hydrocarbon groups optionally substituted with one or more fluorine atoms; R.sup.3 is hydrogen or a group L.sup.1-R.sup.7; R.sup.4 is selected from hydrogen; methoxy; and optionally substituted C.sub.1-3 alkyl; and R.sup.4a is selected from hydrogen and a C.sub.1-3 alkyl group; wherein R.sup.z, Alk.sup.1, Cyc.sup.1, L.sup.1 and R.sup.7 are defined herein; provided that the compound is other than 6-benzyl-3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and 3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and salts and tautomers thereof.

The compounds are inhibitors of ERK1/2 kinases and will be useful in the treatment of ERK1/2-mediated conditions. The compounds are therefore useful in therapy, in particular in the treatment of cancer.

Claims

1. A method for: (i) inhibiting the activity of ERK1/2; (ii) treating lung cancer, melanoma, pancreatic cancer, or colorectal cancer; (iii) treating leukemia or lymphoma; (iv) treating a haematological malignancy or condition of lymphoid lineage or of myeloid lineage; (v) treating an adenoma or carcinoma; (vi) the prophylaxis or treatment of a disease state or condition selected from tumours of epithelial origin; haematological malignancies and premalignant haematological disorders and disorders of borderline malignancy; tumours of mesenchymal origin; neural crest cell-derived tumours; tumours of the central or peripheral nervous system; endocrine tumours; ocular and adnexal tumours; germ cell and trophoblastic tumours; and paediatric and embryonal tumours; or syndromes, congenital or otherwise, which leave the patient susceptible to malignancy; (vii) the prophylaxis or treatment of pancreatic cancers; (viii) the prophylaxis or treatment of NRas melanoma and NRas AML; (ix) the prophylaxis or treatment of KRas lung cancer, KRas pancreatic cancer or KRas colorectal cancer (CRC); or (x) the prophylaxis or treatment of BRAF colorectal cancer (CRC), BRAF lung cancer or BRAF melanoma, said method comprising administering to a subject a therapeutically effective amount of a compound selected from: (a) a compound having the formula (2): ##STR02201## or a pharmaceutically acceptable salt or tautomer thereof; and (b) a compound having the formula (5): ##STR02202## or a pharmaceutically acceptable salt or tautomer thereof; wherein n is 1 or 2; Z is selected from C—R.sup.z and N; R.sup.z is selected from hydrogen; halogen; methoxy; and C.sub.1-3 alkyl optionally substituted with hydroxy or methoxy; R.sup.1 is selected from: -(Alk.sup.1).sub.t-Cyc.sup.1; wherein t is 0 or 1; and Alk.sup.1 is a C.sub.1-4 straight chain or branched alkylene group optionally substituted with 1 or 2 hydroxy groups; and C.sub.1-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R.sup.5 selected from hydroxy; oxo; fluorine; and cyano; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by O or N; Cyc.sup.1 is a cyclic group selected from (a) 3 to 9 membered non-aromatic monocyclic and bicyclic carbocyclic and heterocyclic groups containing 0, 1, 2, or 3 heteroatom ring members selected from O, N, S, S(O) and S(O).sub.2; (b) 5 to 6 membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and (c) 3 to 7 membered monocyclic carbocyclic groups; wherein each cyclic group (a), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R.sup.6 selected from hydroxy; oxo; fluorine; amino; NH(Hyd.sup.1); N(Hyd.sup.1).sub.2; O-Hyd.sup.1; —C(═O)—Hyd.sup.1; —C(═O)—O—Hyd.sup.1 and Hyd.sup.1; where Hyd.sup.1 is a C.sub.1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy; R.sup.2 is selected from hydrogen; halogen; and C.sub.1-3 hydrocarbon groups optionally substituted with one or more fluorine atoms; R.sup.3 is hydrogen or a group L.sup.1-R.sup.7; R.sup.4 is selected from hydrogen; methoxy; and C.sub.1-3 alkyl optionally substituted with hydroxy, amino, mono- or di-C.sub.1-2 alkylamino, a cyclic amino group or methoxy; wherein the cyclic amino group is a saturated 4-7 membered heterocyclic group containing a nitrogen ring member and optionally a second heteroatom ring member selected from O, N and S, wherein the cyclic amino group is linked via a nitrogen ring member thereof to the C.sub.1-3 alkyl, and wherein the cyclic amino group is optionally substituted with one or two methyl groups; provided that no more than one R.sup.4 can be other than hydrogen or methyl; L.sup.1 is selected from a bond; Alk.sup.2, Alk.sup.2-O and Alk.sup.2-C(═O) wherein Alk.sup.2 is a C.sub.1-4 straight chain or branched alkylene group which is optionally substituted with one or more substituents selected from hydroxy, methoxy, amino, methylamino, dimethylamino and fluorine; R.sup.7 is selected from: hydrogen; CO.sub.2H; NR.sup.8R.sup.9; a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R.sup.10; and an acyclic C.sub.1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C.sub.1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R.sup.10; wherein one or two but not all of the carbon atoms of the acyclic C.sub.1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO.sub.2 or NR.sup.11; R.sup.8 is selected from hydrogen and a C.sub.1-4 hydrocarbon group, the C.sub.1-4 hydrocarbon group being optionally substituted with 1-2 substituents selected from hydroxy, amino, mono-C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, and 4-7 membered saturated heterocyclic rings containing 1-2 heteroatom ring members selected from O and N, wherein the mono-C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, and 4-7 membered saturated heterocyclic rings are each optionally substituted with 1-2 hydroxy or C.sub.1-3 alkyl substituents; R.sup.9 is selected from: hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R.sup.10; and an acyclic C.sub.1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C.sub.1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R.sup.10; wherein one or two but not all of the carbon atoms of the acyclic C.sub.1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO.sub.2 or NR.sup.11; or NR.sup.8R.sup.9 forms a heterocyclic group having from 4 to 12 ring members wherein, in addition to the nitrogen atom of NR.sup.8R.sup.9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O, N and S and oxidised forms of S; and wherein the heterocyclic group is optionally substituted with one or more substituents R.sup.10; R.sup.10 is selected from: halogen; hydroxy; oxo; cyano; OR.sup.12 wherein R.sup.12 is C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl, each being optionally substituted with halogen; an acyclic C.sub.1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C.sub.1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R.sup.13 selected from hydroxy; halogen; cyano; amino; —NH(Hyd.sup.1); —N(Hyd.sup.1).sub.2; and —(O).sub.v-Hyd.sup.1 where v is 0 or 1; wherein one or two but not all of the carbon atoms of the acyclic C.sub.1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO.sub.2 or NR.sup.11; and carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R.sup.13; and R.sup.11 is selected from hydrogen and a C.sub.1-4 hydrocarbon group.

2. The method according to claim 1 for inhibiting the activity of ERK1/2.

3. The method according to claim 1 for treating lung cancer.

4. The method according to claim 3 wherein the lung cancer is selected from adenocarcinoma, small cell lung carcinoma, non-small cell lung carcinomas bronchioalveolar carcinoma, and mesothelioma.

5. The method according to claim 1 for treating leukemia or lymphoma.

6. The method according to claim 1 for treating a haematological malignancy or a related condition of lymphoid lineage or of myeloid lineage.

7. The method according to claim 6 for treating a haematological malignancy or a related condition of lymphoid lineage, wherein the condition is selected from acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and B-cell lymphoma.

8. The method according to claim 7 for treating B-cell lymphoma selected from diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt's lymphoma, mantle cell lymphoma, T-cell lymphoma or leukaemia, natural killer (NK) cell lymphoma, Hodgkin's lymphoma, hairy cell leukaemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, and a post-transplant lymphoproliferative disorder.

9. The method according to claim 6 for treating a haematological malignancy or a related condition of myeloid lineage, wherein the condition is selected from acute myelogenous leukemia (AML), chronic myelogenous leukemia (CIVIL), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome, a myeloproliferative disorder, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukemia.

10. The method according to claim 9 for treating a myeloproliferative disorder selected from polycythaemia vera, essential thrombocythaemia and primary myelofibrosis.

11. The method according to claim 1 for treating an adenoma or carcinoma.

12. The method according to claim 1 for treating KRas lung cancer, KRas pancreatic cancer, KRas colorectal cancer, BRAF colorectal cancer, BRAF lung cancer, or BRAF melanoma.

13. The method according to claim 1 for treating NRas AML.

14. The method according to claim 1 comprising administering to the subject a compound having the formula (9): ##STR02203## or a pharmaceutically acceptable salt or tautomer thereof, wherein v is 0, 1, 2 or 3.

15. The method according to claim 14 wherein: R.sup.4 is hydrogen; v is 0; R.sup.8 is hydrogen; R.sup.9 is an acyclic saturated C.sub.1-3 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy and a phenyl group, the phenyl group being optionally substituted with one or more substituents R.sup.10; R.sup.10 is selected from fluorine, methyl, methoxy and dimethylamino; Alk.sup.2 is selected from CH.sub.2 and CH(CH.sub.3); and Z is CH.

16. The method according to claim 1 comprising administering to the subject any one of Examples 1 to 1134 as described herein.

17. The method according to claim 1 comprising administering to the subject a compound selected from: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide; (2R)-2-(6-{5-Chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(2-methoxypyridin-4-yl)ethyl]propanamide; (R)-2-(6-(5-chloro-2-((2-methoxypyridin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propanamide; (R)-2-(6-(5-chloro-2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-1-(6-(dimethylamino)pyridin-2-yl)-2-hydroxyethyl)propanamide; (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-[6-(4-methylpiperazin-1-yl)pyridin-2-yl]ethyl]propanamide; and (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[3-fluoro-5-(4-methylpiperazin-1-yl)phenyl]ethyl]propanamide; and pharmaceutically acceptable salts thereof.

18. The method according to claim 1 comprising administering the compound or pharmaceutically acceptable salt or tautomer thereof to the subject in combination with another therapeutic agent.

19. A method of treating a subject having a disease state or condition mediated by ERK1/2, said method comprising screening the subject to establish susceptibility of a disease to ERK inhibition, then administering to the subject a therapeutically effective amount of a compound selected from: (a) a compound having the formula (2): ##STR02204## or a pharmaceutically acceptable salt or tautomer thereof; and (b) a compound having the formula (5): ##STR02205## or a pharmaceutically acceptable salt or tautomer thereof; wherein n is 1 or 2; Z is selected from C—R.sup.z and N; R.sup.z is selected from hydrogen; halogen; methoxy; and C.sub.1-3 alkyl optionally substituted with hydroxy or methoxy; R.sup.1 is selected from: -(Alk.sup.1).sub.t-Cyc.sup.1; wherein t is 0 or 1; and Alk.sup.1 is a C.sub.1-4 straight chain or branched alkylene group optionally substituted with 1 or 2 hydroxy groups; and C.sub.1-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R.sup.5 selected from hydroxy; oxo; fluorine; and cyano; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by O or N; Cyc.sup.1 is a cyclic group selected from (a) 3 to 9 membered non-aromatic monocyclic and bicyclic carbocyclic and heterocyclic groups containing 0, 1, 2, or 3 heteroatom ring members selected from O, N, S, S(O) and S(O).sub.2; (b) 5 to 6 membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and (c) 3 to 7 membered monocyclic carbocyclic groups; wherein each cyclic group (a), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R.sup.6 selected from hydroxy; oxo; fluorine; amino; NH(Hyd.sup.1); N(Hyd.sup.1).sub.2; O-Hyd.sup.1; —C(═O)—Hyd.sup.1; —C(═O)—O—Hyd.sup.e and Hyd.sup.1; where Hyd.sup.1 is a C.sub.1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy; R.sup.2 is selected from hydrogen; halogen; and C.sub.1-3 hydrocarbon groups optionally substituted with one or more fluorine atoms; R.sup.3 is hydrogen or a group L.sup.1-R.sup.7; R.sup.4 is selected from hydrogen; methoxy; and C.sub.1-3 alkyl optionally substituted with hydroxy, amino, mono- or di-C.sub.1-2 alkylamino, a cyclic amino group or methoxy; wherein the cyclic amino group is a saturated 4-7 membered heterocyclic group containing a nitrogen ring member and optionally a second heteroatom ring member selected from O, N and S, wherein the cyclic amino group is linked via a nitrogen ring member thereof to the C.sub.1-3 alkyl, and wherein the cyclic amino group is optionally substituted with one or two methyl groups; provided that no more than one R.sup.4 can be other than hydrogen or methyl; L.sup.1 is selected from a bond; Alk.sup.2, Alk.sup.2-O and Alk.sup.2-C(═O) wherein Alk.sup.2 is a C.sub.1-4 straight chain or branched alkylene group which is optionally substituted with one or more substituents selected from hydroxy, methoxy, amino, methylamino, dimethylamino and fluorine; R.sup.7 is selected from: hydrogen; CO.sub.2H; NR.sup.8R.sup.9; a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R.sup.10; and an acyclic C.sub.1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C.sub.1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R.sup.10; wherein one or two but not all of the carbon atoms of the acyclic C.sub.1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO.sub.2 or NR.sup.11; R.sup.8 is selected from hydrogen and a C.sub.1-4 hydrocarbon group, the C.sub.1-4 hydrocarbon group being optionally substituted with 1-2 substituents selected from hydroxy, amino, mono-C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, and 4-7 membered saturated heterocyclic rings containing 1-2 heteroatom ring members selected from O and N, wherein the mono-C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, and 4-7 membered saturated heterocyclic rings are each optionally substituted with 1-2 hydroxy or C.sub.1-3 alkyl substituents; R.sup.9 is selected from: hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R.sup.10; and an acyclic C.sub.1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C.sub.1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R.sup.10; wherein one or two but not all of the carbon atoms of the acyclic C.sub.1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO.sub.2 or NR.sup.11; or NR.sup.8R.sup.9 forms a heterocyclic group having from 4 to 12 ring members wherein, in addition to the nitrogen atom of NR.sup.8R.sup.9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O, N and S and oxidised forms of S; and wherein the heterocyclic group is optionally substituted with one or more substituents R.sup.10; R.sup.10 is selected from: halogen; hydroxy; oxo; cyano; OR.sup.12 wherein R.sup.12 is C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl, each being optionally substituted with halogen; an acyclic C.sub.1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C.sub.1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R.sup.13 selected from hydroxy; halogen; cyano; amino; —NH(Hyd.sup.1); —N(Hyd.sup.1).sub.2; and —(O).sub.v-Hyd.sup.1 where v is 0 or 1; wherein one or two but not all of the carbon atoms of the acyclic C.sub.1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO.sub.2 or NR.sup.11; and carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R.sup.13; and R.sup.11 is selected from hydrogen and a C.sub.1-4 hydrocarbon group.

20. A method of treating a subject who has been screened and has been determined as suffering from, or being at risk of suffering from, a disease or condition which would be susceptible to treatment with an ERK1/2 inhibitor, the method comprising administering to the subject a a therapeutically effective amount of a compound selected from: (a) a compound having the formula (2): ##STR02206## or a pharmaceutically acceptable salt or tautomer thereof; and (b) a compound having the formula (5): ##STR02207## or a pharmaceutically acceptable salt or tautomer thereof; wherein n is 1 or 2; Z is selected from C—R.sup.z and N; R.sup.z is selected from hydrogen; halogen; methoxy; and C.sub.1-3 alkyl optionally substituted with hydroxy or methoxy; R.sup.1 is selected from: -(Alk.sup.1).sub.t-Cyc.sup.1; wherein t is 0 or 1; and Alk.sup.1 is a C.sub.1-4 straight chain or branched alkylene group optionally substituted with 1 or 2 hydroxy groups; and C.sub.1-6 acyclic hydrocarbon groups which are unsubstituted or substituted with 1, 2 or 3 substituents R.sup.5 selected from hydroxy; oxo; fluorine; and cyano; and wherein 1 or 2 but not all of the carbon atoms of the hydrocarbon group can be replaced by O or N; Cyc.sup.1 is a cyclic group selected from (a) 3 to 9 membered non-aromatic monocyclic and bicyclic carbocyclic and heterocyclic groups containing 0, 1, 2, or 3 heteroatom ring members selected from O, N, S, S(O) and S(O).sub.2; (b) 5 to 6 membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatom ring members of which 1 is N and the others, when present, are selected from O, N and S; and (c) 3 to 7 membered monocyclic carbocyclic groups; wherein each cyclic group (a), (b) and (c) is unsubstituted or substituted with 1, 2 or 3 substituents R.sup.6 selected from hydroxy; oxo; fluorine; amino; NH(Hyd.sup.1); N(Hyd.sup.1).sub.2; O-Hyd.sup.1; —C(═O)—Hyd.sup.1; —C(═O)—O—Hyd.sup.1 and Hyd.sup.1; where Hyd.sup.1 is a C.sub.1-4 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from fluorine, hydroxyl and methoxy; R.sup.2 is selected from hydrogen; halogen; and C.sub.1-3 hydrocarbon groups optionally substituted with one or more fluorine atoms; R.sup.3 is hydrogen or a group L.sup.1-R.sup.7; R.sup.4 is selected from hydrogen; methoxy; and C.sub.1-3 alkyl optionally substituted with hydroxy, amino, mono- or di-C.sub.1-2 alkylamino, a cyclic amino group or methoxy; wherein the cyclic amino group is a saturated 4-7 membered heterocyclic group containing a nitrogen ring member and optionally a second heteroatom ring member selected from O, N and S, wherein the cyclic amino group is linked via a nitrogen ring member thereof to the C.sub.1-3 alkyl, and wherein the cyclic amino group is optionally substituted with one or two methyl groups; provided that no more than one R.sup.4 can be other than hydrogen or methyl; L.sup.1 is selected from a bond; Alk.sup.2, Alk.sup.2-O and Alk.sup.2-C(═O) wherein Alk.sup.2 is a C.sub.1-4 straight chain or branched alkylene group which is optionally substituted with one or more substituents selected from hydroxy, methoxy, amino, methylamino, dimethylamino and fluorine; R.sup.7 is selected from: hydrogen; CO.sub.2H; NR.sup.8R.sup.9; a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R.sup.10; and an acyclic C.sub.1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C.sub.1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R.sup.10, wherein one or two but not all of the carbon atoms of the acyclic C.sub.1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO.sub.2 or NR.sup.11; R.sup.8 is selected from hydrogen and a C.sub.1-4 hydrocarbon group, the C.sub.1-4 hydrocarbon group being optionally substituted with 1-2 substituents selected from hydroxy, amino, mono-C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, and 4-7 membered saturated heterocyclic rings containing 1-2 heteroatom ring members selected from O and N, wherein the mono-C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, and 4-7 membered saturated heterocyclic rings are each optionally substituted with 1-2 hydroxy or C.sub.1-3 alkyl substituents; R.sup.9 is selected from: hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R.sup.10; and an acyclic C.sub.1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C.sub.1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R.sup.10; wherein one or two but not all of the carbon atoms of the acyclic C.sub.1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO.sub.2 or NR.sup.11; or NR.sup.8R.sup.9 forms a heterocyclic group having from 4 to 12 ring members wherein, in addition to the nitrogen atom of NR.sup.8R.sup.9, the heterocyclic group optionally contains 1 or 2 further heteroatom ring members selected from O, N and S and oxidised forms of S; and wherein the heterocyclic group is optionally substituted with one or more substituents R.sup.10; R.sup.10 is selected from: halogen; hydroxy; oxo; cyano; OR.sup.12 wherein R.sup.12 is C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl, each being optionally substituted with halogen; an acyclic C.sub.1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C.sub.1-4 alkylamino; and carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R.sup.13 selected from hydroxy; halogen; cyano; amino; —NH(Hyd.sup.1); —N(Hyd.sup.1).sub.2; and —(O).sub.v-Hyd.sup.1 where v is 0 or 1; wherein one or two but not all of the carbon atoms of the acyclic C.sub.1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO.sub.2 or NR.sup.11; and carbocyclic and heterocyclic groups having 3 to 7 ring members of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from N, O and S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or more substituents R.sup.13; and R.sup.11 is selected from hydrogen and a C.sub.1-4 hydrocarbon group.

21. The method according to claim 1 wherein the compound is (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide or a pharmaceutically acceptable salt thereof.

22. The method according to claim 21, wherein the compound is (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1 S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide.

23. The method according to claim 19 wherein the compound is (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1 S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide or a pharmaceutically acceptable salt thereof.

24. The method according to claim 23 wherein the compound is (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1 S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide.

25. The method according to claim 20 wherein the compound is (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1 S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide or a pharmaceutically acceptable salt thereof.

26. The method according to claim 25 wherein the compound is (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1 S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide.

Description

EXAMPLES

[0672] The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples. Compounds are named using an automated naming package such as AutoNom (MDL) or ChemAxon Structure to Name or are as named by the chemical supplier. In the examples, the following abbreviations are used.

[0673] By following methods similar and/or analogous to general procedures below, the compounds set out below were prepared.

[0674] The following synthetic procedures are provided for illustration of the methods used; for a given preparation or step the precursor used may not necessarily derive from the individual batch synthesised according to the step in the description given.

[0675] Where a compound is described as a mixture of two diastereoisomers/epimers, the configuration of the stereocentre is not specified and is represented by straight lines.

[0676] As understood by a person skilled in the art, compounds synthesised using the protocols as indicated may exist as a solvate e.g. hydrate, and/or contain residual solvent or minor impurities. Compounds isolated as a salt form, may be integer stoichiometric i.e. mono- or di-salts, or of intermediate stoichiometry.

[0677] Some of the compounds below are isolated as the salt, for example depending on the acid used in the purification method. Some compounds are isolated as the free base.

Abbreviations

[0678] BINAP, 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene; CDI, 1,1′-carbonyldiimidazole; DCE, 1,2-dichloroethane; DCM, Dichloromethane; DIPEA, diisopropylethylamine; DMSO, dimethylsulfoxide; DMF, N,N-dimethylformamide; DMAP, -(dimethylamino)pyridine; EtOAc, ethyl acetate; h, hour; HATU, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate; HBTU, 3-[Bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate; HCl, Hydrochloric acid; HPLC, High pressure liquid chromatography; LC-MS, Liquid chromatography-mass spectrometry; LiHMDS, lithium bis(trimethylsilyl)amide; mins., Minutes; MeCN, acetonitrile; MS, Mass Spectrometry; NBS, N-bromosuccinimide; NMR, Nuclear Magnetic Resonance Spectroscopy; PdCl.sub.2(dppf).sub.2, (1,1′-Bis(diphenylphosphino)-ferrocene)palladium(II) dichloride; Pd.sub.2(dba).sub.3, tris(dibenzylidine acetone)palladium (0); Petrol, petroleum ether fraction with boiling point range 40-60° C.; PyBOP, benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; RT, room temperature; Sat., Saturated; SCX, solid phase cation exchange resin; SPhos, 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; S-Phos Pd G3, (2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate; TBDMSCl, tert-butyldimethylsilyl chloride; TBTU, O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate; TFA, trifluoroacetic acid; THF, Tetrahydrofuran; XPhos, 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; XantPhos, 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.

Synthetic Methods

[0679] All starting materials and solvents were obtained either from commercial sources or prepared according to the literature citation. Unless otherwise stated all reactions were stirred. Organic solutions were routinely dried over anhydrous magnesium sulfate. Hydrogenations were performed on a Parr hydrogenator, a Thales H-cube flow reactor under the conditions stated or under a balloon of hydrogen. Microwave reactions were performed in a CEM Discover and Smithcreator microwave reactor, heating to a constant temperature using variable power microwave irradiation. Normal phase column chromatography was routinely carried out on an automated flash chromatography system such as CombiFlash Companion or CombiFlash RF system using pre-packed silica (230-400 mesh, 40-63 μm) cartridges. SCX was purchased from Supelco and treated with 1M hydrochloric acid prior to use. Unless stated otherwise the reaction mixture to be purified was first diluted with MeOH and made acidic with a few drops of AcOH. This solution was loaded directly onto the SCX and washed with MeOH. The desired material was then eluted by washing with 1% NH.sub.3 in MeOH.

[0680] Where a compound is described as a mixture of two diastereoisomers/epimers, the configuration of the stereocentre is not specified and is represented by straight lines.

NMR Data

[0681] .sup.1H NMR spectra were acquired on a Bruker Avance III spectrometer at 400 MHz. Either the central peaks of chloroform-d, dimethylsulfoxide-d.sub.6 or an internal standard of tetramethylsilane were used as references. For NMR data, where the number of protons assigned is less than the theoretical number of protons in the molecule, it is assumed that the apparently missing signal(s) is/are obscured by solvent and/or water peaks. In addition, where spectra were obtained in protic NMR solvents, exchange of NH and/or OH protons with solvent occurs and hence such signals are normally not observed.

Analytical and Preparative LC-MS Systems

Analytical LC-MS System and Method Description

[0682] In the following examples, compounds were characterised by mass spectroscopy using the systems and operating conditions set out below. Where atoms with different isotopes are present and a single mass quoted, the mass quoted for the compound is the monoisotopic mass (i.e. .sup.35C; .sup.79Br etc.).

Waters Platform LC-MS System:

HPLC System: Waters 2795

Mass Spec Detector: Micromass Platform LC

PDA Detector: Waters 2996 PDA

[0683] Platform MS conditions:
Capillary voltage: 3.6 kV (3.40 kV on ES negative)
Cone voltage: 30 V

Source Temperature: 120° C.

Scan Range: 125-800 amu

Ionisation Mode: ElectroSpray Positive or

[0684] ElectroSpray Negative or [0685] ElectroSpray Positive & Negative

Waters Fractionlynx LC-MS System:

[0686] HPLC System: 2767 autosampler—2525 binary gradient pump

Mass Spec Detector: Waters ZQ

PDA Detector: Waters 2996 PDA

[0687] Fractionlynx MS conditions:
Capillary voltage: 3.5 kV (3.25 kV on ES negative)
Cone voltage: 40 V (25 V on ES negative)

Source Temperature: 120° C.

Scan Range: 125-800 amu

Ionisation Mode: ElectroSpray Positive or

[0688] ElectroSpray Negative or [0689] ElectroSpray Positive & Negative

Agilent 1200SL-6140 LC-MS System—RAPID:

[0690] HPLC System: Agilent 1200 series SL
Mass Spec Detector: Agilent 6120 or 6140 single quadrupole

Second Detector: Agilent 1200 MWD SL

[0691] Agilent MS conditions:
Capillary voltage: 4000V on ES pos (3500V on ES Neg)

Fragmentor/Gain: 100

Gain: 1

[0692] Drying gas flow: 7.0 L/min

Gas Temperature: 345° C.

[0693] Nebuliser Pressure: 35 psig

Scan Range: 125-800 amu

[0694] Ionisation Mode: ElectroSpray Positive-Negative switching [0695] Columns:

[0696] A range of commercially available columns—both achiral and chiral—may be used such that, in conjunction with the changes in mobile phase, organic modifier and pH, they enabled the greatest cover in terms of a broad range of selectivity. All columns were used in accordance with the manufacturers recommended operating conditions. For example, columns from Waters (including but not limited to Xselect CSH C18, 2.5 μm, 4.6×30 mm; Xbridge BEH C18, 2.5 μm, 4.6×30).

Preparative LC-MS System and Method Description

[0697] Preparative LC-MS is a standard and effective method used for the purification of small organic molecules such as the compounds described herein. The methods for the liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of the crude materials and improved detection of the samples by MS. Optimisation of the preparative gradient LC method will involve varying columns, volatile eluents and modifiers, and gradients. Methods are well known in the art for optimising preparative LC-MS methods and then using them to purify compounds. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC-MS; J Comb Chem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography/mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J Comb Chem.; 2003; 5(3); 322-9.

[0698] Several systems for purifying compounds via preparative LC-MS are described below although a person skilled in the art will appreciate that alternative systems and methods to those described could be used. From the information provided herein, or employing alternative chromatographic systems, a person skilled in the art could purify the compounds described herein by preparative LC-MS.

Waters Fractionlynx System:

[0699] Hardware: [0700] 2767 Dual Loop Autosampler/Fraction Collector [0701] 2525 preparative pump [0702] CFO (column fluidic organiser) for column selection [0703] RMA (Waters reagent manager) as make up pump [0704] Waters ZQ Mass Spectrometer [0705] Waters 2996 Photo Diode Array detector [0706] Waters ZQ Mass Spectrometer [0707] Waters MS running conditions: [0708] Capillary voltage: 3.5 kV (3.2 kV on ES Negative) [0709] Cone voltage: 25 V [0710] Source Temperature: 120° C. [0711] Scan Range: 125-800 amu [0712] Ionisation Mode: ElectroSpray Positive or [0713] ElectroSpray Negative

Agilent 1100 LC-MS Preparative System:

[0714] Hardware: [0715] Autosampler: 1100 series “prepALS” [0716] Pump: 1100 series “PrepPump” for preparative flow gradient and 1100 series “QuatPump” for pumping modifier in prep flow [0717] UV detector: 1100 series “MWD” Multi Wavelength Detector [0718] MS detector: 1100 series “LC-MSD VL” [0719] Fraction Collector: 2דPrep-FC” [0720] Make Up pump: “Waters RMA” [0721] Agilent Active Splitter [0722] Agilent MS running conditions: [0723] Capillary voltage: 4000 V (3500 V on ES Negative) [0724] Fragmentor/Gain: 150/1 [0725] Drying gas flow: 12.0 L/min

[0726] Gas Temperature: 350° C. [0727] Nebuliser Pressure: 50 psig [0728] Scan Range: 125-800 amu [0729] Ionisation Mode: ElectroSpray Positive or [0730] ElectroSpray Negative [0731] Columns: [0732] A range of commercially available columns—both achiral and chiral—may be used such that, in conjunction with the changes in mobile phase, organic modifier and pH, they enabled the greatest cover in terms of a broad range of selectivity. All columns were used in accordance with the manufacturers recommended operating conditions. Typically 5 micron particle sized columns were used where available. For example, columns from Waters (including but not limited to XBridge™ Prep OBD™ C18 and Phenyl; Xselect CSH C18, 5 μm, 19×50 mm; Xbridge BEH C18, 5 μm, 19×50 mm; Atlantis® Prep T3 OBD™ and Sunfire™ Prep OBD C18 5 μm 19×100 mm), Phenomenex (including but not limited to Synergy MAX-RP and LUX™ Cellulose-2), Astec (Chirobiotic™ columns including but not limited to V, V2 and T2) and Diacel® (including but not limited to Chiralpak® AD-H) were available for screening. [0733] Eluents: [0734] Mobile phase eluent was chosen in conjunction with column manufacturers recommended stationary phase limitations in order to optimise a columns separation performance. Typical eluents include but are not limited to a gradient of either 0.1% formic acid in MeCN in 0.1% aqueous formic acid or a gradient of MeCN in aqueous 10 mM ammonium bicarbonate. [0735] Methods:

[0736] Achiral Preparative Chromatography [0737] The compound examples described have undergone HPLC purification, where indicated, using methods developed following recommendations as described in Snyder L. R., Dolan J. W., High-Performance Gradient Elution The Practical Application of the Linear-Solvent-Strength Model, Wiley, Hoboken, 2007.

[0738] Chiral Preparative Chromatography [0739] Preparative separations using Chiral Stationary Phases (CSPs) are the natural technique to apply to the resolution of enantiomeric mixtures. Equally, it can be applied to the separation of diastereomers and achiral molecules. Methods are well known in the art for optimising preparative chiral separations on CSPs and then using them to purify compounds. Such methods are described in Beesley T. E., Scott R. P. W.; Chiral Chromatography; Wiley, Chichester, 1998.

SYNTHESIS OF INTERMEDIATES

Preparation 1: tert-Butyl 2-(6-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate

[0740] ##STR00668##

[0741] A suspension of 6-bromo-2,3-dihydro-1H-isoindol-1-one (20 g, 94 mmol) and tert-butyl 2-bromoacetate (16.94 ml, 113 mmol) in DMF (320 mL) was cooled in an ice bath. Sodium hydride (4.53 g, 113 mmol) was added cautiously portionwise and the reaction was allowed to slowly warm to room temperature for 3 h. The reaction was quenched by the addition a saturated solution of NH.sub.4Cl (650 mL) and the crude product was extracted with DCM (2×650 mL). The combined organic extracts were washed with water (4×650 mL) and brine (2×650 mL). The mixture was passed through a phase separator cartridge and the organic phase was concentrated under vacuum to give the crude product (40.1 g) as a dark orange semi-solid. 30 g of the crude product were purified by chromatography (SiO.sub.2, 2×220 g column, 0-50% EtOAc in isohexane) to afford the title compound as a yellow solid (19.5 g, 77%). LC-MS: [M-.sup.tBu+H].sup.+=270/272.

Preparation 2: tert-Butyl 2-[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-2-yl]acetate

[0742] ##STR00669##

[0743] PdCl.sub.2(dppf), complex with dichloromethane (1.459 g, 1.751 mmol) was added to a degassed solution (by bubbling nitrogen through the solution) of tert-butyl 2-(6-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate (19.23 g, 58.4 mmol), bis(pinacolato)diboron (17.79 g, 70.0 mmol) and potassium acetate (11.57 g, 117 mmol) in 1-4-dioxane (200 mL). The mixture was degassed with nitrogen for a further 10 minutes then heated at 90° C. under nitrogen overnight. The reaction was cooled to room temperature and partitioned between EtOAc (600 mL) and water (600 mL). The aqueous layer was extracted with EtOAc (600 mL) and the combined organic extracts were washed with brine (1 L), dried (MgSO.sub.4), filtered and concentrated under vacuum to give the crude product (27.3 g), which was triturated with isohexane. The resulting precipitate was filtered and dried to afford the title compound as a brown solid (17.1 g, 75%). LC-MS: [M-tBu+H].sup.+=318.

Preparation 3: tert-Butyl 2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]acetate

[0744] ##STR00670##

[0745] A mixture of tert-butyl 2-[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-2-yl]acetate (17.1 g, 44.0 mmol), 2,4,5-trichloropyrimidine (7.4 mL, 66.2 mmol) and potassium carbonate (12.28 g, 88 mmol) in 1,4-dioxane:water (160 mL, 3:1) was degassed by bubbling nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.57 g, 2.199 mmol) was added and degassing with nitrogen continued for 10 minutes. The reaction was then heated at 90° C. under nitrogen overnight. The reaction was cooled to room temperature, diluted with water (500 mL) and the crude product extracted with EtOAc (3×500 mL). The combined organic extracts were washed with brine (1 L), dried (MgSO.sub.4), filtered and concentrated under vacuum to give the crude product, which was purified by chromatography (SiO.sub.2, 2×220 g columns, 0-100% EtOAc in isohexane) to afford the title compound as a yellow solid (12.04 g, 62%). LC-MS: [M-.sup.tBu+H].sup.+=338.

Preparation 4: tert-Butyl 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate

[0746] ##STR00671##

[0747] Oxan-4-amine (5 mL, 48.3 mmol) was added to a mixture of tert-butyl 2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]acetate (12 g, 27.1 mmol) and DIPEA (11.95 mL, 67.7 mmol) in 1,4-dioxane (100 mL). The reaction was then heated at 70° C. for 72 h. The reaction was cooled to room temperature and water (450 mL) was added. The crude product was extracted with EtOAc (2×450 mL) and the combined organic extracts were washed with brine (600 mL), dried (MgSO.sub.4), filtered and concentrated under vacuum to give the crude product (15.6 g). Purification by chromatography (SiO.sub.2, 220 g column, 0-100% EtOAc in isohexane) afforded unreacted starting material (1.8 g, 16%) as a colourless solid and the title compound as a colourless solid (8.86 g, 70.6%). LC-MS: [M-.sup.tBu+H].sup.+=403.

[0748] Further title compound (1.52 g, 76%) could be obtained using the recovered starting material following the same procedure described above. LC-MS: [M+H].sup.+=459.

Preparation 5: Ethyl 5-bromo-2-(bromomethyl)pyridine-3-carboxylate

[0749] ##STR00672##

[0750] A mixture of ethyl 5-bromo-2-methylpyridine-3-carboxylate (5.0 g, 20.48 mmol) and NBS (5.1 g, 28.7 mmol) in carbon tetrachloride (50 mL, 518 mmol) was heated to 100° C. (external temperature). Benzoyl peroxide (0.143 g, 0.443 mmol) was added and the mixture heated at 90° C. for 7h. The mixture was allowed to cool to room temperature and was stirred overnight. The reaction mixture was partitioned between DCM (100 mL) and water (100 mL). The layers were separated and the organic extract was washed with water (2×50 mL) and brine (2×50 mL) and then filtered through a phase separator cartridge. The organic fraction was then concentrated under reduced pressure to afford the crude product as a yellow oil (6.7 g), which was dry-loaded on silica. The crude product was purified by chromatography (SiO.sub.2, 0-100% (10% EtOAc in iso-hexanes) in iso-hexanes) to afford the title compound as a pale yellow oil (3.8 g, 50%). LC-MS: [M+H].sup.+=322/324/326

Preparation 6: tert-Butyl 2-{3-bromo-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl}acetate

[0751] ##STR00673##

[0752] tert-Butyl 2-aminoacetate hydrochloride (2.578 g, 15.38 mmol) was added to a solution of ethyl 5-bromo-2-(bromomethyl)pyridine-3-carboxylate (3.8 g, 10.24 mmol) and DIPEA (5.4 mL, 30.9 mmol) in acetonitrile (60.0 mL, 1149 mmol) and the resulting solution was heated to 75° C. overnight. After a total of 16.5 h the reaction mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was partitioned between EtOAc (100 mL) and a saturated solution of NH.sub.4Cl (50 mL). The layers were separated and the organic fraction was washed with NH.sub.4Cl (50 mL), water (50 mL) and brine (2×50 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude product as an orange solid (3.4 g). The solid was dry-loaded on silica and the product was purified by chromatography (SiO.sub.2, 40 g column, 0-100% EtOAc in iso-hexanes) to afford the title compound as a colourless solid (1.28 g, 37.8%). LC-MS: [M+H].sup.+=327/329.

[0753] Note: THF could also be used as solvent for the reaction.

Preparation 7: tert-Butyl 2-[3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]acetate

[0754] ##STR00674##

[0755] Potassium acetate (0.764 g, 7.78 mmol) and bis(pinacolato)diboron (1.48 g, 5.83 mmol) were added to a stirred solution of tert-butyl 2-{3-bromo-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl}acetate (1.28 g, 3.87 mmol) in 1,4-dioxane (40.0 mL, 468 mmol). The mixture was heated to 40° C. and degassed with nitrogen for 10 minutes. PdCl.sub.2(dppf).sub.2 (0.114 g, 0.156 mmol) was added and the mixture was degassed for a further 10 minutes then heated to 90° C. After 3.5 h the mixture was cooled to room temperature and partitioned between DCM (70 mL) and water (70 mL). The layers were separated and the organic fraction was washed with water (50 mL) and brine (3×50 mL) and then filtered through a phase separating cartridge. The organic filtrate was concentrated under reduced pressure to afford the crude product as a black solid. The boronate ester intermediate was used directly in the next step without further purification. LC-MS: [M+H].sup.+=293 (note: the mass for the boronic ester was not observed—it is possible that the product hydrolysed to the boronic acid under the LC-MS conditions). A mixture of crude tert-butyl 2-[5-oxo-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl] acetate (1.448 g, 3.87 mmol), 2,4,5-trichloropyrimidine (0.670 mL, 5.84 mmol) and potassium carbonate (1.07 g, 7.74 mmol) in 1,4-dioxane (30.0 mL, 351 mmol) and water (10.0 mL, 555 mmol) was degassed with nitrogen at 40° C. After 10 minutes Pd(Ph.sub.3P).sub.4 (0.150 g, 0.130 mmol) was added. The mixture was degassed for a further 10 minutes and then heated to 90° C. After 2 h the reaction mixture was cooled to room temperature and then partitioned between EtOAc (75 mL) and water (75 mL). The layers were separated and the crude product was extracted with EtOAc (75 mL). The combined organic extracts were washed with brine (3×50 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude product as a dark oil (3.17 g). The crude product was dry-loaded on silica and purified by chromatography (SiO.sub.2, 40 g column, 0-100% (1% MeOH in DCM) in DCM). The product was further purified by chromatography (SiO.sub.2, 24 g column, 0-100% EtOAc in iso-hexanes) to afford the title compound as an orange gum (0.729 g, 44%). LC-MS: [M+H].sup.+=395.

Preparation 8: tert-butyl 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)acetate

[0756] ##STR00675##

[0757] A mixture of tert-butyl 2-[3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]acetate (0.729 g, 1.697 mmol), oxan-4-amine (0.265 mL, 2.56 mmol) and DIPEA (0.740 mL, 4.24 mmol) in EtOH (10 mL) was refluxed for 3h. Further oxan-4-amine (0.1 mL, 0.966 mmol) and DIPEA (0.4 mL, 2.292 mmol) were added. After a total of 5 h further oxan-4-amine (0.1 mL, 0.966 mmol) and DIPEA (0.4 mL, 2.292 mmol) were added and the mixture was refluxed overnight. The mixture was cooled to room temperature and was concentrated under reduced pressure. The residue was partitioned between EtOAc (40 mL) and water (40 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (40 mL) and the combined organic extracts were washed with brine (2×30 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the title compound as a dark yellow foam (0.758 g, 92%). LC-MS: [M+H].sup.+=460.

Preparation 9: 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)acetic acid

[0758] ##STR00676##

[0759] TFA (4.0 mL, 51.9 mmol) was added to a stirred solution of tert-butyl 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)acetate (0.758 g, 1.566 mmol) in DCM (20 mL, 311 mmol). The reaction mixture was stirred at room temperature overnight and was concentrated under reduced pressure, then azeotroped with toluene (3×30 mL). The residue was triturated with diethyl ether and the resulting solid was filtered, washed with diethyl ether (3×20 mL) and dried in a vacuum oven at 40° C. to afford the title compound as a beige solid (0.607 g, 86%). LC-MS: [M+H].sup.+=404.

Preparation 10: Methyl 5-chloro-3-fluoro-2-methylbenzoate

[0760] ##STR00677##

[0761] Iodomethane (1.04 mL, 16.6 mmol) was added to a suspension of 5-chloro-3-fluoro-2-methylbenzoic acid (1.57 g, 8.3 mmol) and potassium carbonate (2.30 g, 16.6 mmol) in DMF (30 mL). The reaction was stirred at room temperature for 18 h. A further portion of potassium carbonate (1.15 g, 8.3 mmol) and iodomethane (0.52 mL, 8.3 mmol) were added and the reaction was stirred for a further 3 h. The mixture was diluted with diethyl ether (50 mL) and water (100 mL). The phases were separated and the aqueous phase was extracted with diethyl ether (2×20 mL). The combined organic phases were combined with the crude material prepared from 5-chloro-3-fluoro-2-methylbenzoic acid (0.50 g, 2.7 mmol) from a second experiment according to the procedure described above. The mixture was washed with brine (4×100 mL), dried (MgSO.sub.4) and concentrated under vacuum to give the title compound as a pale green oil (2.18 g, 94%). 1H NMR (400 MHz, DMSO-d6) 7.64 (1H, dd), 7.62 (1H, s), 3.85 (3H, s), 2.35 (3H, d).

Preparation 11: methyl 2-(bromomethyl)-5-chloro-3-fluorobenzoate

[0762] ##STR00678##

[0763] N-Bromosuccinimide (2.30 g, 12.9 mmol) and benzoyl peroxide (75%, 0.174 g, 0.54 mmol) were added to a solution of methyl 5-chloro-3-fluoro-2-methylbenzoate (2.18 g, 10.8 mmol) in chloroform (100 mL). The mixture was heated to 60° C. and stirred for 18 h. The reaction was cooled to RT and hexane (100 mL) was added. The resulting precipitate was removed by filtration and the filtrate was concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-30% DCM in iso-hexane) gave the title compound as a colourless oil (2.34 g, 70% yield, 90% purity). 1H NMR (400 MHz, Chloroform-d) 7.80 (1H, t), 7.31 (1H, dd), 4.97 (2H, d), 3.99 (3H, s).

Preparation 12: tert-butyl 2-(6-chloro-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate

[0764] ##STR00679##

[0765] Diisopropylethylamine (1.86 mL, 10.7 mmol) and methyl 2-(bromomethyl)-5-chloro-3-fluorobenzoate (1 g, 3.55 mmol) were added to a suspension of tert-butylglycine hydrochloride (0.893 g, 5.33 mmol) in acetonitrile (20 mL). The resulting solution was heated to 75° C. and stirred for 18 h. The reaction mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate (15 mL) and 1 M hydrochloric acid (25 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO.sub.4) and concentrated. Purification by chromatography (SiO.sub.2, 0-40% ethyl acetate in iso-hexane) gave the title compound as a colourless solid (823 mg, 77%). LC-MS: [M+Na].sup.+=322.

Preparation 13: tert-butyl 2-[4-fluoro-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-2-yl]acetate

[0766] ##STR00680##

[0767] A reaction tube was charged with tert-butyl 2-(6-chloro-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate (335 mg, 1.12 mmol), bis(pinacolato)diboron (341 mg, 1.34 mmol), potassium acetate (329 mg, 3.35 mmol) and XPhos G3 (19 mg, 0.02 mmol). The tube was evacuated and backfilled with nitrogen (3×). 1,4-Dioxane (2.2 mL) was added and the mixture was heated to 110° C. for 1 h. The reaction was diluted with ethyl acetate (10 mL) and passed through a pad of celite, eluting with ethyl acetate (50 mL) and the filtrate was concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-50% ethyl acetate in iso-hexane) gave the title compound (467 mg, quant. yield, 95% purity) as a colourless solid. LC-MS: [M+Na].sup.+=414.

Preparation 14: tert-butyl 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl]acetate

[0768] ##STR00681##

[0769] A mixture of tert-butyl 2-[4-fluoro-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-2-yl]acetate (200 mg, 0.51 mmol), 2,4,5-trichloropyrimidine (0.086 mL, 0.77 mmol) in a mixture of 1,4-dioxane (1.2 mL) and 2 M aqueous potassium carbonate solution (0.51 mL, 1.0 mmol) was degassed with nitrogen for 5 minutes.

[0770] Tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.03 mmol) was added and degassing continued for 10 minutes. The mixture was heated to 90° C. for 2.5 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×15 mL). The combined organic phases were washed with brine (30 mL), dried (MgSO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-40% ethyl acetate in iso-hexane) gave the title compound as a colourless solid (139 mg, 61% yield, 93% purity). LC-MS: [M+Na].sup.+=434.

Preparation 15: tert-butyl 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate

[0771] ##STR00682##

[0772] A solution of tert-butyl 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl]acetate (139 mg, 0.34 mmol), oxan-4-amine (0.070 mL, 0.67 mmol) and diisopropylethylamine (0.15 mL, 0.85 mmol) in 1,4-dioxane (2 mL) was heated to 85° C. and stirred for 18 h. The reaction was diluted with ethyl acetate (10 mL) and water (10 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with 1 M hydrochloric acid (30 mL), brine (30 mL), dried (MgSO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-70% ethyl acetate in iso-hexane) gave the title compound as a colourless solid (102 mg, 62%). LC-MS: [M+H].sup.+=477.

Preparation 16: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid

[0773] ##STR00683##

[0774] Trifluoroacetic acid (0.8 mL, 10.4 mmol) was added to a solution of tert-butyl 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate (102 mg, 0.21 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was concentrated under vacuum, azeotroped with toluene (3×5 mL) and acetonitrile (10 mL) to give the title compound (93 mg, quant. yield) as a colourless solid. LC-MS: [M+H].sup.+=421.

Preparation 17: 4-chloro-N-(oxan-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0775] ##STR00684##

[0776] A solution of oxan-4-amine (2.1 mL, 20.3 mmol) and diisopropylethylamine (4.25 mL, 23.9 mmol) in THF (130 mL) was added to a stirred solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2.7 mL, 19.7 mmol) in THF (130 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-50% ethyl acetate in iso-hexane) gave the title compound (1.66 g, 29%) and its regioisomer 2-chloro-N-(oxan-4-yl)-5-(trifluoromethyl)pyrimidin-4-amine (1.23 g, 22%) as colourless solids. 1H NMR (400 MHz, DMSO-d6) 8.63-8.53 (2H, m), 4.05-3.90 (1H, m), 3.90-3.82 (2H, m), 3.43-3.33 (2H, m), 1.84-1.74 (2H, m), 1.59-1.45 (2H, m). LC-MS: [M+H].sup.+=284.

Preparation 18: tert-butyl 2-(6-{2-[(oxan-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate

[0777] ##STR00685##

[0778] A mixture of tert-butyl 2-[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-2-yl]acetate (202 mg, 0.53 mmol), 4-chloro-N-(oxan-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (224 mg, 0.80 mmol) and potassium carbonate (147 mg, 1.06 mmol) in a mixture of 1,4-dioxane (1.5 mL) and water (0.5 mL) was degassed with nitrogen for 5 minutes. XPhos Pd G3 (14 mg, 0.016 mmol) was added and degassing continued for 10 minutes. The reaction was then heated to 90° C. for 2 h. The reaction was cooled to RT and diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-100% ethyl acetate in iso-hexane) gave the title compound as a colourless oil (142 mg, 35%). LC-MS: [M+H].sup.+=493.

Preparation 19: 2-(6-{2-[(oxan-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid

[0779] ##STR00686##

[0780] Trifluoroacetic acid (1 mL, 13.0 mmol) was added to a solution of tert-butyl 2-(6-{2-[(oxan-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate (135 mg, 0.26 mmol) in DCM (4 mL). The reaction mixture was stirred at RT for 18 h. The reaction mixture was concentrated under vacuum, azeotroped with toluene (3×10 mL), triturated with diethyl ether, filtered and dried to give the title compound (76 mg, 53%) as a colourless solid. LC-MS: [M+H].sup.+=437.

Preparation 20: tert-butyl 6-bromo-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate

[0781] ##STR00687##

[0782] Di-tert-butyl dicarbonate (2.47 g, 11.3 mmol) was added to a suspension of 6-bromo-2,3-dihydro-1H-isoindol-1-one (2.00 g, 9.43 mmol), DMAP (0.058 g, 0.47 mmol) and triethylamine (1.58 mL, 11.3 mmol) in DCM (50 mL) and the mixture was stirred at room temperature for 18 h. The resulting solution was diluted with water (50 mL). The phases were separated and the aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with brine (100 mL), dried (MgSO.sub.4) and absorbed on silica. Purification by chromatography (SiO.sub.2, 50-100% ethyl acetate in iso-hexane) gave the title compound (2.44 g, 81%) as a colourless solid. LC-MS: [M+Na].sup.+=334.

Preparation 21: tert-butyl 5-bromo-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-isoindole-2-carboxylate

[0783] ##STR00688##

[0784] LiHMDS (1 M in THF, 7.69 mL, 7.69 mmol) was added to a solution of tert-butyl 6-bromo-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate (2.00 g, 6.41 mmol) in THF (50 mL) at −78° C. The mixture was stirred for 1 h, then warmed to −50° C. for 10 min and cooled to −78° C. 2-(Trimethylsilyl)ethoxymethyl chloride (2.27 mL, 12.8 mmol) was added dropwise and the mixture was warmed to 0° C. over a period of 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (5 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine (30 mL), dried (MgSO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-15% ethyl acetate in iso-hexane) gave the title compound (950 mg, 33%) as a yellow oil. LC-MS: [M+H].sup.+=464.

Preparation 22: 6-bromo-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-isoindol-1-one

[0785] ##STR00689##

[0786] A solution of HCl (4 M in 1,4-dioxane, 8 mL, 32 mmol) was added dropwise to tert-butyl 5-bromo-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-isoindole-2-carboxylate (950 mg, 2.15 mmol) at 0° C. The solution was stirred at room temperature for 15 minutes then added to saturated aqueous sodium bicarbonate solution (5 mL). The mixture was extracted with ethyl acetate (2×15 mL). The combined organic phases were washed with saturated brine (10 mL), dried (MgSO.sub.4) and concentrated under vacuum to afford the title compound (707 mg, 93%) as a yellow oil. LC-MS: [M+H].sup.+=342.

Preparation 23: methyl 2-(5-bromo-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-isoindol-2-yl)acetate

[0787] ##STR00690##

[0788] Sodium hydride (60% dispersion in mineral oil, 99 mg, 2.5 mmol) was added to a solution of 6-bromo-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-isoindol-1-one (707 mg, 2.07 mmol) in THF (17 mL) at 0° C. The mixture was stirred for 15 minutes before methyl 2-bromoacetate (0.27 mL, 2.48 mmol) was added. The mixture was warmed to room temperature and stirred for 4 h. The reaction was quenched with saturated aqueous ammonium chloride solution (5 mL) and extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with brine (10 mL), dried (MgSO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-30% ethyl acetate in iso-hexane) gave the title compound (590 mg, 69%) as a yellow oil. LC-MS: [M+Na].sup.+=436.

Preparation 24: methyl 2-[3-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-isoindol-2-yl]acetate

[0789] ##STR00691##

[0790] A reaction tube was charged with methyl 2-(5-bromo-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-isoindol-2-yl)acetate (600 mg, 1.45 mmol), bis(pinacolato)diboron (441 mg, 1.74 mmol), potassium acetate (426 mg, 4.34 mmol) and XPhos Pd G3 (25 mg, 0.029 mmol). The tube was evacuated and backfilled with nitrogen (3×). 1,4-Dioxane (2.9 mL) was added and the mixture was heated to 90° C. for 1 h. The reaction was cooled to room temperature and diluted with ethyl acetate (10 mL), then passed through a pad of celite, eluting with ethyl acetate (30 mL). After concentration of the filtrate, purification by chromatography (SiO.sub.2, 0-40% ethyl acetate in iso-hexane) gave the title compound (635 mg, 91%) as a colourless oil. LC-MS: [M+Na].sup.+=484.

Preparation 25: methyl 2-[5-(2,5-dichloropyrimidin-4-yl)-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-isoindol-2-yl]acetate

[0791] ##STR00692##

[0792] A mixture of methyl 2-[3-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-isoindol-2-yl]acetate (640 mg, 1.39 mmol), 2,4,5-trichloropyrimidine (0.233 mL, 2.08 mmol) in a mixture of 1,4-dioxane (3.5 mL) and 2 M aqueous potassium carbonate solution (1.39 mL, 2.77 mmol) was degassed with nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.069 mmol) was added and degassing continued for 10 minutes. The mixture was heated to 90° C. for 2.5 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×15 mL). The combined organic phases were washed with brine (30 mL), dried (MgSO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-40% ethyl acetate in iso-hexane) gave the title compound (370 mg, 54%) as a yellow oil. LC-MS: [M+Na].sup.+=504.

Preparation 26: methyl 2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-isoindol-2-yl)acetate

[0793] ##STR00693##

[0794] A solution of methyl 2-[5-(2,5-dichloropyrimidin-4-yl)-3-oxo-1-{[2-(trimethylsilyl) ethoxy]methyl}-2,3-dihydro-1H-isoindol-2-yl]acetate (200 mg, 0.415 mmol), oxan-4-amine (0.086 mL, 0.83 mmol) and diisopropylethylamine (0.18 mL, 1.04 mmol) in 1,4-dioxane (3 mL) was heated to 85° C. and stirred for 18 h. The reaction was diluted with ethyl acetate (10 mL) and water (10 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with 1 M hydrochloric acid (30 mL), brine (30 mL), dried (MgSO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-70% ethyl acetate in iso-hexane) gave the title compound (150 mg, 66%) as a colourless solid. LC-MS: [M+H].sup.+=547.

Preparation 27: N-tert-butyl-2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-isoindol-2-yl)-N-methylacetamide

[0795] ##STR00694##

[0796] A solution of lithium hydroxide (1 M aqueous, 0.091 mL, 0.091 mmol) was added to a stirred solution of methyl 2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-isoindol-2-yl)acetate (50 mg, 0.091 mmol) in THF (1.4 mL) and water (0.4 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (10 mL) and water (5 mL). The phases were separated and the aqueous phase was acidfied with 1 M hydrochloric acid to pH ˜3. The resulting colourless precipitate was collected by filtration, washed with water (5 mL) and dried under vacuum. The residue was suspended in DCM (1.8 mL) and DMF (0.2 mL). HATU (42 mg, 0.11 mmol) and diisopropylethylamine (0.048 mL, 0.27 mmol) were added. The mixture was stirred for 5 minutes, before N-tert-butyl-methylamine (0.012 mL, 0.10 mmol) was added. The mixture was stirred at room temperature for 2 h before being diluted with ethyl acetate (10 mL) and water (15 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with 1 M hydrochloric acid (50 mL), saturated aqueous sodium bicarbonate (50 mL), brine (3×50 mL), dried (MgSO.sub.4) and concentrated under vacuum to give the title compound as an off white solid (50 mg, 82% yield, 90% purity). LC-MS: [M+H].sup.+=602.

Preparation 28: tert-butyl 5-bromo-1-methyl-3-oxo-2,3-dihydro-1H-isoindole-2-carboxylate

[0797] ##STR00695##

[0798] LiHMDS (1M in THF, 3.52 mL, 3.52 mmol) was added to a solution of tert-butyl 6-bromo-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate (Preparation 20) (1.00 g, 3.20 mmol) in THF (15 mL) at −78° C. The mixture was stirred for 1 h before iodomethane (0.22 mL, 3.5 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 45 minutes. Saturated aqueous ammonium chloride solution (20 mL) and ethyl acetate (20 mL) were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phases were washed with brine (30 mL), dried (MgSO.sub.4) and absorbed on silica. Purification by chromatography (SiO.sub.2, 0-20% ethyl acetate in iso-hexane) gave the title compound (332 mg, 31%) as a colourless solid. LC-MS: [M-.sup.tBu+H].sup.+=270.

Preparation 29: 6-bromo-3-methyl-2,3-dihydro-1H-isoindol-1-one

[0799] ##STR00696##

[0800] Trifluoroacetic acid (0.50 mL, 6.5 mmol) was added to a mixture of tert-butyl 5-bromo-1-methyl-3-oxo-2,3-dihydro-1H-isoindole-2-carboxylate (330 mg, 0.991 mmol) in DCM (5 mL) and the mixture was stirred for 1h. The mixture was concentrated under vacuum and azeotroped with toluene (2×5 mL). The residue was dissolved in ethyl acetate (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL) was added. The phases were separated and the aqueous phase was extracted with ethyl acetate (10 mL). The combined organic phases were washed with brine (20 mL), dried (MgSO.sub.4) and concentrated under vacuum to give the title compound (174 mg, 75%) as a colourless solid. LC-MS: [M+H].sup.+=226.

Preparation 30: tert-butyl 2-(5-bromo-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate

[0801] ##STR00697##

[0802] Prepared according to Preparation 1 from 6-bromo-3-methyl-2,3-dihydro-1H-isoindol-1-one (170 mg, 0.752 mmol) and tert-butyl 2-bromoacetate (0.13 mL, 0.90 mmol). The title compound (218 mg, 80%) was obtained as a colourless solid. LC-MS: [M-.sup.tBu+H].sup.+=284.

Preparation 31: tert-butyl 2-[5-(2,5-dichloropyrimidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-2-yl]acetate

[0803] ##STR00698##

[0804] A mixture of tert-butyl 2-(5-bromo-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate (215 mg, 0.632 mmol), potassium acetate (186 mg, 1.90 mmol) in 1,4-dioxane (4 mL) was degassed with nitrogen for 10 minutes before bis(pinacolato)diboron (193 mg, 0.758 mmol) and PdCl.sub.2(dppf).sub.2 (23 mg, 0.032 mmol) were added. The reaction was heated to 100° C. under nitrogen for 4 h. The reaction was diluted with ethyl acetate (20 mL) and water (20 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO.sub.4) and concentrated. The residue was dissolved in 1,4-dioxane (1 mL) and added to a degassed mixture of 2,4,5-trichloropyrimidine (85 mg, 0.47 mmol) and potassium carbonate (86 mg, 0.62 mmol) in a mixture of 1,4-dioxane (3 mL) and water (1 mL). Tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol) was added and the mixture heated to 100° C. under nitrogen for 18 h. The mixture cooled to room temperature and diluted with ethyl acetate (20 mL) and water (20 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with brine (25 mL), dried (MgSO.sub.4) and absorbed onto silica. Purification by chromatography (SiO.sub.2, 0-40% ethyl acetate in iso-hexane) gave the title compound (34 mg, 26%) as a colourless solid. LC-MS: [M-.sup.tBu+H].sup.+=352.

Preparation 32: tert-butyl 2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate

[0805] ##STR00699##

[0806] A mixture of tert-butyl 2-[5-(2,5-dichloropyrimidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-2-yl]acetate (32 mg, 0.078 mmol), oxan-4-amine (0.012 mL, 0.12 mmol) and diisopropylethylamine (0.041 mL, 0.24 mmol) in ethanol (0.75 mL) was heated to 80° C. for 3 days. The reaction was diluted with ethyl acetate (10 mL) and water (10 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic phases were dried (MgSO.sub.4) and absorbed onto silica. Purification by chromatography (SiO.sub.2, 0-3% methanol in DCM) gave the title compound (22 mg, 50% yield, 85% purity) as a colourless solid. LC-MS: [M+H].sup.+=473.

Preparation 33: Benzyl (1-methylcyclobutyl)carbamate

[0807] ##STR00700##

[0808] DIPEA (474 μl, 2.71 mmol) was added to a solution of 1-methylcyclobutanamine hydrochloride (150 mg, 1.233 mmol) in THF (20 mL) at 0° C. and the mixture was stirred at 0° C. for 10 minutes. Benzyl chloroformate (194 μl, 1.357 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature, and stirred for 2 hours. The reaction mixture was concentrated under vacuum and the residue was diluted with EtOAc (50 mL), washed successively with 1M HCl (50 mL), saturated aqueous solution of NaHCO.sub.3 (50 mL), brine (50 mL), and dried via a hydrophobic phase separator. The organic extract was concentrated under vacuum to afford benzyl (1-methylcyclobutyl)carbamate (288 mg, 72% (68% purity)) as a pale yellow oil. 1H NMR (400 MHz, CDCl.sub.3) 7.47-7.30 (m, 5H), 5.07 (s, 2H), 4.88 (br. s, 1H), 2.34-2.30 (m, 2H), 2.00-1.93 (m, 2H), 1.79-1.76 (m, 2H), 1.44 (s, 3H); (32% wt benzyl chloroformate).

Preparation 34: Benzyl methyl(1-methylcyclobutyl)carbamate

[0809] ##STR00701##

[0810] Sodium hydride (60% in mineral oil, 79 mg, 1.97 mmol) was added in portions to a solution of benzyl (1-methylcyclobutyl)carbamate (288 mg, 1.313 mmol) in DMF (2 mL) at 0° C. and methyl iodide (99 μl, 1.576 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, then diluted with EtOAc (5 mL), washed with water (4×10 mL), brine (10 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated under vacuum. The crude product was purified by chromatography (SiO.sub.2, 4 g column, 0-25% ethyl acetate in iso-hexane) to afford benzyl methyl(1-methylcyclobutyl)carbamate (154 mg, 50%) as a clear colourless oil. 1H NMR (400 MHz, CDCl.sub.3) 7.36-7.30 (m, 5H), 5.09 (s, 2H), 2.73 (s, 3H), 2.25-2.22 (m, 2H), 1.93-1.91 (m, 2H), 1.67-1.64 (m, 2H), 1.34 (s, 3H).

Preparation 35: N,1-Dimethylcyclobutan-1-amine

[0811] ##STR00702##

[0812] A solution of benzyl methyl(1-methylcyclobutyl)carbamate (154 mg, 0.660 mmol) in EtOAc (6 mL) was hydrogenated in the H-cube (10% Pd—C, Full H2 mode, room temperature, 1 mL/min) for one hour. The reaction mixture was used without further treatment in the next step.

Preparation 36: 2-cyclopropyl-N-methylpropan-2-amine

[0813] ##STR00703##

[0814] Prepared from 2-cyclopropylpropan-2-amine following an analogous/similar procedure as described for Preparations 33-35.

Preparation 37: tert-butyl (2-(tert-butylamino)ethyl)carbamate

[0815] ##STR00704##

[0816] A stirred suspension of 4 Å molecular sieve beads (˜2 g) in DMF (6 ml) was treated with cesium hydroxide monohydrate (1148 mg, 6.84 mmol) and stirred for 10 minutes. The suspension was treated with tert-butylamine (718 μl, 6.84 mmol) and stirred for 30 minutes. Tert-butyl (2-bromoethyl)carbamate (1800 mg, 8.03 mmol) was added and the mixture was stirred overnight, then filtered. The filtrate was evaporated and the residue was dissolved in ether (20 ml), washed successively with brine (20 ml), water (20 ml) then dried (Na2SO.sub.4) and evaporated to give tert-butyl (2-(tert-butylamino)ethyl)carbamate (680 mg, 1.572 mmol, 23.0%) as a pale yellow oil. LC-MS: [M+H].sup.+=217.

Preparation 38: N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-methylpropan-2-amine

[0817] ##STR00705##

[0818] TBDMSCl (577 mg, 3.83 mmol) was added to a stirred solution of 2-(tert-butylamino)ethanol (305 mg, 2.55 mmol) and imidazole (521 mg, 7.65 mmol) in DMF (6 mL) and the reaction mixture was stirred at room temperature overnight. A further quantity of imidazole (521 mg, 7.65 mmol) was added, followed by TBDMS-CI (577 mg, 3.83 mmol) and stirring continued at room temperature overnight. The reaction mixture was diluted with EtOAc (30 mL), washed with water (3×30 mL) and brine (30 mL) dried (MgSO.sub.4), filtered and concentrated under vacuum to give crude N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-methylpropan-2-amine as an oil (104 mg, 17%). 1H NMR (400 MHz, DMSO-d6) 3.58 (t, 2H), 2.55 (t, 2H), 1.16 (br. s, 1H), 1.00 (s, 9H), 0.86 (s, 9H), 0.03 (s, 6H).

Preparation 39: methyl (1,1,1-trifluoro-3-phenylpropan-2-yl)carbamate

[0819] ##STR00706##

[0820] Methyl chloroformate (0.343 mL, 4.44 mmol) was added dropwise to a solution of 1,1,1-trifluoro-3-phenylpropan-2-amine (840 mg, 4.44 mmol) and pyridine (1.44 mL, 17.8 mmol) in chloroform (80 mL) at 0° C. The solution was warmed to room temperature and stirred for 18 h. Ice water (30 mL) was added slowly to the mixture and the solution was stirred for 15 minutes. The phases were separated and the aqueous phase was extracted with chloroform (2×30 mL). The combined organic phases were washed with 3 M hydrochloric acid (2×50 mL) and brine (30 mL), dried (Na2SO.sub.4) and concentrated under vacuum. Recrystallisation from iso-hexane gave the title compound (906 mg, 3.59 mmol, 81%) as colourless needles. 1H NMR (400 MHz, DMSO-d6) 7.94 (1H, d), 7.34-7.28 (4H, m), 7.27-7.19 (1H, m), 4.47-4.31 (1H, m), 3.46 (3H, s), 3.04 (1H, dd), 2.77 (1H, dd).

Preparation 40: 3-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one

[0821] ##STR00707##

[0822] A solution of methyl (1,1,1-trifluoro-3-phenylpropan-2-yl)carbamate (550 mg, 2.23 mmol) in polyphosphoric acid (14.2 g, 145 mmol) was heated to 140° C. for 1 h. The mixture was poured onto ice water (40 mL) and extracted with chloroform (3×25 mL). The combined organic phases were washed with water (20 mL), brine (20 mL), dried (Na2SO.sub.4) and concentrated under vacuum. Recrystallisation from iso-hexane gave the title compound (232 mg, 48%) as colourless needles. LC-MS: [M+H].sup.+=216.

Preparation 41: 3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline

[0823] ##STR00708##

[0824] A solution of 3-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one (200 mg, 0.93 mmol) in THF (15 mL) was added dropwise to a solution of borane THF complex (1 M in THF, 6.5 mL, 6.5 mmol) in THF (15 mL). The reaction was heated to 70° C. for 2 h, then cooled to RT. Methanol (5 mL) was added and the mixture was concentrated under vacuum. The residue was dissolved in methanol (20 mL) and 6 M hydrochloric acid (20 mL) and heated to 65° C. for 2 h, then stirred at room temperature for 18 h. The solution was basified to pH 10 with 10% sodium hydroxide solution. The mixture was extracted with DCM (3×20 mL) and the combined organic phases were washed with brine, dried (Na2SO.sub.4) and concentrated under vacuum. The residue was dissolved in methanol (2 mL) and loaded onto a column of SCX (2 g). The column was washed with methanol and then the product was eluted with 0.7 M ammonia in methanol. The mixture was concentrated under vacuum to give the title compound (125 mg, 67%) as a tan solid. LC-MS: [M+H].sup.+=202.

Preparation 42: 6-bromo-2-[(3-methyloxetan-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one

[0825] ##STR00709##

[0826] A stirred suspension of 6-bromo-2,3-dihydro-1H-isoindol-1-one (300 mg, 1.42 mmol) in DMF (4 mL) was cooled in an ice-bath and treated with sodium hydride (60% dispersion in mineral oil, 68 mg, 1.70 mmol) and stirred and cooled for 15 min. The mixture was treated with 3-(bromomethyl)-3-methyloxetane (280 mg, 1.70 mmol) and stirred at RT for 18 h. Brine (20 mL) was added and the crude product was extracted with ethyl acetate (2×20 mL). The combined extracts were washed with brine (20 mL), dried (MgSO.sub.4) and evaporated. The residue was purified by chromatography (SiO.sub.2, 20-100% ethyl acetate in iso-hexane) to afford the title compound (342 mg, 81%) as a yellow solid. LC-MS: [M+H].sup.+=296/298.

Preparations 43-47

[0827] Prepared following an analogous/similar procedure as described for Preparation 42:

TABLE-US-00006 Preparation Structure Name MS: [M + H].sup.+ 43 [00710] 6-bromo-2-(2-methoxyethyl)-2,3- dihydro-1H-isoindol-1-one 270/272 44 [00711] 6-bromo-2-[(oxolan-2-yl)methyl]-2,3- dihydro-1H-isoindol-1-one 296/298 45 [00712] 6-bromo-2-[(1-methyl-1H-1,2,3-triazol- 4-yl)methyl]-2,3-dihydro-1H-isoindol- 1-one 307/309 46 [00713] 6-bromo-2-[(5-tert-butyl-1,2-oxazol-3- yl)methyl]-2,3-dihydro-1H-isoindol-1- one 349/351 47 [00714] tert-butyl 2-[(6-bromo-1-oxo-2,3- dihydro-1H-isoindo1-2- yl)methyl]pyrrolidine-1-carboxylate 295/297 [M-BOC + H].sup.+

Preparation 48: 6-bromo-2-[2-(morpholin-4-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[0828] ##STR00715##

[0829] Sodium hydride (60% dispersion in mineral oil, 34 mg, 1.40 mmol) was added to a suspension of 6-bromo-2,3-dihydro-1H-isoindol-1-one (250 mg, 1.18 mmol) in DMF (5 mL) and the mixture was stirred for 5 min after hydrogen gas evolution ceased. 4-(2-bromoethyl)morpholine (0.18 mL, 1.3 mmol) was added to the resulting brown solution and the mixture was stirred at RT for 18 h. The mixture was diluted with ethyl acetate and transferred into a separating funnel. Water was added and the crude product was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO.sub.4) and concentrated under vacuum. The residue was triturated with a mixture of diethyl ether and iso-hexane and the resulting precipitate was filtered, washed with iso-hexane and dried under suction to afford the title compound (196 mg, 50%) as a pale yellow solid. LC-MS: [M+1-1].sup.+=325/327.

Preparation 49: 2-[(3-methyloxetan-3-yl)methyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one

[0830] ##STR00716##

[0831] A mixture of 6-bromo-2-[(3-methyloxetan-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one (338 mg, 1.14 mmol), potassium acetate (336 mg, 3.42 mmol) and bis(pinacolato)diboron (348 mg, 1.37 mmol) in 1,4-dioxane (5 mL) was degassed with nitrogen at 40° C. for 10 min. The mixture was treated with PdCl.sub.2(dppf).sub.2 (42 mg, 0.057 mmol), degassed for a further 10 min and stirred at 90° C. for 2 h. The mixture was allowed to cool, diluted with ethyl acetate (20 mL), washed with brine (20 mL), dried (MgSO.sub.4) and evaporated. The residue was triturated with a mixture of ether (10 mL) and iso-hexane (10 mL) and the resulting precipitate was collected by filtration, washed with iso-hexane (20 mL) and dried to give the title compound (326 mg, 82%) as a chocolate-brown powder. The product was used without further purification in the next step. LC-MS: [M+H].sup.+=344.

Preparations 50-52

[0832] Prepared following an analogous/similar procedure to that described above for Preparation 49:

TABLE-US-00007 Preparation Structure Name MS: [M + H].sup.+ 50 [00717] 2-[(1-methyl-1H-1,2,3-triazol-4- yl)methyl]-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2,3-dihydro- 1H-isoindo1-1-one 355 51 [00718] 2-[(5-tert-butyl-1,2-oxazol-3- yl)methyl]-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2,3-dihydro- 1H-isoindol-1-one 397 52 [00719] tert-butyl 2-{[1-oxo-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)- 2,3-dihydro-1H-isoindol-2- yl]methyl}pyrrolidine-1-carboxylate 343 [M-Boc + H].sup.+

Preparation 53: 6-(2,5-dichloropyrimidin-4-yl)-2-[(3-methyloxetan-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one

[0833] ##STR00720##

[0834] A mixture of 2-[(3-methyloxetan-3-yl)methyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (326 mg, 0.95 mmol), 2,4,5-trichloropyrimidine (261 mg, 1.43 mmol), 2 M aqueous potassium carbonate solution (0.95 mL, 1.9 mmol) and 1,4-dioxane (10 mL) was stirred and degassed with nitrogen at 40° C. for 10 min, treated with Pd(PPh.sub.3).sub.4 (55 mg, 0.048 mmol) and degassed for a further 10 min. The mixture was stirred at 90° C. for 5 h, allowed to cool and diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic phases were washed with brine (20 mL), dried (Na.sub.2SO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 10-100% ethyl acetate in iso-hexane) gave the title compound (252 mg, 73%) as an orange solid. LC-MS: [M+H].sup.+=364.

Preparations 54-55

[0835] Prepared following an analogous/similar procedure to that described for Preparation 53:

TABLE-US-00008 Preparation Structure Name MS: [M + H].sup.+ 54 [00721] 2-[(5-tert-butyl-1,2-oxazol-3- yl)methyl]-6-(2,5-dichloropyrimidin-4- yl)-2,3-dihydro-1H-isoindol-1-one 417 55 [00722] tert-butyl 2-{[6-(2,5-dichloropyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]methyl}pyrrolidine-1-carboxylate 363 [M-Boc + H].sup.+

Preparation 56: 6-(2,5-dichloropyrimidin-4-yl)-2-[(1-methyl-1H-1,2,3-triazol-4-yl)methyl]-2,3-dihydro-1H-isoindol-1-one

[0836] ##STR00723##

[0837] A mixture of 2,4,5-trichloropyrimidine (179 mg, 0.98 mmol), 2-[(1-methyl-1H-1,2,3-triazol-4-yl)methyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (231 mg, 0.65 mmol) and S-Phos Pd G3 (3 mg, 0.004 mmol) in 1,4-dioxane (8 mL) was treated with 1 M aqueous sodium carbonate (2 mL, 2 mmol) degassed with nitrogen for 10 min and stirred at 50° C. for 1.5 h. The mixture was allowed to cool and partitioned between ethyl acetate (20 mL) and brine (20 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (15 mL). The combined organic phases were dried (Na.sub.2SO.sub.4) and concentrated. Purification by chromatography (SiO.sub.2, 0-5% methanol in DCM) gave the title compound (223 mg, 82%) as a yellow solid. LC-MS: [M+H].sup.+=375.

Preparation 57: 6-(2,5-dichloropyrimidin-4-yl)-2-[2-(morpholin-4-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[0838] ##STR00724##

[0839] Bis(pinacolato)diboron (178 mg, 0.70 mmol), followed by PdCl.sub.2(dppf).sub.2 (24 mg, 0.029 mmol) was added to a degassed (nitrogen bubbling) mixture of 6-bromo-2-[2-(morpholin-4-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (190 mg, 0.58 mmol) and potassium acetate (172 mg, 1.75 mmol) in 1,4-dioxane (4 mL) and the mixture was stirred at 100° C. for 1.5 h. The mixture was allowed to cool to RT and was diluted with ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried (MgSO.sub.4) and concentrated under vacuum to afford crude 2-[2-(morpholin-4-yl)ethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one. The product was used without further purification and characterization in the next step. A solution of this material (210 mg, 0.56 mmol) in 1,4-dioxane (2 mL) followed by Pd(PPh.sub.3).sub.4 (33 mg, 0.028 mmol) were added to a degassed mixture (nitrogen bubbling) of 2,4,5-trichloropyrimidine (155 mg, 0.85 mmol) and potassium carbonate (156 mg, 1.13 mmol) in 1,4-dioxane/H.sub.2O (3:1, 8 mL) and the mixture was stirred at 100° C. under nitrogen for 1.5 h. The mixture was allowed to cool to room temperature and was diluted with ethyl acetate, then transferred into a separating funnel. Water was added and the crude product was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO.sub.4) and absorbed on silica. The crude product was purified by chromatography (SiO.sub.2, 0-10% MeOH in DCM then 10% [1% NH.sub.3 in MeOH] in DCM) to afford the title compound (113 mg, 49%) as an orange oil. LC-MS: [M+H].sup.+=393.

Preparations 58-59

[0840] Prepared following an analogous/similar procedure to that described for Preparation 57:

TABLE-US-00009 Preparation Structure Name MS: [M + H].sup.+ 58 [00725] 6-(2,5-dichloropyrimidin-4-yl)-2- [(oxolan-2-yl)methyl]-2,3-dihydro-1H- isoindol-1-one 364 59 [00726] 6-(2,5-dichloropyrimidin-4-yl)-2-(2- methoxyethyl)-2,3-dihydro-1H- isoindol-1-one 338

Preparations 60-61

[0841] Prepared from the corresponding amines (Preparations 37 and 38 respectively) following an analogous/similar procedure to that described for Example 2:

TABLE-US-00010 Preparation Structure Name MS: [M + H].sup.+ 60 [00727] tert-butyl N-{2[N-tert-butyl-2-(6-{5- chloro-2-[oxan-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)acetamido]ethyl}carbamate 501 [M-Boc + H] 61 [00728] N-tert-butyl-N-{2-[(tert- butyldimethylsilyl)oxy]ethyl{-2-(6-{5- chloro-2-[(oxan-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindo1-2- yl)acetamide 616

Preparation 62: N-[(2,4-dimethoxyphenyl)methyl]oxan-4-amine

[0842] ##STR00729##

[0843] A solution of oxan-4-amine (1.67 g, 16.6 mmol) and 2,4-dimethoxybenzaldehyde (2.50 g, 15.0 mmol) in dichloromethane (25 mL) was stirred for 1 h, treated with sodium triacetoxyborohydride (3.19 g, 15.0 mmol) and stirred at RT for 18 h. The mixture was diluted with dichloromethane (30 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL), followed by brine (50 mL), dried (Na.sub.2SO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-5% 7M methanolic ammonia solution in dichloromethane) to afford N-(2,4-dimethoxybenzyl)oxan-4-amine (2.68 g, 67%) as a pale yellow oil. LC-MS: [M+H].sup.+=252.

Preparation 63: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one

[0844] ##STR00730##

[0845] A stirred mixture of 6-bromo-2,3-dihydro-1H-isoindol-1-one (780 mg, 3.68 mmol), bis(pinacolato)diboron (1.089 g, 4.28 mmol) and potassium acetate (1.26 g, 12.87 mmol) in anhydrous 1,4-dioxane (12 mL) was degassed with nitrogen for 5 minutes. 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (150 mg, 0.18 mmol) was then added and the reaction heated under nitrogen at 100° C. for 16 hours. After cooling to room temperature the mixture was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum to yield the title compound (1.1 g, 115%) which was used crude without purification. MS: [M+H].sup.+=260.

Preparation 64: 6-(2,5-dichloropyrimidin-4-yl)-2,3-dihydro-1H-isoindol-1-one

[0846] ##STR00731##

[0847] A mixture of 2,4,5-trichloropyrimidine (5.25 g, 28.6 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (5.25 g, 20.3 mmol) and S-Phos Pd G3 (79 mg, 0.10 mmol) in 1,4-dioxane (250 mL) was treated with 1 M aqueous sodium carbonate (60.8 mL, 60.8 mmol), degassed with nitrogen for 10 min and stirred at 50° C. for 1 h. The mixture was allowed to cool to RT and stirred for 18 h. The mixture was partitioned between ethyl acetate (250 mL) and water (250 mL) and the resulting suspension was filtered. The solid was suspended in ethyl acetate and the mixture was stirred for 3 days. The precipitate was filtered, washed with ethyl acetate and dried to the title compound (7.11 g, 125%) as a brown solid. LC-MS: [M+H].sup.+=280.

[0848] Notes: No further product was obtained from the biphasic filtrate. The yield obtained was over 100%, which could be due to the presence of inorganic salts and/or water as 1H NMR analysis of the product did show contamination with organic species.

Preparation 65: 6-(5-chloro-2-{[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-2,3-dihydro-1H-isoindol-1-one

[0849] ##STR00732##

[0850] A stirred suspension of 6-(2,5-dichloropyrimidin-4-yl)-2,3-dihydro-1H-isoindol-1-one (1.00 g, 3.57 mmol), N-[(2,4-dimethoxyphenyl)methyl]oxan-4-amine (0.987 g, 3.93 mmol) and diisopropylethylamine (1.25 mL, 7.16 mmol) in sulfolane (10 mL) was heated to 100° C. for 18 h. The mixture was allowed to cool and was partitioned between water (75 mL) and ethyl acetate (75 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 mL). Brine (50 mL) was added to the combined organic phases and the mixture was filtered. The phases from the filtrate were separated and the organic extracts were washed with water (6×50 mL), dried (Na.sub.2SO.sub.4) and concentrated. Purification by chromatography (SiO.sub.2, 20-100% of ethyl acetate in iso-hexane) gave the title compound (504 mg, 28%) as a yellow foam. LC-MS: [M+H].sup.+=495.

Preparation 66: 6-(5-chloro-2-{[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-2-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one

[0851] ##STR00733##

[0852] A solution of 6-(5-chloro-2-{[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-2,3-dihydro-1H-isoindol-1-one (50 mg, 0.10 mmol) in THF (0.5 mL) was cooled to −78° C. and treated with a lithium bis(trimethylsilyl)amide (1 M in THF, 0.15 mL, 0.15 mmol). The solution was stirred for 30 min, then treated with 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole (20 mg, 0.15 mmol), and the mixture allowed to warm to RT and stirred for 18 h. A further portion of lithium bis(trimethylsilyl)amide (1 M in THF, 0.15 mL, 0.15 mmol) was added and the reaction was stirred for 10 min, before 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole (10 mg, 0.075 mmol) was added and the mixture stirred for 4 h. The mixture was treated with tetrabutylammonium iodide (3 mg, 0.008 mmol) and stirred for 3 days. Brine (5 mL) was added and the mixture was extracted with ethyl acetate (3×5 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO.sub.4) and concentrated. Purification by chromatography (SiO.sub.2, 10-100% ethyl acetate in iso-hexane) gave the title compound (11 mg, 0.015 mmol, 15%) as a yellow glass. LC-MS: [M+H].sup.+=591.

Preparation 67: 6-(5-chloro-2-{[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-2-[(3-methyl-1,2-oxazol-5-yl)methyl]-2,3-dihydro-1H-isoindol-1-one

[0853] ##STR00734##

[0854] A stirred suspension of 6-(5-chloro-2-{[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.20 mmol) in THF (2 mL) was cooled to −78° C. and treated with a lithium bis(trimethylsilyl)amide (1 M in THF, 0.3 mL, 0.3 mmol). The resulting suspension was stirred for 15 min before 5-(bromomethyl)-3-methylisoxazole (53 mg, 0.30 mmol) was added. The resulting suspension was allowed to reach RT and the resulting orange solution was stirred for 18 h. The mixture was treated at room temperature with more 5-(bromomethyl)-3-methylisoxazole (53 mg, 0.30 mmol) and stirred for 5 h. Lithium bis(trimethylsilyl)amide (1M in THF, 0.15 mL, 0.15 mmol) was added and the mixture was stirred for 15 min before 5-(bromomethyl)-3-methylisoxazole (53 mg, 0.30 mmol) was added and the mixture stirred for 3 days. Brine (5 mL) was added and the mixture was extracted with ethyl acetate (3×5 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO.sub.4) and concentrated. Purification by chromatography (SiO.sub.2, 10-100% ethyl acetate in iso-hexane) gave the title compound (79 mg, 67%) as a yellow foam. LC-MS: [M+H].sup.+=590.

Preparations 68-69

[0855] Prepared following a similar/analogous procedure to that described in Preparation 67:

TABLE-US-00011 Preparation Structure Name MS: [M + H].sup.+ 68 [00735] 6-(5-chloro-2-{[(2,4- dimethoxyphenyl)methyl](oxan-4- yl)amino}pyrimidin-4-yl)-2-[(5-methyl- 1,2-oxazol-3-yl)methyl]-2,3-dihydro- 1H-isoindol-1-one 590 69 [00736] ethyl 2-[6-(5-chloro-2-{[(2,4- dimethoxyphenyl)methyl](oxan-4- yl)amino}pyrimidin-4-yl)-1-oxo-2,3- dihydro-1H-isoindol-2-yl]acetate 581

Preparation 70: 6-(5-chloro-2-{[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3-dihydro-1H-isoindol-1-one

[0856] ##STR00737##

[0857] Ethyl 2-[6-(5-chloro-2-{[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]acetate (0.285 g, 0.49 mmol) was dissolved in anhydrous MeOH (2.5 mL) and the mixture was cooled to 0° C. Lithium borohydride (2 M in THF, 1.3 mL, 2.6 mmol) was added. The reaction was stirred for 10 min then warmed to RT. The reaction mixture was diluted with methanol (2 mL) and stirred for 2 h. A saturated solution of ammonium chloride (30 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine (3×20 mL), dried (MgSO.sub.4) and concentrated to give the title compound (0.228 g, 88%) as an off-white solid. The product was used without further purification in the next step. LC-MS: [M+H].sup.+=539.

Preparation 71: 2-[6-(5-chloro-2-{[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]ethyl methanesulfonate

[0858] ##STR00738##

[0859] Triethylamine (0.11 mL, 0.79 mmol) followed by methanesulfonyl chloride (0.045 mL, 0.58 mmol) were added to a solution of 6-(5-chloro-2-{[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3-dihydro-1H-isoindol-1-one (0.228 g, 0.39 mmol) in DCM (4.0 mL) and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was partitioned between DCM (30 mL) and a saturated solution of ammonium chloride (30 mL). The phases were separated and the organic phase was washed with a saturated solution of ammonium chloride (20 mL), water (2×20 mL) and brine (2×20 mL). The organic phase was filtered through a phase separating cartridge and then concentrated to give the title compound (0.220 g, 88%) as a colourless foam. The product was used without further purification in the next step. LC-MS: [M+H].sup.+=617.

Preparation 72: 6-(5-chloro-2-{[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-2-[2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[0860] ##STR00739##

[0861] Triethylamine (0.017 mL, 0.12 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.013 mL, 0.10 mmol) were added to a solution of 2-[6-(5-chloro-2-{[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]ethyl methanesulfonate (51 mg, 0.080 mmol) in acetonitrile (1.0 mL) in a microwave vial. The reaction mixture was heated in the microwave (CEM, 100° C., max Power=200 W, max pressure=200 psi) for 30 min. The reaction mixture was concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-5% methanol in DCM) gave the title compound (54 mg, 103%) as a yellow gum. LC-MS: [M+H].sup.+=654.

Preparation 73: 6-bromo-2-[2-(tert-butoxy)ethyl]-2,3-dihydro-1H-isoindol-1-one

[0862] ##STR00740##

[0863] A mixture of methyl 5-bromo-2-(bromomethyl)benzoate (300 mg, 0.97 mmol), 2-(tert-butoxy)ethanamine (171 mg, 1.46 mmol) and DIPEA (0.51 mL, 2.2 mmol) in MeCN (5 mL) was stirred at 75° C. for 3 days. The mixture was allowed to cool to RT and was diluted with ethyl acetate, then transferred into a separating funnel. 1N HCl was added and the crude product was extracted with ethyl acetate. The combined organic extracts were washed with NaHCO.sub.3, brine, dried (MgSO.sub.4) and concentrated under vacuum to give the title compound (297 mg, 98%) as a thick tan oil. The product was used without further purification in the next step. LC-MS: [M+H].sup.+=312/314.

Preparation 74: methyl (2S)-2-(6-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-3-hydroxypropanoate

[0864] ##STR00741##

[0865] Prepared following an analogous/similar procedure to that described in Preparation 73. LC-MS: [M+H].sup.+=314/316.

Preparation 75: 6-bromo-2-[2-(cyclo pentyloxy)ethyl]-2,3-dihydro-1H-isoindol-1-one

[0866] ##STR00742##

[0867] Prepared following an analogous/similar procedure to that described in Preparation 73. In this case, purification by chromatography (SiO.sub.2, 0-100% ethyl acetate in iso-hexane) gave the title compound. LC-MS: [M+H].sup.+=m/z 324/326.

Preparation 76: tert-butyl (2R)-2-(6-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)propanoate

[0868] ##STR00743##

[0869] Prepared following an analogous/similar procedure to that described in Preparation 73. The reaction was carried out in THF at 75° C. in this case. LC-MS: [M+Na].sup.+=362/364.

Preparation 77: tert-butyl 2-(6-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-2-methylpropanoate

[0870] ##STR00744##

[0871] Prepared following an analogous/similar procedure to that described in Preparation 73. In this case, the reaction was carried out in THF at 75° C. and the product was purified by chromatography (SiO.sub.2, 10-50% of ethyl acetate in iso-hexane). LC-MS: [M-.sup.tBu+H].sup.+=298/300.

Preparation 78: 6-bromo-2-(2-hydroxypropyl)-2,3-dihydro-1H-isoindol-1-one

[0872] ##STR00745##

[0873] Triethylamine (0.68 mL, 4.90 mmol) and 1-aminopropan-2-ol (0.30 mL, 3.57 mmol) were added to a solution of methyl 5-bromo-2-(bromomethyl)benzoate (1.00 g, 3.25 mmol) in THF (33 mL). The reaction was heated to 70° C. and stirred for 18 h. After cooling to RT, the reaction mixture was concentrated under vacuum and absorbed onto silica. Purification by chromatography (SiO.sub.2, 0-2.5% MeOH in ethyl acetate) gave the title compound (704 mg, 79%) as an off-white solid. LC-MS: [M+H].sup.+=270/272.

Preparation 79: 6-bromo-2-[2-(2-oxopyrrolidin-1-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[0874] ##STR00746##

[0875] Triethylamine (0.30 mL, 2.2 mmol) followed by 1-(2-aminoethyl)pyrrolidin-2-one oxalate (212 mg, 0.97 mmol) were added to a solution of methyl 5-bromo-2-(bromomethyl)benzoate (272 mg, 0.88 mmol) in MeOH (10 mL). The mixture was stirred at 50° C. for 18 h. The reaction mixture was cooled to RT and concentrated under vacuum. The residue was dissolved in ethyl acetate (10 mL), washed with water (10 mL), dried (MgSO.sub.4) and concentrated under vacuum to afford a colourless powder. Trituration with diethyl ether gave the title compound (100 mg, 33%) as a colourless solid. 1H NMR (400 MHz, CDCl.sub.3): 7.92 (1H, d), 7.63 (1H, dd), 7.32 (1H, d), 4.45 (2H, s), 3.80 (2H, t), 3.60 (2H, t), 3.52 (2H, t), 2.23 (2H, t), 1.98 (2H, m).

Preparation 80: 6-bromo-2-[2-(oxolan-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[0876] ##STR00747##

[0877] Triethylamine (0.28 mL, 2.0 mmol) followed by 2-(oxolan-2-yl)ethan-1-amine (171 mg, 1.48 mmol) were added to a solution of methyl 5-bromo-2-(bromomethyl)benzoate (500 mg, 1.35 mmol) in THF (15 mL). The mixture was heated to 70° C. for 18 h. The mixture was concentrated under vacuum and the residue was triturated with diethyl ether (20 mL). The resulting precipitate was filtered to afford a pale tan powder. The powder was dissolved in DCM (4 mL), washed with water (10 mL) and the organic phase was separated with a hydrophobic phase separator and concentrated under vacuum to give the title compound (253 mg, 60%) as a pale tan solid. LC-MS: [M+H].sup.+=310/312.

Preparation 81: methyl (2S)-2-(6-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-3-[(tert-butyldimethylsilyl)oxy]propanoate

[0878] ##STR00748##

[0879] TBDMS-Cl (297 mg, 1.97 mmol) was added to a solution of methyl (2S)-2-(6-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-3-hydroxypropanoate (412 mg, 1.31 mmol) and imidazole (268 mg, 3.93 mmol) in DMF (3 mL) and the mixture was stirred for 18 h. The mixture was diluted with ethyl acetate and transferred into a separating funnel. Water was added and the crude product was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO.sub.4) and absorbed on silica. Purification by chromatography (SiO.sub.2, 0-20% ethyl acetate in iso-hexane) gave the title compound (432 mg, 77%) as a colourless oil. LC-MS: [M+H]+=428/430.

Preparation 82: 2-(2-hydroxypropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one

[0880] ##STR00749##

[0881] A stirred mixture of 6-bromo-2-(2-hydroxypropyl)-2,3-dihydro-1H-isoindol-1-one (200 mg, 0.740 mmol), potassium acetate (218 mg, 2.22 mmol) and bis(pinacolato)diboron (226 mg, 0.888 mmol) in dioxane (5 mL) was degassed at 40° C. with bubbling nitrogen for 10 min. The mixture was treated with PdCl.sub.2(dppf).sub.2 (27 mg, 0.037 mmol), degassed for a further 10 min and stirred at 90° C. for 2 h. The mixture was allowed to cool and was diluted with ethyl acetate (20 mL), washed with brine (20 mL), dried (MgSO.sub.4) and concentrated. The residue was triturated with a mixture of ether (10 mL) and isohexane (10 mL) to give a solid. The solid was collected by filtration and washed with isohexane (20 mL) to give the title compound (192 mg, 80%) as a chocolate-brown powder. LC-MS: [M+H].sup.+=318.

Preparation 83: 2-[2-(oxolan-2-yl)ethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one

[0882] ##STR00750##

[0883] PdCl.sub.2(dppf).sub.2 (18 mg, 0.024 mmol) was added to a degassed (nitrogen bubbling) solution of 6-bromo-2-[2-(oxolan-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (250 mg, 0.806 mmol), bis(pinacolato)diboron (246 mg, 0.967 mmol) and potassium acetate (160 mg, 1.61 mmol) in 1,4-dioxane (3 mL). The mixture was degassed for a further 10 min then heated to 90° C. for 3 h. The reaction was cooled to RT and partitioned between ethyl acetate (10 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL). The combined organic phases were washed with brine (10 mL), dried (MgSO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-100% ethyl acetate in iso-hexane) gave the title compound (173 mg, 51%). LC-MS: [M+H].sup.+=358.

Preparation 84: 2-[2-(tert-butoxy)ethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one

[0884] ##STR00751##

[0885] XPhos Pd G3 (16 mg, 0.019 mmol) was added to a degassed (nitrogen bubbling) mixture of 6-bromo-2-[2-(tert-butoxy)ethyl]-2,3-dihydro-1H-isoindol-1-one (304 mg, 0.974 mmol), bis(pinacolato) diboron (297 mg, 1.17 mmol) and potassium acetate (287 mg, 2.92 mmol) in 1,4-dioxane (5 mL) and the mixture was stirred at 90° C. for 1.5 h. The mixture was cooled to RT and diluted with NaHCO.sub.3, water and ethyl acetate, then transferred into a separating funnel. The crude product was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (MgSO.sub.4), and concentrated under vacuum. The crude product was used without further purification and characterization in the next step. Quantitative yield was assumed.

Preparation 85: methyl (2S)-3-[(tert-butyldimethylsilyl)oxy]-2-[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-2-yl]propanoate

[0886] ##STR00752##

[0887] Prepared following the procedure described in Preparation 84.

Preparation 86: tert-butyl 2-methyl-2-[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-2-yl]propanoate

[0888] ##STR00753##

[0889] X-Phos Pd G3 (13 mg, 0.015 mmol) was added to a degassed (nitrogen bubbling) solution of tert-butyl 2-(6-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-2-methylpropanoate (273 mg, 0.771 mmol), bis(pinacolato)diboron (235 mg, 0.925 mmol) and potassium acetate (229 mg, 2.31 mmol) in 1-4-dioxane (5 mL). The mixture was degassed for a further 10 min then heated to 90° C. for 2 h. The reaction was cooled to RT and diluted with ethyl acetate. The mixture was filtered through celite and concentrated under vacuum to give the title compound (401 mg, 93%, 72% purity) as a yellow gum. The product was used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6): 7.91 (1H, m), 7.88 (1H, dd), 7.62 (1H, d), 4.64 (2H, s), 1.54 (6H, s), 1.32 (9H, s), 1.16 (12H, s).

Preparation 87: 2-[2-(2-oxopyrrolidin-1-yl)ethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one

[0890] ##STR00754##

[0891] Prepared following the procedure described in Preparation 86. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.27 (1H, d), 7.94 (1H, dd), 7.44 (1H, d), 4.49 (2H, s), 3.81 (2H, t), 3.60 (2H, t), 3.51 (2H, t), 2.22 (2H, t), 1.96 (2H, tt), 1.35 (12H, s). (The product was contaminated with 40 wt % pinacol and 18 wt % 1,4-dioxane).

Preparation 88: 2-[2-(cyclopentyloxy)ethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one

[0892] ##STR00755##

[0893] Prepared following the procedure described in Preparation 86. The product was purified by chromatography (SiO.sub.2, 0-100% ethyl acetate in iso-hexane). LC-MS: [M+H].sup.+=372.

Preparation 89: tert-butyl (2R)-2-[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-2-yl]propanoate

[0894] ##STR00756##

[0895] Prepared following the procedure described in Preparation 86. The crude product was purified by chromatography (SiO.sub.2, 0-50% ethyl acetate in iso-hexane) to give the title compound (1.653 g, 99%) as an off white solid. LC-MS: [M+Na].sup.+=410.

Preparation 90: 2-[2-(cyclopentyloxy)ethyl]-6-(2,5-dichloropyrimidin-4-yl)-2,3-dihydro-1H-isoindol-1-one

[0896] ##STR00757##

[0897] A mixture of 2-[2-(cyclopentyloxy)ethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (144 mg, 0.349 mmol), 2,4,5-trichloropyrimidine (0.060 mL, 0.52 mmol) and potassium carbonate (103 mg, 0.745 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was heated to 40° C. and degassed (nitrogen bubbling) for 10 min. Pd(PPh.sub.3).sub.4 (15 mg, 0.013 mmol) was added and the mixture was degassed for a further 10 min and then heated to 90° C. for 1.75 h. The mixture was allowed to cool to RT and was partitioned between ethyl acetate (30 mL) and water (30 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were washed with brine (30 mL), dried (MgSO.sub.4) and concentrated onto silica. Purification by chromatography (SiO.sub.2, 0-100% ethyl acetate in iso-hexane) gave the title compound (102 mg, 64%) as a yellow gum. LC-MS: [M+H]+=392.

Preparations 91-94

[0898] Prepared following an analogous/similar procedure to that described for Preparation 90:

TABLE-US-00012 MS: Preparation Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 91 [00758] 2-[2-(tert-butoxy)ethyl]-6- (2,5-dichloropyrimidin-4- yl)-2,3-dihydro-1H- isoindol-1-one — 380 92 [00759] tert-butyl 2-[6-(2,5- dichloropyrimidin-4-yl)-1 oxo-2,3-dihydro-1H- isoindol-2-yl]-2- methylpropanoate (DMSO-d6): 9.04 (1H, s), 8.09 (1H, d), 8.05 (1H, dd), 7.81 (1H, d), 4.73 (2H, s), 1.56 (6H. s), 1.36 (9H, s). — 93 [00760] 6-(2,5-dichloropyrimidin- 4-yl)-2-[2-(2- oxopyrrolidin-1-yl)ethyl]- 2,3-dihydro-1H-isoindol- 1-one — 391 94 [00761] tert-butyl (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1- oxo-2,3-dihydro-1H- isoindol-2-yl]propanoate — 430

Preparation 95: 3-[(tert-butyldimethylsilyl)oxy]-2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

[0899] ##STR00762##

[0900] Pd(PPh.sub.3).sub.4 (57 mg, 0.049 mmol) was added to a degassed mixture (nitrogen bubbling) of (S)-methyl (2S)-3-[(tert-butyldimethylsilyl)oxy]-2-[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-2-yl]propanoate (470 g, 0.989 mmol), 2,4,5-trichloropyrimidine (272 mg, 1.48 mmol) and potassium carbonate (273 mg, 1.98 mmol) in a mixture of 1,4-dioxane (9 mL) and water (3 mL). The mixture was stirred at 90° C. for 2.5 h. The mixture was cooled to room temperature and was diluted with ethyl acetate, then transferred into a separating funnel. 1 M HCl was added and the crude product was extracted with ethyl acetate. The combined organic phases were washed with brine, dried (MgSO.sub.4) and absorbed on silica. Purification by chromatography (SiO.sub.2, 0-50% ethyl acetate in isohexane, then 0-10% methanol in DCM) to afford (S)-methyl 3-[(tert-butyldimethylsilyl)oxy]-2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoate (68 mg, 10%) as a colourless semi-solid (LC-MS: [M+H].sup.+=496), and (S)-3-[(tert-butyldimethylsilyl)oxy]-2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid (87 mg, 14%) as a pale yellow solid. LC-MS: [M-CO.sub.2+H].sup.+=437.

[0901] Note: The product may have epimerized during the reaction as shown by chiral HPLC analysis of the final product.

Preparation 96: 6-(2,5-dichloropyrimidin-4-yl)-2-(2-hydroxypropyl)-2,3-dihydro-1H-isoindol-1-one

[0902] ##STR00763##

[0903] A mixture of 2,4,5-trichloropyrimidine (166 mg, 0.903 mmol), 2-(2-hydroxypropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (191 mg, 0.602 mmol) and S-Phos Pd G3 (2 mg, 3 μmol) in 1,4-dioxane (8 mL) was treated with 1 M aqueous sodium carbonate (1.8 mL, 1.8 mmol), degassed with bubbling nitrogen for 10 min and stirred at 50° C. for 2 h. The mixture was partitioned between ethyl acetate (20 mL) and brine (20 mL). The phases were separated and the organic phase was dried (Na.sub.2SO.sub.4) and concentrated. Purification by chromatography (SiO.sub.2, 20-100% ethyl acetate in iso-hexane) the title compound (118 mg, 56%) as a yellow solid. LC-MS: [M+H].sup.+=338.

Preparation 97: 6-(2,5-dichloropyrimidin-4-yl)-2-[2-(oxolan-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[0904] ##STR00764##

[0905] Prepared following an analogous/similar procedure to that described in Preparation 96. LC-MS: [M+H].sup.+=378.

Preparation 98: tert-butyl (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)propanoate

[0906] ##STR00765##

[0907] Prepared following a similar procedure to that described in Preparation 8. The reaction was carried out in EtOH at 80° C. for 3 days. LC-MS: [M+H].sup.+=473.

Preparation 99: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)propanoic acid

[0908] ##STR00766##

[0909] Prepared following a similar procedure to that described in Preparation 9. LC-MS: [M+H].sup.+=417. Note: The product may have partially epimerized during the reaction as shown by chiral HPLC analysis of the final product.

Preparation 100: tert-butyl 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-2-methylpropanoate

[0910] ##STR00767##

[0911] Prepared following a similar procedure to that described in Preparation 8. The reaction was carried out in 1,4-dioxane at 60° C. overnight. Further oxan-4-amine (2 equ.) and DIPEA (2.5 equ.) were added and the mixture heated at 60° C. overnight. LC-MS: [M+H].sup.+=487.

Preparation 101: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-2-methylpropanoic acid

[0912] ##STR00768##

[0913] The product was prepared following an analogous/similar procedure as described in Preparation 9. LC-MS: [M+H].sup.+=431.

Preparation 102: tert-butyl (1-(tert-butylamino)-4-(methylthio)-1-oxobutan-2-yl)carbamate

[0914] ##STR00769##

[0915] Tert-butylamine (1.11 mL, 10.5 mmol) and diisopropylethylamine (7.92 mL, 45.4 mmol) were added to a mixture of rac-(tert-butoxycarbonyl)methionine (2.60 g, 10.4 mmol), EDC (2.10 g, 11.0 mmol) and HOBT (2.08 g, 13.6 mmol) in DCM (100 mL). The reaction was stirred at RT for 24 h. The reaction was diluted with water (100 mL). The phases were separated and the aqueous phase was extracted with DCM (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (200 mL), 1 M hydrochloric acid (200 mL), dried (MgSO.sub.4) and concentrated to give the title compound (2.79 g, 83%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6) 7.31 (1H, s), 6.78 (1H, d), 3.92 (1H, q), 2.45-2.35 (2H, m), 2.03 (3H, s), 1.85-1.67 (2H, m), 1.38 (9H, s), 1.25 (9H, s).

Preparation 103: (3-((tert-butoxycarbonyl)amino)-4-(tert-butylamino)-4-oxobutyl)dimethylsulfonium iodide

[0916] ##STR00770##

[0917] Iodomethane (1.03 mL, 16.4 mmol) was added to a solution of tert-butyl (1-(tert-butylamino)-4-(methylthio)-1-oxobutan-2-yl)carbamate (1.00 g, 3.28 mmol) in DCM (3 mL). The reaction was stirred at RT in the dark for 4 h, before being diluted with DCM (10 mL). The reaction was stirred at RT for 3 days. The resulting solid was isolated by filtration, washing with diethyl ether (2×20 mL) to give the title compound (1.05 g, 2.24 mmol, 68% yield) as a colourless solid. 1H NMR (400 MHz, DMSO-d6) 7.48 (1H, s), 6.95 (1H, d), 4.04-3.95 (1H, m), 3.24 (2H, t), 2.92-2.85 (6H, m), 2.07-1.87 (2H, m), 1.40 (9H, s), 1.27 (9H, s).

Preparation 104: tert-butyl (1-(tert-butyl)-2-oxopyrrolidin-3-yl)carbamate

[0918] ##STR00771##

[0919] Sodium hydride (60% dispersion in mineral oil, 113 mg, 2.82 mmol) was added to a solution of (3-((tert-butoxycarbonyl)amino)-4-(tert-butylamino)-4-oxobutyl)dimethylsulfonium iodide (1.05 g, 2.35 mmol) in DMF (15 mL) at 0° C. The reaction was stirred at 0° C. for 15 min then warmed to RT and stirred for 1 h. The reaction was quenched with water (2 mL) and then diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with water (50 mL), brine (2×50 mL), dried (MgSO.sub.4) and concentrated under vacuum to give the title compound (633 mg, 2.10 mmol, 89% yield, 85% purity) as a yellow oil that solidified on standing. 1H NMR (400 MHz, DMSO-d6) 7.01 (1H, d), 4.05-3.96 (2H, m), 3.40-3.32 (1H, m), 3.24 (1H, td), 2.18-2.08 (1H, m), 1.72-1.59 (1H, m), 1.39 (9H, s), 1.31 (9H, s).

Preparation 105: 3-amino-1-(tert-butyl)pyrrolidin-2-one hydrochloride

[0920] ##STR00772##

[0921] A solution of HCl (4 M in 1,4-dioxane, 2.6 mL, 10.5 mmol) was added to a solution of tert-butyl (1-(tert-butyl)-2-oxopyrrolidin-3-yl)carbamate (633 mg, 2.1 mmol) in 1,4-dioxane (2.5 mL). The reaction was stirred at RT for 18 h. The solvent was removed under vacuum to give the title compound (400 mg, 94%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 8.44 (3H, br. s), 3.91-3.82 (1H, m), 3.60-3.41 (2H, m), 3.37 (1H, td), 2.34-2.24 (1H, m), 1.91-1.77 (1H, m), 1.35 (9H, s).

Preparation 106: 6-bromo-2-(1-methyl-2-oxopiperidin-3-yl)-2,3-dihydro-1H-isoindol-1-one

[0922] ##STR00773##

[0923] A solution of methyl 5-bromo-2-(bromomethyl)benzoate (500 mg, 1.62 mmol), 3-amino-1-methylpiperidin-2-one (208 mg, 1.62 mmol), triethylamine (0.27 mL, 2.0 mmol) in THF (10 mL) was heated to 70° C. for 18 h. The reaction was concentrated under vacuum and diluted with ethyl acetate (10 mL) and water (10 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with 1 M hydrochloric acid (20 mL), brine (20 mL), dried (MgSO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-10% methanol in DCM) gave the title compound (208 mg, 39%) as a colourless solid. LC-MS: [M+H].sup.+=323.

Preparation 107: 6-bromo-2-(1-tert-butyl-2-oxopyrrolidin-3-yl)-2,3-dihydro-1H-isoindol-1-one

[0924] ##STR00774##

[0925] Prepared according to Preparation 106 from 3-amino-1-(tert-butyl)pyrrolidin-2-one hydrochloride (473 mg, 2.46 mmol) and triethylamine (0.75 mL, 5.4 mmol). The title compound (533 mg, 60%) was obtained as a tan solid. LC-MS: [M+H].sup.+=351.

Preparation 108: 2-(1-tert-butyl-2-oxopyrrolidin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one

[0926] ##STR00775##

[0927] A mixture of 6-bromo-2-(1-tert-butyl-2-oxopyrrolidin-3-yl)-2,3-dihydro-1H-isoindol-1-one (533 mg, 1.52 mmol), bis(pinacolato)diboron (462 mg, 1.82 mmol) and potassium acetate (298 mg, 3.03 mmol) in 1,4-dioxane (12 mL) was degassed with nitrogen for 10 min before PdCl.sub.2(dppf) (33 mg, 0.046 mmol) was added. The degassing was continued for a further 10 min before the reaction was heated to 90° C. for 18 h. The reaction was diluted with ethyl acetate (20 mL) and water (20 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-100% ethyl acetate in iso-hexane) gave the title compound (308 mg, 50%) as a tan solid. LC-MS: [M+H].sup.+=399.

Preparation 109: 2-(1-methyl-2-oxopiperidin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one

[0928] ##STR00776##

[0929] A mixture of 6-bromo-2-(1-methyl-2-oxopiperidin-3-yl)-2,3-dihydro-1H-isoindol-1-one (208 mg, 0.64 mmol), bis(pinacolato)diboron (196 mg, 0.77 mmol) and potassium acetate (126 mg, 1.29 mmol) in 1,4-dioxane (5 mL) was degassed with nitrogen for 10 min before PdCl.sub.2(dppf) (14 mg, 0.019 mmol) was added. The degassing was continued for a further 10 min before the reaction was heated to 90° C. for 18 h. The reaction was diluted with ethyl acetate (20 mL) and water (20 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO.sub.4) and concentrated to give the title compound (288 mg, 81%, 67% purity) as a brown oil. LC-MS: [M+H].sup.+=371.

Preparation 110: methyl ethanimidothioate hydroiodide

[0930] ##STR00777##

[0931] Iodomethane (0.83 mL, 13.3 mmol) was added to a stirred solution of thioacetamide (1.00 g, 13.0 mmol) in acetone (45 mL). The solution was heated to 60° C. for 18 h. Upon cooling to RT, a solid began to precipitate out of solution. The reaction volume was reduced to about a third of its initial volume and the solid collected by filtration, washing with acetone, to give the title compound (790 mg, 27%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6): 11.6 (2H, br. s), 2.67 (3H, s), 2.58 (3H, s).

Preparation 111: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetohydrazide

[0932] ##STR00778##

[0933] CDI (44 mg, 0.27 mmol) was added to a suspension of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (100 mg, 0.246 mmol) in DCM (2 mL). The reaction was stirred at RT for 15 min, before 1 M hydrazine in THF (0.37 mL, 0.37 mmol) was added and the reaction mixture was stirred for 18 h. Saturated aqueous NaHCO.sub.3 (15 mL) was added and the crude product was extracted with DCM (2×15 mL). The combined organic phases were passed through a phase separating cartridge then concentrated under vacuum to give the title compound (67 mg, 64%) as a colourless solid. The product was used without further purification in the next step. LC-MS: [M+H].sup.+=417.

Preparation 112: 2-[(1-Methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-ol

[0934] ##STR00779##

[0935] A stirred mixture of 2-(methylsulfanyl)pyrimidin-4-ol (522 mg, 3.67 mmol), 1-methyl-1H-pyrazol-5-ylamine (428 mg, 4.41 mmol) and pivalic acid (3.9 mL) was heated at 130° C. (thermally) under nitrogen for 16 hours. The reaction mixture was allowed to cool slowly and, at approximately 70° C., petrol (˜4 mL) was added. The mixture was allowed to cool to room temperature after which the precipitate was filtered and washed with further petrol to yield crude 2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-ol (650 mg, 93%, 70% pure) as a colourless solid which was used as is. MS: [M+H].sup.+=192.

Preparation 113: 4-Chloro-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine

[0936] ##STR00780##

[0937] A stirred mixture of 2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-ol (320 mg, 2.25 mmol, 70% pure) and POCl.sub.3 (2.5 mL, 27.01 mmol) was heated at 70° C. for 1 hour, under nitrogen. After cooling to room temperature the excess POCl.sub.3 was removed by concentration under vacuum. The residue was diluted with equal parts of CH.sub.2Cl.sub.2 and NaHCO.sub.3 (sat. aq.) and stirred until the evolution of gas ceased. The phases were then separated and the aqueous extracted again with CH.sub.2Cl.sub.2. The combined organic phases were washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum to yield the title compound used as crude (254 mg, 54%, 70% pure). MS: [M+H].sup.+=210.

Preparation 114: Methyl N-[2-(4-chlorophenyl)ethyl]carbamate

[0938] ##STR00781##

[0939] A stirred solution of 2-(4-chlorophenyl)ethan-1-amine (11.30 g, 71.16 mmol) and DIPEA (13.64 mL, 78.27 mmol) in anhydrous THF (158 mL) at 4° C. under nitrogen was treated slowly with methyl chloroformate (6.4 mL, 78.27 mmol). The solution was slowly allowed to warm to room temperature and after a total of 2 hours the reaction was quenched with NH.sub.4Cl (aq., sat.). The mixture was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum to yield methyl N-[2-(4-chlorophenyl)ethyl]carbamate (15.4 g, 101%) as a yellow solid which was used as is. MS: [M+H].sup.+=214.

Preparation 115: 7-Chloro-1,2,3,4-tetrahydroisoquinolin-1-one

[0940] ##STR00782##

[0941] The following reaction was put on in duplicate. Methyl N-[2-(4-chlorophenyl)ethyl]carbamate (7.5 g, 35.10 mmol) in an ice bath, was slowly treated with trifluoromethanesulfonic acid (120 mL) with stirring under nitrogen. After 15 minutes the ice bath was removed, and after a further 30 minutes the reaction was heated to 70° C. (thermally) for 24 hours. After cooling to room temperature, both reactions were combined by pouring onto ice, and once melted, the mixture was further diluted with water. The mixture was extracted with IPA:CHCl.sub.3 (1:3, ×3) and the combined organic layers were washed with brine and dried over MgSO.sub.4. The filtrate was concentrated under vacuum. The residue was triturated with diethyl ether and the precipitate filtered to yield 7-chloro-1,2,3,4-tetrahydroisoquinolin-1-one (8.5 g, 67%) as a colourless solid. MS: [M+H].sup.+=182. The filtrate was concentrated under vacuum to yield a further 2 g of product crude.

Preparation 116: 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-isoquinolin-1-one

[0942] ##STR00783##

[0943] A stirred mixture of 7-chloro-1,2,3,4-tetrahydroisoquinolin-1-one (500 mg, 2.75 mmol) bis(pinacolato)diboron (839 mg, 3.30 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (135 mg, 0.28 mmol) and AcOK (811 mg, 8.26 mmol) in anhydrous 1,4-dioxane (18 mL) was degassed with nitrogen for 10 minutes. Tris(dibenzylidene-acetone)dipalladium (0) (63 mg, 0.07 mmol) was then added and degassing continued for another 10 minutes. The mixture was heated at 80° C. under nitrogen for a total of 18 hours. After cooling to room temperature the mixture was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO, filtered and concentrated under vacuum to yield crude 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-1-one (0.8 g, 107%) which was used as is. MS: [M+H].sup.+=274.

Preparation 117: 6-bromo-2-(cyclopropylmethyl)-2,3-dihydro-1H-isoindol-1-one

[0944] ##STR00784##

[0945] A stirred solution of 6-bromo-2,3-dihydro-1H-isoindol-1-one (350 mg, 1.65 mmol) and cyclopropylmethyl bromide (0.198 μL, 1.98 mmol) in DMF (6 mL) was cooled in an ice bath under nitrogen. Then NaH (99 mg, 2.48 mmol) was added in portions. The reaction was stirred for 1 hour and then quenched with NH.sub.4Cl (sat., aq.). The mixture was extracted with IPA:CHCl.sub.3 (1:3, ×3). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum to yield the title compound as a brown oil (˜30% pure) which was used crude. MS: [M+H].sup.+=266/268.

Preparation 118: N-benzyl-2-(6-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-methylacetamide

[0946] ##STR00785##

[0947] Prepared using a similar procedure to Preparation 117 above, using N-benzyl-2-chloro-N-methylacetamide. MS: [M+H].sup.+=373/375.

Preparations 119: N-benzyl-N-methyl-2-[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-2-yl]acetamide

[0948] ##STR00786##

[0949] Prepared from N-benzyl-2-(6-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-methylacetamide using a similar procedure to Preparation 116. MS: [M+H].sup.+=337.

Preparation 120: 2,5-Dichloropyrimidin-4-ol

[0950] ##STR00787##

[0951] A stirred solution of 2,4,5-trichloropyrimidine (1.1 mL, 9.72 mmol) in 1,4-dioxane (10 mL) was treated with water (2 mL) and then NaOH (11.7 mL, 1M). The reaction was heated at 50° C. in a reacti vial for 24 hours, after which the reaction was allowed to cool and was then diluted with EtOAc. The organic layer (containing starting material) was discarded. The pH of the aqueous was adjusted to ˜6 with citric acid (5%, aq.) and the product was re-extracted with IPA:CHCl.sub.3 (1:3×3). These combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum to yield the title compound (410 mg, 26%) which was used crude. MS: [M+H].sup.+=165.

Preparation 121: 5-Chloro-2-[(1,5-dimethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-ol

[0952] ##STR00788##

[0953] A stirred solution of 2,5-dichloropyrimidin-4-ol (410 mg, 2.46 mmol), 1,5-dimethyl-1H-pyrazol-4-amine (602 mg, 5.41 mmol) and p-toluenesulfonic acid monohydrate (702 mg, 3.69 mmol) in 1,4-dioxane (5 mL) was heated in a reacti vial at 105° C. for 24 hours. The reaction was then stirred at room temperature for 2 days, diluted with water, and the product was extracted with CHCl.sub.3:IPA (3:1, ×3). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum to yield crude 5-chloro-2-[(1,5-dimethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-ol (280 mg, 48%, 80% pure) as a yellow solid. MS: [M+H].sup.+=240.

Preparation 122: 4,5-Dichloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-amine

[0954] ##STR00789##

[0955] To 5-chloro-2-[(1,5-dimethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-ol (280 mg, 1.17 mmol) was added POCl.sub.3 (0.7 mL, 7.01 mmol) under nitrogen. The mixture was stirred at 90° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and NaHCO.sub.3 (sat. aq.) was carefully added. The mixture was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum to yield the title compound (210 mg, 70%) as a yellow solid which was used as is. MS: [M+H].sup.+=258.

Preparation 123: tert-Butyl 2-(6-{2-chloropyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate

[0956] ##STR00790##

[0957] Prepared from 2,4-dichloropyrimidine using a similar procedure to Preparation 3.

Preparation 124: Methyl 3-(6-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)propanoate

[0958] ##STR00791##

[0959] To a stirred solution of 6-bromo-2,3-dihydro-1H-isoindol-1-one (550 mg, 2.59 mmol), 18-crown-6 (69 mg, 0.26 mmol) and methyl 3-bromopropionate (350 μL, 3.11 mmol) in DMF (9 mL) was added Cs.sub.2CO.sub.3 (2.113 g, 6.48 mmol) under nitrogen. The reaction was heated to 70° C. (thermally) slowly and maintained at this temperature for 18 hours. After cooling and the reaction was quenched with NH.sub.4Cl (sat., aq.). The mixture was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried over MgSO, filtered and concentrated under vacuum to yield methyl 3-(6-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)propanoate as a yellow oil. LC-MS was consistent with a complex mixture which was taken on as is. To the residue was added bis(pinacolato)diboron (0.746 g, 2.91 mmol), AcOK (0.491 mg, 5.00 mmol) and anhydrous 1,4-dioxane (8 mL). The reaction was degassed with nitrogen for 5 minutes. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (61 mg, 0.08 mmol) was then added and the reaction heated at 90° C. under nitrogen for 16 hours. The reaction was allowed to cool to room temperature and was then diluted with water. The mixture was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried over MgSO, filtered and concentrated under vacuum to yield the title compound (1.5 g, 168%) which was used without further purification. MS: [M+H].sup.+=346.

Preparation 125: Methyl 3-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoate

[0960] ##STR00792##

[0961] A stirred mixture of methyl 3-[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-2-yl]propanoate (1.5 g, 2.17 mmol, ˜50% pure), 2,4,5-trichloropyrimidine (370 μL, 3.26 mmol), K.sub.2CO.sub.3 (600 mg, 4.35 mmol) and 1,4-dioxane: water (3:1, 11 mL) was degassed with nitrogen for 5 minutes. Pd(PPh.sub.3).sub.4 (120 mg, 0.11 mmol) was then added and the reaction heated at 100° C. under nitrogen for a total of 3 hours. The mixture was allowed to cool to room temperature, diluted with water, and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO, filtered and concentrated under vacuum and the residue was purified by biotage (0-100 EtOAc/petrol, and then 0-10% MeOH) to yield the title compound (620 mg, 78%) as a red oil. MS: [M−H].sup.+=364.

Preparation 126: tert-Butyl 2-(7-{2,5-dichloropyrimidin-4-yl}-1-oxo-1,2,3,4-tetrahydro-isoquinolin-2-yl)acetate

[0962] ##STR00793##

[0963] Prepared from 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-isoquinolin-1-one (Preparation 116) using similar procedures to Preparation 3 and Preparation 1 respectively. LC-MS: [M+H].sup.+=408.

Preparation 127: 2-Chloro-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethan-1-one

[0964] ##STR00794##

[0965] A stirred solution of 1,2,3,4-tetrahydroisoquinoline (2.6 g, 19.48 mmol) and DIPEA (3.7 mmol, 21.25 mmol) in anhydrous CH.sub.2Cl.sub.2 (89 mL) under nitrogen, was cooled in an ice water bath. Chloroacetyl chloride (1.4 mL, 17.71 mmol) was added very slowly, after which the reaction was stirred for 30 minutes, still in the ice water bath. The reaction was quenched with NH.sub.4Cl (sat., aq.) and the product extracted with EtOAc (×3). The combined organic layers were washed with water and brine, dried over MgSO.sub.4, filtered and concentrated under vacuum to yield the title compound (4.6 g, 124%) which was used as is. MS: [M+H].sup.+=210.

Preparation 128: 6-(2,5-Dichloropyrimidin-4-yl)-2-[2-oxo-2-(1,2,3,4-tetrahydro isoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[0966] ##STR00795##

[0967] A stirred solution of 6-bromo-2,3-dihydro-1H-isoindol-1-one (3.4 g, 14.16 mmol) and 2-chloro-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethan-1-one (3.6 g, 17.00 mmol) in DMF (47 mL) was cooled in an ice bath under nitrogen before adding NaH (0.70 g, 17.00 mmol) in portions. The reaction was allowed to warm to room temperature over an hour and was then quenched with NH.sub.4Cl (sat., aq.). The pH was adjusted to pH 7 with citric acid (5%, aq.) and the product was extracted with IPA:CHCl.sub.3 (1:3, ×3). The combined organic layers were washed brine, dried over MgSO.sub.4, filtered and concentrated under vacuum to yield 6-bromo-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one as a brown solid which was used crude. MS: [M+H].sup.+=385. To the residue was added bis(pinacolato)diboron (4.236 g, 16.51 mmol), AcOK (2.787 mg, 28.40 mmol) and anhydrous 1,4-dioxane (71 mL). The reaction was degassed with nitrogen for 10 minutes. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (348 mg, 0.43 mmol) was then added and the reaction heated at 90° C. under nitrogen for 1.5 hours. The reaction was allowed to cool to room temperature and was then diluted with water. The product was extracted with EtOAc (×3) and the combined organic layers washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum to yield crude 2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (90% pure by LC-MS UV) which was used as is. MS: [M+H].sup.+=433. A stirred mixture of this material, 2,4,5-trichloropyrimidine (2.442 ml mg, 21.30 mmol), K.sub.2CO.sub.3 (3.925 mg, 28.40 mmol) and 1,4-dioxane/water (3:1, 57 mL) was degassed with nitrogen for 10 minutes. Pd(PPh.sub.3).sub.4 (810 mg, 0.70 mmol) was then added and the reaction heated at 90° C. under nitrogen for a total of 16 hours. The reaction was allowed to cool to room temperature and was then diluted with water. The product was extracted with EtOAc (×3) and the combined organic layers were washed with water and brine, dried over MgSO.sub.4, filtered and concentrated under vacuum. The residue was purified by biotage (0-100% petrol/EtOAc) to yield the title compound (4.81 g, 75% over 3 steps) as a colourless solid. MS: [M+H].sup.+=453.

Preparations 129-132

[0968] Prepared using a similar procedure to Preparation 128 from the corresponding 5-substituted 2,4-dichloropyrimidines:

TABLE-US-00013 MS: Preparation Structure Name [M + H].sup.+ 129 [00796] 6-(2-chloro-5-methylpyrimidin-4-yl)- 2-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin-2-yl)ethyl]- 2,3-dihydro-1H-isoindol-1-one 433 130 [00797] N-tert-butyl-2-[6-(2-chloro-5- methylpyrimidin-4-yl)-1-oxo-2,3- dihydro-1H-isoindol-2-yl]-N- methylacetamide 387 131 [00798] 6-(2-chloro-5-cyclopropylpyrimidin- 4-yl)-2-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin-2-yl)ethyl]- 2,3-dihydro-1H-isoindol-1-one 459 132 [00799] 6-(2-chloro-5-ethylpyrimidin-4-yl)-2- [2-oxo-2-(1,2,3,4- tetrahydroisoquinolin-2-yl)ethyl]- 2,3-dihydro-1H-isoindol-1-one 447

Preparation 133: tert-Butyl N-{8-oxabicyclo[3.2.1]octan-3-yl}carbamate

[0969] ##STR00800##

[0970] A stirred mixture of 8-oxabicyclo[3.2.1]octane-3-carboxylic acid (250 mg, 1.60 mmol) in tert-butyl alcohol (2 mL) was treated with DIPEA (341 μL, 1.96) and then diphenylphosphoryl azide (392 μL, 1.77 mmol). The mixture was heated to reflux for 5 hours and then stirred at room temperature for 16 hours. The solvents were evaporated under vacuum. The residue was taken up in EtOAc and the resulting solution washed with water, brine and dried over MgSO.sub.4, filtered and concentrated under vacuum. The residue was purified by biotage (0-100% EtOAc/petrol) to yield the title compound (200 mg, 55%) as a colourless solid. .sup.1H NMR (400 MHz, Me-d.sub.3-OD): 4.39 (2H, s), 3.89-3.74 (1H, m), 1.99-1.90 (2H, m), 1.90-1.83 (2H, m), 1.83-1.74 (2H, m), 1.59-1.49 (2H, m), 1.45 (9H, s).

Preparation 134: 8-Oxabicyclo[3.2.1]octan-3-amine hydrochloride

[0971] ##STR00801##

[0972] A solution of tert-butyl N-{8-oxabicyclo[3.2.1]octan-3-yl}carbamate (190 mg, 0.84 mmol) in EtOAc saturated with HCl (3 mL) was stirred at room temperature for 1 hour and evaporated under vacuum. The residue was treated with MeOH and concentrated to dryness under vacuum to yield the title compound (122 mg, 114%, contains 20% starting material) as a colourless solid. .sup.1H NMR (400 MHz, Me-d.sub.3-OD): 4.52-4.46 (2H, m), 3.59-3.51 (1H, m), 2.08-1.98 (2H, m), 1.94-1.88 (2H, m), 1.85-1.79 (2H, m), 1.76-1.67 (2H, m).

Preparation 135: 4-Bromo-5-chloro-N-(oxan-4-yl)pyridin-2-amine

[0973] ##STR00802##

[0974] A stirred mixture of 2-amino-4-bromo-5-chloropyridine (500 mg, 2.34 mmol) and tetrahydro-4H-pyran-4-one (654 μL, 7.01 mmol) in 1,2-dichloroethane (6 mL) was treated with sodium triacetoxyborohydride (1.277 g, 5.84 mmol). After 5 days the mixture was treated with NaOH (1 M, 5 ml). After 30 minutes, the mixture was diluted with water and extracted with CH.sub.2Cl.sub.2 (×3). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum. The residue was purified by biotage (0-50% EtOAc) to yield 4-bromo-5-chloro-N-(oxan-4-yl)pyridin-2-amine (530 mg, 78%) as a yellow solid. MS: [M+H].sup.+=291/293/295.

Preparation 136: 2-(6-{5-Chloro-2-[(oxan-4-yl)amino]pyridin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid

[0975] ##STR00803##

[0976] A stirred solution of tert-butyl 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyridin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate (Example 185, 165 mg, 0.36 mmol) in THF/MeOH/water (5:1:1, 4 mL) was treated with NaOH (0.5 mL, 1M). After 18 hours, water was added and the pH adjusted to pH 4-5 with citric acid (5%, aq.). The mixture was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum to yield the title compound (131 mg, 91%) as a colourless solid. MS: [M+H].sup.+=402.

Preparation 137: 2-(6-{2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid

[0977] ##STR00804##

[0978] Prepared from Example 133 using a similar procedure to Example 1. MS: [M+H].sup.+=369.

Preparation 138: 5-chloro-2-[(2-methylpyridin-4-yl)amino]pyrimidin-4-ol

[0979] ##STR00805##

[0980] A solution of 4-amino-2-methylpyridine (594 mg, 5.5 mmol), 2,5-dichloropyrimidin-4-ol (413 mg, 2.5 mmol) and tosic acid (713 mg, 3.8 mmol) in dioxane (5 mL) was heated at 100° C. for 60 h.

[0981] The solution was poured into water (15 mL), basified to ˜pH 8 with saturated aqueous NaHCO.sub.3 and extracted with a 1:3 v/v mixture of IPA and CHCl.sub.3 (3×20 mL). The combined organic phases were dried (MgSO.sub.4) and evaporated under vacuum. The residue was used without further purification. MS: [M+H].sup.+=237.

Preparation 139: 4,5-dichloro-N-(2-methylpyridin-4-yl)pyrimidin-2-amine

[0982] ##STR00806##

[0983] A solution of 5-chloro-2-[(2-methylpyridin-4-yl)amino]pyrimidin-4-ol (2.5 mmol, assumed) in phosphorus oxychloride (1.5 mL, 15 mmol) was heated at 90° C. for 1 h. After cooling, the solution was poured into saturated NaHCO.sub.3 (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were dried (MgSO.sub.4) and evaporated under vacuum. The residue was used without further purification. MS: [M+H].sup.+=255.

Preparation 140: N-tert-butyl-3-[(tert-butyldimethylsilyl)oxy]-2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-methylpropanamide

[0984] ##STR00807##

[0985] The product was prepared following an analogous/similar procedure as described in Example 2. In this case, further 0.4 eq. of reagents (N,2-dimethylpropan-2-amine, DIPEA, HATU) were added after 40 minutes and the mixture was stirred for a further 45 minutes. LC-MS: [M+H].sup.+=551. Note: The product may have partially epimerized during the reaction as shown by chiral HPLC analysis of the final product.

Preparation 141: 2-chloro-N-phenethylpropanamide

[0986] ##STR00808##

[0987] DIPEA (1.9 mL, 10.88 mmol) and then 2-chloropropanoyl chloride (0.950 mL, 9.79 mmol) were added to a stirred solution of 2-phenylethanamine (1.1 mL, 8.73 mmol) in DCM (50 mL, 777 mmol) at room temperature and the resulting pale yellow solution was stirred for 3 h. The reaction mixture was diluted with DCM (50 mL) and washed with saturated aqueous NH.sub.4Cl (50 mL), water (50 mL), saturated aqueous NaHCO.sub.3 (50 mL) and brine (50 mL). The organic fraction was filtered through a phase separating cartridge and then concentrated under reduced pressure and dried in the vacuum oven overnight to give a light brown solid. This material was dry-loaded on silica and purified by chromatography (SiO.sub.2, 40 g column, 0-100% EtOAc in iso-hexanes) to afford the title compound as an off-white solid (1.82 g, 96%). LC-MS: [M+H].sup.+=212.

Preparation 142: 1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one

[0988] ##STR00809##

[0989] A mixture of 2-chloro-N-phenethylpropanamide (1.82 g, 8.43 mmol) and aluminium chloride (5 g, 37.5 mmol) was heated to 150° C. The resulting dark oil, which started to formed at 90° C. was heated at 150° C. under nitrogen for 4h. The reaction mixture was allowed to cool to room temperature and was then carefully quenched by the sequential addition of MeOH (10 mL), 10% aq HCl (10 mL) and then EtOAc (20 mL). The mixture was partitioned between water (50 mL) and EtOAc (50 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic extracts were dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude product as an orange solid (1.3 g). The crude product was dry-loaded on silica and purified by chromatography (SiO.sub.2, 40 g column, 0-100% (10% MeOH in DCM) in DCM) to afford the title compound as a pale yellow solid (0.639 g, 39%). 1H NMR (400 MHz, DMSO-d6) 7.37 (t (br), 1H), 7.12-7.22 (m, 4H), 4.28 (q, 1H), 3.70-3.78 (m, 1H), 3.14-3.29 (m, 2H), 2.90-3.00 (m, 1H), 1.35 (d, 3H).

Preparation 143: 1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

[0990] ##STR00810##

[0991] 1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (0.102 g, 0.524 mmol) was suspended in THF (5.0 mL, 61.0 mmol) in an oven-dried round bottom flask and the mixture was cooled to 0° C. Boran tetrahydrofuran complex (1 M solution in THF) (1.60 mL, 1.600 mmol) was added and the resulting yellow solution was stirred at 0° C. for 5 minutes, then refluxed under nitrogen for 4h. Further boran tetrahydrofuran (1 M solution in THF) (1.60 mL, 1.60 mmol) was added and the mixture left to reflux under nitrogen for a further 1 h. The mixture was allowed to cool to room temperature, then cooled with an ice bath. The reaction was quenched by dropwise addition of MeOH (5 mL) and the reaction mixture was concentrated under reduced pressure and coevaporated with MeOH (3×10 mL) to afford the crude product as a pale yellow film. The crude product was dissolved in MeOH (+a few drops of AcOH), absorbed onto SCX, washed with MeOH and then eluted with 1% NH.sub.3 in MeOH. Evaporation of the solvent under reduced pressure afforded the title compound as a yellow oil (0.056 g, 0.278 mmol, 53.0%, 80% purity). 1H NMR (400 MHz, DMSO-d6): 7.09-7.11 (m, 2H), 7.04-7.06 (m, 2H), 3.32 (s (br, overlapped with HDO), 1H), 2.96-3.04 (ddt, 1H), 2.71-2.90 (m, 5H), 2.61 (dd, 1H), 1.24 (d, 3H).

Preparation 144: 2-(2-(2-oxopropyl)phenyl)acetic acid

[0992] ##STR00811##

[0993] A solution of 2,2′-(1,2-phenylene)diacetic acid (2 g, 10.09 mmol) in THF (140 mL) was cooled to 0° C. 1.6M methyllithium in diethyl ether (14 mL, 22.40 mmol) was added dropwise and the mixture was stirred at 0° C. for 6 h. A further quantity of 1.6M methyllithium in diethyl ether (14 mL, 22.40 mmol) was added and the reaction mixture allowed to warm to room temperature overnight. The mixture was cooled to 0° C., and quenched with 1M HCl (120 mL). The aqueous layer was extracted with EtOAc (2×120 mL) and the combined organic extracts were dried (MgSO.sub.4), filtered and concentrated under vacuum to afford the crude product (2.13 g). The crude product was purified by chromatography (SiO.sub.2, 120 g column, 0-100% EtOAc (0.5% HCOOH) in isohexane) to afford 2-(2-(2-oxopropyl)phenyl)acetic acid (887 mg, 4.38 mmol, 43.4%) as an orange oil. LC-MS: [M+H].sup.+=193; [M−H].sup.−=191.

Preparation 145: 4-methyl-2,3-dihydro-1H-3-benzazepin-2-one

[0994] ##STR00812##

[0995] A mixture of 2-(2-(2-oxopropyl)phenyl)acetic acid (400 mg, 1.977 mmol) and ammonium acetate (305 mg, 3.95 mmol) in toluene (11 mL) was heated in a microwave (CEM, 120° C., 150W) for 3 h. The reaction mixture was concentrated under vacuum and the crude product obtained from a separate experiment carried on the same scale was combined. The crude product was purified by chromatography on silica gel (40 g column, 0-100% EtOAc in isohexane) to afford 4-methyl-1H-benzo[d]azepin-2(3H)-one (370 mg, 2.136 mmol, 49.3%) as a brown solid. LC-MS: [M+H].sup.+=174.

Preparation 146: 4-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one

[0996] ##STR00813##

[0997] 4-methyl-2,3-dihydro-1H-3-benzazepin-2-one (264 mg, 1.448 mmol) was dissolved in MeOH (15 mL) and the reaction mixture was hydrogenated in the H-Cube (10% Pd/C, 30×4 mm, Full hydrogen, 25° C., 1 mL/min) until completion of the reaction as monitored by LC-MS analysis. The reaction mixture was concentrated under vacuum and combined with a crude product obtained from a separate experiment carried out on 100 mg scale. The crude product was purified by chromatography (SiO.sub.2, 24 g column, 0-100% EtOAc in isohexane) to afford 4-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (186 mg, 1.051 mmol, 51.9%) as a colourless solid. LC-MS: [M+H].sup.+=176.

Preparation 147: 2-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

[0998] ##STR00814##

[0999] 1M borane in THF (2.1 mL, 2.100 mmol) was added to a stirred solution of 4-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (183 mg, 1.034 mmol) in THF (40 mL) under nitrogen and the mixture was stirred at room temperature overnight. A further quantity of 1M borane in THF (2.1 mL, 2.100 mmol) was added and stirring continued at room temperature overnight. The reaction mixture was concentrated under vacuum to give a colourless semi-solid (230 mg), which was dissolved in the minimum of MeOH and loaded onto SCX. The column was washed with MeOH (3 column volumes) and the compound was eluted with 1% NH.sub.3 in MeOH (3 column volumes). Evaporation of the solvent under vacuum afforded 2-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (113 mg). 1H NMR (400 MHz, DMSO-d6) 7.04-7.07 (m, 4H), 3.07 (ddd, 1H), 2.87 (ddd, 1H), 2.58-2.80 (m, 4H), 2.47-2.54 (m, 2H (overlapped with DMSO)), 1.06 (d, 3H).

Preparation 148: methyl 2,3,4,5-tetrahydro-1H-3-benzazepine-2-carboxylate

[1000] ##STR00815##

[1001] Thionyl chloride (0.160 mL, 2.196 mmol) was added dropwise to a solution of 2,3,4,5-tetrahydro-1H-benzo[d]azepine-2-carboxylic acid hydrochloride (250 mg, 1.098 mmol) in methanol (10 mL) and the mixture was heated at 65° C. for 18 h. The mixture was allowed to cool to room temperature and was concentrated under vacuum. The crude product was loaded onto a column of SCX (3 g) in methanol (2 mL). The column was washed with MeOH and the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated under vacuum to afford methyl 2,3,4,5-tetrahydro-1H-benzo[d]azepine-2-carboxylate (218 mg, 1.009 mmol, 92%) as a brown oil. 1H NMR (400 MHz, DMSO-d6): 7.05-7.17 (m, 4H), 3.60 (s, 3H), 3.43 (dd, 1H), 3.18 (s (br), 1H), 3.12 (ddd, 1H), 3.05-3.08 (m, 2H), 2.89 (ddd, 1H), 2.78 (ddd, 1H), 2.61 (ddd, 1H).

Preparation 149: (2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl)methanol

[1002] ##STR00816##

[1003] Lithium borohydride (2 M in THF) (1.062 mL, 2.124 mmol) was added to a solution of methyl 2,3,4,5-tetrahydro-1H-3-benzazepine-2-carboxylate (218 mg, 1.062 mmol) in THF (2 mL, 24.41 mmol) and the mixture was stirred at room temperature overnight. The reaction was quenched with 1 M HCl (5 mL) and the crude mixture was loaded onto a column of SCX (5 g). The column was washed with MeOH. The mixture was concentrated under vacuum and the residue was dissolved in 2 M NaOH (5 mL) and extracted with EtOAc (3×5 mL). The combined organic phases were washed with brine (10 mL), dried (MgSO.sub.4) and concentrated under vacuum to give the title compound (100 mg, 0.406 mmol, 38.2%) as a colourless oil. 1H NMR (400 MHz, DMSO-d6): 7.04-7.14 (m, 4H), 4.72 (s (br), 1H), 3.22-3.39 (m, 2H), 3.18 (ddd, 1H), 2.91 (ddd, 1H), 2.61-2.84 (m, 3H), 2.43-2.50 (m, 3H—overlapped with DMSO-d6). LC-MS: [M+H].sup.+=178.

Preparation 150: 2-(2-iodophenyl)ethanamine

[1004] ##STR00817##

[1005] A solution of borane tetrahydrofuran complex (1M in THF) (24.69 ml, 24.69 mmol) was added to a stirred solution of 2-(2-iodophenyl)acetonitrile (1.702 ml, 8.23 mmol) in THF (23.6 ml). The reaction mixture was heated to reflux under nitrogen for 2 h and was allowed to cool to room temperature. The mixture was then cooled to 0° C., and 6M HCl (4 mL) was added. The mixture was then basified with 2 M NaOH and extracted with DCM (3×20 ml). The organic layer was washed with water and brine, dried (MgSO.sub.4), and concentrated under vacuum to afford the title compound (2 g, 7.69 mmol, 93%), which was used in the next step without further purification. LC-MS: [M+H].sup.+=248.

Preparation 151: 2,2,2-trifluoro-N-(2-iodophenethyl)acetamide

[1006] ##STR00818##

[1007] Trifluoroacetic anhydride (2.325 ml, 16.46 mmol) in DCM (5 ml) was added dropwise to an ice cold solution of 2-(2-iodophenyl)ethanamine (2.033 g, 8.23 mmol) and triethylamine (3.44 ml, 24.69 mmol) in DCM (10 ml). The reaction mixture was stirred at room temperature overnight. The mixture was then diluted with EtOAc (500 mL), washed sequentially with 10% aqueous HCl (100 mL), water (100 mL), brine (100 mL), dried (MgSO.sub.4) and evaporated under vacuum to give an oil. Purification by chromatography (SiO.sub.2, 40 column, 0-20% EtOAc in isohexane) afforded the title compound (2.5 g, 6.92 mmol, 84%) as a yellow oil. LC-MS: [M+H].sup.+=344.

Preparation 152: 2,2,2-trifluoro-N-[2-(2-iodophenyl)ethyl]-N-(prop-2-en-1-yl)acetamide

[1008] ##STR00819##

[1009] 2,2,2-trifluoro-N-(2-iodophenethyl)acetamide (2.45 g, 7.14 mmol) was added to a stirred suspension of KOH (1.202 g, 21.42 mmol) and tetrabutylammonium hydrogen sulfate (0.242 g, 0.714 mmol) in toluene (73.8 ml) and the solution was stirred at room temperature for 10 minutes. The resulting mixture was treated with allyl bromide (0.618 ml, 7.14 mmol) followed immediately by Pd(PPh.sub.3).sub.4 (0.660 g, 0.571 mmol) and the yellow suspension was heated at 60° C. under nitrogen for 20 minutes. The mixture was cooled to 0° C. and treated dropwise with water (5 mL) with stirring. The layers were separated and the aqueous layer was extracted with DCM (50 ml). The combined organic extracts were dried (MgSO.sub.4), filtered and concentrated under vacuum. The residue was purified by chromatography (SiO.sub.2, 80 g column, 0-10% of EtOAc in Hexane) to afford the title compound (1.9 g, 4.71 mmol, 66.0%) as a yellow oil. LC-MS: [M+H].sup.+=384.

Preparation 153: 2,2,2-trifluoro-1-(1-methylidene-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)ethan-1-one

[1010] ##STR00820##

[1011] A stirred suspension of 2,2,2-trifluoro-N-[2-(2-iodophenyl)ethyl]-N-(prop-2-en-1-yl)acetamide (1.9 g, 4.96 mmol), palladium (II) acetate (0.111 g, 0.496 mmol), triphenylphosphine (0.260 g, 0.992 mmol), potassium acetate (1.460 g, 14.88 mmol), tetrabutylammonium bromide (1.758 g, 5.45 mmol) in DMF (96 ml, 1240 mmol) was degassed with nitrogen for 10 minutes. The resulting mixture was stirred at 80° C. under nitrogen for 5 h and was allowed to cool to room temperature. The mixture was cooled to 0° C. and diluted with water (75 ml) and Et.sub.2O (75 ml). The layers were separated and the aqueous layer was extracted with Et.sub.2O (50 ml×2). The combined organic extracts were dried (MgSO.sub.4) and evaporated to give a brown oil. The residue was purified by chromatography (SiO.sub.2, 80 g column, 0-10% of EtOAc in Hexane) to afford the title compound (850 mg, 3.30 mmol, 66.5%) as a colourless oil. LC-MS: [M+H].sup.+=256.

Preparation 154: 2,2,2-trifluoro-1-[1-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]ethan-1-one

[1012] ##STR00821##

[1013] A solution of 2,2,2-trifluoro-1-(1-methylidene-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)ethan-1-one (260 mg, 1.019 mmol) in THF (3 mL, 36.6 mmol) was treated with borane tetrahydrofuran complex (1M in THF) (1.121 mL, 1.121 mmol), and stirred at room temperature for 1 h. Water (1.5 mL), saturated aqueous NaHCO.sub.3 (1.5 mL), and 30% H.sub.2O.sub.2 (0.6 mL) were added sequentially and the reaction stirred for 1 h. The reaction mixture was diluted with EtOAc (20 mL) and the layers were separated. The organic extract was then washed with brine (10 mL), dried (MgSO.sub.4) and concentrated to give a brown oil. The residue was purified by chromatography (SiO.sub.2, 12 g column, 0-40% of EtOAc in Hexane) to afford the title compound (70 mg, 0.243 mmol, 23 9%) as a colourless oil. LC-MS: [M+H].sup.+=274.

Preparation 155: (2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl)methanol

[1014] ##STR00822##

[1015] A solution of 2,2,2-trifluoro-1-[1-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]ethan-1-one (65 mg, 0.238 mmol) in MeOH (1 ml, 24.72 mmol) was treated with 2N NaOH (0.238 ml, 0.476 mmol) and the mixture was stirred at room temperature overnight. Acetic acid (0.041 ml, 0.714 mmol) was added and the mixture was diluted with MeOH (4 ml), then loaded onto a column of SCX (2 g). The column was washed with MeOH and the product was eluted with 0.7 M ammonia in MeOH. Evaporation of the solvent under vacuum afforded the title compound (35 mg, 0.188 mmol, 79%) as a thick colourless oil. LC-MS: [M+H].sup.+=178.

Preparation 156: 2-methyl-1-phenoxypropan-2-amine

[1016] ##STR00823##

[1017] Methyl magnesium bromide (3M in Et.sub.2O) (1314 μl, 3.94 mmol) was added to a solution of 2-phenoxyacetonitrile (138 μl, 1.127 mmol) in THF (5 mL) under nitrogen. The resulting mixture was refluxed under nitrogen for 1 hour and titanium (IV) isopropoxide (330 μl, 1.127 mmol) was added dropwise. After heating overnight under nitrogen at 50° C., brine (10 mL) was added. The mixture was extracted with DCM (2×20 mL), and the combined organic extracts were washed with brine (10 mL), dried (Na.sub.2SO.sub.4) and evaporated under vacuum to give the title compound (136 mg, 69%) as a brown oil. 1H NMR (400 MHz, CDCl.sub.3): 7.26-7.31 (m, 2H), 6.89-6.97 (m, 3H), 3.70 (s, 2H), 1.25 (s, 6H) (2 exchangeable protons were not observed).

Preparation 157: tert-butyl 5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

[1018] ##STR00824##

[1019] Di-tert-butyl dicarbonate (1.324 g, 6.07 mmol) was added in THF (5 mL) to a solution of 5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline (1.143 g, 5.05 mmol) in THF (15 mL) and the mixture was stirred at room temperature for 3 days. The reaction mixture was absorbed onto silica and the crude product was purified by chromatography (SiO.sub.2, 40 g column, 0-10% EtOAc in isohexane) to afford the title compound (1.549 g, 93%) as a colourless oil, which solidified on standing to a colourless solid. 1H NMR (400 MHz, CDCl.sub.3): 7.42 (dd, 1H), 7.02-7.10 (m, 2H), 5.19 (m (br), 1H), 4.18 (m (br), 1H), 3.15 (m (br), 1H), 2.70-2.94 (m, 2H), 1.49 (s, 9H), 1.44 (d, 3H). LC-MS: [M-.sup.tBu+H].sup.+=270.

Preparation 158: tert-butyl 5-formyl-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

[1020] ##STR00825##

[1021] Tert-butyl lithium (1.7 M in pentane) (6.03 ml, 10.25 mmol) was added dropwise over 10 minutes to a stirred solution of tert-butyl 5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (1.535 g, 4.66 mmol) in THF (26 mL) at −78° C. under nitrogen and the resulting dark orange/red solution was stirred at −78° C. for 30 minutes. Morpholine-4-carbaldehyde (0.700 ml, 6.99 mmol) was added dropwise and the resulting pale-yellow solution allowed to warm slowly to room temperature and stirred for 1.5 h. The reaction was quenched carefully with saturated aqueous NH.sub.4Cl (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (1×100 mL), dried (MgSO.sub.4), filtered and concentrated under vacuum to afford a pale yellow oil (1.377 g) (1399-40-4a). The crude product was purified by chromatography (SiO.sub.2, 24 g column, 0-50% EtOAc in isohexane) to afford the title compound (793 mg, 2.71 mmol, 58.1%) as a pale yellow oil. LC-MS: [M+Na].sup.+=298.

Preparation 159: tert-butyl 5-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

[1022] ##STR00826##

[1023] Sodium borohydride (120 mg, 3.18 mmol) was added to an ice-cooled stirred solution of tert-butyl 5-formyl-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (777 mg, 2.65 mmol) in 1:1 THF/MeOH (19 mL) under nitrogen. The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction was ice-cooled, quenched with saturated aqueous NH.sub.4Cl (75 mL) and extracted with DCM (3×75 mL). The combined organic extracts were washed with brine (1×100 mL), dried (MgSO.sub.4), filtered and concentrated under vacuum to afford the title compound (756 mg, 2.59 mmol, 98%) a colourless gum. 1H NMR (400 MHz, CDCl.sub.3): 7.18-7.26 (m, 2H), 7.09 (dd, 1H), 5.06-5.32 (m (br), 1H), 4.70 (d, 1H), 4.66 (d, 1H), 3.98-4.31 (m, (br), 1H), 3.07-3.33 (m (br), 1H), 2.77-2.91 (m, 2H), 1.49 (s, 9H), 1.45 (d, 3H). (1 exchangeable proton was not observed).

Preparation 160: (1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)methanol

[1024] ##STR00827##

[1025] HCl (4M in dioxane) (12.6 mL, 50.4 mmol) was added dropwise at 0° C. to tert-butyl 5-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (700 mg, 2.52 mmol) and the resulting solution was stirred at room temperature for 3 h. The mixture was concentrated under vacuum and the residue was loaded onto a column of SCX (10 g) in MeOH (15 ml). The column was washed with MeOH (2×15 ml) and the product was eluted with 0.7 M ammonia in MeOH. Evaporation of the solvents under vacuum afforded the title compound (366 mg, 81%) as a colourless solid. LC-MS: [M+H].sup.+=178.

Preparation 161: 5-{[(tert-butyldimethylsilyl)oxy]methyl}-1-methyl-1,2,3,4-tetrahydro-isoquinoline

[1026] ##STR00828##

[1027] To a stirred solution of (1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)methanol (366 mg, 2.065 mmol) in DMF (6.4 mL) under nitrogen at 0° C. was added imidazole (422 mg, 6.19 mmol) and tert-butylchlorodimethylsilane (467 mg, 3.10 mmol). The reaction was allowed to warm slowly to room temperature and stirred for 3 days. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL). The organic extracts were combined and washed with brine (3×20 mL) and then dried (MgSO.sub.4), filtered and concentrated under vacuum to afford a 3:2 mixture of the title compound and 5-{[(tert-butyldimethylsilyl)oxy]methyl}-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbaldehyde as a colourless oil (659 mg). The product was used without further purification in the next step. LC-MS: [M+H].sup.+=292.

Preparation 162: 2-[2-(5-{[(tert-butyldimethylsilyl)oxy]methyl}-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-oxoethyl]-6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1H-isoindol-1-one

[1028] ##STR00829##

[1029] HATU (644 mg, 1.694 mmol) was added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (650 mg, 1.614 mmol), 5-{[(tert-butyldimethylsilyl)oxy]methyl}-1-methyl-1,2,3,4-tetrahydro-isoquinoline (659 mg, 1.356 mmol) and triethylamine (337 μl, 2.420 mmol) in DCM (10 ml) and the mixture was stirred for 3 h. The reaction mixture was concentrated under vacuum and then diluted with EtOAc (30 mL) and washed with 1M HCl (30 ml), saturated aqueous NaHCO.sub.3 (30 mL), water (30 mL) and brine (30 mL), dried (MgSO.sub.4), filtered and concentrated under vacuum to give a yellow oil. The residue was purified by chromatography (SiO.sub.2, 12 g column, 0-6% MeOH in DCM) to afford the title compound (390 mg, 0.490 mmol, 30.4%) as a colourless solid. LC-MS: [M+H].sup.+=676.

Preparation 163: tert-Butyl 2-[(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)methyl]pyrrolidine-1-carboxylate

[1030] ##STR00830##

[1031] Prepared from tert-butyl 2-{[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}pyrrolidine-1-carboxylate (Preparation 55) using a similar procedure to that described for Preparation 4.

Preparation 164: (2S)—N-tert-butyl-3-[(tert-butyldimethylsilyl)oxy]-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-methylpropanamide

[1032] ##STR00831##

[1033] Prepared from N-tert-butyl-3-[(tert-butyldimethylsilyl)oxy]-2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-methylpropanamide (Preparation 140) using a similar procedure to that described for Preparation 4.

Preparation 165: tert-butyl 2-[6-(2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]acetate

[1034] ##STR00832##

[1035] Prepared in an analogous manner to preparation 3 using 2,4-dichloropyrimidine. MS: [M-tBu+H].sup.+=304.

Preparation 166: 2-[6-(2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]acetic acid

[1036] ##STR00833##

[1037] Preparation 165 was treated with TFA as described in Preparation 9. MS: [M+H].sup.+=304.

Preparation 167: 2-[6-(2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide

[1038] ##STR00834##

[1039] Prepared from Preparation 166 using a method analogous to Example 2. MS: [M+1-1].sup.+=453.

Preparation 168: 2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]acetic acid

[1040] ##STR00835##

[1041] Preparation 3 was treated with TFA as described in Preparation 9. MS: [M+H].sup.+=338.

Preparations 169-171

[1042] The following were prepared from preparation 168 and the corresponding amine using a method analogous to Example 2.

TABLE-US-00014 Preparation Structure Name MS: [M + H].sup.+ 169 [00836] 2-[6-(2,5-dichloropyrimidin-4- yl)-1-oxo-2,3-dihydro-1H- isoindol-2-yl]-N-[(1S)-2- hydroxy-1-(3- methoxyphenyl)ethyl]acetamide 487 170 [00837] 2-[6-(2,5-dichloropyrimidin-4- yl)-1-oxo-2,3-dihydro-1H- isoindol-2-yl]-N-[(1S,2S)-2- hydroxy-1- phenylpropyl]acetamide 471 171 [00838] 2-[6-(2,5-dichloropyrimidin-4- yl)-1-oxo-2,3-dihydro-1H- isoindol-2-yl]-N-[(1R)-1-(3- methoxyphenyl)ethyl]acetamide 471

Preparation 172: tert-butyl 2-[6-(5-amino-2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]acetate

[1043] ##STR00839##

[1044] tert-Butyl 2-[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-2-yl]acetate (Preparation 2) was coupled with 5-amino-2,4-dichloropyrimidine (1.97 g, 12 mmol) in a manner analogous to preparation 3 to give the title compound (2 g, 5.3 mmol). MS: [M+H].sup.+=375.

Preparation 173: tert-butyl 2-[6-(5-bromo-2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]acetate

[1045] ##STR00840##

[1046] A solution of tert-butyl 2-[6-(5-amino-2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]acetate (374 mg, 1 mmol) in MeCN (5 mL) was cooled to 0° C. tert-Butyl nitrite (0.23 mL, 2 mmol) was added, followed by copper (I) bromide (144 mg, 1 mmol). The reaction was stirred overnight whilst warming to room temperature, then water (10 mL) was added. The layers were separated and the aqueous fraction was extracted with DCM (2×10 mL). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography (SiO.sub.2, 25 g column, 20-100% EtOAc in petrol) to give the title compound (175 mg, 40%). MS: [M+H-.sup.tBu].sup.+=384.

Preparation 174: tert-butyl 2-(6-{5-bromo-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate

[1047] ##STR00841##

[1048] tert-Butyl 2-[6-(5-bromo-2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]acetate (175 mg, 0.4 mmol) was treated with oxan-4-amine in a manner analogous to preparation 4 to give the title compound (100 mg, 50%). MS: [M+H].sup.+=503.

Preparation 175: 2-(6-{5-bromo-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid

[1049] ##STR00842##

tert-Butyl 2-(6-{5-bromo-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate (100 mg, 0.2 mmol) was treated with TFA as described in preparation 9 to give the title compound (90 mg, quant.). MS: [M+H].sup.+=447.

Preparation 176: 2-[6-(5-bromo-2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide

[1050] ##STR00843##

[1051] Prepared from (2S)-2-amino-2-(3-methoxyphenyl)ethan-1-ol and 2-[6-(5-bromo-2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl] acetic acid in a manner analogous to Example 2. MS: [M+H].sup.+=384.

Preparations 177 and 178

[1052] Prepared in similar manner to preparation 176 using the corresponding amine.

TABLE-US-00015 Preparation Structure Name MS: [M + H].sup.+ 177 [00844] 2-[6-(5-bromo-2-chloropyrimidin-4- yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-(3- methoxyphenyl)ethyl]acetamide 515 178 [00845] 2-[6-(5-bromo-2-chloropyrimidin-4- yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1S,2S)-2-hydroxy-1- phenylpropyl]acetamide 515

Preparation 179: methyl 5-(2,5-dichloropyrimidin-4-yl)-2-methylbenzoate

[1053] ##STR00846##

[1054] Prepared from methyl 5-bromo-2-methylbenzoate in a manner analogous to preparation 7. MS: [M+H].sup.+=297.

Preparation 180: methyl 2-(bromomethyl)-5-(2,5-dichloropyrimidin-4-yl)benzoate

[1055] ##STR00847##

[1056] NBS (156 mg, 0.88 mmol) and AlBN (3 mg, 1% by weight of reactant) were added to a solution of methyl 5-(2,5-dichloropyrimidin-4-yl)-2-methylbenzoate (260 mg, 0.88 mmol) in 1,2-dichloroethane (3 mL). The solution was heated to 80° C. for 2 hours. The reaction was quenched by the addition of water (5 mL) and allowed to cool. The layers were separated and the aqueous fraction was further extracted with DCM (2×10 mL). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. The residue was used without further purification, although contaminated with starting material (10%) and methyl 2-(dibromomethyl)-5-(2,5-dichloropyrimidin-4-yl)benzoate (7%). MS: [M+H].sup.+=375.

Preparation 181: tert-butyl N-[(1R)-2-hydroxy-1-{[(1R)-1-(3-methoxyphenyl)ethyl]carbamoyl}ethyl]carbamate

[1057] ##STR00848##

[1058] A solution of N-Boc-D-serine (103 mg, 0.5 mmol), (1R)-1-(3-methoxyphenyl)ethan-1-amine (0.1 mL, 0.5 mmol), HATU (210 mg, 0.55 mmol) and triethylamine (0.3 mL, 1.5 mmol) in DCM (10 mL) was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate (10 mL) was added and the layers were separated. The aqueous fraction was further extracted with DCM (2×10 mL) and the combined organic fractions were dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography (SiO.sub.2, 25 g column, 0-100% EtOAc in petrol) to give the title compound (164 mg, 97%). MS: [M+H].sup.+=339.

Preparation 182: (2R)-2-amino-3-hydroxy-N-[(1R)-1-(3-methoxyphenyl)ethyl]propanamide

[1059] ##STR00849##

[1060] TFA (0.5 mL) was added to a solution of tert-butyl N-[(1R)-2-hydroxy-1-{[(1R)-1-(3-methoxyphenyl)ethyl]carbamoyl}ethyl]carbamate (164 mg, 0.49 mmol) in DCM (2 mL). The resulting solution was stirred at room temperature for 2 hours, then concentrated in vacuo. Toluene (5 mL) was added to the residue and this was concentrated again. This procedure was repeated. The compound was used without purification. MS: [M+1-1].sup.+=239.

Preparations 183-206

[1061] The following were prepared in an analogous manner to the sequence in preparations 181 and 182.

TABLE-US-00016 Preparation Structure Name MS: [M + H].sup.+ 183 [00850] (2R)-2-amino-3-hydroxy-N- [(1S)-2-hydroxy-1-(3- methoxyphenyl)ethyl]- propanamide 255 184 [00851] (2R)-2-amino-N-[(1R)-1-(2- fluoro-5- methoxyphenyl)propyl]-3- hydroxypropanamide 271 185 [00852] (2R)-2-amino-N-[(1R)-2,3- dihydro-1H-inden-1-yl]-3- hydroxypropanamide 221 186 [00853] (2R)-2-amino-N-[(1R)-1-(2H- 1,3-benzodioxol-5-yl)ethyl]-3- hydroxypropanamide 253 187 [00854] (2R)-2-amino-3-hydroxy-N- [(1R)-1-(3- methylphenyl)ethyl]- propanamide 233 188 [00855] (2R)-2-amino-3-hydroxy-N- [(1R)-1-[3- (trifluoromethyl)phenyl]ethyl]- propanamide 277 189 [00856] (2R)-2-amino-N-[(1R)-1-(2- fluoro-5- methoxyphenyl)ethyl]-3- hydroxypropanamide 257 190 [00857] (2R)-2-amino-N-[(1R)-1-(3- methoxyphenyl)ethyl]-3- hydroxypropanamide 253 191 [00858] (2R)-2-amino-3-hydroxy-N- [(1S,2S)-2-hydroxy-1- phenylpropyl]propanamide 239 192 [00859] (2R)-2-amino-N-[(1R)-1-[3- (difluoromethyl)phenyl]ethyl]- 3-hydroxypropanamide 259 193 [00860] (2R)-2-amino-N-[(1R)-1-[3- (difluoromethoxy)phenyl]- ethyl]-3-hydroxypropanamide 275 194 [00861] (2R)-2-amino-3-hydroxy-N- [(3- methoxyphenyl)methyl]- propanamide 225 195 [00862] (2R)-2-amino-3-hydroxy-N-[2- (3-methoxyphenyl)propan-2- yl]propanamide 253 196 [00863] (2R)-2-amino-N-[(1R)-1-(2- fluoro-5-methylphenyl)ethyl]- 3-hydroxypropanamide 241 197 [00864] (2R)-2-amino-N-[(1R)-1-(2- fluoro-3- methoxyphenyl)ethyl]-3- hydroxypropanamide 257 198 [00865] (2R)-2-amino-N-[(1R)-1-(3- fluoro-5-methylphenyl)ethyl]- 3-hydroxypropanamide 241 199 [00866] (2R)-2-amino-N-[(1R)-1-(4- fluoro-3- methoxyphenyl)ethyl]-3- hydroxypropanamide 257 200 [00867] (2R)-2-amino-N-[(1R)-1-(3- fluoro-5- methoxyphenyl)ethyl]-3- hydroxypropanamide 257 201 [00868] (2R)-2-amino-3-hydroxy-N- [(1R)-1-(6-methylpyridin-2- yl)ethyl]propanamide 224 202 [00869] (2R)-2-amino-3-hydroxy-N- [(1R)-1-(6-methoxypyridin-2- yl)ethyl]propanamide 240 203 [00870] (2R)-2-amino-3-hydroxy-N- [(1R)-1-(5-methoxy-2- methylphenyl)ethyl] propanamide 253 204 [00871] (2R)-2-amino-N-[(1R)-1-[5- (difluoromethyl)-2- fluorophenyl]ethyl]-3- hydroxypropanamide 277 205 [00872] (2R)-2-amino-3-hydroxy-N- [(1- hydroxycyclopropyl)(phenyl) methyl]propanamide 251 206 [00873] (2R)-2-amino-N-[(1S)-2- hydroxy-1-(3- methoxyphenyl)ethyl]- butanamide 253

Preparation 207: (2R)-2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-3-hydroxy-N-[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]propanamide

[1062] ##STR00874##

[1063] A solution of methyl 2-(bromomethyl)-5-(2,5-dichloropyrimidin-4-yl)benzoate (preparation 180, 281 mg, 0.75 mmol), (2R)-2-amino-3-hydroxy-N-[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]-propanamide (preparation 189, 207 mg, 0.75 mmol) and DIPEA (0.26 mL, 1.5 mmol) in MeCN (5 mL) was heated to 80° C. overnight. The mixture was concentrated and the residue taken up in water (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous fraction was further extracted with EtOAc (10 mL). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography (SiO.sub.2, 25 g column, 0-100% EtOAc in petrol) to give the title compound (110 mg, 27%). MS: [M+H].sup.+=539.

Preparations 208-224

[1064] The following were prepared in an analogous manner to preparation 207.

TABLE-US-00017 Preparation Structure Name MS: [M + H].sup.+ 208 [00875] (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]- N-[(1R)-1-(2-fluoro-5- methoxyphenyl)ethyl]-3- hydroxypropanamide 519 209 [00876] (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]- N-[(1R)-1-(3- ethoxyphenyl)ethyl]-3- hydroxypropanamide 515 210 [00877] (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]- 3-hydroxy-N-[(1S,2S)-2- hydroxy-1- phenylpropyl]propanamide 501 211 [00878] (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1 H-isoindol-2-yl]- N-[(1R)-1-[3- (difluoromethyl)phenyl]ethyl]- 3-hydroxypropanamide 521 212 [00879] (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]- N-[(1R)-1-[3- (difluoromethoxy)phenyl]- ethyl]-3-hydroxypropanamide 537 213 [00880] (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]- 3-hydroxy-N-[(3- methoxyphenyl)methyl]- propanamide 487 214 [00881] (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]- 3-hydroxy-N-[2-(3- methoxyphenyl)propan-2- yl]propanamide 515 215 [00882] (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]- N-[(1R)-1-(2-fluoro-5- methylphenyl)ethyl]-3- hydroxypropanamide 503 216 [00883] (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]- N-[(1R)-1-(2-fluoro-3- methoxyphenyl)ethyl]-3- hydroxypropanamide 519 217 [00884] (2R)-2-(6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]- N-[(1R)-1-(3-fluoro-5- methylphenyl)ethyl]-3- hydroxypropanamide 503 218 [00885] (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]- N-[(1R)-1-(4-fluoro-3- methoxyphenyl)ethyl]-3- hydroxypropanamide 519 219 [00886] (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]- N-[(1R)-1-(2-fluoro-5- methoxyphenyl)ethyl]-3- hydroxypropanamide 519 220 [00887] (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]- 3-hydroxy-N-[(1R)-1-(6- methylpyridin-2- yl)ethyl]propanamide 486 221 [00888] (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]- 3-hydroxy-N-[(1R)-1-(6- methoxypyridin-2- yl)ethyl]propanamide 502 222 [00889] (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]- 3-hydroxy-N-[(1R)-1-(5- methoxy-2- methylphenyl)ethyl]- propanamide 515 223 [00890] (2R)-2-[6-(2,5- dichloropyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H-isoindol-2-yl]- N-[(1R)-1-[5-(difluoromethyl)- 2-fluorophenyl]ethyl]-3- hydroxypropanamide 539 224 [00891] 2-[6-(2,5-dichloropyrimidin-4- yl)-1-oxo-2,3-dihydro-1H- isoindol-2-yl]-3-hydroxy-N-[(1- hydroxycyclopropyl)(phenyl) methyl]propanamide 513

Preparation 225: methyl 5-(2,5-dichloropyrimidin-4-yl)-3-fluoro-2-methylbenzoate

[1065] ##STR00892##

[1066] A solution of methyl 5-chloro-3-fluoro-2-methylbenzoate (412 mg, 2.04 mmol), bis(pinacolato)diboron (621 mg, 2.45 mmol), KOAc (599 mg, 6.12 mmol) and XPhos palladacycle G3 (34 mg, 0.041 mmol) in dioxane (4 mL) was heated to 100° C. in a microwave for 1 hour. The resulting mixture was poured into a solution of 2,4,5-trichloropyrimidine (0.3 mL, 2.79 mmol) in dioxane (5 mL) and 1M aqueous sodium carbonate (4 mL, 4 mmol). The reaction was degassed by bubbling through nitrogen, then heated to 90° C. overnight. The reaction was allowed to cool, diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic fractions were dried, filtered and concentrated. The residue was purified by chromatography (SiO.sub.2, 25 g column, 0-40% EtOAc in petrol) to give the title compound (400 mg, 62%). MS: [M+H].sup.+=315.

Preparation 226: methyl 2-(bromomethyl)-3-fluoro-5-(2,5-dichloropyrimidin-4-yl)benzoate

[1067] ##STR00893##

[1068] Preparation 225 was brominated using a similar procedure to preparation 180. 1H NMR (400 MHz, CDCl.sub.3): 8.73 (1H, s), 8.39 (1H, s), 7.88 (1H, dd), 5.06 (2H, d), 4.02 (3H, s).

Preparation 227: (2R)-2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-3-hydroxy-N-[(1R)-1-(3-methoxyphenyl)ethyl]propanamide

[1069] ##STR00894##

[1070] Preparation 226 was treated with preparation 182 as described in preparation 207. MS: [M+H]+=519.

Preparation 228: tert-butyl 2-(7-bromo-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)acetate

[1071] ##STR00895##

[1072] To 7-bromo-3,4-dihydro-2H-isoquinolin-1-one (0.500 g, 2.22 mmol) in DMF (7.40 mL), cooled to 0° C. (ice bath) was added sodium hydride (60% in min. oil, 0.098 g, 2.44 mmol) portionwise. The reaction was stirred for 30 min at 0° C. Tert-butyl bromoacetate (0.361 mL, 2.44 mmol) was added and the reaction stirred for 1 h. Water was added and the aqueous extracted with ethyl acetate (3×). The combined organics washed with saturated brine solution (3×), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (gradient elution, 0-50%, ethyl acetate/petrol 40-60° C.), to give the titled compound (694 mg), MS: [M+H].sup.+=284 (−tBu).

Preparation 229: tert-butyl 2-[1-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-2-yl]acetate

[1073] ##STR00896##

[1074] tert-butyl 2-(7-bromo-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)acetate (0.694 g, 2.05 mmol), bispinacolatodiboron (0.676 g, 2.66 mmol) [1,1′-bis(diphenylphosphino)ferroncene]dichloropalladium(II) (0.075 g, 0.10 mmol) and potassium acetate (0.502 g, 5.12 mmol) were dissolved in dioxane (5.12 mL) and degassed under nitrogen (5 mins). The reaction was heated to 90° C. for 18h. After this time, water and ethyl acetate were added. The mixture was filtered through a phase separator and the organic layer separated. This was dried over sodium sulfate, filtered and concentrated in vacuo, to give the titled compound (777 mg) as a brown solid which was used straight away as a crude mixture.

Preparation 230: tert-butyl 2-[7-(2,5-dichloropyrimidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl]acetate

[1075] ##STR00897##

[1076] To tert-butyl 2-[1-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-2-yl]acetate (0.777 g, 2.01 mmol), 2,4,5-trichloropyrimidine (0.555 g, 3.03 mmol) and tetrakis(triphenylphosphine)palladium(0) in dioxane (5.58 mL) and water (2.79 mL) was added potassium carbonate (0.555 g, 4.02 mmol). The reaction was heated to 100° C. for 1h. The organic layer was separated and washed with saturated brine solution. Passed through a passed separator and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (gradient elution, 0-100%, ethyl acetate/petrol 40-60° C.), to give the titled compound (0.701 g), MS: [M+H].sup.+=352 (−tBu).

Preparation 231: tert-butyl 2-(7-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)acetate

[1077] ##STR00898##

[1078] To tert-butyl 2-[7-(2,5-dichloropyrimidin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl]acetate (0.701 g, 1.72 mmol) and 4-aminooxan (0.973 g, 8.61 mmol) in DMF (8.61 mL) was added diisopropylethylamine (0.900 mL, 5.17 mmol). The reaction was heated to 70° C. for 18h. The reaction was concentrated in vacuo and the residue was purified by reverse phase biotage MeCN/water, 0-40% gradient elution to give the titled compound (0.497 g), MS: [M+H].sup.+=473.

Preparation 232: (2R)-2-[6-(2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

[1079] ##STR00899##

[1080] tert-butyl (2R)-2-[6-(2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoate (1.10 g, 2.95 mmol) was dissolved in DCM (19.7 mL) and TFA (9.83 mL), and stirred for 4 h at room temperature. The reaction was concentrated in vacuo and precipitated from diethyl ether. The solid was triturated with diethyl ether and dried in vacuo. To give the titled compound (0.922 g), MS: [M+H].sup.+=318.

Preparation 233: 2-(7-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)acetic acid

[1081] ##STR00900##

[1082] Prepared as above except using tert-butyl 2-(7-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)acetate to give the titled compound (0.305 g) MS: [M+H]+=417.

Preparation 234: (2R)-2-[6-(2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(3-methylphenyl)ethyl]propanamide

[1083] ##STR00901##

[1084] To (2R)-2-[6-(2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid (0.499 g, 1.57 mmol), (2S)-2-amino-2-(3-methylphenyl)ethan-1-ol hydrochloride (0.353 g, 1.89 mmol) and TBTU (0.758 g, 2.36 mmol) in DMF (7.87 mL) was added diisopropylethylamine (1.10 mL, 6.30 mmol). The reaction was stirred at room temperature for 1 h. Water was added and the aqueous was extracted with ethyl acetate (3×). The combined organics were washed concentrated in vacuo. The crude product was purified by column chromatography on silica gel (gradient elution, 0-100%, ethyl acetate/petroleum spirit 40-60° C., to give the titled compound (0.279 g) MS: [M−H].sup.−=449.

Preparation 235: (2R)-2-[6-(2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]propanamide

[1085] Prepared as above except using (2S)-2-amino-2-(3-methoxyphenyl)ethan-1-ol hydrochloride, and the workup was using water was added, the precipitate which formed was collected by vacuum filtration and washed with water and petrol. Dried in a vacuum oven at 40° C. for 2 h, to give the titled compound (0.338 g) MS: [M−H].sup.−=465.

Preparation 236: 2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1R)-1-(3-methoxyphenyl)ethyl]acetamide

[1086] ##STR00902##

[1087] To 2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]acetic acid (1.00 g, 2.97 mmol), (R)-(+)-1-(3-methoxyphenyl)ethylamine) (0.672 g, 4.45 mmol) and HATU (1.693 g, 4.45 mmol) in DMF (14.84 mL) was added diisopropylethylamine (2.07 mL, 11.87 mmol). The reaction was stirred at room temperature for 2 h. Water was added and the aqueous was extracted with ethyl acetate (3×). The combined organics were concentrated in vacuo. The crude product was purified by column chromatography on silica gel (gradient elution, 0-100%, ethyl acetate/petrol 40-60° C.), to give 813 mg, 1H NMR (400 MHz, DMSO-d6): 9.03 (1H, s), 8.57 (1H, d), 8.13 (1H, d), 8.05 (1H, dd), 7.82 (1H, d), 7.28-7.20 (1H, m), 6.94-6.85 (2H, m), 6.85-6.77 (1H, m), 4.99-4.89 (1H, m), 4.63 (2H, s), 4.27 (2H, s), 3.76 (3H, s), 1.38 (3H, d).

Preparation 237: tert-butyl (2R)-2-[6-(5-chloro-2-fluoropyridin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoate

[1088] ##STR00903##

[1089] A mixture of tert-butyl (2R)-2-[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-2-yl]propanoate (Intermediate 89, 1.13 g, 2.92 mmol), 2-fluoro,4-iodo,5-chloropyridine (1.50 g, 5.84 mmol, 2 eq.), Pd(PPh.sub.3).sub.4 (337 mg, 0.1 eq.) aqueous sodium carbonate (2.92 mL, 2M, 5.84 mmol) and dioxane (20 mL) was heated under nitrogen at 90° C. overnight. The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with further EtOAc. The combined organic layer was washed with water (×2) and brine before it was dried (MgSO.sub.4), filtered and concentrated to give a brown solid. Purified by silica column, eluting 20-100% EtOAc in petrol to give the title compound (403 mg) as a white solid. LC-MS: [M+H].sup.+=391

Preparation 238: (2R)-2-[6-(5-chloro-2-fluoropyridin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

[1090] ##STR00904##

[1091] To a solution of tert-butyl (2R)-2-[6-(5-chloro-2-fluoropyridin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoate (403 mg, 1.03 mmol) in DCM (8 mL) was added 4M HCl in dioxane (2.58 mL, 10.3 mmol, 10 eq.) and the reaction stirred at room temperature for 20h. The reaction mixture was concentrated to dryness to give the title compound (291 mg). LC-MS: [M+H].sup.+=335

Preparation 239: (2R)-2-[6-(5-chloro-2-fluoropyridin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]propanamide

[1092] ##STR00905##

[1093] To a solution of (2R)-2-[6-(5-chloro-2-fluoropyridin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid (145 mg, 0.43 mmol) in DCM (2 mL) was added triethylamine (242 mL, 1.73 mmol, 4 eq), (2S)-2-amino-2-(3-methoxyphenyl)ethan-1-ol hydrochloride salt (97 mg, 0.48 mmol, 1.1 eq.) and TBTU (153 mg, 0.48 mmol, 1.1 eq.) and the reaction stirred for 66 h. The reaction mixture was partitioned between DCM and water. The aqueous was extracted with further DCM and then the combined organic phase washed with water (×2), sodium bicarbonate (×2) and brine before it was dried (MgSO.sub.4), filtered and concentrated. Purified by silica column, eluting 50-100% EtOAc in petrol followed by 0-10% MeOH in EtOAc to give the title compound (108 mg). LC-MS: [M+H].sup.+=484

Preparation 240: 1-(7-nitro-1.2.4,5-tetrahydro-3H-benzo[d]azepin-3-Methan-1-one

[1094] ##STR00906##

[1095] Sulfuric acid (35.0 mL, 35.0 mmol) was added dropwise to a stirred solution of 2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.0 g, 20.4 mmol) in 1,4-dioxane (35 mL) and the solvent was removed in vacuo to afford a sticky paste. A small volume of iso-propanol (ca. 5 mL) was added to induce solidification followed by EtOAc (50 mL) and the resulting mixture was stirred at room temperature for 1 h. The solid was collected by filtration, and the filter cake was washed with EtOAc (25 mL) and iso-hexane (50 mL) to afford 2,3,4,5-tetrahydro-1H-benzo[d]azepine sulfate (4.0 g, 16.1 mmol, 79%) as an off-white solid. The product was used without further purification in the next step.

[1096] 2,3,4,5-tetrahydro-1H-benzo[d]azepine sulfate (4.0 g, 16.3 mmol) was added at 0° C. in small portions to a stirred mixture of nitric acid (70% w/w, 10.0 mL, 157.0 mmol) and sulfuric acid (95% w/w, 10.0 ml, 178.0 mmol) and the resulting mixture was stirred at 0° C. for 2 h. The cold reaction mixture was poured into ice and allowed to warm to room temperature. The mixture was basified by addition of saturated aqueous NaHCO.sub.3 and extracted with EtOAc (3×300 mL). The organic extracts were combined, then dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a brown solid (3.5 g, 112%). LC-MS: [M+H].sup.+=504. The product was used without further purification in the next step.

[1097] Crude 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.5 g) was dissolved in DCM (40 mL) and DIPEA (3.13 mL, 17.94 mmol) was added, followed by drop-wise addition of acetic anhydride (1.69 mL, 17.94 mmol). The mixture was stirred at room temperature for 3 h and was diluted with DCM (50 mL), then washed with saturated aqueous NaHCO.sub.3 (50 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford a brown solid (5 g). The crude product was purified by chromatography (SiO.sub.2, 40 g column, 0-5% MeOH in DCM) to afford the title compound (2.40 g, 7.68 mmol, 47%) as a tan solid. LC-MS: [M+H].sup.+=235.

Preparation 241: 1-(7-amino-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethan-1-one

[1098] ##STR00907##

[1099] A mixture of 1-(7-nitro-4,5-dihydro-1H-benzo[d]azepin-3(2H)-yl)ethanone (2.40 g, 7.68 mmol) and Pd—C(150 mg, 0.141 mmol) in EtOH (18 mL) was hydrogenated at 2 Bar for 16 h. The heterogenous mixture was filtered, washed with EtOH (2×40 mL) and then concentrated to give a red solid. The crude product was loaded onto a column of SCX (10 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to afford a red solid. The red solid was recrystallised from hot EtOH (˜10 mL) and the resulting solid was filtered, washed with EtOH, and dried in vacuo to afford the title compound (650 mg) as a yellow solid. The filter cake was further washed with EtOH (50 mL) and then concentrated to give a second crop of the title compound (440 mg) as a brown solid. The filter cake was further washed with EtOH (50 mL) and then concentrated to give a third crop of the title compound as a brown solid (200 mg). The three fractions were combined to give the title compound (1.29 g, 78%) as a brown solid. LC-MS (poor chromophore): [M+H].sup.+=205.

Preparation 242: 1-(7-chloro-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethan-1-one

[1100] ##STR00908##

[1101] A solution of 1-(7-amino-4,5-dihydro-1H-benzo[d]azepin-3(2H)-yl)ethanone (800 mg, 3.92 mmol) in MeCN (19.6 ml) was added dropwise to a mixture of copper (II) chloride (632 mg, 4.70 mmol) and butyl nitrite (0.687 mL, 5.88 mmol) in MeCN (19.6 mL). The resulting mixture was stirred at room temperature for 16 h. Water (50 mL) was added and the crude product was extracted with EtOAc (3×50 mL). The combined organic extracts were dried (MgSO.sub.4), filtered and concentrated in vacuo to give a brown solid. The crude product was purified by chromatography (SiO.sub.2, 24 g column, 50-100% EtOAc/isohexane) to afford the title compound (260 mg, 1.10 mmol, 28%) as a colourless oil which solidified on standing to give a tan solid. LC-MS (poor chromophore): [M+H].sup.+=224.

Preparation 243: 7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[1102] ##STR00909##

[1103] A mixture of 1-(7-chloro-4,5-dihydro-1H-benzo[d]azepin-3(2H)-yl)ethanone (40 mg, 0.18 mmol) and 6 M HCl (2.0 mL, 12.00 mmol) was heated under reflux and stirred for 18 h. The reaction was basifed with 2 M NaOH (aq.) and extracted with EtOAc (3×15 mL). The organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the title compound as a yellow oil. The product (80% NMR purity) was used without further purification in the next step. LC-MS (poor chromophore): [M+H].sup.+=182.

Preparation 244: tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate

[1104] ##STR00910##

[1105] A solution of di-tert-butyldicarbonate (1.11 mL, 4.76 mmol) in DCM (4 mL) was added dropwise to a suspension of 6-bromo-1,2,3,4-tetrahydroisoquinoline (0.990 g, 4.67 mmol) in DCM (6 mL) and the mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo to give tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.564 g, 4.66 mmol, 100%) as an orange oil. The product was used without further purification in the next step. .sup.1H NMR (DMSO-d6) δ: 7.39 (1H, d), 7.36 (1H, dd), 7.14 (1H, d), 4.45 (2H, s), 3.53 (2H, dd), 2.77 (2H, dd), 1.43 (9H, s).

Preparation 245: tert-butyl 6-(4-isopropylpiperazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[1106] ##STR00911##

[1107] A microwave tube was charged with RuPhos-Pd G3 (25 mg, 0.030 mmol) and sodium tert-butoxide (92 mg, 0.953 mmol). The tube was evacuated and backfilled with nitrogen (×3). A solution of tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (200 mg, 0.596 mmol) in THF (1.2 mL) was added, followed by 1-isopropylpiperazine (111 μL, 0.774 mmol) and the mixture was stirred overnight at 65° C. under nitrogen. The reaction was cooled to room temperature, diluted with EtOAc (10 mL) and filtered through celite, eluting with EtOAc (50 mL). The filtrate was concentrated and the crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-10% (0.7 M Ammonia/MeOH) in DCM) to afford the title compound (125 mg, 49%) as a yellow oil. .sup.1H NMR (DMSO-d6) δ: 6.98 (1H, d), 6.77 (1H, dd), 6.69 (1H, d), 4.38 (2H, s), 3.50 (2H, dd), 3.10-3.03 (4H, m), 2.71 (2H, dd), 2.68-2.62 (1H, m), 2.59-2.52 (4H, m), 1.43 (9H, s), 1.00 (6H, d).

Preparation 246: 6-(4-isopropylpiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline

[1108] ##STR00912##

[1109] A mixture of tert-butyl 6-(4-isopropylpiperazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (125 mg, 0.29 mmol) and TFA (0.34 mL, 4.38 mmol) in DCM (1 mL) was stirred overnight at room temperature. The reaction mixture was loaded onto a column of SCX (2 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to afford 6-(4-isopropylpiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline (80 mg, 0.29 mmol, 100%) as a yellow oil. 1H NMR (DMSO-d6) δ: 6.83 (d, 1H), 6.70 (dd, 1H), 6.58 (d, 1H), 4.10 (s, 1H), 3.73 (s, 2H), 3.07-3.00 (m, 4H), 2.90 (dd, 2H), 2.71-2.58 (m, 3H), 2.59-2.51 (m, 4H), 1.00 (d, 6H).

Preparation 247: tert-butyl 6-(pyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[1110] ##STR00913##

[1111] A microwave tube was charged with tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.300 g, 0.835 mmol), 2-chloropyrimidine (0.080 g, 0.696 mmol) and Sphos-Pd G3 (11 mg, 0.014 mmol). The tube was evacuated and back-filled with nitrogen (×3). 1,4-dioxane (7 ml) was added, followed by 2 M lithium hydroxide (aq.) (1.39 ml, 2.78 mmol). The tube was evacuated and back-filled with nitrogen (×2) and stirred overnight at 80° C. The cooled reaction mixture was diluted with EtOAc (15 mL) and water (15 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×15 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO.sub.4) and concentrated. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-50% EtOAc in iso-hexane) to afford the title compound (106 mg, 46%) as a colourless oil. .sup.1H NMR (DMSO-d6) δ: 8.89 (2H, d), 8.24-8.17 (2H, m), 7.44 (1H, t), 7.33 (1H, d), 4.58 (2H, s), 3.60 (2H, dd), 2.89 (2H, dd), 1.45 (9H, s).

Preparation 248: 6-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline

[1112] ##STR00914##

[1113] Prepared using a similar procedure to preparation 246. The product was obtained in 90% purity and was used without further purification in the next step. .sup.1H NMR (DMSO-d6) δ: 8.87 (2H, d), 8.19-8.09 (2H, m), 7.41 (1H, t), 7.16 (1H, d), 4.08 (1H, s), 3.92 (2H, s), 2.99 (2H, dd), 2.79 (2H, dd).

Preparation 249: tert-butyl (2-(4-bromophenyl)propan-2-yl)carbamate

[1114] ##STR00915##

[1115] Boc-anhydride (278 μl, 1.197 mmol) and triethylamine (306 μl, 2.195 mmol) were added to a solution of 2-(4-bromophenyl)propan-2-amine.HCl (250 mg, 0.998 mmol) in DCM (10 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with 1 M HCl (aq.) (5 mL), and brine (5 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to afford the title compound (332 mg, 101%) as a colourless oil which solidified on standing. 1H NMR (Chloroform-d) δ: 7.47-7.38 (m, 2H), 7.31-7.22 (m, 2H), 4.91 (s, 1H), 1.59 (s, 6H), 1.52 (d, 9H).

Preparation 250: tert-butyl (2-(4-cyanophenyl)propan-2-yl)carbamate

[1116] ##STR00916##

[1117] Zinc cyanide (99 mg, 0.845 mmol) and Pd(PPh.sub.3).sub.4 (122 mg, 0.106 mmol) were added to a solution of tert-butyl (2-(4-bromophenyl)propan-2-yl)carbamate (332 mg, 1.057 mmol) in DMF (1 mL). The reaction mixture was heated at 100° C. overnight. The mixture was cooled to room temperature, and partitioned between water (2 mL) and Et.sub.2O (3 mL). The crude product was extracted with Et.sub.2O (2×3 mL) and the combined organic extracts were dried (MgSO.sub.4) and concentrated in vacuo to give an oil. Purification by chromatography (SiO.sub.2, 0-50% EtOAc in iso-hexane) gave the title compound. LC-MS: [M+Na].sup.+=283

Preparation 251: 4-(2-aminopropan-2-yl)benzonitrile

[1118] ##STR00917##

[1119] tert-Butyl (2-(4-cyanophenyl)propan-2-yl)carbamate (100 mg, 0.384 mmol) was stirred in formic acid (1 mL) for 3 h at room temperature. The reaction mixture was added dropwise to a stirred solution of sodium carbonate (3.0 g, 28.3 mmol) in water (10 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL) and the combined organic phases were washed with brine (10 mL), dried (Na.sub.2SO.sub.4) and concentrated to dryness in vacuo to give the title compound (57 mg, 91%) as a colourless oil. The product was used without further purification in the next step. .sup.1H NMR (CDCl.sub.3) δ: 7.68-7.62 (m, 4H), 1.56-1.50 (m, 6H).

Preparation 252: tert-butyl 6-bromo-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

[1120] ##STR00918##

[1121] Boc-anhydride (0.360 mL, 1.550 mmol) was added to a solution of 6-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline (292 mg, 1.291 mmol) in DCM (5 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the crude product was purified by chromatography (12 g column, 0-20% EtOAc in iso-hexane) to afford the title compound (307 mg, 67%) as a colourless oil. LC-MS: [M-.sup.tBu].sup.+=270.

Preparation 253: tert-butyl 6-cyano-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

[1122] ##STR00919##

[1123] A solution of tert-butyl 6-bromo-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (85 mg, 0.261 mmol) and zinc cyanide (32 mg, 0.274 mmol) in DMA (2 mL) was degassed with nitrogen for 10 min. and Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol) was added in 4 portions. The reaction mixture was then heated to 100° C. (block temp) under nitrogen for 2 h and was allowed to cool to room temperature. The mixture was filtered over celite eluting with EtOAc (50 mL). The filtrate was washed with sat. NaHCO.sub.3 (aq.) (2×10 mL), water (2×10 mL) and brine (2×10 mL). The organic layer was then dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-20% EtOAc in iso-hexane) to afford the title compound (56 mg, 78%) as a colourless solid. LC-MS: [M-.sup.tBu].sup.+=217.

Preparation 254: 1-methyl-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile

[1124] ##STR00920##

[1125] tert-Butyl 6-cyano-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (56 mg, 0.206 mmol) was dissolved in DCM (2.6 mL) and TFA (317 μl, 4.11 mmol) was added at 0° C. The reaction was allowed to warm to room temperature and stirred for 1.5 h. The reaction mixture was loaded onto a column of SCX (2 g) in MeOH. The column was washed with MeOH and the product was then eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to afford the title compound (32 mg, 86%) as a colourless oil. The product was used without further purification in the next step. LC-MS: [M+H].sup.+=173 (poor chromophore).

Preparation 255: 2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol

[1126] ##STR00921##

[1127] A solution of 2,2,2-trifluoro-1-(1-methylene-4,5-dihydro-1H-benzo[d]azepin-3(2H)-yl)ethanone (preparation 153) (200 mg, 0.784 mmol) in MeOH (9.5 mL):DCM (10 mL) was cooled to −78° C., then treated with ozone until the solution turned blue (about 15 min.). Nitrogen was bubbled through until disappearance of the blue colour, then NaBH.sub.4 (89 mg, 2.351 mmol) was added and the resulting solution was stirred for 3 h while warming to 20° C. The reaction mixture was concentrated to give 2,2,2-trifluoro-1-(1-hydroxy-4,5-dihydro-1H-benzo[d]azepin-3(2H)-yl)ethanone (100 mg, 49% yield) as a oil, which was used without further characterization and purification in the next step. The crude product was dissolved in MeOH (3.3 mL) was treated with 2 M NaOH (aq.) (0.784 mL, 1.567 mmol), and stirred at rt for 4 h. Acetic acid (0.135 mL, 2.351 mmol) was added and and the mixture was diluted with MeOH (4 mL), then loaded onto a column of SCX (2 g) The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to afford 2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol (38 mg, 27% yield) as a colourless solid. LC-MS: [M+H].sup.+=164.

Preparation 256: tert-butyl 7-amino-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate

[1128] ##STR00922##

[1129] A mixture of tert-butyl 7-nitro-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (1.94 g, 6.64 mmol) and Pd—C(0.127 g, 0.119 mmol) in EtOH (18 mL):THF (4 mL) was hydrogenated at 2 Bar for 16 h. The resulting mixture was filtered through celite, washed with EtOH (2×10 mL) and then concentrated to give the title compound as a yellow oil (1.74 g, 90%). LC-MS [M-.sup.tBu+H].sup.+=207

Preparation 257: tert-butyl 7-bromo-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate

[1130] ##STR00923##

[1131] A solution of tert-butyl 7-amino-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (1.742 g, 6.64 mmol) in MeCN (33 ml) was added dropwise to a mixture of copper (II) bromide (1.780 g, 7.97 mmol) and butyl nitrite (1.164 ml, 9.96 mmol) in MeCN (33 ml) at 60° C. The reaction mixture was then heated at 80° C. for 2 h then left to stir at room temperature overnight. Water (50 mL) was added and the crude product was extracted with EtOAc (3×50 mL). The combined organic extracts were dried (MgSO.sub.4) and filtered. The filtrate was concentrated in vacuo to dryness to give the crude product as a brown oil, which was purified by chromatography (SiO.sub.2, 24 g column, 0-20% of EtOAc in iso-hexane) to afford the title compound (450 mg, 19%) as a colourless oil. LC-MS [M-.sup.tBu+H].sup.+=270 (for .sup.79Br).

Preparation 258: tert-butyl 7-cyano-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate

[1132] ##STR00924##

[1133] A solution of tert-butyl 7-bromo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (440 mg, 1.349 mmol) and zinc cyanide (166 mg, 1.416 mmol) in DMA (10 mL) was degassed for 10 min.

[1134] with nitrogen then Pd(PPh.sub.3).sub.4 (156 mg, 0.135 mmol) was added and the reaction mixture was then heated to 100° C. under nitrogen for 2 h. The reaction mixture was allowed to cool to room temperature and then filtered over celite eluting with EtOAc (50 mL). The filtrate was washed with sat. NaHCO.sub.3 (aq.) (2×10 mL), water (2×10 mL) and brine (2×10 mL). The organic layer was then dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-20% EtOAc in iso-hexane) to afford the title compound (240 mg, 65%) as a colourless oil which solidified on standing to give a colourless solid. LC-MS: [M-.sup.tBu+H].sup.+=217.

Preparation 259: 2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-carbonitrile

[1135] ##STR00925##

[1136] tert-Butyl 7-cyano-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (50 mg, 0.184 mmol) was dissolved in DCM (2.4 mL) and TFA (283 μl, 3.67 mmol) was added at 0° C. The reaction was allowed to warm to room temperature and stirred for 1.5 h. The crude reaction mixture was loaded onto a column of SCX (2 g) in MeOH. The column was washed with MeOH and the product was eluted with 0.7 M ammonia in MeOH. The resulting solution was concentrated in vacuo to give the title compound (27 mg, 81%) as a colourless oil. LC-MS: [M+H].sup.+=173.

Preparation 260: tert-butyl (2-oxo-1-phenylpropyl)carbamate

[1137] ##STR00926##

[1138] Triethylamine (580 μL, 4.16 mmol) was added to a solution of 1-amino-1-phenylpropan-2-one hydrochloride (350 mg, 1.885 mmol) and Boc-anhydride (462 mg, 2.074 mmol) in THF (14 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between sat. NaHCO.sub.3 (aq.) (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL) and the combined organic extracts were washed with water (50 mL), brine (50 mL), dried (MgSO.sub.4) filtered and concentrated in vacuo to give the crude product (470 mg). Purification by chromatography (SiO.sub.2, 40 g column, 0-100% EtOAc in iso-hexane) afforded the title compound (183 mg, 38%) as a colourless oil, which solidified on standing. .sup.1H NMR (DMSO-d6) δ: 7.60 (1H, d), 7.42-7.23 (5H, m), 5.25 (1H, d), 2.03 (3H, s), 1.38 (9H, s).

Preparation 261: tert-butyl (2-hydroxy-1-phenylpropyl)carbamate

[1139] ##STR00927##

[1140] Sodium borohydride (31.9 mg, 0.825 mmol) was added to a solution of tert-butyl (2-oxo-1-phenylpropyl)carbamate (210 mg, 0.825 mmol) in MeOH (3 mL) at 0° C. and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried (MgSO.sub.4), filtered and concentrated in vacuo to give the crude product as a white solid (200 mg). The crude product was purified by chromatography (SiO.sub.2, 40 g column, 0-10% THF in DCM) to afford the title compound (172 mg, 80%) as a white solid. The product was obtained as a 84:16 mixture of cis- and trans-isomers as determined by .sup.1H NMR and was used without further purification in the next step. LC-MS: [M-.sup.tBu+H].sup.+=196.

Preparation 262: 1-amino-1-phenylpropan-2-ol

[1141] ##STR00928##

[1142] TFA (1.3 mL, 16.70 mmol) was added to a stirred solution of tert-butyl (2-hydroxy-1-phenylpropyl)carbamate (0.170 g, 0.338 mmol) in DCM (5 mL) and the reaction mixture was stirred at room temperature for 2 h. The crude reaction mixture was loaded onto a column packed with SCX. The column was washed with MeOH (3 column volumes), and the product eluted with 1% NH.sub.3 in MeOH (3 column volumes). The resulting solution was concentrated in vacuo to give the title compound (104 mg, 95%) as an oil. The product was obtained as a 10:1 mixture of cis- and trans-isomers as determined by .sup.1H NMR and was used without further purification in the next step. LC-MS: [M+H].sup.+=152.

Preparation 263: methyl (S)-2-amino-3-(4-fluorophenyl)propanoate hydrochloride

[1143] ##STR00929##

[1144] Methanol (10 mL) was stirred and cooled in an ice-bath and treated dropwise with acetyl chloride (1.8 mL, 25.3 mmol). The solution was stirred for 10 min., treated with (S)-2-((tert-butoxycarbonyl)amino)-3-(4-fluorophenyl)propanoic acid (730 mg, 2.58 mmol) and stirred at room temperature overnight. The solution was evaporated to give the title compound (610 mg, 99%) as a yellow solid. LC-MS: [M+H].sup.+=198.

Preparation 264: methyl (S)-2-((ethoxycarbonyl)amino)-3-(4-fluorophenyl)propanoate

[1145] ##STR00930##

[1146] A stirred suspension of (S)-methyl 2-amino-3-(4-fluorophenyl)propanoate.HCl (610 mg, 2.61 mmol) in DCM (10 mL) and pyridine (439 μl, 5.43 mmol) was cooled in an ice-bath and treated dropwise with a solution of ethyl chloroformate (266 μl, 2.77 mmol) in DCM (1 mL). The resulting solution was allowed to warm to room temperature and the resulting yellow suspension was stirred for 30 min. The suspension was partitioned between water (20 mL) and ethyl acetate (20 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic extracts were washed with water (20 mL), were dried (MgSO.sub.4) and evaporated to give a yellow oil (683 mg) which was purified by chromatography (SiO.sub.2, 12 g column, 0-25% EtOAc in iso-hexane) to afford the title compound (648 mg, 91%) as a colourless oil. LC-MS: [M+H].sup.+=270.

Preparation 265: 2-ethyl 3-methyl (S)-7-fluoro-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate

[1147] ##STR00931##

[1148] A stirred suspension of (S)-methyl 2-((ethoxycarbonyl)amino)-3-(4-fluorophenyl)propanoate (646 mg, 2.399 mmol) and paraformaldehde (76 mg, 2.52 mmol) in acetic acid (3 mL) was treated dropwise with concentrated sulfuric acid (1 mL) and stirred overnight to give a clear solution. The mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with sat. NaHCO.sub.3 (aq.) (2×20 mL) followed by brine (20 mL), were dried (MgSO.sub.4) and evaporated. The residue was purified by chromatography (SiO.sub.2, 12 g column, 0-25% EtOAc in iso-hexane) to afford the title compound (492 mg, 72%) as colourless oil. LC-MS: [M+H].sup.+=282.

(note: the product was also analysed by .sup.1H NMR, which showed a mixture of tetrahydroquinoline conformations)

Preparation 266: (S)-7-fluoro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride

[1149] ##STR00932##

[1150] A mixture of (S)-2-ethyl 3-methyl 7-fluoro-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (487 mg, 1.731 mmol) and 5 N hydrochloric acid (8 mL) was stirred and heated under reflux for 24 h and then stirred at room temperature for 2 days to give a white solid suspended in a yellow solution. The mixture was refluxed for a further 6 h to give a clear solution, then a white precipitate. The mixture was allowed to cool and filtered. The solid was washed with water (5 mL) and dried to give the title compound (204 mg, 50%) as a cream solid. Further product (170 mg, 38%) was obtained in 90% purity by concentrating the filtrate under vacuum. Both products were combined and used without further purification in the next step. LC-MS: [M+H].sup.+=196.

Preparation 267: methyl (S)-7-fluoro-1,2,3,4-tetrahydroisoquinoline-3-carboxylate

[1151] ##STR00933##

[1152] Methanol (10 mL) was stirred and cooled in an ice-bath and treated dropwise with acetyl chloride (1 mL, 14.06 mmol). The mixture was stirred for 10 min., treated with (S)-7-fluoro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.HCl (374 mg, 1.615 mmol) and stirred overnight to give a clear solution. The solution was evaporated and the residue was partitioned between ether (10 mL) and sat. NaHCO.sub.3 (aq.) (10 ml). The layers were separated and the aqueous layer was extracted with ether (2×10 mL). The combined organic extracts were washed with brine (10 mL), were dried (Na.sub.2SO.sub.4) and evaporated to give the title compound (313 mg, 88%) as a brown oil. LC-MS: [M+H].sup.+=210.

Preparation 268: 2-(tert-butyl) 3-methyl (S)-7-fluoro-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate

[1153] ##STR00934##

[1154] A stirred solution of (S)-methyl 7-fluoro-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (300 mg, 1.434 mmol) and triethylamine (0.440 ml, 3.15 mmol) in THF (5 mL) was treated with Boc-anhydride (0.366 mL, 1.577 mmol) and stirred at room temperature for 3 days. The solution was evaporated and the residue was taken up in ether (20 mL), washed with 1 M aqueous potassium hydrogen sulphate solution (10 mL) followed by saturated aqueous sodium bicarbonate solution (10 mL), brine (10 mL), then dried (MgSO.sub.4) and evaporated. The residue was purified by chromatography (SiO.sub.2, 12 g column, 0-25% EtOAc in iso-hexane) to afford the title compound (426 mg, 94%) as a colourless oil. LC-MS: [M-CO.sub.2tBu+H].sup.+=210.

Preparation 269: tert-butyl (S)-7-fluoro-3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[1155] ##STR00935##

[1156] A stirred solution of (S)-2-tert-butyl 3-methyl 7-fluoro-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (148 mg, 0.478 mmol) in THF (3 mL) was treated dropwise with a 2 M solution of lithium borohydride in THF (0.48 mL, 0.960 mmol) and the mixture was stirred at room temperature overnight. The mixture was quenched by the cautious addition of water (10 mL) and extracted with ether (3×10 mL). The combined organic extracts were washed with brine (10 mL), were dried (Na.sub.2SO.sub.4) and evaporated. The residue was purified by chromatography (SiO.sub.2, 4 g column, 0-50% EtOAc in iso-hexane) to afford the title compound (116 mg, 83%) as a colourless oil. LC-MS [M-CO.sub.2tBu+H].sup.+=182.

Preparation 270: (S)-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-3-yl)methanol hydrochloride

[1157] ##STR00936##

[1158] A stirred solution of (S)-tert-butyl 7-fluoro-3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (108 mg, 0.384 mmol) in ether (2 mL) was treated with a 2 M solution of hydrogen chloride solution in ether (2 mL, 4.00 mmol) and the mixture was stirred for 1 h. Further 2 M solution of hydrogen chloride solution in ether (2 mL, 4.00 mmol) was added and the mixture was stirred at room temperature for 4 h. The resulting white suspension was concentrated under vacuum to afford the title compound (127 mg, 76%) as a white solid. LC-MS: [M+H].sup.+=182.

Preparation 271: 3-(2-aminopropan-2-yl)benzonitrile

[1159] ##STR00937##

[1160] Prepared from 2-(3-bromophenyl)propan-2-amine using a similar procedure to preparations 249, 250 and 251. .sup.1H NMR (CDCl.sub.3) δ: 7.78 (1H, dd), 7.70 (1H, ddd), 7.43 (1H, ddd), 7.36 (1H, dd), 1.61 (2H, s (br)), 1.42 (6H, s).

Preparation 272: tert-butyl 7-(hydroxymethyl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate

[1161] ##STR00938##

[1162] A stirred solution of tert-butyl 7-bromo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (350 mg, 1.073 mmol) in THF (10 mL) was treated under nitrogen dropwise over 15 min. at −70 to −65° C. with tert-butyllithium (1.7 M in pentane, 1.39 mL, 2.360 mmol) and stirred at −70° C. for 30 min. to give a dark red solution. The solution was treated dropwise with morpholine-4-carbaldehyde (236 μl, 2.360 mmol) and stirred at room temperature for 1 h. The resulting yellow solution was quenched by the cautious addition of sat. NH.sub.4Cl (aq.) (50 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO.sub.4) and evaporated to give tert-butyl 7-formyl-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate as a colourless oil which was used without further purification in the next step. NaBH.sub.4 (57 mg, 1.500 mmol) was added to a solution of tert-butyl 7-formyl-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (138 mg, 0.500 mmol) in 2M NaOH (500 μl, 1.000 mmol) and MeOH (2 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated, and then diluted with EtOAc (10 mL) and water (10 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×15 mL). The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-50% EtOAc in iso-hexane) to afford the title compound (53 mg, 36%) as a colourless oil. .sup.1H NMR (DMSO-d6) δ: 7.07 (3H, q), 5.09 (1H, t), 4.43 (2H, d), 3.47-3.41 (4H, m), 2.85-2.78 (4H, m), 1.42 (9H, s). LC-MS: [M+Na].sup.+=300 (very weak chromophore).

Preparation 273: (2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)methanol

[1163] ##STR00939##

[1164] tert-Butyl 7-(hydroxymethyl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (53 mg, 0.191 mmol) was dissolved in DCM (2.5 mL), cooled in an ice bath, and TFA (294 μl, 3.82 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 1.5 h. The crude reaction mixture was loaded onto a column of SCX (2 g) in MeOH. The column was washed with MeOH and the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to afford the title compound (45 mg, 133%) as a colourless oil. .sup.1H NMR (CDCl.sub.3) δ: 7.19-7.07 (3H, m), 4.65 (2H, s), 3.05-2.95 (9H, m). (exchangeable proton was not observed)

Preparation 274: 7-(((tert-butyldimethylsilyl)oxy)methyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[1165] ##STR00940##

[1166] Imidazole (52 mg, 0.762 mmol) and tert-butylchlorodimethylsilane (42 mg, 0.279 mmol) were added to a solution of (2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)methanol (45 mg, 0.254 mmol) in DCM (2 mL) at 0° C. The reaction mixture was stirred overnight at room temperature, then diluted with ethyl acetate (5 mL) and water (5 mL). The layers were separated and the organic layer was washed with brine (5 mL), dried (MgSO.sub.4), evaporated in vacuo to give the title compound (49 mg, 66%) as a pale yellow oil. .sup.1H NMR (CDCl.sub.3) δ: 7.12-7.02 (3H, m), 4.69 (2H, s), 3.02-2.90 (9H, m), 0.94 (9H, s), 0.10 (6H, s).

Preparation 275: (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide

[1167] ##STR00941##

[1168] 2-methylpropane-2-sulfinamide (200 mg, 1.650 mmol) followed by copper (II) sulfate (527 mg, 3.30 mmol) were added to a solution of 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (0.346 ml, 1.815 mmol) in DCM (5 mL) and the mixture was stirred at room temperature overnight under nitrogen. The reaction mixture was filtered, washing through with DCM. The filtrate was evaporated and the crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-40% EtOAC in iso-hexane) to afford the title compound (325 mg, 70%) as a colourless oil which solidified on standing. .sup.1H NMR (CDCl.sub.3) δ: 8.06 (1H, t), 4.54 (2H, d), 1.21 (9H, s), 0.92 (9H, s), 0.10 (6H, s). LC-MS: [M+H].sup.+=278.

Preparation 276: (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide

[1169] ##STR00942##

[1170] Prepared using a similar procedure to preparation 275. .sup.1H NMR (CDCl.sub.3) δ: 8.05 (1H, t), 4.54 (2H, d), 1.20 (9H, s), 0.91 (9H, s), 0.09 (6H, s).

Preparation 277: N-(2-((tert-butyldimethylsilyl)oxy)-1-(imidazo[1,2-a]pyridin-8-yl)ethyl)-2-methylpropane-2-sulfinamide

[1171] ##STR00943##

[1172] n-BuLi (2.5 M in hexanes, 0.216 mL, 0.541 mmol) was added dropwise to a solution of 8-bromoimidazo[1,2-a]pyridine (97 mg, 0.491 mmol) in dry THF (2 mL) at −78° C. and the mixture was stirred for 1 h before (E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide (150 mg, 0.541 mmol) in THF (0.5 mL) was added. The reaction mixture was stirred at −78° C. for 1 h, then warmed to rt and stirred for 1 h. The reaction was quenched with sat. NH.sub.4Cl (aq.) (30 mL) and left to stand overnight. The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic extracts were washed with brine (30 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to give a yellow oil. The residue was purified by chromatography (SiO.sub.2, 12 g column, 0 to 6% of MeOH in DCM) to afford the title compound (82 mg, 38%) as a colourless solid. LCMS: [M+H].sup.+=396.

Preparation 278: 2-amino-2-(imidazo[1,2-a]pyridin-8-yl)ethan-1-ol (1427-17)

[1173] ##STR00944##

[1174] HCl (4 M solution in dioxane, 0.19 mL, 0.748 mmol) was added to a stirred solution of N-(2-((tert-butyldimethylsilyl)oxy)-1-(imidazo[1,2-a]pyridin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (82 mg, 0.187 mmol) in MeOH (1 mL) at 0° C. and the reaction was stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo to give the title compound (45 mg, 102%). The product was used without further purification in the next step. LCMS: [M+H].sup.+=178.

Preparation 278: N-(2-((tert-butyldimethylsilyl)oxy)-1-(1,3-dihydroisobenzofuran-4-yl)ethyl)-2-methylpropane-2-sulfinamide

[1175] ##STR00945##

[1176] Prepared using a similar procedure to preparation 277. LCMS: [M+H].sup.+=398.

Preparation 280: 2-amino-2-(1,3-dihydroisobenzofuran-4-yl)ethan-1-ol

[1177] ##STR00946##

[1178] Prepared using a similar procedure to preparation 278. LCMS: [M+H].sup.+=180.

Preparation 281: tert-butyl (S)-(1-(3-bromophenyl)-2-hydroxyethyl)carbamate

[1179] ##STR00947##

[1180] DIPEA (0.207 mL, 1.188 mmol) and Boc-Anhydride (0.138 mL, 0.594 mmol) were added to a suspension of (S)-2-amino-2-(3-bromophenyl)ethanol.HCl (150 mg, 0.594 mmol) in DCM (2 mL) and the reaction was stirred at rt overnight. The solution was washed with water (10 mL) and the aqueous layer was extracted with DCM (30 mL). The combined organic extracts were dried (MgSO.sub.4) and concentrated in vacuo. The crude product was adsorbed onto silica and purified by chromatography (SiO.sub.2, 12 g column, 0-70% EtOAc in iso-hexane) to afford the title compound (164 mg, 86%) as an off white solid. LCMS: [M+Na].sup.+=338.

Preparation 282: tert-butyl (S)-(1-(3-(furan-2-yl)phenyl)-2-hydroxyethyl)carbamate

[1181] ##STR00948##

[1182] A mixture of (S)-tert-butyl (1-(3-bromophenyl)-2-hydroxyethyl)carbamate (50 mg, 0.158 mmol) and furan-2-ylboronic acid (35 mg, 0.316 mmol) in 1,4-dioxane (1 mL) and sodium carbonate (2 M aq.) (0.237 mL, 0.474 mmol) was degassed with nitrogen for 10 min. Pd(PPh.sub.3).sub.4 (18.27 mg, 0.016 mmol) was added and the mixture degassed for a further 5 min. The mixture was heated to 90° C. for 6 h, then cooled to room temperature and diluted with water (20 mL) and EtOAc (20 mL). The phases were separated and the aqueous was extracted with EtOAc (2×15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO.sub.4) and concentrated. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-40% EtOAc in iso-hexanes) to afford the title compound (38 mg, 78%) as a yellow oil which solidified on standing to give a yellow solid. LCMS: [M+Na].sup.+=326.

Preparation 283: tert-butyl ((1S)-2-hydroxy-1-(3-(tetrahydrofuran-2-yl)phenyl)ethyl)carbamate

[1183] ##STR00949##

[1184] A mixture of (S)-tert-butyl (1-(3-(furan-2-yl)phenyl)-2-hydroxyethyl)carbamate (18 mg, 0.059 mmol), and Pd on carbon (3R38H) (1.5 mg, 0.423 μmol) or Pd on alumina (5R325) (1.5 mg, 0.705 μmol) in ethanol (2 ml, 34.3 mmol) was separately hydrogenated at room temperature and 1 bar overnight. The reaction mixtures were then filtered through celite and concentrated to obtain an off white solid. The residues was redissolved in ethanol (2 mL) and Pd on carbon (3R38H) (3 mg, 2.82 μmol) or Pd on alumina (5R325)) (1.5 mg, 0.705 μmol) was added and the mixtures hydrogenated separately at room temperature and 1.5 bar overnight. The suspensions were filtered through celite and the filter cake washed with EtOH (10 mL). The filtrate was concentrated to give the title compound as a colourless oil. palladium on carbon (3R38H) (16 mg, 83%, 95% purity (NMR)); Pd on alumina (5R325): (19 mg, 94%, 90% purity (NMR)). .sup.1H NMR (CDCl.sub.3) δ: 7.34-7.29 (1H, m), 7.26-7.23 (2H, m), 7.18 (1H, d), 5.22 (1H, s), 4.87 (1H, td), 4.77 (1H, s), 4.14-4.04 (1H, m), 3.99-3.88 (1H, m), 3.83 (2H, d), 2.39-2.26 (1H, m), 2.09-1.93 (2H, m), 1.85-1.71 (1H, m), 1.43 (9H, s). (exchangeable OH was not observed).

Preparation 284: (2S)-2-amino-2-(3-(tetrahydrofuran-2-yl)phenyl)ethan-1-ol

[1185] ##STR00950##

[1186] tert-Butyl ((1S)-2-hydroxy-1-(3-(tetrahydrofuran-2-yl)phenyl)ethyl)carbamate (19 mg, 0.062 mmol) was dissolved in DCM (1 mL) and TFA (0.080 mL, 1.041 mmol) was added at room temperature and the mixture was stirred for 3 h. The crude reaction mixture was loaded onto a column of SCX (1.5 g) in MeOH. The column was washed with MeOH and the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to afford the title compound (12 mg, 87%) as a colourless oil. LCMS: [M+H].sup.+=208.

Preparation 285 (S)—N—((S,E)-2-(benzyloxy)propylidene)-2-methylpropane-2-sulfinamide

[1187] ##STR00951##

[1188] (S)-2-Methylpropane-2-sulfinamide (1.332 g, 10.99 mmol) was added to a solution of (S)-2-(benzyloxy)propanal (1.823 g, 9.99 mmol) and titanium (IV) isopropoxide (7.32 mL, 24.98 mmol) in THF (20 mL) and the mixture was stirred at room temperature overnight. The mixture was poured into brine (50 mL) and filtered through a pad of celite, eluting with EtOAc (200 mL). The filtrate was washed with brine (100 mL), dried (MgSO.sub.4) and concentrated. The crude product was purified by chromatography (SiO.sub.2, 24 g column, 0-50% EtOAc in iso-hexane) to afford the title compound (1.36 g, 48%) as a colourless oil. .sup.1H NMR (CDCl.sub.3) δ: 8.07 (1H, d), 7.38-7.32 (4H, m), 7.32-7.28 (1H, m), 4.65 (1H, d), 4.48 (1H, d), 4.39-4.28 (1H, m), 1.41 (3H, d), 1.23 (9H, s) (note: the product was obtained as a 10:1 mixture of stereoisomers).

Preparation 286: (S)—N-((1S,2S)-2-(benzyloxy)-1-(3-methoxyphenyl)propyl)-2-methylpropane-2-sulfinamide

[1189] ##STR00952##

[1190] 1-Bromo-3-methoxybenzene (1.421 mL, 11.22 mmol) was added to magnesium (0.300 g, 12.34 mmol) in diethyl ether (6 mL) and the mixture was heated to reflux for 1 h. 1,2-dibromoethane (2 drops) was added and the mixture was refluxed for 1 h then cooled to room temperature. Separately, (S,E)-N—((S)-2-(benzyloxy)propylidene)-2-methylpropane-2-sulfinamide (0.5 g, 1.870 mmol) in THF (9.4 mL) was cooled to −78° C. 3 mL of the Grignard reagent generated above was added dropwise and was stirred for 2 h. A further 1 mL of Grignard solution was added dropwise and the mixture stirred for 1 h. The reaction was quenched by addition of sat. NH.sub.4Cl (aq.) (5 mL) and allowed to warm to room temperature overnight. Brine (15 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO.sub.4) and concentrated. The crude product was purified by chromatography (SiO.sub.2, 24 g column, 0-50% EtOAc in iso-hexane) to afford the title compound (230 mg, 30%) as a colourless oil. .sup.1H NMR (CDCl.sub.3) δ: 7.43-7.30 (5H, m), 7.28-7.23 (1H, m), 6.95-6.88 (1H, m), 6.88-6.83 (2H, m), 4.72 (1H, d), 4.51 (1H, s (br)), 4.44 (1H, d), 4.28 (1H, dd), 3.81 (3H, s), 3.72-3.61 (1H, m), 1.16 (9H, s), 1.08 (3H, d) (note: A further mixed fraction (200 mg) containing a 1.1:1 mixture of diastereoisomers was also obtained).

Preparation 287: (S)—N-((1S,2S)-2-(benzyloxy)-1-(3-ethylphenyl)propyl)-2-methylpropane-2-sulfinamide

[1191] ##STR00953##

[1192] 1-Bromo-3-ethylbenzene (2.076 g, 11.22 mmol) was added to magnesium (277 mg, 11.41 mmol) in Et.sub.2O (3.7 mL). The mixture was heated to reflux for 1 h, then 1,2-dibromoethane (2 drops) was added and the mixture was refluxed again. After initiation occurred the mixture was heated for 1 h then allowed to cool to room temperature. Separately, (S,E)-N—((S)-2-(benzyloxy)propylidene)-2-methylpropane-2-sulfinamide (556 mg, 1.87 mmol) in toluene (9.4 mL) was cooled to −78° C. 2.5 mL of the Grignard reagent generated above was added dropwise and the mixture was stirred for 2 h. The reaction was quenched by addition of sat. NH.sub.4Cl (aq.) (5 mL) and allowed to warm to room temperature. Brine (25 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO.sub.4) and concentrated. The crude product was purified by chromatography (SiO.sub.2, 24 g column, 0-50% EtOAc in isohexane) to afford the title compound (482 mg, 64.2%) as a colourless oil. .sup.1H NMR (CDCl.sub.3) δ: 7.37-7.21 (7H, m), 7.16-7.07 (3H, m), 4.70 (1H, d), 4.50 (1H, s), 4.42 (1H, d), 4.26 (1H, dd), 3.71-3.59 (1H, m), 2.63 (2H, q), 1.22 (2H, t), 1.13 (9H, s), 1.05 (3H, d).

Preparations 288-290

[1193] Prepared using an analogous procedure to Preparation 287, from (S)—N—((S,E)-2-(benzyloxy)propylidene)-2-methylpropane-2-sulfinamide (Preparation 285) and the corresponding aryl bromide:

TABLE-US-00018 Preparation Structure Name .sup.1H NMR (400 MHz) 288 [00954] (S)-N-((1S,2S)-2- (benzyloxy)-1-(m- tolyl)propyl)-2- methylpropane-2- sulfinamide .sup.1H NMR (DMSO-d6) δ: 7.42- 7.29 (5H, m), 7.34-7.16 (1H, m), 7.19-7.06 (3H, m), 4.65 (1H, d), 4.63 (1H, s (br)), 4.49 (1H, d), 4.14 (1H, dd), 3.76-3.64 (1H, m), 2.29 (3H, s), 1.04 (9H, s), 0.96 (3H, d) 289 [00955] (S)-N-((1S,2S)-2- (benzyloxy)-1-(3- ethoxyphenyl) propyl)-2- methylpropane-2- sulfinamide .sup.1H NMR (DMSO-d6) δ: 7.43- 7.28 (5H, m), 7.33-7.17 (1H, m), 6.92-6.79 (3H, m), 4.67 (1H, d), 4.64 (1H, d), 4.49 (1H, d), 4.16 (1H, dd), 4.06-3.92 (2H, m), 3.77- 3.65 (1H, m), 1.32 (3H, t), 1.05 (9H, s), 0.97 (3H, d). 290 [00956] (S)-N-((1S,2S)-2- (benzyloxy)-1-(3- ethoxy-5- fluorophenyl) propyl)- 2-methylpropane- 2-sulfinamide .sup.1H NMR (DMSO-d6) δ: 7.43- 7.26 (5H, m), 6.79-6.66 (3H,m), 4.78 (1H, d), 4.61 (1H, d), 4.48 (1H, d), 4.21 (1H, dd), 4.08-3.90 (2H, m), 3.79-3.61 (1H, m), 1.30 (3H, t), 1.05 (9H, s), 0.99 (3H, d).

Preparation 291: (1S,2S)-1-amino-1-(3-methoxyphenyl)propan-2-ol hydrochloride

[1194] ##STR00957##

[1195] HCl (4 M in 1,4-dioxane) (0.8 mL, 3.20 mmol) was added to a solution of (S)—N-((1S,2S)-2-(benzyloxy)-1-(3-methoxyphenyl)propyl)-2-methylpropane-2-sulfinamide (230 mg, 0.612 mmol) in methanol (6 mL, 148 mmol) and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue was stirred with diethyl ether (5 mL). The resulting white solid was collected by filtration to give (1S,2S)-2-(benzyloxy)-1-(3-methoxyphenyl)propan-1-amine hydrochloride. The crude solid was dissolved in methanol (6 mL, 148 mmol) and Pd/C (10%, Type 39) (50 mg, 0.470 mmol) followed by HCl (4 M in 1,4-dioxane) (0.8 mL, 3.20 mmol) were added. The mixture was stirred under an atmosphere of hydrogen (5 bar) for 2 h., then filtered through celite, eluting with methanol. The filtrate was concentrated and triturated with diethyl ether. The resulting solid was collected by filtration to give the title compound (94 mg, 67% yield) as a tan solid. .sup.1H NMR (DMSO-d6) δ: 8.33 (3H, s (br)), 7.34 (1H, dd), 7.16-7.07 (1H, m), 7.05 (1H, d), 6.96 (1H, ddd), 5.64 (1H, s), 3.93-3.88 (2H, m), 3.77 (3H, s), 0.94 (3H, d).

Preparations 292-295

[1196] Prepared using an analogous procedure to Preparation 291, from the corresponding protected sulfoximine (preparation 287-290):

TABLE-US-00019 Preparation Structure Name .sup.1H NMR (400 MHz) 292 [00958] (1S,2S)-1-amino-1- (3- ethylphenyl)propan- 2-ol hydrochloride .sup.1H NMR (DMSO-d6) δ: 8.33 (3H, s (br)), 7.38-7.27 (3H, m), 7.27-7.21 (1H, m), 5.64 (1H, d), 3.91 (2H, d), 2.62 (2H, q), 1.20 (3H, t), 0.92 (3H, d). 293 [00959] (1S,2S)-1-amino-1- (m-tolyl)propan-2- ol hydrochloride .sup.1H NMR (DMSO-d6) δ: 8.37 (3H, s (br)), 7.36-7.26 (3H, m), 7.24-7.17 (1H, m), 5.65 (1H, d), 4.00-3.83 (2H, m), 2.32 (3H, s), 0.92 (3H, d). 294 [00960] (1S,2S)-1-amino-1- (3- ethoxyphenyl)- propan-2-ol hydrochloride .sup.1H NMR (DMSO-d6) δ: 8.43 (3H, s (br)), 7.31 (1H, dd), 7.19-7.13 (1H, m), 7.04 (1H, d), 6.93 (1H, dd), 5.66 (1H, d), 4.04 (2H, q), 4.00- 3.83 (2H, m), 1.33 (3H, t), 0.92 (3H, d). 295 [00961] (1S,2S)-1-amino-1- (3-ethoxy-5- fluorophenyl)- propan-2-ol hydrochloride .sup.1H NMR (DMSO-d6) δ: 8.48 (3H, s (br)), 7.46-7.27 (5H, m), 7.05-6.95 (2H, m), 6.87 (1H, ddd), 4.64 (1H, d), 4.53 (1H, d), 4.25-4.15 (1H, m), 4.05 (2H, q), 3.97-3.84 (1H, m), 1.33 (3H, t), 1.01 (3H, d).

Preparation 296: (S)—N—((S)-2-((tert-butyldimethylsilyl)oxy)-1-(3-(1,1-difluoroethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[1197] ##STR00962##

[1198] nBuLi (2.5 M in hexanes) (1.600 ml, 4.00 mmol) was added to a solution of 1-bromo-3-(1,1-difluoroethyl)benzene (884 mg, 4.00 mmol) in Et.sub.2O (1.6 ml, 15.39 mmol) at −78° C. The reaction was stirred for 1 h, before being added dropwise to a solution of (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide (555 mg, 2 mmol) in Et.sub.2O (10 ml, 96 mmol) at −78° C. The reaction was stirred for 1 h then quenched with NH.sub.4Cl (5 mL) and allow to warm to room temperature. The phases were separated and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO.sub.4) and concentrated. The crude product was purified by chromatography (SiO.sub.2, 40 g column, 0-50% EtOAc in isohexane) to afford the title compound (414 mg, 45.9%) as a colourless oil. 1H NMR (Chloroform-d) δ: 7.49 (s, 1H), 7.47-7.34 (m, 3H), 4.57 (ddd, 1H), 4.29 (d, 1H), 3.80 (dd, 1H), 3.61 (dd, 1H), 1.90 (td, 3H), 1.23 (s, 9H), 0.90 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H).

(note: the other diastereoisomer S)—N—((R)-2-((tert-butyldimethylsilyl)oxy)-1-(3-(1,1-difluoroethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (153 mg, 16.95%) was also isolated as a colourless oil.)

Preparation 297: (S)-2-amino-2-(3-(1,1-difluoroethyl)phenyl)ethan-1-ol hydrochloride

[1199] ##STR00963##

[1200] HCl (4 M in 1,4-dioxane) (0.987 ml, 3.95 mmol) was added to a solution of (S)—N—((S)-2-((tert-butyldimethylsilyl)oxy)-1-(3-(1,1-difluoroethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.414 g, 0.987 mmol) in methanol (4.93 ml, 0.987 mmol) and the mixture was stirred overnight at room temperature. The solvent was removed and the residue was triturated with diethyl ether (5 mL). The resulting solid was isolated by filtration washing with diethyl ether (10 mL) to give the title compound (181 mg, 76%) as a white solid. 1H NMR (DMSO-d6) δ: 8.50 (s, 3H), 7.75 (5, 1H), 7.66-7.51 (m, 3H), 5.58 (t, 1H), 4.38 (dd, 1H), 3.80-3.65 (m, 2H), 1.99 (t, 3H).

Preparation 298: (S)-2-(dibenzylamino)-2-phenylethan-1-ol

[1201] ##STR00964##

[1202] (S)-2-amino-2-phenylethanol (500 mg, 3.64 mmol) in MeCN (25 ml, 479 mmol) was treated with benzyl chloride (1.270 ml, 10.93 mmol) and potassium carbonate (1763 mg, 12.76 mmol) and the suspension stirred and heated at 90° C. for four days. The suspension was cooled, filtered and the solids washed with DCM (50 ml). The filtrate was concentrated to dryness and the residue purified by chromatography (SiO.sub.2, 12 g column, 15% EtOAc in isohexane) to afford the title compound (660 mg, 52.5%) as a viscous oil. LCMS: [M+H].sup.+=318.

Preparation 299: (S)-2-(dibenzylamino)-2-phenylacetaldehyde

[1203] ##STR00965##

[1204] Sulfur trioxide pyridine complex (0.983 g, 6.17 mmol) was added to a solution of (S)-2-(dibenzylamino)-2-phenylethanol (0.49 g, 1.544 mmol) and triethylamine (1.721 mL, 12.35 mmol) in DCM (10 mL, 155 mmol) and DMSO (5 mL, 70.5 mmol) at 0° C. The reaction was warmed to room temperature and stirred for 2 h, then diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (3×30 mL), dried (MgSO.sub.4) and concentrated to afford the title compound (462 mg, 81%), which was used without further purification in the next step. 1H NMR (CDCl.sub.3) δ: 9.73 (d, 1H), 7.48-7.21 (m, 15H), 4.40-4.35 (m, 1H), 3.93-3.84 (m, 2H), 3.52-3.47 (m, 2H).

Preparation 300: (1S,2S)-1-(dibenzylamino)-1-phenylbutan-2-ol

[1205] ##STR00966##

[1206] Diethylzinc (1 M in hexanes) (2.930 mL, 2.93 mmol) was added dropwise to a solution of (S)-2-(dibenzylamino)-2-phenylacetaldehyde (462 mg, 1.465 mmol) in toluene (5.86 mL, 1.465 mmol) at 0° C. The reaction was stirred for 2 h at 0° C. and allowed to warm to room temperature overnight. The reaction was quenched with NH.sub.4Cl (20 mL) and the phases were separated. The aqueous phase was extracted with diethyl ether (3×20 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO.sub.4) and concentrated. The crude product was purified by chromatography (SiO.sub.2, 24 g column, 0-20% EtOAc in isohexane) to afford the title compound (174 mg, 0.478 mmol, 33% yield) as a colourless oil. 1H NMR (400 MHz, CDCl.sub.3) δ 7.51-7.28 (m, 10H), 7.30-7.14 (m, 5H), 4.48 (s, 1H), 4.20-4.07 (m, 1H), 3.96 (d, 2H), 3.49 (d, 1H), 3.02 (d, 2H), 1.30-1.22 (m, 1H), 1.13-0.98 (m, 1H), 0.86 (t, 3H).

Preparation 301: (1S,2S)-1-amino-1-phenylbutan-2-ol hydrochloride

[1207] ##STR00967##

[1208] A mixture of (1S,2S)-1-(dibenzylamino)-1-phenylbutan-2-ol (174 mg, 0.504 mmol) and palladium on carbon (Type 39L, 10%) (20 mg, 9.40 μmol) in MeOH (5 mL, 124 mmol) was stirred under hydrogen atmosphere (5 bar) for 3 h. The catalyst was removed by filtration and replaced with fresh catalyst and the reaction was stirred under hydrogen atmosphere (5 bar) for 3 h. A portion of HCl (4 M in 1,4-dioxane) (0.252 mL, 1.007 mmol) was added and the reaction stirred under hydrogen atmosphere (5 bar) for 1 h. The catalyst was removed by filtration and the solvent was removed in vacuo. The residue was dissolved in MeOH (12 mL). The reaction mixture was hydrogenated in the H-Cube (10% Pd/C, 30×4 mm, 20 bar, 60° C., 1 mL/min) on continuous flow for 2 h. HCl (2 M in diethyl ether) (0.504 mL, 1.007 mmol) was added and the solvent was removed in vacuo to give a yellow oil. Repeated evaporation from diethyl ether gave the title compound (70 mg, 0.330 mmol, 66% yield) as a yellow foam. 1H NMR (DMSO-d6) δ: 8.43 (s, 3H), 7.62-7.49 (m, 2H), 7.48-7.34 (m, 3H), 4.02-3.93 (m, 1H), 3.76-3.66 (m, 1H), 1.22-1.06 (m, 2H), 0.80 (t, 3H).

Preparation 302: 2-((2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)methyl)isoindoline-1,3-dione

[1209] ##STR00968##

[1210] DIAD (74.0 μl, 0.381 mmol) was added dropwise to a stirred solution of 2,2,2-trifluoro-1-(1-(hydroxymethyl)-4,5-dihydro-1H-benzo[d]azepin-3(2H)-yl)ethanone (preparation 154) (80 mg, 0.293 mmol), phthalimide (56.0 mg, 0.381 mmol) and triphenylphosphine (100 mg, 0.381 mmol) in THF (2.9 mL) and the resulting orange solution was stirred at room temperature for 5 h. The mixture was diluted with EtOAc (10 mL) and water (10 mL). The phases were separated and the aqueous layer was extracted with EtOAc (10 mL). The combined organic extracts were dried (MgSO.sub.4), filtered and reduced in vacuo to give an oil. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-100% EtOAc in Isohexane) to afford the title compound (90 mg, 46%) as a white solid. LC-MS: [M+H].sup.+=403.

Preparation 303: 2-((2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)methyl)isoindoline-1,3-dione

[1211] ##STR00969##

[1212] 2-((3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)methyl)isoindoline-1,3-dione (90 mg, 0.224 mmol) was dissolved in methanol (941 μl) and was treated with 2M NaOH (224 μl, 0.447 mmol), then stirred at room temperature for 4 h. Acetic acid (38.4 μl, 0.671 mmol) was added and reaction diluted with MeOH (4 ml) and then loaded onto a column packed with SCX (2 g) The column was washed with MeOH and the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to afford 2-(((2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)methyl)carbamoyl)benzoic acid (56 mg, 0.173 mmol, 77% yield) as a colourless solid, which was dissolved in 4M HCl in dioxane (1678 μl, 6.71 mmol) and refluxed for 2 h. The reaction mixture was allowed to cool to room temperature and loaded onto a column packed with SCX (2 g). The column was washed with MeOH and the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to afford the title compound (30 mg, 42%) as a colourless solid. LC-MS: [M+H].sup.+=307.

Preparation 304: tert-butyl (S)-(2-(2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetamido)-2-phenylethyl)carbamate

[1213] ##STR00970##

[1214] DIPEA (0.036 ml, 0.209 mmol) followed by HATU (0.079 g, 0.209 mmol) were added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (0.08 g, 0.199 mmol) and (S)-tert-butyl (2-amino-2-phenylethyl)carbamate (0.049 g, 0.209 mmol) in DMF (1 mL) and the mixture was stirred for 40 minutes. The mixture was diluted with EtOAc and transferred into a separating funnel. 1N HCl was added and the product was extracted with EtOAc. THe combined organic extracts were washed with NaHCO.sub.3, water, brine, dried (MgSO.sub.4) and concentrated under vacuum to afford the title compound (0.112 g, 91%) as a colourless glass. The product was used without further purification and characterization in the next step.

Preparation 305: 2-(2-(7-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-2-oxoethyl)-6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)isoindolin-1-one

[1215] ##STR00971##

[1216] Triethylamine (69.2 μl, 0.496 mmol) was added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (50 mg, 0.124 mmol), 7-(((tert-butyldimethylsilyl)oxy)methyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (45 mg, 0.154 mmol) and HATU (51.9 mg, 0.137 mmol) in DMF (0.5 mL). The reaction was stirred at room temperature for 1h and water (15 mL) was added. The resulting precipitate was filtered and washed with water (15 mL). Purification by chromatography (SiO.sub.2, 50-100% ethyl acetate in iso-hexane) gave the title compound (46 mg, 54%) as a colourless foam. LC-MS: [M+H].sup.+=676.

Preparation 306: (R)—N-(1-(3-bromophenyl)ethyl)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetamide

[1217] ##STR00972##

[1218] Prepared using a similar procedure to Example 405. LC-MS: [M+H].sup.+=584.

Preparation 307: (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-(1-(3-formylphenyl)ethyl)acetamide

[1219] ##STR00973##

[1220] A microwave vial was charged with (R)—N-(1-(3-bromophenyl)ethyl)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetamide (58.5 mg, 0.1 mmol), 3-oxobenzo[d]isothiazole-2(3H)-carbaldehyde 1,1-dioxide (31.7 mg, 0.150 mmol), sodium carbonate (10.60 mg, 0.100 mmol), Pd(OAc).sub.2 (0.674 mg, 3.00 μmol) and 1,4-bis(diphenylphosphino)butane (1.919 mg, 4.50 μmol). The vial was capped and evacuated and back-filled with nitrogen (3×). Triethylsilane (31.9 μl, 0.200 mmol) was added in degassed (nitrogen sparged for 10 minutes) DMF (0.8 mL) and the mixture stirred at room temperature for 10 minutes. The mixture was heated to 80° C. and stirred overnight, then allowed to cool to room temperature. The mixture was diluted with EtOAc (20 mL) and washed with brine (20 mL). The organic extracts were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-100% EtOAc in isohexane) to afford the title compound (10 mg, 18%) as a white solid. LC-MS: [M+H].sup.+=534.

Preparation 308: (R)—N-(1-(3-(allyloxy)phenyl)ethyl)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetamide

[1221] ##STR00974##

[1222] A solution of (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-(1-(3-hydroxyphenyl)ethyl)acetamide (100 mg, 0.192 mmol), potassium carbonate (132 mg, 0.958 mmol) and allyl bromide (49.7 μl, 0.575 mmol) in DMF (1 mL) was stirred at room temperature overnight. Water (2 mL) and EtOAc (2 mL) were added and the layers were separated. The organic layer was washed with brine (2 mL), dried (MgSO.sub.4) and concentrated in vacuo. Purification by chromatography (SiO.sub.2, 0-100% EtOAc in iso-hexane) gave the title compound (51 mg, 45%) as a colourless glass. LCMS: [M+H].sup.+=562.

Preparation 309: (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-(1-(3-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)phenyl)ethyl)acetamide

[1223] ##STR00975##

[1224] DIAD (44.7 μl, 0.230 mmol) was added dropwise to a solution of (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-(1-(3-hydroxyphenyl)ethyl)acetamide (100 mg, 0.177 mmol), phthalimide (33.8 mg, 0.230 mmol) and triphenylphosphine (60.2 mg, 0.230 mmol) in THF (2 mL) and the mixture was stirred overnight at room temperature. Water (4 mL) and EtOAc (4 mL) were added and the layers were separated. The organic layer was washed with brine (4 mL), dried (MgSO.sub.4) and concentrated in vacuo. Purification by chromatography (SiO.sub.2, 1-10% (1% NH.sub.3 in MeOH) in DCM) gave the title compound (50 mg, 40%) as a colourless glass. LCMS: [M+H].sup.+=695.

Preparation 310: 2-((3-(2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)methyl)isoindoline-1,3-dione

[1225] ##STR00976##

[1226] Prepared using a similar procedure to Example 548. LC-MS: [M+H].sup.+=691

Preparation 311: N-(1-(2-bromophenyl)ethyl)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetamide

[1227] ##STR00977##

[1228] Prepared using a similar procedure to Example 553 (H2O/1M HCl). LC-MS: [M+H].sup.+=584.

Preparation 312: tert-butyl (2-(N-benzyl-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetamido)ethyl)carbamate

[1229] ##STR00978##

[1230] Prepared using a similar procedure to Example 548. LC-MS: [M+Na].sup.+=657.

Preparation 313: (S)—N-(1-(4-bromophenyl)-2-hydroxyethyl)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetamide

[1231] ##STR00979##

[1232] HATU (614 mg, 1.614 mmol) was added to a solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (500 mg, 1.241 mmol), (S)-2-amino-2-(4-bromophenyl)ethanol hydrochloride (407 mg, 1.614 mmol) and triethylamine (0.865 mL, 6.21 mmol) in DMF (8 mL, 103 mmol) and the mixture was stirred at room temperature for 2 h. The reaction was diluted with water (20 mL) and the resulting white precipitate was filtered and dried on standing. Purification by chromatography (SiO.sub.2, 0-10% MeOH in DCM) gave the title compound (560 mg, 68%) as a colourless solid. LCMS: [M+H].sup.+=600.

Preparation 314: Mixture of 6-bromo-2-(2-methoxyethyl)isoindolin-1-one and 6-bromo-2,3-bis(2-methoxyethyl)isoindolin-1-one

[1233] ##STR00980##

[1234] Sodium hydride (60% wt in mineral oil) (0.113 g, 2.83 mmol) was added to a stirred solution of 6-bromoisoindolin-1-one (0.5 g, 2.358 mmol) and 1-bromo-2-methoxyethane (0.277 ml, 2.83 mmol) in DMF (12 mL) under nitrogen at 0° C. The resulting orange solution was allowed to warm slowly to room temperature and stirred for 3 days. The reaction was quenched with water (15 mL) and extracted with EtOAc (3×15 mL). The organic extracts were combined and washed with brine (50 mL), dried (MgSO.sub.4), filtered, and concentrated in vacuo to afford a yellow oil. The crude product was purified by chromatography (SiO.sub.2, 24 g GRACE column, 0-100% EtOAc in isohexane) to afford a mixture of 6-bromo-2-(2-methoxyethyl)isoindolin-1-one (549 mg, 62.9%) and 6-bromo-2,3-bis(2-methoxyethyl)isoindolin-1-one as a yellow oil (˜3:1 ratio by LCMS and NMR analyses). Further purification by chromatography (SiO.sub.2, 24 g GRACE column, 0-10% MeOH in DCM) did not improve ratio of products, which was used without further purification in the next step. LCMS: [M+H].sup.+=270 and 328.

Preparation 315: 6-(2,5-dichloropyrimidin-4-yl)-2,3-bis(2-methoxyethyl)isoindolin-1-one

[1235] ##STR00981##

[1236] Prepared using a similar procedure to preparation 63. LCMS: [M+H].sup.+=396

Preparation 316: 6-(2,5-dichloropyrimidin-4-yl)-2,3-bis(2-methoxyethyl)isoindolin-1-one

[1237] ##STR00982##

[1238] Prepared using a similar procedure to preparation 57 except SPhos-Pd G3 was used instead of Pd(PPh.sub.3).sub.4 in the second step. In the second step, 1% mol of catalyst was added after 3 h and the mixture was stirred for a further 3 days at 50° C. The product was further purified by chromatography (80 g column, 0-100% EtOAc in iso-hexane) to afford 6-(2,5-dichloropyrimidin-4-yl)-2-(2-methoxyethyl)isoindolin-1-one (225 mg, 0.632 mmol, 32.0% yield) as a pale yellow gum and the title compound (120 mg, 15.4%) as an orange/brown gum. The product was used without further purification in the next step. LMCS: [M+H].sup.+=396

[1239] Note: the product was obtained in 70% purity and was contaminated with 6-(2,5-dichloropyrimidin-4-yl)-2-(2-methoxyethyl)isoindolin-1-one.

Preparation 317: tert-butyl 5-bromo-1-(2-methoxy-2-oxoethyl)-3-oxoisoindoline-2-carboxylate

[1240] ##STR00983##

[1241] Prepared from tert-butyl 6-bromo-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate (preparation 20) and methyl 2-bromoacetate using a similar procedure to Preparation 28. LCMS: [M-Boc].sup.+=286.

Preparation 318: methyl 2-(5-bromo-3-oxoisoindolin-1-yl)acetate

[1242] ##STR00984##

[1243] HCl (4 M in dioxane) (8.69 ml, 34.7 mmol) was added dropwise at 0° C. to tert-butyl 5-bromo-1-(2-methoxy-2-oxoethyl)-3-oxoisoindoline-2-carboxylate (890 mg, 2.316 mmol) and the resulting solution was stirred at room temperature for 1 h. The reaction was concentrated and azeotroped with MeCN (2×25 ml) to afford the title compound (610 mg, 2.126 mmol, 92% yield) as a yellow solid. LCMS: [M-.sup.tBu].sup.+=284.

Preparation 319: tert-butyl 2-(5-bromo-1-(2-methoxy-2-oxoethyl)-3-oxoisoindolin-2-yl)acetate

[1244] ##STR00985##

[1245] Prepared from methyl 2-(5-bromo-3-oxoisoindolin-1-yl)acetate using a similar procedure to preparation 1 (H2O). LCMS: [M+Na].sup.+=420.

Preparation 320: tert-butyl 2-(1-(2-methoxy-2-oxoethyl)-3-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)acetate

[1246] ##STR00986##

[1247] Prepared from tert-butyl 2-(5-bromo-1-(2-methoxy-2-oxoethyl)-3-oxoisoindolin-2-yl)acetate using a similar procedure to Preparation 84. LCMS: [M-.sup.tBu].sup.+=446.

Preparation 321: tert-butyl 2-(5-(2,5-dichloropyrimidin-4-yl)-1-(2-methoxy-2-oxoethyl)-3-oxoisoindolin-2-yl)acetate

[1248] ##STR00987##

[1249] Prepared from tert-butyl 2-(5-(2,5-dichloropyrimidin-4-yl)-1-(2-methoxy-2-oxoethyl)-3-oxoisoindolin-2-yl)acetate using a similar procedure to Preparation 53. LC-MS: [M-.sup.tBu].sup.+=410.

Preparation 322: tert-butyl 2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-(2-methoxy-2-oxoethyl)-3-oxoisoindolin-2-yl)acetate

[1250] ##STR00988##

[1251] A solution of tert-butyl 2-(5-(2,5-dichloropyrimidin-4-yl)-1-(2-methoxy-2-oxoethyl)-3-oxoisoindolin-2-yl)acetate (630 mg, 1.081 mmol), oxan-4-amine (134 μl, 1.297 mmol) and DIPEA (378 μl, 2.162 mmol) in ethanol (5404 μl, 1.081 mmol) was heated to 85° C. and stirred overnight. The reaction was diluted with EtOAc (10 mL) and water (10 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO.sub.4), filtered, and concentrated to give a yellow oil. The crude product was purified by chromatography (SiO.sub.2,40 g column, 0-100% EtOAc in isohexanes) to afford the title compound (350 mg, 61.0%) as a colourless solid. LCMS: [M+H].sup.+=531.

Preparation 323: 2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-(2-methoxy-2-oxoethyl)-3-oxoisoindolin-2-yl)acetic acid

[1252] ##STR00989##

[1253] A solution of tert-butyl 2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-(2-methoxy-2-oxoethyl)-3-oxoisoindolin-2-yl)acetate (350 mg, 0.593 mmol) in DCM (6 ml, 93 mmol) and TFA (2.194 ml, 28.5 mmol) was stirred at room temperature for 3 h then concentrated in vacuo. The residue was azeotroped with toluene (3×5 mL) and acetonitrile (5 ml) to afford the title compound (315 mg, 98%) as a white solid. LCMS: [M+H].sup.+=475

Preparation 324: methyl 2-(2-(2-(tert-butyl(methyl)amino)-2-oxoethyl)-5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-3-oxoisoindolin-1-yl)acetate

[1254] ##STR00990##

[1255] Prepared from 2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-(2-methoxy-2-oxoethyl)-3-oxoisoindolin-2-yl)acetic acid using a similar procedure to Example 407. LCMS: [M+H].sup.+=544.

Preparation 325: methyl 2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-3-oxo-2-(2-oxo-2-((1-phenylcyclopropyl)amino)ethyl)isoindolin-1-yl)acetate

[1256] ##STR00991##

[1257] Prepared using a similar procedure to Example 547. LCMS: [M+H].sup.+=590.

Preparation 326: methyl 2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-3-oxo-2-(2-oxo-2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-Methyl)isoindolin-1-yl)acetate

[1258] ##STR00992##

[1259] Prepared using a similar procedure to Example 547. LCMS: [M+H].sup.+=604.

Preparation 327: methyl 2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-2-(2-(methyl(phenethyl)amino)-2-oxoethyl)-3-oxoisoindolin-1-yl)acetate

[1260] ##STR00993##

[1261] Prepared using a similar procedure to Example 552. LCMS: [M+H].sup.+=592.

Preparation 328: methyl 2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-3-oxo-2-(2-oxo-2-((2-phenylpropan-2-yl)amino)ethyl)isoindolin-1-yl)acetate

[1262] ##STR00994##

[1263] Prepared using a similar procedure to Example 552. LCMS: [M+H].sup.+=592.

Preparation 329: methyl 2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-2-(2-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-2-oxoethyl)-3-oxoisoindolin-1-yl)acetate

[1264] ##STR00995##

[1265] HATU (0.576 g, 1.516 mmol) was added to an ice-cooled solution of 2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-(2-methoxy-2-oxoethyl)-3-oxoisoindolin-2-yl)acetic acid (0.5 g, 1.011 mmol), (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (0.166 g, 1.112 mmol), and triethylamine (0.423 ml, 3.03 mmol) in DMF (10 mL) under nitrogen and the mixture was stirred for 16 h. The reaction mixture was diluted with water (50 mL) and the resulting precipitate filtered, washed with water (3×10 mL) and dried (MgSO.sub.4) to give the title compound (472 mg, 74.0%) as a pale pink solid. LCMS: [M+H].sup.+=606.

Preparation 330: methyl 2-(2-(2-(((1S,2R)-2-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-1-yl)amino)-2-oxoethyl)-5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-3-oxoisoindolin-1-yl)acetate

[1266] ##STR00996##

[1267] TBSCl (0.222 g, 1.473 mmol) in DCM (3 mL) was added to a stirred solution of methyl 2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-2-(2-(((1 S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-2-oxoethyl)-3-oxoisoindolin-1-yl)acetate (0.465 g, 0.737 mmol), DMAP (9.00 mg, 0.074 mmol), and triethylamine (0.205 ml, 1.473 mmol) in DCM (4.4 mL) and the mixture was stirred at room temperature overnight. Further portions of DMAP (9.00 mg, 0.074 mmol), triethylamine (0.205 ml, 1.473 mmol) and TBSCl (0.555 g, 3.68 mmol) in DCM (1 mL) were added and stirring continued overnight. TBSCl (1.110 g, 7.37 mmol) in DCM (1 mL) was added and the reaction stirred overnight. The mixture was diluted with DCM (20 mL) and washed with water (20 mL) and brine (20 mL). The organic extracts were combined, dried (MgSO.sub.4), filtered, and concentrated in vacuo. The crude product was purified by chromatography (SiO.sub.2, 40 g column, 0-5% MeOH in DCM) to afford the title compound (257 mg, 46.5%) as a pale yellow solid. LCMS: [M+H].sup.+=720.

Preparation 331: 2-(2-(2-(tert-butyl(methyl)amino)-2-oxoethyl)-5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-3-oxoisoindolin-1-yl)acetic acid

[1268] ##STR00997##

[1269] 1 M LiOH (0.202 ml, 0.202 mmol) was added to a stirred solution of methyl 2-(2-(2-(tert-butyl(methyl)amino)-2-oxoethyl)-5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-3-oxoisoindolin-1-yl)acetate (100 mg, 0.184 mmol) in THF (2.4 ml, 29.3 mmol)/water (0.8 ml, 44.4 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (10 ml) and water (5 ml) and the aqueous phase was acidfied with 1 M HCl to pH ˜3. The aqueous phase was further extracted with EtOAc (2×10 ml). The combined organic extracts were dried (MgSO.sub.4), filtered, and concentrated in vacuo to afford the title compound (81 mg, 79%) as colourless solid. LCMS: [M+H].sup.+=530.

[1270] Prepared using an analogous procedure to preparation 331 from the appropriate carboxylic ester. The precursor ester used in Preparation 336 can be prepared by methods analagous to those set out in Preparations 321 to 330 above.

TABLE-US-00020 Preparation Structure Name MS: [M + H].sup.+ 332 [00998] 2-(5-(5-chloro-2-((oxan-4- yl)amino)pyrimidin-4-yl)-3- oxo-2-(2-oxo-2-((1- phenylcyclopropyl)amino)- ethyl)isoindolin-1-yl)acetic acid 576 333 [00999] 2-(5-(5-chloro-2-((oxan-4- yl)amino)pyrimidin-4-yl)-3- oxo-2-(2-oxo-2-(1,2,4,5- tetrahydro-3H- benzo[d]azepin-3- yl)ethyl)isoindolin-1- yl)acetic acid 590 334 [01000] 2-(5-(5-chloro-2-((oxan-4- yl)amino)pyrimidin-4-yl)-2- (2- (methyl(phenethyl)amino)- 2-oxoethyl)-3- oxoisoindolin-1-yl)acetic acid 578 335 [01001] 2-(5-(5-chloro-2-((oxan-4- yl)amino)pyrimidin-4-yl)-3- oxo-2-(2-oxo-2-((2- phenylpropan-2- yl)amino)ethyl)isoindolin- 1-yl)acetic acid (1399-87) 578 336 [01002] 2-(5-(5-chloro-2-((oxan-4- yl)amino)pyrimidin-4-yl)-2- (2-(((R)-1-(3- methoxyphenyl)ethyl) amino)-2-oxoethyl)-3- oxoisoindolin-1-yl)acetic acid 594 337 [01003] 2-(2-(2-(((1S,2R)-2-((tert- butyldimethylsilyl)oxy)-2,3- dihydro-1H-inden-1- yl)amino)-2-oxoethyl)-5-(5- chloro-2-((oxan-4- yl)amino)pyrimidin-4-yl)-3- oxoisoindolin-1-yl)acetic acid 706

Preparation 338: 2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-(2-hydroxyethyl)-3-oxoisoindolin-2-yl)-N—((R)-1-(3-methoxyphenyl)ethyl)acetamide

[1271] ##STR01004##

[1272] Prepared using a similar procedure to Example 601. LC-MS: [M+H].sup.+=580. This compound also appears in Example 700 below.

Preparation 339: N-((1S,2R)-2-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-(2-hydroxyethyl)-3-oxoisoindolin-2-yl)acetamide

[1273] ##STR01005##

[1274] Prepared using a similar procedure to Example 601. LC-MS: [M+H].sup.+=692.

Preparation 340: N-(tert-butyl)-2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-3-oxoisoindolin-2-yl)-N-methylacetamide

[1275] ##STR01006##

[1276] DIAD (24.49 μl, 0.126 mmol) was added dropwise to a stirred solution of N-(tert-butyl)-2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-(2-hydroxyethyl)-3-oxoisoindolin-2-yl)-N-methylacetamide (example XX) (50 mg, 0.097 mmol), phthalimide (18.53 mg, 0.126 mmol) and triphenylphosphine (33.0 mg, 0.126 mmol) in THF (953 μl). The resulting orange solution was stirred at room temperature for 5 h, then diluted with EtOAc (10 mL). Water (10 mL) was added and the phases were separated. The aqueous layer was extracted with EtOAc (10 mL) and the combined organic extracts were dried (MgSO.sub.4), filtered and reduced in vacuo to give an oil. The crude product was purified by chromatography (12 g column, 0-100% EtOAc in Isohexane) to afford the title compound (48 mg, 76%) as a white solid.

Preparations 341-345

[1277] Prepared using an analogous procedure to preparation 340 from the appropriate alcohol.

TABLE-US-00021 Preparation Structure Name MS: [M + H].sup.+ 341 [01007] 2-(2-(5-(5-chloro-2- ((oxan-4- yl)amino)pyrimidin-4- yl)-3-oxo-2-(2-oxo-2- (1,2,4,5- tetrahydro-3H- benzo[d]azepin-3- yl)ethyl)isoindolin-1- yl)ethyl)isoindoline-1,3- dione 705 342 [01008] 2-(5-(5-chloro-2-((oxan- 4-yl)amino)pyrimidin-4- yl)-1-(2-(1,3- dioxoisoindolin-2- yl)ethyl)-3- oxoisoindolin-2-yl)-N- (2-phenylpropan-2- yl)acetamide (1427-19) 693 343 [01009] 2-(5-(5-chloro-2-((oxan- 4-yl)amino)pyrimidin-4- yl)-1-(2-(1,3- dioxoisoindolin-2- yl)ethyl)-3- oxoisoindolin-2-yl)-N- ((R)-1-(3- methoxyphenyl)ethyl)- acetamide 709 344 [01010] N-((1S,2R)-2-((tert- butyldimethylsilyl)oxy)- 2,3-dihydro-1H-inden-1- yl)-2-(5-(5-chloro-2- ((oxan-4- yl)amino)pyrimidin-4- yl)-1-(2-(1,3- dioxoisoindolin-2- yl)ethyl)-3- oxoisoindolin-2- yl)acetamide 821

Preparation 345: 2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-3-oxoisoindolin-2-yl)-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)acetamide

[1278] ##STR01011##

[1279] HCl (4.0 M in dioxane) (74.0 μl, 0.296 mmol) was added to a stirred solution of N-((1S,2R)-2-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-3-oxoisoindolin-2-yl)acetamide (81 mg, 0.059 mmol) in dioxane (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and purified by chromatography (SiO.sub.2, 12 g column, 0-10% MeOH in DCM) to afford the title compound (25 mg, 57.4%) as a white solid. LCMS: [M+H].sup.+=707.

Preparation 346: methyl 5-bromo-2-ethylbenzoate

[1280] ##STR01012##

[1281] A mixture of methyl 5-bromo-2-iodobenzoate (5.0 g, 14.67 mmol) and PdCl.sub.2(dppf).sub.2 (0.107 g, 0.147 mmol) in THF (30 mL) was evacuated and back-filled with nitrogen (×3), then maintained under a nitrogen atmosphere. The mixture was ice-cooled and DIETHYLZINC (1.0 M in hexane) (8.07 ml, 8.07 mmol) added carefully over 15 min. The cooling bath was removed and the mixture was heated to 65° C. and stirred for 3.5 h. After cooling to room temperature, the reaction mixture was poured into ice-cold 1 M HCl (50 mL). The aqueous phase was extracted with EtOAc (3×50 mL) and the combined organic extracts were washed with saturated brine (100 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford a dark brown oil (4.1 g). The crude product was dissolved in EtOAc (5 mL) and iso-hexane (100 mL) was added. The mixture was allowed to stand at room temperature for 1 h and the resulting precipitate was filtered through a pad of silica, washing with 5% EtOAc/iso-hexane (200 mL). The filtrate was concentrated in vacuo to give methyl 5-bromo-2-ethylbenzoate (3.89 g, 54.6%) as a pale orange oil (3.89 g). The product was used without further purification in the next step. 1H NMR (Chloroform-d) δ: 7.94 (1H, d), 7.53 (1H, dd), 7.15 (1H, dd), 3.89 (3H, s), 2.93 (2H, q), 1.21 (3H, t). (note: the product was obtained as a ˜1:1:0.5 mixture with starting material and des-iodo starting material as shown by NMR).

Preparation 347: methyl 5-bromo-2-(1-bromoethyl)benzoate

[1282] ##STR01013##

[1283] Benzoyl peroxide (75 wt %, remainder water) (0.129 g, 0.400 mmol) and NBS (1.709 g, 9.60 mmol) were added to a stirred solution of methyl 5-bromo-2-ethylbenzoate (3.89 g, 8.00 mmol) in CHCl.sub.3 (80 ml, 8.00 mmol) and the mixture was heated to reflux and stirred for 18 h. After cooling to room temperature, further portions of Benzoyl peroxide (75 wt %, remainder water) (0.026 g, 0.080 mmol) and NBS (0.427 g, 2.400 mmol) were added and the mixture heated to reflux and stirred for 2 h. After cooling to room temperature, the mixture was washed with water (100 mL) and the aqueous phase was extracted with DCM (100 mL). The organic extracts were combined and washed with water (100 mL), 10 wt % Na.sub.2SO.sub.3 (100 mL) and brine (100 mL), then dried (MgSO.sub.4), filtered and concentrated in vacuo to afford a yellow oil (4.5 g). The crude product was purified by chromatography (SiO.sub.2, 120 g column, 0-50% DCM in isohexane) to afford the title compound (1.442 g, 55.4%) as a white solid. 1H NMR (Chloroform-d) δ: 7.98 (1H, d), 7.69 (1H, d), 7.65 (1H, dd), 6.24 (1H, q), 3.93 (3H, s), 2.01 (3H, d).

Preparation 348: tert-butyl 2-(5-bromo-1-methyl-3-oxoisoindolin-2-yl)acetate

[1284] ##STR01014##

[1285] DIPEA (1.627 ml, 9.32 mmol) was added to a stirred suspension of methyl 5-bromo-2-(1-bromoethyl)benzoate (1.0 g, 3.11 mmol) and tert-butyl 2-aminoacetate hydrochloride (0.781 g, 4.66 mmol) in MeCN (31.1 ml, 3.11 mmol) and the mixture was heated to 75° C. and stirred under nitrogen for 16 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was taken up in EtOAc (100 mL) and washed with 1 M HCl (50 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and the combined organic extracts were washed with brine (100 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to give a pale yellow oil (954 mg). The crude product was purified by chromatography (SiO.sub.2, 40 g column, 0-50% EtOAc in isohexane) to afford the title compound (627 mg, 55.2%) as a pale yellow oil. LCMS: [M+Na].sup.+=362.

Preparation 349: (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid trifluoroacetic acid salt

[1286] ##STR01015##

[1287] Prepared from tert-butyl (2R)-2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoate (preparation 94) using a similar procedure to preparations 9 and 19. LCMS: [M+H].sup.+=352.

Preparation 350: tert-butyl 2-(6-(5-chloro-2-(methylamino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetate

[1288] ##STR01016##

[1289] DIPEA (486 μl, 2.78 mmol) was added to a stirred solution of tert-butyl 2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetate (280 mg, 0.696 mmol) and methylamine hydrochloride (94 mg, 1.392 mmol) in dioxane (1.8 mL) and ethanol (1.8 mL). The mixture was heated in a sealed tube to 80° C. and stirred for 16 h. After cooling, the reaction was diluted with

[1290] EtOAc (20 mL) and water (20 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (60 mL), dried (MgSO.sub.4) and concentrated. The crude product was purified by chromatography (SiO.sub.2, 24 g column, 0-100% EtOAc in isohexane) to afford the title compound (230 mg, 0.586 mmol, 84% yield) as a colourless solid. LC-MS: [M+H].sup.+=389.

Preparation 351: 2-(6-(5-chloro-2-(methylamino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetic acid

[1291] ##STR01017##

[1292] TFA (879 μl, 11.41 mmol) was added to a stirred solution of tert-butyl 2-(6-(5-chloro-2-(methylamino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetate (224 mg, 0.570 mmol) in DCM (6 mL) and the mixture was stirred at room temperature for 2 h. An additional portion of TFA (439 μl, 5.70 mmol) was added and the mixture stirred at room temperature for a further 1.5 h. The solvent was removed in vacuo and the residue was azeotroped with toluene (3×3 mL) and MeCN (3×3 mL) to give the title compound (224 mg, 112%) as a pale yellow solid LC-MS: [M+H].sup.+=333. (note: product could be TFA salt).

Preparation 352: ((R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-2-hydroxy-1-(3-methoxyphenyl)ethyl)propanamide

[1293] ##STR01018##

[1294] DIPEA (0.982 ml, 5.62 mmol) and HATU (1051 mg, 2.76 mmol) were added to a stirred solution of (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (660 mg, 1.874 mmol), and (S)-2-amino-2-(3-methoxyphenyl)ethanol hydrochloride (420 mg, 2.061 mmol) in acetonitrile (5 ml, 1.874 mmol). The resulting solution was stirred at ambient temperature for 1h, then concentrated under vacuum. The residue was dissolved in a small quantity of DCM and purified by chromatography (SiO.sub.2, 12 g column, 100% EtOAc) to afford the title compound (728 mg, 71.3%) as a cream coloured solid. LCMS: [M+H].sup.+=501.

Preparation 353: (S)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-(2-hydroxy-1-(m-tolyl)ethyl)acetamide

[1295] ##STR01019##

[1296] A solution of tert-butyl 2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetate (1.5 g, 3.80 mmol) in 1:1 DCM:TFA (15 mL) was stirred under nitrogen for 2h. The mixture was concentrated under vacuum and the residue was azeotroped with toluene, then Et.sub.2O to afford 2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetic acid (1.287 g, 3.81 mmol, 100% yield) as a white solid. The product was used without further purification and characterization in the next step. HATU (0.295 g, 0.776 mmol) was added to a mixture of 2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetic acid (0.25 g, 0.739 mmol), (S)-2-amino-2-(m-tolyl)ethanol hydrochloride (0.146 g, 0.776 mmol) and DIPEA (0.387 ml, 2.218 mmol) in DMF (2.5 mL) and the mixture was stirred for 45 minutes. The mixture was diluted with EtOAc and transferred into a separating funnel. 1N HCl was added and the product was extracted with EtOAc. The precipitate that formed in the organic extract was filtered and dried under suction to afford the title compound (0.18 g, 51.7%) as a white solid. The filtrate was washed with NaHCO.sub.3, water, brine, dried (MgSO.sub.4) concentrated under vacuum to afford a second batch of title compound (0.17 g, 048.8%). The products were used without further purification and characterization in the next step.

Preparation 354: ((S)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-(1-(2-fluoro-5-methoxyphenyl)-2-hydroxyethyl)acetamide

[1297] ##STR01020##

[1298] Prepared using a similar procedure to Example 353.

Preparation 355: (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-2-hydroxy-1-(m-tolyl)ethyl)propanamide

[1299] ##STR01021##

[1300] Prepared using a similar procedure to Example 353.

Preparation 356: Mixture of (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-1-(3-fluoro-5-methylphenyl)-2-hydroxyethyl)propanamide and (R)-2-(6-(2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-5-chloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-1-(3-fluoro-5-methylphenyl)-2-hydroxyethyl)propanamide (3:2)

[1301] ##STR01022##

[1302] TBTU (0.096 g, 0.298 mmol) was added to a mixture of (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (0.1 g, 0.284 mmol), (S)-2-amino-2-(3-fluoro-5-methylphenyl)ethanol hydrochloride (0.061 g, 0.298 mmol) and DIPEA (0.149 ml, 0.852 mmol) in DMF (1 mL) and the mixture was stirred for 2h. The mixture was diluted with EtOAc and transferred into a separating funnel. 1N HCl was added and the product was extracted with

[1303] EtOAc. The combined organic extracts were washed with water, NaHCO.sub.3, brine, dried (MgSO.sub.4) concentrated under vacuum to afford crude. The product was used without further purification and characterization in the next step. (note: the ratio of components was estimated from LCMS analysis of the reaction mixture, which showed formation of a 3:2 mixture).

Preparation 357: (R)-2-(6-(2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-5-chloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-(1-(2-fluoro-5-methoxyphenyl)ethyl)acetamide

[1304] ##STR01023##

[1305] A mixture of 2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetic acid (0.1 g, 0.296 mmol), (R)-1-(2-fluoro-5-methoxyphenyl)ethanamine, HCl (0.067 g, 0.325 mmol), TBTU (0.114 g, 0.355 mmol) and DIPEA (0.207 ml, 1.183 mmol) in DMF (1 mL) was stirred at room temperature for 20 h. The mixture was diluted with EtOAc (20 mL) and the solution was washed sequentially with 1M HCl (15 mL), NaHCO.sub.3 (15 mL), water (10 mL) and brine (10 mL). The organic solution was passed through a hydrophobic frit and concentrated in vacuo to afford the title compound (147 mg, 77%) as a pale brown solid. LC-MS: [M+H].sup.+=588. The product was used without further purification in the next step. (note: the product contained ˜7% (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-(1-(2-fluoro-5-methoxyphenyl)ethyl)acetamide (LCMS)).

Preparation 358: (2-(2-nitroethoxy)propan-2-yl)benzene

[1306] ##STR01024##

[1307] 2-nitroethanol (1.0 mL, 13.95 mmol) followed by TFA (0.100 mL, 1.298 mmol) were added to a stirred solution of 2-phenylpropan-2-ol (1.0 g, 7.34 mmol) in DCM (5.0 mL, 78 mmol). The resulting solution was stirred at room temperature overnight, then concentrated under vacuum.

[1308] The residues was azeoptroped with MeOH (3×20 mL) to afford the crude product as a pale yellow oil (2.16 g), which was purified by chromatography (12 g column, 0-50% EtOAc in isohexane) to afford the title compound (764 mg, 35.8%) as a colourless oil. 1H NMR (400 MHz, CDCl.sub.3) δ 7.44-7.32 (m, 4H), 7.30-7.21 (m, 1H), 4.54-4.38 (m, 2H), 3.78-3.55 (m, 2H), 1.56 (s, 6H).

Preparation 359: 2-((2-phenylpropan-2-yl)oxy)ethan-1-amine

[1309] ##STR01025##

[1310] A solution of ammonium chloride (0.214 g, 4.00 mmol) in water (3.5 mL, 194 mmol) was added to a suspension of (2-(2-nitroethoxy)propan-2-yl)benzene (0.764 g, 2.63 mmol) and iron (1.47 g, 26.3 mmol) in ethanol (17.0 mL, 291 mmol) and the resulting mixture was heated to 80° C. for 135 minutes. The mixture was cooled to room temperature and filtered through celite (washing through with EtOH). The filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The pH of the aqueous layer was adjusted to 8 by the addition of saturated aqueous NaHCO.sub.3 and then extracted with EtOAc (3×30 mL).

[1311] This combined organic extracts were dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the title compound as a pale yellow oil (158 mg, 98%). 1H NMR (400 MHz, Chloroform-d) δ 7.44-7.39 (m, 2H), 7.34 (ddd, J=7.8, 6.8, 1.2 Hz, 2H), 7.26-7.22 (m, 1H), 3.25 (t, J=5.3 Hz, 2H), 3.07 (s (br), 2H), 2.90 (t, J=5.3 Hz, 2H), 1.56 (s, 6H).

Preparation 360: 6-bromo-2-(2-((2-phenylpropan-2-yl)oxy)ethyl)isoindolin-1-one

[1312] ##STR01026##

[1313] Prepared from methyl 5-bromo-2-(bromomethyl)benzoate and 2-((2-phenylpropan-2-yl)oxy)ethan-1-amine using a similar procedure to preparation 73. In the case, the product was purified by chromatography (SiO.sub.2, 12 g column, 0-50% EtOAc in isohexanes) LC-MS: [M+Na]+=396.

Preparation 361: 2-(2-((2-phenylpropan-2-yl)oxy)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

[1314] ##STR01027##

[1315] Prepared from 6-bromo-2-(2-((2-phenylpropan-2-yl)oxy)ethyl)isoindolin-1-one using a similar procedure to preparation 84. LC-MS: [M+Na].sup.+=444.

Preparation 362: 6-(2,5-dichloropyrimidin-4-yl)-2-(2-((2-phenylpropan-2-yl)oxy)ethyl)isoindolin-1-one

[1316] ##STR01028##

[1317] Prepared from 2-(2-((2-phenylpropan-2-yl)oxy)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one using a similar procedure to preparation 90. LC-MS: [M+Na].sup.+=464.

Preparation 363: methyl 5-bromo-2-formylnicotinate

[1318] ##STR01029##

[1319] Triethylamine (6.12 ml, 43.9 mmol) was added to a stirred suspension of methyl 5-bromo-2-chloronicotinate (10.0 g, 39.9 mmol) and potassium vinyltrifluoroborate (5.88 g, 43.9 mmol) in ethanol (200 ml, 39.9 mmol). The system was evacuated and back-filled with nitrogen (×3). PdCl.sub.2(dppf).sub.2 (0.584 g, 0.798 mmol) was added and the system was evacuated and back-filled with nitrogen (×3). The mixture was heated to 80° C. and stirred under nitrogen for 2.5 h. After cooling to room temperature, the mixture was filtered through Celite. The filtrate was concentrated and partitioned between EtOAc (200 mL) and water (200 mL). The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography (220 g column, 0-20% EtOAc in isohexane) to afford the title compound (4.993 g, 20.42 mmol, 51.1% yield) as a pale green solid. LCMS: [M+H].sup.+=242.

Preparation 364: methyl 5-bromo-2-formylnicotinate

[1320] ##STR01030##

[1321] A mixture of ozone/oxygen was bubbled through a stirred solution of methyl 5-bromo-2-vinylnicotinate (1.0 g, 4.13 mmol) in DCM (41.3 ml, 4.13 mmol) cooled to −78° C. After 5 minutes, the solution turned blue. Oxygen was bubbled through the reaction mixture until the solution turned back to yellow, then placed under a nitrogen atmosphere. Dimethyl sulfide (0.917 ml, 12.39 mmol) was added and the mixture was allowed to warm slowly to room temperature overnight. The mixture was diluted with DCM (50 mL) and washed with water (100 mL) and brine (100 mL). The organic extracts were dried (MgSO.sub.4), filtered and concentrated in vacuo to afford methyl 5-bromo-2-formylnicotinate (718 mg, 64.1%) as sticky brown gum. 1H NMR (Chloroform-d) δ: 10.27 (s, 1H), 8.92 (d, 1H), 8.23 (d, 1H), 3.98 (s, 3H).

Preparation 365: tert-butyl (R)-2-(3-bromo-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)propanoate

[1322] ##STR01031##

[1323] Procedure A: Prepared following the procedure described in Preparation 6. LCMS: [M+H].sup.+=341.

[1324] Procedure B: DIPEA (0.382 mL, 2.189 mmol) was added to a stirred solution of (R)-tert-butyl 2-aminopropanoate hydrochloride (0.398 g, 2.189 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 10 minutes before being added to a stirred solution of methyl 5-bromo-2-formylnicotinate (539 mg, 1.988 mmol) in DCM (15 mL). The mixture was stirred at room temperature for 2 h, before sodium triacetoxyborohydride (633 mg, 2.99 mmol) was added and the mixture stirred at room temperature for 24 h. The mixture was diluted with DCM (30 mL) and washed with NaHCO.sub.3 (50 mL). The aqueous phase was extracted with DCM (2×50 mL) and the combined organic extracts were washed with brine (75 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford a brown solid (700 mg). The crude product was adsorbed onto silica and purified by chromatography on (24 g column, 0-100% EtOAc in isohexane) to the title compound (277 mg, 0.804 mmol, 40.4% yield) as a pale yellow solid. LCMS: [M+H].sup.+=341.

Preparation 366: tert-butyl (R)-2-(5-oxo-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)propanoate

[1325] ##STR01032##

[1326] Prepared following the procedure described in Preparation 86. The crude product was purified by chromatography (SiO.sub.2, 0-50% ethyl acetate in iso-hexane) to give the title compound (1.653 g, 99%) as an off white solid. LC-MS: [M-C.sub.8H.sub.10].sup.+=307.

Preparation 367: tert-butyl (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)propanoate

[1327] ##STR01033##

[1328] Prepared using a similar procedure to Preparation 53. LCMS: [M+H].sup.+=409.

Preparation 368: 2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)acetic acid

[1329] ##STR01034##

[1330] TFA (4.0 mL, 51.9 mmol) was added to a solution of crude tert-butyl 2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)acetate (0.989 g, 2.002 mmol) in DCM (20.0 mL, 311 mmol). The resulting solution was stirred at room temperature overnight, then concentrated under vacuum. The residue was azeotroped with toluene (3×30 mL) and then dried in a vacuum oven overnight. LCMS: [M+H].sup.+=339.

Preparation 369: (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)propanoic acid

[1331] ##STR01035##

[1332] A solution of (R)-tert-butyl 2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)propanoate (Preparation 367, 0.38 g, 0.928 mmol) in 1:1 DCM:TFA (5 mL) was stirred for 3h. The mixture was concentrated under vacuum and the residue was azeoptroped with toluene. The residue was triturated with Et.sub.2O and the resulting suspension was concentrated under vacuum to afford the title compound (0.418 g, 0.929 mmol, 100% yield) as a yellow solid. The products were used without further purification and characterization in the next step. Quantitative yield was assumed.

Preparation 370: (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-N—((S)-2-hydroxy-1-(3-methoxyphenyl)ethyl)propanamide

[1333] ##STR01036##

[1334] A solution of (R)-tert-butyl 2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)propanoate (0.35 g, 0.855 mmol) in 1:1 DCM:TFA (5 mL) was stirred for 2.5h. The mixture was concentrated under vacuum and the residue was azeoptroped with toluene. The residue was triturated with a ˜5:1 Isohexane:Et.sub.2O mixture and the resulting precipitate was filtered, washed with Isohexane and dried under suction to afford (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)propanoic acid (0.206 g, 53.5%) as a white solid. The filtrate was concentrated under vacuum and the residue was suspended in Et.sub.2O. The suspension was concentrated to dryness under vacuum to afford (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)propanoic acid (0.044 g, 0.125 mmol, 14.57% yield) as a white solid. The products were used without further purification and characterization in the next step. HATU (0.133 g, 0.350 mmol) was added to a mixture of (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)propanoic acid (0.15 g, 0.333 mmol), (S)-2-amino-2-(3-methoxyphenyl)ethanol hydrochloride (0.071 g, 0.350 mmol) and DIPEA (0.180 ml, 1.033 mmol) in DMF (1.5 mL) and the mixture was stirred for 45 minutes. The mixture was diluted with EtOAc and transferred into a separating funnel. Saturated aqueous NH.sub.4Cl was added and the product was extracted with EtOAc. THe combined organic extracts were washed with NaHCO.sub.3, water, brine, dried (MgSO.sub.4) concentrated under vacuum to afford crude (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N—((S)-2-hydroxy-1-(3-methoxyphenyl)ethyl)propanamide (0.160 g, 96%). The product was used without further purification and characterization in the next step.

Preparation 371: (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-N—((S)-2-hydroxy-1-(m-tolyl)ethyl)propanamide

[1335] ##STR01037##

[1336] Prepared using a similar procedure to preparation 370.

Preparation 372: (S)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-N-(2-hydroxy-1-(m-tolyl)ethyl)acetamide

[1337] ##STR01038##

[1338] HATU (83 mg, 0.219 mmol) was added to an ice-cooled solution of 2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)acetic acid (62 mg, 0.146 mmol), (S)-2-amino-2-(m-tolyl)ethanol hydrochloride (30.2 mg, 0.161 mmol) and triethylamine (61.2 μl, 0.439 mmol) in DMF (1.4 mL) under nitrogen. The mixture was stirred at room temperature for 2 h, then diluted with EtOAc (30 mL). The organic phase was washed with water (30 mL), brine (3×30 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to give a yellow/brown solid (80 mg, 94%). The crude product was used without further purification in the next step. LCMS: [M+H].sup.+=472.

Preparation 373: Mixture of (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-N-(1-(m-tolyl)ethyl)acetamide and (R)-2-(3-(2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-5-chloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N-(1-(m-tolyl)ethyl)acetamide

[1339] ##STR01039##

[1340] TBTU (54.6 mg, 0.233 mmol) was added to a stirred solution of 2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)acetic acid, TFA (120 mg, 0.212 mmol), (R)-1-(m-tolyl)ethanamine hydrochloride (54.6 mg, 0.318 mmol) and DIPEA (148 μl, 0.847 mmol) in dioxane (2 ml). The resulting mixture was stirred at room temperature for 4h, then partitioned between DCM (50 ml) and 1N HCl (50 ml). The organic phase was collected, washed with NaHCO.sub.3 (50 ml), dried (MgSO.sub.4) and concentrated to give the title mixture (˜1:1) as a gum. The product was used without further purification in the next step. LCMS: [M+H].sup.+=456 and 555.

Preparation 374: Mixture of (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N—((S)-2-hydroxy-1-(m-tolyl)ethyl)propanamide with (R)-2-(3-(2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-5-chloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N—((S)-2-hydroxy-1-(m-tolyl)ethyl)propanamide (3:2)

[1341] ##STR01040##

[1342] TBTU (0.096 g, 0.299 mmol) was added to a mixture of ((R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)propanoic acid (0.128 g, 0.284 mmol), (S)-2-amino-2-(m-tolyl)ethanol hydrochloride (0.056 g, 0.299 mmol) and DIPEA (0.154 ml, 0.881 mmol) in DMF (1 mL) and the mixture was stirred for 3.5h. The mixture was diluted with EtOAc and transferred into a separating funnel. NH.sub.4Cl was added and the product was extracted with EtOAc. The combined organic extracts were washed with NaHCO.sub.3, water, brine, dried (MgSO.sub.4) concentrated under vacuum to afford crude (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N—((S)-2-hydroxy-1-(m-tolyl)ethyl)propanamide compound with (R)-2-(3-(2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-5-chloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N—((S)-2-hydroxy-1-(m-tolyl)ethyl)propanamide (3:2) (0.149 g, 0.284 mmol, 100% yield) as an orange solid. The product was used without further purification and characterization in the next step. Quantitative yield was assumed.

Preparation 375: Mixture of (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N—((S)-2-hydroxy-1-(3-methoxyphenyl)ethyl)propanamide with (R)-2-(3-(2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-5-chloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl-N—((S))-2-hydroxy-1-(3-methoxyphenyl)ethyl)propanamide (1:1)

[1343] ##STR01041##

[1344] Prepared using a similar procedure to preparation 374.

Preparation 376: methyl 2-(bromomethyl)-5-chloro-3-fluorobenzoate

[1345] ##STR01042##

[1346] NBS (5.30 g, 29.8 mmol) and benzoyl peroxide (0.401 g, 1.241 mmol) were added to a solution of methyl 5-chloro-3-fluoro-2-methylbenzoate (5.03 g, 24.83 mmol) in chloroform (200 mL, 2480 mmol) and the mixture was heated to reflux and stirred overnight. The reaction was cooled to room temperature and hexane (300 mL) was added. The resulting precipitate was removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified by chromatography (SiO.sub.2, 120 g column, 0-30% DCM in isohexane) to afford the title compound (5.908 g, %) as a colourless oil. The product was used without further purification in the next step. 1H NMR (CDCl.sub.3) δ: 7.78 (dd, 1H), 7.29 (dd, 1H), 4.94 (d, 2H), 3.96 (s, 3H).

Preparation 377: tert-butyl (R)-2-(6-chloro-4-fluoro-1-oxoisoindolin-2-yl)propanoate

[1347] ##STR01043##

[1348] A mixture of methyl 2-(bromomethyl)-5-chloro-3-fluorobenzoate (1.54 g, 5.20 mmol), (R)-tert-butyl 2-aminopropanoate hydrochloride (1.43 g, 7.87 mmol) and DIPEA (3.0 mL, 17.18 mmol) in MeCN (30.0 mL, 574 mmol) was heated to 75° C. overnight, then allowed to cool to room temperature and stirred for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (30 mL) and 1 M HCl (30 mL). The layers were separated and the aqueous fraction was extracted with EtOAc (30 mL). The combined organic extracts were washed with brine (3×50 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude product as a pale beige solid (1.52 g). The product was used without further purification in the next step. LCMS: [M-.sup.tBu+H].sup.+=258.

Preparation 378: tert-butyl (R)-2-(4-fluoro-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)propanoate

[1349] ##STR01044##

[1350] A mixture of (R)-tert-butyl 2-(6-chloro-4-fluoro-1-oxoisoindolin-2-yl)propanoate (1.52 g, 4.84 mmol), bis(pinacolato)diboron (1.47 g, 5.79 mmol) and potassium acetate (1.44 g, 14.67 mmol) in 1,4-dioxane (10.0 mL, 117 mmol) was degassed (bubbling nitrogen) for 10 minutes at 40° C. XPhos Pd G3 (0.054 g, 0.064 mmol) was added and the mixture was degassed for a further 10 minutes and then heated to 100° C. for 65 minutes. The reaction mixture was cooled to room temperature and filtered through celite, washing with EtOAc (3×50 mL). The filtrate was concentrated under reduced pressure to afford the crude product as a grey gum (4.4 g). Purification by chromatography (SiO.sub.2, 24 g column, 0-50% EtOAc in iso-hexane) afforded the title compound (1.98 g, 91%) as an off-white solid. LCMS: [M-.sup.tBu+H].sup.+=350.

Preparation 379: tert-butyl (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)propanoate

[1351] ##STR01045##

[1352] mixture of (R)-tert-butyl 2-(4-fluoro-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)propanoate (1.98 g, 4.40 mmol), 2,4,5-trichloropyrimidine (0.800 mL, 6.98 mmol) and potassium carbonate (1.23 g, 8.90 mmol) in 1,4-dioxane (12.0 mL, 140 mmol) and water (4.0 mL, 222 mmol) was degassed (bubbling nitrogen) at 40° C. for 10 minutes. Pd(Ph.sub.3P).sub.4 (0.250 g, 0.216 mmol) was added and the mixture degassed for a further 10 minutes then heated to 90° C. for 3.5h. The mixture was cooled to room temperature and then partitioned between EtOAc (30 mL) and water (30 mL). The layers were separated and the aqueous fraction was extracted with EtOAc (30 mL). The combined organic extracts were washed with brine (3×30 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude product as an orange oil. Purification by chromatography (SiO.sub.2, 24 g column, 0-50% EtOAc in iso-hexane) afforded the title compound (1.15 g, 60.1%) as an off-white solid. LCMS: [M-.sup.tBu+H].sup.+=370.

Preparation 380: tert-butyl (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)propanoate

[1353] ##STR01046##

[1354] DIPEA (0.370 mL, 2.118 mmol) and oxan-4-amine (0.120 mL, 1.159 mmol) were added to a mixture of (R)-tert-butyl 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)propanoate (0.298 g, 0.685 mmol) in 1,4-dioxane (5.0 mL, 58.5 mmol) and the mixture was stirred at 90° C. for 21h. Further oxan-4-amine (0.120 mL, 1.159 mmol) and DIPEA (0.370 mL, 2.118 mmol) was added and the mixture was stirred at 90° C. for a further 5 h, then cooled to room temperature and partitioned between EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous was extracted with EtOAc (50 mL). The combined organic extracts was washed with brine (3×30 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude product which was dried in a vacuum oven over for 3 days to afford the title compound (0.303 g, 89%) as a yellow gum. The product was used without further purification in the next step. LCMS: [M+H].sup.+=491.

Preparation 381: (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)propanoic acid

[1355] ##STR01047##

[1356] TFA (1.0 mL, 12.98 mmol) was added to a stirred solution of (R)-tert-butyl 2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)propanoate (0.303 g, 0.611 mmol) in DCM (5.0 mL, 78 mmol) and the mixture was stirred for 22.5h, then concentrated under vacuum. The residue was azeotroped with toluene (3×30 mL) to afford the crude product which was dried in a vacuum oven overnight to give a yellow gum (347 mg). The crude was triturated with ether (10 mL) and the resulting suspension was decantated to give a solid, which was dried in a vacuum oven overnight. The ether filtrate was combined with the solid and concentrated under reduced pressure, then azeotroped with MeCN (3×10 mL) and dried a the vacuum oven to afford the title compound (279 g, 95%) as a yellow solid. LCMS: [M+H]+=435.

Preparation 382: 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)acetic acid

[1357] ##STR01048##

[1358] A stirred solution of tert-butyl 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)acetate (390 mg, 0.918 mmol) in dichloromethane (2 ml) was treated with TFA (2 ml) and stirred at room temperature for 2 h. The mixture was evaporated and the residue was taken up in toluene (3×10 ml) and evaporated to give 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)acetic acid (356 mg, 0.910 mmol, 99% yield) as a cream foam. LCMS: [M+H].sup.+=356.

Preparation 383: (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(1-(3-methoxyphenyl)ethyl)acetamide

[1359] ##STR01049##

[1360] A stirred solution of 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)acetic acid (100 mg, 0.281 mmol), (R)-1-(3-methoxyphenyl)ethanamine (48 mg, 0.317 mmol) and triethylamine (0.117 ml, 0.842 mmol) in DMF (1 ml) was cooled in an ice-bath, treated with T3P (50% solution in ethyl acetate, 0.25 ml, 0.424 mmol) and stirred at room temperature for 3h. The solution was diluted with water (5 ml) and extracted with ethyl acetate (3×5 ml). The combined organic extracts were washed with 1M KHSO.sub.4 (5 ml) followed by NaHCO.sub.3 (5 ml), brine (2×5 ml), then dried (Na.sub.2SO.sub.4) and evaporated to give the title compound (131 mg, 89%) as a cream solid. LCMS: [M+H].sup.+=489.

Preparation 384: (S)-2-(6-(2-((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)-5-chloropyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(2-hydroxy-1-(3-methoxyphenyl)ethyl)acetamide

[1361] ##STR01050##

[1362] A stirred solution of 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)acetic acid (100 mg, 0.281 mmol), (S)-2-amino-2-(3-methoxyphenyl)ethanol, HCl (69 mg, 0.339 mmol) and DIPEA (0.196 ml, 1.123 mmol) in DMF (2 ml) was treated with HATU (117 mg, 0.309 mmol) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate (10 ml), washed successively with 1M KHSO.sub.4 (10 ml), NaHCO.sub.3 (10 ml), brine (2×10 ml), then dried (MgSO.sub.4) and evaporated. The residue was suspended in a mixture of ethyl acetate and dichloromethane (˜5 ml), absorbed onto silica and purified by chromatography (SiO.sub.2, 12 g column, 50-100% EtOAc in isohexane) to afford the title compound (62 mg, 35.4%). LCMS: [M+H].sup.+=605.

Preparation 385: (tert-butyl (R)-2-(6-(5-chloro-2-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)propanoate

[1363] ##STR01051##

[1364] A stirred solution of (R)-tert-butyl 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)propanoate (100 mg, 0.235 mmol), (S)-2-aminopropan-1-ol (27 mg, 0.359 mmol) and Hunig's base (102 μl, 0.586 mmol) in dioxane (2 ml) was stirred at 70° C. (bath) overnight. LC/MS showed the mixture to contain mostly the required product and 14% starting material. The solution was allowed to cool, was diluted with ethyl acetate (10 ml), was washed with 1M aqueous potassium hydrogen sulphate solution (5 ml) followed by saturated aqueous sodium bicarbonate solution (5 ml) and then brine (5 ml), was dried (MgSO.sub.4) and evaporated. The residue was purified on 12 g graceresolv silica cartridge, using a gradient of 50 to 100% of ethyl acetate in isohexane as eluent to give (R)-tert-butyl 2-(6-(5-chloro-2-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)propanoate (67 mg, 0.138 mmol, 59.0% yield). LCMS: [M+H].sup.+=465.

Preparation 386: (R)-2-(6-(5-chloro-2-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)propanoic acid trifluoroacetate

[1365] ##STR01052##

[1366] A stirred solution of (R)-tert-butyl 2-(6-(5-chloro-2-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)propanoate (65 mg, 0.140 mmol) in dichloromethane (4 ml) was treated with TFA (4 ml) and stirred at room temp. for 2 h. The residue was taken up in toluene (3×5 ml) and evaporated to give (R)-2-(6-(5-chloro-2-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)propanoic acid (91 mg, 0.140 mmol, 100% yield) as a yellow glass. LCMS: [M+H].sup.+=409.

Preparation 387: methyl 3-((tert-butyldimethylsilyl)oxy)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoate

[1367] ##STR01053##

[1368] The title compound could be obtained by following Preparation 95.

[1369] Alternatively, the following procedure could be used: A stirred mixture of methyl 3-((tert-butyldimethylsilyl)oxy)-2-(1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)propanoate (1.448 g, 3.05 mmol), 2,4,5-trichloropyrimidine (0.511 mL, 4.57 mmol) in dioxane (8 ml) and sodium carbonate (2M aqueous solution) (3.1 mL, 6.20 mmol) was degassed with nitrogen for 10 minutes, treated with Pd(PPh.sub.3).sub.4 (0.176 g, 0.152 mmol) and stirred at 80° C. under nitrogen for 3.5 h. The mixture was allowed to cool, diluted with brine (25 ml) and extracted with ethyl acetate (3×25 ml). The combined extracts were washed with brine (25 ml), (Na.sub.2SO.sub.4) and evaporated. The residue was purified by chromatography (SiO.sub.2, 40 g column, 0-50% EtOAc in isohexane) to give the title compound (862 mg, 51.3%) as a cream foam. LC-MS: [M+H].sup.+=496.

Preparation 388: Methyl 3-((tert-butyldimethylsilyl)oxy)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoate

[1370] ##STR01054##

[1371] Prepared using a similar procedure to Example 102. LC-MS: [M+H].sup.+=561.

Preparation 389: 3-((tert-butyldimethylsilyl)oxy)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid

[1372] ##STR01055##

[1373] 1M LiOH (249 μl, 0.249 mmol) was added to a solution of methyl 3-((tert-butyldimethylsilyl)oxy)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoate (70 mg, 0.125 mmol) in 3:1 THF (1.8 mL): water (0.6 mL) and the reaction mixture was stirred for 4 h at room temperature. EtOAc (5 mL) was added, and the layers separated. The aqueous layer was acidified with 1M HCl (0.5 mL) and extracted with EtOAc. The combined organic extracts were dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give the crude title compound (52 mg, 50.3%) as a yellow gum LC-MS: [M+H].sup.+=547.

Preparation 390: (tert-butyl ((R)-4-hydroxy-1-(((R)-1-(3-methoxyphenyl)ethyl)amino)-1-oxobutan-2-yl)carbamate

[1374] ##STR01056##

[1375] Triethylamine (0.260 mL, 1.865 mmol), (R)-1-(3-methoxyphenyl)ethanamine (0.150 mL, 1.015 mmol) followed by PyBOP (0.520 g, 0.999 mmol) were added to a stirred solution of (R)-2-((tert-butoxycarbonyl)amino)-4-hydroxybutanoic acid (0.200 g, 0.912 mmol) in DMF (2.0 mL, 25.8 mmol) and the mixture was stirred overnight, then partitioned between DCM (20 mL) and water (20 mL). The layers were separated and the aqueous fraction was extracted with DCM (20 mL).

[1376] The combined organic extracts were washed with brine (3×20 mL), filtered through a phase separating cartridge and concentrated under reduced pressure. The residue was dried a vacuum oven overnight. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-100% EtOAc in iso-hexane) to afford the title compound (0.116 g, 0.296 mmol, 32.5% yield) as a pale yellow gum. 1H NMR (DMSO-d6, 400 MHz) δ 8.15 (1H, d), 7.21 (1H, t), 6.85 (2H, d), 6.83-6.73 (2H, m), 4.87 (1H, t), 4.50 (1H, t), 4.06-3.99 (1H, m), 3.74 (3H, s), 3.45-3.35 (2H, m), 1.80-1.53 (2H, m), 1.39-1.33 (12H, m).

Preparation 391: (R)-2-amino-4-hydroxy-N—((R)-1-(3-methoxyphenyl)ethyl)butanamide trifluoroacetate

[1377] ##STR01057##

[1378] TFA (0.200 mL, 2.60 mmol) was added was added to a suspension of tert-butyl ((R)-4-hydroxy-1-(((R)-1-(3-methoxyphenyl)ethyl)amino)-1-oxobutan-2-yl)carbamate (0.110 g, 0.281 mmol) in

[1379] DCM (1.0 mL, 15.54 mmol) and the resulting mixture was stirred a room temperature for 4.5h The reaction mixture was concentrated under reduced pressure and azeotroped with toluene (3×20 mL), then dried in a vacuum oven for 5 days to afford the title compound (0.083 g, 94%) as a white solid. The product was used without further purification in the next step. 1H NMR (DMSO-d6) δ: 8.95 (s (br), 1H), 8.08 (s (br), 3H), 7.25 (dd, 1H), 6.92-6.85 (m, 2H), 6.85-6.75 (m, 1H), 4.98-4.86 (m, 1H), 3.96-3.76 (m, 2H), 3.75 (s, 3H), 1.96-1.65 (m, 2H), 1.37 (d, 3H) (note: CH proton was not observed and was overlapped with DMSO or water peak).

Preparation 392: tert-butyl ((2R,3S)-3-hydroxy-1-(((R)-1-(3-methoxyphenyl)ethyl)amino)-1-oxobutan-2-yl)carbamate

[1380] ##STR01058##

[1381] A solution of (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-hydroxybutanoic acid (500 mg, 2.281 mmol) and (R)-1-(3-methoxyphenyl)ethanamine (371 μl, 2.509 mmol) in DMF (3 mL) was stirred at room temperature, triethylamine (636 μl, 4.56 mmol) and PyBop (1306 mg, 2.509 mmol) were added, and the resulting mixture was stirred overnight at room temperature. The reaction was partitioned with DCM (10 mL) and water (10 mL). The organic layer was extracted with DCM (2×10 mL). The combined organic layers were washed with brine (2×10 mL), filtered via a hydrophobic phase separator and concentrated in vacuo. Purification by chromatography (SiO.sub.2, 0-10% MeOH in DCM) gave the title compound (504 mg, 87%) as a colourless gum. 1H NMR (DMSO-d6) δ: 8.15 (d, 1H), 7.20 (dd, 1H), 6.91-6.84 (m, 2H), 6.78 (dd, 1H), 6.32 (d, 1H), 4.97-4.85 (m, 1H), 4.74 (d, 1H), 3.92-3.87 (m, 2H), 3.73 (s, 3H), 1.40 (s, 9H), 1.35 (d, 3H), 1.01 (d, 3H).

Preparation 393: (2R,3S)-2-amino-3-hydroxy-N—((R)-1-(3-methoxyphenyl)ethyl)butanamide hydrochloride

[1382] ##STR01059##

[1383] HCl (1 ml, 4.00 mmol) was added to a solution of tert-butyl ((2R,3S)-3-hydroxy-1-(((R)-1-(3-methoxyphenyl)ethyl)amino)-1-oxobutan-2-yl)carbamate (504 mg, 1.187 mmol) in DCM (5 mL), and the resulting mixture stirred at room temperature for 3 h. The reaction was concentrated under reduced pressure and azeotroped with toluene (10 mL) to afford the title compound (394 mg, 99%). The product was used without further purification in the next step. 1H NMR (DMSO-d6) δ: 9.06 (d, J=8.1 Hz, 1H), 8.17 (s, 3H), 7.24 (dd, 1H), 6.98-6.84 (m, 2H), 6.81 (ddd, 1H), 5.57 (d, 1H), 5.02-4.86 (m, 1H), 3.94-3.78 (m, 1H), 3.74 (s, 3H), 3.63-3.55 (m, 1H), 1.39 (d, 3H), 1.05 (d, 3H).

Preparation 394: tert-butyl (S)-2-(6-bromo-1-oxoisoindolin-2-yl)propanoate

[1384] ##STR01060##

[1385] Prepared using a similar procedure to preparation 73. LCMS: [M-.sup.tBu].sup.+=284.

Preparation 395: tert-butyl (R)-2-(6-bromo-1-oxoisoindolin-2-yl)butanoate

[1386] ##STR01061##

[1387] Prepared using a similar procedure to preparation 73. LCMS: [M-.sup.tBu].sup.+=298.

Preparation 396: tert-butyl (S)-2-(1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)propanoate

[1388] ##STR01062##

[1389] Prepared using a similar procedure to preparation 89. LCMS: [M-.sup.tBu].sup.+=332.

Preparation 397: tert-butyl (R)-2-(1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)butanoate

[1390] ##STR01063##

[1391] Prepared using a similar procedure to preparation 88. 1H NMR (Chloroform-d) δ: 8.37-8.31 (m, 1H), 7.97 (dd, 1H), 7.46 (dd, 1H), 4.91 (dd, 1H), 4.69 (d, 1H), 4.34 (d, 1H), 2.18-2.02 (m, 1H), 1.89-1.72 (m, 1H), 1.43 (s, 9H), 1.35 (s, 12H), 0.94 (t, 3H).

Preparation 398: tert-butyl (S)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoate

[1392] ##STR01064##

[1393] Prepared using a similar procedure to preparation 90. LCMS: [M-.sup.tBu].sup.+=352.

Preparation 399: tert-butyl (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)butanoate

[1394] ##STR01065##

[1395] A stirred solution of (R)-tert-butyl 2-(1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)butanoate (576 mg, 1.435 mmol), 2,4,5-trichloropyrimidine (241 μl, 2.153 mmol), and sodium carbonate (2.0 M aq.) (1.43 mL, 2.87 mmol) in dioxane (13 mL) and H.sub.2O (3 mL) was degassed with nitrogen for 10 minutes. Pd(PPh.sub.3).sub.4 (83 mg, 0.072 mmol) was added and the system degassed with nitrogen for a further 5 minutes. The reaction was heated to 90° C. and stirred overnight. After cooling to room temperature, the reaction was partitioned between water (30 ml) and ethyl acetate (40 ml). The phases were separated and the aqueous was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO.sub.4) and concentrated to give the crude product. Purification by chromatography (SiO.sub.2, 0-100% EtOAc in isohexane) afforded the title compound (331 mg, 54.6%) as a colourless gum. LCMS: [M-.sup.tBu].sup.+=366.

Preparation 400: methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[1396] ##STR01066##

[1397] A mixture of methyl 5-bromo-2-methylbenzoate (5.0 g, 21.83 mmol), bis(pinacolato)diboron (6.7 g, 26.4 mmol) and potassium acetate (4.3 g, 43.8 mmol) in 1,4-dioxane (50.0 mL, 585 mmol) was degassed (bubbling nitrogen) at 40° C. for 10 minutes. PdCl.sub.2(dppf).sub.2 (0.800 g, 1.093 mmol) was added and the mixture was degassed for a further 10 minutes and then heated to 90° C. After 3.5 h the reaction mixture was cooled to room temperature, filtered through celite, washing with EtOAc. The filtrate was concentrated under reduced pressure to afford a dark solid. The crude product was purified by chromatography (SiO.sub.2, 120 g column, 0-100% (20% EtOAc in iso-hexanes) in iso-hexanes) to afford two fractions (2.44 g, 39.7%) and (0.821 g, 12.26%) of the title compound. Both fractions were combined in the next step.). LCMS: [M+H].sup.+=277.

Preparation 401: methyl 5-(2,5-dichloropyrimidin-4-yl)-2-methylbenzoate

[1398] ##STR01067##

[1399] A mixture of methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.26 g, 10.63 mmol), 2,4,5-trichloropyrimidine (1.6 mL, 13.96 mmol) and potassium carbonate (2.94 g, 21.27 mmol) in 1,4-dioxane (30.0 mL, 351 mmol) and water (10.0 mL, 555 mmol) was degassed (bubbling nitrogen) at 40° C. for 10 minutes. Pd(Ph.sub.3P).sub.4 (0.266 g, 0.230 mmol) was added and the mixture degassed for a further 10 minutes and then heated to 90° C. After 5 h the reaction mixture was allowed to cool to room temperature and was partitioned between EtOAc (100 mL) and water (100 mL). The layers were separated and the aqueous fraction was extracted with EtOAc (100 mL). The combined organic extracts were washed with brine (3×100 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude product as a pale yellow solid (4.27 g). The crude product was purified by chromatography (SiO.sub.2, 12 g column, 10-100% DCM in iso-hexane) to afford the title compound (2.27 g, 70.5%). LCMS: [M+H].sup.+=297.

Preparation 402: methyl 2-(bromomethyl)-5-(2,5-dichloropyrimidin-4-yl)benzoate

[1400] ##STR01068##

[1401] NBS (0.493 g, 2.77 mmol) followed by benzoyl peroxide (0.038 g, 0.118 mmol) were added to a stirred solution of methyl 5-(2,5-dichloropyrimidin-4-yl)-2-methylbenzoate (0.698 g, 2.302 mmol) in chloroform (15.0 mL, 186 mmol) and the resulting mixture was heated to reflux overnight. After 24 h the reaction mixture was allowed to cool to room temperature and iso-hexane (20 mL) was added. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford the crude product which was dried in a vacuum oven for 3 days to give the title compound (0.924 g, 85%) as a yellow solid. The product was used without further purification in the next step. 1H NMR (DMSO-d6) δ: 9.05 (s, 1H), 8.32 (d, 1H), 8.07 (dd, 1H), 7.82 (d, 1H), 5.10 (s, 2H), 3.92 (s, 3H).

Preparation 403: (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-4-hydroxy-N—((R)-1-(3-methoxyphenyl)ethyl)butanamide (1432-65)

[1402] ##STR01069##

[1403] A mixture of crude methyl 2-(bromomethyl)-5-(2,5-dichloropyrimidin-4-yl)benzoate (0.075 g, 0.160 mmol), crude (R)-2-amino-4-hydroxy-N—((R)-1-(3-methoxyphenyl)ethyl)butanamide (0.080 g, 0.254 mmol) and DIPEA (0.110 mL, 0.630 mmol) in MeCN (5.0 mL, 96 mmol) was heated to 80° C. overnight. After 17 h the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (30 mL) and NH.sub.4Cl (30 mL). The layers were separated and the organic fraction was washed with NH.sub.4Cl (20 mL), water (20 mL), NaHCO.sub.3 (2×20 mL) and brine (3×20 mL), then dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude product as a pale yellow gum (74 mg). The crude product was purified by chromatography (SiO.sub.2, 4 g column, 0-100% EtOAc in iso-hexanes) to afford the title compound (0.023 g, 27.1%) as a glassy white solid. LCMS: [M+H].sup.+=515.

Preparation 404: (2R,3S)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-3-hydroxy-N—((R)-1-(3-methoxyphenyl)ethyl)butanamide

[1404] ##STR01070##

[1405] DIPEA (0.553 mL, 3.17 mmol) was added to a mixture of crude methyl 2-(bromomethyl)-5-(2,5-dichloropyrimidin-4-yl)benzoate (298 mg, 0.791 mmol) and (2R,3S)-2-amino-3-hydroxy-N—((R)-1-(3-methoxyphenyl)ethyl)butanamide (374 mg, 1.187 mmol) in MeCN (8 mL, 153 mmol). The resulting mixture was heated to 80° C. (external temperature) for 6 hours, then overnight at room temperature. The reaction mixture was concentrated in vacuo. Purification by chromatography (SiO.sub.2, 0-100% EtOAc in iso-hexanes) gave the title compound (2R,3S)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-3-hydroxy-N—((R)-1-(3-methoxyphenyl)ethyl)butanamide (326 mg, 0.576 mmol, 72.7% yield). LCMS: [M+H].sup.+=515.

Preparation 405: (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-2-hydroxy-1-(m-tolyl)ethyl)propanamide

[1406] ##STR01071##

[1407] HATU (404 mg, 1.063 mmol) was added to a stirred mixture of (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (260 mg, 0.709 mmol), (S)-2-amino-2-(m-tolyl)ethanol hydrochloride (146 mg, 0.780 mmol) and DIPEA (309 μl, 1.772 mmol) in acetonitrile (2 ml) and the mixture was stirred for 0.5h. The mixture was diluted with DCM (100 ml) and the solution washed with 1M HCl (2×50 ml). The organic phase was collected, dried (MgSO.sub.4), filtered and concentrated to afford the title compound (400 mg, 93%) as a foam. The product was used without further purification in the next step. LCMS: [M+H].sup.+=485.

Preparation 406: tert-butyl (S)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoate

[1408] ##STR01072##

[1409] Prepared using a similar procedure to preparation 111. LCMS: [M+H].sup.+=473.

Preparation 407 tert-butyl (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)butanoate

[1410] ##STR01073##

[1411] Prepared using a similar procedure to preparation 2. LCMS: [M+H].sup.+=487.

Preparation 408: (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid

[1412] ##STR01074##

[1413] TFA (1 mL, 12.98 mmol) was added to a stirred solution of (R)-tert-butyl 2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoate (304 mg, 0.745 mmol) in DCM (4 mL) and reaction mixture stirred at 40° C. for 1h. The solution was concentrated in vacuo and the residue azeotroped with toluene (3×10 mL), triturated with diethyl ether (10 ml), filtered and dried to afford the title compound (260 mg, 0.709 mmol, 95% yield) as a white solid. The product was used without further purification in the next step. LCMS: [M+H].sup.+=352.

Preparation 409: (S)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid

[1414] ##STR01075##

[1415] Prepared using a similar procedure to preparation 408. LCMS: [M+H].sup.+=417.

Preparation 410 (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)butanoic acid

[1416] ##STR01076##

[1417] Prepared using a similar procedure to preparation 408. LCMS: [M+H].sup.+=431.

Preparation 411: 3-((tert-butyldimethylsilyl)oxy)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid and mixture of 2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-3-hydroxypropanoic acid and 2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-3-methoxypropanoic acid

[1418] ##STR01077##

[1419] A stirred solution of methyl 3-((tert-butyldimethylsilyl)oxy)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoate (0.580 g, 1.034 mmol) in THF (3 ml) was treated with a solution of lithium hydroxide (0.05 g, 2.088 mmol) in water (1 ml) followed by methanol (1 ml) to give an homogenous solution which was stirred at room temperature overnight. The mixture was was diluted with brine (10 min) and extracted with ether (10 ml). The combined organic extracts were dried and concentrated under vacuum to afford 3-((tert-butyldimethylsilyl)oxy)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (116 mg, 14.36%, LCMS: [M+H].sup.+=547) as an orange solid. The aqueous layer was acidified with 1M KHSO.sub.4 and extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (10 ml), dried (Na.sub.2SO.sub.4) and evaporated. The residue was dissolved in TFA (4 ml), stirred for 2 minutes and evaporated. The residue was suspended in toluene (3×10 ml) and evaporated, then dissolved in THF (3 ml), treated with a solution of lithium hydroxide (0.1 g, 4.18 mmol) in water (1 ml) followed by methanol (1 ml) to give an homogenous solution which was stirred overnight. The mixture was diluted with brine (10 min), washed with ether (10 ml), acidified with 1M KHSO.sub.4 and extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (10 ml), dried (Na.sub.2SO.sub.4) and evaporated to give a mixture of 2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-3-hydroxypropanoic acid and 2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-3-methoxypropanoic acid as an orange foam (555 mg, LCMS: [M+H]+=433 and 447).

Preparation 412: Mixture of 3-((tert-butyldimethylsilyl)oxy)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid and 2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-3-methoxypropanoic acid

[1420] ##STR01078##

[1421] A stirred solution of a mixture of 2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-3-hydroxypropanoic acid and 2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-3-methoxypropanoic acid 548 mg) and imidazole (259 mg, 3.80 mmol) in DMF (2 ml) was treated with TBDMS-Cl (286 mg, 1.898 mmol) and stirred overnight. The solution was quenched with brine (20 ml), acidified with 1M KHSO.sub.4 and extracted with ethyl acetate (20 ml and 2×10 ml). The combined extracts were washed with brine (2×20 ml), dried (MgSO.sub.4) and evaporated to give the title mixture as a yellow oil (629 mg).). LCMS: [M+H].sup.+=447 and 547.

Preparation 413: 3-((tert-butyldimethylsilyl)oxy)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((R)-1-(3-methoxyphenyl)ethyl)propanamide (1419-38)

[1422] ##STR01079##

[1423] A stirred solution of 3-((tert-butyldimethylsilyl)oxy)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (629 mg, 1.150 mmol) (mixture with 2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-3-methoxypropanoic acid (629 mg)), (R)-1-(3-methoxyphenyl)ethanamine (209 mg, 1.382 mmol) and DIPEA (0.8 ml, 4.58 mmol) in DMF (4 ml) was treated with HATU (481 mg, 1.265 mmol) and stirred for 3 h. The mixture was diluted with ethyl acetate (40 ml), was washed successively with 1N KHSO.sub.4 (20 ml), NaHCO.sub.3 (20 ml), brine (2×10 ml), then dried (MgSO.sub.4) and evaporated. The residue was purified by chromatography (SiO.sub.2, 25 g column, 10-100% EtOAc in isohexane) to afford the title compound (261 mg, 31.7%) as a cream foam. LCMS: [M+H].sup.+=680.

[1424] Note: 2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-3-methoxy-N—((R)-1-(3-methoxyphenyl)ethyl)propanamide, which was further purified by reversed phase preparative HPLC on a Waters Xbridge BEH C18 OBD, 130 Å, 5 μm, 19 mm×50 mm column, using a gradient of 20 to 50% of acetonitrile in 10 mM aqueous ammonium bicarbonate solution at 28 ml/min as eluent was also isolated from this reaction.

Preparation 414: 3-((tert-butyldimethylsilyl)oxy)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((R)-1-(m-tolyl)ethyl)propanamide

[1425] ##STR01080##

[1426] Triethylamine (39.7 μl, 0.285 mmol) was added to a mixture of 3-((tert-butyldimethylsilyl)oxy)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (52 mg, 0.095 mmol), (R)-1-phenylethanamine (13.82 mg, 0.114 mmol) and HATU (39.8 mg, 0.105 mmol) in DMF (0.5 mL) and the mixture was stirred for 1h. Water (5 mL) was added, and the resulting precipitate filtered, washed with water (5 mL). Purification by chromatography (SiO.sub.2, 20-100% ethyl acetate in iso-hexane) afforded the title compound (24 mg, 38.4%) as a colourless powder. LCMS: [M+H].sup.+=650.

Preparation 415: tert-butyl (R)-2-(3-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)propanoate

[1427] ##STR01081##

[1428] Oxan-4-amine (0.540 ml, 5.22 mmol) and DIPEA (1.140 ml, 6.53 mmol) were added to a solution of (R)-tert-butyl 2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)propanoate (Preparation 367, 1.526 g, 2.61 mmol) in 1,4-dioxane (13.05 ml, 2.61 mmol) and the mixture stirred at 90° C. for 24 h, then cooled to room temperature. The mixture was concentrated in vacuo and the residue was dissolved in EtOAc (100 mL). The organic solution was washed sequentially with NH.sub.4Cl (50 mL), NaHCO.sub.3 (50 mL) and brine, then dried (MgSO.sub.4), filtered and absorbed on silica. The crude product was purified by chromatography (SiO.sub.2, 40 g column, 0-100% EtOAc in isohexane) to afford the title compound (910 mg, 66.2%) as an orange oil. LCMS: [M+H].sup.+=474.

Preparation 416: (R)-2-(3-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)propanoic acid

[1429] ##STR01082##

[1430] A stirred solution of (R)-tert-butyl 2-(3-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)propanoate (Preparation 415, 910 mg, 1.920 mmol) in dichloromethane (9 mL) was treated with TFA (8 mL) and the mixture was stirred at room temperature for 2 h. The solution was concentrated in vacuo and residual TFA removed by co-evaporation with toluene (3×20 mL). The residue was triturated with diethyl ether (20 mL) and the solid collected by filtration, washed with diethyl ether (10 mL) and dried under suction to afford the title compound (588 mg, 68.9%) as a yellow solid. The filtrate was concentrated in vacuo and then evaporated from diethyl ether (3 mL) to afford a second batch of the title compound (209 mg, 24.75%) as a yellow solid. LCMS: [M+H].sup.+=418.

Preparation 417: (R)-2-(6-(5-chloro-2-((2-methyl-2H-1,2,3-triazol-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid

[1431] ##STR01083##

[1432] A solution of (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (Preparation 349) (2 g, 4.77 mmol) and 2-methyl-2H-1,2,3-triazol-4-amine hydrobromide (0.939 g, 5.25 mmol) in dry DMF (25 ml) was treated with cesium carbonate (3.26 g, 10.02 mmol) and the suspension sonicated for 15 minutes to form a finely divided suspension. The suspension was degassed for 3 minutes by passing a stream of nitrogen through the mixture. t-BuBrettPhos Allyl (Pd-175) (0.186 g, 0.239 mmol) was added and the suspension stirred at 70° C. for 1 h. Diethyl ether (70 ml) was added to the cooled reaction mixture and the resulting solid was collected by filtration. The filtrate was discarded and the solid dissolved in water (100 ml). The solution was treated with 1M HCl until pH 1 and the mixture was extracted with 2-methyl THF ((2×150 ml). The organic extract was dried (MgSO.sub.4), filtered and absorbed on silica. The crude product was purified by chromatography (SiO.sub.2, 40 g column, 40-80% 2-methyl THF in isohexane) to afford the title compound (1.6 g, 72.1%) as a yellow solid. LCMS: [M+H].sup.+=414.

Preparation 418: (1R)-1-[6-(4-Methylpiperazin-1-yl)pyridin-2-yl]ethan-1-amine

[1433] ##STR01084##

[1434] A solution of (1R)-1-(6-fluoropyridin-2-yl)ethan-1-amine hydrochloride (1.0 g, 5.6 mmol) in N-methyl-piperazine (6.0 mL, 54 mmol) was heated at 100° C. for 16 h. The reaction mixture was cooled, 1M Na.sub.2CO.sub.3 (30 mL) was added and the product was extracted with CHCl.sub.3/2-propanol (9:1, 2×30 mL). The combined organic phases were dried, filtered and concentrated to dryness to afford the title compound as a brown oil (1.23 g, 99%). MS: [M+H].sup.+=221. 1H NMR (400 MHz, DMSO-d6): 7.46 (1H, dd), 6.71-6.56 (2H, m), 3.79 (1H, q), 3.46 (4H, t), 2.39 (4H, t), 2.21 (3H, s), 1.79 (2H, s), 1.24 (3H, d).

Preparation 419: 6-(2,5-Dichloropyrimidin-4-yl)-2-{2-[(1-hydroxy-2-phenylpropan-2-yl)amino]ethyl}-2,3-dihydro-1H-isoindol-1-one

A. 2-[(2-Aminoethyl)amino]-2-phenylpropan-1-ol

[1435] ##STR01085##

[1436] To 2-amino-2-phenylpropan-1-ol (100 mg, 0.66 mmol) in CHCl.sub.3 (2.2 mL) was added tert-butyl n-(2-oxoethyl)carbamate (134 mg, 0.76 mmol) and then sodium triacetoxyborohydride (217 mg, 0.99 mmol), at room temperature under nitrogen. The mixture was stirred for 16 hours. The reaction was quenched with NaHCO.sub.3 (sat., aq.) and the product extracted with CHCl3 (×3). The combined organic layers were washed with water, brine and dried over MgSO.sub.4. The product was filtered and evaporated to dryness. The product was purified by biotage (0-100% EtOAc in petrol). To the residue was added HCl in EtOAc (sat.). The mixtu rewash stirred for 2 hours and evaporated to dryness, and again from MeOH to yield a light brown foam (81 mg, 42%). .sup.1H NMR (Me-d3-OD): 7.66 (2H, d), 7.59-7.44 (3H, m), 4.17 (1H, d), 3.88 (1H, d), 3.31 (2H, d), 3.20-3.02 (2H, m), 1.84 (3H, s). LC-MS: [M+H].sup.+=195.

B. 6-(2,5-Dichloropyrimidin-4-yl)-2-{2-[(1-hydroxy-2-phenylpropan-2-yl)amino]ethyl}-2,3-dihydro-1H-isoindol-1-one

[1437] ##STR01086##

[1438] Methyl 2-(bromomethyl)-5-(2,5-dichloropyrimidin-4-yl)benzoate (Preparation 180) (52 mg, 0.14 mmol) and 2-[(2-aminoethyl)amino]-2-phenylpropan-1-ol (38 mg, 0.17 mmol) and DIPEA (53 μL, 0.31 mmol) in THF (0.5 mL) was stirred at room temperature for 24 hours. The sample was concentrated and purified by preparative HPLC to yield the product as a colourless oil (10 mg, 16%). .sup.1H NMR (Me-d3-OD): 8.86 (1H, s), 8.33 (1H, d), 8.16 (1H, dd), 7.76 (1H, d), 7.41-7.37 (2H, m), 7.23-7.17 (3H, m), 4.63 (1H, d), 4.58-4.50 (1H, m), 3.83-3.72 (2H, m), 3.68-3.59 (2H, m), 2.89-2.79 (1H, m), 2.72-2.62 (1H, m), 1.52 (3H, s). LC-MS: [M+H].sup.+=457.

Preparation 420: (R)-2-(6-bromo-1-oxoisoindolin-2-yl)propanoic acid

[1439] ##STR01087##

[1440] A stirred solution of (R)-tert-butyl 2-(6-bromo-1-oxoisoindolin-2-yl)propanoate (61.7 mmol) in DCM (100 mL) was treated with TFA (75 mL, 973 mmol) and stirred at room temperature for 2 h. The mixture was concentrated and the residue was evaporated with toluene (3×100 mL), then triturated with diethyl ether, filtered and dried in vacuo at 50° C. overnight to afford the title compound (16.22 g, 92%) as an off-white solid. LCMS: [M+H].sup.+=284.

Preparation 421: (R)-2-(6-bromo-1-oxoisoindolin-2-yl)-N—((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propanamide

[1441] ##STR01088##

[1442] A stirred solution of (S)-2-amino-2-(3-fluoro-5-methoxyphenyl)ethanol hydrochloride (1.716 g, 7.74 mmol), (R)-2-(6-bromo-1-oxoisoindolin-2-yl)propanoic acid (2 g, 7.04 mmol) and triethylamine (3.92 ml, 28.2 mmol) in DMF (10 ml) was treated with TBTU (2.373 g, 7.39 mmol) and stirred at room temperature for 1.5 h. Saturated aqueous NH.sub.4Cl (100 mL) was added and the resulting precipitate was filtered, washed with water, then dried in a vacuum oven at 40° C. overnight to give a light brown solid (2.94 g). The crude product was purified by chromatography (SiO.sub.2, 0-10% (1% NH.sub.3MeOH) in DCM) to afford the tile compound (2.6 g, 80%) as a cream coloured foam. LCMS: [M+H].sup.+=451.

Preparation 422: (R)—N—((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)-2-(1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)propanamide

[1443] ##STR01089##

[1444] A mixture of (R)-2-(6-bromo-1-oxoisoindolin-2-yl)-N—((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propanamide (2.6 g, 5.76 mmol), bis(pinacolato)diboron (2.195 g, 8.64 mmol), potassium acetate (1.696 g, 17.28 mmol) and XPhos G3 (0.244 g, 0.288 mmol) was evacuated and back-filled with nitrogen (×3). 1,4-dioxane (11.52 ml, 5.76 mmol) was added and the system evacuated and back-filled with nitrogen (×3). The mixture was heated to 90° C. and stirred for 1.5 h. The reaction mixture was allowed to cool, diluted with EtOAc (50 mL), then filtered through a bed of celite, washing with EtOAc (100 mL). The mixture was concentrated to give the crude product as a dark brown gum. The crude product was purified by chromatography (SiO.sub.2, 0-10% MeOH in DCM) to afford the title compound (1.52 g, 47.5%) as a white solid. LCMS: [M+H].sup.+=499.

Preparation 423: (R)-2-(6-bromo-1-oxoisoindolin-2-yl)-N—((S)-1-(6-(dimethylamino)pyridin-2-yl)-2-hydroxyethyl)propanamide

[1445] ##STR01090##

[1446] TBTU (0.831 g, 2.59 mmol) was added to a mixture of (S)-2-amino-2-(6-(dimethylamino)pyridin-2-yl)ethanol (0.491 g, 2.71 mmol), (R)-2-(6-bromo-1-oxoisoindolin-2-yl)propanoic acid (0.7 g, 2.464 mmol) and triethylamine (1.374 ml, 9.86 mmol) in DMF (12.32 ml, 2.464 mmol) and the mixture was stirred overnight at room temperature. Water (100 mL) was added and the resulting precipitate was filtered, washed with water, dried under reduced pressure, then in a vacuum oven overnight. The crude product was triturated with Et.sub.2O, filtered and dried to afford the title compound (844 mg, 75%) as a pale brown solid. LCMS: [M+H].sup.+=447.

Preparation 424: (R)—N—((S)-1-(6-(dimethylamino)pyridin-2-yl)-2-hydroxyethyl)-2-(1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)propanamide

[1447] ##STR01091##

[1448] A mixture of (R)-2-(6-bromo-1-oxoisoindolin-2-yl)-N—((S)-1-(6-(dimethylamino)pyridin-2-yl)-2-hydroxyethyl)propanamide (0.800 g, 1.788 mmol bis(pinacolato)diboron (0.681 g, 2.68 mmol), potassium acetate (0.527 g, 5.37 mmol) and XPhos Pd G3 (0.076 g, 0.089 mmol) was evacuated and back-filled with nitrogen (×3). 1,4-dioxane (3.58 ml, 1.788 mmol) was added and the system evacuated and back-filled with nitrogen (×3). The mixture was heated to 90° C. and stirred for 1.5 h, then left to stand at room temperature overnight. The reaction mixture was diluted with EtOAc (50 mL), filtered through celite washing with EtOAc (100 mL). The filtrate was concentrated to give a dark brown gum. The crude product was triturated with diisopropyl ether (50 mL), sonicated and left to stir to give a light brown solid which was collected by filtration and dried in a vacuum oven at 40° C. to give the title compound (763 mg, 82%). LCMS: [M+H].sup.+=495.

Preparation 425: 5-chloro-2-((2-methoxypyridin-4-yl)amino)pyrimidin-4-ol

[1449] ##STR01092##

[1450] Cs.sub.2CO.sub.3 (1.775 g, 5.45 mmol) was added to a solution of 2,5-dichloropyrimidin-4-ol (0.428 g, 2.59 mmol) and 2-methoxypyridin-4-amine (0.354 g, 2.85 mmol) in DMF (8 mL, 103 mmol). The mixture was degassed (3× with nitrogen) then [Pd(allyl)tBuBrettPhos)]OTf (Pd-175) (0.071 g, 0.091 mmol) was added. The reaction was further degassed then placed under nitrogen and heated to 90° C. for 3 h. The mixture was allowed to cool to room temperature and Et.sub.2O (30 mL) was added. The resulting yellow-brown solid was collected by filtration and washed with Et.sub.2O (15 mL). The filtrate was concentrated in vacuo then combined with the solid and suspended in DCM (20 mL). 4M HCl in dioxane (4.5 mL) was added whilst stirring then the mixture stirred before collecting the pale brown solid by filtration in vacuo. The solid was washed with DCM (15 mL) then air dried to afford the crude title compound (2.48 g). The product, which contained a mixture of cesium salts, was used without further purification in the next step. LCMS: [M+H].sup.+=253.

Preparation 426: 4,5-dichloro-N-(2-methoxypyridin-4-yl)pyrimidin-2-amine

[1451] ##STR01093##

[1452] POCl.sub.3 (0.966 ml, 10.36 mmol) was added to a stirred suspension of 5-chloro-2-((2-methoxypyridin-4-yl)amino)pyrimidin-4-ol (654 mg, 2.59 mmol) in toluene (10 ml, 94 mmol) and the mixture was heated to 90° C. for 2.5 h. An additional 0.75 mL of POCl.sub.3 was added then stirring continued at 90° C. for 4 h. The mixture was allowed to cool to ambient temperature then an additional 0.5 mL of POCl.sub.3 was added and heating at 90° C. continued for 3 h. A further portion POCl.sub.3 (0.5 mL) was added and heating at 90° C. was continued for 3 hour. The mixture was concentrated in vacuo and the residue was azeotroped with toluene (3×5 mL) then suspended in water (45 mL) and basified to pH=14 with 2M NaOH (aq). The yellow solid was collected by filtration then washed with water (20 mL), air dried overnight then in a dessicator to afford the title compound (277 mg, 33%). The product was used without further purification in the next step. LCMS: [M+H].sup.+=271.

Preparation 427: 5-chloro-2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-ol

[1453] ##STR01094##

[1454] Cs.sub.2CO.sub.3 (27.0 g, 83 mmol) was added to a solution of 2,5-dichloropyrimidin-4-ol (6.5 g, 39.4 mmol) and 2-methylpyrimidin-4-amine (4.51 g, 41.4 mmol) in DMF (100 mL, 1291 mmol). The mixture was degassed (3× with nitrogen) then [Pd(allyl)tBuBrettPhos)]OTf (Pd-175) (0.646 g, 0.827 mmol) was added. The reaction was further degassed then placed under nitrogen and heated to 95° C. for 3 h, then at room temperature overnight. Et.sub.2O (300 mL) was added and the resulting pale yellow solid collected by filtration and washed with Et.sub.2O (150 mL). The solid was suspended in DCM (100 mL) and 4M HCl in dioxane (60 mL) was added in portions (pH=1). The pale yellow solid was collected by filtration and washed with DCM (50 mL) then dried in vacuo to afford the title compound (38.66 g). The product, which contained a mixture of cesium salts, was used without further purification in the next step. LCMS: [M+H].sup.+=238.

Preparation 428: 4,5-dichloro-N-(2-methylpyrimidin-4-yl)pyrimidin-2-amine

[1455] ##STR01095##

[1456] POCl.sub.3 (14.69 mL, 158 mmol) was added to a stirred suspension of 5-chloro-2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-ol (9.36 g, 39.4 mmol) in toluene (150 mL, 1408 mmol). The reaction was heated to 90° C. for 130 minutes then the solvents were removed in vacuo. The residue was azeotroped with toluene (3×75 mL) then suspended in water (300 mL). The stirred suspension was basified to pH=14 with 2M NaOH (aq, 100 mL) then diluted with water (100 mL). The resulting pale yellow solid was collected by filtration in vacuo then washed with water (100 mL then 50 mL). The solid was transferred to a flask using MeCN (100 mL) and toluene (75 mL) then concentrated in vacuo. The yellow solid was then azeotroped with toluene (2×75 mL) to afford the title compound (7.7 g, 73%). LCMS: [M+H].sup.+=256.

Preparation 429: (R)-2-(6-(5-chloro-2-((2-methoxypyridin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid

[1457] ##STR01096##

[1458] A 250 mL round bottom flask was charged with (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (4.85 g, 13.50 mmol), 2-methoxypyridin-4-amine (2.51 g, 20.25 mmol), cesium carbonate (9.24 g, 28.4 mmol), and Xantphos (0.391 g, 0.675 mmol). The system was evacuated and back-filled with nitrogen (×3) and DMF (90 ml, 13.50 mmol) was added. The mixture was once again evacuated and back-filled with nitrogen (×3) then heated to 75° C. and stirred for 15 minutes, before addition of palladium(II) acetate (0.152 g, 0.675 mmol) in a single portion. The mixture was stirred at 75° C. for 110 minutes, then cooled with an ice bath and poured onto Et.sub.2O (400 mL). The resulting precipitate was collected by filtration and washed with further portions of Et.sub.2O (2×100 mL) then dried to give the crude material as a light brown solid. The crude product was dissolved in DCM containing 5% AcOH in MeOH, absorbed on silica and purified by chromatography (SiO.sub.2, 3-10% (5% (AcOH in 10% MeOH/DCM) in DCM) to afford the product as a cream solid. The solid was triturated with Et.sub.2O, filtered and washed with further portions of Et.sub.2O (3×50 mL). The solid was then collected and azeotroped with toluene (3×40 mL). Further trituration with Et.sub.2O afforded the title compound (4.744 g, 79%) as a white solid. LCMS: [M+H].sup.+=440.

EXAMPLES

Compounds of Formula (1)

Example 1: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid

[1459] ##STR01097##

[1460] Method A: TFA (75 mL, 954 mmol) was added to a stirred solution of tert-Butyl 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl) acetate (Preparation 4) (8.9 g, 19.39 mmol) in DCM (150 mL) and the reaction was stirred at room temperature overnight. The mixture was concentrated under vacuum and the residue was azeotroped with toluene (3×150 mL) then triturated with diethyl ether. The resulting precipitate was filtered and dried to afford the title compound (7.49 g, 18.41 mmol, 95%) as a colourless solid. 1H NMR (400 MHz, Me-d.sub.3-OD): 8.35 (1H, s), 8.23 (1H, d), 8.06 (1H, dd), 7.71 (1H, dd), 4.70 (2H, s), 4.32 (2H, s), 4.11-4.02 (1H, m), 4.02-3.95 (2H, m), 3.55 (2H, td), 2.05-1.98 (2H, m), 1.70-1.57 (2H, m). LC-MS: [M+H].sup.+=403.

[1461] Method B: tert-Butyl 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate (Preparation 4) (1.2 g) was taken up in EtOAc saturated in HCl (5 mL) sealed with a stopper and stirred for 2 hours at room temperature. Ethyl ester was present by trans-esterification, as well as desired product. The reaction was evaporated under vacuum and taken up in THF/MeOH/water (5:1:1, 2 mL) and NaOH (1 M, 0.5 ml) was added. The mixture was stirred at room temperature for 24 hours, diluted with water, and the pH adjusted to ˜pH 4-5 with citric acid (5%, aq.). The mixture was extracted with CHCl.sub.3:IPA (3:1, ×3) and the combined organic layers washed with brine, dried over MgSO, filtered and concentrated under vacuum to yield the product which was used crude for further reactions. Purification of a portion (˜60 mg) by preparative HPLC gave the title compound (16 mg, 25%) as a colourless solid. 1H NMR (400 MHz, Me-d.sub.3-OD): 8.35 (1H, s), 8.23 (1H, d), 8.06 (1H, dd), 7.71 (1H, dd), 4.70 (2H, s), 4.32 (2H, s), 4.11-4.02 (1H, m), 4.02-3.95 (2H, m), 3.55 (2H, dt), 2.05-1.98 (2H, m), 1.70-1.57 (2H, m).

Example 2: N-tert-butyl-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-methylacetamide

[1462] ##STR01098##

[1463] Triethylamine (0.071 mL, 0.51 mmol) was added to a solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 70 mg, 0.17 mmol), N-tert-butyl-methylamine (0.021 mL, 0.17 mmol) and HATU (71 mg, 0.19 mmol) in DCM (2.7 mL) and DMF (0.3 mL). The mixture was stirred at RT for 18 h. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with brine (3×20 mL), dried (MgSO.sub.4) and concentrated. Purification by chromatography (SiO.sub.2, 0-5% methanol in EtOAc) gave the title compound (46 mg, 56%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6) 8.45 (1H, s), 8.03-8.02 (1H, m), 7.97 (1H, dd), 7.74 (1H, d), 7.62 (1H, br. s), 4.53 (2H, s), 4.39 (2H, s), 3.96-3.85 (3H, m), 3.40-3.34 (2H, m), 2.92 (3H, s), 1.84 (2H, br. d), 1.57-1.47 (2H, m), 1.35 (9H, s). LC-MS: [M+H].sup.+=472.

Examples 3-88

[1464] Prepared using an analogous procedure to Example 2, from 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) and the corresponding amine:

TABLE-US-00022 MS: [M + Example Structure Name .sup.1H NMR (400 MHz) H].sup.+ 3 [01099] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(1- methylcyclobutyl)- acetamide (DMSO-d6) 8.45 (1H, s), 8.19 (1H, s), 8.03-8.02 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.63 (1H, br. s), 4.59 (2H, s), 4.14 (2H, s), 3.98-3.84 (3H, m), 3.41-3.35 (2H, m), 2.31-2.23 (2H, m), 1.92-1.72 (6H, m), 1.58-1.48 (2H, m), 1.38 (3H, s). 470 4 [01100] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(1- methylcyclohexyl)- acetamide (DMSO-d6) 8.45 (1H, s), 8.02- 8.01 (1H, m), 7.97 (1H, dd), 7.74 (1H, d), 7.62 (1H, br. s), 7.50 (1H, s), 4.58 (2H, s), 4.18 (2H, s), 3.97-3.85 (3H, m), 3.41-3.34 (2H, m), 2.03-2.00 (2H, m), 1.86-1.83 (2H, m), 1.57-1.37 (7H, m), 1.31-1.20 (6H, m). 498 5 [01101] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-(2- methylpyrrolidin-1-yl)- 2-oxoethyl]-2,3- dihydro-1H-isoindol-1- one (DMSO-d6, VT T = 373 K) 8.40 (1H, s), 8.10-8.07 (1H, m), 8.01 (1H, dd), 7.74-7.70 (1H, m), 7.13 (1H, d), 4.63 (2H, s), 4.37 (2H, s), 4.12 (1H, s), 4.05-3.94 (1H, m), 3.89 (2H, dt), 3.58- 3.37 (4H, m), 1.99 (2H, s), 1.91 (3H, d), 1.68-1.50 (3H, m), 1.21 (3H, s). 470 6 [01102] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2-(3- phenylpyrrolidin-1- yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.46 (1H, s), 8.04 (1H, s), 7.99 (1H, dd), 7.76 (1H, d), 7.62 (1H, br. s), 7.37-7.32 (4H, m), 7.29-7.25 (1H, m), 4.61 (2H, d), 4.46 (2H, dd), 3.77-4.04 (4H, m), 3.64 (1H, m), 3.49 (1H, m), 3.38 (3H, m), 3.24 (1H, m), 2.21-2.40 (1H, m), 1.92-2.13 (1H, m), 1.84- 1.87 (2H, m), 1.53 (2H, ddd). 532 7 [01103] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(3- methyloxetan-3- yl)acetamide (DMSO-d6) 8.60 (s, 1H), 8.44 (1H, s), 8.03 (1H, d), 7.98 (1H, dd), 7.75 (1H, d), 7.60 (1H, br. s), 4.61-4.59 (4H, m), 4.29 (2H, d), 4.19 (2H, s), 3.94-3.85 (3H, m), 3.40-3.37 (2H, m), 1.85 (2H, d), 1.57-1.47 (5H, m). 472 8 [01104] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(4,4- difluorocyclohexyl)- acetamide (DMSO-d6) 8.44 (1H, s), 8 12 (1H, d), 8.02 (1H, s), 7.98 (1H, dd), 7.74 (1H, d), 7.60 (1H, br. s), 4.58 (2H, s), 4.19 (2H, s), 3.92-3.80 (4H, m), 3.17 (1H, d), 1.99-1.79 (9H, m), 1.57-1.47 (4H, m). 520 9 [01105] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-(2,3-dihydro- 1H-isoindol-2-y1)-2- oxoethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.45 (1H, s), 8.06- 8.04 (1H, br. m), 7.99 (1H, dd), 7.77 (1H, d), 7.62 (1H, br. s), 7.40-7.37 (2H, m), 7.35-7.32 (2H, m), 4.97 (2H, s), 4.70 (2H, s), 4.62 (2H, s), 4.54 (2H, s), 3.97-3.90 (1H, m), 3.90-3.83 (2H, m), 3.38 (2H, t), 1.89-1.81 (2H, m), 1.58-1.48 (2H, m). 504 10 [01106] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-(4.4- difluoropiperidin-1-yl)- 2-oxoethyl]-2,3- dihydro-1H-isoindol-1- one (DMSO-d6) 8.45 (1H, s), 8.04 (1H, d), 7.99 (1H, dd), 7.76 (1H, d), 7.61 (1H, br. s), 4.57 (2H, s), 4.55 (2H, s), 3.95-3.86 (3H, m), 3.63-3.58 (4H, m), 3.38-3.35 (2H, m), 2.16-1.84 (6H, m), 1.58-1.48 (2H, m). 506 11 [01107] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(1,1,1- trifluoro-2- methylpropan-2- yl)acetamide (DMSO-d6) 8.44 (1H, s), 8.24 (1H, s), 8.02 (1H, t), 7.98 (1H, dd), 7.74 (1H, d), 7.61 (1H, s), 4.58 (2H, s), 4.24 (2H, s), 3.98- 3.81 (3H, m), 3.42-3.33 (2H, m), 1.84 (2H, d), 1.57-1.47 (8H, m). 512 12 [01108] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2-(5,6,7,8- tetrahydro-1,7- naphthyridin-7- yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.48-8.37 (2H, m), 8.06-8.02 (1H, m), 7.99 (1H, dd), 7.76 (1H, d), 7.64 (2H, d), 7.30-7.20 (1H, m), 4.79 (1H, s), 4.68-4.55 (5H, m), 3.98-3.79 (4H, m), 3.76 (1H, t), 3.39 (2H, d), 2.97 (1H, t), 2.83 (1H, t), 1.85 (2H, d), 1.53 (2H, qd). 519 13 [01109] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-(7-fluoro-3- methyl-1,2,3,4- tetrahydroisoquinolin- 2-yl)-2-oxoethyl]-2,3- dihydro-1H-isoindol-1- one (DMSO-d6, 353 K) 8.41 (1H, s), 8.09-8.06 (1H, m), 8.00 (1H, dd), 7.73 (1H, dd), 7.28-7.20 (2H, m), 7.08 (1H, dd), 7.02 (1H, td), 4.91 (1H, d), 4.75-4.27 (6H, m), 3.96 (1H, ddt), 3.88 (2H, dt), 3.41 (2H, td), 2.69 (1H. d), 1.89 (2H, dd), 1.66-1.51 (2H, m), 1.10 (3H, d). 550 14 [01110] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(1- hydroxy-2- methylpropan-2-yl)-N- methylacetamide (DMSO-d6) 8.45 (1H, s), 8.02 (1H, d), 7.97 (1H, dd), 7.74 (1H. d), 7.62 (1H, br. s), 4.77 (1H, t), 4.54 (2H, s), 4.40 (2H, s), 3.94- 3.86 (3H, m), 3.56 (2H, d), 3.40-3.35 (2H, m), 2.96 (3H, s), 1.86-1.83 (2H, m), 1.57-1.47 (2H, m), 1.29 (6H, s). 488 15 [01111] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(1- methylcyclo propyl)acetamide (DMSO-d6) 8.45 (1H, s), 8.36 (1H, s), 8.02-8.01 (1H, br. m), 7.97 (1H, dd), 7.74 (1H, d), 7.62 (1H, br. s), 4.56 (2H, s), 4.09 (2H, s), 3.98-3.82 (3H, m), 3.37-3.40 (2H, m), 1.88-1.80 (2H, m), 1.57-1.47 (2H, m), 1.27 (3H, s), 0.64-0.61 (2H, m), 0.54-0.51 (2H, m). 456 16 [01112] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(1- methylcyclopentyl)- acetamide (DMSO-d6) 8.45 (1H, s), 8.02- 8.01 (1H, m), 7.97 (1H, dd). 7.85 (1H, s), 7.74 (1H, d), 7.63 (1H, br. s), 4.58 (2H, s), 4.14 (2H, s), 3.97-3.85 (3H, m), 3.37 (2H, t), 2.00-1.92 (2H, m), 1.87- 1.81 (2H, br. m), 1.70-1.46 (8H, m), 1.32 (3H, s). 484 17 [01113] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-(2-oxo-2- {1H,2H,3H,4H- pyrrolo[1,2-a]pyrazin- 2-yl}ethyl)-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.46 (1H, s), 8.04 (1H, s), 7.99 (1H, dd), 7.76 (1H, d), 7.63 (1H, br. s), 6.72 (1H. m), 6.03 (1H, dt), 5.87 (1H, m), 4.80 (1H, s), 4.58-4.62 (5H, m), 4.10 (1H, m), 3.82-3.99 (6H, m), 3.34-3.41 (2H, m), 1.85 (2H, m), 1.53 (2H, ddd). 507 18 [01114] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-(2,5- dimethylmorpholin-4- yl)-2-oxoethyl]-2,3- dihydro-1H-isoindol-1- one (DMSO-d6, 373 K) 8.41 (1H, s), 8.08 (1H, d), 8.01 (1H, dd), 7.74 (1H, d), 7.27 (1H, d), 4.60 (2H, d), 4.49 (1H, d), 4.43 (1H, d), 4.18 (0.68H, m), 3.86-3.99 (5H, m), 3.61-3.69 (2H, m), 3.35- 3.48 (4H, m), 1.89 (2H, m), 1.59 (2H, m), 1.15-1.28 (8H, m) (additional hydrogen count due to presence of rotamers and stereoisomers). 500 19 [01115] 2-(6-{5-chloro-2- [(oxan-4-yl)amino) pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N- methyl-N-(2- methylbutan-2- yl)acetamide (DMSO-d6) 8.46 (1H, s), 8.03 (1H, s), 7.97 (1H, dd), 7.75 (1H, d), 7.63 (1H, br. s), 4.54 (2H, s), 4.43 (2H,s), 3.93 (1H, m), 3.87 (2H, m), 3.37-3.41 (2H, m), 2.93 (3H, s), 1.80-1.86 (4H, m), 1.53 (2H, ddd), 1.31 (6H, s), 0.76 (3H, t). 486 20 [01116] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-{2-oxo-2-[(2S)-2- (trifluoromethyl) piperidin-1-yl]ethyl}- 2,3-dihydro-1H- isoindol-1-one (DMSO-d6) 8.45 (1H, s), 8.03 (1H, d), 7.98 (1H, dd), 7.75 (1H d), 7.62 (1H, s), 5.20-5.08 (0.75H, m, major rotamer), 4.98-4.84 (0.25H, m, minor rotamer). 4.77-4.32 (4H, m), 3.98-3.82 (4H, m), 3.42-3.34 (2H, m), 3.16 (0.75H, t, major rotamer), 2.66 (0.25H, t, minor rotamer), 2.04-1.43 (10H, m). 538 21 [01117] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo 2,3-dihydro-1H- isoindol-2-yl)-N-(4- methyloxan-4- yl)acetamide (DMSO-d6) 8.45 (1H, s), 8.03 (1H, br. s), 7.98 (1H, dd), 7.75 (2H, m), 7.63 (1H, br. s), 4.60 (2H, s), 4.22 (2H, s), 3.83-3.98 (3H, m), 3.51-3.62 (4H, m), 3.35-3.41 (2H, m), 2.01-2.04 (2H, m), 1.81-1.88 (2H, m), 1.45-1.58 (4H, m), 1.31 (3H, s). 500 22 [01118] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(2- cyclopropylpropan-2- yl)acetamide (DMSO-d6) 8.45 (1H, s), 8.03 (1H, dd), 7.98 (1H, dd), 7.74 (1H, dd), 7.67 (1H, s), 7.61 (1H, br. s), 4.59 (2H, s), 4.17 (2H, s), 3.99-3.79 (3H, m), 3.44-3.34 (2H, m), 1.85 (2H, d), 1.64-1.45 (2H, m), 1.30-1.22 (1H, m), 1.18 (6H, s), 0.33 (4H, ddt). 484 23 [01119] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-{2-oxo-2-[3- (trifluoromethyl)- 1,2,3,4-tetrahydro isoquinolin-2-yl]ethyl}- 2,3-dihydro-1H- isoindol-1-one (DMSO-d6) 8.46 (1H, s), 8.05 (1H, s), 8.00 (1H, dd), 7.77 (1H, d), 7.63 (1H, s), 7.34-7.19 (4H, m), 5.51-5.41 (0.6H, m), 5.49- 5.32 (0.4H, m), 5.11-4.99 (1H, m), 4.84-4.52 (4.6H, m), 4.20 (0.4H, d), 4.00-3.81 (3H, m), 3.48-3.35 (2H, m), 3.30-3.05 (2H, m), 1.85 (2H, d), 1.53 (2H, qd). 586 24 [01120] 2-(2-{2-azabicyclo [2.2.1]heptan-2-yl}-2- oxoethyl)-6-{5-chloro- 2-[(oxan-4-yl)amino] pyrimidin-4-yl}-2,3- dihydro-1H-isoindol-1- one (DMSO-d6) 8.45 (1H, s), 8.02 (1H, s), 7.98 (1H, dd), 7.74 (1H, d), 7.61 (1H, br. s), 4.59-4.19 (5H, m), 3.97-3.83 (3H, m), 3.48-3.43 (0.5H, br. m), 3.40- 3.35 (2H, m), 3.23-3.17 (1H, m), 3.01-2.98 (0.5H, m), 2.63- 2.54 (1H, m), 1.86-1.83 (2H, m), 1.73-1.34 (8H, m). 482 25 [01121] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-(2.2- dimethylpiperidin-1- yl)-2-oxoethyl]-2,3- dihydro-1H-isoindol-1- one (DMSO-d6) 8.46 (1H, s), 8.03 (1H, s), 7.98 (1H, dd), 7.75 (1H, d), 7.63 (1H, br. s), 4.53 (2H, s), 4.39 (2H, s), 3.90-3.97 (1H, m), 3.87 (2H, m), 3.34-3.41 (4H, m), 1.85 (2H, m), 1.48-1.67 (8H, m), 1.39 (6H, s). 498 26 [01122] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(2- methylpentan-2- yl)acetamide (DMSO-d6) 8.44 (1H, s), 8.01 (1H, d), 7.97 (1H, dd), 7.74 (1H, d), 7.63 (1H, s), 7.63 (1H, br. s), 4.58 (2H, s), 4.14 (2H, s), 3.89- 3.97 (1H, m), 3.86 (2H, m), 3.35-3.40 (2H, m), 1.81-1.87 (2H, m), 1.47-1.61 (4H, m), 1.19-1.29 (2H, m), 1.22 (6H, s), 0.86 (3H, t). 486 27 [01123] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(3- methylpentan-3- yl)acetamide (DMSO-d6) 8.44 (1H, s), 0.01 (1H, d), 7.96 (1H, dd), 7.74 (1H, d), 7.61 (1H, br. s), 7.44 (1H, s), 4.58 (2H, s), 4.17 (2H, s), 3.89- 3.97 (1H, m), 3.86 (2H, m), 3.34-3.40 (2H, m), 1.80-1.87 (2H, m), 1.75 (1H, qt), 1.72 (1H, qt), 1.46-1.57 (4H, m), 1.13 (3H, s), 0.78 (6H, t). 486 28 [01124] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-(octahydro- 1H-isoindol-2-yl)-2- oxoethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.45 (1H, br. s), 8.03 (1H, br. s), 7.99 (1H, dd), 7.75 (1H, d), 7.63 (1H, br. s), 4.58 (2H, s), 4.42 (1H, d), 4.35 (1H, d), 3.93 (1H, m), 3.87 (2H, m), 3.54 (1H, dd), 3.31-3.42 (4H, m), 3.22 (1H, dd), 2.30 (1H, m), 2.15 (1H, m), 1.85 (2H, m), 1.28-1.63 (10H, m). 510 29 [01125] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-(2-{octahydro cyclopenta[b]pyrrol-1- yl}-2-oxoethyl)-2,3- dihydro-1H-isoindol-1- one (DMSO-d6) 8.46 (1H, br. s), 8.03 (1H, br. s), 7.98 (1H, dd), 7.75 (1H, d), 7.63 (1H, br. s), 4.59 (2H, m), 4.32-4.52 (4H, m), 4.16 (0.75H, ddd), 3.93 (1H, m), 3.87 (2H, m), 3.62 (1.25H, m), 3.49 (0.75H, m), 3.31-3.40 (2H, m), 3.25 (0.75H, m), 2.80 (0.5H, m), 2.62 (0.75H, m), 2.12 (0.5H, m), 2.10 (0.75H, m), 1.36-1.90 (12H, m). (partial integrals due to the presence of rotamers). 496 30 [01126] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N- methyl-N-(oxan-4- yl)acetamide (DMSO-d6, VT T = 350 K) 8.42 (1H, s), 8.07 (1H, d), 8.01 (1H, dd), 7.74 (1H, d), 7.28 (1H, br. d), 4.59 (2H, s), 4.49 (2H, br. s), 3.86-4.00 (5H, m), 3.38-3.44 (5H, m), 3.05 (3H, br. s), 1.89 (2H, m), 1.80 (2H, m), 1.50- 1.64 (4H, m). 500 31 [01127] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1 -oxo- 2,3-dihydro-1H- isoindol-2-yl)-N- [(1R,2R)-2- methylcyclopropyl]- acetamide (DMSO-d6, VT T = 350 K) 8.45 (1H, s), 8.18 (1H, d), 8.02 (1H, d), 7.98 (1H, dd), 7.74 (1H, d), 7.63 (1H, br. s), 4.58 (2H, s), 4.13 (2H, s), 3.93 (1H, m), 3.87 (2H, m), 3.39 (2H, m), 2.35 (1H, m), 1.85 (2H, m), 1.53 (2H, m), 1.00 (3H, d), 0.77-0.84 (1H, m), 0.58-0.63 (1H, m), 0.40-0.44 (1H, m). 456 32 [01128] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-(2-{octahydro cyclopenta[c]pyrrol-2- yl}-2-oxoethyl)-2,3- dihydro-1H-isoindol-1- one (DMSO-d6) 8.44 (1H, s), 8.02 (1H, d), 7.97 (1H, dd), 7.74 (1H, d), 7.62 (1H, br. s), 4.57 (2H, s), 4.36 (2H, s), 3.93-3.85 (3H, m), 3.72 (1H, dd), 3.55 (1H, dd), 3.41-3.34 (2H, m), 3.29 (1H, dd), 3.12 (1H, dd), 2.76-2.69 (1H, m), 2.63-2.56 (1H, m), 1.86-1.69 (5H, m), 1.60-1.37 (5H, m). 496 33 [01129] 2-(2-{2-azabicyclo [2.2.2]octan-2-y l}-2- oxoethyl)-6-{5-chloro- 2-[(oxan-4-yl)amino] pyrimidin-4-yl}-2,3- dihydro-1H-isoindol-1- one (DMSO-d6) 8.45 (1H, s), 8.03- 8.02 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.62 (1H, br. s), 4.58 (2H, d), 4.39 (2H, d), 3.94- 3.85 (3H, m), 3.55 (1H, d), 3.41-3.35 (2H, m), 3.27 (1H, d), 1.94-1.83 (4H, m), 1.72-1.47 (10H, m). 496 34 [01130] 2-(6-{5-chloro-2- [(oxan-4-yl)amino) pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N- methyl-N-(2,2,2- trifluoroethyl)- acetamide (DMSO-d6) 8.45 (1H, s), 8.04- 8.03 (1H, m), 7.99 (1H, dd), 7.75 (1H, dd), 7.61 (1H, br. s), 4.59 (2H, s), 4.55 (2H, s), 4.43 (0.6H, q), 4.19 (1.4H, q), 3.96- 3.85 (3H, m), 3.41-3.31 (2H, m), 3.19 (2H, s), 2.95 (1H, s), 1.86-1.83 (2H, m), 1.57-1.48 (2H, m). 499 35 [01131] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(2- phenylpropan-2- yl)acetamide (DMSO-d6) 8.45 (1H, s), 8.39 (1H, s), 8.01 (1H, dd), 7.96 (1H, dd), 7.72 (1H, d), 7.62 (1H, br. s), 7.38-7.33 (2H, m), 7.29 (2H, dd), 7.22-7.08 (1H, m), 4.56 (2H, s), 4.26 (2H, s), 3.91-3.83 (3H, m), 3.44-3.34 (2H, m), 1.84 (2H. d), 1.58 (6H, s), 1.56- 1.45 (2H, m). 520 36 [01132] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(2,6- dimethyloxan-4- yl)acetamide (DMSO-d6) 8.45 (1H, s), 8.26 (0.5H, d), 8.06 (0.5H, d), 8.02 (1H, br. s), 7.99-7.95 (1H, m), 7.74 (1H, d), 7.62 (1H, br. s), 4.59 (2H, d), 4.20 (2H, d), 4.05- 4.01 (0.5H, m), 3.94-3.90 (0.5H, m), 3.88-3.81 (3H, m), 3.78- 3.71 (1H, m), 3.46-3.37 (3H, m), 1.84 (2H, d), 1.74 (1H, dd), 1.60-1.47 (3H, m), 1.34-1.26 (1H, m), 1.08 (3H, d), 1.04 (3H, d), 1.01-0.95 (1H, m). 514 37 [01133] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(2- methyloxan-4- yl)acetamide (DMSO-d6) 8.44 (1H, s), 8.27 (0.8H, d), 8.10 (0.2H, d), 8.02 (1H, s), 7.97 (1H, d), 7.74 (1H, d), 7.61 (1H, br. s), 4.60 (1.6H, s), 4.58 (0.4H, s), 4.26 (1.6H, s), 4.17 (0.4H, s), 4.03-4.02 (1H, m), 3.94-3.85 (3H, m), 3.7 4-3.64 (3H, m), 3.40-3.37 (2H, m), 1.86-1.82 (2H, m), 1.69- 1.47 (5H, m), 1.44-1.36 (1H, m), 1.06 (3H, d). 500 38 [01134] 2-(6-{5-chloro-2- [(oxan-4-yl)amino) pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(3,3- difluoro-1-methyl cyclobutyl)acetamide (DMSO-d6) 8.49 (2H, d), 8.03 (1H, d) 7.98 (1H, dd), 7.74 (1H, d), 7.62 (1H, br. s), 4.59 (2H, s), 4.18 (2H, s), 3.98-3.83 (3H, m), 3.37 (2H, t), 2.95-2.84 (2H, m), 2.69-2.54 (2H, m), 1.88-1.80 (2H, m), 1.60-1.46 (2H, m), 1.43 (3H, s). 506 39 [01135] 2-(2-{8-azabicyclo [3.2.1]octan-8-yl}-2- oxoethyl)-6-{5-chloro- 2-[(oxan-4-yl)amino] pyrimidin-4-yl}-2,3- dihydro-1H-isoindol-1- one (DMSO-d6) 8.45 (1H, s), 8.03 (1H, d), 7.99 (1H, dd), 7.75 (1H, d) ,7.61 (1H, br. s), 4.61 (2H, s), 4.32-4.47 (4H, m), 3.85-3.97 (3H, m), 3.36-3.41 (2H, m), 1.97-2.04 (1H, m), 1.42-1.86 (13H, m). 496 40 [01136] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N- methyl-N-(2-phenyl ethyl)acetamide (DMSO-d6) 8.45 (1H, s), 8.03 (1H, d), 7.98 (1H, m), 7.74 (1H, m), 7.61 (1H, br. s), 7.19-7.37 (5H, m), 4.51 (1H, s), 4.43 (1H, s), 4.37 (1H, s), 4.20 (1H, s), 3.85-3.98 (3H, m), 3.60 (1H, br. t), 3.51 (1H, br. t), 3.35-3.40 (2H, m), 3.01 (1.5H, s), 2.91 (1H, br. t), 2.88 (1.5H, s), 2.77 (1H, br. t), 1.85 (2H, m), 1.53 (2H, m). 520 41 [01137] 2-[2-(azepan-1-yl)-2- oxoethyl]-6-{5-chloro- 2-[(oxan-4-yl)amino] pyrimidin-4-yl}-2,3- dihydro-1H-isoindol-1- one (DMSO-d6) 8.46 (1H, s), 8.03 (1H, d), 7.98 (1H, dd), 7.75 (1H, d), 7.63 (1H, br. s), 4.59 (2H, s), 4.47 (2H, s), 3.99-3.86 (3H, m), 3.52 (2H, t), 3.46-3.34 (4H, m), 1.85 (2H, br. d), 1.78-1.73 (2H, m), 1.66-1.45 (8H, m). 484 42 [01138] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2-(2,3,4,5- tetrahydro-1H-3- benzazepin-3- yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.45 (1H, s), 8.03 (1H, d), 7.98 (1H, dd), 7.74 (1H, d), 7.62 (1H, br. s), 7.23-7.08 (4H, m), 4.56 (4H, d), 3.98-3.82 (3H, m), 3.70-3.54 (4H, m), 3.37 (2H, t), 3.00-2.95 (2H, m), 2.88-2.83 (2H, m), 1.88-1.81 (2H, m), 1.57-1.47 (2H, m). 532 43 [01139] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2-(2,3,4,5- tetrahydro-1H-2- benzazepin-2- yl)ethyl]-2.3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.44 (1H, s), 8.06- 7.88 (2H, m), 7.70 (1H, d), 7.61 (1H, br. s), 7.45-7.41 (0.5H, m), 7.26-7.06 (3.5H, m), 4.69 (1H, s), 4.50-4.44 (5H, m), 3.97-3.74 (5H, m), 3.36 (2H, t), 3.02-2.96 (2H, br. m), 1.89-1.75 (3H, m), 1.72-1.62 (1H, m), 1.56-1.47 (2H, m). 532 44 [01140] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-[(4- chloro-2-methoxy phenyl)methyl] acetamide (DMSO-d6) 8.49 (t, 1H), 8.44 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.61 (br. s, 1H), 7.19 (d, 1H), 7.06 (d, 1H), 7.98 (dd, 1H), 4.61 (s, 2H), 4.27 (s, 2H), 4.22 (d, 2H), 3.90-3.84 (m, 3H), 3.83 (s, 3H), 3.40- 3.34 (m, 2H), 1.86-1.82 (m, 2H), 1.57-1.47 (m, 2H). 556 45 [01141] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-[(5- chloro-2-methoxy phenyl)methyl] acetamide (DMSO-d6) 8.52 (t, 1H), 8.44 (s, 1H), 8.04 (d, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.61 (br. s, 1H), 7.28 (dd, 1H), 7.20 (d, 1H), 7.01 (d, 1H), 4.62 (s, 2H), 4.29 (s, 2H), 4.24 (d, 2H), 3.93-3.85 (m, 3H), 3.80 (s, 3H), 3.40- 3.35 (m. 2H), 1.86-1.83 (m, 2H), 1.57-1.47 (m, 2H). 556 46 [01142] 2-{2-[(4aR,8aR)- decahydroisoquinolin- 2-yl]-2-oxoethyl}-6-{5- chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2,3-dihydro-1H- isoindol-1-one (DMSO-d6, VT T = 350K) 8.41 (s, 1H), 8.07 (m, 1H), 8.00 (dd, 1H), 7.73 (dd, 1H). 7.28 (d, 1H), 4.59 (s, 2H), 4.44 (br. s, 2H). 3.92-4.02 (m, 1H), 3.85-3.92 (m, 2H), 3.64-3.83 (m, 1H), 3.38-3.45 (m, 2H), 3.00-3.31 (m, 1H), 1.85-1.93 (m, 3H), 1.26-1.80 (m, 15H). 524 47 [01143] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(2- cyclohexylpropan-2- yl)acetamide (DMSO-d6) 8.45 (s, 1H), 8.02 (dd, 1H), 7.75 (d, 1H), 7.62 (s (br), 1H), 7.55 (s, 1H), 4.58 (s, 2H), 4.16 (s, 2H), 3.90-3.98 (m, 1H), 3.83-3.91 (m, 2H), 3.34- 3.42 (m, 2H), 1.81-1.91 (m, 3H), 1.59-1.78 (m, 6H), 1.48- 1.58 (m, 2H), 1.20 (s, 6H), 1.05- 1.20 (m, 2H), 0.91-0.99 (m, 2H). 526 48 [01144] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-[2-(3- fluorophenyl)propan- 2-yl]acetamide (DMSO-d6) 8.45 (s, 2H), 8.01 (d, 1H), 7.96 (dd, 1H), 7.72 (d, 1H), 7.61 (s, 1H), 7.33 (ddd, 1H), 7.19 (m, 1H), 7.13 (m, 1H), 7.00 (m, 1H), 4.56 (s, 2H), 4.27 (s, 2H), 3.82-3.97 (m, 3H), 3.35-3.42 (m, 2H), 1.83-1.88 (m, 2H), 1.57 (s, 6H), 1.47-1.57 (m, 2H). 538 49 [01145] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-[(1S)- 1,2,3.4-tetrahydro naphthalan-1-yl] acetamide (DMSO-d6) 8.54 (d, 1H), 8.45 (s, 1H), 8.04 (d, 1H), 7.98 (dd, 1H), 7.76 (d, 1H), 7.62 (br. s, 1H), 7.14-7.22 (m, 3H), 7.08- 7.13 (m, 1H), 4.99-5.05 (m, 1H), 4.64 (s, 2H), 4.27 (s, 2H), 3.83-3.98 (m, 3H), 3.35-3.41 (m, 2H), 2.67-2.81 (m, 2H), 1.81-1.94 (m, 4H), 1.67-1.78 (m, 2H), 1.47-1.58 (m, 2H). 532 50 [01146] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-[(1R)- 1,2,3,4-tetrahydro naphthalen-1-yl] acetamide (DMSO-d6) 8.54 (d, 1H), 8.45 (s, 1H), 8.04 (d, 1H), 7.98 (dd, 1H), 7.76 (d, 1H), 7.62 (br. s, 1H), 7.14-7.22 (m, 3H), 7.08- 7.13 (m, 1H), 4.99-5.05 (m, 1H), 4.64 (s, 2H), 4.27 (s, 2H), 3.83-3.98 (m, 3H), 3.35-3.41 (m, 2H), 2.67-2.81 (m, 2H), 1.81-1.94 (m, 4H), 1.67-1.78 (m, 2H), 1.47-1.58 (m, 2H). 532 51 [01147] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(2,3- dihydro-1H-inden-2- yl)acetamide (DMSO-d6) 8.47 (s, 1H), 8.45 (s, 1H), 8.02 (d, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.61 (br. s, 1H), 7.23-7.22 (m, 2H), 7.16- 7.14 (m, 2H), 4.60 (s. 2H), 4.52- 4.47 (m, 1H), 4.19 (s, 2H), 3.95-3.85 (m, 3H), 3.40-3.37 (m, 2H), 3.18 (dd, 2H), 2.80 (dd, 2H), 1.86-1.83 (m, 2H), 1.57-1.47 (m, 2H). 518 52 [01148] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-[(5- fluoro-2-methoxy phenyl)methyl] acetamide (DMSO-d6) 8.53 (t, 1H), 8.44 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.61 (br. s, 1H), 7.08-6.96 (m, 3H), 4.62 (s, 2H), 4.30 (s, 2H), 4.25 (d, 2H), 3.95-3.85 (m, 3H), 3.79 (s, 3H), 3.39-3.34 (m, 2H), 1.86-1.83 (m, 2H), 1.57-1.47 (m, 2H). 540 53 [01149] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-[2-(4- chlorophenyl)propan- 2-yl]acetamide (DMSO-d6) 8.45 (s, 1H), 8.44 (s, 1H), 8.01 (d, 1H), 7.96 (dd, 1H), 7.72 (d, 1H), 7.61 (br. s, 1H), 7.38-7.32 (m, 4H), 4.55 (s, 2H), 4.25 (s, 2H), 3.93-3.85 (m, 3H), 3.40-3.35 (m, 2H), 1 86-1.83 (m, 2H), 1.56-1.51 (m, 8H). 554 54 [01150] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-[(4- fluoro-2-methoxy phenyl)methyl] acetamide (DMSO-d6) 8.48-8.45 (m, 2H), 8.04 (d, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.61 (br. s, 1H), 7.21 (dd, 1H), 6.90 (dd, 1H),6.75 (td, 1H), 4.62 (s, 2H), 4.27 (s, 2H), 4.22 (d, 2H), 3.95-3.86 (m, 3H), 3.82 (s, 3H), 3.40- 3.37 (m, 2H), 1.86-1.84 (m, 2H), 1.58-1.48 (m, 2H). 540 55 [01151] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl)-2-{2-[(3S)-3- (hydroxy methyl)- 1,2,3.4-tetrahydro isoquinolin-2-yl]-2- oxoethyl}-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6, VT T = 353K) 8.41 (s, 1H), 8.07 (d, 1H), 8.00 (dd, 1H), 7.72 (d, 1H), 7.26 (d, 1H), 7.19 (s, 4H), 5.00-4.75 (br. s, 3H), 4.62-4.60 (m, 4H), 4.52- 4.17 (br. s, 2H), 4.00-3.86 (m, 3H), 3.44-3.38 (m, 4H), 2.95- 2.85 (br. s, 1H), 1.92-1.87 (m, 2H), 1.63-1.53 (m, 2H). 548 56 [01152] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-[2-(4- fluorophenyl)propan- 2-yl]acetamide DMSO-d6) 8.44 (s, 1H), 8.40 (s, 1H), 8.00 (d, 1H), 7.95 (dd, 1H), 7.71 (d, 1H), 7.60 (br. s, 1H), 7.39-7.35 (m, 2H), 7.11-7.07 (m, 2H), 4.54 (s, 2H), 4.24 (s, 2H), 3.93-3.84 (m, 3H), 3.41- 3.36 (m, 2H), 1.85-1.82 (m, 2H), 1.57 (s, 6H), 1.56-1.47 (m, 2H). 538 57 [01153] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N- methyl-N-(1- methylcyclopentyl) acetamide DMSO-d6) 8.45 (s, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.74 (d, 1H), 7.61 (br. s, 1H), 4.53 (s, 2H), 4.39 (s, 2H), 3.95-3.85 (m, 3H), 3.40-3.34 (m, 2H), 2.96 (s, 3H), 1.96-1.93 (m, 2H), 1.86- 1.78 (m, 4H), 1.62- 1.50 (m, 6H), 1.19 (s, 3H). 498 58 [01154] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N- methyl-N-(1-methyl cyclobutyl)acetamide (DMSO-d6, VT T = 353K) 8.40 (s, 1H), 8.05 (d, 1H), 7.99 (dd, 1H), 7.72 (d, 1H), 7.25 (d, 1H), 4.58 (s, 2H), 4.33 (s, 2H), 3.99 3.86 (m, 3H), 3.44-3.38 (m, 2H), 2.80 (s, 3H), 2.27 (br. s, 2H), 1.98-1.87 (m, 4H), 1.75- 1.62 (m, 2H), 1.59-1.53 (m, 2H), 1.38 (br. s, 3H). 484 59 [01155] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-y1)-N-[2- (3-chlorophenyl) propan-2-yl]acetamide (DMSO-d6) 8.48 (s, 1H), 8.44 (s, 1H), 8.02 (d, 1H), 7.96 (dd, 1H), 7.72 (d, 1H), 7.62 (s (br), 1H), 7.36 (m, 1H), 7.30-7.33 (m, 2H), 7.23-7.27 (m, 1H), 4.55 (s, 2H), 4.26 (s, 2H), 3.82- 3.97 (m, 3H), 3.35-3.41 (m, 2H), 1.81-1.89 (m, 2H), 1.57 (s, 6H), 1.47-1.57 (m, 2H). 554 60 [01156] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N- cyclopentyl-N- methylacetamide (DMSO-d6, VT T = 350K) 8.41 (s, 1H), 8.07 (d, 1H), 8.00 (dd, 1H), 7.72 (d, 1H), 7.21 (d, 1H), 4.59 (s, 2H), 4.39-4.60 (m, 1H), 4.47 (s, 2H), 3.93-4.02 (m, 1H), 3.86-3.91 (m, 2H), 3.42 (ddd, 2H), 2.85 (s (br), 3H), 1.86-1.93 (m, 2H), 1.66-1.85 (m, 4H), 1.53-1.65 (m, 6H). 484 61 [01157] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2-(2,3,4,5- tetrahydro-1H-1- benzazepin-1- yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.44 (s, 1H), 7.99- 7.95 (m, 2H), 7.74 (d, 1H), 7.61 (br. s, 1H), 7.46-7.40 (m, 2H), 7.35-7.32 (m, 2H), 4.66-4.47 (m, 3H), 4.32 (d, 1H), 3.95- 3.84 (m, 3H), 3.76 (d, 1H), 3.40- 3.34 (m, 2H), 2.84-2.79 (m, 2H), 2.64-2.57 (m, 1H), 1.99- 1.94 (m, 1H), 1.85-1.71 (m, 4H), 1.57-1.47 (m, 2H), 1.34- 1.31 (m, 1H). 532 62 [01158] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2-(1,2,3,4- tetrahydroquinolin-1- yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.62 (br. s, 2H), 7.23-7.12 (m, 3H), 4.61 (s, 4H), 3.93- 3.85 (m, 3H), 3.75 (dd, 2H), 3.37 (dd, 2H), 2.75 (dd, 2H), 1.96-1.91 (m, 2H), 1.86-1.83 (m, 2H), 1.57-1.47 (m, 2H). 518 63 [01159] 2-(6-{5-chloro-2- [(oxan-4-yl)amino) pyrimidin-4-yl}-1 -oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-[(2- methoxyphenyl)methyl]- acetamide (DMSO-d6) 8.47-8.44 (m, 2H), 8.04-8.02 (m, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.61 (brs, 1H), 7.27-7.18 (m, 2H), 6.99- 6.90 (m, 2H), 4.62 (s, 2H), 4.27- 4.26 (m, 4H), 3.96-3.83 (m, 3H), 3.80 (s, 3H), 3.37 (t, 2H), 1.86-1.83 (m, 2H), 1.57-1.57 (m, 2H). 522 64 [01160] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-(1,1-dimethyl- 1,2,3,4- tetrahydroisoquinolin- 2-yl)-2-oxoethyl]-2,3- dihydro-1H-isoindol-1- one (DMSO-d6) 8.45 (s, 1H), 8.05- 8 04 (m, 1H), 7.99 (dd, 1H), 7.75 (d, 1H), 7.62 (br s, 1H), 7.40 (d, 1H), 7.27-7.21 (m, 1H), 7.17-7.12 (m, 2H), 4.57-4.56 (m, 4H), 3.98-3.83 (m, 3H), 3.60-3.58 (m, 2H), 3.37 (t, 2H), 2.86-2.83 (m, 2H), 1.86-1.83 (br m, 2H), 1.74 (s, 6H), 1.57-1.48 (m, 2H). 546 65 [01161] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-{2-oxo-2-[4-(1,3- thiazol-2-y1)piperidin- 1-yl]ethyl}-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.45 (s, 1H), 8.03- 8.02 (m, 1H), 7.98 (dd, 1H), 7.76-7.73 (m, 2H), 7.68 (m, 1H), 7.63 (d, 1H), 4.57-4.47 (m, 4H), 4.38 (d, 1H), 4.01 (d, 1H), 3.96-3.82 (m, 3H), 3.42-3.22 (m, 4H), 2.86-2.79 (m, 1H), 2.14-2.06 (m, 2H),1.86-1.70 (m, 3H), 1.60-1.47 (m, 3H). 553 66 [01162] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2-(3- phenylazetidin-1- yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.45 (br. s, 1H), 8.04 (d, 1H), 7.99 (dd, 1H), 7.76 (d, 1H), 7.63 (s (br), 1H), 7.37- 7.43 (m, 4H), 7.27-7.31 (m, 1H), 4.63-4.67 (m, 1H), 4.60 (s, 2H), 4.26-4.36 (m, 4H), 3.84- 3.98 (m, 5H), 3.36-3.42 (m, 2H), 1.85 (m, 2H), 1.53 (m, 2H). 518 67 [01163] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N- methyl-N-(2- phenylpropan-2-yl) acetamide (DMSO-d6) 8.43 (s, 1H), 7.98 (d, 1H), 7.93 (dd, 1H), 7.69 (d, 1H), 7.60 (br. s, 1H), 7.27-7.25 (m, 4H), 7.15-7.12 (m, 1H), 4.40 (s, 4H), 3.92-3.84 (m, 3H), 3.40-3.36 (m, 2H), 3.12 (s, 3H), 1.85-1.81 (m, 2H), 1.60 (s, 6H), 1.56-1.46 (m, 2H). 534 68 [01164] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-{2-oxo-2-[(3S)-3- phenylpiperidin-1- yl]ethyl}-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.45 (s, 1H), 8.03- 8.02 (m, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.61 (br. s, 1H), 7.34-7.20 (m, 5H), 4.60-4.35 (m, 5H), 3.99-3.85 (m, 4H), 3.41-3.34 (m, 2H), 3.27-3.10 (m, 1H), 2.74-2.60 (m, 2H), 1.95-1.73 (m, 5H), 1.57-1.47 (m, 3H). 546 69 [01165] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-{2-oxo-2-[(3R)-3- phenylpiperidin-1- yl]ethyl}-2.3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.45 (s, 1H), 8.03- 8.02 (m, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.61 (br. s, 1H), 7.34-7.21 (m, 5H), 4.60-4.35 (m, 5H), 3.99-3.85 (m, 4H), 3.41-3.34 (m, 2H), 3.27-3.10 (m, 1H), 2.74-2.60 (m, 2H), 1.95-1.73 (m, 5H), 1.57-1.47 (m, 3H). 546 70 [01166] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2-(4- phenylpiperazin-1- yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.45 (1H, s), 8.03 (1H, d), 7.99 (1H, dd), 7.75 (1H d), 7.59 (1H, br. s), 7.24 (2H, dd), 6.98 (2H, d), 6.82 (1H, dd), 4.58 (2H, s), 4.54 (2H, s), 3.95- 3.91 (1H, m), 3.88-3.85 (2H, m), 3.69-3.67 (2H, m), 3.63- 3.61 (2H, m), 3.40-3.35 (2H, m), 3.23-3.21 (2H, m), 3.15- 3.13 (2H, m), 1.87-1.83 (2H, m), 1.58-1.49 (2H, m). 547 71 [01167] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2-(4- phenylpiperidin-1- yl)ethyl]-2.3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.45 (1H, s), 8.04 (1H, d), 7.99 (1H, dd), 7.75 (1H, d), 7.61 (1H, br. s), 7.33-7.18 (5H, m), 4.59 (2H, s), 4.53- 4.47 (3H, m), 4.05 (1H, d), 3.95- 3.85 (3H, m), 3.41-3.35 (2H, m), 3.19 (1H, t), 2.83-2.66 (2H, m), 1.86-1.79 (4H, m), 1.68-1.64 (1H, m), 1.58-1.48 (3H, m). 546 72 [01168] N-tert-butyl-2-(6-{5- chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-y1)-N- ethylacetamide (DMSO-d6) 8.45 (1H, s), 8.03 (1H, d), 7.98 (1H, dd), 7.75 (1H, d), 7.62 (1H, br. s), 4.58 (2H, s), 4.44 (2H, s), 3.96-3.86 (3H, m), 3.46-3.35 (4H, m), 1.87- 1.84 (2H, m), 1.58-1.54 (2H. m), 1.39 (9H, s), 1.23 (3H, t). 486 73 [01169] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-y1)-N- (2,2-dimethyloxan-4- yl)acetamide (DMSO-d6) 8.45 (1H, s), 8.05- 8.03 (2H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.61 (1H, br. s), 4.59 (2H, s), 4.17 (2H, s), 3.98- 3.86 (4H, m), 3.66-3.54 (2H, m), 3.41-3.35 (2H, m), 1.87- 1.84 (2H, m), 1.71-1.66 (2H, m), 1.58-1.48 (2H, m), 1.36- 1.20 (2H, m), 1.16 (3H, s), 1.14 (3H, s). 514 74 [01170] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-(1-methyl- 1,2,3,4- tetrahydroisoquinolin- 2-yl)-2-oxoethyl]-2,3- dihydro-1H-isoindol-1- one (DMSO-d6) 8.45 (1H, s), 8.04- 8.02 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.61 (1H, br. s), 7.27-7.14 (4H, m), 5.43 (0.75H, q), 5.24 (0.25H, q), 4.72-4.47 (4H, m), 4.42-4.37 (0.5H, m), 3.97-3.83 (4H, m), 3.59-3.52 (0.5H, m), 3.37 (2H, t), 3.14- 2.75 (2H, m), 1.86-1.83 (2H, br. m), 1.57-1.47 (3H, m), 1.38 (2H, d). (A mixture of rotamers was observed). 532 75 [01171] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2-(2,3,4,5- tetrahydro-1,4- benzoxazepin-4- yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.44 (1H, s), 8.02- 7.93 (2H, m), 7.71 (1H, dd), 7.61 (1H, br. s), 7.47-7.45 (0.5H, m), 7.29-7.17 (1.5H, m), 7.11-6.97 (2H, m), 4.73 (1H, s), 4.60 (1H, s), 4.53-4.50 (4H, m), 4.21-4.19 (1H, m), 4.11-4.09 (1H, m), 3.97-3.80 (5H, m). 3.36 (2H, t), 1.89-1.79 (2H, m), 1.57-1.47 (2H, m). 534 76 [01172] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidirv4- yl}-2-[2-(2-methyl- 2,3,4,5-tetrahydro-1H- 3-benzazepin-3-yl)-2- oxoethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.44 (s, 1H), 8.01- 7.96 (m, 2H), 7.70 (t, 1H), 7.61 (br s, 1H), 7.15-6.99 (m, 4H), 4 81-4.71 (m, 0.5H), 4.57-4.25 (m, 5H), 3.97-3.85 (m, 3.5H), 3.45-3.34 (m, 2.5H), 3.06-2.82 (m, 4.5H), 1.88-1.81 (m, 2H), 2.57-1.47 (m, 2H), 1.10 (d, 1.3H), 0.98 (d, 1.7H). (A mixture of rotamers was observed). 546 77 [01173] N-benzyl-2-(6-{5- chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2- yl)acetamide (DMSO-d6) 8.63 (t, 1H), 8.44 (s, 1H), 8.04 (s, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.60 (brs, 1H), 7.35-7.22 (m, 5H), 4.61 (s, 2H), 4.31 (d, 2H), 4.26 (s, 2H), 3.98-3.85 (m, 3H). 3.37 (t, 2H), 1.86-1.83 (m, 2H), 1.57-1.47 (m, 2H). 492 78 [01174] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(2- methyl-1-phenyl propan-2-yl) acetamide (DMSO-d6) 8.45 (s, 1H), 8.05- 8.04 (m, 1H), 7.99 (dd, 1H), 7.76 (d, 1H), 7.61 (br s, 1H), 7.58 (s, 1H), 7.31-7.27 (m, 2H), 7.24-7.20 (m, 1H) 7.14-7.12 (m, 2H), 4.63 (s, 2H), 4.13 (s, 2H), 3.97-3.85 (m, 3H), 3.41-3.35 (m, 2H), 2.97 (s, 2H), 1.87-1.84 (m, 2H), 1.58-1.48 (m, 2H), 1.23 (s, 6H). 534 79 [01175] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-[(1S)- 2-hydroxy-1-phenyl ethyl]acetamide (DMSO-d6) 8.56 (d, 1H), 8.44 (s, 1H), 8.03-8.02 (m, 1H), 7.97 (dd, 1H), 7.73 (d, 1H). 7.60 (br s, 1H), 7.35-7.30 (m. 4H), 7.27- 7.22 (m, 1H), 4.93-4.85 (m, 2H), 4.59 (s, 2H), 4.29 (dd, 2H) 3.97-3.85 (m, 3H), 3.59-3.56 (m, 2H), 3.39-3.34 (m, 2H), 1.85-1.82 (m, 2H), 1.57-1.47 (m, 2H). 522 80 [01176] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-[(1R)- 1-phenylethyl] acetamide (DMSO-d6) 8.60 (d, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.61 (s (br), 1H), 7.31-7.37 (m, 4H), 7.24 (m, 1H), 4 97 (dq, 1H), 4.59 (s, 2H), 4.28 (d, 1H), 4.23 (d, 1H), 3.82-3.98 (m, 3H), 3.33-3.42 (m, 2H), 1.80-1.89 (m, 2H), 1.46-1.59 (m, 2H), 1.39 (d, 3H). 506 81 [01177] N-benzyl-2-(6-{5- chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-y1)-N-(2- hydroxyethyl) acetamide (DMSO-d6) 8.45 (s, 1H), 8.03- 7.96 (m, 2H), 7.76-7.73 (m, 1H), 7.62 (brs, 1H). 7.44-7.24 (m, 5H), 5.03 (t, 0.8H), 4.74- 4.48 (m, 6.2H), 3.97-3.85 (m, 3H), 3.62-3.47 (m, 2H), 3.42- 3.30 (m. 4H), 1.86-1.83 (m, 2H), 1.52 (qd, 2H). 536 82 [01178] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl)-1-oxo- 2.3-dihydro-1H- isoindol-2-yl)-N- [(1S,2R)-2-hydroxy- 2.3-dihydro-1H-inden- 1-yl]acetamide (DMSO-d6) 8.45 (s, 1H), 8.25 (d, 1H), 8.05-8.04 (m, 1H), 7.98 (dd, 1H), 7.76 (d, 1H), 7.62 (br s, 1H), 7.25-7.18 (m, 4H), 5.22 (dd, 1H), 5.09 (d, 1H), 4.66 (s, 2H), 4.46-4.38 (m, 1H), 4.38 (s, 2H), 3.97-3.85 (m, 3H), 3.43- 3.34 (m, 2H), 3.06 (dd, 1H), 2.81 (dd, 1H), 1.86-1.83 (m, 2H), 1.59-1.45 (m, 2H). 534 83 [01179] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(1- phenylcyclobutyl) acetamide (DMSO-d6) 8.79 (1H, s), 8.45 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, s), 7.46-7.37 (2H, m), 7.32 (2H, dd), 7.26-7.13 (1H, m), 4.56 (2H, s), 4.22 (2H, s), 3.90 (3H, dd), 3.39 (2H, d), 2.48-2.40 (4H, m), 2.09- 1.94 (1H, m), 1.90- 1.76 (3H, m), 1.53 (2H, m). 532 84 [01180] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(3- phenyloxetan-3- yl)acetamide (DMSO-d6) 9.21 (s, 1H), 8.44 (s, 1H), 8.05-8.04 (m, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.61 (br s, 1H), 7.56-7.51 (m, 2H), 7.42- 7.38 (m, 2H), 7.32-7.28 (m, 1H), 4.90 (d, 2H), 4.69 (d, 2H), 4.62 (s, 2H), 4.33 (s, 2H), 3.96- 3.84 (m, 3H), 3.39-3.34 (m, 2H), 1.86-1.82 (m, 2H), 1.57- 1.47 (m, 2H). 534 85 [01181] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-{2-[1- (hydroxy methyl)- 1,2,3,4-tetrahydro isoquinolin-2-yl]-2- oxoethyl}-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.44 (s, 1H), 8.04- 8.03 (m, 1H), 7.99-7.96 (m, 1H), 7.76-7.72 (m, 1H), 7.62 (s (br), 1H), 7.29-7.15 (m, 4H), 5.44 (t, 0.6H), 5.35 (t, 0.4 H), 5.14-5.11 (m, 0.6H), 4.90-4.87 (m, 0.4H), 4.75-4.44 (m, 4.5H), 3.97-3.61 (m, 6H), 3.40-3.34 (m, 2H), 3.17-2.84 (m, 1.5H), 2.79-2.76 (m, 1H), 1.86-1.83 (m (br), 2H), 1.57-1.47 (m, 2H) (a mixture of rotamers was observed). 548 86 [01182] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-[1- (hydroxymethyl)-2,3- dihydro-1H-inden-1- yl]acetamide (DMSO-d6) 8.44 (s, 1H), 8.08 (s, 1H), 8.01-8.00 (m, 1H), 7.96 (dd, 1H), 7.72 (d, 1H), 7.61 (s (br), 1H), 7.33-7.30 (m, 1H), 7.20-7.12 (m, 3H), 5.01 (t (br), 1H), 4.60-4.50 (m, 2H), 4.27- 4.19 (m, 2H), 3.97-3.84 (m, 3H), 3.68-3.64 (m, 1H), 3.57- 3.53 (m, 1H), 3.41-3.33 (m, 2H), 2.95-2.88 (m, 1H),2.84- 2.76 (m, 1H), 2.39-2.24 (m, 2H), 1.85-1.82 (m, 2H), 1.57- 1.47 (m, 2H). 548 87 [01183] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-{2-[1-(hydroxyl methyl)-2.3.4,5- tetrahydro-1H-3- benzazepin-3-yl]-2- oxoethy l}-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.45 (1H, s), 8.02 (1H, s), 7.98 (1H, ddd), 7.73 (1H, dd), 7.63 (1H, s), 7.22- 7.02 (4H, m), 5.11 (0.6H, dd), 4.77 (0.6H, d), 4.62-4.34 (3.8H, m), 4.00-3.34 (11H, m), 3.25-3.10 (1H, m), 3.02 (1H, t), 2.92-2.74 (1H, m), 1.85 (2H, d), 1.53 (2H, qd) (a 3:2 mixture of rotamers was observed). 562

Example 88: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-(2-oxo-2-{5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-6-yl}ethyl)-2,3-dihydro-1H-isoindol-1-one

[1465] ##STR01184##

[1466] HATU (0.079 g, 0.21 mmol) was added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) (0.08 g, 0.20 mmol), 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.028 g, 0.21 mmol) and DIPEA (0.036 mL, 0.21 mmol) in DMF (1 mL) and the mixture was stirred for 1 h. 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (8.05 mg, 0.060 mmol) followed by HATU (0.023 g, 0.060 mmol) were added and the mixture was stirred for a further 2.75 h. Further portions of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.081 g, 0.60 mmol), HATU (0.079 g, 0.21 mmol) and DIPEA (0.139 ml, 0.79 mmol) were added and the mixture was stirred for a further 1.5 h, then diluted with EtOAc and transferred into a separating funnel. 1N HCl was added and the crude product was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO.sub.3, brine, then dried (MgSO.sub.4). The acidic aqueous layer was basified to pH 8-9 by the addition of 2N NaOH and the crude product was extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO.sub.4) and absorbed on silica. The crude product was purified by chromatography (SiO.sub.2, 0-10% MeOH in DCM) to afford a colourless solid. The product was dissolved in MeOH and loaded on a column packed with SCX. The column was washed with MeOH and the compound eluted with 1% NH.sub.3 in MeOH to afford a colourless solid. The solid was dissolved in DCM (and few drops MeOH) and the solution was filtered through cotton wool. The filtrate was concentrated under vacuum to afford the title compound (0.022 g, 20%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6, VT T=350K) 8.96 (s, 1H), 8.64 (s, 1H), 8.42 (s, 1H), 8.08 (dd, 1H), 8.01 (dd, 1H), 7.74 (dd, 1H), 7.28 (d (br), 1H), 4.78 (s (br), 2H), 4.61 (m, 4H), 3.92-4.03 (m, 1H), 3.86-3.92 (m, 4H), 3.38-3.86 (m, 2H), 3.00 (s, 2H), 1.85-1.93 (m, 2H), 1.53-1.64 (m, 2H). LC-MS: [M+H].sup.+=520.

Example 89: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)acetamide

[1467] ##STR01185##

[1468] HATU (0.079 g, 0.21 mmol) was added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) (0.08 g, 0.20 mmol), 1,2,3,4-tetrahydronaphthalen-2-amine (0.031 g, 0.21 mmol) and DIPEA (0.036 mL, 0.21 mmol) in DMF (1 mL) and the mixture was stirred for 30 minutes. The resulting thick suspension was diluted with 1N HCl and the precipitate was filtered, washed successively with water, NaHCO.sub.3, water and dried under suction. The resulting solid was dried in a vacuum oven at 40° C. overnight to afford the title compound (0.096 g, 90%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6) 8.45 (s, 1H), 8.25 (d, 1H), 8.04 (d, 1H), 7.99 (dd, 1H), 7.76 (d, 1H), 7.62 (s (br), 1H), 7.05-7.12 (m, 4H), 4.62 (s, 2H), 4.23 (s, 2H), 3.84-4.05 (m, 4H), 3.34-3.42 (m, 2H), 2.98 (dd, 1H), 2.78-2.90 (m, 2H), 2.67 (dd, 1H), 1.92-2.00 (m, 1H), 1.80-1.90 (m, 2H), 1.64-1.75 (m, 1H), 1.47-1.59 (m, 2H). LC-MS: [M+H].sup.+=532.

Example 90: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-(2,3-dihydro-1H-inden-1-yl)acetamide

[1469] ##STR01186##

[1470] Prepared according to Example 2 using diisopropylethylamine as base and DMF as solvent. In this case, the product obtained after purification by chromatography was dissolved in EtOAc and further washed successively with 1N HCl, water, saturated aqueous NaHCO.sub.3, brine, then dried (MgSO.sub.4), filtered and concentrated under vacuum. 1H NMR (400 MHz, DMSO-d6) 8.54 (d, 1H), 8.45 (s, 1H), 8.04 (d, 1H), 7.98 (dd, 1H), 7.76 (d, 1H), 7.62 (s (br), 1H), 7.18-7.27 (m, 4H), 5.34 (dd, 1H), 4.64 (s, 2H), 4.27 (s, 2H), 3.83-3.98 (m, 3H),3.36-3.42 (m, 2H), 2.94 (ddd, 1H), 2.77-2.85 (m, 1H), 2.36-2.44 (m, 1H), 1.79-1.89 (m, 3H), 1.48-1.58 (m, 2H). LC-MS: [M+H].sup.+=518.

Example 91: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-{2-oxo-248-(trifluoro methyl)-1,2,3,4-tetrahydroisoquinolin-2-Methyl}-2,3-dihydro-1H-isoindol-1-one

[1471] ##STR01187##

[1472] Prepared according to Example 2 using diisopropylethylamine as base and DMF as solvent. In this case, the product obtained after purification by chromatography was dissolved in EtOAc and further washed successively with 1N HCl, water, saturated aqueous NaHCO.sub.3, brine, then dried (MgSO.sub.4), filtered and concentrated under vacuum. 1H NMR (400 MHz, DMSO-d6, VT T=350K) 8.41 (s, 1H), 8.07 (d, 1H), 8.01 (dd, 1H), 7.73 (dd, 1H), 7.61 (d, 1H), 7.54 (d, 1H), 7.44 (m, 1H), 7.28 (d, 1H), 4.86 (s, 2H), 4.61 (s, 2H), 4.58 (s, 2H), 3.92-4.02 (m, 1H), 3.88 (m, 2H), 3.82 (m, 2H), 3.43 (dd, 1H), 3.40 (dd, 1H), 1.85-1.92 (m, 2H), 1.53-1.64 (m, 2H) (2 protons overlapped with water peak). LC-MS: [M+H].sup.+=586.

Example 92: N-[2-(tert-butylamino)ethyl]-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamide

[1473] ##STR01188##

[1474] A mixture of tert-butyl N-{2-[N-tert-butyl-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamido]ethyl}carbamate (Preparation 60, 63 mg, 0.105 mmol) in formic acid (1 mL) was stirred for 3 h. The solution was added dropwise to a stirred aqeuous solution of sodium carbonate (3 g, 28.3 mmol) in water (20 mL) and extracted with ethyl acetate (20 mL then 2×10 mL). The combined organic extracts were washed with brine (20 ml), dried (Na.sub.2SO.sub.4), filtered and evaporated. The residue was purified by chromatography (SiO.sub.2, 4 g column, 0-5% of 7M methanolic ammonia solution in dichloromethane) to give the title compound (30 mg, 56%) as a colourless foam and not the expected N-tert-butyl-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-(2-aminoethyl)acetamide. 1H NMR (400 MHz, DMSO-d6) 8.44 (s, 1H), 8.05 (t, 1H), 8.05-8.00 (m, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.60 (s, 1H), 4.59 (s, 2H), 4.18 (s, 2H), 3.97-3.81 (m, 3H), 3.41-3.32 (m, 2H), 3.11 (m, 2H), 2.55-2.51 (m, 2H), 1.84 (d, 2H), 1.62-1.32 (m, 3H), 1.00 (s, 9H). LC-MS: [M+H].sup.+=501.

Example 93: N-tert-butyl-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-(2hydroxyethyl)acetamide

[1475] ##STR01189##

[1476] 1M TBAF in THF (70.1 μl, 0.070 mmol) was added to a solution of N-tert-butyl-N-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamide (Preparation 61, 36 mg, 0.058 mmol) in anhydrous THF (1 mL) at 0° C. The reaction mixture was allowed to warm to RT and stirred for 1 h. The reaction mixture was partitioned between EtOAc (15 mL) and water (15 mL) and the organic layer was washed with brine (15 mL), dried (MgSO.sub.4), filtered and concentrated under vacuum to give the crude product (46 mg). The crude product was purified by chromatography (SiO.sub.2, 0-10% MeOH in EtOAc) to give a colourless glass, which was triturated with diethyl ether and dried to afford the title compound (13 mg, 44%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6) 8.45 (s, 1H), 8.02-8.01 (br m, 1H), 7.97 (dd, 1H), 7.74 (d, 1H), 7.62 (br s, 1H), 5.00 (t, 1H), 4.53 (d, 4H), 3.99-3.84 (m, 3H), 3.61-3.56 (m, 2H), 3.47-3.34 (m, 4H), 1.86-1.83 (br m, 2H), 1.57-1.47 (m, 2H), 1.37 (s, 9H). LC-MS: [M+H].sup.+=502.

Example 94: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-(2-cyclopropylpropan-2-yl)-N-methylacetamide

[1477] ##STR01190##

[1478] Prepared according to Example 2. Following purification by chromatography (SiO.sub.2), the product was further purified by preparative HPLC (Varian, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water). 1H NMR (400 MHz, CDCl.sub.3) 8.30 (s, 1H), 8.28 (d, 1H), 7.96 (dd, 1H), 7.53 (d, 1H), 5.16 (d, 1H), 4.62 (s, 2H), 4.42 (s, 2H), 4.06-3.96 (m, 3H), 3.56-3.51 (m, 2H), 3.09 (s, 3H), 2.07-2.02 (m, 2H), 1.60-1.50 (m, 2H), 1.31 (s, 6H), 1.27-1.23 (m, 1H), 0.53-0.48 (m, 2H), 0.41-0.37 (m, 2H). LC-MS: [M+H].sup.+=498.

Example 95: N-tert-butyl-2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-N-methylacetamide

[1479] ##STR01191##

[1480] N,2-dimethylpropan-2-amine (0.015 mL, 0.13 mmol), DIPEA (0.035 mL, 0.2 mmol) followed by HATU (52 mg, 0.14 mmol) were added to a stirred solution of 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)acetic acid (Preparation 9) (41 mg, 0.088 mmol) in DMF (2 mL) and the resulting solution was stirred at room temperature for 1.5 h. The reaction mixture was partitioned between ethyl acetate (30 mL) and a saturated solution of NH.sub.4Cl (20 mL). The layers were separated and the organic phase was washed with NH.sub.4Cl (20 mL), water (2×20 mL), saturated NaHCO.sub.3 (2×20 mL) and brine (2×20 mL). The organic phase was dried (MgSO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-10% methanol in DCM) gave the title compound (17 mg, 39%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6) 9.10 (1H, s), 8.50 (1H, s), 8.42 (1H, d), 7.72 (1H, s), 4.58 (2H, s), 4.44 (2H, s), 4.02-3.82 (3H, m), 3.38 (2H, t), 2.93 (3H, s), 1.86 (2H, br. d), 1.53 (2H, m), 1.36 (9H, s). LC-MS: [M+H].sup.+=473.

Example 96: N-tert-butyl-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-methylacetamide

[1481] ##STR01192##

[1482] Diisopropylethylamine (0.11 mL, 0.64 mmol was added to a suspension of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Preparation 16) (90 mg, 0.21 mmol) and HATU (98 mg, 0.26 mmol) in a mixture of DCM (1.8 mL) and DMF (0.2 mL). The reaction was stirred for 5 min before N-tert-butyl-methylamine (0.028 mL, 0.24 mmol) was added. The mixture was stirred at RT for 18 h. The mixture was diluted with ethyl acetate (10 mL) and water (15 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with hydrochloric acid (1 M, 50 mL), saturated aqueous sodium bicarbonate (50 mL), brine (3×50 mL), dried (MgSO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-5% methanol in DCM) gave the title compound (72 mg, 67%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6) 8.47 (1H, s), 7.91 (1H, d), 7.82 (1H, dd), 7.67 (1H, s), 4.60 (2H, s), 4.40 (2H, s), 3.98-3.89 (1H, m), 3.86 (2H, d), 3.43-3.34 (2H, m), 2.92 (3H, s), 1.84 (2H, d), 1.60-1.46 (2H, m), 1.35 (9H, s). LC-MS: [M+H].sup.+=490.

Example 97: N-tert-butyl-N-methyl-2-(6-{2-[(oxan-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamide

[1483] ##STR01193##

[1484] A stirred solution of 2-(6-{2-[(oxan-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Preparation 19) (73 mg, 0.17 mmol) in DCM (2.7 mL) and DMF (0.3 mL), was treated with triethylamine (70 μL, 0.50 mmol), N-tert-butyl-methylamine (21 μL, 0.17 mmol) and HATU (70 mg, 0.18 mmol). After 2 h the mixture was diluted with ethyl acetate (30 mL) and washed with 1 M hydrochloric acid (30 mL), saturated aqueous sodium bicarbonate (30 mL), water (30 mL), brine (30 mL), dried (MgSO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-10% methanol in ethyl acetate) gave a glass, which was triturated with diethyl ether, and dried to give the title compound (46 mg, 54%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6) 8.72-8.67 (1H, m), 8.23 (1H, dd), 7.76-7.72 (3H, m), 4.53 (2H, s), 4.39 (2H, s), 4.11-3.81 (3H, m), 3.43-3.31 (2H, m), 2.92 (3H, s), 1.89-1.80 (2H, br. m), 1.62-1.49 (2H, m), 1.35 (9H, s). LC-MS: [M+H].sup.+=506.

Example 98: N-tert-butyl-2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-(hydroxymethyl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-methylacetamide

[1485] ##STR01194##

[1486] Trifluoroacetic acid (0.12 mL, 1.5 mmol) was added to a solution of N-tert-butyl-2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-isoindol-2-yl)-N-methylacetamide (Preparation 27, 50 mg, 0.075 mmol, 90% purity) in DCM (0.9 mL) at 0° C. The reaction was allowed to warm to RT and stirred for 1.5 h. The mixture was added to ice cold saturated aqueous sodium bicarbonate solution (20 mL) and extracted with DCM (2×15 mL). The combined organic phases were combined and dried (MgSO.sub.4) and concentrated under vacuum. Preparative HPLC (acidic method, 20-50% MeCN) gave the title compound (13 mg, 34%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6) 8.45 (1H, s), 8.03-7.95 (2H, m), 7.80 (1H, d), 7.60 (1H, d), 5.00 (1H, t), 4.69 (1H, t), 4.57 (1H, d), 4.28 (1H, d), 4.00-3.81 (5H, m), 3.43-3.34 (2H, m), 2.95 (3H, s), 1.85 (2H, d), 1.60-1.47 (2H, m), 1.36 (9H, s). LC-MS: [M+H].sup.+=502.

Example 99: 2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-(hydroxymethyl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-methylacetamide

[1487] ##STR01195##

[1488] The title compound was obtained as a side-product of Example 98 (6 mg, 18%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6) 8.45 (1H, s), 8.14 (1H, d), 8.02-7.96 (2H, m), 7.79 (1H, d), 7.60 (1H, d), 5.14 (1H, dd), 4.75 (1H, t), 4.34 (1H, d), 4.07 (1H, d), 3.91 (5H, m), 3.38 (2H, t), 2.63 (3H, d), 1.85 (2H, d), 1.53 (2H, m). LC-MS: [M+H].sup.+=446.

Example 100: 2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-(hydroxymethyl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-cyclopentylacetamide

[1489] ##STR01196##

[1490] A solution of lithium hydroxide (1 M aqueous, 0.24 mL, 0.24 mmol) was added to a stirred solution of methyl 2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-3-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-isoindol-2-yl)acetate (Preparation 26, 130 mg, 0.24 mmol) in THF (3.5 mL) and water (1 mL). The resulting mixture was stirred at RT for 2 h. The reaction mixture was diluted with ethyl acetate (10 mL) and water (5 mL). The phases were separated and the aqueous phase was acidfied with 1 M hydrochloric acid to pH ˜3. The resultant colourless precipitate was collected by filtration, washing with water (5 mL) and dried under vacuum. The residue was suspended in DCM (4 mL). HATU (108 mg, 0.285 mmol) and diisopropylethylamine (0.048 mL, 0.27 mmol) were added. The mixture was stirred for 5 min, before cyclopentylamine (0.026 mL, 0.26 mmol) was added. The mixture was stirred at RT for 2 h before being diluted with ethyl acetate (10 mL) and water (10 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with 1 M hydrochloric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL), brine (3×10 mL), dried (MgSO.sub.4) and concentrated under vacuum. The residue was dissolved in DCM (3 mL) and trifluoroacetic acid (0.37 mL, 4.8 mmol) was added. The mixture was stirred at RT for 18 h. The solvent was removed under vacuum and the residue was dissolved in methanol (0.9 mL). Potassium carbonate (99 mg, 0.71 mmol) was added and the mixture was stirred at RT for 3 h. The reaction mixture was concentrated under vacuum and redissolved in water (10 mL) and 10% methanol in DCM (10 mL). The phases were separated and the aqueous phase was extracted with 10% methanol in DCM (2×10 mL). The combined organic phases were dried (MgSO.sub.4) and concentrated under vacuum. The resulting solid was recrystallised from hot ethanol (˜5 mL). The resultant solid was filtered, rinsing with ethanol (2 mL) to give the title compound (60 mg, 50%) as a colourless solid. 1H NMR (DMSO-d6, 400 MHz) 8.45 (1H, s), 8.20 (1H, d), 8.05-7.91 (2H, m), 7.79 (1H, d), 7.59 (1H, d), 4.75 (1H, t), 4.32 (1H, d), 4.08 (1H, d), 3.98-3.82 (5H, m), 3.55-3.30 (3H, m), 1.91-1.75 (5H, m), 1.72-1.60 (2H, m), 1.60-1.34 (6H, m). LC-MS: [M+H].sup.+=500.

Example 101: N-tert-butyl-2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-methylacetamide

[1491] ##STR01197##

[1492] Trifluoroacetic acid (0.05 mL, 0.6 mmol) was added to a solution of tert-butyl 2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate (Preparation 32, 20 mg, 0.042 mmol) in DCM (0.5 mL). The mixture was stirred at RT for 5 h. The solvent was removed under vacuum and the residue was azeotroped with toluene (3×5 mL), then diethyl ether (5 mL). The residue was dissolved in a DMF (0.5 mL). N-tert-butyl-methylamine (0.005 mL, 0.04 mmol) was added, followed by diisopropylethylamine (0.015 mL, 0.084 mmol) and HATU (16 mg, 0.042 mmol) and the mixture was stirred at RT for 45 min. The reaction was diluted with ethyl acetate (5 mL) and 1 M hydrochloric acid (5 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate solution (5 mL), brine (5 mL), dried (MgSO.sub.4) and absorbed onto silica. Purification by chromatography (SiO.sub.2, 0-3% methanol in DCM) gave the title compound (15 mg, 75%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6) 8.45 (1H, s), 8.01 (1H, br. s), 7.99 (1H, dd), 7.77 (1H, d), 7.60 (1H, br. d), 4.70 (1H, qt), 4.57 (1H, d), 4.11 (1H, d), 3.93 (1H, m), 3.86 (2H, m), 3.37 (2H, m), 2.94 (3H, s), 1.84 (2H, m), 1.52 (2H, m), 1.44 (3H, d), 1.34 (9H, s). LC-MS: [M+H].sup.+=486.

Example 102: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[(3-methyloxetan-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one

[1493] ##STR01198##

[1494] A stirred solution of 6-(2,5-dichloropyrimidin-4-yl)-2-[(3-methyloxetan-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one (Preparation 53, 249 mg, 0.684 mmol) and diisopropylethylamine (0.36 mL, 2.1 mmol) in 1,4-dioxane (10 mL) was treated with oxan-4-amine (0.21 mL, 2.1 mmol) and stirred at 80° C. for 18 h. The mixture was allowed to cool, was diluted with brine (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with brine (20 mL), dried (Na.sub.2SO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 50-100% ethyl acetate in iso-hexane) gave the title compound (106 mg, 36%) as a cream powder. 1H NMR (400 MHz, DMSO-d6): 8.44 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.72 (1H, d), 7.60 (1H, s), 4.60-4.52 (4H, m), 4.30 (2H, d), 3.99-3.81 (3H, m), 3.79 (2H, s), 3.43-3.33 (2H, m), 1.84 (2H, d), 1.59-1.45 (2H, m), 1.24 (3H, s). LC-MS: [M+H].sup.+=429.

Examples 103-107

[1495] Prepared following similar/analogous methods to Example 102.

TABLE-US-00023 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 103 [01199] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-(2-methoxyethyl)- 2,3-dihydro-1H- isoindol-1-one (CDCl.sub.3): 8.30 (2H, m), 7.97 (1H, dd), 7.54 (1H, d), 5.15 (1H, br. d), 4.60 (2H, s), 4.05 (1H, m), 3.99 (2H, dt), 3.83 (2H, t), 3.66 (2H, t), 3.55 (2H, dt), 3.37 (3H, s), 2.05 (2H, m), 1.56 (2H, m). 403 104 [01200] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-(morpholin-4- yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6) 8.45 (1H, br. s), 8.01 (1H, s), 7.97 (1H, dd), 7.74 (1H, d), 7.61 (1H, br. s), 4.64 (2H, s), 3.86-3.96 (3H, m), 3.68 (2H, m), 3.56 (4H, m), 3.39 (2H, m), 2.57 (2H, m), 2.44 (4H, m), 1.85 (2H, m), 1.53 (2H, ddd). 458 105 [01201] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[(oxolan-2- yl)methyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6): 8.45 (1H, br. s), 8.02 (1H, d), 7.96 (1H, dd), 7.74 (1H, d), 7.61 (1H, br. s), 4.68 (1H, d), 4.61 (1H, d), 4.08 (1H, m), 3.84-3.96 (3H, m), 3.80 (1H, dd), 3.66 (2H, m), 3.55 (1H, dd), 3.39 (2H, m), 1.93-2.01 (1H, m), 1.84 (4H, m), 1.48-1.62 (3H, m). 429 106 [01202] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[(1-methyl-1H- 1,2,3-triazol-4- yl)methyl]-2,3-dihydro- 1H-isoindol-1-one DMSO-d6): 8.44 (1H, s), 8.04 (1H, s), 8.02 (1H, dd), 7.96 (1H, dd), 7.72 (1H, d), 7.60 (1H, s), 4.80 (2H, s), 4.55 (2H, s), 4.01 (3H, s), 3.97- 3.80 (3H, m), 3.41-3.33 (2H, m), 1.84 (2H, d), 1.59-1.46 (2H, m). 440 107 [01203] 2-[(5-tert-butyl-1,2- oxazol-3-yl)methyl]-6- {5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2,3-dihydro-1H- isoindol-1-one DMSO-d6): 8.44 (1H, s), 8.04 (1H, dd), 7.98 (1H, dd), 7.74 (1H, d), 7.60 (1H, d), 6.22 (1H, s), 4.79 (2H, s), 4.59 (2H, s), 3.97-3.83 (3H, m), 3.41-3.33 (2H, m), 1.84 (2H, d), 1.52 (2H, qd), 1.27 (9H, s). 482

Example 108: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[2-(oxolan-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1496] ##STR01204##

[1497] Prepared according to the procedure for Example 102. The reaction was carried out in 1,4-dioxane, 60° C. for 18 h in this case. 1H NMR (400 MHz, CDCl.sub.3) 8.32 (1H, s), 8.27 (1H, d), 7.96 (1H, dd), 7.54 (1H, dd), 5.15 (1H, d), 4.49 (2H, s), 4.07-3.96 (3H, m), 3.90-3.85 (2H, m), 3.77-3.70 (3H, m), 3.54 (2H, td), 2.07-2.02 (3H, m), 1.95-1.87 (4H, m), 1.61-1.49 (3H, m). LC-MS: [M+H].sup.+=443.

Example 109: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-(2-hydroxypropyl)-2,3-dihydro-1H-isoindol-1-one

[1498] ##STR01205##

[1499] Prepared according to the procedure for Example 102. The reaction was carried out in 1,4-dioxane, 80° C. for 18 h. 1H NMR (400 MHz, DMSO-d6): 8.44 (1H, s), 8.00 (1H, dd), 7.95 (1H, dd), 7.73 (1H, d), 7.60 (1H, s), 4.88 (1H, d), 4.65 (2H, d), 4.00-3.77 (4H, m), 3.55-3.33 (4H, m), 1.84 (2H, d), 1.52 (2H, qd), 1.08 (3H, d). LC-MS: [M+H].sup.+=403.

Example 110: 2-[2-(tert-butoxy)ethyl]-6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1H-isoindol-1-one

[1500] ##STR01206##

[1501] Prepared according to the procedure for Example 102. The reaction was carried out in 1:1 EtOH:dioxane at 80° C. for 18 h. 1H NMR (400 MHz, DMSO-d6): 8.45 (1H, s), 8.02 (1H, d), 7.96 (1H, dd), 7.74 (1H, d), 7.61 (1H, br. s), 4.64 (2H, s), 3.83-3.97 (3H, m), 3.65 (2H, t), 3.56 (2H, t), 3.35-3.40 (2H, m), 1.81-1.89 (2H, m), 1.47-1.58 (2H, m), 1.13 (9H, s). LC-MS: [M+H].sup.+=445.

Example 111: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[2-(2-oxopyrrolidin-1-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1502] ##STR01207##

[1503] Prepared according to the procedure for Example 102. The reaction was carried out in 1,4-dioxane at 60° C. for 2 days. 1H NMR (400 MHz, CDCl.sub.3): 8.31 (1H, s), 8.24 (1H, d), 7.96 (1H, dd), 7.54 (1H, d), 5.16 (1H, d), 4.56 (2H, s), 4.07-3.96 (3H, m), 3.85-3.82 (2H, m), 3.64-3.61 (2H, m), 3.57-3.51 (4H, m), 2.25-2.21 (2H, m), 2.07-1.96 (4H, m), 1.61-1.54 (2H, m). LC-MS: [M+H].sup.+=456.

Example 112: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[2-(cyclopentyloxy)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1504] ##STR01208##

[1505] Prepared according to the procedure for Example 102. The reaction was carried out in 1:1 EtOH:dioxane at 80° C. for 18 h. Further oxan-4-amine (1.5 equ.) and DIPEA (2.55 equ.) were added after 18 h and the mixture was stirred for a further 24 h. 1H NMR (400 MHz, DMSO-d6): 8.45 (1H, s), 8.01 (1H, dd), 7.96 (1H, dd), 7.75 (1H, d), 7.67-7.52 (1H, m), 4.61 (2H, s), 3.98-3.81 (4H, m), 3.68 (2H, t), 3.58 (2H, t), 3.42-3.34 (2H, m), 1.85 (2H, br. d), 1.71-1.39 (10H, m). LC-MS: [M+H].sup.+=457.

Example 113: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[(pyrrolidin-2-yl)methyl]-2,3-dihydro-1H-isoindol-1-one

[1506] ##STR01209##

[1507] A stirred solution of tert-butyl 2-[(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)methyl]pyrrolidine-1-carboxylate (Preparation 163, 35 mg, 0.066 mmol) in dichloromethane (1 mL) was treated with TFA (1 mL) and stirred for 30 min. The solution was concentrated and the residue was partitioned between ethyl acetate (5 mL) and saturated aqueous sodium bicarbonate solution (5 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organic phases were washed with brine (5 mL), dried (Na.sub.2SO.sub.4) and concentrated. Purification by chromatography (SiO.sub.2, 0-10% 7M methanolic ammonia solution in dichloromethane) gave the title compound (21 mg, 73%) as a colourless foam. 1H NMR (400 MHz, DMSO-d6): 8.44 (1H, s), 8.00 (1H, d), 7.95 (1H, dd), 7.72 (1H, d), 7.60 (1H, s), 4.77-4.52 (2H, m), 3.97-3.81 (3H, m), 3.56 (1H, dd), 3.45-3.35 (4H, m), 2.87-2.69 (2H, m), 1.90-1.31 (9H, m). LC-MS: [M+H].sup.+=428.

Example 114: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one

[1508] ##STR01210##

[1509] A stirred solution of 6-(5-chloro-2-{[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-2-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one (11 mg, 0.019 mmol) in dichloromethane (1 mL) was treated with TFA (1 mL) and stirred for 30 min. The mixture was concentrated under vacuum and dissolved in ethyl acetate (5 mL), washed with saturated aqueous sodium bicarbonate solution (5 mL), brine (5 mL) and was filtered through a phase-separating cartridge, then concentrated. Purification by chromatography (SiO.sub.2, 0-5% methanol in dichloromethane) gave the title compound (5.7 mg, 68%) as a yellow powder. 1H NMR (400 MHz, DMSO-d6): 8.45 (1H, s), 8.04 (1H, d), 7.99 (1H, dd), 7.76 (1H, d), 7.63 (1H, s), 4.89 (2H, s), 4.63 (2H, s), 3.98-3.82 (3H, m), 3.43-3.28 (2H, m), 2.57 (3H, s), 1.88-1.80 (2H, m), 1.59-1.45 (2H, m). LC-MS: [M+H].sup.+=441.

Examples 115-117

[1510] Prepared following a similar/analogous procedure to that described above for Example 114. Example 115: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[(3-methyl-1,2-oxazol-5-yl)methyl]-2,3-dihydro-1H-isoindol-1-one

##STR01211##

[1511] In this case, the product was purified by reverse phase preparative HPLC on a Waters XSelect CSH C18 OBD, 130 Å, 5 μm, 19 mm×50 mm column, using a gradient of 25 to 45% of acetonitrile in water with 0.1% fomic acid in both at 28 ml/min as eluent, followed by evaporation of the clean fractions and azeoptroping successively with MeCN and diethyl ether. 1H NMR (400 MHz, DMSO-d6): 8.44 (1H, s), 8.05 (1H, d), 7.99 (1H, dd), 7.74 (1H, d), 7.61 (1H, s), 6.35 (1H, s), 4.89 (2H, s), 4.59 (2H, s), 3.96-3.80 (3H, m), 3.43-3.28 (2H, m), 2.20 (3H, s), 1.89-1.79 (2H, m), 1.60-1.44 (2H, m). LC-MS: [M+H].sup.+=440.

Example 116: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[(5-methyl-1,2-oxazol-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one

[1512] ##STR01212##

[1513] 1H NMR (400 MHz, DMSO-d6): 8.44 (1H, s), 8.04 (1H, d), 7.98 (1H, dd), 7.73 (1H, d), 7.62 (1H, s), 6.21 (1H, d), 4.78 (2H, s), 4.56 (2H, s), 3.98-3.82 (3H, m), 3.41-3.34 (2H, m), 2.37 (3H, d), 1.84 (2H, d), 1.60-1.43 (2H, m). LC-MS: [M+H].sup.+=440.

Example 117: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1514] ##STR01213##

[1515] 1H NMR (400 MHz, DMSO-d6): 8.44 (1H, s), 8.00 (1H, dd), 7.94 (1H, dd), 7.72 (1H, d), 7.60 (1H, s), 7.13-7.00 (4H, m), 4.65 (2H, s), 3.98-3.82 (3H, m), 3.78 (2H, t), 3.66 (2H, s), 3.41-3.34 (2H, m), 2.83-2.71 (6H, m), 1.88-1.78 (2H, m), 1.59-1.43 (2H, m). LC-MS: [M+H].sup.+=504.

Example 118: N-tert-butyl-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N,2-dimethylpropanamide

[1516] ##STR01214##

[1517] The product was prepared following an analogous/similar procedure as described in Example 2. In this case, after 1h, further N,2-dimethylpropan-2-amine (1.2 equ.) was added and the reaction was left stirring overnight. Additional N,2-dimethylpropan-2-amine (1.2 equ.), and HATU (1.1 equ.) were added and the mixture stirred for 4 hours. A final 1.2 equivalents of N,2-dimethylpropan-2-amine (1.2 equ.) were added and the reaction was stirred overnight. 1H NMR (400 MHz, DMSO-d6): 8.44 (s, 1H), 7.98 (s, 1H), 7.97 (d, 1H), 7.74 (d, 1H), 7.59 (d, 1H), 4.71 (s, 2H), 3.91-3.85 (m, 3H), 3.40-3.37 (m, 2H), 2.66 (s, 3H), 1.85-1.82 (m, 2H), 1.53-1.47 (m, 8H), 1.34 (s, 9H). LC-MS: [M+H].sup.+=500.

Example 119: (2R)—N-tert-butyl-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-methylpropanamide

[1518] ##STR01215##

[1519] The product was prepared following an analogous/similar procedure as described in Example 2. 1H NMR (400 MHz, DMSO-d6): 8.44 (1H, s), 8.04-8.00 (1H, m), 7.97 (1H, dd), 7.76 (1H, d), 7.61 (1H, br. s), 5.26 (1H, q), 4.60 (1H, d), 4.52 (1H, d), 3.98-3.79 (3H, m), 3.43-3.30 (2H, m), 2.91 (3H, s), 1.89-1.78 (2H, m), 1.60-1.45 (2H, m), 1.36-1.32 (12H, m). LC-MS: [M+H].sup.+=486.

[1520] Note: The product may have partially epimerized during the reaction as shown by chiral HPLC analysis of the final product.

Example 120: N-tert-butyl-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-3-hydroxy-N-methylpropanamide

[1521] ##STR01216##

[1522] TBAF (1M in THF, 0.055 mL, 0.055 mmol) was added to a solution of (2S)—N-tert-butyl-3-[(tert-butyldimethylsilyl)oxy]-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-methylpropanamide (Preparation 164, 28 mg, 0.045 mmol) in THF (0.5 mL) and the mixture was stirred for 1 h. The reaction was quenched by the addition of saturated aqueous NaHCO.sub.3 and water and the mixture was diluted with ethyl acetate, then transferred into a separating funnel. The crude product was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (MgSO.sub.4), filtered and absorbed on silica. Purification by chromatography (SiO.sub.2, 0-10% MeOH in DCM) gave the title compound (13 mg, 55%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6): 8.46 (1H, s), 8.03 (1H, d), 7.98 (1H, dd), 7.78 (1H, d), 7.63 (1H, br. s), 5.24 (1H, dd), 7.93 (1H, t), 4.61 (2H, s), 3.71-3.97 (5H, m), 3.36-3.41 (2H, m), 2.97 (3H, s), 1.85 (2H, m), 1.53 (2H, m), 1.35 (9H, s). LC-MS: [M+H].sup.+=502.

Example 121: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-(1-methyl-2-oxopiperidin-3-yl)-2,3-dihydro-1H-isoindol-1-one

[1523] ##STR01217##

[1524] A mixture of 2,4,5-trichloropyrimidine (0.13 mL, 1.17 mmol), 2-(1-methyl-2-oxopiperidin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (Preparation 109) (288 mg, 0.78 mmol) and potassium carbonate (215 mg, 1.56 mmol) in 1,4-dioxane (2 mL) and water (0.6 mL) was degassed with nitrogen for 10 mins. Tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.039 mmol) was added and the reaction was heated to 100° C. for 1 h. The mixture cooled to RT and diluted with ethyl acetate (20 mL) and water (20 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with brine (25 mL), dried (MgSO.sub.4) and concentrated under vacuum. The residue was dissolved in 1,4-dioxane (5 mL) and oxan-4-amine (0.14 mL, 1.4 mmol) and diisopropylethylamine (0.30 mL, 1.70 mmol) were added. The mixture was heated to 90° C. for 18 h. The reaction was diluted with water (10 mL) and ethyl acetate (10 mL). The aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with 1 M hydrochloric acid (25 mL). The acidic aqueous phase was basified with 2 M sodium hydroxide solution to pH 8 and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with brine (25 mL), dried (MgSO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-10% methanol in DCM) gave the title compound (80 mg, 25%) as a pale yellow foam. 1H NMR (400 MHz, DMSO-d6) 8.45 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.72 (1H, d), 7.63 (1H, s), 4.75 (1H, dd), 4.54 (1H, d), 4.32 (1H, d), 3.98-3.78 (3H, m), 3.41-3.33 (4H, m), 2.85 (3H, s), 2.18-2.04 (1H, m), 2.04-1.93 (3H, m), 1.84 (2H, d), 1.52 (2H, qd). LC-MS: [M+H].sup.+=456.

Example 122: 2-(1-tert-butyl-2-oxopyrrolidin-3-yl)-6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1H-isoindol-1-one

[1525] ##STR01218##

[1526] Prepared according to Example 121 from 2-(1-tert-butyl-2-oxopyrrolidin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (Preparation 108) (150 mg, 0.38 mmol). The title compound (96 mg, 50%) was obtained as a pale yellow foam. 1H NMR (400 MHz, DMSO-d6) 8.45 (1H, s), 8.03 (1H, dd), 7.98 (1H, dd), 7.75 (1H, d), 7.64 (1H, s), 4.94 (1H, dd), 4.62 (1H, d), 4.31 (1H, d), 3.99-3.81 (3H, m), 3.59-3.51 (1H, m), 3.49-3.34 (3H, m), 2.30-2.20 (1H, m), 2.15-2.00 (1H, m), 1.84 (2H, d), 1.54 (2H, dt), 1.37 (9H, s). LC-MS: [M+H].sup.+=484.

Example 123: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[(5-methyl-4H-1,2,4-triazol-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one

[1527] ##STR01219##

[1528] Triethylamine (0.065 mL, 0.47 mmol), ammonium acetate (120 mg, 1.55 mmol) and silica gel (120 mg) were added to a solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetohydrazide (Preparation 111) (66 mg, 0.16 mmol) and methyl ethanimidothioate hydroiodide (36 mg, 0.16 mmol) in DMF (2 mL). The reaction was heated at 120° C. for 2.5 h. The reaction was cooled to RT, diluted with ethyl acetate (20 mL) and filtered through celite. The filtrate was washed with water (20 mL) and brine (2×20 mL) then dried (MgSO.sub.4) and concentrated under vacuum. Purification by chromatography (SiO.sub.2, 0-10% methanol in ethyl acetate) to give a colurless glass, which was triturated with diethyl ether and dried to give the title compound (36 mg, 52%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6) 13.50 (1H, s), 8.44 (1H, s), 8.03 (1H, d), 7.97 (1H, dd), 7.73 (1H, d), 7.61 (1H, br. s), 4.74 (2H, s), 4.59 (2H, s), 3.97-3.85 (3H, m), 3.37 (2H, t), 2.29 (3H, s), 1.84 (2H, br. d), 1.57-1.47 (2H, m). LC-MS: [M+H].sup.+=440.

Example 124: 6-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1H-isoindol-1-one

[1529] ##STR01220##

[1530] A stirred mixture of 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (Preparation 113) (250 mg, 1.19 mmol, 70% pure), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (Preparation 63) (773 mg, 2.39 mmol), K.sub.2CO.sub.3 (330 mg, 2.39 mmol) and 1,4-dioxane: water (3:1, 4 mL) was degassed with nitrogen for 5 minutes. Pd(PPh.sub.3).sub.4 (68 mg, 0.06 mmol) was then added and the reaction heated under nitrogen at 90° C. for a total of 24 hours. After cooling to room temperature the mixture was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO, filtered and concentrated under vacuum. The residue was purified by preparative HPLC to yield 6-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1H-isoindol-1-one (46 mg, 12%). .sup.1H NMR (400 MHz, Me-d.sub.3-OD): 8.54 (1H, d), 8.51 (1H, d), 8.40 (1H, dd), 7.73 (1H, dd), 7.48-7.45 (2H, m), 6.39 (1H, d), 4.56 (2H, s), 3.80 (3H, s). MS: [M+H].sup.+=307.

Examples 125-135

[1531] Prepared from the corresponding boronate ester and substituted 4-chloropyrimidine using an analogous procedure to Example 124:

TABLE-US-00024 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 125 [01221] 7-{2-[(1-methyl-1H- pyrazol-5-yl)amino] pyrimidin-4-yl}-1,2,3,4- tetrahydroisoquinolin-1- one (Me-d.sub.3-OD): 8.71 (1H, d), 8.48 (1H, d), 8.26 (1H, dd), 7.48-7.45 (2H, m), 7.42 (1H, d), 6.38 (1H, d), 3.79 (3H, s), 3.56 (2H, t), 3.09 (2H, t). 321 126 [01222] 2-(cyclopropyl methyl)- 6-{2-[(1-methyl-1H- pyrazol-5-yl)amino] pyrimidin-4-yl}- 2,3-dihydro-1H-isoindol- 1-one (Me-d.sub.3-OD): 8.52-8.50 (2H, m), 8.38 (1H, dd), 7.73 (1H, dd), 7.48 (1H, d), 7.46 (1H, d), 6.39(1H, d), 4.72 (2H, s), 3.80 (3H, s), 3.54 (2H, d), 1.20-1.11 (1H, m), 0.68-0.60 (2H, m), 0.44-0.37 (2H, m). 361 127 [01223] N-benzyl-N-methyl-2-(6- {2-[(1-methyl-1H- pyrazol-5-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H-isoindol- 2-yl)acetamide (Me-d.sub.3-OD): 8.55 (0.6H, d), 8.51 (1.4H, dd), 8.42-8.37 (1H, m), 7.73 (1H, t), 7.52- 7.26 (8H, m), 6.39 (1H, d), 4.73 (0.7H, s), 4.70 (1.3H, s), 4.67-4.63 (4H, m), 3.80 (3H, s), 3.09 (2H, s), 2.98 (1H, s). 468 128 [01224] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}- 2,3-dihydro-1H-isoindol- 1-one (Me-d.sub.3-OD): 8.36 (1H, s), 8.24 (1H, s), 8.08 (1H, dd), 7.72 (1H, d), 4.57 (2H, s), 4.12-4.02 (1H, m), 4.02-3.93 (2H, m), 3.59-3.51 (2H, m), 2.02 (2H, dd), 1.69-1.57 (2H, m). 345 129 [01225] N-methyl-2-(6-{2-[(1- methyl-1H-pyrazol-5- yl)amino]pyrimidin-4-yl}- 1-oxo-2,3-dihydro-1H- isoindol-2-yl)-N-(2- phenylethyl) acetamide (Me-d3-OD): 8.55-8.48 (2H, m), 8.42-8.35 (1H, m), 7.70 (1H, dd), 7.49-7.43 (2H, m), 7.41-7.36 (1H, m), 7.34-7.19 (4H, m), 6.39 (1H, dd), 4.58 (1H, s), 4.52 (1H, s), 4.35 (1H, s), 4.14 (1H, s), 3.80 (1.7H, s), 3.79 (1.3H, s), 3.71 (1H, t), 3.64 (1H, t), 3.07-2.99 (4H, m), 2.89 (1H, t). 482 130 [01226] 6-{5-chloro-2-[(1,5- dimethyl-1H-pyrazol-4- yl)amino]pyrimidin-4-yl}- 2,3-dihydro-1H-isoindol- 1-one (DMSO-d.sub.6): 9.05 (1H, s), 8.68 (1H, s), 8.49 (1H, s), 8.03 (1H, s), 7.99 (1H, d), 7.73 (1H, d), 7.50 (1H, s), 4.47 (2H, s), 3.71 (3H, s), 2.18 (3H, s). 355 131 [01227] N-benzyl-2-(6-{5-chloro- 2-[(oxan-4-yl)amino] pyrimidin-4-yl}- 1-oxo-2,3-dihydro-1H- isoindol-2-yl)-N- methylacetamide (Me-d.sub.3-OD): 8.35 (1H, s), 8.24 (1H, d), 8.13-8.03 (1H, m), 7.76-7.60 (1H, m), 7.44- 7.27 (5H, m), 4.72 (2H, d), 4.68-4.63 (4H, m), 4.12-4.02 (1H, m), 3.98 (2H, dt), 3.54 (2H, dt), 3.09 (2H, s), 2.98 (1H, s), 2.01 (2H, d), 1.70- 1.56 (2H, m). 504 132 [01228] 7-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}- 1,2,3,4-tetra hydroisoquinolin-1-one (DMSO-d.sub.6): 8.42 (1H, s), 8.26 (1H, d), 8.01 (1H, s), 7.86 (1H, dd), 7.59-7.51 (1H, m), 7.45 (1H, d), 3.99-3.83 (3H, m), 3.45-3.37 (4H, m), 2.99 (2H, t), 1.89-1.80 (2H, m), 1.60-1.47 (2H, m). 359 133 [01229] tert-butyl 2-(6-{2-[(oxan- 4-yl)amino] pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)acetate (CDCl.sub.3): 8.48 (1H, s), 8.37 (1H, d), 8.29 (1H, dd), 7.57 (1H, d), 7.06 (1H, d), 4.60 (2H, s), 4.34 (2H, s), 4.24- 4.12 (1H, m), 4.07-3.98 (2H, m), 3.66-3.55 (2H, m), 2.11 (2H, d), 1.69-1.55 (2H, m), 1.50 (9H, s). 425 134 [01230] tert-butyl 2-(6-{5-fluoro- 2-[(oxan-4-yl)amino] pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H- isoindol-2-yl)acetate (Me-d3-OD): 8.49 (1H, s), 8.35 (1H, d), 8.31 (1H, d), 7.73 (1H, d), 4.71-4.62 (2H, m), 4.36 (2H, s), 4.16-4.04 (1H, m), 4.04-3.95 (2H, m), 3.59 (2H, t), 2.04 (2H, d), 1.71-1.57 (2H, m), 1.51 (9H, s). 443 135 [01231] 6-{5-chloro-2-[(1-methyl- 1H-pyrazol-5-yl)amino] pyrimidin-4-yl}-2- [2-oxo-2-(1,2,3,4- tetrahydro isoquinolin-2- yl)ethyl]-2,3-dihydro-1H- isoindol-1-one (Me-d3-OD): 8.52 (1H, d), 8.28 (1H, s), 8.13-8.06 (1H, m), 7.42 (1H, d), 7.25-7.13 (5H, m), 6.38-6.33 (1H, m), 4.75-4.64 (6H, m), 3.83 (2H, q), 3.80-3.73 (3H, m), 3.02 (1H, t), 2.90 (1H, t). 514

Example 136: 6-{5-methyl-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1H-isoindol-1-one formate salt

[1532] ##STR01232##

[1533] A stirred mixture of 2,4-dichloro-5-methylpyrimidine (157 mg, 0.96 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (Preparation 63) (250 mg, 0.96 mmol), K.sub.2CO.sub.3 (266 mg, 1.93 mmol) and 1,4-dioxane: water (3:1, 3 mL) was degassed with nitrogen for 5 minutes. Pd(PPh.sub.3).sub.4 (55 mg, 0.05 mmol) was then added and the mixture heated at 80° C. under nitrogen for a total of 16 hours. The reaction was allowed to cool to room temperature and then diluted with water. The mixture was extracted with EtOAc (×3) and the combined organic layers were filtered and evaporated under vacuum to yield 6-(2-chloro-5-methylpyrimidin-4-yl)-2,3-dihydro-1H-isoindol-1-one as a colourless solid. MS: [M+H].sup.+=260/262. A solution of this material (50 mg, 0.19 mmol) and DIPEA (117 μL, 0.67 mmol) in anhydrous 1,4-dioxane (1.9 mL) was treated with 4-aminooxan (41 μL, 0.39 mmol) and sealed in a reacti vial. The reaction was stirred at 90° C. for 16 hours and then allowed to cool. The mixture was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO, filtered and concentrated under vacuum. The residue was purified by preparative HPLC to yield the title compound (7 mg, 11%) as a colourless solid. .sup.1H NMR (400 MHz, Me-d.sub.3-OD): 8.23 (1H, s), 8.15 (1H, s), 8.02 (1H, d), 7.88 (1H, dd), 7.72 (1H, dd), 4.56 (2H, s), 4.12-4.02 (1H, m), 4.00 (1H, t), 3.97 (1H, t), 3.55 (2H, dt), 2.21 (3H, s), 2.06-1.98 (2H, m), 1.69-1.55 (2H, m). MS: [M+H].sup.+=325.

Example 137: tert-Butyl 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate

[1534] ##STR01233##

[1535] A stirred solution of tert-butyl 2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]acetate (Preparation 3) (1.87 g, 6.58 mmol, ˜60% pure) and DIPEA (2.865 mL, 16.44 mmol) in anhydrous 1,4-dioxane (21.9 mL) was treated with 4-aminooxan (0.998 mL, 9.86 mmol) under nitrogen. The reaction was heated to 90° C. for 16 hours. The reaction was allowed to cool, diluted with water, and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum. A −100 mg portion of the residue was purified by preparative HPLC to yield the title compound as a colourless solid (63 mg). .sup.1H NMR (400 MHz, Me-d.sub.3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.09 (1H, dd), 7.73 (1H, dd), 4.68 (2H, s), 4.37 (2H, s), 4.12-4.02 (1H, m), 4.02-3.94 (2H, m), 3.60-3.51 (2H, m), 2.05-1.97 (2H, m), 1.69-1.58 (2H, m), 1.51 (9H, s). MS: [M+H].sup.+=459.

Example 138: 3-(6-{5-Chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)propanoic acid

[1536] ##STR01234##

[1537] A stirred solution of methyl 3-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoate (Preparation 125, 550 mg, 1.50 mmol) and DIPEA (785 μL, 4.51 mol) in anhydrous 1,4-dioxane (7.5 mL) was treated with 4-aminooxan (277 μL, 1.95 mmol). The reaction was heated to 90° C. under nitrogen for 16 hours. The reaction was allowed to cool and then NaOH (3 ml, 1M) was added. The mixture was stirred at room temperature for 24 hours. The pH was adjusted to ˜pH 5 with citric acid (5%, aq.) before the product was extracted with CHCl.sub.3:IPA (3:1, ×2). The combined organic layers were washed with brine, dried over MgSO, filtered and concentrated under vacuum, and the residue purified by preparative HPLC to give the title compound (104 mg, 17%) as a colourless solid. .sup.1H NMR (400 MHz, Me-d.sub.3-OD): 8.35 (1H, s), 8.20 (1H, d), 8.05 (1H, dd), 7.70 (1H, dd), 4.68 (2H, s), 4.11-4.02 (1H, m), 4.02-3.92 (4H, m), 3.59-3.51 (2H, m), 2.71 (2H, t), 2.06-1.97 (2H, m), 1.69-1.57 (2H, m). MS: [M+H].sup.+=417.

Example 139: 6-{5-Chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[3-oxo-3-(pyrrolidin-1-yl)propyl]-2,3-dihydro-1H-isoindol-1-one

[1538] ##STR01235##

[1539] A stirred solution of 3-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)propanoic acid (Example 138) (99 mg, 0.24 mmol) in anhydrous 1,4-dioxane: DMF (3:1, 3 mL) under nitrogen was treated with DIPEA (62 μL, 0.36 mmol), HBTU (138 mg, 0.36 mmol) and then pyrrolidine (25 μL, 0.36 mmol). The reaction was stirred for 16 hours at room temperature and quenched by adding NaHCO.sub.3 (aq., sat.). The product was extracted with EtOAc (×3) and the combined organic layers washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound (69 mg, 61%) as a colourless solid. .sup.1H NMR (400 MHz, Me-d.sub.3-OD): 8.35 (1H, s), 8.20 (1H, d), 8.05 (1H, dd), 7.70 (1H, dd), 4.69 (2H, s), 4.10-4.03 (1H, m), 4.02-3.94 (4H, m), 3.58-3.51 (4H, m), 3.43 (2H, t), 2.81 (2H, t), 2.05-1.94 (4H, m), 1.93-1.85 (2H, m), 1.70-1.57 (2H, m). MS: [M+H].sup.+=470.

Example 140: tert-Butyl 2-(7-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)acetate

[1540] ##STR01236##

[1541] Prepared using a similar procedure to Example 137. A small portion of the crude (˜40 mg) was purified by preparative HPLC to yield the title compound (7 mg) as a yellow solid. .sup.1H NMR (400 MHz, Me-d.sub.3-OD): 8.43 (1H, d), 8.33 (1H, s), 7.97 (1H, dd), 7.45 (1H, d), 4.28 (2H, s), 4.09-4.04 (1H, m), 3.99 (2H, dd), 3.75 (2H, t), 3.59-3.51 (2H, m), 3.17 (2H, t), 2.01 (2H, s), 1.69-1.56 (2H, m), 1.51 (9H, s). MS: [M+H].sup.+=473.

Example 141: N-tert-Butyl-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamide

[1542] ##STR01237##

[1543] A stirred solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 60 mg, 0.10 mmol, 70% pure) in anhydrous 1,4-dioxane/DMF (3:1, 1.5 mL) under nitrogen was treated with DIPEA (36 μL, 0.21 mmol), HBTU (81 mg, 0.21 mmol) and then tert-butylamine (17 μL, 0.16 mmol). The reaction was stirred for 4 days at room temperature and quenched by adding water. The product was extracted with EtOAc (×3) and the combined organic layers washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum. Purification by preparative HPLC gave the title compound (32 mg, 70%) as a colourless solid. .sup.1H NMR (400 MHz, Me-d.sub.3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.71 (1H, dd), 4.66 (2H, s), 4.28 (2H, s), 4.11-4.02 (1H, m), 4.02-3.95 (2H, m), 3.59-3.51 (2H, m), 2.05-1.97 (2H, m), 1.69-1.58 (2H, m), 1.38 (9H, s). MS: [M+H].sup.+=458.

Examples 142-158

[1544] Prepared using a similar procedure to Example 141.

TABLE-US-00025 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 142 [01238] 6-{5-chloro-2-[(oxan- 4-yl)amino] pyrimidin-4-yl}-2-[2- (2-methylpiperidin-1- yl)-2-oxoethyl]-2,3- dihydro-1H-isoindol- 1-one (Me-d.sub.3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.72 (1H, dd), 4.62 (4H, s), 4.44-4.26 (1H, m), 4.11-4.03 (1H, m), 4.03-3.94 (2H, m), 3.86-3.70 (1H, m), 3.55 (2H, dt), 2.05-1.98 (2H, m), 1.86- 1.57 (7H, m), 1.40 (2H, d), 1.24 (2H, d). 484 143 [01239] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H- isoindol-2-yl)-N- cyclohexyl-N- methylacetamide (Me-d.sub.3-OD): 8.36 (1H, s), 8.24 (1H, s), 8.08 (1H, dd), 7.72 (1H, dd), 4.67 (2H, s), 4.62 (1H, s), 4.56 (1H, s), 4.39-4.28 (0.5H, m), 4.11- 4.02 (1H, m), 4.02-3.95 (2H, m), 3.81-3.70 (0.5H, m), 3.59- 3.51 (2H, m), 3.01 (2H, s), 2.88 (1H, s), 2.05-1.98 (2H, m), 1.94-1.77 (3H, m), 1.76- 1.33 (8H, m), 1.27-1.15 (1H, m). 498 144 [01240] 6-{5-chloro-2-[(oxan- 4-yl)amino] pyrimidin-4-yl}-2-[2- oxo-2-(piperidin-1- yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d.sub.6): 8.45 (1H, s), 8.03 (1H, s), 7.99 (1H, dd), 7.75 (1H, d), 7.62-7.55 (1H, m), 4.57 (2H, s), 4.46 (2H, s), 3.99-3.90 (1H, m), 3.87 (2H, d), 3.50-3.42 (4H, m), 3.38 (2H, t), 1.89-1.82 (2H, m), 1.65-1.51 (6H, m), 1.51-1.43 (2H, m). 470 145 [01241] 2-(2-{4-azaspiro[2.5] octan-4-yl}-2- oxoethyl)-6-{5- chloro-2-[(oxan-4- yl)amino] pyrimidin- 4-yl}-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.36 (1H, s), 8.24 (1H, s), 8.08 (1H, dd), 7.72 (1H, d), 4.76-4.62 (4H, m), 4.12-3.95 (4H, m), 3.68- 3.59 (1H, m), 3.59-3.51 (2H, m), 2.02 (2H, d), 1.95-1.49 (8H, m), 1.27-0.70 (4H, m). 496 146 [01242] 6-{5-chloro-2-[(oxan- 4-yl)amino] pyrimidin-4-yl}-2-[2- oxo-2-(pyrrolidin-1- yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.72 (1H, dd), 4.70 (2H, s), 4.51 (2H, s), 4.12-4.02 (1H, m), 4.02-3.96 (2H, m), 3.62 (2H, t), 3.55 (2H, dt), 3.49 (2H, t), 2.11-1.98 (4H, m), 1.98-1.90 (2H, m), 1.69-1.57 (2H, m). 456 147 [01243] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H- isoindol-2-yl)-N- cyclopropyl-N- methylacetamide (DMSO-d.sub.6): 8.45 (1H, s), 8.03 (1H, d), 7.99 (1H, dd), 7.75 (1H, d), 7.59 (1H, br s), 4.62- 4.58 (4H, m), 3.99-3.91 (1H, m), 3.91-3.84 (2H, m), 3.43- 3.38 (2H, m), 2.90-2.81 (4H, m), 1.90-1.81 (2H, m), 1.60- 1.47 (2H, m), 0.95-0.83 (4H, m). 456 148 [01244] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H- isoindol-2-yl)-N- cyclohexyl acetamide (DMSO-d.sub.6): 8.45 (1H, s), 8.04-8.02 (1H, m), 8.01-7.96 (2H, m), 7.74 (1H, d), 7.63- 7.54 (1H, m), 4.59 (2H, s), 4.17 (2H, s), 3.98-3.90 (1H, m), 3.90-3.83 (2H, m), 3.61- 3.52 (1H, m), 1.85 (2H, d), 1.79-1.65 (4H, m), 1.61-1.47 (3H, m), 1.31-1.10 (5H, m). 484 149 [01245] 6-{5-chloro-2-[(oxan- 4-yl)amino] pyrimidin-4-yl}-2-[2- (2-ethylpiperidin-1- yl)-2-oxoethyl]-2,3- dihydro-1H-isoindol- 1-one (DMSO-d.sub.6): 8.45 (1H, s), 8.03 (1H, s), 7.98 (1H, dd), 7.75 (1H, d), 7.59 (1H, br s), 4.64- 4.38 (4.5H, m), 4.27 (0.5H, d), 3.99-3.83 (3.5H, m), 3.72 (0.5H, d), 3.43-3.35 2.5H, m), 3.14-3.02 (0.5H, m), 1.90- 1.22 (12H, m), 0.97-0.85 (1.5H, m), 0.78 (1.5H, t). 498 150 [01246] 6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin- 4-yl}-2-[2-oxo-2- (1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3- dihydro-1H-isoindol- 1-one (Me-d.sub.3-OD): 8.36 (1H, s), 8.25 (1H, s), 8.11-8.06 (1H, m), 7.74-7.69 (1H, m), 7.25- 7.19 (4H, m), 4.73 (1.5H, s), 4.72-4.66 (4.5H, m), 4.11- 4.03 (1H, m), 4.03-3.95 (2H, m), 3.89-3.81 (2H, m), 3.55 (2H, dt), 3.03 (1H, t), 2.92 (1H, t), 2.05-1.98 (2H, m), 1.70-1.58 (2H, m). 518 151 [01247] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H- isoindol-2-yl)-N-(2- methylbutan-2- yl)acetamide (Me-d.sub.3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.71 (1H, d), 4.67 (2H, s), 4.30 (2H, s), 4.11-4.02 (1H, m), 4.02-3.95 (2H, m), 3.55 (2H, dt), 2.05-1.98 (2H, m), 1.77 (2H, q), 1.70-1.57 (2H, m), 1.33 (6H, s), 0.91 (3H, t). 472 152 [01248] 6-{5-chloro-2-[(oxan- 4-yl)amino] pyrimidin-4-yl}-2-[2- (3-methyl-1,2,3,4- tetrahydro isoquinolin-2-yl)-2- oxoethyl]-2,3- dihydro-1H-isoindol- 1-one (Me-d.sub.3-OD): 8.36 (1H, s), 8.25 (1H, d), 8.09 (1H, d), 7.72 (1H, dd), 7.30-7.16 (4H, m), 5.04 (0.5H, d), 4.97-4.90 (0.5H, m), 4.76-4.59 (5H, m), 4.63-4.58 (0.5H, m), 4.35 (0.5H, d), 4.12-4.02 (1H, m), 4.02-3.94 (2H, m), 3.59-3.51 (2H, m), 3.30-3.23 (0.5H, m), 3.17-3.07 (0.5H, m), 2.83- 2.68 (1H, m), 2.02 (2H, d), 1.69-1.58 (2H, m), 1.27 (1.5H, d), 1.12 (1.5H, d). 532 153 [01249] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H- isoindol-2-yl)-N- cyclopentyl acetamide (Me-d.sub.3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.72 (1H, dd), 4.68 (2H, s), 4.32 (2H, s), 4.21-4.13 (1H, m), 4.10-4.02 (1H, m), 4.02- 3.95 (2H, m), 3.55 (2H, dt), 2.05-1.92 (4H, m), 1.80-1.69 (2H, m), 1.69-1.57 (4H, m), 1.57-1.48 (2H, m). 470 154 [01250] 2-(6-{5-chloro-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H- isoindol-2-yl)-N- (oxan-4-yl) acetamide (Me-d.sub.3-OD): 8.36 (1H, s), 0.24 (1H, s), 8.08 (1H, dd), 7.72 (1H, dd), 4.68 (2H, s), 4.35 (2H, s), 4.10-4.02 (1H, m), 4.02-3.91 (5H, m), 3.59- 3.45 (4H, m), 2.05-1.98 (2H, m), 1.91-1.83 (2H, m), 1.69- 1.53 (4H, m). 486 155 [01251] 6-{2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2- (1,2,3,4-tetrahydro isoquinolin-2- yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (CDCl3): 8.49 (1H, s), 8.38 (1H, d), 8.29 (1H, d), 7.56 (1H, t), 7.26-7.20 (2H, m), 7.20-7.12 (2H, m), 7.06 (1H, d), 5.19 (1H, d), 4.76 (2H, s), 4.66 (2H, d), 4.59 (2H, d), 4.26-4.14 (1H, m), 4.08-3.99 (2H, m), 3.90-3.80 (2H, m), 3.67-3.56 (2H, m), 2.99-2.87 (2H, m), 2.12 (2H, d), 1.79 (2H, s), 1.71-1.56 (2H, m). 484 156 [01252] N-tert-butyl-N- methyl-2-(6-{2- [(oxan-4-yl)amino] pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H- isoindol-2- yl)acetamide (CDCI3): 8.48 (1H, s), 8.38 (1H, d), 8.29 (1H, dd), 7.57 (1H, d), 7.07 (1H, d), 5.13 (1H, d), 4.65 (2H, s), 4.44 (2H, s), 4.28-4.13 (1H, m), 4.11-3.98 (2H, m), 3.69-3.56 (2H, m), 3.01 (3H, s), 2.22- 2.04 (2H, m), 1.66-1.60 (2H, m), 1.45 (9H, s). 438 157 [01253] N-tert-butyl-2-(6-{5- fluoro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3- dihydro-1H-isoindol- 2-yl)-N-methyl acetamide (Me-d3-OD): 8.51 (1H, s), 8.36 (1H, d), 8.31 (1H, d), 7.73 (1H, d), 4.65 (2H, s), 4.52 (2H, s), 4.17-4.05 (1H, m), 4.05-3.93 (2H, m), 3.66- 3.54 (2H, m), 3.06 (3H, s), 2.05 (2H, d), 1.74-1.54 (2H, m), 1.46 (9H, s). 456 158 [01254] 6-{5-fluoro-2-[(oxan- 4-yl)amino] pyrimidin-4-yl}-2-[2- oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3- dihydro-1H-isoindol- 1-one (CDCl3): 8.58 (1H, s), 8.30- 8.25 (2H, m), 7.63-7.54 (1H, m), 7.25-7.15 (4H, m), 4.76 (2H, s), 4.67 (2H, d), 4.59 (2H, d), 4.12-3.99 (3H, m), 3.89-3.81 (2H, m), 3.64-3.56 (2H, m), 2.98-2.89 (2H, m), 2.10 (2H, d), 1.66-1.60 (2H, m). 502

Examples 159-179

[1545] These were synthesised by the following procedure.

[1546] General S.sub.NAR displacement.

[1547] A mixture of 6-(2,5-dichloropyrimidin-4-yl)-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Preparation 128, 130 mg, 0.29 mmol), amine (0.57 mmol) and DIPEA (0.100 μL, 0.57 mmol) in anhydrous 1,4-dioxane (2.0 mL) was stirred in a reacti vial at 90° C. for 16 hours. The mixture was allowed to cool to room temperature and was then diluted with water. The product was extracted with EtOAc (×3) and the combined organic layers were washed with water and brine, dried over MgSO.sub.4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC to yield the product.

TABLE-US-00026 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 159 [01255] tert-butyl 4-[(5-chloro- 4-{3-oxo-2-[2-oxo-2- (1,2,3,4-tetrahydro isoquinolin-2-yl)ethyl]- 2,3-dihydro-1H- isoindol-5-yl}pyrimidin- 2-yl)amino]piperidine- 1-carboxylate (Me-d.sub.3-OD): 8.36 (1H, s), 8.25 (1H, s), 8.08 (1H, d), 7.74-7.69 (1H, m), 7.24-7.17 (4H, m), 4.75-4.62 (6H, m), 4.09-3.99 (3H, m), 3.89-3.79 (2H, m), 3.06-2.89 (4H, m), 2.05 (1H, d), 2.01 (1H, s), 1.50-1.46 (11H, m). 615 160 [01256] 6-{5-chloro-2-[(2,3- dihydroxypropyl)amino] pyrimidin-4-yl}-2-[2- oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.38 (1H, s), 8.26 (1H, s), 8.13-8.07 (1H, m), 7.75-7.69 (1H. m)t 7.24-7.19 (4H, m), 4.76-4.65 (6H, m), 3.89-3.81 (3H, m), 3.66-3.54 (3H, m), 3.47 (1H, dd), 3.03 (1H, t), 2.92 (1H, t). 508 161 [01257] 6-{5-chloro-2-[(1,3- dihydroxypropan-2- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.38 (1H, s), 8.27 (1H, s), 8.13-8.08 (1H, m), 7.75-7.69 (1H, m), 7.24-7.19 (4H, m), 4 74-4.66 (6H, m), 4.21-4.14 (1H, m), 3.85 (2H, q), 3.78-3.74 (4H, m), 3.03 (1H, t), 2.92 (1H, t). 508 162 [01258] 6-{5-chloro-2-[(2- methoxyethyl)amino] pyrimidin-4-yl}-2-[2- oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.36 (1H, s), 8.26 (1H, s), 8.12-8.07 (1H, m), 7.72 (1H, dd), 7.24-7.19 (4H, m), 4.75-4.66 (6H, m), 3.88-3.82 (2H, m), 3.63-3.58 (4H, m), 3.40 (3H, s), 3.03 (1H, t), 2.92 (1H, t). 492 163 [01259] 6-{5-chloro-2-[(oxetan- 3-yl)amino]pyrimidin- 4-yl}-2-[2-oxo-2- (1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.39 (1H, s), 8.26 (1H, s), 8.12-8.07 (1H, m), 7.72 (1H, dd), 7.21 (4H, d), 5.13- 5.06 (1H, m), 4.96 (2H, t), 4.77- 4.63 (8H, m), 3.88-3.81 (2H, m), 3.04 (1H, t), 2.92 (1H, t). 490 164 [01260] 6-{5-chloro-2- [(propan-2- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.34 (1H, s), 8.26 (1H, S), 8.09 (1H, d), 7.71 (1H dd), 7.25-7.15 (4H, m), 4.75- 4.63 (6H, m), 4.21-4.11 (1H, m), 3.89-3.80 (2H, m), 3.03 (1H, t), 2.92 (1H, t), 1.26 (6H, d). 476 165 [01261] 6-{2-[(1- acetylpiperidin-4- yl)amino]-5- chloropyrimidin-4-yl}- 2-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.37 (1H, s), 8.25 (1H, s), 8.12-8.07 (1H, m), 7.72 (1H, dd), 7.24-7.17 (4H, m), 4.75-4.66 (6H, m), 4.48-4.40 (1H, m), 4.15-4.07 (1H, m), 3.94 (1H, d), 3.88-3.81 (2H, m), 3.30-3.26 (1H, m), 3.03 (1H, t), 2.97-2.86 (2H, m), 2.18-2.06 (5H, m), 1.53 (2H, d). 559 166 [01262] 6-{5-chloro-2-[(oxolan- 3-yl)amino]pyrimidin- 4-yl}-2-[2-oxo-2- (1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.38 (1H, s), 8.27 (1H, s), 8.13-8.08 (1H, m), 7.75-7.69 (1H, m), 7.24-7.18 (4H, m), 4 74-4.66 (6H, m), 4.59-4.52 (1H, m), 4.04-3.96 (2H, m), 3.89-3.82 (3H, m), 3.74 (1H, dd), 3.03 (1H, t), 2.92 (1H, t), 2.37-2.27 (1H, m), 2.04- 1.95 (1H, m). 504 167 [01263] 6-[2-(tert-butylamino)- 5-chloropyrimidin-4- yl]-2-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.34 (1H, s), 8.30- 8.23 (1H, m), 8.12-8.05 (1H, m), 7.75-7.68 (1H, m), 7.25- 7.16 (4H, m), 4.77-4.63 (6H, m), 3.88-3.80 (2H, m), 3.03 (1H, t), 2.92 (1H, t), 1.48 (9H, s). 490 168 [01264] 6-( 5-ch loro-2-{[trans- 4- hydroxycyclohexyl] amino}pyrimidin-4-yl)-2- [2-oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d.sub.6): 8.43 (1H, s), 8.04 (1H, s), 7.99 (1H, d), 7.75 (1H, d), 7.43 (1H, s), 7.21 (4H, d), 4.76 (1H, s), 4.63 (1H, s), 4.59 (4H, s), 4.50 (1H, s), 3.77 (1H, t), 3.73-3.61 (2H, m), 3 44-3.35 (1H, m), 2.94 (1H, t), 2.82 (1H, t), 1.88 (4H, dd), 1.37-1.18 (4H, m). 532 169 [01265] 6-[5-chloro-2- (cyclohexylamino) pyrimidin-4-yl]-2- [2-oxo-2-(1.2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.33 (1H, s), 8.24 (1H, s), 8.10-8.05 (1H, m), 7.74-7.68 (1H, m), 7.24-7.17 (4H, m), 4.75-4.62 (6H, m), 3.88-3.79 (3H, m), 3.03 (1H, t), 2.92 (1H, t), 2.07-2.00 (2H, m), 1.85-1.76 (2H, m), 1.73-1.62 (1H, m), 1.46-1.28 (5H, m). 516 170 [01266] 6-(5-chloro-2-{[trans- 4- methoxycyclohexyl] amino}pyrimidin-4-yl)- 2-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d.sub.6): 8.43 (1H, s), 8.04 (1H, s), 7.99 (1H, dd), 7.75 (1H, d), 7.53-7.42 (1H, m), 7.21 (4H, d), 4.76 (1H, s), 4.63 (1H, s), 4.59 (4H, s), 3.77 (1H, t), 3.74- 3.64 (2H, m), 3.24 (3H, s), 3.17- 3.05 (1H, m), 2.94 (1H, t), 2.82 (1H, t), 2.06-1.91 (4H, m), 1.39- 1.28 (2H, m), 1.26-1.15 (2H, m). 546 171 [01267] 6-(5-chloro-2-{[trans- 3- hydroxycyclobutyl] amino}pyrimidin-4-yl)-2- [2-oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d.sub.6): 8.44 (1H, s), 8.05 (1H, s), 8.03-7.97 (1H, m), 7.89-7.84 (1H, m), 7.75 (1H, d), 7.25-7.18 (5H, m), 4.97 (1H, d) 4.64-4.57 (6H, m), 4.37-4.28 (2H, m), 3.77 (1H, t), 3.70 (1H, t), 2.94 (1H, t), 2.82 (1H, t), 2.28-2.21 (2H, m), 2.19-2.12 (2H, m). 504 172 [01268] 6-(5-chloro-2-{[cis-3- hydroxycyclobutyl] amino}pyrimidin-4-yl)-2- [2-oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d.sub.6): 8.42 (1H, s), 8.04 (1H, s), 8.02-7.96 (1H, m), 7.84-7.77 (1H, m), 7.75 (1H, d), 7.21 (4H, d), 4.77 (1H, s), 4.60 (6H, d), 3.88-3.75 (3H, m), 3.70 (1H, t), 2.94 (1H, t), 2.85-2.78 (1H, m), 2.63-2.54 (1H, m), 1.89-1.79 (2H, m). [M − H] ion 502 173 [01269] 6-{2-[(1-acetylazetidin- 3-yl)amino]-5- chloropyrimidin-4-yl}- 2-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (DMSO-d.sub.6): 8.51 (1H, s), 8.23 (1H, br s), 8.07 (1H, s), 8.01 (1H, dd), 7.76 (1H, d), 7.25- 7.19 (4H, m), 4.77 (0.8H, s), 4.63 (1.2H, s), 4.62-4.54 (5H, m), 4.40 (1H, t), 4.12 (1H, t), 4.03 (1H, dd), 3.87-3.80 (1H, m), 3.77 (1H, t), 3.70 (1H, t), 2.94 (1H, t), 2.82 (1H, t), 1.76 (3H, s). 531 174 [01270] 6-{5-chloro-2-[(2,2- dimethyloxan-4- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.36 (1H, s), 8.26 (1H, s), 8.13-8.07 (1H, m), 7.75-7.68 (1H, m), 7.24-7.17 (4H, m), 4.75-4.66 (6H, m), 4.30-4.20 (1H, m), 3.88-3.77 (4H, m), 3.03 (1H, t), 2.92 (1H, t), 2.04-1.95 (2H, m), 1.56-1.46 (1H, m), 1.46-1.33 (1H, m), 1.32 (3H, s), 1.26 (3H, s). 546 175 [01271] 6-{5-chloro-2-[(2- methyloxan-4- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.38 (0.7H, s), 8.35 (0.3H, s), 8.26 (0.7H, s), 8.24 (0.3H, s), 8.12-8.06 (1H, m), 7.71 (1H, dd), 7.24-7.16 (4H, m), 4 76-4.62 (6H, m), 4.32-4.25 (0.7H, m), 4.11-3.97 (0.7H, m), 3.94-3.78 (4.3H, m), 3.61-3.49 (0.7H, m), 3.03 (1H, t), 2.91 (1H, t), 2.10-1.98 (0.8H m), 1.96-1.79 (2.2H, m), 1.67- 1.58 (0.7H, m), 1.52 (0.3H, dd), 1.21 (0.9H, d), 1.18 (2.1H, d). 532 176 [01272] 6-{5-chloro-2-[(3- methyloxan-4- yl)amino]pyrimidin-4- yl}-2-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.37 (1H, s), 8.34 (1H, s), 8.25 (1H, s), 8.12-8.05 (1H, m), 7.72 (1H, dd), 7.25- 7.16 (4H, m), 4.76-4.63 (6H, m), 4.32-4.24 (0.5H, m), 4.03- 3.75 (4.5H, m), 3.73-3.57 (1.5H, m), 3.57-3.48 (0.5H, m), 3.03 (1H, t), 2.92 (1H, t), 2.26-2.17 (0.5H, m), 2.04-1.98 (0.5H, m), 1.96-1.85 (0.5H, m), 1.85-1.70 (1H, m), 1.66-1.55 (0.5H, m), 1.02 (1.5H, d), 0.92 (1.5H, d). 532 177 [01273] 6-[5-chloro-2-({8- oxabicyclo[3.2.1]octan- 3-yl}amino)pyrimidin- 4-yl]-2-[2-oxo-2- (1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.35 (1H, br s), 8.28-8.24 (1H, m), 8.12-8.07 (1H, m), 7.75-7.69 (1H, m), 7.21 (4H, d), 4.74-4.67 (6H, m), 4.45 (2H, s), 4.41-4.32 (1H, m), 3.88-3.82 (2H, m), 3.03 (1H, t), 2.92 (1H, t), 2.03-1.90 (6H, m), 1.73-1.63 (2H, m). [M − H] 542 178 [01274] 6-[5-chloro-2-({2- oxaspiro[3.3]heptan-6- yl}amino)pyrimidin-4- yl]-2-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one (Me-d.sub.3-OD): 8.34 (1H, s), 8.24 (1H, s), 8.11-8.06 (1H, m), 7.74-7.68 (1H, m), 7.24-7.17 (4H, m), 4.78 (2H, s), 4.73 (1H, s), 4.72-4.61 (7H, m), 4.30-4.20 (1H, m), 3.85 (2H, q), 3.03 (1H, t), 2.92 (1H, t), 2.78-2.70 (2H, m), 2.28-2.20 (2H, m). 530

Examples 179-182

[1548] Prepared using a similar procedure to Examples 159-179 from the corresponding 2-chloropyrimidines (Preparations 129-132) and amines.

TABLE-US-00027 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 179 [01275] 6-{5-methyl-2-[(oxan-4- yl)amino]pyrimidin-4-yl}- 2-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin-2- yl)ethyl]-2,3-dihydro-1H- isoindol-1-one (CDCl3): 8.22 (1H, s), 8.08 (1H, s), 7.85-7.72 (1H, m), 7.56 (1H, t), 7.25-7.15 (4H, m), 4.76 (2H, s), 4.66 (2H, d), 4.59 (2H, d), 4.21-4.06 (1H, m), 4.04-3.97 (2H, m), 3.89-3.82 (2H, m), 3.62-3.53 (2H, m), 2.98-2.90 (2H, m), 2.22 (3H, s), 2.12-2.05 (2H, m), 1.64-1.59 (2H, m). 498 180 [01276] N-tert-butyl-N-methyl-2- (6-{5-methyl-2-[(oxan-4- yl)amino] pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl) acetamide (CDCl3): 8.16 (1H, s), 8.05 (1H, s), 7.75 (1H, dd), 7.57 (1H, d), 4.64 (2H, s), 4.44 (2H, s), 4.09 (1H, d), 4.04-3.76 (2H, m), 3.62-3.37 (2H, m), 3.05-2.90 (3H, m), 2.20 (3H, s), 2.13-2.01 (2H, m), 1.71-1.56 (2H, m), 1.44 (9H, s). 452 181 [01277] 6-{5-cyclopropyl-2- [(oxan-4-yl)amino] pyrimidin-4-yl}-2-[2- oxo-2-(1,2,3,4- tetrahydroisoquinolin-2- yl)ethyl]-2,3-dihydro-1H- isoindol-1-one (CDCl3): 8.27 (1H, s), 8.11 (1H, s), 7.70-7.65 (1H, m), 7.59-7.54 (1H, m), 7.25-7.13 (4H, m), 4.76 (2H, s), 4.72-4.63 (2H, m), 4.60 (2H, d), 4.16-4.06 (1H, m), 4.05-3.96 (2H, m), 3.90-3.75 (2H, m), 3.62-3.52 (2H, m), 3.00-2.89 (2H, m), 2.11-2.03 (2H, m), 1.90-1.79 (1H, m), 1.68-1.55 (2H, m), 0.93-0.81 (2H, m), 0.56-0.49 (2H, m). 360 182 [01278] 6-{5-ethyl-2-[(oxan-4- yl)amino]pyrimidin-4-yl}- 2-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin-2- yl)ethyl]-2,3-dihydro-1H- isoindol-1-one (CDCl3): 8.27 (1H, s), 8.02 (1H, s), 7.73-7.68 (1H, m), 7.58-7.53 (1H, m), 7.26-7.14 (4H, m), 4.76 (2H, s), 4.66 (2H, d), 4.59 (2H, d), 4.22-4.04 (1H, m), 4.04-3.97 (2H, m), 3.89-3.81 (2H, m), 3.61-3.52 (2H, m), 2.98-2.89 (2H, m), 2.57 (2H, q), 2.12-2.04 (2H, m), 1.61-1.52 (2H, m), 1.09 (3H, t). 512

Example 183: 6-{5-chloro-2-[(piperidin-4-yl)amino]pyrimidin-4-yl}-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one Hydrochloride

[1549] ##STR01279##

[1550] Prepared according to the above general procedure with the following additional deprotection step. A mixture of tert-butyl 4-[(5-chloro-4-{3-oxo-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-5-yl}pyrimidin-2-yl)amino]piperidine-1-carboxylate (˜80 mg, 0.13 mmol), EtOAc saturated with HCl (2 mL) and MeOH (2 mL) was stirred at room temperature for 2 hours, and was then concentrated to dryness under vacuum. EtOAc was then added and the new precipitate was isolated by filtration and then re-dissolved in MeOH. The solution was re-evaporated under vacuum to yield the title compound as the HCl salt (74 mg, 102%) as a very pale yellow solid. MS: [M+H].sup.+=517.

Example 184: 6-{5-Chloro-2-[(1,5-dimethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1551] ##STR01280##

[1552] A stirred mixture of 4,5-dichloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (Preparation 122, 233 mg, 0.27 mmol, 70% pure), 2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (Preparation 128, 112 mg, 0.18 mmol) and K.sub.2CO.sub.3 (50 mg, 0.36 mmol) in 1,4-dioxane: water (3:1, 2 mL) was degassed with nitrogen for 10 minutes. Pd(PPh.sub.3).sub.4 (10 mg, 0.0.01 mmol) was then added and the mixture heated at 90° C. under nitrogen for a total of 16 hours. The reaction was allowed to cool to room temperature and was then diluted with water. The product was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC to yield the title compound (45 mg, 47%) as a pale yellow solid. .sup.1H NMR (400 MHz, Me-d.sub.3-OD): 8.40 (1H, s), 8.26 (1H, s), 8.09 (1H, d), 7.74-7.66 (1H, m), 7.58 (1H, s), 7.25-7.19 (4H, m), 4.77-4.63 (6H, m), 3.84 (2H, q), 3.79 (3H, s), 3.03 (1H, t), 2.92 (1H, t), 2.25 (3H, s). MS: [M+H].sup.+=528.

Example 185: tert-Butyl 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyridin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate

[1553] ##STR01281##

[1554] A stirred mixture of 4-bromo-5-chloro-N-(oxan-4-yl)pyridin-2-amine (Preparation 135, 310 mg, 1.06 mmol), tert-butyl 2-[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-2-yl]acetate (Preparation 2, 397 mg, 1.06 mmol) and K.sub.2CO.sub.3 (294 mg, 2.13 mmol) in 1,4-dioxane/water (3:1, 4 mL) was degassed with nitrogen for 10 minutes. Pd(PPh.sub.3).sub.4 (61 mg, 0.05 mmol) was then added and the mixture heated at 90° C. under nitrogen for a total of 16 hours. After cooling to room temperature the mixture was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum. Approximately 40 mg of the residue was purified by preparative HPLC to yield the title compound (10 mg) as a colourless solid. .sup.1H NMR (400 MHz, Me-d.sub.3-OD): 8.05 (1H, s), 7.86 (1H, s), 7.73 (1H, dd), 7.71 (1H, dd), 6.57 (1H, s), 4.66 (2H, s), 4.37 (2H, s), 4.02-3.93 (3H, m), 3.61-3.53 (2H, m), 2.05-1.97 (2H, m), 1.62-1.53 (2H, m), 1.51 (9H, s). MS: [M+H].sup.+=458.

Example 186: 6-{5-chloro-2-[(oxan-4-yl)amino]pyridin-4-yl}-2-[2-(3-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-oxoethyl]-2,3-dihydro-1H-isoindol-1-one

[1555] ##STR01282##

[1556] A stirred solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyridin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Preparation 136, 130 mg, 0.32 mmol) in anhydrous 1,4-dioxane (3.2 mL) under nitrogen was treated with DIPEA (113 μL, 0.65 mmol), HBTU (250 mg, 0.65 mmol) and then 3-methyl-1,2,3,4-tetrahydro-isoquinoline (71 mg, 0.49 mmol). After 16 hours the mixture was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound (57 mg, 34%) as a colourless solid. .sup.1H NMR (400 MHz, Me-d.sub.3-OD): 8.05 (1H, s), 7.87 (1H, s), 7.74-7.67 (2H, m), 7.23 (4H, d), 6.57 (1H, s), 5.04 (1H, d), 4.73-4.64 (5H, m), 4.64-4.60 (1H, m), 4.38-4.31 (1H, m), 3.99 (3H, d), 3.60-3.54 (4H, m), 3.17-3.08 (1H, m), 2.82-2.69 (1H, m), 2.01 (2H, d), 1.62-1.50 (2H, m), 1.27 (2H, d), 1.12 (2H, d). MS: [M+H].sup.+=531.

Example 187: 6-[5-chloro-2-(phenylamino)pyrimidin-4-yl]-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1557] ##STR01283##

[1558] Potassium carbonate (69 mg, 0.5 mmol) was added to a solution of aniline (0.035 mL, 0.38 mmol) and 6-(2,5-dichloropyrimidin-4-yl)-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Preparation 128, 113 mg, 0.25 mmol) in MeCN (2 mL). Nitrogen was bubbled through the mixture for 5 mins, before XPhos (9 mg, 0.013 mmol) and bis (dibenzylideneacetone)palladium (7 mg, 0.013 mmol) were added. The resulting mixture was heated under microwave irradiation to 150° C. for 30 mins. The mixture was partitioned between water (10 mL) and EtOAc (3×10 mL). The combined organic phases were dried (MgSO.sub.4) and evaporated under vacuum and the residue purified by preparative HPLC (acidic method) to give the title compound (9 mg, 7%). 1H NMR (400 MHz, Me-d3-OD): 8.51 (1H, s), 8.33 (1H, s), 8.16 (1H, dd), 7.71 (1H, s), 7.45 (1H, dd), 7.37-7.25 (3H, m), 7.24-7.19 (4H, m), 7.01 (1H, t), 5.50 (2H, s), 4.69 (4H, d), 3.84 (2H, q), 3.03 (1H, t), 2.91 (1H, t). MS: [M+H].sup.+=510.

Example 188: 6-{5-chloro-2-[(2-methylpyridin-4-yl)amino]pyrimidin-4-yl}-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1559] ##STR01284##

[1560] Prepared from 4,5-dichloro-N-(2-methylpyridin-4-yl)pyrimidin-2-amine (Preparation 139) and 2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (Preparation 128) using a similar procedure to that described in Example 124. 1H NMR (400 MHz, Me-d3-OD): 8.75 (1H, s), 8.36 (1H, s), 8.32 (1H, s), 8.29 (1H, d), 8.22 (1H, d), 7.99-7.88 (2H, m), 7.78 (1H, dd), 7.27-7.14 (4H, m), 4.77-4.63 (6H, m), 3.89-3.80 (2H, m), 3.04 (1H, t), 2.92 (1H, t), 2.69-2.54 (3H, m). MS: [M+H].sup.+=525.

Example 189: 6-{2-[(oxan-4-yl)amino]-5-(ethenyl)pyrimidin-4-yl}-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1561] ##STR01285##

[1562] A solution of 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[2-oxo-2-(1,2,3,4-tetrahydro-isoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example 150, 52 mg, 0.1 mmol), potassium vinyltrifluoroborate (16 mg, 0.12 mmol) and cesium fluoride (30 mg, 0.2 mmol) in DME (1 mL) and water (1 mL) was degassed by bubbling nitrogen through it for 5 mins. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (8 mg, 0.01 mmol) was added and the resulting mixture was heated by microwave irradiation at 140° C. for 20 mins. The mixture was partitioned between water (10 mL) and EtOAc (3×10 mL). The combined organic phases were dried (MgSO.sub.4), evaporated under vacuum and purified using preparative hplc (basic method).

[1563] The resulting solid was triturated with MeOH and Et.sub.2O to give the title compound (2 mg, 4%). 1H NMR (400 MHz, CDCl.sub.3): 8.55 (1H, s), 8.13 (1H, s), 7.86-7.78 (1H, m), 7.55 (1H, t), 7.25-7.15 (4H, m), 6.58 (1H, dd), 5.61 (1H, d), 5.17 (1H, d), 4.76 (2H, s), 4.66 (2H, d), 4.58 (2H, d), 4.22-4.09 (1H, m), 4.01 (2H, d), 3.89-3.80 (2H, m), 3.64-3.44 (2H, m), 3.01-2.87 (2H, m), 2.09 (2H, d), 1.67-1.52 (2H, m). MS: [M+H].sup.+=510.

Example 190: 6-{2-[(oxan-4-yl)amino]-5-(prop-1-en-2-yl)pyrimidin-4-yl}-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1564] ##STR01286##

[1565] Prepared in a manner analogous to Example 190 using potassium isopropenyl trifluoroborate. 1H NMR (400 MHz, CDCl.sub.3): 8.37-8.04 (2H, m), 7.52 (2H, s), 7.34-6.99 (4H, m), 6.22-5.90 (1H, m), 5.12 (1H, d), 4.95-4.49 (6H, m), 4.15 (1H, s), 4.01 (2H, s), 3.84 (2H, s), 3.58 (2H, s), 2.94 (2H, d), 2.07 (2H, s), 1.86-1.48 (5H, m). MS: [M+H].sup.+=524.

Example 191: 6-{2-[(oxan-4-yl)amino]-5-(propan-2-yl)pyrimidin-4-yl}-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1566] ##STR01287##

[1567] A solution of 6-{2-[(oxan-4-yl)amino]-5-(prop-1-en-2-yl)pyrimidin-4-yl}-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Example 190, 30 mg, 0.057 mmol) in MeOH (3 mL) was treated with palladium on carbon (10 wt. %) (5 mg, 0.005 mmol) and shaken under an atmosphere of hydrogen for 96 h. The reaction mixture was filtered through celite, washing with MeOH and concentrated. The residue was redissolved in MeOH and poured onto an SCX ion exchange cartridge. The cartridge was washed with MeOH and the product was eluted with a 2M solution of ammonia in MeOH. The solvent was removed under vacuum to give the title compound (1.5 mg, 5%). 1H NMR (400 MHz, CDCl.sub.3): 8.37 (1H, s), 7.98-7.93 (1H, m), 7.70-7.61 (1H, m), 7.55 (1H, t), 7.25-7.14 (4H, m), 4.76 (2H, s), 4.66 (2H, d), 4.58 (2H, d), 4.20-4.04 (1H, m), 4.04-3.94 (2H, m), 3.91-3.77 (2H, m), 3.63-3.50 (2H, m), 3.10-2.87 (3H, m), 2.14-2.02 (2H, m), 1.65-1.49 (2H, m), 1.32-1.16 (6H, m). MS: [M+H].sup.+=526.

Example 192: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-{2-[5-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl]-2-oxoethyl}-2,3-dihydro-1H-isoindol-1-one

[1568] ##STR01288##

[1569] TBAF (1M in THF) (0.588 ml, 0.588 mmol) was added to a solution of 2-[2-(5-{[(tert-butyldimethylsilyl)oxy]methyl}-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-oxoethyl]-6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1H-isoindol-1-one (390 mg, 0.490 mmol) in THF (5 ml, 61.0 mmol) and the mixture was stirred for 1 h. The reaction was quenched by the addition of saturated aqueous NaHCO.sub.3 and water (15 ml) and the mixture was diluted with EtOAc (30 ml). The layers were separated and the aqueous phase was further extracted with EtOAc (2×20 ml). The combined organic extracts were washed with brine (15 ml), dried (MgSO.sub.4) and concentrated under vacuum. The residue was purified by chromatography (SiO.sub.2, 12 g column, 0-8% of MeOH in DCM) to afford the title compound (170 mg, 0.299 mmol, 61.1%) as a colourless solid. 1H NMR (400 MHz, 297K, DMSO-d6) δ 8.45 (s (br), 1H), 8.04 (m, 1H), 7.99 (dd, 1H), 7.75 (d, 1H), 7.63 (s (br), 1H), 7.12-7.31 (m, 3H), 5.44 (q, 0.7H), 5.23 (q, 0.3H), 5.07-5.13 (m, 1H), 4.41-4.71 (m, 6H), 3.82-4.06 (m, 4H), 3.47-3.57 (m, 0.7H), 3.33-3.42 (m, 2H), 3.03-3.13 (m, 0.3H), 2.73-2.96 (m, 1.4H), 2.60-2.71 (m, 0.6H), 1.80-1.90 (m, 2H), 1.47-1.61 (m, 2.9H), 1.40 (d, 2.1H). LC-MS: [M+H].sup.+=562.

Example 193: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[2-(1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)-2-oxoethyl]-2,3-dihydro-1H-isoindol-1-one

[1570] ##STR01289##

[1571] Prepared according to Example 2 using diisopropylethylamine as base and DMF as solvent. The product was further purified by preparative HPLC (Basic Method) (0.007 g, 11.6% yield) in this case. 1H NMR (400 MHz, 297K, DMSO-d6) δ 8.45 (1H, s), 8.03 (1H, d), 7.98 (1H, dd), 7.73 (1H, d), 7.62 (1H, br. s), 7.22-7.06 (4H, m), 4.64-4.52 (1H, m), 4.51-4.37 (3H, m), 3.99-3.74 (5H, m), 3.66 (1H, t), 3.53-3.37 (3.5H, m), 3.21-3.10 (1.5H, m), 3.08-2.79 (1H, m), 1.85 (d, 2H), 1.53 (2H, qd), 1.32 (1.3H, d), 1.20 (1.7H, d). 1H NMR (400 MHz, DMSO-d6, T=373K) δ 8.40 (1H, s), 8.08 (1H, d), 8.00 (1H, dd), 7.71-7.66 (1H, m), 7.21-7.04 (5H, m), 4.55-4.37 (4H, m), 4.04-3.93 (1H, m), 3.89 (2H, dt), 3.85-3.79 (1H, m), 3.68 (2H, br. s), 3.59-3.37 (4H, m), 3.29-3.20 (1H, m), 3.14-3.07 (1H, m), 1.92-1.87 (2H, m), 1.65-1.55 (2H, m), 1.30 (3H, br. d). LC-MS: [M+H].sup.+=546.

Example 194: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-(1-phenylcyclopropyl)acetamide

[1572] ##STR01290##

[1573] 1-phenylcyclopropanamine (30.6 mg, 0.218 mmol) in DMF (1.0 mL) was added to an ice-cooled stirred solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) (80 mg, 0.199 mmol), 1-propanephosphonic anhydride (T3P, 50% wt in EtOAc) (176 μl, 0.298 mmol) and triethylamine (83 μl, 0.596 mmol) in DMF (3.0 mL) under nitrogen. The reaction was allowed to warm to room temperature and stirred for 20 h. The reaction mixture was diluted with 1 M HCl (aq.) (10 mL) and extracted with EtOAc (20 mL).

[1574] The combined organic extracts were washed with saturated NaHCO.sub.3 solution (1×20 mL), brine (2×20 mL), dried (MgSO.sub.4), filtered and concentrated under vacuum to afford the title compound (78 mg, 0.148 mmol, 74.3%) as a pale yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.87 (1H, s), 8.44 (1H, s), 8.03 (1H, dd), 7.97 (1H, dd), 7.80-7.70 (1H, m), 7.67-7.56 (1H, br m), 7.33-7.23 (2H, m), 7.21-7.10 (3H, m), 4.60 (2H, s), 4.24 (2H, s), 3.98-3.79 (3H, m), 3.43-3.33 (2H, m), 1.91-1.79 (2H, m), 1.52 (2H, qd), 1.17 (4H, s). LC-MS: [M+H].sup.+=518.

Example 195: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-{2-[2-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-oxoethyl}-2,3-dihydro-1H-isoindol-1-one

[1575] ##STR01291##

[1576] Prepared according to Example 2. Following purification by chromatography (SiO.sub.2), the product was further purified by preparative HPLC (Gilson, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water) to afford the title compound as a colourless solid (7 mg, 9%). 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.01 (1H, dt), 7.97 (1H, ddd), 7.70 (1H, dd), 7.63 (1H, br. s), 7.16-7.04 (3.4H, m), 7.02-6.95 (0.6H, m), 4.99 (0.6H, t), 4.73 (0.4H, t), 4.66-4.30 (4.6H, m), 4.25-4.11 (1.4H, m), 3.98-3.82 (4H, m), 3.56-3.36 (3H, m), 3.08-2.83 (5H, m), 1.85 (2H, d), 1.53 (2H, qd) (mixture of rotamers was observed). LC-MS: [M+H].sup.+=562.

Example 196: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-(2-methyl-1-phenoxypropan-2-yl)acetamide

[1577] ##STR01292##

[1578] A stirred mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) (70 mg, 0.170 mmol), 2-methyl-1-phenoxypropan-2-amine (29.6 mg, 0.170 mmol) and triethylamine (71.2 μL, 0.511 mmol) in DMF (1 mL) was cooled in an ice bath. 1-Propanephosphonic anhydride (T3P, 50% wt in EtOAc) (150 μL, 0.252 mmol) was added, the ice bath was removed and the reaction mixture allowed to warm to room temperature for 2 h. Water (5 mL) was added, and the resulting colourless precipitate was filtered and purified by preparative HPLC (basic method) to give the title compound (25 mg, 0.045 mmol, 26.2% yield) as a colourless powder. 1H NMR (CDCl.sub.3, 400 MHz) δ 8.35-8.29 (2H, m), 8.01 (1H, dd), 7.51 (1H, dd), 7.20-7.14 (2H, m), 6.88 (1H, tt), 6.75-6.70 (2H, m), 6.23 (1H, s), 5.18 (1H, d), 4.50 (2H, s), 4.19 (2H, s), 4.13-3.95 (5H, m), 3.54 (2H, td), 2.09-2.01 (2H, m), 1.57 (2H, dtd), 1.45 (6H, s). LC-MS: [M+H].sup.+=550.

[1579] Examples 197 to 295 were synthesised as follows.

[1580] To the HATU or TBTU (1.5 eq.) and 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) (1.0 eq.) was added DCM (0.05-0.10 M), then DIPEA (1.2 to 3.5 eq.) under nitrogen. After 10 minutes the amine coupling partner was added. The mixture was stirred for 2-16 hours at room temperature. The reaction was quenched by diluting with citric acid (5%, aq.) and extracting with EtOAc (×3). The combined organic layers were washed with brine and dried over MgSO.sub.4. The products were filtered and evaporated to dryness. The product was purified by silica chromatography or reverse-phase preparative HPLC.

TABLE-US-00028 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 197 [01293] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(2- phenylethyl)acetamide (Me-d3-OD): 8.38-8.35 (1H, m), 8.25-8.23 (1H, m), 8.08 (1H, dd), 7.70 (1H, dd), 7.30-7.17 (5H, m), 4.57 (2H, s), 4.30 (2H, s), 4.10-4.02 (1H, m), 4.02-3.95 (2H, m), 3.59-3.51 (2H, m), 3.51-3.47 (2H, m), 2.84 (2H, t), 2.06-1.98 (2H, m), 1.69-1.59 (2H, m). 506 198 [01294] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(2- cyclohexylethyl)acetamide (Me-d3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.72 (1H, d), 4 67 (2H, s), 4 33 (2H, s), 4.11-4.02 (1H, m), 4.02-3.95 (2H, m), 3.55 (2H, td), 3.27 (2H, t), 2.05-1.98 (2H, m), 1.82-1.56 (7H, m), 1.44 (2H, q), 1.40-1.13 (4H, m), 1.02-0.89 (2H, m). 512 199 [01295] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(2- cyclohexylethyl)-N- methylacetamide (Me-d3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.72 (1H, d), 4.67 (2H, d), 4.57 (2H, d), 4.12-4.02 (1H, m), 4.02-3.94 (2H, m), 3.55 (2H, dt), 3.50-3.41 (2H, m), 3.13 (2H, s), 2.97 (1H, s), 2.05-1.98 (2H, m), 1.88-1.53 (8H, m), 1.48 (1H, q), 1.41-1.17 (4H, m), 1.12-0.91 (2H, m). 526 200 [01296] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[2- (dimethylamino)ethyl]- N-(2-phenylethyl) acetamide (Me-d3-OD): 8.36 (1H, d), 8.23 (1H, d), 8.12- 8.04 (1H, m), 7.70 (1H, dd), 7.42-7.17 (5H, m), 4.65 (1H, s), 4.60 (1H, s), 4.43 (1H, s), 4.25 (1H, s), 4.12-4.03 (1H, m), 4.03-3.93 (2H, m), 3.70 (1H, t), 3.65-3.49 (4H, m), 3.46-3.39 (1H, m), 3.03 (1H, t), 2.91 (1H, t), 2.55 (2H, q), 2.33 (3H, s), 2.30 (3H, s), 2.06-1.97 (2H, m), 1.70-1.58 (2H, m). 577 201 [01297] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(2- hydroxyethyl)-N-(2- phenylethyl)acetamide (Me-d3-OD): 8.36 (1H, d), 8.23 (1H, dd), 8.11- 8.04 (1H, m), 7.70 (1H, dd), 7.41-7.16 (5H, m), 4.67 (1H, s), 4.62 (1H, s), 4.42 (1H, s), 4.24 (1H, s), 4.11-4.03 (1H, m), 3.99 (2H, d), 3.81- 3.70 (3H, m), 3.67-3.61 (1H, m), 3.59-3.45 (4H, m), 3.03 (1H, t), 2.91 (1H, t), 2.05-1.98 (2H, m), 1.70-1.57 (2H, m). 550 202 [01298] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (1-ethyl-1H-pyrazol-3- yl)ethyl]acetamide (Me-d3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.71 (1H, d), 7.54 (1H, d), 6.24 (1H, d), 5.15 (1H, q), 4.69 (2H, s), 4.39 (2H, s), 4.14 (2H, q), 4.11-4.02 (1H, m), 4.02-3.94 (2H, m), 3.55 (2H, dt), 2.06- 1.98 (2H, m), 1.70-1.56 (2H, m), 1.51 (3H, d), 1.43 (3H, t). 524 203 [01299] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[2- hydroxy-1-(1-methyl- 1H-pyrazol-4-yl)ethyl] acetamide (Me-d3-OD): 8.35 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.71 (1H, d), 7.59 (1H, s), 7.48 (1H, s), 5.06 (1H, t), 4.69 (2H, s), 4.40 (2H, s), 4.11-4.02 (1H, m), 4.02-3.92 (2H, m), 3.87 (3H, s), 3.78 (2H, dq), 3.54 (2H, dt), 2.06-1.96 (2H, m), 1.69-1.57 (2H, m). 526 204 [01300] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{[4- (hydroxymethyl)-1,3- thiazol-2-yl]methyl) acetamide (Me-d3-OD): 8.36 (1H, s), 8.25 (1H, d), 8.08 (1H, dd), 7.72 (1H, d), 7.34 (1H, t), 4.71 (4H, s), 4.67 (2H, d), 4.44 (2H, s), 4.11-4.02 (1H, m), 4.02-3.93 (2H, m), 3.54 (2H, dt), 2.04-1.96 (2H, m), 1.69-1.57 (2H, m). 529 205 [01301] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [1-(5-chloro-3- fluoropyridin-2- yl)ethyl]acetamide (Me-d3-OD): 8.40 (1H, d), 8.35 (1H, s), 8.23 (1H, d), 8.07 (1H, dd), 7.75 (1H, dd), 7.70 (1H, dd), 5.40 (1H, dq), 4.65 (2H, s), 4.42 (1H, d), 4.39 (1H, d), 4.11- 4.02 (1H, m), 4.01-3.95 (2H, m), 3.54 (2H, dt), 2.04-1.98 (2H, m), 1.69-1.57 (2H, m), 1.50 (3H, d). 559 206 [01302] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[2- hydroxy-1-(pyridin-2- yl)ethyl]acetamide (Me-d3-OD): 8.53 (1H, dq), 8.35 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.82 (1H, dt), 7.71 (1H, dd), 7.49 (1H, d), 7.32 (1H, ddd), 5.14 (1H, t), 4.69 (2H, s), 4.48 (2H, s), 4.11-4.02 (1H, m), 4.02-3.95 (2H, m), 3.95-3.84 (2H, m), 3.54 (2H, dt), 2.04-1.98 (2H, m), 1.71-1.56 (2H, m). 523 207 [01303] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[2- hydroxy-1-(pyridin-3- yl)ethyl]acetamide (Me-d3-OD): 8.59 (1H, d), 8.47 (1H, dd), 8.35 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.91- 7.86 (1H, m), 7.71 (1H, dd), 7.45(1H, ddd), 5.09 (1H, t), 4.68 (2H, s), 4.47 (1H, d), 4.43 (1H, d), 4.11-4.02 (1H, m), 4.02-3.95 (2H, m), 3.85 (2H, dd), 3.55 (2H, dt), 2.04-1.98 (2H, m), 1.70-1.58 (2H, m). 523 208 [01304] 2-(6-{5-chloro-2-((oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[2- hydroxy-1-(pyridin-4- yl)ethyl]acetamide (Me-d3-OD): 8.53-8.49 (2H, m), 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.71 (1H, d), 7.47 (2H, d), 5.06 (1H, t), 4.69 (2H, s), 4.48 (2H, d), 4.10-4.02 (1H, m), 4.02-3.94 (2H, m), 3.86 (1H, dd), 3.82 (1H, dd), 3.54 (2H, dt), 2.04-1.98 (2H, m), 1.69-1.58 (2H, m). 523 209 [01305] 2-(6-{5-chloro-2-((oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(6- methoxypyridin-2- yl)ethyl]acetamide (Me-d3-OD): 8.35 (1H, s), 8.23 (1H, d), 8.07 (1H, dd), 7.70 (1H, d), 7.61 (1H, dd), 6.93 (1H, d), 6.64 (1H, d), 5.05 (1H, q), 4.68 (2H, s), 4.43 (2H, s), 4.11- 4.02 (1H, m), 4.02-3.95 (2H, m), 3.84 (3H, s), 3.54 (2H, dt), 2.04-1.98 (2H, m), 1.69-1.57 (2H, m), 1.51 (3H, d). 537 210 [01306] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- hydroxy-3-(3- methoxyphenyl)propan- 2-yl]acetamide (Me-d3-OD): 8.36 (1H, s), 8.23(1H, d), 8.08 (1H, dd), 7.67 (1H, dd), 7.19-7.13 (1H, m), 6.84-6.80 (2H, m), 6.78-6.73 (1H, m), 4.43 (2H, s), 4.28 (2H, s), 4.26-4.17 (1H, m), 4.11-4.02 (1H, m), 4.02-3.94 (2H, m), 3.77 (3H, s), 3.64-3.51 (4H, m), 2.94 (1H, dd), 2.73 (1H, dd), 2.05-1.98 (2H, m), 1.70-1.57 (2H, m). 566 211 [01307] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (3-fluoropyridin-2- yl)ethyl]acetamide (Me-d3-OD): 8.37 (1H, dt), 8.35 (1H, s), 8.23 (1H, d), 8.07(1H, dd), 7.70 (1H, dd), 7.58 (1H, ddd), 7.37 (1H, quintet), 5.48-5.41 (1H, m), 4.66 (2H, s), 4.44 (1H, d), 4.41 (1H, d), 4.11-4.02 (1H, m), 4.02-3.95 (2H, m), 3.54 (2H, td), 2.04-1.98 (2H, m), 1.70-1.56 (2H, m), 1.51 (3H, d). 525 212 [01308] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(3-fluoropyridin- 2-yl)ethyl]acetamide (Me-d3-OD): 8.37 (1H, dt), 8.35 (1H, s), 8.23 (1H, s), 8.07 (1H, dd), 7.70 (1H, d), 7.58 (1H, ddd), 7.41-7.34 (1H, m), 5.44 (1H, q), 4.66 (2H, s), 4.44 (1H, d), 4.41 (1H, d), 4 11-4.02 (1H, m), 4.02-3.94 (2H, m), 3.54 (2H, td), 2.05- 1.98 (2H, m), 1.70-1.57 (2H, m), 1.51 (3H, d). 525 213 [01309] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (1-methyl-1H-pyrazol-4- yl)ethyl]acetamide (Me-d3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.71 (1H, dd), 7.56 (1H, s), 7.45 (1H, s), 5.08 (1H, q), 4.68 (2H, s), 4.35 (2H, s), 4.12-4.02 (1H, m), 4.02-3.93 (2H, m), 3.86 (3H, s), 3.55 (2H, td), 2.05-1.97 (2H, m), 1.70-1.57 (2H, m), 1.50 (3H, d). 510 214 [01310] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[2- hydroxy-1-(1-methyl- 1H-pyrazol-3- yl)ethyl]acetamide (Me-d3-OD): 8.36 (1H, s), 8.24 (1H, s), 8.10- 8.06 (1H, m), 7.72 (1H, d), 7.51 (1H, d), 6.28 (1H, d), 5.17-5.13 (1H, m), 4.70 (2H, s), 4.44 (2H, s), 4.10-4.02 (1H, m), 3.99 (2H, d), 3.91- 3.84 (4H, m), 3.83-3.78 (1H, m), 3.58-3.51 (2H, m), 2.06-1.98 (2H, m), 1.69-1.58 (2H, m). 526 215 [01311] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (1,3-dimethyl-IH- pyrazol-4-yl)ethyl] acetamide (Me-d3-OD): 8.36 (1H, s), 8.24(1H, d), 8.08 (1H, dd), 7.71 (1H, d), 7.48 (1H, s), 5.09-4.99 (1H, m), 4.68 (2H, s), 4.33 (2H, s), 4.13-4.02 (1H, m), 4.02-3.94 (2H, m), 3.79 (3H, s), 3.55 (2H, td), 2.21 (3H, s), 2.06-1.97 (2H, m), 1.70-1.57 (2H, m), 1.48 (3H, d). 524 216 [01312] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (1,3-thiazol-4- yl)ethyl]acetamide (Me-d3-OD): 8.97 (1H, d), 8.35 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.71 (1H, dd), 7.47 (1H, dd), 5.29 (1H, q), 4.69 (2H, s), 4.41 (2H, s), 4.11-4.02 (1H, m), 4.02-3.95 (2H, m), 3.54 (2H, td), 2.06-1.97 (2H, m), 1.70-1.60 (2H, m), 1.58 (3H, d). 513 217 [01313] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (1,5-dimethyl-1H- pyrazol-4-yl)ethyl] acetamide (DMSO-d6): 8.45 (1H, s), 8.30 (1H, d), 8.04- 8.02 (1H, m), 7.98 (1H, dd), 7.74 (1H, d) 7.58 (1H, br s), 7.31 (1H, s), 4.92-4.83 (1H, m), 4.58 (2H, s), 4.17 (2H, s), 3.98-3.90 (1H, m), 3.90-3.83 (2H, m), 3.68 (3H, s), 3.38 (2H, t), 2.18 (3H, s), 1.89-1.81 (2H, m), 1.60-1.47 (2H, m), 1.36 (3H, d). 524 218 [01314] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (2-methyl-1,3-thiazol-4- yl)ethyl]acetamide (Me-d3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.71 (1H, dd), 7.21 (1H, d), 5.17 (1H, q), 4.69 (2H, s), 4.40 (2H, s), 4.12-4.02 (1H, m), 4.02-3.95 (2H, m), 3.61-3.48 (2H, m), 2.69 (3H, s), 2.05-1.97 (2H, m), 1.69-1.58 (2H, m), 1.54 (3H, d). 527 219 [01315] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (pyridin-3-yl)ethyl] acetamide (Me-d3-OD): 8.57 (1H, d), 8.44 (1H, dd), 8.35 (1H, s), 8.23 (1H, d), 8.07 (1H, dd), 7.89- 7.84 (1H, m), 7.70 (1H, dd), 7.44 (1H, ddd), 5.13 (1H, q), 4.67 (2H, s), 4.42 (1H, d), 4.38 (1H, d), 4 10-4.02 (1H, m), 4.01-3.94 (2H, m), 3.54 (2H, td), 2.04-1.97 (2H, m), 1.68-1.58 (2H, m), 1.55 (3H, d). 507 220 [01316] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(pyridin-2- yl)ethyl]acetamide (Me-d3-OD): 8.50 (1H, ddd), 8.36 (1H, s), 8.24 (1H, d), 8.07 (1H, dd), 7.82 (1H, dt), 7.71 (1H, dd), 7.46 (1H, d), 7.30 (1H, ddd), 5.12 (1H, q), 4.68 (2H, s), 4.44 (2H, s), 4.11-4.02 (1H, m), 4.02-3.94 (2H, m), 3.54 (2H, td), 2.04-1.98 (2H, m), 1.69-1.57 (2H, m), 1.53 (3H, d). 507 221 [01317] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[2- hydroxy-1-(2-methyl- 1,3-thiazol-4-yl)ethyl] acetamide (Me-d3-OD): 8.35 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.71 (1H, dd), 7.28 (1H, d), 5.18 (1H, t), 4.70 (2H, s), 4.45 (2H, s), 4.11-4.02 (1H, m), 4.02-3.96 (2H, m), 3.93 (1H, dd), 3.86 (1H, dd), 3.54 (2H, td), 2.69 (3H, s), 2.04-1.97 (2H, m), 1.70-1.56 (2H, m). 543 222 [01318] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(2- methyl-4,5,6,7- tetrahydro-2H-indazol- 4-yl)acetamide (Me-d3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.72 (1H, d), 7.47 (1H, s), 5.01 (1H, dd), 4.70 (2H, s), 4.37 (1H, d), 4.33 (1H, d), 4.12-4.02 (1H, m), 4.02-3.95 (2H, m), 3.82 (3H, s), 3.55 (2H, td), 2.67-2.59 (2H, m), 2.05-1.97 (4H, m), 1.89-1.70 (2H, m), 1.70-1.56 (2H, m). 536 223 [01319] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [1-(propan-2-yl)-1H- pyrazol-4-yl]ethyl} acetamide (Me-d3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.71 (1H, dd), 7.64 (1H, s), 7.47 (1H, s), 5.09 (1H, q), 4.68 (2H, s), 4.56-4.43 (1H, m), 4.35 (2H, s), 4.11- 4.02 (1H, m), 4.02-3.95 (2H, m), 3.54 (2H, td), 2.04-1.98 (2H, m), 1.69-1.58 (2H, m), 1.50 (3H, d), 1.48 (6H, d). 538 224 [01320] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (1,3-thiazol-2-yl)ethyl] acetamide (Me-d3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.74 (1H, d), 7.72 (1H, d), 7.52 (1H, d), 5.40 (1H, q), 4.70 (2H, s), 4.45 (1H, d), 4.43 (1H, d), 4.11-4.02 (1H, m), 4.02-3.95 (2H, m), 3.55 (2H, td), 2.05- 1.98 (2H, m), 1.69-1.58 (5H, m). 513 225 [01321] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (6-methylpyridin-3- yl)ethyl]acetamide (Me-d3-OD): 8.41 (1H, d), 8.35 (1H, s), 8.23 (1H, d), 8.07 (1H, dd), 7.74 (1H, dd), 7.70 (1H, d), 7.29 (1H, d), 5.09 (1H, q), 4.66 (2H, s), 4.41 (1H, d), 4.36 (1H, d), 4.11-4.03 (1H, m), 4.02-3.95 (2H, m), 3.54 (2H, td), 2.52 (3H, s), 2.04-1.97 (2H, m), 1.69-1.58 (2H, m), 1.53 (3H, d). 521 226 [01322] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [1-(3,5-dimethylphenyl) propan-2-yl]acetamide (Me-d3-OD): 8.36 (1H, s), 8.23 (1H, d), 8.08 (1H, dd), 7.68 (1H, dd), 6.83 (3H, br s), 4.45 (2H, s), 4.25 (2H, s), 4.23-4.14 (1H, m), 4.12-4.02 (1H, m), 4.02-3.95 (2H, m), 3.55 (2H, td), 2.73 (1H, dd), 2.70 (1H, dd), 2.26 (6H, s), 2.04-1.97 (2H, m), 1.70-1.57 (2H, m), 1.18 (3H, d). 548 227 [01323] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (4,5-dimethyl-1,3- thiazol-2-yl)ethyl] acetamide (Me-d3-OD): 8.35 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.72 (1H, dd), 5.25 (1H, q), 4.69 (2H, s), 4.43 (1H, d), 4.41 (1H, d), 4 11-4.02 (1H, m), 4.02-3.95 (2H, m), 3.54 (2H, td), 2.34 (3H, s), 2.29 (2H, s), 2.28 (1H, s), 2.05-1.98 (2H, m), 1.70-1.61 (2H, m), 1.59 (3H, d). 541 228 [01324] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (1-methyl-1H-pyrazol-5- yl)propan-2- yl]acetamide (DMSO-d6): 8.45 (1H, s), 8.11 (1H, d), 8.05- 8.03 (1H, m), 7.99 (1H, dd), 7.74 (1H, d), 7.58 (1H, br d), 7.29 (1H, d), 6.05 (1H, d), 4.53 (2H, s), 4.17 (1H, d), 4.15 (1H, d), 4.09-3.99 (1H, m), 3.99-3.91 (1H, m), 3.91-3.83 (2H, m), 3.75 (3H, s), 3.38 (2H, t), 2.81 (1H, dd), 2.73 (1H, dd), 1.90-1.81 (2H, m), 1.60-1.47 (2H, m), 1.12 (3H, d). 524 229 [01325] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(pyridin-4- yl)ethyl]acetamide (DMSO-d6): 8.68 (1H, d), 8.53-8.50 (2H, m), 8.44 (1H, s), 8.05-8.02 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.58 (1H, br d), 7.35-7.32 (2H, m), 4.98-4.90 (1H, m), 4.60 (2H, s), 4.29 (2H, s), 3.98-3.90 (1H, m), 3.90-3.82 (2H, m), 3.38 (2H, t), 1.90-1.80 (2H, m), 1.60-1.47 (2H, m), 1.39 (3H, d). 507 230 [01326] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (2-methoxypyridin-4- yl)ethyl]acetamide (DMSO-d6): 8.63 (1H, d), 8.44 (1H, s), 8.10 (1H, dd), 8.04-8.02 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.58 (1H, br d), 6.94 (1H, dd), 6.75-6.73 (1H, m), 4.94-4.85 (1H, m), 4.59 (2H, s), 4.28 (2H, s), 3.98-3.91 (1H, m), 3.91-3.85 (2H, m), 3.84 (3H, s), 3.38 (2H, t), 1.90-1.79 (2H, m), 1.60-1.47 (2H, m), 1.37 (3H, d). 537 231 [01327] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(pyrazin-2- yl)ethyl]acetamide (DMSO-d6): 8.74 (1H, d), 8.67 (1H, d), 8.61 (1H, dd), 8.55 (1H, d), 8.44 (1H, s), 8.04-8.02 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.58 (1H, br d), 5.11-5.02 (1H, m), 4.60 (2H, s), 4.29 (2H, s), 3.98-3.90 (1H, m), 3.90-3.82 (2H, m), 3.38 (2H, t), 1.89-1.81 (2H, m), 1.60-1.48 (2H, m), 1.45 (3H, d). 508 232 [01328] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(6- methoxypyridin-2- yl)ethyl]acetamide (DMSO-d6): 8.45 (1H, s), 8.42 (1H, d), 8.05- 8.03 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.66 (1H, dd), 7.58 (1H, br d), 6.96 (1H, d), 6.68 (1H, d), 4.90-4.83 (2H, m), 4.62 (2H, s), 4.34 (2H, s), 3.98-3.85 (3H, m), 3.84 (3H, s), 3.81- 3.74 (1H, m), 3.74-3.64 (1H, m), 3.38 (2H, t), 1.89-1.81 (2H, m), 1.60-1.47 (2H, m). 553 233 [01329] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- {5H,6H,7H- cyclopenta[b]pyridin-7- yl}acetamide (DMSO-d6): 8.52 (1H, d), 8.45 (1H, s), 8.42- 8.39 (1H, m), 8.05-8.03 (1H, m), 7.99 (1H, dd), 7.76 (1H, d), 7.69-7.65 (1H, m), 7.62-7.55 (1H, m), 7.22 (1H, ddd), 5.28 (1H, q), 4.65 (2H, s), 4.27 (2H, d), 3.99- 3.90 (1H, m), 3.90-3.83 (2H, m), 3.43-3.33 (2H, m), 2.99-2.90 (1H, m), 2.89-2.79 (1H, m), 1.91-1.78 (4H, m), 1.59-1.48 (2H, m). 519 234 [01330] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (2-ethyl-1,3-thiazol-4- yl)ethyl]acetamide (DMSO-d6): 8.55 (1H, d), 8.45 (1H, s), 8.05- 8.02 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.58 (1H, br d), 7.25 (1H, d), 5.10-5.00 (1H, m), 4.61 (2H, s), 4.27 (1H, d), 4.25 (1H, d), 3.99-3.90 (1H, m), 3.90-3.82 (2H, m), 3.38 (2H, t), 2.97 (2H, q), 1.89-1.81 (2H, m), 1.61-1.47 (2H, m), 1.42 (3H, d), 1.30 (3H, t). 541 235 [01331] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (6-methylpyridin-2- yl)ethyl]acetamide (DMSO-d6): 8.57 (1H, d), 8.44 (1H, s), 8.04- 8.02 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.65 (1H, t), 7.58 (1H, br d), 7.16 (1H, d), 7.12 (1H, d), 4.99-4.90 (1H, m), 4.62 (1H, d), 4.60 (1H, d), 4.28 (2H, s), 3.99- 3.90 (1H, m), 3.90-3.82 (2H, m), 3.38 (2H, t), 2.45 (3H, s), 1.89-1.81 (2H, m), 1.60-1.47 (2H, m), 1.40 (3H, d). 521 236 [01332] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [2-(propan-2-yl)-1,3- thiazol-4-yl]ethyl} acetamide (DMSO-d6): 8.54 (1H, d), 8.45 (1H, s), 8.05- 8.03 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.58 (1H, br d), 7.26 (1H, d), 5.10-5.00 (1H, m), 4.62 (2H, s), 4.28 (1H, d), 4.25 (1H, d), 3.99-3.90 (1H, m), 3.90-3.82 (2H, m), 3.38 (2H, t), 3.29- 3.21 (1H, m), 1.89-1.81 (2H, m), 1.60-1.47 (2H, m), 1.42 (3H, d), 1.33 (6H, d). 555 237 [01333] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (hydroxymethyl) cyclopentyl]acetamide (Me-d3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.71 (1H, d), 4.68 (2H, s), 4.34 (2H, s), 4.10-4.02 (1H, m), 4.02-3.92 (2H, m), 3.55 (2H, td), 2.03-1.90 (4H, m), 1.84-1.73 (5H, m), 1.72-1.57 (5H, m). 500 238 [01334] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(4-chloropyridin- 2-yl)ethyl]acetamide (DMSO-d6): 8.66 (1H, d), 8.51 (1H, dd) 8.44 (1H, s), 8.04-8.02 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.58 (1H, br d), 7.50 (1H, d), 7.42 (1H, dd), 5.04-4.95 (1H, m), 4.60 (2H, s), 4.30 (2H, s), 3.99-3.91 (1H, m), 3.91-3.82 (2H, m), 3.38 (2H, t), 1.89-1.81 (2H, m), 1.60-1.46 (2H, m), 1.42 (3H, d). 541 239 [01335] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-[6- (hydroxymethyl)pyridin- 2-yl]ethyl]acetamide (DMSO-d6): 8.59 (1H, d), 8.44 (1H, s), 8.05- 8.02 (1H, m), 7.98 (1H, dd), 7.80-7.72 (2H, m), 7.58 (1H, br d), 7.34 (1H, d), 7.23 (1H, d), 5.35 (1H, t), 5.02-4.92 (1H, m), 4.61 (2H, d), 4.55 (2H, d), 4 29 (2H, s), 3.99-3.90 (1H, m), 3.90-3.82 (2H, m), 3.38 (2H, t), 1.89-1.81 (2H, m), 1.59-1.48 (2H, m), 1.40 (3H, d). 537 240 [01336] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-[6- (difluoromethyl)pyridin- 2-yl]ethyl]acetamide (DMSO-d6): 8.70 (1H, d), 8.44 (1H, s), 8.04- 8.02 (1H, m), 8.02-7.96 (2H, m), 7.74 (1H, d), 7.57 (3H, dd), 6.92 (1H, t), 5.08-4.98 (1H, m), 4.62 (1H, d), 4.59 (1H, d), 4.30 (2H, s), 3.99-3.90 (1H, m), 3.90-3.81 (2H, m), 3.38 (2H, t), 1.89-1.81 (2H, m), 1.59-1.48 (2H, m), 1.44 (3H, d). 557 241 [01337] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(6-cyanopyridin- 2-yl)ethyl]acetamide (DMSO-d6): 8.75 (1H, d), 8.44 (1H, s), 8.08- 8.02 (2H, m), 7.98 (1H, dd), 7.93 (1H, dd), 7.76-7.71 (2H, m), 7.58 (1H, br d), 5.07-4.99 (1H, m), 4.61 (1H, d), 4.59 (1H, d), 4.29 (2H, s), 3.98-3.90 (1H, m), 3.90-3.82 (2H, m), 3.38 (2H, t), 1.89-1.81 (2H, m), 1.59-1.48 (2H, m), 1.43 (3H, d). 532 242 [01338] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-[6- (trifluoromethyl)pyridin- 2-yl]ethyl]acetamide (DMSO-d6): 8.75 (1H, d), 8.44 (1H, s), 8.08 (1H, t), 8.04-8.02 (1H, m), 7.98 (1H, dd), 7.78 (1H, d), 7.72 (2H, t), 7.58 (1H, br d), 5.09- 5.00 (1H, m), 4.61 (1H, d), 4.58 (1H, d), 4.30 (2H, s), 3.98-3.90 (1H, m), 3.90-3.82 (2H, m), 3.38 (2H, t), 1.90-1.80 (2H, m), 1.59-1.48 (2H, m), 1.45 (3H, d). 575 243 [01339] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(2- methylpyridin-4- yl)ethyl]acetamide (DMSO-d6): 8.64 (1H, d), 8.44 (1H, s), 8.38 (1H, d), 8.05-8.02 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.58 (1H, br d), 7.19 (1H, s), 7.15-7.11 (1H, m), 4.95-4.85 (1H, m), 4.60 (2H, s), 4.28 (2H, s), 3.98-3.90 (1H, m), 3.90-3.82 (2H, m), 3 38 (2H, t), 1.89-1.81 (2H, m), 1.59-1.47 (2H, m), 1.38 (3H, d). 521 244 [01340] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2(3-dihydro- 1H-isoindol-2-yl)-N- [(2S)-1-hydroxy-3-(3- methoxyphenyl)propan- 2-yl]acetamide (Me-d3-OD): 8.36 (1H, s), 8.24-8.22 (1H, m), 8.08 (1H, dd), 7.68 (1H, dd), 7.19-7.14 (1H, m), 6.84-6.80 (2H, m), 6.78-6.73 (1H, m), 4.43 (2H, s), 4.28 (2H, s), 4.25-4.18 (1H, m), 4.11-4.02 (1H, m), 4.02-3.95 (2H, m), 3.77 (3H, s), 3.61-3.50 (4H, m), 2.98-2.90 (1H, m), 2.79-2.68 (1H, m), 2.05-1.98 (2H, m), 1.69-1.58 (2H, m). 566 245 [01341] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (1,3-dimethyl-1H- pyrazol-4-yl)propan-2- yl]acetamide (DMSO-d6): 8.45 (1H, s), 8.05-8.03 (1H, m), 8.01-7.96 (2H, m), 7.75 (1H, d), 7.59 (1H, br d), 7.14 (1H, s), 4.55 (2H, s), 4.17 (1H, d), 4.15 (1H, d), 3.99-3.90 (1H, m), 3.90-3.78 (3H, m), 3.68 (3H, s), 3.38 (2H, t), 2.49-2.37 (2H, m), 2.16 (3H, s), 1.85 (2H, d), 1.61-1.47 (2H, m), 1.03 (3H, d). 538 246 [01342] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2(3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(1,3- thiazol-4-yl)ethyl] acetamide (DMSO-d6): 9.07 (1H, d), 8.53 (1H, d), 8.45 (1H, s), 8.05-8.03 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.58 (1H, br d), 7.50 (1H, dd), 5.15- 5.08 (1H, m), 4.89 (1H, t), 4.61 (2H, s), 4.32 (1H, d), 4.30 (1H, d), 3.99-3.90 (1H, m), 3.90-3.83 (2H, m), 3.81-3.74 (1H, m), 3.72-3.65 (1H, m), 3.38 (2H, t), 1.90-1.81 (2H, m), 1.60-1.47 (2H, m). 529 247 [01343] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-2-hydroxy-1-(1,3- thiazol-2-yl)ethyl] acetamide (DMSO-d6): 8.86 (1H, d), 8.45 (1H, s), 8.05- 8.03 (1H, m), 7.99 (1H, dd), 7.77-7.73 (2H, m), 7.64 (1H, d), 7.58 (1H, br d), 5.23-5.17 (1H, m), 5.11 (1H, t), 4.62 (2H, s), 4.35 (1H, d), 4.32 (1H, d), 3.98-3.90 (1H, m), 3.90-3.80 (3H, m), 3.80-3.72 (1H, m), 3 38 (2H, t), 1.90-1.80 (2H, m), 1.60-1.47 (2H, m). 529 248 [01344] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (1,3-thiazol-2-yl)propan- 2-yl]acetamide (DMSO-d6): 8.45 (1H, s), 8.18 (1H, d), 8.05- 8.03 (1H, m), 7.99 (1H, dd), 7.75 (1H, d), 7.70 (1H, d), 7.63-7.54 (2H, m), 4.55 (1H, d), 4.53 (1H, d), 4.23-4.10 (3H, m), 3.99-3.90 (1H, m), 3.90-3.82 (2H, m), 3.42-3.35 (2H, m), 3.16 (1H, dd), 3.13 (1H, dd), 1.90-1.81 (2H, m), 1.61-1.47 (2H, m), 1.13 (3H, d). 527 249 [01345] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [4-(trifluoromethyl)-1,3- thiazol-2-yl]ethyl} acetamide (DMSO-d6): 9.04 (1H, d), 8.45 (1H, s), 8.43- 8.41 (1H, m), 8.05-8.03 (1H, m), 7.99 (1H, dd), 7.75 (1H, d), 7.58 (1H, br d), 5.30-5.22 (1H, m), 4.63 (1H, d), 4.61 (1H, d), 4.31 (2H, s), 3.98-3.90 (1H, m), 3.90-3.83 (2H, m), 3.38 (2H, dd), 1.90-1.81 (2H, m), 1.59-1.48 (5H, m). 581 250 [01346] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (pyrimidin-5- yl)ethyl]acetamide (DMSO-d6): 9.09 (1H, s), 8.78 (2H, s), 8.70 (1H, d), 8.44 (1H, s), 8.05-8.02 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.58 (1H, br d), 5.06- 4.98 (1H, m), 4.59 (2H, s), 4.28 (2H, s), 3.98- 3.90 (1H, m), 3.90-3.83 (2H, m), 3.38 (2H, t), 1.90-1.80 (2H, m), 1.59-1.48 (2H, m), 1.46 (3H, d). 508 251 [01347] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- {5H,6H,7H- cyclopenta[b]pyridin-5- yl}acetamide (DMSO-d6): 8.58 (1H, d), 8.45 (1H, s), 8.40- 8.37 (1H, m), 8.05-8.03 (1H, m), 7.99 (1H, dd), 7.76 (1H, d), 7.62-7.55 (2H, m), 7.20 (1H, dd), 5.36 (1H, q), 4.64 (2H, s), 4.27 (2H, s), 3.99- 3.90 (1H, m), 3.90-3.82 (2H, m), 3.38 (2H, t), 3.02-2.85 (2H, m), 2.48-2.41 (2H, m), 1.88-1.82 (2H, m), 1.61-1.47 (2H, m). 519 252 [01348] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (4-methyl-1,3-thiazol-2- yl)ethyl]acetamide (DMSO-d6): 8.89 (1H, d), 8.45 (1H, s), 8.05- 8.03 (1H, m), 7.99 (1H, dd), 7.75 (1H, d), 7.58 (1H, br d), 7.16-7.14 (1H, m), 5.24-5.15 (1H, m), 4.63 (1H, d), 4.61 (1H, d), 4.28 (2H, s), 3.98-3.90 (1H, m), 3.87 (2H, d), 3.38 (2H, t), 2.34 (3H, d), 1.89-1.82 (2H, m), 1.59-1.48 (5H, m) 527 253 [01349] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (3-methylpyridin-2- yl)ethyl]acetamide (DMSO-d6): 8.55 (1H, d), 8.44 (1H, s), 8.40 (1H, d), 8.02 (1H, s), 7.99-7.96 (1H, m), 7.73 (1H, d), 7.61-7.54 (2H, m), 7.21 (1H, dd), 5.28- 5.20 (1H, m), 4.58 (2H, s), 4.24 (2H, d), 3.97- 3.90 (1H, m), 3.90-3.83 (2H, m), 3.38 (2H, t), 2.34 (3H, s), 1.90-1.81 (2H, m), 1.59-1.47 (2H, m), 1.37 (3H, d). 521 254 [01350] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(1- {imidazo[2,1-b][1,3] thiazol-6-yl}ethyl) acetamide (DMSO-d6): 8.47 (1H, d), 8.44 (1H, s), 8.04- 8.03 (1H, m), 7.98 (1H, dd), 7.87 (1H, d) 7.75 (1H, d), 7.61-7.56 (2H, m), 7.21 (1H, d), 5.05- 4.96 (1H, m), 4.61 (2H, s), 4.24 (2H, s), 3.98- 3.90 (1H, m), 3.90-3.82 (2H, m), 3.38 (2H, t), 1.85 (2H, d), 1.59-1.48 (2H, m), 1.43 (3H, d). 552 255 [01351] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(2- hydroxycyclohexyl) acetamide (DMSO-d6): 8.45 (1H, s), 8.04 (1H, s), 7.98 (1H, dd), 7.89 (1H, d), 7.75 (1H, d), 7.62-7.55 (1H, m), 4.60 (2H, s), 4.55 (1H, d), 4.23 (1H, d), 4.18 (1H, d), 3.98- 3.90 (1H, m), 3.90-3.83 (2H, m), 3.49-3.34 (3H, m), 3.28-3.24 (1H, m), 1.89-1.82 (3H, m), 1.82-1.76 (1H, m), 1.66-1.49 (4H, m), 1.27 (1H, t), 1.21-1.15 (3H, m). 500 256 [01352] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(2- hydroxycyclohexyl) acetamide (DMSO-d6): 8.45 (1H, s), 8.04-8.02 (1H, m), 7.98 (1H, dd), 7.76 (2H, dd), 7.58 (1H, br d), 4.61-4.58 (3H, m), 4.25 (1H, d), 4.23 (1H, d), 3.98-3.90 (1H, m), 3.90-3.83 (2H, m), 3.77-3.72 (1H, m), 3.72-3.64 (1H, m), 3.38 (2H, td), 1.89-1.82 (2H, m), 1.73-1.64 (1H, m), 1.64-1.48 (5H, m), 1.48-1.36 (2H, m), 1.28 (2H, d). 500 257 [01353] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}- 2-{2-[(3S)-3- hydroxypiperidin-1-yl]-2- oxoethyl}-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6): 8.45 (1H, s), 8.03 (1H, s), 7.99 (1H, dd), 7.74 (1H, d), 7.58 (1H, br s), 4.90 (1H, dd), 4.56 (2H, s), 4.49-4.45 (2H, m), 4.04 (0.5H, d), 4.00-3.91 (1H, m), 3.87 (2H, d), 3.70-3.61 (1H, m), 3.60-3.53 (0.5H, m), 3.52-3.30 (4H, m), 3.22 (0.5H, dd), 3.15-3.06 (0.5H, m), 1.90-1.65 (4H, m), 1.61-1.28 (4H, m). 486 258 [01354] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (2,4-dimethyl-1,3- thiazol-5-yl)ethyl] acetamide (DMSO-d6): 8.62 (1H, d), 8.44 (1H, s), 8.03 (1H, s), 7.98 (1H, dd), 7.74 (1H, d), 7.58 (1H, br d), 5.20-5.12 (1H, m), 4.57 (2H, s), 4.20 (1H, d), 4.18 (1H, d), 3.98-3.90 (1H, m), 3.90-3.82 (2H, m), 3.38 (2H, t), 2.55 (3H, s), 2.26 (3H, s), 1.89-1.81 (2H, m), 1.59-1.48 (2H, m), 1.41 (3H, d). 541 259 [01355] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R,2S)-2-hydroxy-1- (thiophen-2-yl)propyl] acetamide (Me-d3-OD): 8.35 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.70 (1H, dd), 7.32 (1H, dd), 7.11- 7.08 (1H, m), 7.00 (1H, dd), 5.20 (1H, d), 4.67 (2H, s), 4.44 (1H, d), 4.40 (1H, d), 4.18-3.93 (5H, m), 3.55 (2H, td), 2.01 (2H, d), 1.69-1.57 (2H, m), 1.19 (3H, d). 542 260 [01356] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S,2S)-2-hydroxy-1- (pyridin-2-yl)propyl] acetamide (DMSO-d6): 8.54-8.51 (1H, m), 8.46-8.42 (2H, m), 8.03 (1H, s), 7.98 (1H, dd), 7.79-7.72 (2H, m), 7.63-7.54 (1H, m), 7.39 (1H, d), 7.27 (1H, ddd), 4.84 (1H, dd), 4.81 (1H, d), 4.60 (2H, s), 4.39 (1H, d), 4.37 (1H, d), 4.16-4.08 (1H, m), 3.98-3.90 (1H, m), 3.90-3.84 (2H, m), 3.38 (2H, t), 1.89-1.82 (2H, m), 1.60-1.47 (2H, m), 1.05 (3H, d). 537 261 [01357] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1- (thiophen-3- yl)ethyl]acetamide (Me-d3-OD): 8.35 (1H, s), 8.24 (1H, d), 8.07 (1H, dd), 7.71 (1H, d), 7.40 (1H, dd), 7.35- 7.32 (1H, m), 7.13 (1H, dd), 5.18 (1H, dd), 4.69 (2H, s), 4.44 (1H, d), 4.43 (1H, d), 4.11-4.02 (1H, m), 4.02-3.93 (2H, m), 3.86 (1H, dd), 3.79 (1H, dd), 3.54 (2H, td), 2.05-1.98 (2H, m), 1.69-1.57 (2H, m) 528 262 [01358] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S,2S)-2-hydroxy-1- (6-methoxypyridin-2- yl)propyl]acetamide (DMSO-d6): 8.45 (1H, s), 8.30 (1H, d), 8.05- 8.03 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.66 (1H, dd), 7.58 (1H, br d), 6.97 (1H, d), 6.67 (1H, d), 4.77-4.73 (2H, m), 4.61 (2H, s), 4.40 (1H, d), 4.38 (1H, d), 4.22-4.14 (1H, m), 3.98-3.91 (1H, m), 3.91-3.84 (2H, m), 3.83 (3H, s), 3.38 (2H, t), 1.89-1.81 (2H, m), 1.60-1.47 (2H, m), 1.08 (3H, d). 567 263 [01359] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-2-hydroxy-1- (thiophen-2- yl)ethyl]acetamide (Me-d3-OD): 8.35 (1H, s), 8.24 (1H, d), 8.07 (1H, dd), 7.71 (1H, d), 7.32 (1H, dd), 7.08 (1H, dt), 6.99 (1H, dd), 5.36-5.31 (1H, m), 4.68 (2H, s), 4.44 (1H, d), 4.41 (1H, d), 4.09-4.02 (1H, m), 4.02-3.93 (2H, m), 3.89 (1H, dd), 3.84 (1H, dd), 3.54 (2H, td), 2.04-1.98 (3H, m), 1.69-1.57 (2H, m). 528 264 [01360] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S,2S)-2-hydroxy-1- (6-methylpyridin-2- yl)propyl]acetamide (DMSO-d6): 8.44 (1H, s), 8.36 (1H, d), 8.04- 8.03 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.64 (1H, t), 7.58 (1H, br d), 7.18 (1H, d), 7.12 (1H, d), 4.81-4.75 (2H, m), 4.61 (2H, s), 4.38 (2H, s), 4.16-4.08 (1H, m), 3.98-3.90 (1H, m), 3.90-3.82 (2H, m), 3.38 (2H, t), 2.44 (3H, s), 1.89-1.81 (2H, m), 1.60-1.47 (2H, m), 1.05 (3H, d). 551 265 [01361] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(6- methylpyridin-2- yl)ethyl]acetamide (DMSO-d6): 8.48 (1H, d), 8.44 (1H, s), 8.05- 8.03 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.64 (1H, t), 7.58 (1H, br d), 7.16 (1H, d), 7.12 (1H, d), 4.94-4.88 (1H, m), 4.86 (1H, t), 4.61 (2H, s), 4.33 (2H, s), 3.98- 3.90 (1H, m), 3.90-3.82 (2H, m), 3.78-3.70 (1H, m), 3.70-3.63 (1H, m), 3.38 (2H, t), 1.89-1.81 (2H, m), 1.60-1.47 (2H, m). 537 266 [01362] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-(3-fluoropyridin- 2-yl)-2-hydroxyethyl] acetamide (DMSO-d6): 8.56 (1H, d), 8.46-8.43 (2H, m), 8.03-8.01 (1H, m), 7.98 (1H, dd), 7.73 (1H, d), 7.68 (1H, ddd), 7.58 (1H, br d), 7.44-7.39 (1H, m), 5.32 (1H, q), 4.95 (1H, br s), 4.58 (2H, s), 4.30 (1H, d), 4.26 (1H, d), 3.99-3.90 (1H, m), 3.90-3.82 (2H, m), 3.69 (2H, d), 3.42- 3.37 (2H, m), 1.85 (2H, d), 1.60-1.47 (2H, m). 541 267 [01363] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}- 2-{2-[(3R)-3- hydroxypyrrolidin-1-yl]- 2-oxoethyl}-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6): 8.45 (1H, s), 8.05-8.03 (1H, m), 7.99 (1H, dd), 7.75 (1H, d), 7.59 (1H, br d), 5.07 (0.5H, d), 4.96 (0.5H, d), 4.59 (2H, s), 4.48-4.32 (2.5H, m), 4.31-4.26 (0.5H, m), 4.00-3.91 (1H, m), 3.91-3.81 (2H, m), 3.67-3.53 (1.5H, m), 3.50-3.31 (4.5H, m), 2.06-1.70 (4H, m), 1.60-1.48 (2H, m). 472 268 [01364] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(2- hydroxycyclopentyl) acetamide (Me-d3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.72 (1H, dd), 4.69 (2H, s), 4.36 (2H, s), 4.11-3.94 (5H, m), 3.55 (2H, dt), 2.18-2.08 (1H, m), 2.05-1.92 (3H, m), 1.86-1.70 (2H, m), 1.70-1.47 (4H, m). 486 269 [01365] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (2,5-dimethyl-1,3- thiazol-4-yl)ethyl] acetamide (DMSO-d6): 8.53 (1H, d), 8.44 (1H, s), 8.03- 8.01 (1H, m), 7.97 (1H, dd), 7.73 (1H, d), 7.58 (1H, br d), 5.09-4.99 (1H, m), 4.58 (2H, s), 4.20 (2H, s), 3.99-3.90 (1H, m), 3.90-3.82 (2H, m), 3.38 (2H, t), 2.57 (3H, s), 2.34 (3H, s), 1.89-1.81 (2H, m), 1.60-1.46 (2H, m), 1.39 (3H, d). 541 270 [01366] N-[(1R)-1-(3-tert- butylphenyl)ethyl)-2-(6- {5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}- 1-oxo-2,3-dihydro-1H- isoindol-2-yl)acetamide (Me-d3-OD): 8.35 (1H, s), 8.23 (1H, d), 8.07 (1H, dd), 7.70 (1H, dd), 7.41-7.39 (1H, m), 7.30 (1H, dt), 7.29-7.24 (1H, m), 7.19-7.15 (1H, m), 5.07 (1H, q), 4.66 (2H, s), 4.40 (1H, d), 4.38 (1H, d), 4.11-4.02 (1H, m), 4.02-3.95 (2H, m), 3.54 (2H, td), 2.06-1.97 (2H, m), 1.69-1.58 (2H, m), 1.50 (3H, d), 1.33 (9H, s). 562 271 [01367] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(6-methylpyridin- 2-yl)ethyl]acetamide (DMSO-d6): 8.57 (1H, d), 8.44 (1H, s), 8.04- 8.02 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.65 (1H, t), 7.58 (1H, br d), 7.16 (1H, d), 7.12 (1H, d), 4.99-4.89 (1H, m), 4.62 (1H, d), 4.60 (1H, d), 4.28 (2H, s), 3.99- 3.90 (1H, m), 3.90-3.82 (2H, m), 3.38 (2H, t), 2.45 (3H, s), 1.89-1.81 (2H, m), 1.59-1.48 (2H, m), 1.40 (3H, d). 521 272 [01368] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}- 2-{2-[2-(hydroxymethyl) piperidin-1-yl]-2- oxoethyl}-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6): 8.45 (1H, s), 8.03 (1H, s), 7.98 (1H, dd), 7.74 (1H, d), 7.58 (1H, br d), 5.01- 4.93 (1H, m), 4.71-4.23 (5H, m), 4.07-3.98 (1H, m), 3.98-3.91 (1H, m), 3.87 (2H, d), 3.75 (1H, d), 3.59-3.43 (1H, m), 3.38 (2H, t), 3.10 (0.5H, s), 2.71-2.60 (0.5H, m), 1.92-1.21 (10H, m). 500 273 [01369] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}- 2-{2-[(2S)-2- (hydroxymethyl) pyrrolidin-1-yl]-2- oxoethyl}-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6): 8.45 (1H, s), 8.04 (1H, s), 8.01- 7.96 (1H, m), 7.75 (1H, dd), 7.59 (1H, br d), 5.06 (0.3H, t), 4.72 (0.7H, t), 4.59 (2H, s), 4.53 (0.7H, s), 4.38 (1.3H, s), 4.13-4.09 (0.3H, m), 4.00-3.90 (1.7H, m), 3.90-3.82 (2H, m), 3.56-3.31 (6H, m), 2.01-1.74 (6H, m), 1.61-1.47 (2H, m). 486 274 [01370] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}- 2-{2-[(2R)-2- (hydroxymethyl) pyrrolidin-1-yl]-2- oxoethyl}-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6): 8.45 (1H, s), 8.05-8.02 (1H, m), 8.01-7.96 (1H, m), 7.75 (1H, dd), 7.58 (1H, br d), 5.06 (0.3H, t), 4.72 (0.7H, t), 4.59 (2H, s), 4.54 (0.7H, s), 4.38 (1.3H, s), 4.14-4.05 (0.3H, m), 4.00-3.90 (1.7H, m), 3.90-3.81 (2H, m), 3.56-3.32 (6H, m), 2.03-1.78 (6H, m), 1.60-1.48 (2H, m). 486 275 [01371] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S,2R)-2- hydroxycyclopentyl] acetamide (DMSO-d6): 8.45 (1H, s), 8.04-8.03 (1H, m), 7.98 (1H, dd), 7.80 (1H, d), 7.74 (1H, d), 7.58 (1H, br m), 4.67 (1H, d), 4.60 (2H, s), 4.26 (1H, d), 4.23 (1H, d), 3.98-3.91 (2H, m), 3.91-3.83 (3H, m), 3.38 (2H, t), 1.89-1.66 (5H, m), 1.61-1.42 (5H, m). 486 276 [01372] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R,2S)-2- hydroxycyclopentyl] acetamide (DMSO-d6): 8.45 (1H, s), 8.03 (1H, s), 7.98 (1H, dd), 7.80 (1H, d), 7.74 (1H, d), 7.58 (1H, br d), 4.67 (1H, d), 4.60 (2H, s), 4.26 (1H, d), 4.23 (1H, d), 3.98-3.92 (2H, m), 3.91-3.83 (3H, m), 3.38 (2H, t), 1.85 (2H, d), 1.81-1.65 (3H, m), 1.62-1.41 (5H, m). 486 277 [01373] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}- 2-{2-[(3R)-3- hydroxypiperidin-1-yl]-2- oxoethyl}-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6): 8.45 (1H, s), 8.04-8.02 (1H, m), 7.99 (1H, dd), 7.74 (1H, d), 7.58 (1H, br d), 4.89 (1H, br s), 4.56 (2H, s), 4.49-4.44 (2H, m), 4.07-4.01 (0.5H, m), 3.98-3.91 (1H, m), 3.90-3.83 (2H, m), 3.65 (1H, t), 3.56 (0.5H, dd), 3.42-3.34 (4H, m), 3.25-3.19 (0.5H, m), 3.15-3.07 (0.5H, m), 1.90-1.66 (4H, m), 1.61-1.28 (4H, m). 486 278 [01374] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}- 2-{2-[(2R,6S)-2,6- dimethylpiperidin-1-yl]- 2-oxoethyl}-2,3-dihydro- 1H-isoindol-1-one (DMSO-d6): 8.45 (1H, s), 8.03 (1H, s), 7.99 (1H, dd), 7.75 (1H, d), 7.59 (1H, br d), 4.69- 4.44 (4H, m), 4.44-4.10 (2H, m), 4.00-3.90 (1H, m), 3.90-3.81 (2H, m), 3.38 (2H, t), 1.92-1.72 (3H, m), 1.72-1.37 (7H, m), 1.37-1.02 (6H, m). 498 279 [01375] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}- 2-[2-(4- cyclopropylpiperidin-1- yl)-2-oxoethyl]-2,3- dihydro-1H-isoindol-1- one (DMSO-d6): 8.45 (1H, s), 8.04-8.02 (1H, m), 7.99 (1H, dd), 7.75 (1H, d), 7.58 (1H, br d), 4.57 (2H, s), 4.49 (1H, d), 4.45 (1H, d), 4.31 (1H, d), 3.99-3.82 (4H, m), 3.42-3.35 (2H, m), 3.01 (1H, t), 2.62-2.53 (1H, m), 1.89-1.82 (2H, m), 1.80-1.68 (2H, m), 1.59-1.48 (2H, m), 1.37-1.23 (1H, m), 1.23-1.08 (1H, m), 0.86-0.75 (1H, m), 0.64-0.54 (1H, m), 0.41-0.35 (2H, m), 0.14-0.09 (2H, m). 510 280 [01376] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(2S)-1-hydroxy-3,3- dimethylbutan-2- yl]acetamide (DMSO-d6): 8.45 (1H, s), 8.04 (1H, s), 7.98 (1H, dd), 7.77-7.71 (2H, m), 7.59 (1H, br d), 4.60 (2H, s), 4.43 (1H, t), 4.29 (1H, d), 4.26 (1H, d), 3.99-3.90 (1H, m), 3.90-3.82 (2H, m), 3.69-3.55 (2H, m), 3.42-3.36 (2H, m), 1.90-1.81 (2H, m), 1.59-1.48 (2H, m), 0.88 (9H, s). 502 281 [01377] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S,2S)-1-cyclopropyl- 2-hydroxypropyl] acetamide (DMSO-d6): 8.45 (1H, s), 8.05-8.03 (1H, m), 7.98 (1H, dd), 7.83 (1H, d), 7.75 (1H, d), 7.58 (1H, br d), 4.63 (1H, d), 4.59 (2H, s), 4.27 (1H, d), 4.24 (1H, d), 3.99-3.90 (1H, m), 3.90-3.82 (2H, m), 3.79-3.71 (1H, m), 3.38 (2H, t), 3.09 (1H, td), 1.85 (2H, d), 1.60-1.47 (2H, m), 1.06 (3H, d), 1.04-0.94 (1H, m), 0.48-0.40 (1H, m), 0.40-0.32 (1H, m), 0.25-0.20 (2H, m). 500 282 [01378] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-[6-(difluoromethyl) pyridin-2-yl]-2- hydroxyethyl]acetamide (DMSO-d6): 8.63 (1H, d), 8.44 (1H, s), 8.03 (1H, s), 8.01-7.96 (2H, m), 7.74 (1H, d), 7.61- 7.54 (3H, m), 6.92 (1H, t), 5.02-4.97 (1H, m), 4.95 (1H, t), 4.61 (2H, d), 4.35 (2H, s), 3.98- 3.90 (1H, m), 3.90-3.82 (2H, m), 3.82-3.68 (2H, m), 3.38 (2H, t), 1.90- 1.81 (2H, m), 1.60-1.47 (2H, m). 573 283 [01379] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-[6- (trifluoromethyl)pyridin- 2-yl]ethyl]acetamide (DMSO-d6): 8.67 (1H, d), 8.44 (1H, s), 8.08 (1H, t), 8.04-8.02 (1H, m), 7.98 (1H, dd), 7.79 (1H, d), 7.73 (1H, d), 7.70 (1H, d), 7.58 (1H, br d), 5.03-4.95 (2H, m), 4.61 (1H, d), 4.59 (1H, d), 4.35 (2H, s), 3.93 (1H, d), 3.90-3.82 (2H, m), 3.82-3.70 (2H, m), 3.43-3.34 (2H, m), 1.89-1.81 (2H, m), 1.59-1.48 (2H, m). 591 284 [01380] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(5- methylthiophen-3- yl)ethyl]acetamide (Me-d3-OD): 8.36 (1H, s), 8.26-8.23 (1H, m), 8.08 (1H, dd), 7.71 (1H, dd), 7.05-7.03 (1H, m), 6.81-6.78 (1H, m), 5.07 (1H, dd), 4.69 (2H, s), 4.43 (2H, s), 4.11-4.02 (1H, m), 4.02-3.93 (2H, m), 3.83 (1H, dd), 3.75 (1H, dd), 3.55 (2H, td), 2.46 (3H, d), 2.05-1.97 (2H, m), 1.69-1.57 (2H, m). 542 285 [01381] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-(1,5-dimethyl- 1H-pyrazol-3- yl)ethyl]acetamide (DMSO-d6): 8.45 (1H, s), 8.36 (1H, d), 8.04- 8.02 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.58 (1H, br d), 5.93 (1H, s), 4.95-4.87 (1H, m), 4.61 (2H, s), 4.21 (2H, s), 3.98-3.91 (1H, m), 3.87 (2H, d), 3.66 (3H, s), 3.38 (2H, t), 2.21 (3H, s), 1.85 (2H, d), 1.60- 1.47 (2H, m), 1.34 (3H, d). 524 286 [01382] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(1,5-dimethyl- 1H-pyrazol-3- yl)ethyl]acetamide (DMSO-d6): 8.45 (1H, s), 8.36 (1H, d), 8.04- 8.02 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.58 (1H, br d), 5.93 (1H, s), 4.96-4.87 (1H, m), 4.61 (2H, s), 4.21 (2H, s), 3.98-3.90 (1H, m), 3.90-3.83 (2H, m), 3.66 (3H, s), 3.38 (2H, t), 2.21 (3H, s), 1.90-1.81 (2H, m), 1.60-1.47 (2H, m), 1.34 (3H, d). 524 287 [01383] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-(6-cyanopyridin- 2-yl)-2-hydroxyethyl] acetamide (DMSO-d6): 8.69 (1H, d), 8.44 (1H, s), 8.07- 8.01 (2H, m), 7.98 (1H, dd), 7.94 (1H, dd), 7.76-7.69 (2H, m), 7.58 (1H, br d), 5.02-4.95 (2H, m), 4.61 (1H, d), 4.59 (1H, d), 4.34 (2H, s), 3.98-3.90 (1H, m), 3.90-3.82 (2H, m), 3.77-3.71 (2H, m), 3.38 (2H, t), 1.89-1.81 (2H, m), 1.60-1.47 (2H, m). 548 288 [01384] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)- N-[1- (4-ethyl-1,3-thiazol-2- yl)ethyl]acetamide (DMSO-d6): 8.89 (1H, d), 8.45 (1H, s), 8.05- 8.03 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.62- 7.55 (1H, m), 7.15 (1H, s), 5.24-5.16 (1H, m), 4.63 (1H, d), 4.61 (1H, d), 4.28 (2H, s), 3.99- 3.90 (1H, m), 3.90-3.83 (2H, m), 3.38 (2H, t), 2.73-2.68 (2H, m), 1.89-1.81 (2H, m), 1.59-1.47 (5H, m), 1.21 (3H, t). 541 289 [01385] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (hydroxymethyl) cyclohexyl]acetamide (DMSO-d6): 8.45 (1H, s), 8.04-8.02 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.63-7.53 (1H, m), 7.35 (1H, s), 4.62 (1H, t), 4.59 (2H, s), 4.23 (2H, s), 3.99-3.90 (1H, m), 3.90-3.82 (2H, m), 3.45 (2H, d), 3.38 (2H, t), 2.05-1.98 (2H, m), 1.85 (2H, d), 1.60- 1.40 (7H, m), 1.35-1.14 (3H, m). 514 290 [01386] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-(5-fluoro-6- methylpyridin-2-yl)-2- hydroxyethyl]acetamide (DMSO-d6): 8.51 (1H, d), 8.45 (1H, s), 8.04- 8.02 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.62- 7.55 (2H, m), 7.26 (1H, dd), 4.91 (1H, q), 4.86 (1H, t), 4.61 (2H, s), 4.32 (2H, s), 3.99-3.90 (1H, m), 3.90-3.82 (2H, m), 3.76-3.62 (2H, m), 3.38 (2H, t), 2.43 (3H, d), 1.85 (2H, d), 1.60- 1.47 (2H, m). 555 291 [01387] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-(6- ethoxypyridin-2-yl)-2- hydroxyethyl]acetamide (Me-d3-OD): 8.36 (1H, s), 8.25 (1H, s), 8.09 (1H, dd), 7.72 (1H, d), 7.65-7.60 (1H, m), 6.96 (1H, dd), 6.65 (1H, d), 5.05 (1H, t), 4.71 (2H, s), 4.47 (2H, s), 4.34- 4.20 (2H, m), 4.11-4.02 (1H, m), 4.02-3.96 (2H, m), 3.93 (1H, dd), 3.87 (1H, dd), 3.55 (2H, td), 2.05-1.98 (2H, m), 1.70-1.57 (2H, m), 1.31 (3H, t). 567 292 [01388] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-(6-ethylpyridin- 2-yl)-2-hydroxyethyl] acetamide TFA (Me-d3-OD): 8.47-8.39 (1H, m), 8.36 (1H, s), 8.24-8.21 (1H, m), 8.08 (1H, dd), 7.90-7.85 (1H, m), 7.83-7.78 (1H, m), 7.71 (1H, d), 5.19 (1H, t), 4.70 (1H, d), 4.67 (1H, d), 4.50 (1H, d), 4.45 (1H, d), 4.10- 4.02 (1H, m), 4.01-3.93 (4H, m), 3.54 (2H, td), 3.12-3.05 (2H, m), 2.04-1.96 (2H, m), 1.70-1.56 (2H, m), 1.41 (3H, t). 551 293 [01389] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(1- cyclopropyl-2- hydroxyethyl)acetamide (DMSO-d6): 8.45 (1H, s), 8.05-8.03 (1H, m), 7.98 (1H, dd), 7.94 (1H, d), 7.75 (1H, d), 7.58 (1H, br d), 4.65 (1H, t), 4.59 (2H, s), 4.23 (1H, d), 4.21 (1H, d), 3.98-3.90 (1H, m), 3.90-3.84 (2H, m), 3.52-3.42 (2H, m), 3.38 (2H, t), 1.89-1.81 (2H, m), 1.59-1.48 (2H, m), 0.96-0.86 (1H, m), 0.47-0.39 (1H, m), 0.39-0.31 (1H, m), 0.29-0.16 (2H, m). 486 294 [01390] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(2R)-1,1,1-trifluoro-3- hydroxypropan-2- yl]acetamide (DMSO-d6): 8.71 (1H, d), 8.45 (1H, s), 8.05- 8.04 (1H, m), 7.99 (1H, dd), 7.76 (1H, d), 7.59 (1H, br d), 5.20 (1H, t), 4.60 (2H, s), 4.59-4.51 (1H, m), 4.37 (1H, d), 4.31 (1H, d), 3.99-3.90 (1H, m), 3.90-3.82 (2H, m), 3.74-3.66 (1H, m), 3.66-3.58 (1H, m), 3.38 (2H, td), 1.90-1.81 (2H, m), 1.61-1.47 (2H, m). 514 295 [01391] 2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(1- {imidazo[1,2-a]pyridin- 2-yl}ethyl)acetamide (DMSO-d6): 8.56 (1H, d), 8.53-8.49 (1H, m), 8.45 (1H, s), 8.05-8.03 (1H, m), 7.98 (1H, dd), 7.79 (1H, s), 7.75 (1H, d), 7.58 (1H, br d), 7.50 (1H, dd), 7.24-7.19 (1H, m), 6.86 (1H, td), 5.17-5.09 (1H, m), 4.63 (2H, s), 4.27 (2H, s), 3.98-3.90 (1H, m), 3.90-3.83 (2H, m), 3.38 (2H, t), 1.89-1.81 (2H, m), 1.59-1.51 (2H, m), 1.49 (3H, d). 546

Examples 296 and 297: tert-Butyl 3-{1-[2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamido]ethyl}piperidine-1-carboxylate

[1581] ##STR01392##

[1582] To HATU (1.2 eq.) and 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) (1.0 eq.) was added DCM (0.1 M), DIPEA (1.2 eq.) and then 3-(1-amino-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (1.5 eq.) was added under nitrogen. The mixture was stirred for 4 hours at room temperature. The reaction was quenched by diluting with water and extracting with EtOAc (×3). The combined organic layers were washed with brine and dried over MgSO.sub.4. The products were filtered and evaporated to dryness. The diastereomers (Examples 296 and 297) were separated by preparative HPLC.

[1583] First diastereomer (Example 296): 1H NMR (400 MHz, Me-d3-OD): 8.35 (1H, s), 8.24 (1H, d), 8.08 (1H, dd), 7.72 (1H, dd), 4.68 (2H, s), 4.35 (2H, s), 4.12-4.02 (1H, m), 4.02-3.95 (3H, m), 3.92-3.77 (2H, m), 3.54 (2H, dt), 2.92-2.82 (1H, m), 2.82-2.58 (1H, m), 2.01 (2H, d), 1.94-1.85 (1H, m), 1.76-1.69 (1H, m), 1.69-1.58 (2H, m), 1.57-1.49 (1H, m), 1.47 (9H, s), 1.44-1.37 (1H, m), 1.31 (1H, d), 1.21 (3H, d). LC-MS: [M+H].sup.+=613.

[1584] Second diastereomer (Example 297): 1H NMR (400 MHz, Me-d3-OD): 8.36 (1H, s), 8.25 (1H, d), 8.08 (1H, dd), 7.72 (1H, d), 4.70 (2H, s), 4.37 (2H, s), 4.11-4.03 (2H, m), 4.02-3.93 (3H, m), 3.86-3.77 (1H, m), 3.55 (2H, dt), 2.83-2.71 (1H, m), 2.56 (1H, s), 2.01 (2H, d), 1.96-1.86 (1H, m), 1.76-1.69 (1H, m), 1.69-1.58 (2H, m), 1.48 (10H, s), 1.33-1.21 (2H, m), 1.19 (3H, d). LC-MS: [M+H].sup.+=613.

Examples 298 and 299: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[1-(piperidin-3-yl)ethyl]acetamide HCl

[1585] ##STR01393##

[1586] To each diastereomer of tert-butyl 3-{1-[2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamido]ethyl}piperidine-1-carboxylate (Example 296 or 297), was added HCl saturated in EtOAc and the reactions were stirred for 2 hours. The mixture was evaporated in vacuo, and again after addition of MeOH (×2) to yield the Example 298 or 299 as a colourless solid (HCl salt).

[1587] First diastereomer (Example 298): 1H NMR (400 MHz, Me-d3-OD): 8.44 (1H, s), 8.26 (1H, d), 8.20 (0.5H, d), 8.12 (1H, dd), 7.76 (1H, dd), 4.74 (1H, d), 4.70 (1H, d), 4.42 (1H, d), 4.30 (1H, d), 4.15-4.04 (1H, m), 4.04-3.96 (3H, m), 3.55 (2H, td), 3.40-3.34 (2H, m), 2.92 (1H, td), 2.78 (1H, t), 2.05-1.88 (5H, m), 1.78-1.61 (3H, m), 1.44-1.33 (1H, m), 1.23 (3H, d).

[1588] Second diastereomer (Example 299): 1H NMR (400 MHz, Me-d3-OD): 8.36 (1H, s), 8.22 (1H, s), 8.21 (0.5, m), 8.08 (1H, dd), 7.73 (1H, d), 4.74 (1H, d), 4.69 (1H, d), 4.40 (1H, d), 4.29 (1H, d), 4.11-4.02 (1H, m), 4.02-3.94 (2H, m), 3.93-3.83 (1H, m), 3.54 (2H, td), 3.41 (1H, d), 2.99-2.86 (1H, m), 2.76 (1H, t), 2.04-1.93 (4H, m), 1.88-1.58 (4H, m), 1.44-1.33 (1H, m), 1.24 (3H, d).

Examples 300 and 301: N-[1-(1-acetylpiperidin-3-yl)ethyl]-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamide

[1589] ##STR01394##

[1590] To HATU (1.2 eq.) and 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[1-(piperidin-3-yl)ethyl]acetamide HCl (Example 298 or 299) (1.0 eq.) was added DCM (0.1 M), DIPEA (1.2 eq.) and then acetic acid (1.2 eq.) was added under nitrogen. The mixture was stirred for 4 hours at room temperature. The reaction was quenched by diluting with citric acid (5%, aq.) and extracting with EtOAc (×3). The combined organic layers were washed with brine and dried over MgSO.sub.4. The products were filtered and evaporated to dryness to yield the diastereomer Examples 300 or 301.

[1591] First diastereomer (Example 300): 1H NMR (400 MHz, (Me-d3-OD): 8.36 (1H, s), 8.24 (1H, d), 8.11-8.05 (1H, m), 7.72 (1H, d), 4.69 (2H, d), 4.49-4.32 (3H, m), 4.10-4.02 (1H, m), 4.02-3.84 (3H, m), 3.83-3.68 (1H, m), 3.58-3.47 (2H, m), 3.18-3.10 (0.5H, m), 2.91 (0.5H, dd), 2.73-2.54 (1H, m), 2.05-1.93 (3H, m), 1.86-1.75 (1H, m), 1.69-1.58 (2H, m), 1.55-1.32 (6H, m), 1.23 (1.5H, d), 1.21 (1.5H, d). LC-MS: [M+H].sup.+=555.

[1592] Second diastereomer (Example 301): 1H NMR (400 MHz, (Me-d3-OD): 8.36 (1H, s), 8.25-8.22 (1H, m), 8.08 (1H, dt), 7.76-7.71 (1H, m), 4.73-4.69 (2H, m), 4.52-4.32 (3H, m), 4.10-4.02 (1H, m), 4.02-3.96 (2H, m), 3.93-3.75 (2H, m), 3.55 (2H, td), 3.14-3.05 (0.5H, m), 2.89 (0.5H, dd), 2.73-2.63 (0.5H, m), 2.49 (0.5H, dd), 2.02 (2H, d), 1.97-1.92 (1H, m), 1.86-1.73 (1H, m), 1.69-1.55 (3H, m), 1.52-1.34 (5H, m), 1.21 (2H, d), 1.19 (1H, d). LC-MS: [M+H].sup.+=555.

Example 302: 6-{5-Chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-{2-[(1-hydroxy-2-phenylpropan-2-yl)amino]ethyl}-2,3-dihydro-1H-isoindol-1-one

[1593] ##STR01395##

[1594] To 6-(2,5-dichloropyrimidin-4-yl)-2-{2-[(1-hydroxy-2-phenylpropan-2-yl)amino]ethyl}-2,3-dihydro-1H-isoindol-1-one (Preparation 419) (10 mg, 0.02 mmol) in EtOH was added 4-aminooxan (7 μL, 0.07 mmol) and DIPEA (11 μL, 0.07 mmol). The mixture was stirred in reacti vial at 90° C. for 24 hours. The mixture was evaporated in vacuo and purified directly by preparative HPLC to yield the product as a colourless solid (2 mg, 18%). 1H NMR (400 MHz, Me-d3-OD): 8.37 (1H, s), 8.23 (1H, d), 8.07 (1H, dd), 7.69 (1H, d), 7.40-7.33 (2H, m), 7.19-7.14 (3H, m), 4.65-4.47 (2H, m), 4.12-4.03 (1H, m), 4.03-3.95 (2H, m), 3.80-3.65 (2H, m), 3.63-3.51 (4H, m), 2.83-2.75 (1H, m), 2.66-2.57 (1H, m), 2.05-1.98 (2H, m), 1.70-1.58 (2H, m), 1.49 (3H, s). LC-MS: [M+H].sup.+=522.

Example 303: 2-(6-{5-Chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[6-(dimethylamino)pyridin-2-yl]-2-hydroxyethyl]acetamide

[1595] ##STR01396##

[1596] (2S)-2-Amino-2-(6-bromopyridin-2-yl)ethanol HCl (100 mg, 0.40 mmol) was taken up in dimethylamine (3.0 mL, 2M in THF). The mixture was heated by microwave at 60° C. for 1 hr, followed by 120° C. for a total of 18 hr. The reaction was quenched by diluting with K.sub.2CO.sub.3 (sat., aq.) and extracting with EtOAc (×3). The combined organic layers were washed with brine and dried over MgSO.sub.4. The product was filtered and evaporated in vacuo and used in the next reaction as is. LC-MS: [M+H].sup.+=182. To the TBTU (99 mg, 0.30 mmol) and 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) (80 mg, 0.20 mmol) was added DCM (4.0 mL), then DIPEA (52 μL, 0.30 mmol) under nitrogen. After 10 minutes the amine was added. The mixture was stirred for 4 hours at room temperature. The reaction was quenched by diluting with citric acid (5%, aq.) and extracting with EtOAc (×3). The combined organic layers were washed with brine and dried over MgSO.sub.4. The product was filtered and evaporated in vacuo. The product was purified by preparative HPLC, and dried by genevac, to yield 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[6-(dimethylamino)pyridin-2-yl]-2-hydroxyethyl]acetamide (Example 303) as a colourless solid (53 mg, 47%). 1H NMR (400 MHz, DMSO-d6): 8.45 (1H, s), 8.28 (1H, d), 8.05-8.03 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.63-7.53 (1H, m), 7.45 (1H, dd), 6.55 (1H, d), 6.50 (1H, d), 4.82-4.76 (2H, m), 4.62 (2H, s), 4.34 (1H, d), 4.31 (1H, d), 3.99-3.90 (1H, m), 3.90-3.82 (2H, m), 3.77-3.70 (1H, m), 3.68-3.61 (1H, m), 3.38 (2H, t), 2.98 (6H, s), 1.89-1.81 (2H, m), 1.60-1.48 (2H, m). LC-MS: [M+H].sup.+=566.

Example 304: Methyl 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetate

[1597] ##STR01397##

[1598] The title compound was prepared using a similar procedure to Preparation 4.

[1599] 1H NMR (400 Mz, Me-d3-OD): 8.36 (1H, s), 8.24 (1H, s), 8.10 (1H, dd), 7.73 (1H, dd), 4.69 (2H, s), 4.49 (2H, s), 4.11-4.02 (1H, m), 4.02-3.95 (2H, m), 3.80 (3H, s), 3.59-3.51 (2H, m), 2.06-1.98 (2H, m), 1.70-1.58 (2H, m). LC-MS: [M+H].sup.+=417.

Examples 305-316

[1600] Prepared using an analogous procedure to Example 2, from 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) and the corresponding amine:

TABLE-US-00029 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 305 [01398] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(oxan-3- yl)methyl]acetamide 1H NMR (400 MHz, CDCl3): 8.34 (1H, s), 8.30 (1H, s), 8.02 (1H, dd), 7.57 (1H, d), 6.64 (1H, s), 5.31 (1H, d), 4.63 (2H, s), 4.28 (2H, s), 4.14-4.04 (1H, m), 4.04-3.89 (2H, m), 3.89-3.71 (2H, m), 3.63-3.46 (2H, m), 3.45-3.30 (1H, m), 3.25-3.07 (3H, m), 2.12-1.97 (2H, m), 1.83-1.76 (2H, m), 1.70-1.36 (4H, m), 1.34-1.17 (1H, m). 500 306 [01399] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(oxan-4- yl)methyl]acetamide 1H NMR (400 MHz, CDCl3): 8.35 (1H, s), 8.33 (1H, s), 8.04 (1H, dd), 7.60 (1H, d), 6.49 (1H, s), 5.18 (1H, d), 4.64 (2H, s), 4.28 (2H, s), 4.17-4.06 (1H, m), 4.06-3.92 (4H, m), 3.61-3.48 (3H, m), 3.42-3.30 (2H, m), 3.23-3.11 (2H, m), 2.12-2.04 (2H, m), 1.83-1.70 (1H, m), 1.59-1.54 (2H, m), 1.38-1.20 (3H, m). 500 307 [01400] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- {[(1S,2S)-2- hydroxycyclo- hexyl]methyl}acetamide 1H NMR (400 MHz, CDCl3): 8.39-8.32 (1H, m), 8.30 (1H, s), 8.03 (1H, d), 7.58 (1H, d), 6.82 (1H, s), 5.33-5.17 (1H, m), 4.72- 4.52 (2H, m), 4.39-4.18 (2H, m), 4.18-3.88 (3H, m), 3.88-3.71 (1H, m), 3.64-3.47 (3H, m), 3.04-2.88 (1H, m), 2.07 (2H, d), 1.88-1.67 (5H, m), 1.65-1.53 (4H, m), 1.48-1.38 (3H, m). 514 308 [01401] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- {[(1S,2R)-2- hydroxycyclo- hexyl]methyl}acetamide 1H NMR (400 MHz, CDCl3): 8.34 (1H, s), 8.31 (1H, s), 8.03 (1H, dd), 7.59 (1H, d), 7.06 (1H, s), 5.26 (1H, d), 4.64 (2H, s), 4.30 (2H, d), 4.14-3.95 (3H, m), 3.87-3.75 (1H, m), 3.61-3.46 (2H, m), 3.24-3.15 (1H, m), 2.97-2.86 (1H, m), 2.06 (2H, d), 1.91 (1H, d), 1.73-1.52 (6H, m), 1.46-1.33 (1H, m), 1.33-1.11 (3H, m), 1.11-0.96 (1H, m). 514 309 [01402] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- (cyclohexyl- methyl)acetamide 1H NMR (400 MHz, CDCl3): 8.35 (1H, s), 8.33 (1H, s), 8.04 (1H, dd), 7.60 (1H, d), 6.32 (1H, s), 5.18 (1H, d), 4.63 (2H, s), 4.28 (2H, s), 4.17-3.96 (3H, m), 3.62-3.49 (2H, m), 3.12 (2H, t), 2.07 (2H, d), 1.70 (5H, d), 1.53- 1.38 (2H, m), 1.33-1.13 (4H, m), 0.98-0.86 (2H, m). 498 310 [01403] N-[(1-acetylpiperidin- 3-yl)methyl]-2-(6-{5- chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2- yl)acetamide 1H NMR (400 MHz, CDCl3): 8.32 (1H, d), 8.26 (1H, d), 8.04- 7.94 (1H, m), 7.56 (1H, d), 7.09 (1H, s), 4.64 (2H, s), 4.30 (2H, d), 4.10-4.02 (2H, m), 3.99 (2H, d), 3.58-3.50 (3H, m), 3.40-3.24 (1H, m), 3.24-3.08 (1H, m), 3.08-2.94 (1H, m), 2.86-2.70 (1H, m), 2.41-2.22 (2H, m), 2.06-2.04 (2H, m), 2.00 (3H, s), 1.82 (1H, d), 1.77-1.64 (2H, m), 1.64-1.50 (2H, m). 541 311 [01404] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1- cyclohexylethyl]acetamide 1H NMR (400 MHz, CDCl3): 8.35 (1H, s), 8.34 (1H, s), 8.04 (1H, dd), 7.60 (1H, d), 6.07 (1H, d), 5.16 (1H, d), 4.64 (2H, s), 4.34-4.18 (2H, m), 4.17-4.05 (1H, m), 4.05-3.94 (2H, m), 3.92-3.80 (1H, m), 3.62-3.53 (2H, m), 3.51 (3H, d), 2.08 (2H, d), 1.77-1.67 (3H, m), 1.67-1.59 (3H, m), 1.38-1.26 (1H, m), 1.10 (3H, d), 1.00-0.90 (3H, m). 512 312 [01405] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1- hydroxycyclo- hexyl)methyl]acetamide 1H NMR (400 MHz, CDCl3): 8.35 (1H, s), 8.34 (1H, s), 8.04 (1H, dd), 7.60 (1H, d), 6.61-6.46 (1H, m), 5.15 (1H, d), 4.65 (2H, s), 4.33 (2H, s), 4.20-4.05 (1H, m), 4.05-3.93 (2H, m), 3.66-3.45 (2H, m), 3.32 (2H, d), 2.08 (2H, d), 1.66-1.60 (2H, m), 1.47-1.38 (3H, m), 1.38-1.20 (4H, m), 0.94-0.79 (3H, m). 514 313 [01406] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- {[1- (hydroxymethyl)cyclo- hexyl]methyl}acetamide 1H NMR (400 MHz, CDCl3): 8.36 (1H, s), 8.33 (1H, s), 8.05 (1H, dd), 7.61 (1H, d), 6.79 (1H, d), 5.17 (1H, d), 4.64 (2H, s), 4.31 (2H, s), 4.17-4.05 (1H, m), 4.05-3.91 (2H, m), 3.66-3.46 (2H, m), 3.31 (2H, d), 3.25 (3H, t), 2.07 (2H, d), 1.45 (6H, s), 1.39-1.32 (2H, m), 1.32-1.22 (3H, m). 528 314 [01407] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1-methyl-2- oxopiperidin-3- yl)methyl]acetamide 1H NMR (400 MHz, CDCl3): 8.35 (1H, s), 8.34 (1H, s), 8.04 (1H, dd), 7.60 (1H, d), 6.06 (1H, d), 5.16 (1H, d), 4.64 (2H, s), 4.37-4.19 (2H, m), 4.16-4.05 (1H, m), 4.05-3.96 (2H, m), 3.92-3.80 (1H, m), 3.62-3.53 (2H, m), 3.51 (3H, d), 2.08 (2H, d), 1.75-1.60 (6H, m), 1.38-1.11 (4H, m), 0.99-0.91 (3H, m). 528 315 [01408] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [2,2,2-trifluoro-1-(3- methoxy- phenyl)ethyl]acetamide 1H NMR (400 MHz, Me-d3-OD): 8.33 (1H, s), 8.22 (1H, s), 8.05 (1H, dd), 7.67 (1H, d), 7.34 (1H, t), 7.09 (2H, d), 7.04-6.94 (1H, m), 5.73 (1H, q), 4.65 (2H, s), 4.57-4.42 (2H, m), 4.08-3.90 (3H, m), 3.83 (3H, s), 3.60-3.46 (2H, m), 2.02-1.96 (2H, m), 1.70-1.54 (2H, m). 591 316 [01409] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(S)-(1- hydroxycyclopro- pyl)(phenyl)methyl]acetamide 1H NMR (400 MHz, Me-d3-OD): 8.30 (1H, s), 8.21 (1H, s), 8.01 (1H, d), 7.62 (1H, d), 7.44 (2H, d), 7.39-7.29 (2H, m), 7.25 (1H, t), 4.80 (1H, s), 4.61 (2H, s), 4.54-4.36 (2H, m), 4.06-3.88 (3H, m), 3.50 (2H, t), 1.97 (2H, d), 1.80-1.51 (2H, m), 0.85-0.64 (4H, m). 549

Example 317: N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]-2-(6-{2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamide

[1601] ##STR01410##

[1602] Prepared using a method analogous to Preparation 4 from 2-[6-(2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide (Preparation 167) with EtOH as solvent. 1H NMR (400 MHz, CDCl.sub.3): 8.47 (1H, s), 8.39 (1H, d), 8.29 (1H, dd), 7.57 (1H, d), 7.25 (1H, t), 7.12 (1H, d), 7.05 (1H, d), 6.89 (1H, d), 6.85 (1H, d), 6.82 (1H, dd), 5.20 (1H, d), 5.08 (1H, q), 4.77-4.53 (2H, m), 4.44-4.28 (2H, m), 4.27-4.11 (1H, m), 4.09-3.98 (2H, m), 3.94-3.82 (2H, m), 3.78 (3H, s), 3.68-3.54 (2H, m), 2.12 (2H, d), 1.70-1.64 (2H, m). MS: [M+H].sup.+=518.

Examples 318-325

[1603] Prepared using a method analogous to Preparation 4 from 2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide (Preparation 169) with EtOH as solvent.

TABLE-US-00030 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 318 [01411] 2-(6-{5-chloro-2- [(oxolan-3- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(3- methoxyphenyl)ethyl]- acetamide 1H NMR (400 MHz, CDCl3): 8.36 (1H, s), 8.33 (1H, s), 8.04 (1H, d), 7.57 (1H, d), 7.25 (1H, t), 7.20 (1H, d), 6.89 (1H, d), 6.85 (1H, s), 6.81 (1H, dd), 5.49 (1H, d), 5.07 (1H, q), 4.76-4.57 (3H, m), 4.43-4.24 (2H, m), 4.05-3.97 (2H, m), 3.92-3.85 (3H, m), 3.83-3.73 (5H, m), 2.44-2.29 (1H, m), 1.98-1.87 (1H, m). 538 319 [01412] 2-[6-(5-chloro-2- {[(oxolan-3- yl)methyl]amino}- pyrimidin-4-yl)-1-oxo-2,3- dihydro-1H-isoindol-2- yl]-N-[(1S)-2-hydroxy- 1-(3- methoxyphenyl)ethyl]- acetamide 1H NMR (400 MHz, CDCl3): 8.38-8.33 (1H, m), 8.32 (1H, s), 8.04 (1H, d), 7.57 (1H, d), 7.24 (1H, t), 7.18 (1H, d), 6.89 (1H, d), 6.85 (1H, d), 6.81 (1H, dd), 5.42 (1H, s), 5.08 (1H, q), 4.75-4.49 (2H, m), 4.49-4.23 (2H, m), 3.98-3.80 (5H, m), 3.80-3.71 (4H, m), 3.71-3.60 (1H, m), 3.53-3.46 (3H, m), 2.16-2.05 (1H, m), 1.76-1.67 (1H, m). 552 320 [01413] 2-[6-(5-chloro-2- {[(oxolan-2- yl)methyl]amino}- pyrimidin-4-yl)-1-oxo-2,3- dihydro-1H-isoindol-2- yl]-N-[(1S)-2-hydroxy- 1-(3- methoxyphenyl)ethyl]- acetamide 1H NMR (400 MHz, CDCl3): 8.34 (1H, s), 8.32 (1H, s), 8.04 (1H, d), 7.55 (1H, d), 7.27-7.15 (2H, m), 6.89 (1H, d), 6.85 (1H, d), 6.81 (1H, dd), 5.61 (1H, d), 5.08 (1H, q), 4.76-4.55 (2H, m), 4.45-4.28 (2H, m), 4.22-4.04 (1H, m), 3.98-3.82 (3H, m), 3.80 (1H, d), 3.77 (3H, s), 3.74-3.65 (1H, m), 3.55-3.43 (2H, m), 1.97 (3H, s), 1.73-1.66 (1H, m). 552 321 [01414] 2-(6-{2-[(1- acetylazetidin-3- yl)amino]-5- chloropyrimidin-4-yl}- 1-oxo-2,3-dihydro-1H- isoindol-2-yl)-N-[(1S)- 2-hydroxy-1-(3- methoxyphenyl)ethyl]- acetamide 1H NMR (400 MHz, CDCl3): 8.39 (1H, s), 8.34 (1H, s), 8.06 (1H, d), 7.59 (1H, d), 7.25 (1H, d), 6.89 (1H, d), 6.86 (1H, s), 6.82 (1H, dd), 5.15-4.97 (1H, m), 4.81-4.55 (3H, m), 4.53- 4.23 (4H, m), 4.10-3.96 (1H, m), 3.88 (3H, s), 3.81-3.71 (3H, m), 2.86-2.57 (1H, m), 1.89 (3H, s). 565 322 [01415] 2-[6-(5-chloro-2- {[(1S,2S)-2- hydroxycyclohexyl]- amino}pyrimidin-4-yl)-1- oxo-2,3-dihydro-1H- isoindol-2-yl]-N-[(1S)- 2-hydroxy-1-(3- methoxyphenyl)ethyl]- acetamide 1H NMR (400 MHz, CDCl3): 8.29 (1H, d), 8.20 (1H, s), 7.97 (1H, d), 7.62-7.41 (2H, m), 7.21 (1H, t), 6.96-6.83 (2H, m), 6.78 (1H, dd), 5.13-5.00 (1H, m), 4.86 (1H, s), 4.77-4.50 (2H, m), 4.50-4.22 (2H, m), 4.22-3.99(1H, m), 3.95 (1H, d), 3.91-3.77 (3H, m), 3.75 (3H, s), 3.73-3.59 (2H, m), 3.28-2.95 (2H, m), 2.13-2.02 (2H, m), 1.75-1.58 (2H, m). 566 323 [01416] 2-(6-{2-[(1- acetylpiperidin-4- yl)amino]-5- chloropyrimidin-4-yl}- 1-oxo-2,3-dihydro-1H- isoindol-2-yl)-N-[(1S)- 2-hydroxy-1-(3- methoxyphenyl)ethyl]- acetamide 1H NMR (400 MHz, CDCl3): 8.35 (1H, s), 8.31 (1H, s), 8.02 (1H, dd), 7.57 (1H, d), 7.25 (1H, t), 6.89 (1H, d), 6.85 (1H, s), 6.81 (1H, dd), 5.08 (1H, q), 4.75-4.56 (2H, m), 4.54-4.27 (3H, m), 3.95-3.81 (3H, m), 3.77 (3H, s), 3.34-3.10 (1H, m), 3.10-2.68 (3H, m), 2.21- 2.01 (5H, m), 1.55-1.22 (2H, m). 593 324 [01417] 2-[6-(5-chloro-2- {[trans-4- methoxycyclohexyl]- amino}pyrimidin-4-yl)-1- oxo-2,3-dihydro-1H- isoindol-2-yl]-N-[(1S)- 2-hydroxy-1-(3- methoxyphenyl)ethyl]- acetamide 1H NMR (400 MHz, CDCl3): 8.31 (1H, s), 8.24 (1H, s), 7.97 (1H, d), 7.61 (1H, s), 7.50 (1H, d), 7.20 (1H, t), 6.95-6.83 (2H, m), 6.76 (1H, dd), 5.28 (1H, s), 5.07 (1H, s), 4.74-4.50 (2H, m), 4.50-4.20 (2H, m), 3.99- 3.76 (3H, m), 3.73 (3H, s), 3.36 (3H, s), .28-3.09 (1H, m), 2.13 (5H, dd), 1.47-1.26 (4H, m). 580 325 [01418] 2-[6-(5-chloro-2-{[(2S)- 1-hydroxypropan-2- yl]amino}pyrimidin-4- yl)-1-oxo-2,3-dihydro- 1H-isoindol-2-yl]-N- [(1S)-2-hydroxy-1-(3- methoxyphenyl)ethyl]- acetamide 1H NMR (400 MHz, CDCl3): 8.29 (1H, s), 8.23 (1H, s), 7.99 (1H, dd), 7.62 (1H, d), 7.50 (1H, d), 7.21 (1H, t), 6.92-6.82 (2H, m), 6.78 (1H, dd), 5.59 (1H, s), 5.11-5.02 (1H, m), 4.75-4.49 (2H, m), 4.48-4.22 (2H, m), 4.23-4.10 (1H, m), 3.92-3.79 (2H, m), 3.77-3.61 (7H, m), 1.27 (3H, d). 526

Examples 326-328

[1604] Prepared using a method analogous to Preparation 4 from 2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S,2S)-2-hydroxy-1-phenylpropyl]acetamide (Preparation 170) with EtOH as solvent.

TABLE-US-00031 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 326 [01419] 2-[6-(5-chloro-2-{[(2S)- 1-hydroxypropan-2- yl]amino}pyrimidin-4- yl)-1-oxo-2,3-dihydro- 1H-isoindol-2-yl]-N- [(1S,2S)-2-hydroxy-1- phenylpropyl]- acetamide 1H NMR (400 MHz, CDCl3): 8.30 (1H, s), 8.27 (1H, s), 8.01 (1H, dd), 7.60-7.40 (2H, m), 7.30-7.28 (4H, m), 7.27-7.18 (1H, m), 5.55 (1H, d), 4.88 (1H, dd), 4.77-4.49 (2H, m), 4.49-4.24 (2H, m), 4.24-4.12 (1H, m), 4.12-4.01 (1H, m), 3.80-3.61 (2H, m), 3.31-3.18 (1H, m), 1.28 (3H, d), 1.18 (3H, d). 510 327 [01420] 2-(6-{5-chloro-2- [(oxetan-3- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S,2S)-2-hydroxy-1- phenylpropyl]- acetamide 1H NMR (400 MHz, Me-d3- OD): 8.38 (1H, s), 8.24 (1H, s), 8.07 (1H, d), 7.69 (1H, d), 7.43-7.31 (4H, m), 7.31-7.21 (1H, m), 5.13-5.03 (1H, m), 4.95 (2H, t), 4.73-4.57 (4H, m), 4.57-4.29 (2H, m), 4.09-3.99 (1H, m), 3.39-3.34 (1H, m), 1.46-1.19 (1H, m), 1.13 (3H, d). 508 328 [01421] 2-[6-(5-chloro-2- {[trans-4- methoxycyclohexyl]- amino}pyrimidin-4-yl)-1- oxo-2,3-dihydro-1H- isoindol-2-yl]-N- [(1S,2S)-2-hydroxy-1- phenylpropyl] acetamide 1H NMR (400 MHz, Me-d3- OD): 8.34 (1H, s), 8.23 (1H, s), 8.10-8.03 (1H, m), 7.70 (1H, d), 7.43-7.30 (4H, m), 4.66 (2H, s), 4.52-4.36 (2H, m), 4.09-4.00 (1H, m), 3.81 (1H, d), 3.37 (3H, s), 3.32-3.19 (3H, m), 2.18-2.03 (4H, m), 1.46- 1.27 (4H, m), 1.12 (3H, d). 564

Example 329: 2-[6-(5-chloro-2-{[trans-4-hydroxycyclohexyl]amino}pyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1R)-1-(3-methoxyphenyl)ethyl]acetamide

[1605] ##STR01422##

[1606] Prepared using a method analogous to Preparation 4 from 2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1R)-1-(3-methoxyphenyl)ethyl]acetamide (Preparation 171) with EtOH as solvent. 1H NMR (400 MHz, CDCl.sub.3): 8.33 (1H, s), 8.29 (1H, s), 8.02 (1H, d), 7.55 (1H, d), 7.20 (1H, t), 7.03-6.85 (2H, m), 6.82 (1H, s), 6.76 (1H, dd), 5.39 (1H, d), 5.14-5.02 (1H, m), 4.72-4.52 (2H, m), 4.30 (2H, s), 3.94 (2H, d), 3.75 (3H, s), 1.85-1.72 (8H, m), 1.47 (3H, d). MS: [M+H].sup.+=564.

Examples 330 and 331: 6-{5-chloro-2-[(oxan-4-yl)amino]pyridin-4-yl}-2-{2-[(3S)-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl]-2-oxoethyl}-2,3-dihydro-1H-isoindol-1-one and 6-{5-chloro-2-[(oxan-4-yl)amino]pyridin-4-yl}-2-{2-[(3R)-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl]-2-oxoethyl}-2,3-dihydro-1H-isoindol-1-one

[1607] ##STR01423##

[1608] Example 186 (106 mg, 0.20 mmol) was separated using chiral, preparative HPLC to give the two enantiomers as colourless solids.

[1609] Example 330 (3 mg) 1H NMR (400 MHz, Me-d3-OD): 8.76 (1H, s), 8.64-8.57 (1H, m), 8.28 (1H, s), 7.68 (1H, d), 7.27-7.20 (4H, m), 5.15-4.98 (1H, m), 4.74-4.64 (6H, m), 4.41-4.28 (1H, m), 4.14-3.92 (2H, m), 3.73-3.63 (2H, m), 3.20-3.05 (1H, m), 2.84-2.69 (1H, m), 2.05 (3H, d), 1.87-1.71 (2H, m), 1.12 (3H, d). MS: [M+H].sup.+=531.

[1610] Example 331 (3 mg) 1H NMR (400 MHz, Me-d3-OD): 8.76 (1H, s), 8.67-8.52 (1H, m), 8.32-8.27 (1H, m), 7.69 (1H, d), 7.27-7.20 (4H, m), 5.10-4.97 (1H, m), 4.73-4.66 (6H, m), 4.41-4.27 (1H, m), 4.05 (2H, d), 3.68 (2H, dd), 3.19-3.04 (1H, m), 2.81-2.70 (1H, m), 2.09-1.99 (3H, m), 1.84-1.73 (2H, m), 1.12 (3H, d). MS: [M+H].sup.+=531.

Example 332: 6-(5-chloro-2-{[2-(propan-2-yl)oxan-4-yl]amino}pyrimidin-4-yl)-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1611] ##STR01424##

[1612] Prepared in an analogous manner to Examples 159-179 using racemic 2-iso-propyloxan-4-amine as a 1:1 mixture of diastereomers. 1H NMR (400 MHz, Me-d3-OD): 8.41-8.30 (1H, m), 8.30-8.15 (1H, m), 8.09 (1H, t), 7.75-7.64 (1H, m), 7.29-7.11 (4H, m), 5.50 (2H, s), 4.71 (2H, d), 4.68 (2H, s), 4.36-4.26 (1H, m), 3.94-3.72 (4H, m), 3.47-3.38 (1H, m), 3.08-2.97 (1H, m), 2.97-2.85 (1H, m), 2.04 (2H, s), 1.96-1.61 (4H, m), 1.07-0.83 (6H, m). MS: [M+H].sup.+=560.

Example 333: 2-(6-{5-bromo-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide

[1613] ##STR01425##

[1614] Prepared from 2-(6-{5-bromo-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Preparation 175) and the corresponding amine in a manner analogous to Preparation 2. 1H NMR (400 MHz, CDCl.sub.3): 8.44 (1H, s), 8.20 (1H, s), 7.93 (1H, d), 7.58-7.40 (2H, m), 7.21 (1H, t), 6.95-6.83 (2H, m), 6.83-6.72 (1H, m), 5.35 (1H, d), 5.08 (1H, q), 4.77-4.52 (2H, m), 4.52-4.20 (2H, m), 4.20-3.93 (3H, m), 3.93-3.79 (2H, m), 3.74 (3H, s), 3.54 (2H, t), 2.05 (2H, d), 1.67-1.48 (2H, m). MS: [M+H].sup.+=596.

Example 334: 2-(6-{5-bromo-2-[(propan-2-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide

[1615] ##STR01426##

[1616] Prepared from 2-[6-(5-bromo-2-chloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide (Preparation 176) and iso-propylamine in a manner analogous to Preparation 4. 1H NMR (400 MHz, CDCl.sub.3): 8.45 (1H, s), 8.29 (1H, s), 8.04-7.92 (1H, m), 7.58 (1H, d), 7.26-7.24 (1H, m), 7.07-6.94 (1H, m), 6.88 (1H, d), 6.86-6.77 (2H, m), 5.13-5.01 (2H, m), 4.73-4.55 (2H, m), 4.35 (2H, d), 4.23-4.12 (1H, m), 3.94-3.84 (2H, m), 3.78 (3H, s), 1.28 (6H, d). MS: [M+H].sup.+=554.

Examples 335 and 336

[1617] Prepared in a similar manner to Example 334 from Preparations 177 and 178.

TABLE-US-00032 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 335 [01427] 2-[6-(5-bromo-2- {[(2S)-1- hydroxypropan-2- yl]amino}pyrimidin-4- yl)-1-oxo-2,3-dihydro- 1H-isoindol-2-yl]-N- [(1R)-1-(3- methoxyphenyl)ethyl]- acetamide 1H NMR (400 MHz, CDCl3): 8.41 (1H, s), 8.21 (1H, s), 7.95 (1H, dd), 7.53 (1H, d), 7.20 (1H, t), 6.91 (1H, d), 6.87 (1H, d), 6.83 (1H, s), 6.76 (1H, dd), 5.51 (1H, d), 5.14-5.03 (1H, m), 4.68-4.51 (2H, m), 4.29 (2H, s), 4.24-4.10 (1H, m), 3.81-3.62 (5H, m), 1.47 (3H, d), 1.29 (3H, d). 554 336 [01428] 2-(6-{5-bromo-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S,2S)-2-hydroxy-1- phenylpropyl]- acetamide 1H NMR (400 MHz, CDCl3): 8.43 (1H, s), 8.21 (1H, s), 7.93 (1H, dd), 7.51 (2H, dd), 7.29 (3H, s), 7.27-7.19 (1H, m), 5.41- 5.29 (1H, m), 4.91-4.81 (1H, m), 4.71-4.54 (2H, m), 4.45-4.26 (2H, m), 4.10- 4.02 (2H, m), 3.53 (2H, t), 3.42-3.35 (1H, m), 1.76 (2H, dd), 1.63-1.52 (2H, m), 1.42-1.34 (1H, m), 1.18 (4H, d). 580

Example 337: (2R)-2-(6-{5-chloro-2-[(propan-2-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-3-hydroxy-N-[(1R)-1-(3-methoxyphenyl)ethyl]propanamide

[1618] ##STR01429##

[1619] A stirred solution of methyl 2-(bromomethyl)-5-(2,5-dichloropyrimidin-4-yl)benzoate (Preparation 180, 100 mg, 0.27 mmol), (2R)-2-amino-3-hydroxy-N-[(1R)-1-(3-methoxyphenyl)ethyl]propanamide (Preparation 182, 95 mg, 0.4 mmol) and DIPEA (0.09 mL, 0.5 mmol) in MeCN (3 mL) was heated to 90° C. for 3 hours. iso-Propylamine (0.1 mL, 1.17 mmol) was added and heating continued overnight. The reaction was concentrated and partitioned between water (10 mL) and EtOAc (10 mL). The aqueous fraction was further extracted with EtOAc (2×10 mL) and the combined organic fractions were dried over magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase column chromatography (20-60% MeCN in water) to give the title compound (52 mg, 37%). 1H NMR (400 MHz, CDCl3): 8.38-8.25 (2H, m), 8.05 (1H, d), 7.61-7.52 (1H, m), 7.26 (1H, d), 7.20 (1H, d), 6.91 (1H, d), 6.87 (1H, d), 6.81 (1H, dd), 5.12 (1H, d), 5.09-5.00 (1H, m), 4.92 (1H, t), 4.85-4.72 (2H, m), 4.27-4.12 (2H, m), 4.06 (1H, d), 3.80 (4H, d), 1.44 (3H, d), 1.28 (6H, d). MS: [M+H].sup.+=524

Examples 338-343

[1620] The following compounds were made from methyl 2-(bromomethyl)-5-(2,5-dichloropyrimidin-4-yl)benzoate (Preparation 180) in a similar way to example 337 using the appropriate amine (Preparations 183-187) and oxan-4-amine.

TABLE-US-00033 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 338 [01430] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-3- hydroxy-N-[(1S)-2- hydroxy-1-(3- methoxyphenyl)ethyl]- propanamide 1H NMR (400 MHz, Me- d3-OD): 8.35 (1H, s), 8.31-8.21 (1H, m), 8.12- 8.02 (1H, m), 7.75-7.66 (1H, m), 7.26 (1H, t), 7.00-6.88 (2H, m), 6.88- 6.81 (1H, m), 5.11 (1H, dd), 5.00 (1H, dd), 4.89 (1H, d), 4.78-4.72 (1H, m), 4.18-4.02 (3H, m), 3.98 (2H, d), 3.89-3.79 (3H, m), 3.79-3.70 (2H, m), 3.54 (2H, dd), 2.02 (2H, d), 1.71-1.55 (2H, m). 582 339 [01431] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(2-fluoro-5- methoxyphenyl)- propyl]-3- hydroxypropanamide 1H NMR (400 MHz, Me- d3-OD): 8.49-828 (1H, m), 8.28-8.14 (1H, m), 8.07 (1H, d), 7.71 (1H, d), 7.00 (1H, t), 6.96- 6.88 (1H, m), 6.86-6.76 (1H, m), 5.09 (1H, t), 5.06-5.01 (1H, m), 4.18- 3.90 (7H, m), 3.79 (3H, s), 3.54 (2H, t), 3.43 (1H, t), 2.09-1.94 (2H, m), 1.86-1.79 (2H, m), 1.75-1.54 (2H, m), 1.53- 1.39 (1H, m), 1.01-0.81 (3H, m). 598 340 [01432] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-2,3-dihydro-1H- inden-1-yl]-3- hydroxypropanamide 1H NMR (400 MHz, CDCl3): 8.35-8.29 (1H, m), 8.15 (1H, s), 8.02- 7.94 (1H, m), 7.59-7.51 (1H, m), 7.28-7.22 (1H, m), 7.22-7.14 (3H, m), 5.50-5.30 (2H, m), 5.07- 4.99 (1H, m), 4.77 (2H, s), 4.30-4.16 (1H, m), 4.16-4.04 (2H, m), 4.00 (2H, d), 3.54 (2H, t), 3.07-2.89 (1H, m), 2.89- 2.75 (1H, m), 2.63-2.46 (1H, m), 2.09-2.01 (2H, m), 1.83-1.72 (1H, m), 1.69-1.50 (2H, m). 548 341 [01433] (2R)-N-[(1R)-1-(2H- 1,3-benzodioxol-5- yl)ethyl]-2-(6-{5- chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-3- hydroxypropanamide 1H NMR (400 MHz, CDCl3): 8.35 (1H, s), 8.32 (1H, s), 8.06 (1H, d), 7.65 (1H, d), 6.95 (1H, d), 6.79 (3H, d), 5.96 (2H, s), 5.07-4.93 (1H, m), 4.89 (1H, d), 4.88-4.66 (2H, m), 4.27 (1H, dd), 4.21-4.10 (1H, m), 4.10-3.94 (3H, m), 3.62-3.48 (2H, m), 1.69 (2H, d), 1.42 (3H, d) 0.96-0.79 (2H, m). 580 342 [01434] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino[pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-3- hydroxy-N-[(1R)-1-(3- methylphenyl)ethyl]- propanamide 1H NMR (400 MHz, CDCl3): 8.38-8.33 (1H, m), 8.30 (1H, s), 8.03 (1H, dd), 7.59 (1H, d), 7.27-7.20 (1H, m), 7.17- 7.06 (4H, m), 5.24 (1H, d), 5.10-4.99 (1H, m), 4.99-4.89 (1H, m), 4.87- 4.66 (2H, m), 4.23 (1H, dd), 4.14-3.95 (4H, m), 3.62-3.51 (2H, m), 2.35 (3H, s), 2.13-2.04 (2H, m), 1.63-1.54 (2H, m), 1.44 (3H, d). 550 343 [01435] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(3- methoxyphenyl)ethyl]- butanamide 1H NMR (400 MHz, Me- d3-OD): 8.35 (1H, s), 8.22 (1H, s), 8.08 (1H, dd), 7.72 (1H, d), 7.31- 7.21 (1H, m), 6.98-6.88 (2H, m), 6.84 (1H, dd), 5.14-5.10 (1H, m), 4.97 (1H, t), 4.86 (1H, d), 4.70 (1H, d), 4.12-4.01 (1H, m), 4.01-3.90 (2H, m), 3.82 (3H, s), 3.79- 3.66 (2H, m), 3.60-3.52 (2H, m), 2.01 (2H, d), 1.70-1.52 (4H, m), 1.14 (3H, t). 566

Examples 344-367

[1621] The following were prepared in an analogous manner to Preparation 4 using the appropriate dichloropyrimidine (Preparations 207-224, 227) and the corresponding amine with EtOH as solvent.

TABLE-US-00034 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 344 [01436] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-3- hydroxy-N-[(1R)-1-[3- (trifluoromethyl)phenyl]- ethyl]propanamide 1H NMR (400 MHz, CDCl3): 8.31 (1H, s), 8.18 (1H, s), 7.96 (1H, d), 7.89 (1H, d), 7.59 (1H, s), 7.56-7.46 (3H, m), 7.42 (1H, t), 5.46 (1H, d), 5.17-5.03 (2H, m), 4.87-4.64 (2H, m), 4.64-4.64 (1H, m), 4.09- 3.94 (5H, m), 3.53 (2H, t), 2.04 (2H, d), 1.57 (2H, dd), 1.48 (3H, d). 604 345 [01437] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(2-fluoro-5- methoxyphenyl)ethyl]- 3- hydroxypropanamide 1H NMR (400 MHz, CDCl3): 8.36 (1H, s), 8.33 (1H, s), 8.04 (1H, dd), 7.59 (1H, d), 7.21 (1H, d), 6.98 (1H, t), 6.82 (1H, dd), 6.79-6.72 (1H, m), 5.26-5.16 (2H, m), 4.90 (1H, t), 4.87- 4.67 (2H, m), 4.26 (1H, dd), 4.12-3.95 (5H, m), 3.79 (3H, s), 3.62-3.51 (2H, m), 2.08 (2H, d), 1.65-1.58 (2H, m), 1.46 (3H, d). 584 346 [01438] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(3- ethoxyphenyl)ethyl]-3- hydroxypropanamide 1H NMR (400 MHz, CDCl3): 8.34 (1H, s), 8.27 (1H, s), 8.01 (1H, dd), 7.56 (1H, d), 7.29 (1H, d), 7.23 (1H, t), 6.89 (1H, d), 6.86 (1H, d), 6.78 (1H, dd), 5.37- 5.22 (1H, m), 5.09-5.00 (1H, m), 5.00-4.92 (1H, m), 4.83-4.70 (2H, m), 4.19 (1H, dd), 4.16-3.97 (7H, m), 3.56 (2H, t), 2.09-2.04 (2H, m), 1.66- 1.52 (2H, m), 1.44 (3H, d), 1.40 (3H, t). 580 347 [01439] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-3- hydroxy-N-[(1S,2S)-2- hydroxy-1- phenylpropyl]- propanamide 1H NMR (400 MHz, CDCl3): 8.32 (1H, s), 8.22 (1H, s), 8.03 (1H, d), 7.97 (1H, dd), 7.50 (1H, d), 7.36-7.30 (3H, m), 7.27-7.20 (1H, m), 5.45 (1H, s), 5.21-5.11 (1H, m), 4.92-4.66 (3H, m), 4.17-3.92 (7H, m), 3.54 (2H, t), 2.04 (2H, d), 1.66-1.47 (2H, m), 1.45-1.22 (1H, m), 1.10 (3H, d). 566 348 [01440] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-[3- (difluoromethyl)- phenyl]ethyl]-3- hydroxypropanamide 1H NMR (400 MHz, CDCl3): 8.34 (1H, s), 8.25 (1H, s), 8.00 (1H, dd), 7.55 (2H, d), 7.49- 7.38 (4H, m), 6.63 (1H, t), 5.32 (1H, d), 5.15- 5.04 (1H, m), 5.00 (1H, t), 4.76 (2H, s), 4.17 (1H, dd), 4.13-3.94 (5H, m), 3.60-3.50 (2H, m), 2.06 (2H, d), 1.66-1.51 (2H, m), 1.48 (3H, d). 586 349 [01441] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-[3- (difluoromethoxy)- phenyl]ethyl]-3- hydroxypropanamide 1H NMR (400 MHz, CDCl3): 8.35 (1H, s), 8.28 (1H, s), 8.02 (1H, dd), 7.57 (1H, d), 7.38 (1H, d), 7.33 (1H, t), 7.18 (1H, d), 7.09 (1H, s), 7.02 (1H, d), 6.53 (1H, t), 5.26 (1H, d), 5.11-5.01 (1H, m), 4.95 (1H, t), 4.84-4.69 (2H, m), 4.22 (1H, dd), 4.11- 3.98 (4H, m), 3.61-3.51 (2H, m), 2.14-2.03 (2H, m), 1.63-1.57 (2H, m), 1.46 (3H, d). 602 350 [01442] (2R)-2-{6-[5-chloro-2- (methylamino)- pyrimidin-4-yl]-1-oxo-2,3- dihydro-1H-isoindol-2- yl}-3-hydroxy-N-[(1R)- 1-(3- methoxyphenyl)ethyl]- propanamide 1H NMR (400 MHz, CDCl3): 8.35 (1H, s), 8.29 (1H, s), 8.04 (1H, d), 7.55 (1H, d), 7.32 (1H, d), 7.26 (1H, t), 6.92 (1H, d), 6.88 (1H, d), 6.80 (1H, dd), 5.31 (1H, s), 5.10-4.99 (1H, m), 4.96 (1H, t), 4.83- 4.69 (2H, m), 4.21 (1H, dd), 4.05 (1H, dd), 3.80 (3H, s), 3.05 (3H, d), 1.45 (3H, d). 496 351 [01443] (2R)-2-[6-(5-chloro-2- {[(2S)-1- hydroxypropan-2- yl]amino}pyrimidin-4- yl)-1-oxo-2,3-dihydro- 1H-isoindol-2-yl]-3- hydroxy-N-[(1R)-1-(3- methoxyphenyl)ethyl]- propanamide 1H NMR (400 MHz, CDCl3): 8.31 (1H, s), 8.28-8.20 (1H, m), 8.00 (1H, dd), 7.50 (1H, d), 7.27-7.19 (1H, m), 7.08 (1H, t), 6.76 (1H, d), 6.73-6.64 (2H, m), 5.46 (1H, d), 5.11-5.01 (1H, m), 5.01-4.92 (1H, m), 4.79-4.68 (1H, m), 4.51 (1H, d), 4.28-4.14 (2H, m), 4.06 (1H, dd), 3.82- 3.75 (1H, m), 3.68 (1H, dd), 3.62 (3H, s), 1.48 (3H, d), 1.30 (4H, d). 540 352 [01444] (2R)-2-[6-(5-chloro-2- {[trans-4- methoxycyclohexyl]- amino}pyrimidin-4-yl)-1- oxo-2,3-dihydro-1H- isoindol-2-yl]-3- hydroxy-N-[(1R)-1-(3- methoxyphenyl)ethyl]- propanamide 1H NMR (400 MHz, CDCl3): 8.33 (1H, s), 8.27 (1H, d), 8.01 (1H, t), 7.52 (1H, d), 7.18 (1H, d), 7.13-7.03 (1H, m), 6.74 (1H, d), 6.72- 6.66 (2H, m), 5.17 (1H, d), 5.10-5.00 (1H, m), 4.97 (1H, t), 4.78-4.71 (1H, m), 4.51 (1H, d), 4.24 (1H, dd), 4.06 (1H, dd), 3.91-3.82 (1H, m), 3.38 (3H, s), 3.36 (2H s), 3.26-3.17 (1H, m), 3.17-3.08 (1H, m), 2.76- 2.66 (1H, m), 2.19 (2H, d), 2.14-2.03 (4H, m), 1.89 (2H, d), 1.49 (3H, d). 594 353 [01445] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-3- hydroxy-N-[(3- methoxyphenyl)- methyl]propanamide 1H NMR (400 MHz, DMSO-d6): 8.43 (1H, s), 8.05 (1H, s), 7.98 (1H, dd), 7.76 (1H, d), 7.24- 7.17 (1H, m), 6.84-6.80 (2H, m), 6.78 (1H, dd), 4.90 (1H, dd), 4.77 (1H, d), 4.70 (1H, d), 4.27 (2H, s), 3.98-3.91 (3H, m), 3.87 (2H, d), 3.72 (3H, s), 3.43-3.32 (3H, m), 1.85 (2H, d), 1.61- 1.47 (2H, m). 552 354 [01446] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-3- hydroxy-N-[2-(3- methoxyphenyl)- propan-2-yl]propanamide 1H NMR (400 MHz, CDCl3): 8.35 (2H, d), 8.05 (1H, d), 7.59 (1H, d), 7.17 (1H, s), 7.13 (1H, d), 6.86 (1H, d), 6.82 (1H, s), 6.73 (1H, dd), 5.24 (1H, d), 4.97- 4.87 (1H, m), 4.78 (1H, d), 4.63 (1H, d), 4.21 (1H, dd), 4.03 (3H, d), 3.90-3.74 (1H, m), 3.69 (3H, s), 3.57 (2H, t), 2.13-1.96 (2H, m), 1.70 (6H, s), 1.62-1.54 (2H, m). 580 355 [01447] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(2-fluoro-5- methylphenyl)ethyl]-3- hydroxypropanamide 1H NMR (400 MHz, CDCl3): 8.35 (1H, s), 8.33 (1H, s), 8.04 (1H, dd), 7.60 (1H, d), 7.20 (1H, d), 7.08 (1H, d), 7.06-7.00 (1H, m), 6.93 (1H, dd), 5.29-5.14 (2H, m), 4.91(1H, t), 4.86- 4.67 (2H, m), 4.24 (1H, dd), 4.14-3.98 (4H, m), 3.63-3.51 (2H, m), 2.31 (3H, s), 2.07 (2H, d), 1.61-1.54 (2H, m), 1.45 (3H, d). 568 356 [01448] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(2-fluoro-3- methoxyphenyl)ethyl]- 3- hydroxypropanamide 1H NMR (400 MHz, CDCl3): 8.34 (1H, s), 8.30 (1H, s), 8.02 (1H, dd), 7.58 (1H, d), 7.34 (1H, d), 7.11-6.99 (1H, m), 6.93-6.81 (2H, m), 5.33-5.20 (2H, m), 4.96 (1H, t), 4.84-4.70 (2H, m), 4.20 (1H, dd), 4.15- 3.94 (4H, m), 3.88 (3H, s), 3.64-3.48 (2H, m), 2.07 (2H, d), 1.67-1.50 (2H, m), 1.46 (3H, d). 584 357 [01449] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(3-fluoro-5- methylphenyl)ethyl]-3- hydroxypropanamide 1H NMR (400 MHz, CDCl3): 8.36 (1H, s), 8.33 (1H, s), 8.05 (1H, dd), 7.61 (1H, d), 7.14 (1H, d), 6.90 (1H, s), 6.81 (2H, t), 5.20 (1H, d), 5.08-4.95 (1H, m), 4.90 (1H, t), 4.88-4.61 (2H, m), 4.35-4.21 (1H, m), 4.11-3.98 (4H, m), 3.69 (1H, s), 3.63-3.50 (2H, m), 2.35 (3H, s), 2.11-2.06 (2H, m), 1.60- 1.53 (2H, m), 1.42 (3H, d). 568 358 [01450] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(4-fluoro-3- methoxyphenyl)ethyl]- 3- hydroxypropanamide 1H NMR (400 MHz, CDCl3): 8.35 (1H, s), 8.31 (1H, s), 8.04 (1H, dd), 7.60 (1H, d), 7.24 (1H, d), 7.04 (1H, dd), 6.93 (1H, dd), 6.88-6.79 (1H, m), 5.23 (1H, d), 5.09-4.97 (1H, m), 4.89 (1H, t), 4.86-4.77 (2H, m), 4.28-4.19 (1H, m), 4.11-3.98 (5H, m), 3.90 (3H, s), 3.62-3.49 (2H, m), 2.07 (2H, d), 1.62- 1.54 (2H, m), 1.44 (3H, d). 584 359 [01451] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(3-fluoro-5- methoxyphenyl)ethyl]- hydroxypropanamide 1H NMR (400 MHz, CDCl3): 8.36 (1H, s), (2R)-2-(6-{5-chloro-2- 8.32 (1H, s), 8.04 (1H, dd), 7.60 (1H, d), 7.16 (1H, d), 6.71-6.58 (2H, m), 6.57-6.44 (1H, m), 5.20 (1H, d), 5.06-4.95 (1H, m), 4.90 (1H, t), 4.87-4.65 (2H, m), 4.35- 4.21 (1H, m), 4.11-3.97 (4H, m), 3.80 (3H, s), 3.74-3.64 (1H, m), 3.62- 3.49 (2H, m), 2.11-2.06 (2H, m), 1.43(3H, d). 584 360 [01452] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-3- hydroxy-N-[(1R)-1-(6- methylpyridin-2- yl)ethyl]propanamide 1H NMR (400 MHz, Me- d3-OD): 8.35 (1H, s), 8.26 (1H, s), 8.08 (1H, dd), 7.72 (1H, d), 7.67 (1H, t), 7.22 (1H, d), 7.14 (1H, d), 5.11-4.99 (2H, m), 4.87 (1H, d), 4.80-4.75 (1H, m), 4.18- 4.02 (3H, m), 3.98 (2H, d), 3.59-3.48 (2H, m), 2.47 (3H, s), 2.01 (2H, d), 1.70-1.55 (2H, m), 1.48 (3H, d). 551 361 [01453] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-3- hydroxy-N-[(1R)-1-(6- methoxypyridin-2- yl)ethyl]propanamide 1H NMR (400 MHz, CDCl3): 8.36 (1H, s), 8.32 (1H, s), 7.69 (1H, d), 7.61 (1H, d), 7.54 (1H, dd), 6.79 (1H, d), 6.61 (1H, d), 5.23 (1H, d), 5.12-5.00 (2H, m), 4.88-4.66 (2H, m), 4.31 (1H, dd), 4.15-4.06 (2H, m), 4.05-3.97 (2H, m), 3.73 (3H, s), 3.61-3.52 (2H, m), 2.08 (2H, d), 1.62-1.55 (2H, m), 1.43 (3H, d). 567 362 [01454] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-3- hydroxy-N-[(1R)-1-(5- methoxy-2- methylphenyl)ethyl]- propanamide 1H NMR (400 MHz, Me- d3-OD): 8.33 (1H, s), 8.23 (1H, d), 8.10-7.99 (1H, m), 7.66 (1H, dd), 7.03 (1H, dd), 6.90 (1H, dd), 6.76-6.59 (1H, m), 5.23-5.11 (1H, m), 5.11- 5.01 (1H, m), 4.87 (1H, d), 4.81 (5H, s), 4.76- 4.63 (1H, m), 4.15-3.84 (5H, m), 3.53 (2H, t), 2.29 (3H, d), 2.00 (2H, d), 1.71-1.54 (2H, m), 1.41 (3H, dd). 580 363 [01455] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-[5- (difluoromethyl)-2- fluorophenyl]ethyl]-3- hydroxypropanamide 1H NMR (400 MHz, Me- d3-OD): 8.34 (1H, d), 8.24 (1H, d), 8.12-8.00 (1H, m), 7.68 (1H, dd), 7.60-7.42 (1H, m), 7.42- 7.26 (1H, m), 7.26-7.18 (1H, m), 6.74 (1H, dt), 5.35-5.23 (1H, m), 5.14- 5.01 (1H, m), 4.87 (1H, d), 4.77-4.69 (1H, m), 4.23-4.01 (3H, m), 3.97 (2H, d), 3.64-3.48 (2H, m), 2.01 (2H, d), 1.70- 1.55 (2H, m), 1.51 (3H, dd). 604 364 [01456] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-3- hydroxy-N-[(1- hydroxycyclopropyl)- (phenyl)methyl]- propanamide 1H NMR (400 MHz, Me- d3-OD): 8.36 (1H, s), 8.26 (1H, s), 8.19-8.03 (1H, m), 7.71 (1H, dd), 7.45 (1H, d), 7.36 (2H, t), 7.32-7.16 (2H, m), 5.20-5.06 (1H, m), 4.88 (1H, d), 4.79 (1H, s), 4.16-4.03 (4H, m), 3.99 (2H, d), 3.80-3.68 (1H, m), 3.56 (2H, d), 2.01 (2H, s), 1.67-1.60 (2H, m), 0.89 (4H, s). 578 365 [01457] (2R)-2-[6-(5-chloro-2- {[(2S)-1- hydroxypropan-2- yl]amino}pyrimidin-4- yl)-1-oxo-2,3-dihydro- 1H-isoindol-2-yl]-3- hydroxy-N-[2-(3- methoxyphenyl)- propan-2-yl]propanamide 1H NMR (400 MHz, Me- d3-OD): 8.32 (1H, s), 8.26 (1H, s), 8.04 (1H, d), 7.63 (1H, d), 7.14 (1H, t), 6.93 (1H, d), 6.89 (1H, t), 6.70 (1H, dd), 5.06 (1H, dd), 4.78- 4.58 (2H, m), 4.23-4.11 (1H, m), 4.11-3.90 (2H, m), 3.68 (3H, s), 3.67- 3.52 (2H, m), 1.68 (3H, s), 1.61 (3H, s), 1.26 (3H, d). 554 367 [01458] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-4-fluoro-1-oxo-2,3- dihydro-1H-isoindol-2- yl)-3-hydroxy-N-[(1R)- 1-(3- methoxyphenyl)ethyl]- propanamide 1H NMR (400 MHz, CDCl3): 8.37 (1H, s), 8.17 (1H, d), 7.77 (1H, dd), 6.91 (2H, d), 6.88- 6.79 (2H, m), 5.19 (1H, d), 5.11-5.00 (1H, m), 4.90-4.73 (3H, m), 4.33- 4.22 (1H, m), 4.11-3.98 (4H, m), 3.83 (3H, s), 3.60-3.54 (2H, m), 2.07 (2H, d), 1.65-1.58 (2H, m), 1.46 (3H, d). 584

Examples 368-400

[1622] The compounds in the table below were prepared using procedures analogous to that described in Preparation 231, starting from the appropriate halo substituted pyrimidine.

TABLE-US-00035 LCMS Example Structure Name [M + H].sup.+ NMR 368 [01459] 2-(6-{5-chloro-2- [(1,3- dihydroxypropan-2- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H- isoindol-2-yl)-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 526 1H NMR (400 MHz, Me- d3-OD): 8.37 (1H, s), 8.26 (1H, s), 8.09 (1H, d), 7.70 (1H, d), 7.25 (1H, t), 7.01-6.88 (2H, m), 6.88-6.78 (1H, m), 5.11-4.96 (1H, m), 4.66 (2H, s), 4.49-4.32 (2H, m), 4.24-4.12 (1H, m), 3.86-3.79 (3H, m), 3.79- 3.71 (4H, m), 1.50 (3H, d). 369 [01460] 2-[6-(5-chloro-2- {[(3R,4S)-3- hydroxyoxan-4- yl]amino}pyrimidin- 4-yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 552 1H NMR (400 MHz, Me- d3-OD): 8.36 (1H, s), 8.24 (1H, s), 8.08 (1H, dd), 7.70 (1H, d), 7.25 (1H, t), 6.94 (2H, d), 6.82 (1H, dd), 5.14-4.97 (1H, m), 4.66 (2H, s), 4.57-4.31 (2H, m), 4.02- 3.87 (3H, m), 3.81 (3H, s), 3.73-3.56 (1H, m), 3.56-3.42 (1H, m), 3.29- 3.03 (1H, m), 2.25-2.09 (1H, m), 1.78-1.56 (1H, m), 1.48 (3H, d). 370 [01461] 2-[6-(5-chloro-2- {[(2S)-1- hydroxypropan-2- yl]amino}pyrimidin- 4-yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 510 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, d), 8.42 (1H, s), 8.06- 7.95 (2H, m), 7.74 (1H, d), 7.24 (2H, t), 6.93- 6.86 (2H, m), 6.84-6.77 (1H, m), 4.98-4.89 (1H, m), 4.69-4.54 (3H, m), 4.25 (2H, s), 4.03-3.93 (1H, m), 3.76 (3H, s), 3.53-3.44 (1H, m), 3.39- 3.31 (1H, m), 1.37 (3H, d), 1.14 (3H, d). 371 [01462] 2-[6-(5-chloro-2- {[trans-4- hydroxycyclohexyl] amino}pyrimidin-4- yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]-N- [(1S)-2-hydroxy-1- (3- methoxyphenyl)- ethyl]acetamide 564 1H NMR (400 MHz, DMSO-d6): 8.50 (1H, d), 8.42 (1H, s), 8.06- 7.93 (2H, m), 7.74 (1H, d), 7.42 (1H, s), 7.24 (1H, t), 6.90 (2H, d), 6.85-6.78 (1H, m), 4.92- 4.82 (2H, m), 4.60 (2H, s), 4.50 (1H, s), 4.36- 4.23 (2H, m), 3.75 (3H, s), 3.71-3.52 (3H, m), 3.45-3.34 (1H, m), 1.97- 1.66 (4H, m), 1.38-1.11 (4H, m). 372 [01463] 2-(6-{5-chloro-2- [(propan-2- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H- isoindol-2-yl)-N- [(1S)-2-hydroxy-1- (3- methoxyphenyl)- ethyl]acetamide 508 1H NMR (400 MHz, DMSO-d6): 8.51 (1H, d), 8.42 (1H, s), 8.07- 7.94 (2H, m), 7.74 (1H, d), 7.42 (1H, d), 7.23 (1H, t), 6.90 (2H, d), 6.85-6.78 (1H, m), 4.92- 4.82 (2H, m), 4.60 (2H, s), 4.40-4.23 (2H, m), 4.10-3.98 (1H, m), 3.75 (3H, s), 3.63-3.51 (2H, m), 1.18 (6H, d). 373 [01464] 2-[6-(5-chloro-2- {[(2R)-1- hydroxypropan-2- yl]amino}pyrimidin- 4-yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 510 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, d), 8.43 (1H, s), 8.06- 7.95 (2H, m), 7.74 (1H, d), 7.24 (2H, t), 6.90 (2H, d), 6.84-6.77 (1H, m), 4.98-4.89 (1H, m), 4.65 (1H, t), 4.60 (2H, s), 4.25 (2H, s), 4.03- 3.93 (1H, m), 3.76 (3H, s), 3.53-3.45 (1H, m), 3.39-3.33 (1H, m), 1.37 (3H, d), 1.14(3H, d). 374 [01465] 2-(6-{5-chloro-2-[(2- hydroxy-2- methylpropyl)amino]- pyrimidin-4-yl}-1- oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 524 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, d), 8.43 (1H, s), 8.04 (1H, s), 7.99 (1H, dd), 7.75 (1H, d), 7.28-7.16 (2H, m), 6.94-6.86 (2H, m), 6.84-6.77 (1H, m), 4.99-4.89 (1H, m), 4.60 (2H, s), 4.50 (1H, s), 4.25 (2H, s), 3.76 (3H, s), 3.33 (2H, d), 1.38 (3H, d), 1.13 (6H, s). 375 [01466] 2-(6-{5-chloro-2-[(2- hydroxypropyl)- amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 510 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, d), 8.43 (1H, s), 8.04 (1H, s), 7.99 (1H, d), 7.74 (1H, d), 7.40 (1H, s), 7.24 (1H, t), 6.90 (2H, d), 6.84-6.77 (1H, m), 4.99-4.89 (1H, m), 4.67 (1H, d), 4.60 (2H, s), 4.25 (2H, s), 3.87- 3.79 (1H, m), 3.76 (3H, s), 3.28-3.21 (2H, m), 1.38 (3H, d), 1.08 (3H, d). 376 [01467] 2-(6-{5-chloro-2-[(2- acetamidoethyl)- amino]pyrimidin-4-yl}- 1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 537 1H NMR (400 MHz, DMSO-d6): 8.56 (1H, d), 8.45 (1H, s), 8.02 (2H, d), 7.91 (1H, d), 7.75 (1H, d), 7.54 (1H, s), 7.24 (1H, t), 6.90 (2H, d), 6.84-6.77 (1H, m), 4.98-4.89 (1H, m), 4.60 (2H, s), 4.26 (2H, s), 3.76 (3H, s), 3.42- 3.32 (2H, m), 3.28-3.20 (2H, m), 1.79 (3H, s), 1.38 (3H, d). 377 [01468] 2-(6-{5-chloro-2-[(2- cyanoethyl)amino]- pyrimidin-4-yl}-1- oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 505 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, d), 8.50 (1H, s), 8.09- 7.94 (2H, m), 7.88 (1H, s), 7.75 (1H, d), 7.28- 7.21 (1H, m), 6.93-6.86 (2H, m), 6.84-6.77 (1H, m), 4.99-4.89 (1H, m), 4.60 (2H, s), 4.25 (2H, s), 3.76 (3H, s), 3.56 (2H, q), 2.80 (2H, t), 1.38 (3H, d). 378 [01469] 2-(6-{5-chloro-2- [(cyanomethyl)- amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 489 1H NMR (400 MHz, DMSO-d6): 8.62 (1H, s), 8.56 (1H, d), 8.21- 7.94 (3H, m), 7.80-7.72 (1H, m), 7.28-7.21 (1H, m), 6.93-6.85 (2H, m), 6.84-6.77 (1H, m), 4.98- 4.90 (1H, m), 4.61 (2H, s), 4.35 (2H, d), 4.26 (2H, s), 3.79-3.72 (3H, m), 1.38 (3H, d). 379 [01470] 2-[6-(5-chloro-2-{[3- hydroxy-2- (hydroxymethyl)- propyl]amino}- pyrimidin- 4-yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 526 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, d), 8.44 (1H, s), 8.08- 7.93 (2H, m), 7.74 (1H, d), 7.36-7.20 (2H, m), 6.94-6.85 (2H, m), 6.85- 6.77 (1H, m), 4.99-4.89 (1H, m), 4.73 (1H, d), 4.60 (2H, s), 4.52 (1H, t), 4.26 (2H, s), 4.13- 4.00 (3H, m), 3.76 (3H, s), 3.72-3.63 (1H, m), 3.49-3.33 (3H, m), 3.26 (1H, dd), 1.38 (3H, d). 380 [01471] 2-(6-{5-chloro-2-[(2- hydroxyethyl)- amino]- pyrimidin-4-yl}-1- oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 496 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, d), 8.43 (1H, s), 8.04 (1H, s), 7.99 (1H, d), 7.74 (1H, d), 7.43 (1H, s), 7.28-7.21 (1H, m), 6.90 (2H, d), 6.84-6.77 (1H, m), 4.99-4.89 (1H, m), 4.69-4.55 (3H, m), 4.25 (2H, s), 3.76 (3H, s), 3.54 (2H, q), 3.38 (2H, q), 1.38 3H, d). 381 [01472] 2-[6-(5-chloro-2- {[trans-3- hydroxycyclobutyl]- amino}pyrimidin-4- yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 522 1H NMR (400 MHz, DMSO-d6): 8.56 (1H, d), 8.43 (1H, s), 8.04 (1H, s), 7.98 (1H, d), 7.86 (1H, s), 7.74 (1H, d), 724 (1H, t), 6.90 (2H, d), 6.85-6.76 (1H, m), 5.00-4.88 (2H, m), 4.60 (2H, s), 4.39-4.19 (4H, m), 3.76 (3H, s), 2.36-2.07 (4H, m), 1.38 (3H, d). 382 [01473] 2-[6-(5-chloro-2-{[1- (hydroxymethyl)- cyclopropyl]- amino}- pyrimidin-4-yl)-1-oxo- 2,3-dihydro-1H- isoindol-2-yl]-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 522 1H NMR (400 MHz, DMSO-d6): 8.56 (1H, d), 8.43 (1H, s), 8.04 (1H, s), 7.99 (1H, dd), 7.74 (1H, d), 7.39 (1H, s), 7.28-7.20 (1H, m), 6.94-6.86 (2H, m), 6.84- 6.77 (1H, m), 5.35 (1H, s), 4.99-4.89 (1H, m), 4.60 (2H, s), 4.25 (2H, s), 3.76 3H, s), 3.50 (2H, d), 1.38 (3H, d), 0.55 (4H, s), 383 [01474] 2-[6-(5-chloro-2-{[3- (hydroxymethyl)- oxetan-3- yl]amino}pyrimidin- 4-yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 538 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, d), 8.44 (1H, s), 8.04 (2H, d), 7.96 (1H, d), 7.74 (1H, d), 7.28-7.20 (1H, m), 6.93-6.85 (2H, m), 6.84-6.76 (1H, m), 5.06 (1H, t), 4.99-4.89 (1H, m), 4.66-4.57 (4H, m), 4.53 (2H, d), 4.25 (2H, s), 3.79-3.73 (5H, m), 1.38 (3H, d). 384 [01475] 2-(6-{2-[(1- acetylpiperidin-4- yl)amino]-5- chloropyrimidin-4- yl}-1-oxo-2,3- dihydro-1H- isoindol-2-yl)-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 577 1H NMR (400 MHz, DMSO-d6): 8.56 (1H, d), 8.45 (1H, s), 8.05- 7.94 (2H, m), 7.74 (1H, d), 7.60 (1H, s), 7.28- 7.21 (1H, m), 6.93-6.86 (2H, m), 6.84-6.77 (1H, m), 4.98-4.89 (1H, m), 4.60 (2H, s), 4.25 (3H, s), 4.02-3.91 (1H, m), 3.85-3.70 (4H, m), 3.20- 3.09 (1H, m), 2.80-2.66 (1H, m), 2.00 (3H, s), 1.98-1.78(2H, m), 1.52- 1.26 (5H, m). 385 [01476] 2-(6-{5-chloro-2- [(oxetan-3- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H- isoindol-2-yl)-N- [(1S)-2-hydroxy-1- (3- methoxyphenyl)- ethyl]acetamide 524 1H NMR (400 MHz, DMSO-d6): 8.53-8.46 (2H, m), 8.31 (1H, s), 8.05 (1H, s), 7.99 (1H, dd), 7.75 (1H, d), 7.24 (1H, t), 6.90 (2H, d), 6.85-6.78 (1H, m), 4.97- 4.82 (3H, m), 4.77 (2H, t), 4.60 (2H, s), 4.55 (2H, t), 4.38-4.22 (2H, m), 3.76 (3H, s), 3.63- 3.53 (2H, m). 386 [01477] 2-{6-[5-chloro-2-({2- oxaspiro[3.3]heptan-6- yl}amino)pyrimidin- 4-yl]-1-oxo-2,3- dihydro-1H- isoindol-2-yl}-N- [(1S)-2-hydroxy-1- (3- methoxyphenyl)- ethyl]acetamide 564 1H NMR (400 MHz, DMSO-d6): 8.50 (1H, d), 8.43 (1H, s), 8.03 (1H, s), 7.97 (1H, d), 7.82 (1H, s), 7.74 (1H, d), 7.24 (1H, t), 6.90 (2H, d), 6.85-6.78 (1H, m), 4.91-4.80 (2H, m), 4.60 (4H, d), 4.50 (2H, s), 4.37-4.23 2H, m), 4.20-4.07 (1H, m), 3.75 (3H, s), 3.67-3.51 (2H, m), 2.64-2.55 (2H, m), 2.18 (2H, d). 387 [01478] 2-(6-{5-chloro-2- [(propan-2- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H- isoindol-2-yl)-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 492 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, d), 8.42 (1H, s), 8.04 (1H, s), 7.99 (1H, d), 7.74 (1H, d), 7.42 (1H, d), 7.24 (1H, t), 6.93- 6.86 (2H, m), 6.84-6.77 (1H, m), 4.99-4.89 (1H, m), 4.60 (2H, s), 4.25 (2H, s), 4.10-3.98 (1H, m), 3.76 (3H, s), 1.38 (3H, d), 1.18 (6H, d). 388 [01479] 2-(6-{5-chloro-2-[(1- hydroxy-2- methylpropan-2- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H- isoindol-2-yl)-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 524 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, d), 8.43 (1H, s), 8.05 (1H, s), 7.99 (1H, dd), 7.75 (1H, d), 7.28-7.21 (1H, m), 6.94-6.86 (2H, m), 6.86-6.76 (2H, m), 4.99-4.89 (1H, m), 4.82 (1H, t), 4.60 (2H, s), 4.25 (2H, s), 3.76 (3H, s), 3.53 (2H, d), 1.38 (3H, d), 1.33 (6H, s). 389 [01480] 2-{6-[5-chloro-2- (methylamino)- pyrimidin-4-yl]-1-oxo-2,3- dihydro-1H- isoindol-2-yl}-N- [(1S)-2-hydroxy-1- (3- methoxyphenyl)- ethyl]acetamide 482 1H NMR (400 MHz, DMSO-d6): 8.50 (1H, d), 8.44 (1H, s), 8.02 (2H, d), 7.74 (1H, d), 7.47 (1H, s), 7.24 (1H, t), 6.90 (2H, d), 6.85- 6.78 (1H, m), 4.91-4.82 (2H, m), 4.60 (2H, s), 4.37-4.22 (2H, m), 3.75 (3H, s), 3.63-3.53 (2H, m), 2.84 (3H, d). 390 [01481] 2-[6-(5-chloro-2- {[(1R,3R)-3- hydroxycyclopentyl] amino}pyrimidin-4- yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 536 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, d), 8.42 (1H, s), 8.07- 7.94 (2H, m), 7.74 (1H, d), 7.56 (1H, d), 7.28- 7.21 (1H, m), 6.93-6.87 (2H, m), 6.84-6.77 (1H, m), 4.99-4.89 (1H, m), 4.60 (2H, s), 4.46 (1H, d), 4.37 (1H, dd), 4.26 (2H, s), 4.24-4.16 (1H, m), 3.76 (3H, s), 2.15- 2.02 (1H, m), 1.98-1.83 (2H, m), 1.75-1.62 (1H, m), 1.54-1.41 (2H, m), 1.38 (3H, d). 391 [01482] 2-[6-(5-chloro-2- {[(1S,3R)-3- hydroxycyclopentyl] amino}pyrimidin-4- yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 536 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, d), 8.42 (1H, s), 8.06- 7.94 (2H, m), 7.74 (1H, d), 7.46 (1H, d), 7.28- 7.21 (1H, m), 6.93-6.87 (2H, m), 6.84-6.77 (1H, m), 4.99-4.89 (1H, m), 4.60 (2H, d), 4.25 (2H, s), 4.20-4.08 (2H, m), 3.76 (3H, s), 2.25-2.14 (1H, m), 1.98-1.85 (1H, m), 1.79-1.55 (3H, m), 1.55-1.43 (1H, m), 1.38 (3H, d). 392 [01483] 2-[6-(5-chloro-2- {[(3R)-oxan-3- yl]amino}pyrimidin- 4-yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]-N- ](1S)-2-hydroxy-1- (3- methoxyphenyl)- ethyl]acetamide 552 1H NMR (400 Mhz, DMSO-d6): 8.50 (1H, d), 8.45 (1H. s), 8.06 7.94 (2H, m), 7.74 (1H, d), 7.48 (1H, s), 7.24 (1H, t), 6.93-6.86 (2H, m), 6.85-6.78 (1H, m), 4.92-4.82 (2H, m), 4.60 (2H, s), 4.39-4.21 (2H, m,), 3.87 (2H, d), 3.79 3.69 (4H, m), 3.63-3.52 (2H, m), 3.12 (1H, t), 1.97 (1H, s), 1.70 (1H, s), 1.56 (2H, t). 393 [01484] 2-[6-(5-chloro-2- {[(2S)-1- methoxypropan-2- yl]amino}pyrimidin- 4-yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]-N- [(1S)-2-hydroxy-1- (3- methoxyphenyl)- ethyl]acetamide 540 1H NMR (400 MHz, DMSO-d6): 8.50 (1H, d), 8.43 (1H, s), 8.07- 7.96 (2H, m), 7.74 (1H, d), 7.39 (1H, d), 7.24 (1H, t), 6.90 (2H, d), 6.85-6.78 (1H, m), 4.91- 4.82 (2H, m), 4.60 (2H, s), 4.36-4.30 (1H, m), 4.30-4.23 (1H, m), 4.21- 4.11 (1H, m), 3.75 (3H, s), 3.63-3.52 (2H, m), 3.43 (1H, dd), 3.26 (3H, s), 1.15 (3H, d). 394 [01485] 2-[6-(5-chloro-2- {[(2S,3R)-3- hydroxybutan-2- yl]amino}pyrimidin- 4-yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 524 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, d), 8.42 (1H, s), 8.06- 7.95 (2H, m), 7.74 (1H, d), 7.28-7.13 (2H, m), 6.93-6.86 (2H, m), 6.84- 6.77 (1H, m), 4.99-4.89 (1H, m), 4.60 (2H, s), 4.25 (2H, s), 3.90-3.80 (1H, m), 3.76 (3H, s), 3.73-3.63 (1H, m), 1.38 (3H, d), 1.10 (6H, dd). 395 [01486] 2-[6-(5-chloro-2- {[(3S)-oxan-3- yl]amino}pyrimidin- 4-yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]-N- [(1S)-2-hydroxy-1- (3- methoxyphenyl)- etyl]acetamide 552 1H NMR (400 MHz, DMSO-d6): 8.50 (1H, d), 8.45 (1H, s), 8.04 (1H, s), 7.99 (1H, d), 7.74 (1H, d), 7.48 (1H, d), 7.24 (1H, t), 6.90 (2H, d), 6.85-6.78 (1H, m), 4.91-4.82 (2H, m), 4.60 (2H, s), 4.36-4.23 (2H, m), 3.93-3.80 (2H, m), 3.79-3.70 (4H, m), 3.63-3.53 (2H, m), 3.12 (1H, t), 1.97 (1H, s), 1.70 (1H, s), 1.57 (2H, t). 396 [01487] 2-[6-(5-chloro-2- {[(2S)-1- hydroxybutan-2- yl]amino}pyrimidin- 4-yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 524 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, d), 8.41 (1H, s), 8.07- 7.96 (2H, m), 7.74 (1H, d), 7.28-7.13 (2H, m), 6.90 (2H, d), 6.84-6.77 (1H, m), 4.99-4.89 (1H, m), 4.60 (2H, s), 4.25 (2H, s), 3.91-3.80 (1H, m), 3.76 (3H, s), 3.53- 3.44 (1H, m), 3.44-3.34 (1H, m), 1.77-1.61 (1H, m), 1.54-1.40 (1H, m), 1.38 (3H, d), 0.94-0.87 (3H, m). 397 [01488] 2-[6-(5-chloro-2-{[1- (hydroxymethyl)- cyclobutyl] amino}pyrimidin- 4-yl)-1-oxo-2,3- dihydro-1H- isoindol-2-yl]-N- [(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 536 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, d), 8.46-8.40 (1H, m), 8.05 (1H, s), 8.04-7.96 (1H, m), 7.74 (1H, d), 7.45 (1H, s), 7.28-7.21 (1H, m), 6.93-6.87 (2H, m), 6.84-6.77 (1H, m), 4.98-4.90 (1H, m), 4.72 (1H, t), 4.60 (2H, s), 4.25 (2H, s), 3.76 (3H, s), 3.66 (2H, d), 2.31- 2.19 (2H, m), 2.19-2.07 (2H, m), 1.89-1.68 (2H, m), 1.38 (3H, d). 398 [01489] 2-{6-[5-chloro-2- (ethylamino)pyrimidin- 4-yl]-1-oxo-2,3- dihydro-1H- isoindol-2-yl}-N- [(1S)-2-hydroxy-1- (3- methylphenyl)- ethyl]acetamide 480 1H NMR (400 MHz, DMSO-d6): 8.49 (1H, d), 8.43 (1H, s), 8.04 (1H, s), 8.01-7.92 (1H, m), 7.74 (1H, d), 7.54 (1H, s), 7.21 (1H, t), 7.16-7.09 (2H, m), 7.06 (1H, d), 4.90-4.80 (2H, m), 4.59 (2H, s), 4.38- 4.22 (2H, m), 3.57 (2H, t), 3.37-3.32 (1H, m), 2.30 (3H, s), 1.15 (3H, t). 399 [01490] (2R)-N-[(1S)-2- hydroxy-1-(3- methoxyphenyl)- ethyl]-2-(6-{2-[(oxan-4- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H- isoindol-2- yl)propanamide 532 1H NMR (400 MHz, DMSO-d6): 8.52 (1H, d), 8.47-8.30 (3H, m), 7.74 (1H, d), 7.30-7.18 (3H, m), 6.89 (2H, d), 6.84-6.77 (1H, m), 5.02 (1H, q), 4.88-4.71 (3H, m), 4.60 (1H, d), 4.10- 3.97 (1H, m), 3.90 (2H, d), 3.75 (3H, s), 3.61- 3.50 (2H, m), 3.43 (2H, t), 1.89 2H, d), 1.63- 1.49 (2H, m), 1.45 (3H, d). 400 [01491] (2R)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)- ethyl]-2- (6-{2-[(oxan-4- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H- isoindol-2- yl)propanamide 516 1H NMR (400 MHz, DMSO-d6): 8.50 (1H, d), 8.47-8.30 (3H, m), 7.74 (1H, d), 7.29-7.17 (3H, m), 7.14-7.02 (3H, m), 5.01 (1H, q), 4.86- 4.71 (3H, m), 4.59 (1H, d), 4.10-3.98 (1H, m), 3.90 (2H, d), 3.59-3.50 (2H, m), 3.43 (2H, t), 2.29 (3H, s), 1.90 (2H, d), 1.63-1.49 (2H, m), 1.43(3H, d).

Example 401: 2-(6-{5-chloro-2-[(1,5-dimethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide

[1623] ##STR01492##

[1624] A stirred solution of 2-[6-(2,5-dichloropyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide (Preparation 169, 0.05 g, 0.10 mmol) and 1,5-dimethyl-1H-pyrazol-4-amine (0.011 g, 0.10 mmol) and 4M HCL in dioxane (3 μL, 0.01 mmol) in N-methyl pyrrolidinone (0.23 mL) was heated at 100° C. for 18 h. The reaction mixture was directly purified by reverse phase biotage (gradient elution, 0-40%, MeCN/water), to give the title compound. 1H NMR (400 MHz, DMSO-d6): 9.08-9.03 (1H, m), 8.50 (2H, d), 8.08-7.97 (2H, m), 7.75 (1H, d), 7.49 (1H, s), 7.24 (1H, t), 6.93-6.87 (2H, m), 6.84-6.79 (1H, m), 4.91-4.83 (2H, m), 4.60 (2H, s), 4.36-4.24 (2H, m), 3.75 (3H, s), 3.70 (3H, s), 3.62-3.54 (2H, m), 2.18 (3H, s). MS: [M+H].sup.+=562.

Example 402: 2-(7-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide

[1625] ##STR01493##

[1626] To 2-(7-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)acetic acid (Preparation 233, 0.200 g, 0.48 mmol), (2S)-2-amino-2-(3-methylphenyl)ethan-1-ol hydrochloride (0.088 g, 0.53 mmol) and HATU (0.274 g, 0.53 mmol) in DCM (7.87 mL) was added diisopropylethylamine (1.10 mL, 6.30 mmol). The reaction was stirred at room temperature for 1 h. Water was added and the aqueous was extracted with ethyl acetate (3×). The combined organics were concentrated in vacuo. The crude product was purified by by reverse phase biotage (gradient elution, 0-40%, MeCN/water), to give the title compound. 1H NMR (400 MHz, DMSO-d6): 8.42 (1H, s), 8.37 (1H, d), 8.27 (1H, d), 7.87 (1H, dd), 7.57 (1H, s), 7.44 (1H, d), 7.23 (1H, t), 6.93-6.86 (2H, m), 6.84-6.77 (1H, m), 4.89-4.80 (2H, m), 4.31-4.18 (2H, m), 3.98-3.81 (3H, m), 3.76 (3H, s), 3.68-3.55 (4H, m), 3.38 (2H, t), 3.12-3.00 (2H, m), 1.84 (2H, d), 1.59-1.45 (2H, m). MS: [M+H].sup.+=566.

Example 403: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyridin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]propanamide

[1627] ##STR01494##

[1628] A solution of (2R)-2-[6-(5-chloro-2-fluoropyridin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]propanamide (Preparation 239, 54 mg, 0.11 mmol) in NMP (0.1 mL), N,N-diisopropylethylamine (58 μL, 0.33 mmol, 3 eq.) and 4-aminooxan (58 μL, 0.56 mmol, 5 eq.) was heated in the microwave at 140° C. for 2 hours. Partial reaction—heated for a further 2 hrs at 140° C. The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with further EtOAc and then the combined organics washed with water (×2) and brine, dried (MgSO.sub.4), filtered and concentrated. Purified by silica column, 10 g SNAP—0-10% MeOH in EtOAc. The product was further purified by reverse phase C18 cartridge (30 g SNAP), eluting 45-70% MeCN in water to give the title compound (20 mg) as a white solid. LC-MS: [M+H].sup.+=565. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.51 (1H, d), 8.09 (1H, s), 7.75-7.63 (3H, m), 7.27-7.20 (1H, m), 6.91-6.84 (2H, m), 6.84-6.75 (2H, m), 6.57-6.52 (1H, m), 5.01 (1H, q), 4.88-4.79 (2H, m), 4.75 (1H, d), 4.59 (1H, d), 3.98-3.83 (3H, m), 3.75 (3H, s), 3.60-3.51 (2H, m), 3.42 (2H, dd), 1.89 (2H, d), 1.48-1.41 (5H, m).

Example 404: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-(2-oxo-2-{6-[4-(propan-2-yl)piperazin-1-yl]-1,2,3,4-tetrahydroisoquinolin-2-yl}ethyl)-2,3-dihydro-1H-isoindol-1-one

[1629] ##STR01495##

[1630] Prepared using a similar procedure to Example 2. The product was further purified by SCX (3 g) in MeOH. The column was washed with MeOH and the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to afford the title compound (69 mg, 0.105 mmol, 44% yield) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.06-8.02 (1H, m), 7.99 (1H, dd), 7.75 (1H, d), 7.62 (1H, s (br)), 7.09-7.01 (1H, m), 6.85-6.73 (2H, m), 4.67-4.49 (6H, m), 3.99-3.83 (3H, m), 3.72 (1H, t), 3.65 (1H, t), 3.42-3.35 (2H, m), 3.09 (4H, br. s), 2.87 (1H, t), 2.75 (1H, t), 2.58 (4H, br. s), 1.90-1.82 (2H, m), 1.61-1.47 (2H, m), 1.02 (6H, d) (one proton obscured by solvent peak). LC-MS: [M+H].sup.+=644.

Example 405: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-{2-oxo-2-[6-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-2-yl]ethyl}-2,3-dihydro-1H-isoindol-1-one

[1631] ##STR01496##

[1632] Prepared using a similar procedure to Example 2. The product was further purified by SCX (3 g) in MeOH. The column was washed with MeOH and the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to afford the title compound (63 mg, 46%) as a white solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.91 (2H, d), 8.46 (1H, s), 8.30-8.21 (2H, m), 8.06-8.03 (1H, m), 7.99 (1H, dd), 7.76 (1H, d), 7.62 (1H, br. s), 7.48-7.43 (1H, m), 7.38 (1H, dd), 4.86 (1H, s), 4.71 (1H, s), 4.65-4.59 (4H, m), 3.99-3.80 (4H, m), 3.75 (1H, t), 3.43-3.35 (2H, m), 3.06 (1H, t), 2.93 (1H, t), 1.90-1.82 (2H, m), 1.60-1.47 (2H, m). LC-MS: [M+H].sup.+=596.

Example 406: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[1-(4-chlorophenyl)-2-hydroxyethyl]acetamide

[1633] ##STR01497##

[1634] Prepared using a similar procedure to Example 2. 1H NMR (DMSO-d6) δ: 8.61 (d, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.97 (dd, 1H), 7.74 (d, 1H), 7.62 (s (br)), 1H), 7.45-7.29 (m, 4H), 4.97 (t, 1H), 4.87 (dt, 1H), 4.58 (s, 2H), 4.32 (d, 1H), 4.26 (d, 1H), 3.99-3.79 (m, 3H), 3.57 (dd, 2H), 3.45-3.35 (m, 2H), 1.93-1.77 (m, 2H), 1.60-1.43 (m, 2H). LC-MS: [M+H].sup.+=556.

Example 407: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[2-(4-methyl-4-phenylpiperidin-1-yl)-2-oxoethyl]-2,3-dihydro-1H-isoindol-1-one

[1635] ##STR01498##

[1636] Triethylamine (83 μl, 0.596 mmol) was added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 80 mg, 0.199 mmol), 4-methyl-4-phenylpiperidine (34.8 mg, 0.199 mmol) and HATU (83 mg, 0.218 mmol) in DCM:DMF (3 mL (10:1)). The reaction was stirred at room temperature for 1 h. The mixture was diluted with DCM (5 mL), then washed with 1M HCl (5 mL), saturated aqueous NaHCO.sub.3 (5 mL), brine (5 mL), dried (MgSO.sub.4), then concentrated in vacuo. The crude product was purified by chromatography (SiO.sub.2, 4 g column, 50-100% EtOAc in isohexane) to give a colourless glass. Trituration with diethyl ether and drying to afford the title compound (75 mg, 66%) as a colourless powder. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.73 (d, 1H), 7.61 (bs, 1H), 7.42-7.39 (m, 2H), 7.37-7.33 (m, 2H), 7.23-7.19 (m, 1H), 4.55 (s, 2H), 4.48 (d, 2H), 3.93-3.85 (m, 3H), 3.60-3.51 (m, 2H), 3.45-3.34 (m, 4H), 2.12-2.08 (m, 1H), 2.00-1.96 (m, 1H), 1.86-1.83 (m, 2H), 1.79-1.74 (m, 1H), 1.69-1.65 (m, 1H), 1.57-1.47 (m, 2H), 1.25 (s, 3H). LC-MS: [M+H].sup.+=560.

Examples 408-436

[1637] Prepared using an analogous procedure to Example 407, from 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) and the corresponding amine:

TABLE-US-00036 Example Structure Name .sup.1H NMR (400 MHz) MS: [M + H].sup.+ 408 [01499] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- (4-cyanophenyl)- propan-2-yl]acetamide 1H NMR (400 MHz, DMSO- d6) δ 8.55 (s, 1H), 8.43 (s, 1H), 8.01 (d, 1H), 7.95 (dd, 1H), 7.75 (d, 2H), 7.71 (d, 1H), 7.59 (s (br), 1H), 7.54 (d, 2H), 4.54 (s, 2H), 4.26 (s, 2H), 3.93-3.84 (m, 3H), 3.40-3.34 (m, 2H), 1.86- 1.82 (m, 2H), 1.57 (s, 6H), 1.54-1.47 (m, 2H) 545 409 [01500] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-2-hydroxy-1- phenylethyl]acetamide 1H NMR (400 MHz, DMSO- d6) : 8.56 (d, 1H), 8.44 (s, 1H), 8.03-8.02 (br m, 1H), 7.97 (dd, 1H), 7.73 (d, 1H), 7.60 (s (br), 1H), 7.35-7.30 (m, 4H), 7.27-7.22 (m, 1H), 4.97-4.85 (m, 2H), 4.59 (s, 2H), 4.29 (dd, 2H), 3.97- 3.85 (m, 3H), 3.59-3.56 (m, 2H), 3.40-3.34 (m, 2H), 1.87-1.83 (br m, 2H), 1.57- 1.47 (m, 2H) 522 410 [01501] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1- phenylethyl]acetamide 1H NMR (400 MHz, DMSO- d6) δ: 8.60 (d, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.61 (s (br)), 1H), 7.31-7.37 (m, 4H), 7.24 (m, 1H), 4.97 (dq, 1H), 4.59 (s, 2H), 4.28 (d, 1H), 4.23 (d, 1H), 3.82-3.98 (m, 3H), 3.33-3.43 (m, 2H), 1.80-1.89 (m, 2H), 1.46- 1.59 (m, 2H), 1.39 (d, 3H) 506 411 [01502] (trans) 2-{2- [(4aS, 8aR)- decahydroisoquinolin- 2-yl]-2-oxoethyl}-6-{5- chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2,3-dihydro-1H- isoindol-1-one 1H NMR (400 MHz, DMSO- d6) δ: 8.45 (s, 1H), 8.02- 8.01 (m, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.62 (s (br), 1H), 4.55-4.38 (m, 5H), 4.25-4.22, 3.78-3.74, 3.07- 3.01, 2.71-2.65 and 2.57- 2.51 (m, 2H), 3.97-3.74 (m, 4H), 3.40-3.34 (m, 2H), 1.86-1.83 (br m, 2H), 1.70- 1.47 (m, 8H), 1.31-0.88 (m, 6H) 524 412 [01503] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- {[2- (methoxymethyl) phenyl]methyl} acetamide 1H NMR (400 MHz, DMSO d6) δ: 8.51 (t, 1H), 8.44 (s, 1H), 8.03-8.02 (m, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.62 (s (br), 1H), 7.34-7.23 (m, 4H), 4.62 (s, 2H), 4.46 (s, 2H), 4.35 (d, 2H), 4.27 (s, 2H), 3.97-3.85 (m, 3H), 3.37 (t, 2H), 3.29 (s, 3H), 1.86- 1.83 (br m, 2H), 1.52 (qd, 2H) 536 413 [01504] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-{2-[(3R)-3- (hydroxymethyl)- 1,2,3,4- tetrahydroisoquinolin- 2-yl]-2-oxoethyl}-2,3- dihydro-1H-isoindol-1- one 1H NMR (400 MHz, DMSO- d6 @ 373 K) δ: 8.40 (s, 1H), 8.09-8.08 (m, 1H), 8.01 (dd, 1H), 7.71 (d, 1H), 7.24-7.10 (m, 5H), 5.11-4.15 (br m, 9H), 4.03-3.86 (m, 3H), 3.47-3.31 (m, 4H), 3.07 (s (br), 1H), 1.92-1.89 (br m, 2H), 1.65-1.55 (m, 2H). 548 414 [01505] 2-[2-(6-{5-chloro-2- (oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2- yl)acetyl]-1-methyl- 1,2,3,4- tetrahydroisoquinoline- 6-carbonitrile 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.07- 8.01 (1H, m), 7.99 (1H, dd), 7.80-7.55 (4H, m), 7.50 (1H, t), 5.52 (0.6H, q), 5.37 (0.4H, q), 4.76-4.39 (4H, m), 4.06-3.81 (4H, m), 3.55 (1H, ddd), 3.44-3.34 (1H, m), 3.14-2.76 (3H, m), 1.85 (2H, d), 1.61-1.46 (3H, m), 1.40 (2H, d). (3:2 mixture of rotamers). 557 415 [01506] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(2- phenylbutan-2- yl)acetamide 1H NMR (400 MHz, DMSO- d6) δ: 8.44(s, 1H), 8.19 (s, 1H), 8.01-8.00 (m, 1H), 7.95 (dd, 1H), 7.72 (d, 1H), 7.61 (s (br), 1H), 7.32-7.26 (m, 4H), 7.19-7.14 (m, 1H), 4.60-4.50 (m, 2H), 4.33- 4.25 (m, 2H), 3.95-3.84 (m, 3H), 3.39-3.34 (m, 2H), 2.05-1.96 (m, 1H), 1.85- 1.71 (m, 3H), 1.56-1.47 (m, 5H), 0.76 (t, 3H). 534 416 [01507] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- (2,3-dihydro-1- benzofuran-3- yl)acetamide 1H NMR (400 MHz, DMSO- d6) δ: 8.81 (d, 1H), 8.44 (s, 1H), 8.03-8.02 (m, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.62 (s (br), 1H), 7.36-7.30 (m, 1H), 7.25-7.20 (m, 1H), 6.92 (dt, 1H), 6.85 (d, 1H), 5.57- 5.51 (m, 1H), 4.69-4.64 (m, 1H), 4.60 (s, 2H), 4.27-4.23 (m, 3H), 3.97-3.85 (m, 3H), 3.37 (t, 2H), 1.88-1.81 (br m, 2H), 1.57-1.47 (m, 2H). 520 417 [01508] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- {[2- (hydroxymethyl)phenyl] methyl}acetamide 1H NMR (400 MHz, DMSO- d6) δ: 8.52 (t, 1H), 8.44 (s, 1H), 8.02-8.01 (m, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.62 (s (br), 1H), 7.41-7.37 (m, 1H), 7.27-7.21 (m, 3H), 5.14 (t, 1H), 4.61 (s, 2H), 4.55 (d, 2H), 4.34 (d, 2H), 4.26 (s, 2H), 3.98-3.85 (m, 3H), 3.37 (t, 2H), 1.86-1.82 (br m, 2H), 1.57-1.47 (m, 2H) 522 418 [01509] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- {[2-(2- hydroxyethoxy)phenyl] methyl}acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.44 (2H, d), 8.03 (1H, dd), 7.98 (1H, dd), 7.80- 7.70 (1H, m), 7.62 (1H, s), 7.31-7.14 (2H, m), 6.97 (1H, dd), 6.91 (1H, app td), 4.88 (1H, t), 4.62 (2H, s), 4.31 (2H, d), 4.27 (2H, s), 4.01 (2H, dd), 3.98-3.80 (3H, m), 3.77-3.69 (2H, m), 3.42-3.35 (2H, m), 1.89-1.78(2H, m), 1.59- 1.46 (2H, m). 552 419 [01510] 3-[2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2- yl)acetyl]-2,3,4,5- tetrahydro-1H-3- benzazepine-7- carbonitrile 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.06- 8.02 (1H, m), 7.99 (1H, dd), 7.80-7.55 (4H, m), 7.41 (1H, dd), 4.56 (4H, d), 3.87 (3H, s), 3.73-3.56 (4H, m), 3.38 (2H, t), 3.14-3.00 (2H, m), 3.01-2.86 (2H, m), 1.85 (2H, d), 1.53 (2H, qd). 557 420 [01511] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-3-hydroxy-1- phenylpropyl]acetamide 1H NMR (DMSO-d6) δ 8.57 (d, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.61 (s (br), 1H), 7.37-7.27 (m, 4H), 7.23 (m, 1H), 4.96 (dd, 1H), 4.58 (s, 2H), 4.52 (t, 1H), 4.28 (d, 1H), 4.21 (d, 1H), 3.82-3.98 (m, 3H), 3.46-3.35 (m, 4H), 1.76-1.95 (m, 4H), 1.53 (qd, 2H). 536 421 [01512] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(1- hydroxy-3- phenylpropan-2- yl)acetamide 1H NMR (400 MHz, DMSO- d6) δ 8.45 (s, 1H), 8.05- 8.00 (m, 2H), 7.98 (dd, 1H), 7.72 (d, 1H), 7.62 (s (br), 1H), 7.33-7.16 (m, 5H), 4.84 (t, 1H), 4.44 (d, 1H), 4.37 (d, 1H), 4.17 (d, 1H), 4.10 (d, 1H), 3.83-4.01 (m, 4H), 3.43-3.35 (m, 4H), 2.86 (dd, 1H), 2.65 (dd, 1H), 1.85 (m, 2H), 1.53 (qd, 2H). 536 422 [01513] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(2- hydroxy-1- phenylpropyl)- acetamide 1H NMR (DMSO-d6) δ: 8.51 (dd, 1H), 8.50 (dd, 0.22H), 8.44 (s (br), 1.22H), 8.01 (d, 1.22H), 7.96 (dd, 1.22H), 7.73 (d, 1.22H), 7.62 (s, 1.22H), 7.36-7.26 (m, 4.88H), 7.26-7.19 (m, 1.22H), 4.82 (d, 0.22H), 4.74 (d, 2H), 4.70-4.73 (m, 1.22H), 4.57 (s (br), 2.44H), 4.37 (d, 0.22H), 4.32 (d, 1H), 4.28 (d, 0.22H), 4.25 (d, 1H), 3.98-3.79 (m, 4.88H), 3.42-3.33 (m, 2.44H), 1.88-1.79 (m, 2.44H), 1.58-1.46 (m, 2.44H), 1.02 (d, 3H), 0.99 (d, 0.66H). (82:18 mixture of cis- and trans-isomers). 536 423 [01514] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[2- hydroxy-1-(4- methoxyphenyl)ethyl] acetamide 1H NMR (DMSO-d6) δ: 8.49 (d, 1H), 8.45 (s, 1H), 8.03 (s, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.62(s (br), 1H), 7.24 (d, 2H), 6.89 (d, 2H), 4.88 (t, 1H), 4.83 (dt, 1H), 4.24 (d, 1H), 3.98- 3.81 (m, 3H), 3.74 (s, 3H), 3.54 (dd, 2H), 3.45-3.35 (m, 2H), 1.92-1.77 (m, 2H), 1.61-1.45 (m, 2H). 552 424 [01515] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R)-3-hydroxy-1- phenylpropyl]acetamide 1H NMR (DMSO-d6) δ: 8.57 (d, 1H), 8.45 (s, 1H), 8.02 (d, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.62 (s (br), 1H), 7.37-7.28 (m, 4H), 7.28-7.20 (m, 1H), 4.96 (td, 1H), 4.58 (s, 2H), 4.53 (s (br), 1H), 4.28 (d, 1H), 4.21 (d, 1H), 3.99-3.79 (m, 3H), 3.47-3.36 (m, 4H), 1.96-1.74 (m, 4H), 1.60-1.44 (m, 2H) 536 425 [01516] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (3-fluorophenyl)-2- hydroxyethyl]acetamide 1H NMR (DMSO-d6) δ: 8.59 (d, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.63 (s (br), 1H), 7.42-7.32 (m, 1H), 7.21-7.13 (m, 2H), 7.13- 7.03 (m, 1H), 4.99 (t, 1H), 4.91 (td, 1H), 4.59 (s, 2H), 4.34 (d, 1H), 4.28 (d, 1H), 4.00-3.80 (m, 3H), 3.64- 3.53 (m, 2H), 3.44-3.35 (m, 2H), 1.91-1.79 (m, 2H), 1.60-1.44 (m, 2H) 540 426 [01517] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{2- hydroxy-1-[4-(propan- 2- yloxy)phenyl]ethyl} acetamide 1H NMR (DMSO-d6) δ: 8.48 (d, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.61 (s (br), 1H), 7.21 (d, 2H), 6.86 (d, 2H), 4.86 (t, 1H), 4.82 (dt, 1H), 4.62-4.52 (m, 3H), 4.31 (d, 1H), 4.24 (d, 1H), 4.00-3.81 (m, 3H), 3.55 (dd, 2H), 3.44-3.34 (m, 2H), 1.91-1.78 (m, 2H), 1.60-1.46 (m, 2H), 1.25 (d, 6H) 580 427 [01518] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pynmidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-cyclohexyl-2- hydroxyethyl]- acetamide 1H NMR (400 MHz, DMSO- d6) 6 8.44 (s, 1H), 8.02 (dd, 1H), 7.97 (dd, 1H), 7.81 (d, 1H), 7.74 (d, 1H), 7.62 (s (br), 1H), 4.59 (s, 3H), 4.27- 4.18 (m, 2H), 3.98-3.81 (m, 3H), 3.63-3.56 (m, 1H), 3.42-3.35 (m, 4H), 1.86- 1.83 (br m, 2H), 1.75-1.42 (m, 7H), 1.26-0.84 (m, 6H) 528 428 [01519] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[2- hydroxy-2-(2- methylphenyl)ethyl]- acetamide 1H NMR (DMSO-d6) δ: 8.46 (s, 1H), 8.35 (dd, 1H), 8.03 (d, 1H), 7.99 (dd, 1H), 7.75 (d, 1H), 7.63 (s (br), 1H), 7.45 (d, 1H), 7.23- 7.08 (m, 3H), 5.38 (d, 1H), 4.86 (dt, 1H), 4.56 (s, 2H), 4.26 (d, 1H), 4.19 (d, 1H), 4.01-3.82 (m, 3H), 3.43- 3.29 (m, 3H), 3.04-2.93 (m, 1H), 2.31 (s, 3H), 1.90- 1.79 (m, 2H), 1.61-1.45 (m, 2H). 536 429 [01520] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[2- hydroxy-1-(2- methoxyphenyl)ethyl] acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.50-8.43 (2H, m), 8.06- 8.01 (1H, m), 7.97 (1H, dd), 7.74 (1H, d), 7.62 (1H, br. s), 7.29 (1H, dd), 7.26-7.21 (1H, m), 6.97 (1H, dd), 6.95-6.90 (1H, m), 5.29-5.22 (1H, m), 4.88 (1H, t), 4.59 (2H, s), 4.34 (1H, d), 4.27 (1H, d), 3.98-3.83 (3H, m), 3.79 (3H, s), 3.59-3.52 (1H, m), 3.47-3.36 (3H, m), 1.89- 1.81 (2H, m), 1.59-1.47 (2H, m). 552 430 [01521] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-(4- fluorophenyl)-2- hydroxyethyl]- acetamide 1H NMR (DMSO-d6) δ: 8.57 (d, 1H), 8.45 (s, 1H), 8.03 (dd, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.62 (s (br), 1H), 7.40-7.33 (m, 2H), 7.20-7.11 (m, 2H), 4.95 (t, 1H), 4.88 (m, 1H), 4.59 (s, 2H), 4.32 (d, 1H), 4.26 (d, 1H), 3.97-3.82 (m, 3H), 3.57 (dd, 2H), 3.44-3.33 (m, 2H), 1.90-1.80 (m, 2H), 1.58-1.48 (m, 2H). 540 431 [01522] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-2- methyl-1- phenylpropyl]- acetamide 1H NMR (DMSO-d6) δ: 8.48 (d, 1H), 8.45 (s, 1H), 8.01 (d, 1H), 7.97 (dd, 1H), 7.73 (d, 1H), 7.62 (s (br), 1H), 7.41-7.33 (m, 2H), 7.32-7.26 (m, 2H), 7.26- 7.21 (m, 1H), 4.75 (d, 1H), 4.59 (s, 1H), 4.56 (s, 2H), 4.38 (d, 1H), 4.28 (d, 1H), 3.97-3.81 (m, 3H), 3.43- 3.36 (m, 2H), 1.89-1.79 (m, 2H), 1.58-1.46 (m, 2H), 1.14 (s, 3H), 1.01 (s, 3H). 550 432 [01523] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-(2-fluoro-3- methoxyphenyl)-2- hydroxyethyl]- acetamide 1H NMR (DMSO-d6) δ: 8.63 (d, 1H), 8.45 (s (br), 1H), 8.02 (d, 1H), 7.98 (dd 1H), 7.74 (d, 1H), 7.62 (s (br), 1H), 7.16-7.02 (m, 2H), 6.99-6.93 (m, 1H), 5.21-5.12 (m, 1H), 5.04 (t, 1H), 4.58 (s, 2H), 4.32 (d, 1H), 4.26 (d, 1H), 3.98- 3.83 (m, 3H), 3.82 (s, 3H), 3.59-3.51 (m, 2H), 3.41- 3.34 (m, 2H), 1.90-1.78 (m, 2H), 1.62-1.45 (m, 2H). 570 434 [01524] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-(3-fluoro-5- methylphenyl)-2- hydroxyethyl]acetamide 1H NMR (DMSO-d6) δ: 8.55 (d, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.62 (s (br), 1H), 7.01-6.97 (m, 1H), 6.97-6.87 (m, 2H), 4.96 (t, 1H), 4.85 (td, 1H), 4.59 (s, 2H), 4.33 (d, 1H), 4.28 (d, 1H), 3.99-3.81 (m, 3H), 3.62-3.52 (m, 2H), 3.43- 3.35 (m, 2H), 2.31 (s, 3H), 1.90-1.78 (m, 2H), 1.60- 1.44 (m, 2H). 554 435 [01525] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S,2R)-2-hydroxy-6- methoxy-2,3-dihydro- 1H-inden-1- yl]acetamide 1H NMR (DMSO-d6) δ: 8.46 (s, 1H), 8.23 (d, 1H), 8.05 (d, 1H), 7.99 (dd, 1H), 7.77 (d, 1H), 7.63 (s (br), 1H), 7.14 (d, 1H), 6.82- 6.73 (m, 2H), 5.19 (dd, 1H), 5.05 (d, 1H), 4.67 (s, 2H), 4.46-4.36 (m, 3H), 4.00- 3.82 (m, 3H), 3.74 (s, 3H), 3.44-3.36 (m, 2H), 2.98 (dd, 1H), 2.74 (d, 1H), 1.90- 1.77 (m, 2H), 1.60-1.45 (m, 2H). 564 436 [01526] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [3,3-difluoro-1- (hydroxymethyl) cyclobutyl]acetamide 1H NMR (DMSO-d6) δ: 8.52 (s, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.63 (s (br), 1H), 5.17 (t, 1H), 4.59 (s, 2H), 4.21 (s, 2H), 3.99- 3.81 (m, 3H), 3.51 (d, 2H), 3.43-3.35 (m, 2H), 2.84- 2.63 (m, 4H), 1.89-1.80 (m, 2H), 1.61-1.47(m, 2H). 522

Examples 437-443

[1638] Prepared using an analogous procedure to Example 407, from 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) and the corresponding amine. In these cases, the products were further purified by preparative HPLC (acidic or basic methods as specified):

TABLE-US-00037 Structure/prep. MS: Example Conditions Name .sup.1H NMR (400 MHz) [M + H].sup.+ 437 [01527] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-(3-methyl-3- phenylazetidin-1-yl)-2- oxoethyl]-2,3-dihydro- 1H-isoindol-1-one 1H NMR (400 MHz, CDCl.sub.3) δ 8.30 (d, 2H), 7.98 (d, 1H), 7.56 (d, 1H), 7.38- 7.34 (m, 2H), 7.27-7.25 (m, 1H), 7.21-7.19 (m, 1H), 5.21 (d, 1H), 4.72-4.60 (m, 2H), 4.52 (d, 1H), 4.36-4.22 (m, 4H), 4.08-3.96 (m, 4H), 3.57-3.50 (m, 2H), 2.06- 2.02 (m, 2H), 1.83 (bs, 1H), 1.66 (s, 3H), 1.61-1.51 (m, 2H) 532 438 [01528] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S,2S)-2-hydroxy- 2,3-dihydro-1H-inden- 1-yl]acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.50 (1H, d), 8.45 (1H, s), 8.06-8.01 (1H, m), 7.98 (1H, dd), 7.76 (1H, d), 7.61 (1H, s), 7.23-7.16 (3H, m), 7.16-7.08 (1H, m), 5.33 (1H, d), 5.07 (1H t), 4.65 (2H, d), 4.37-4.19 (3H, m), 3.99-3.80 (3H, m), 3.42-3.33 (2H, m), 3.11 (1H, dd), 2.77-2.63 (1H, m), 1.84 (2H, d), 1.52 (2H, qd). 534 439 [01529] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1R,2S)-2-hydroxy- 2,3-dihydro-1H-inden- 1-yl]acetamide 1H NMR (DMSO, 400 MHz) δ 8.45 (1H, s), 8.25 (1H, d), 8.04 (1H, d), 7.98 (1H, dd), 7.76 (1H, d), 7.62 (1H, bs), 7.26-7.17 (4H, m), 5.22 (1H, dd), 5.09 (1H, d), 4.66 (2H, s), 4.44 (1H, dd), 4.38 (2H, s), 3.95-3.85 (3H, m), 3.42-3.34 (2H, m), 3.06 (1H, dd), 2.81 (1H, dd), 1.85 (2H, d), 1.53 (2H, qd). 534 440 [01530] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-{2-[(3S)-3-(2- hydroxyethyl)-1,2,3,4- tetrahydroisoquinolin- 2-yl]-2-oxoethyl}-2,3- dihydro-1H-isoindol-1- one 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.03 (1H, t), 7.98 (1H, dd), 7.77- 7.72 (1H, m), 7.62 (1H, s), 7.25-7.16 (4H, m), 5.06 (0.7H, d, major rotamer), 4.90-4.81 (0.7H, m, major rotamer), 4.74-4.72 (0.5H, m, minor rotamer), 4.68- 4.44 (5H, m), 4.37-4.33 (0.5H, m, minor rotamer), 4.09 (0.7H, d, major rotamer), 3.99-3.80 (3H, m), 3.55-3.47 (0.7H, m, major rotamer), 3.44-3.34 (3H, m), 3.19 (0.7H, dd, major rotamer), 2.94 (0.5H, dd, minor rotamer), 2.81- 2.64 (1.3H, m), 1.84 (2H, d), 1.70-1.36 (4H, m). 562 441 [01531] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-{2-[(3S)-7-fluoro- 3-(hydroxymethyl)- 1,2,3,4- tetrahydroisoquinolin- 2-yl]-2-oxoethyl}-2,3- dihydro-1H-isoindol-1- one 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.04- 8.03 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.62 (1H, s), 7.23 (1H, ddd), 7.11 (1H, ddd), 7.03 (1H, qd), 5.11 (1H, t), 4.99 (1H, d), 4.88- (5H, m), 4.39-4.32 (1H, m), 4.16 (1H, d), 3.97-3.83 (3H, m), 3.41-3.34 (2H, m), 3.20-3.01 (1H, m), 2.93-2.78 (1H, m), 1.84 (2H, d), 1.60-1.44 (2H, m). 566 442 [01532] N-(2-benzyl-1- hydroxypropan-2-yl)- 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2- yl)acetamide 1H NMR (DMSO-d6, 400 MHz, 90° C.) 6 8.41 (1H, s), 8.09 (1H, d), 8.01 (1H, dd), 7.73 (1H, dd), 7.29-7.14 (6H, m), 7.09 (1H, s), 4.61- 4.57 (3H, m), 4.17 (2H, s), 4.03-3.86 (3H, m), 357- 3.34 (4H, m), 3.11 (1H, d), 2.89 (1H, d), 1.96- 1.82 (2H, m), 1.69-1.50 (2H, m), 1.18 (3H, s). 550 443 [01533] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(3- methylphenyl)ethyl] ac etamide 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, d), 8.44 (1H, s), 8.02 (1H, d), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, s), 7.20 (1H, t), 7.15- 7.07 (2H, m), 7.05 (1H, d), 4.93 (1H, s), 4.83 (1H, q), 4.58 (2H, s), 4.35-4.22 (2H, m), 3.97-3.81 (3H, m), 3.56 (2H, d), 2.29 (3H, s), 1.89- 1.79 (2H, m), 1.59-1.46 (2H, m). (2 protons signals overlapped with water peak). 536

Examples 444, 445 and 456: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide, 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide and 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide

[1639] ##STR01534##

[1640] 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide was prepared using a similar procedure to Example 407. 1H NMR (DMSO-d6) δ: 8.54 (d, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.63 (s (br), 1H), 7.28-7.18 (m, 1H), 6.95-6.85 (m, 2H), 6.84-6.78 (m, 1H), 4.92 (t, 1H), 4.86 (m, 1H), 4.60 (s, 2H), 4.33 (d, 1H), 4.27 (d, 1H), 3.99-3.81 (m, 3H), 3.75 (s, 3H), 3.64-3.51 (m, 2H), 3.43-3.33 (m, 2H), 1.85 (m, 2H), 1.60-1.43 (m, 2H). LC-MS: [M+H].sup.+=552. The enantiomers were separated by preparative HPLC on a Lux C.sub.4 (21.2 mm×250 mm, 5 μm) column, using a 0.1% NH.sub.3 in MeOH at 21 ml/min as eluent to give 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide and and 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide as white solids.

Example 447: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]acetamide

[1641] ##STR01535##

[1642] The title compound can be prepared using a similar procedure to Example 407 or methods analogous thereto.

Example 448: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(4-cyclopropylphenyl)-2-hydroxyethyl]acetamide

[1643] ##STR01536##

[1644] Prepared using a similar procedure to Example 407. In this case, the product was further purified by preparative HPLC (Varian, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water) followed by washing with HCl, NaHCO.sub.3 and brine. 1H NMR (DMSO-d6, 400 MHz) δ 8.51 (1H, d), 8.44 (1H, s), 8.02 (1H, d), 7.97 (1H, dd), 7.73 (1H, d), 7.61 (1H, s), 7.21-7.15 (2H, m), 7.06-6.98 (2H, m), 4.86-4.78 (1H, m), 4.58 (2H, s), 4.33-4.20 (2H, m), 3.98-3.81 (3H, m), 3.54 (2H, d), 3.42-3.36 (2H, m), 1.93-1.78 (3H, m), 1.60-1.45 (2H, m), 0.94-0.88 (2H, m), 0.66-0.60 (2H, m). (note: OH not observed). LCMS: [M+H].sup.+=562.

Example 449: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[2-oxo-2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1645] ##STR01537##

[1646] Prepared using an analogous procedure to Example 95, from 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) and the corresponding amine. 1H NMR (400 MHz, DMSO-d6, VT T=350K) δ: 8.38-8.43 (m, 2H), 8.08 (d, 1H), 8.01 (dd, 1H), 7.73 (dd, 1H), 7.57-7.67 (m (br), 2H), 7.28 (d (br), 1H), 7.23 (dd, 1H), 4.74 (s (br), 1H), 4.61 (s, 2H), 4.60 (s, 2H), 3.82-4.03 (m, 5H), 3.41 (ddd, 2H), 3.01 (m (br), 2H), 1.85-1.94 (m, 2H), 1.53-1.65 (m, 2H). MS: [M+H].sup.+=519.

Example 450: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(2-fluoro-5-methylphenyl)-2-hydroxyethyl]acetamide

[1647] ##STR01538##

[1648] Prepared using a similar procedure to Example 95. In this case and following purification, the product was dissolved in EtOAc (20 mL) and washed with 1 M HCl (10 mL). The layers were separated and the organic extract was washed with water (2×10 mL), NaHCO.sub.3 (10 mL) and brine (3×10 mL), dried (MgSO.sub.4), filtered, concentrated under reduced pressure. 1H NMR (DMSO-d6, 400 MHz) δ 8.60 (1H, d), 8.45 (1H, s), 8.03 (1H, dd), 7.98 (1H, dd), 7.74 (1H, d), 7.63 (1H, br. s), 7.24-7.18 (1H, m), 7.13-6.99 (2H, m), 5.14 (1H, q), 5.04 (1H, t), 4.59 (2H, s), 4.30 (2H, d), 3.97-3.84 (3H, m), 3.61-3.51 (2H, m), 3.40-3.33 (2H, m), 2.29 (3H, s), 1.85 (2H, br. d), 1.53 (2H, qd). LCMS: [M+H].sup.+=554.

Example 451: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S,2S)-2-hydroxy-1-phenylpropyl]acetamide

[1649] ##STR01539##

[1650] HATU (104 mg, 0.273 mmol) was added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (100 mg, 0.248 mmol), (1S,2S)-1-amino-1-phenylpropan-2-ol hydrochloride (51.2 mg, 0.273 mmol), and triethylamine (0.138 mL, 0.993 mmol) in DMF (1.5 mL, 19.37 mmol). The reaction was stirred for 2 h at room temperature. The reaction was diluted with water (20 mL), then extracted with EtOAc (3×10 mL). The combined organic extracts were washed with 1 M HCl (2×20 mL), brine (3×20 mL), dried (MgSO.sub.4) and concentrated. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-10% MeOH in DCM) to afford title compound 2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-((1S,2S)-2-hydroxy-1-phenylpropyl)acetamide (73 mg, 54.3%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.50 (1H, d), 8.45 (1H, s), 8.04-8.01 (1H, m), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, br. s), 7.38-7.28 (4H, m), 7.26-7.20 (1H, m), 4.82 (1H, d), 4.72 (1H, dd), 4.58 (2H, s), 4.37 (1H, d), 4.29 (1H, d), 4.00-3.82 (4H, m), 3.41-3.35 (2H, m), 1.90-1.81 (2H, m), 1.59-1.46 (2H, m), 1.00 (3H, d). LC-MS: [M+H].sup.+=536.

Examples 452-462

[1651] Prepared using an analogous procedure to Example 451, from 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) and the corresponding amine.

TABLE-US-00038 Example Structure Name .sup.1H NMR (400 MHz) MS: [M + H].sup.+ 452 [01540] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S,2R)-2-hydroxy-1- phenylpropyl]acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.51 (1H, d), 8.45 (1H, s), 8.03-8.01 (1H, m), 7.97 (1H, dd), 7.74 (1H, d), 7.62 (1H, br. s), 7.35-7.28 (4H, m), 7.26-7.20 (1H, m), 4.76- 4.70 (2H, m), 4.57 (2H, s), 4.32 (1H, d), 4.26 (1H, d), 4.01-3.82 (4H, m), 3.42- 3.35 (2H, m), 1.89-1.81 (2H, m), 1.60-1.46 (2H, m), 1.03 (3H, d). 536 453 [01541] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(1- hydroxy-2- phenylbutan-2- yl)acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.04- 7.94 (3H, m), 7.73 (1H, d), 7.63 (1H, br. s), 7.32-7.25 (4H, m), 7.21-7.14 (1H, m), 4.85 (1H, t), 4.60 (1H, d), 4.54 (1H, d), 4.34 (2H, s), 3.99- 3.82 (4H, m), 3.74 (1H, dd), 3.42-3.36 (2H, m), 2.04- 1.91 (2H, m), 1.89- 1.82 (2H, m), 1.59-1.45 (2H, m), 0.73 (3H, t) 550 454 [01542] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(2- hydroxy-1-{imidazo[1,2-a] pyridin-8-yl}ethyl) acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.87 (1H, d), 8.45 (1H, s), 8.05 (1H, s), 8.03 (1H, d,), 7.98 (1H, dd), 7.79(1H, d), 7.74 (1H, d), 7.63 (1H, s (br)), 7.63 (d, 1H), 7.43 (1H, dd), 7.05 (1H, d), 5.36 (1H, q), 5.20 (1H, t), 4.59 (2H, s), 4.38 (1H, d), 4.30 (1H, d), 3.85 (5H, td), 3.42-3.37 (2H, m), 1.84 (2H, d), 1.53 (2H, qd). 562 455 [01543] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (1,3-dihydro-2- benzofuran-4-yl)-2- hydroxyethyl]- acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.60 (1H, d), 8.45 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.73 (1H, d), 7.61 (1H, s), 7.32-7.22 (2H, m), 7.19 (1H, d), 5.08 (2H, d), 4.94-501 (3H, 564 m), 4.75 (1H, q), 4.58 (2H, s), 4.36-4.19 (2H, m), 3.90 (3H, dd), 3.67-3.49 (2H, m), 3.39 (1H, d), 1.85 (2H, d), 1.53 (2H, qd) 564 456 [01544] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-[3- (trifluoromethyl)phenyl] ethyl]acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.70 (1H, d), 8.45 (1H, s), 8.03 (1H, dd), 7.98 (1H, dd), 7.80-7.68 (2H, m), 7.68- 7.54 (4H, m), 5.03 (1H, t), 5.01-4.94 (1H, m), 4.59 (2H, s), 4.44-4.23 (2H, m), 3.89 (3H, dd), 3.62 (2H, t), 3.33- 3.43 (2H, m), 1.85 (2H, d), 1.52 (2H, qd). 590 457 [01545] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-(3- ethylphenyl)-2- hydroxyethyl]- acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.54 (1H, d), 8.45 (1H, s), 8.03 (1H, dd), 7.98 (1H, dd), 7.74 (1H, d), 7.62 (1H, s), 7.24 (1H, t), 7.19-7.06 (3H, m), 4.92 (1H, t), 4.86 (1H, q), 4.59 (2H, s), 4.29 (2H, d), 3. 89 (3H, dd), 3.61-3.53 (2H, m), 3.33-3.43 (2H, m), 2.59 (2H, q), 1.85 (2H, d), 1.53 (2H, qd), 1.18 (3H, t). 550 458 [01546] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-(3- cyclopropylphenyl)-2- hydroxyethyl]acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.52 (1H, d), 8.45 (1H, s), 8.03 (1H, dd), 7.98 (1H, dd), 7.74 (1H, d), 7.62 (1H, s), 7.19 (1H, t), 7.11-7.01 (2H, m), 6.93 (1H, dt), 4.91 (1H, t), 4.83 (1H, q), 4.59 (2H, s), 4.29 (2H, dd), 3.90 (3H, dd), 3.55 (2H, t), 3.33-3.43 (2H, m), 1.94-1.79 (3H, m), 1.53 (2H, qd), 0.99-0.88 (2H, m), 0.73-0.58 (2H, m) 562 459 [01547] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-[3- (difluoromethoxy) phenyl]-2- hydroxyethyl]acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.61 (1H, d, J = 8.2 Hz), 8.44 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, s), 7.43-7.35 (1H, m), 7.25-7.18 (2H, m), 7.14 (1H, t), 7.08-7.02 (1H, m), 4.99 (1H,), 4.89 (1H, q), 4.58 (2H, s), 4.38-4.22 (2H, m), 3.89 (3H, dd), 3.58 (2H, t), 3.42-3.34 (2H, m), 1.84 (2H, d), 1.52 (2H, dddd). 588 460 [01548] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-(4-fluoro-3- methoxyphenyl)-2- hydroxyethyl]- acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.54 (1H, d), 8.44 (1H, s), 8.02 (1H, d), 7.97 (1H, dd), 7.74 (1H, d), 7.62 (1H, s), 7.20-7.09 (2H, m), 6.87 (1H, ddd), 4.92 (1H, t), 4.86 (1H, q), 4.59 (2H, s), 4.29 (2H, s), 3.99-3.78 (6H, m), 3.62-3.52 (2H, m), 3.43-3.32 (2H, m), 1.90-1.78 (2H, m), 1.52 (2H, dddd). 570 461 [01549] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-[3- (difluoromethyl)phenyl]- 2-hydroxyethyl]- acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.66 (1H, d), 8.44 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, s), 7.56-7.42 (4H, m), 7.03 (1H, t), 5.03-4.96 (1H, m), 4.96- 4.89 (1H,m), 4.58 (2H, s), 4.33 (1H, d), 4.27 (1H, d), 4.00-3.78 (3H, m), 3.60 (2H, dd), 3.45-3.34 (2H, m), 1.88- 1.78 (2H, m), 1.61-1.43 (2H, m). 572 462 [01550] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S,2S)-1-(3- ethylphenyl)-2- hydroxypropyl]- acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.50-8.44 (2H, m), 8.06-8.00 (1H, m), 7.97 (1H, dd), 7.73 (1H, d), 7.63 (1H, br. s), 7.25- 7.20 (1H, m), 7.18- 7.12 (2H, m), 7.09-7.04 (1H, m), 4.80 (1H, d), 4.70 (1H, dd), 4.58 (2H, s), 4.36 (1H, d), 4.30 (1H, d), 4.00-3.81 (4H, m), 3.42-3.36 (2H, m), 2.59 (2H, q), 1.91-1.81 (2H, m), 1.58- 1.46(2H, m), 1.18 (3H, t), 1.00 (3H, d). 564

Example 463, 464 and 465: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[1-(hydroxymethyl)-6-methoxy-2,3-dihydro-1H-inden-1-yl]acetamide, 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-1-(hydroxymethyl)-6-methoxy-2,3-dihydro-1H-inden-1-yl]acetamide and 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(hydroxymethyl)-6-methoxy-2,3-dihydro-1H-inden-1-yl]acetamide

[1652] ##STR01551##

[1653] Prepared using a similar procedure to Example 451. 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.06 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, s), 7.09 (1H, d), 6.88 (1H, d), 6.77 (1H, dd), 5.02 (1H, t), 4.57 (2H, s), 4.33-4.15 (2H, m), 3.90 (3H, dd), 3.72 (3H, s), 3.64 (1H, dd), 3.56 (1H, dd), 3.33-3.42 (2H, m), 2.83 (1H, ddd), 2.73 (1H, dt), 2.43-2.23 (2H, m), 1.85 (2H, d), 1.53 (2H, qd). LCMS: [M+H].sup.+=578. The enantiomers were separated by chiral preparative HPLC (Gilson, IA column, isocratic 20% EtOH with 80% 4:1 (i-Hexane+0.2% diethylamine):DCM).

Example 466: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-(1,3-dihydroxy-2-phenylpropan-2-yl)acetamide

[1654] ##STR01552##

[1655] Prepared using a similar procedure to Example 451. In this case, the product was further purified by preparative HPLC (Waters, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 20-40% MeCN in Water). 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.06-8.01 (2H, m), 7.97 (1H, dd), 7.74 (1H, d), 7.62 (1H, br. s), 7.37-7.32 (2H, m), 7.31-7.25 (2H, m), 7.22-7.15 (1H, m), 4.88 (2H, t), 4.59 (2H, s), 4.36 (2H, s), 3.99-3.80 (7H, m), 3.42-3.35 (2H, m), 1.90-1.80 (2H, m), 1.59-1.46 (2H, m). LCMS: [M+H].sup.+=552.

Example 467: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-[3-(oxolan-2-yl)phenyl]ethyl]acetamide

[1656] ##STR01553##

[1657] Prepared using a similar procedure to Example 451. After purification, the product was dissolved in EtOAc and further washed with 1N HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with NaHCO.sub.3, brine, dried (MgSO.sub.4) and concentrated under vacuum, to afford the title compound (0.007 g, 0.011 mmol) as a white solid after trituration and evaporation from Et.sub.2O. 1H NMR (DMSO-d6) δ: 8.58 (d, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.63 (s (br), 1H), 7.32-7.24 (m, 2H), 7.24-7.15 (m, 2H), 4.93 (t, 1H), 4.87 (td, 1H), 4.81-4.74 (m, 1H), 4.59 (s, 2H), 4.32 (d, 1H), 4.26 (d, 1H), 4.04-3.76 (m, 5H), 3.62-3.53 (m, 2H), 3.42-3.35 (m, 2H), 2.34-2.23 (m, 1H), 1.98-1.89 (m, 2H), 1.88-1.80 (m, 2H), 1.70-1.59 (m, 1H), 1.58-1.46 (m, 2H). LCMS: [M+H].sup.+=592.

Example 468: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-2,3-dihydro-1H-isoindol-1-one

[1658] ##STR01554##

[1659] DIPEA (0.090 mL, 0.515 mmol), indoline (0.040 mL, 0.356 mmol) and then HATU (0.142 g, 0.373 mmol) were added to a stirred solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 0.100 g, 0.246 mmol) in DMF (2.0 mL, 25.8 mmol) at room temperature. After 2.5 h the reaction mixture was partitioned between EtOAc (30 mL) and NH.sub.4Cl (30 mL). The layers were separated and the aqueous was extracted with EtOAc (30 mL). The combined organic fraction was washed with water (20 mL), NaHCO.sub.3 (20 mL) and brine (2×20 mL) and then concentrated under vacuum. The aqueous layer contained a white solid which was isolated by filtration and then washed with water (10 mL) and then ether (2×10 mL). This solid was triturated with ether (3 mL), sonicated and then the solution was decanted (repeated ×3). The solid was then suspended in MeOH: water (5 mL, 1:1), sonicated and then heated to give a white solution. The solution was allowed to cool overnight and the resulting solid was isolated by decanting the solvent. The solid was dried in a desiccator at 50° C. for 5 h to afford the title compound (0.049 g, 37.2%). 1H NMR (400 MHz, DMSO-d6) δ 8.46 (1H, s), 8.07 (1H, d), 8.01 (2H, dd), 7.79 (1H, d), 7.63 (1H, s), 7.29 (1H, d), 7.16 (1H, t), 7.03 (1H, t), 4.62 (4H, d), 4.23 (2H, t), 3.98-3.85 (3H, m), 3.39 (2H, t), 3.23 (2H, t), 1.86 (2H, d), 1.54 (2H, qd). LC-MS: [M+H].sup.+=504.

Example 469: 2-[2-(7-chloro-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)-2-oxoethyl]-6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1H-isoindol-1-one

[1660] ##STR01555##

[1661] Triethylamine (67.5 μl, 0.484 mmol) was added to a stirred solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 65 mg, 0.161 mmol), 7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (29.3 mg, 0.161 mmol) and HATU (67.5 mg, 0.177 mmol) in DCM (3 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (30 mL) and washed with 1M HCl (30 ml), sat. aq. NaHCO.sub.3 (30 mL), water (30 mL) and brine (30 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by chromatography (SiO.sub.2, 40 g column, 0-10% MeOH in EtOAc) to afford the title compound (50 mg, 0.087 mmol, 54.2%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.04 (1H, d), 7.99 (1H, dd), 7.75 (1H, d), 7.62 (1H, s), 7.29 (1H, dd), 7.25-7.14 (2H, m), 4.56 (4H, t), 4.00-3.82 (3H, m), 3.72-3.55 (4H, m), 3.45-3.34 (2H, m), 2.99 (2H, t), 2.87 (2H, q), 1.85 (2H, d), 1.53 (2H, qd). LC-MS: [M+H].sup.+=566.

Example 470: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-2,3-dihydro-1H-inden-1-yl]acetamide

[1662] ##STR01556##

[1663] DIPEA (0.073 ml, 0.417 mmol) followed by HATU (0.079 g, 0.209 mmol) were added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 0.08 g, 0.199 mmol) and (R)-2,3-dihydro-1H-inden-1-amine hydrochloride (0.035 g, 0.209 mmol) in DMF (1 mL) and the mixture was stirred for 30 minutes. 1N HCl was added and the mixture was diluted with water. The resulting precipitate was filtered, washed with water, NaHCO.sub.3, water and dried under suction. The solid was then dissolved in DCM and brine was added. The layers were separated through a phase separating cartridge and the organic layer was dried (MgSO.sub.4) and concentrated under vacuum to afford the title compound (0.065 g, 62.6%) as a white solid after trituration and evaporation from Et.sub.2O.1H NMR (DMSO-d6) δ: 8.55 (d, 1H), 8.45 (s (br), 1H), 8.04 (d, 1H), 7.99 (dd, 1H), 7.76 (d, 1H), 7.62 (s (br), 1H), 7.23 (m, 4H), 5.34 (dd, 1H), 4.64 (s, 2H), 4.27 (s, 2H), 4.05-3.79 (m, 3H), 3.39 (d, 2H), 2.94 (ddd, 1H), 2.81 (m, 1H), 2.40 (dtd, 1H), 1.83 (m, 3H), 1.53 (qd, 2H). LC-MS: [M+H].sup.+=518.

Example 471: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]acetamide

[1664] ##STR01557##

[1665] HATU (83 mg, 0.218 mmol) followed by triethylamine (83 μl, 0.596 mmol) were added to a solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 80 mg, 0.199 mmol) and (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (29.6 mg, 0.199 mmol) in DMF (3 mL). HCl (1M, 2 mL) followed by water (10 mL) were added. The resulting white precipitate was filtered, washed with NaHCO.sub.3 (10 mL), dried in vacuo at 40° C. The residue was triturated with a mixture of MeOH in Et.sub.2O to give the title compound (63 mg, 58.2%) as a pale tan powder. 1H NMR (CDCl3, 400 MHz) δ 8.33 (1H, s), 8.28 (1H, d), 8.02 (1H, dd), 7.59 (1H, d), 7.25-7.15 (3H, m), 7.08 (1H, d), 5.18 (1H, d), 5.11 (1H, t), 4.67 (2H, s), 4.46-4.36 (4H, m), 4.11-3.94 (3H, m), 3.58-3.50 (2H, m), 3.28 (1H, dd), 2.92 (1H, dd), 2.05 (2H, d), 1.56 (2H, qd) (one exchangeable proton was not observed). LC-MS: [M+H]+=534.

Example 472: N-(2-aminoethyl)-N-benzyl-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamide

[1666] ##STR01558##

[1667] TFA (455 μl, 5.90 mmol) was added to a stirred solution of tert-butyl (2-(N-benzyl-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetamido)ethyl)carbamate (Preparation 312, 75 mg, 0.118 mmol) in DCM (1.2 mL, 0.1 M) under nitrogen. The reaction was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue was azeotroped with toluene (4×3 mL) and MeCN (2×3 mL) to give the crude product as a pale yellow solid (60 mg). The crude product was loaded onto a column of SCX (600 mg) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to afford the title compound (51 mg, 77%) as a white solid. 1H NMR (DMSO-d6, 400 MHz @ 60° C.) δ 8.42 (1H, s), 8.05 (1H, s), 8.03-7.95 (1H, m), 7.73 (1H, t), 7.42-7.24 (6H, m), 4.79-4.44 (6H, m), 4.03-3.80 (3H, m), 3.49-3.27 (4H, m), 2.81-2.66 (2H, m), 1.93-1.83 (2H, m), 1.64-1.49 (2H, m) (NH.sub.2 missing—probably overlapped with water peak). LC-MS: [M+H].sup.+=535.

Example 473: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[2-(2-methoxyphenyl)propan-2-yl]acetamide

[1668] ##STR01559##

[1669] HATU (83 mg, 0.218 mmol) followed by triethylamine (83 μl, 0.596 mmol) were added to a solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 80 mg, 0.199 mmol) and 2-(2-methoxyphenyl)propan-2-amine (32.8 mg, 0.199 mmol) in DMF (1 mL). The reaction mixture was stirred for 1h at room temperature. Water (10 mL) was added and the resulting white precipitate was filtered. The solid was triturated (MeOH/Et.sub.2O) to give the title compound (76 mg, 66.8%) as a colourless powder. 1H NMR (DMSO, 400 MHz) δ 8.44 (1H, s), 8.16 (1H, s), 8.01 (1H, dd), 7.95 (1H, dd), 7.72 (1H, d), 7.62 (1H, bs), 7.24-7.15 (2H, m), 6.97 (1H, dd), 6.85 (1H, td), 4.54 (2H, s), 4.22 (2H, s), 3.99-3.82 (3H, m), 3.80 (3H, s), 3.41-3.35 (2H, m), 1.84 (2H, d), 1.64 (6H, s), 1.52 (2H, qd). LC-MS: [M+H].sup.+=550.

Example 474: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-{[3-(hydroxymethyl)phenyl]methyl}acetamide

[1670] ##STR01560##

[1671] Prepared using a similar procedure to Example 94. 1H NMR (CDCl3, 400 MHz) δ 8.33 (1H, s), 8.22 (1H, s), 7.99 (1H, dd), 7.59-7.54 (1H, m), 7.25-7.12 (4H, m), 6.85 (1H, bs), 5.30 (1H, bs), 4.63 (2H, s), 4.58 (2H, s), 4.42 (2H, d), 4.30 (2H, s), 4.11-3.93 (3H, m), 3.53 (2H, td), 2.09-1.99 (2H, m), 1.62-1.49 (2H, m). (1 exchangeable proton not observed). LC-MS: [M+H].sup.+=522.

Example 475: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[2-hydroxy-1-(2-methylphenyl)ethyl]acetamide

[1672] ##STR01561##

[1673] HATU (83 mg, 0.218 mmol) followed by triethylamine (83 μl, 0.596 mmol) were added to a solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 80 mg, 0.199 mmol) and 2-amino-2-(o-tolyl)ethanol (30.0 mg, 0.199 mmol) in DMF (1 mL). The reaction mixture was stirred for 1h at room temperature. Water (10 mL) was added and the resulting white precipitate was filtered. The crude product was purified by chromatography (SiO.sub.2, 0-5% MeOH in EtOAc) to give the title (12 mg, 11.05%) as a colourless powder. 1H NMR (CDCl.sub.3, 400 MHz) δ 8.33 (1H, s), 8.31-8.28 (1H, m), 8.00 (1H, dd), 7.58-7.53 (1H, m), 7.24-7.10 (4H, m), 7.06 (1H, d), 5.35-5.27 (2H, m), 4.62 (2H, dd), 4.32 (2H, dd), 4.11-3.95 (3H, m), 3.87-3.76 (2H, m), 3.58-3.48 (2H, m), 2.39 (3H, s), 2.05 (2H, d), 1.62-1.50 (2H, m). (1 exchangeable proton in water peak). LC-MS: [M+H].sup.+=536.

Example 476, 477 and 478: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-(1-hydroxy-2-phenylpropan-2-yl)acetamide, 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(2R)-1-hydroxy-2-phenylpropan-2-yl]acetamide, 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(2S)-1-hydroxy-2-phenylpropan-2-yl]acetamide

[1674] ##STR01562##

[1675] HATU (83 mg, 0.218 mmol) followed by triethylamine (83 μl, 0.596 mmol) were added to a solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (80 mg, 0.199 mmol) and 2-amino-2-phenylpropan-1-ol (30.0 mg, 0.199 mmol) in DMF (1 mL). The reaction mixture was stirred for 1h at room temperature. Water (10 mL) was added and the resulting white precipitate was filtered, purified by chromatography (SiO.sub.2, 0-5% MeOH in ethyl acetate), followed by preparative HPLC (acidic) to give the title compound (22 mg, 20.46%) as a colourless powder. 1H NMR (DMSO, 400 MHz) δ 8.44 (1H, s), 8.16 (1H, s), 8.01 (1H, d), 7.96 (1H, dd), 7.72 (1H, d), 7.61 (1H, bs), 7.35-7.25 (4H, m), 7.21-7.15 (1H, m), 5.07 (1H, s), 4.56 (2H, s), 4.30 (2H, s), 3.99-3.81 (3H, m), 3.67 (1H, d), 3.54-3.46 (1H, m), 3.42-3.35 (2H, m), 1.84 (2H, dd), 1.60 (3H, s), 1.58-1.46 (2H, m). LC-MS: [M+H].sup.+=536. The enantiomers were separated by chiral preparative HPLC (Daicel IA 2 cm×25 cm 5 μm, 60% (iso-hexanes+0.2% TFA): 40% EtOH, 60 min run time) to give 2 fractions:

[1676] Fration 1 was further purified by flash chromatography (SiO.sub.2, 0-5% MeOH in DCM) to afford 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(2R)-1-hydroxy-2-phenylpropan-2-yl]acetamide. 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.14 (1H, s), 8.02 (1H, dd), 7.96 (1H, dd), 7.73 (1H, d), 7.62 (1H, br. s), 7.36-7.25 (4H, m), 7.22-7.14 (1H, m), 5.03 (1H, t), 4.57 (2H, s), 4.31 (2H, s), 3.99-3.85 (3H, m), 3.67 (1H, dd), 3.50 (1H, dd), 3.41-3.34 (2H, m), 1.84 (2H, br. d), 1.60 (3H, s), 1.58-1.48 (2H, m) ppm. LC-MS: [M+H].sup.+=536.

[1677] Fration 1 was further purified by flash chromatography (SiO.sub.2, 20% (1% NH.sub.3 in MeOH) in DCM) and then further flash chromatography (SiO.sub.2, 0-10% MeOH in DCM) to afford clean peak 2 (19 mg).

[1678] Peak 2: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(2S)-1-hydroxy-2-phenylpropan-2-yl]acetamide. 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.14 (1H, s), 8.02 (1H, dd), 7.96 (1H, dd), 7.73 (1H, d), 7.62 (1H, br. s), 7.36-7.25 (4H, m), 7.22-7.14 (1H, m), 5.03 (1H, t), 4.57 (2H, s), 4.31 (2H, s), 3.99-3.85 (3H, m), 3.67 (1H, dd), 3.50 (1H, dd), 3.41-3.34 (2H, m), 1.84 (2H, br. d), 1.60 (3H, s), 1.58-1.48 (2H, m) ppm. LC-MS: [M+H].sup.+=536.

Example 479: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[2-(3-cyanophenyl)propan-2-yl]acetamide

[1679] ##STR01563##

[1680] Prepared using a similar procedure to Example 476. 1H NMR (CDCl.sub.3, 400 MHz) δ 8.37-8.30 (2H, m), 8.03 (1H, dd), 7.62-7.54 (3H, m), 7.49 (1H, dt), 7.39-7.33 (1H, m), 6.88 (1H, bs), 5.20 (1H, d), 4.61 (2H, s), 4.23 (2H, s), 4.12-3.94 (3H, m), 3.54 (2H, td), 2.12-2.00 (2H, m), 1.65 (6H, s), 1.59-1.52 (2H, m). LC-MS: [M+H].sup.+=545.

Example 480: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[2-(1-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)-2-oxoethyl]-2,3-dihydro-1H-isoindol-1-one

[1681] ##STR01564##

[1682] Triethylamine (67.5 μl, 0.484 mmol) was added to a stirred solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 65 mg, 0.161 mmol), 2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol (26.3 mg, 0.161 mmol) and HATU (67.5 mg, 0.177 mmol) in DCM (3 mL). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (30 mL) and washed with 1M HCl (30 ml), sat. aq. NaHCO.sub.3 (30 mL), water (30 mL) and brine (30 mL) and dried (MgSO.sub.4). The precipitate that formed in the aqueous layer was collected by filtration, washed with water (5 ml×2), and then dissolved in 20% MeOH:DCM (50 ml). The resulting solution was dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound (38 mg, 42.5%) as a colourless solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.46 (1H, s), 8.06-8.01 (1H, m), 7.99 (1H, dd), 7.75 (1H, d), 7.63 (1H, s), 7.48-7.33 (1H, m), 7.27-7.10 (3H, m), 5.78-5.71 (1H, m), 4.78 (1H, d), 4.68 (1H, s), 4.63 (1H, d), 4.59-4.46 (3H, m), 3.99-3.75 (5H, m), 3.61 (1H, d), 3.40 (2H, d), 3.11 (1H, dd), 2.73 (1H, dd), 1.85 (2H, d), 1.53 (2H, qd). LC-MS: [M+H].sup.+=548. (note: NMR showed several different rotamers).

Example 481: N-[(1S)-2-amino-1-phenylethyl]-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamide

[1683] ##STR01565##

[1684] TFA (0.3 ml, 0.177 mmol) was added to a mixture of (S)-tert-butyl (2-(2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetamido)-2-phenylethyl)carbamate (Preparation 304, 0.11 g, 0.177 mmol) in DCM (1 mL) and the mixture was stirred for 1h. The mixture was concentrated under vacuum and NaHCO.sub.3 and DCM were added. The layers were separated through a phase separating cartridge and the organic layer was concentrated under vacuum. The residue was dissolved in MeOH and loaded on a column packed with SCX. The column was washed with MeOH and the product was eluted with 1% NH.sub.3 in MeOH. The mixture was concentrated under vacuum and the residue was dissolved in DCM and filtered through cotton wool. The mixture was concentrated under vacuum and the residue was triturated with Et.sub.2O, then concentrated under vacuum to afford the title compound (0.072 g, 76%) as a white solid. 1H NMR (DMSO-d6, VT T=350K) δ: 8.41 (s, 1H), 8.32 (s (br, 1H), 8.07 (d, 1H), 8.00 (dd, 1H), 7.72 (dd, 1H), 7.34 (d, 4H), 7.31-7.20 (m, 2H), 4.88 (m, 1H), 4.61 (s, 2H), 4.35 (d, 2H), 4.28 (d, 1H), 4.02-3.83 (m, 3H), 3.41 (td, 3H), 2.95-2.87 (m, 2H), 1.89 (m, 2H), 1.58 (m, 2H). LC-MS: [M+H].sup.+=521.

Example 482 and 483: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-{2-[(1R)-5-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl]-2-oxoethyl}-2,3-dihydro-1H-isoindol-1-one and 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-{2-[(1S)-5-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl]-2-oxoethyl}-2,3-dihydro-1H-isoindol-1-one

[1685] ##STR01566##

[1686] The enantiomers of 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-{2-[5-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl]-2-oxoethyl}-2,3-dihydro-1H-isoindol-1-one (Example 192, 170 mg) were separated by preparative chiral HPLC (Gilson, Chiralpak IA, 2 cm×25 cm, 40% EtOH in 3:1 Hexane (+0.2% TFA):DCM) to afford 6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-2-(2-(5-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)isoindolin-1-one (isomer 1, 20 mg, 7.3%) (rt 24 mins) and 6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-2-(2-(5-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)isoindolin-1-one (isomer 2, 20 mg, 7.3%) as colourless solids. Upon contraction of the solution, the products were obtained as a mixture with c.a. 10% of their trifluoroacetates ((2-(2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)methyl 2,2,2-trifluoroacetate). The colourless solids of each enantiomers were dissolved in methanol (1.5 ml, 37.1 mmol), K.sub.2CO.sub.3 (16.94 mg, 0.123 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and then diluted with DCM (30 ml) and then washed with water (10 mL). The organic was dried (MgSO.sub.4), filtered and concentrated in vacuo to afford both title compounds (17 mg, 6.1%) as colourless solids. LC-MS: [M+H].sup.+=562.

Example 484: 2-{2-[1-(aminomethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-oxoethyl}-6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1H-isoindol-1-one

[1687] ##STR01567##

[1688] A stirred solution of 2-((3-(2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)methyl)isoindoline-1,3-dione (Preparation 310, 20 mg, 0.029 mmol) in ethanol (1 ml) was treated with hydrazine hydrate (5.68 μl, 0.116 mmol) and the resulting white suspension was heated under reflux for 3 h. The reaction mixture was concentrated under vacuum and the residue was purified by chromatography (SiO.sub.2, 12 g column, 0 to 10% of MeOH in DCM) to the title compound (8 mg, 0.014 mmol, 48.8% yield) as a colourless solid. 1H NMR (CD.sub.3OD, 400 MHz) δ 8.39-8.33 (1H, m), 8.26-8.19 (1H, m), 8.14-8.04 (1H, m), 7.73-7.66 (1H, m), 7.29-7.04 (4H, m), 4.72-4.45 (4H, m), 4.25-4.16 (1H, m), 4.10-3.85 (4H, m), 3.55 (2H, td), 3.23-3.12 (1H, m), 3.11-2.77 (3H, m), 2.07-1.97 (2H, m), 1.73-1.55 (2H, m) (exchangeable NH and NH.sub.2 were not observed, 4 protons signals overlapped with MeOD and/or water peaks). LC-MS: [M+H].sup.+=561.

Example 485: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-{2-[7-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-oxoethyl}-2,3-dihydro-1H-isoindol-1-one

[1689] ##STR01568##

[1690] 1M TBAF in THF (81 μl, 0.081 mmol) was added to a stirred solution of 2-(2-(7-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-oxoethyl)-6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)isoindolin-1-one (Preparation 305, 46 mg, 0.067 mmol) in THF (1 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc (30 mL) and water (15 mL). The organic layer was washed with brine (15 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to give the crude product (70 mg). Purification by chromatography (SiO.sub.2, 24 g column, 0-10% MeOH in EtOAc) afforded a glass, which was triturated with diethyl ether and dried to afford the title compound (10 mg, 25.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.03-8.02 (m, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.62 (s (br), 1H), 7.15-7.03 (m, 3H), 5.11 (t, 1H), 4.55 (s, 4H), 4.44 (d, 2H), 3.97-3.85 (m, 3H), 3.67-3.55 (m, 4H), 3.37 (t, 2H), 2.97-2.93 (m, 2H), 2.87-2.81 (m, 2H), 1.86-1.83 (br m, 2H), 1.52 (qd, 2H). LC-MS: [M+H].sup.+=562.

Example 486: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[2-(1-methyl-3-oxo-2,3-dihydro-1H-isoindol-2-yl)-2-oxoethyl]-2,3-dihydro-1H-isoindol-1-one

[1691] ##STR01569##

[1692] A microwave vial was charged with N-(1-(2-bromophenyl)ethyl)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetamide (Preparation 311, 102 mg, 0.167 mmol), 3-oxobenzo[d]isothiazole-2(3H)-carbaldehyde 1,1-dioxide (52.9 mg, 0.251 mmol), sodium carbonate (17.70 mg, 0.167 mmol), Pd(OAc).sub.2 (1.125 mg, 5.01 μmol) and 1,4-bis(diphenylphosphino)butane (3.20 mg, 7.52 μmol). The vial was capped and evacuated and back-filled with nitrogen (3×). Triethylsilane (34.7 μl, 0.217 mmol) was added in degassed (nitrogen sparged for 10 minutes) DMF (0.8 mL) and the mixture stirred at room temperature for 10 minutes. The mixture was heated to 80° C. and stirred under nitrogen overnight. The reaction mixture was diluted with EtOAc (10 mL) and washed with brine (10 mL). The aqueous phase was extracted with EtOAc (1×10 mL) and the combined organic extracts dried (MgSO.sub.4), filtered and concentrated in vacuo to afford a yellow gum (120 mg). The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-100% EtOAc in isohexane) to afford the title compound (16 mg, 17.83%) as a colourless glass. 1H NMR (DMSO-d6) δ: 8.45 (s, 1H), 8.06 (d, 1H), 8.01 (dd, 1H), 7.89 (d, 1H), 7.83-7.75 (m, 2H), 7.72 (dd, 1H), 7.60 (dd, 1H), 7.60 (s (br), 1H), 5.24 (q, 1H), 5.06 (d, 1H), 5.01 (d, 1H), 4.65 (s, 2H), 4.00-3.81 (m, 3H), 3.43-3.33 (m, 2H), 1.91-1.80 (m, 2H), 1.57 (d, 3H), 1.55-1.47 (m, 2H). LC-MS: [M+H].sup.+=532.

Example 487: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[1-(2-fluorophenyl)ethyl]acetamide

[1693] ##STR01570##

[1694] A solution of 1-(2-fluorophenyl)ethanamine (5.5 mg, 0.040 mmol), 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 15 mg, 0.037 mmol) and Hunig's base (0.020 ml, 0.112 mmol) in DMF (0.2 ml) was treated with a solution of HATU (14.5 mg, 0.038 mmol) in DMF (0.2 ml) and shaken until homogeneous. The mixture was allowed to stand for 1 h, then diluted with methanol (40 μL), filtered and purified by reversed phase preparative HPLC on a Waters XSelect CSH C18 OBD, 130 Å, 5 μm, 19 mm×50 mm column, using a gradient of 5 to 95% of acetonitrile in water with 0.1% fomic acid in both at 28 ml/min as eluent. The eluent was evaporated to give a colourless glass (17.3 mg). The product was further purified by reverse phase preparative HPLC on a Waters XBridge BEH C18 OBD, 130 Å, 5 μm, 19 mm×50 mm column, using a gradient of 5 to 95% of acetonitrile in 10 mM aqueous ammonium bicarbonate solution at 28 ml/min as eluent. The clean fractions were combined and evaporated to afford the title compound (11.3 mg, 55.0%) as a white solid. 1H NMR (DMSO, 400 MHz) δ 8.70 (1H, d), 8.44 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.73 (1H, d), 7.63 (1H, s), 7.47-7.38 (1H, m), 7.34-7.25 (1H, m), 7.24-7.08 (2H, m), 5.17 (1H, p), 4.58 (2H, s), 4.26 (2H, s), 3.98-3.81 (3H, m), 3.47-3.35 (2H, m), 1.84 (2H, d), 1.62-1.44 (2H, m), 1.38 (3H, d). LC-MS: [M+H].sup.+=524.

Example 488: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[3-(hydroxymethyl)phenyl]ethyl]acetamide

[1695] ##STR01571##

[1696] Sodium borohydride (0.808 mg, 0.021 mmol) was added to an ice-cooled stirred solution of (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-(1-(3-formylphenyl)ethyl)acetamide (Preparation 307, 10 mg, 0.018 mmol) in 1:1 THF/MeOH (1 mL) under nitrogen. The mixture was allowed to warm to room temperature and stirred overnight. A further portion of sodium borohydride (0.808 mg, 0.021 mmol) was added and stirring continued at room temperature for 1 h. The reaction was quenched with NH.sub.4Cl (aq.) (10 mL) and extracted with DCM (3×10 mL). The organic extracts were combined and washed with brine (1×30 mL) and then dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography (SiO.sub.2, 4 g column, 0-5% MeOH in DCM) to afford the title compound (7 mg, 71.9%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.61 (1H, d), 8.44 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, s), 7.32-7.24 (2H, m), 7.21-7.15 (2H, m), 5.19 (1H, t), 4.94 (1H, dq), 4.58 (2H, s), 4.49 (2H, d), 4.24 (2H, d), 3.98-3.81 (3H, m), 3.42-3.35 (2H, m), 1.84 (2H, d), 1.58-1.46 (2H, m), 1.37 (3H, d). LC-MS: [M+H].sup.+=536.

Example 489-537

[1697] Solutions of generic amine (0.039 mmol), 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 15 mg, 0.037 mmol) and DIPEA (0.026 ml, 0.149 mmol) in DMF (0.2 ml) were treated with solutions of HATU (15.5 mg, 0.041 mmol) in DMF (0.2 ml) and shaken until homogenous. The mixtures were allowed to stand overnight and purified by reversed phase preparative HPLC on a Waters XBridge BEH C18 OBD, 130 Å, 5 μm, 19 mm×50 mm column, using a gradient of either 20 to 50% (conditions A), 35 to 65% (conditions B) or 50 to 80% (conditions C) of acetonitrile in 10 mM aqueous ammonium bicarbonate solution at 28 ml/min as eluent. The clean fractions were evaporated in the genevac. Solid residues were submitted directly, otherwise residues were treated as specified in the table below.

TABLE-US-00039 MS: Example Structure Prep. Name .sup.1H NMR (400 MHz) [M + H].sup.+ 489 [01572] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- {[4- (ethoxymethyl)phenyl] methyl}acetamide 1H NMR (DMSO-d6) δ: 8.64 (t, 1H), 8.44 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.61 (s (br), 1H), 7.27 (d, 2H), 7.24 (d, 2H), 4.61 (s, 2H), 4.42 (s, 2H), 4.29 (d, 2H), 4.26 (s, 2H), 3.98-3.81 (m, 3H), 3.45 (q, 2H), 3.41-3.34 (m, 2H), 1.89-1.78 (m, 2H), 1.58-1.44 (m, 2H), 1.13 (t, 3H). 550 490 [01573] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [4-(pyrimidin-5- yl)phenyl]ethyl} acetamide 1H NMR (DMSO-d6) δ: 9.18 (s, 1H), 9.13 (s, 2H), 8.69 (d, 1H), 8.44 (s, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.82-7.76 (m, 2H), 7.74 (d, 1H), 7.61 (s (br), 1H), 7.53-7.44 (m, 2H), 5.01 (qd, 1H), 4.60 (s, 2H), 4.27 (s, 2H), 4.01-3.77 (m, 3H), 3.44-3.35 (m, 2H), 1.84 (d, 2H), 1.57-1.45 (m, 2H), 1.42 (d, 3H) 584 491 [01574] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(3- propoxyphenyl)methyl] acetamide 1H NMR (DMSO-d6) δ: 8.61 (t, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.62 (s (br), 1H), 7.22 (dd, 1H), 6.86-6.76 (m, 3H), 4.61 (s, 2H), 4.27 (d, 2H), 4.26 (s, 2H), 3.91 (t, 2H), 3.93- 3.80 (m, 3H), 3.38 (d, 2H), 1.90-1.77 (m, 2H), 1.78-1.64 (m, 2H), 1.60-1.45 (m, 2H), 0.97 (t, 3H) 550 492 [01575] A 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (2-oxo-1,2,3,4- tetrahydroquinolin-6- yl)ethyl]acetamide 1H NMR (DMSO-d6) δ: 10.03 (s, 1H), 8.52 (d, 1H), 8.44 (s, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.74 (d, 1H), 7.61 (s, 1H), 7.12 (d, 1H), 7.08 (dd, 1H), 6.79 (d, 1H), 4.93-4.82 (m, (s, 2H), 3.99-3.81 (m, 3H), 3.45-3.35 (m, 2H), 2.89-2.80 (m, 2H), 2.43 (dd, 2H), 1.91-1.78 (m, 2H), 1.60-1.45 (m, 2H), 1.35 (d, 3H) 575 493 [01576] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (2,6- difluorophenyl)ethyl] acetamide 1H NMR (DMSO-d6) δ: 8.73 (d, 1H), 8.44 (s, 1H), 8.00 (d, 1H), 7.96 (dd, 1H), 7.71 (d, 1H), 7.62 (s (br), 1H), 7.38-7.28 (m, 1H), 7.10-7.00 (m, 2H), 5.23 (qd, 1H), 4.55 (s, 2H), 4.25 (d, 1H), 4.19 (d, 1H), 4.00-3.76 (m, 3H), 3.46-3.34 (m, 2H), 1.90-1.77 (m, 2H), 1.57-1.48 (m, 2H), 1.47 (d, 3H) 542 494 [01577] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [5-fluoro-2-(1H- pyrazol-1- yl)phenyl]ethyl} acetamide 1H NMR (DMSO-d6) δ: 8.68 (d, 1H), 8.44 (s, 1H), 8.00 (dd, 1H), 7.99 (dd, 1H), 7.96 (dd, 1H), 7.72 (d, 1H), 7.70 (dd, 1H), 7.61 (s (br), 1H), 7.40 (dd, 1H), 7.36 (dd, 1H) 7.27-7.19 (m, 1H), 6.48 (dd, 1H), 4.88 (qd, 1H), 4.56 (d, 1H), 4.51 (d, 1H), 4.23 (d, 1H), 4.19 (d, 1H), 4.00-3.77 (m, 3H), 3.48-3.34 (m, 2H), 1.95- 1.75 (m, 2H), 1.63- 1.40 (m, 2H), 1.25 (d, 3H) 590 495 [01578] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (4-fluoro-3- methoxyphenyl)ethyl] acetamide 1H NMR (DMSO-d6) δ: 8.59 (d, 1H), 8.44 (s, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.74 (d, 1H), 7.61 (s (br), 1H), 7.13 (dd, 1H), 7.12 (dd, 1H), 6.88 (ddd, 1H), 4.94 (qd, 1H), 4.59 (s, 2H), 4.25 (s, 2H), 3.96-3.85 (m, 3H), 3.84 (s, 3H), 3.44- 3.35 (m, 2H), 1.91- 1.76 (m, 2H), 1.59- 1.44 (m, 2H), 1.37 (d, 3H) 554 496 [01579] A 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- {[3- (ethanesulfonyl)phenyl] methyl}acetamide 1H NMR (DMSO-d6) δ: 8.77 (t, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.82-7.70 (m, 3H), 7.68-7.55 (m, 3H), 4.61 (s, 2H), 4.42 (d, 2H), 4.28 (s, 2H), 3.86 (d, 3H), 3.44- 3.35 (m, 2H), 3.29 (q, 2H), 1.92-1.77 (m, 2H), 1.61-1.46 (m, 2H), 1.10 (t, 3H) 584 497 [01580] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [4-(pyridin-4- yl)phenyl]ethyl} acetamide 1H NMR (DMSO-d6) δ: 8.68 (d, 1H), 8.65- 8.59 (m, 2H), 8.44 (s, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.77 (d, 2H), 7.74 (d, 1H), 7.71- 7.67 (m, 2H), 7.62 (s, 1H), 7.51-7.44 (m, 2H), 5.01 (qd, 1H), 4.60 (s, 2H), 4.27 (s, 2H), 4.01-3.79 (m, 3H), 3.42-3.34 (m, 2H), 1.92-1.76 (m, 2H), 1.58-1.45 (m, 2H), 1.42 (d, 3H) 583 498 [01581] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [3-(1H-1,2,3,4- tetrazol-1- yl)phenyl]ethyl} acetamide 1H NMR (DMSO-d6) δ: 10.12 (s, 1H), 8.74 (d, 1H), 8.44 (s, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.90-7.84 (m, 1H), 7.78 (ddd, 1H), 7.73 (d, 1H), 7.62 (dd, 2H), 7.57-7.50 (m, 1H), 5.06 (qd, 1H), 4.60 (s, 2H), 4.28 (s, 2H), 4.00-3.79 (m, 3H), 3.37 (d, 2H), 1.90- 1.77 (m, 2H), 1.58- 1.47 (m, 2H), 1.45 (d, 3H) 574 499 [01582] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [3-(1H-pyrazol-1- yl)phenyl]ethyl} acetamide 1H NMR (DMSO-d6) δ: 8.70 (d, 1H), 8.51 (dd, 1H), 8.44 (s, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.84-7.78 (m, 1H), 7.75 (dd, 1H), 7.73 (d, 1H), 7.70 (ddd, 1H), 7.62 (s (br), 1H), 7.45 (dd, 1H), 7.31-7.23 (m, 1H), 6.55 (dd, 1H), 5.02 (qd, 1H), 4.60 (s, 2H), 4.27 (s, 2H), 3.98- 3.78 (m, 3H), 3.42- 3.34 (m, 2H), 1.91- 1.78 (m, 2H), 1.59- 1.46 (m, 2H), 1.43 (d, 3H) 572 500 [01583] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (3-fluoro-4- methoxyphenyl)ethyl] acetamide 1H NMR (DMSO-d6) δ: 8.55 (d, 1H), 8.44 (s, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.74 (d, 1H), 7.61 (s (br), 1H), 7.19-7.04 (m, 3H), 4.90 (qd, 1H), 4.58 (s, 2H), 4.24 (s, 2H), 3.98- 3.83 (m, 3H), 3.81 (s, 3H), 3.43-3.33 (m, 2H), 1.92-1.77 (m, 2H), 1.61-1.44 (m, 2H), 1.35 (d, 3H) 554 501 [01584] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [4-(2-methyl-1H- imidazol-1- yl)phenyl]ethyl} acetamide 1H NMR (DMSO-d6) δ: 8.69 (d, 1H), 8.44 (s, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.74 (d, 1H), 7.61 (s (br), 1H), 7.48 (d, 2H), 7.41 (d, 2H), 7.26 (d, 1H), 6.90 (d, 1H), 5.03 (qd, 1H), 4.60 (s, 2H), 4.27 (s, 2H), 3.97-3.78 (m, 3H), 3.42-3.36 (m, 2H), 2.28 (s, 3H), 1.90- 1.77 (m, 2H), 1.59- 1.46 (m, 2H), 1.42 (d, 3H) 586 502 [01585] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [4-(1H-pyrazol-1- yl)phenyl]ethyl} acetamide 1H NMR (DMSO-d6) δ: 8.65 (d, 1H), 8.47 (dd, 1H), 8.44 (s, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.79 (d, 2H), 7.75- 7.70 (m, 2H), 7.61 (s (br), 1H), 7.44 (d, 2H), 6.53 (dd, 1H), 5.00 (qd, 1H), 4.59 (s, 2H), 4.29 (d, 1H), 4.24 (d, 1H), 3.98-3.78 (m, 3H), 3.43-3.35 (m, 2H), 1.90-1.75 (m, 2H), 1.59-1.44 (m, 2H), 1.41 (d, 3H) 572 503 [01586] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(4- cyclopropylphenyl) methyl]acetamide 1H NMR (DMSO-d6) δ: 8.58 (t, 1H), 8.45 (s, 1H), 8.02 (d, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.62 (s (br), 1H), 7.14 (d, 2H), 7.04-6.98 (m, 2H), 4.60 (s, 2H), 4.29-4.16 (m, 4H), 3.98-3.81 (m, 3H), 3.44-3.35 (m, 2H), 1.94-1.77 (m, 3H), 1.61-1.44(m, 2H), 0.95-0.85 (m, 2H), 0.68-0.57 (m, 2H) 532 504 [01587] B N-[(1R)-1-(2H-1,3- benzodioxol-5- yl)ethyl]-2-(6-{5- chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2- yl)acetamide 1H NMR (DMSO-d6) δ: 8.52 (d, 1H), 8.44 (s, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.74 (d, 1H), 7.62 (s (br), 1H), 6.91 (d, 1H), 6.85 (d, 1H), 6.78 (dd, 1H), 5.98 (s, 2H), 4.88 (qd, 1H), 4.58 (s, 2H), 4.25 (d, 1H), 4.20 (d, 1H) 3.99-3.79 (m, 3H), 3.45-3.35 (m, 2H), 1.91-1.77(m, 2H), 1.59-1.44(m, 2H), 1.34 (d, 3H) 550 505 [01588] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-(1- methoxy-2- phenylpropan-2- yl)acetamide 1H NMR (DMSO-d6) δ: 8.43 (s, 1H), 8.27 (s, 1H), 8.01 (d, 1H), 7.95 (dd, 1H), 7.72 (d, 1H), 7.61 (s (br), 1H), 7.37-7.24 (m, 4H), 7.24-7.15 (m, 1H), 4.57 (d, 1H), 4.52 (d, 1H), 4.29 (s, 2H), 3.95- 3.82 (m, 3H), 3.60 (d, 1H), 3.51 (d, 1H), 3.42-3.36 (m, 2H), 3.26 (s, 3H), 1.88- 1.79 (m, 2H), 1.62 (s, 3H), 1.59-1.44 (m, 2H) 550 506 [01589] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (2-methoxy-5- methylphenyl) ethyl]acetamide 1H NMR (DMSO-d6) δ: 8.48 (d, 1H), 8.44 (s, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.73 (d, 1H), 7.61 (s (br), 1H), 7.10 (d, 1H), 7.00 (dd, 1H), 6.84 (d, 1H), 5.19 (qd, 1H), 4.59 (s, 2H), 4.25 (s, 2H), 3.98- 3.79 (m, 3H), 314 (s, 3H), 3.44-3.35 (m, 2H), 2.24 (s, 3H), 1.92- 1.77 (m, 2H), 1.61- 1.44 (m, 2H), 1.28 (d, 550 507 [01590] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [4-(pyridin-3- yl)phenyl]ethyl} acetamide 1H NMR (DMSO-d6) δ: 8.89 (dd, 1H), 8.69 (d, 1H), 8.57 (dd, 1H), 8.45 (s, 1H), 8.07 (ddd, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.70 (d, 2H), 7.62 (s (br), 1H), 7.52-7.43 (m, 3H), 5.02 (qd, 1H), 4.61 (s, 2H), 4.28 (s, 2H), 3.98- 3.81 (m, 3H), 3.42- 3.37 (m, 2H), 1.90- 1.79 (m, 2H), 1.60- 1.47 (m, 2H), 1.43 (d, 3H) 583 508 [01591] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [3-(1H-imidazol-1- yl)phenyl]ethyl} acetamide 1H NMR (DMSO) δ: 8.67 (d, 1H), 8.45 (s, 1H), 8.27 (dd, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.77 (dd, 1H), 7.74 (d, 1H), 7.62 (s (br), 1H), 7.61- (m, 1H), 7.55-7.44 (m, 2H), 7.33 (d, 1H), 7.12 (dd, 1H), 5.03 (qd, 1H), 4.61 (s, 2H), 4.31 (d, 1H), 4.26 (d, 1H), 4.01-3.81 (m, 3H), 3.33-3.45 (m, 2H), 1.91-1.78 (m, 2H), 1.60-1.47 (m, 2H), 1.43 (d, 3H) 572 509 [01592] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [3-(1H-1,2,4-triazol-1- yl)phenyl]ethyl} acetamide 1H NMR (DMSO-d6) δ: 9.32 (s, 1H), 8.73 (d, 1H), 8.45 (s, 1H), 8.26 (s, 1H), 8.03 (d, 1H), 7.97 (dd, 1H), 7.83 (td, 1H), 7.74 (d, 2H), 7.62 (s (br), 1H), 7.53 (dd, 1H), 7.43- 7.36 (m, 1H), 5.05 (qd, 1H), 4.61 (s, 2H), 4.28 (s, 2H), 3.96-3.82 (m, 3H), 3.38 (d, 2H) 1.88-1.80(m, 2H), 1.60-1.45(m, 2H), 1.44 (d, 3H) 573 510 [01593] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (2,3-dimethylphenyl)- 2- hydroxyethyl] acetamide 1H NMR (DMSO-d6) δ: 8.59 (d, 1H), 8.45 (s, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.73 (d, 1H), 7.62 (s (br), 1H), 7.24-7.15 (m, 1H), 7.11-6.99 (m, 2H), 5.23-5.10 (m, 1H), 4.94 (t, 1H), 4.58 (s, 2H), 4.31 (d, 1H), 4.23 (d, 1H), 3.98-3.80 (m, 3H), 3.56-3.44 (m, 2H), 3.42-3.36 (m, 2H), 2.24 (s, 3H), 2.22 (s, 3H), 1.91- 1.77 (m, 2H), 1.60- 1.43 (m, 2H) 550 511 [01594] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- {[3-(1,3-thiazol-2- yl)phenyl]methyl} acetamide 1H NMR (DMSO-d6) δ: 8.75 (t, 1H), 8.44 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.94 (d, 1H), 7.89-7.86 (m, 1H), 7.86-7.81 (m, 1H), 7.80 (d, 1H), 7.75 (d, 1H), 7.62 (s (br), 1H), 7.47 (dd, 1H), 7.42- 7.36 (m, 1H), 4.63 (s, 2H), 4.39 (d, 2H), 4.28 (s, 2H), 3.98-3.78 (m, 3H), 3.43-3.34 (m, 2H), 1.90-1.77 (m, 2H), 1.60-1.44 (m, 2H) 575 512 [01595] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [3-(1H-pyrrol-1- yl)phenyl]ethyl}acetamide 1H NMR (DMSO-d6) δ: 8.65 (d, 1H), 8.44 (s, 1H), 8.03 (d, 1H), 7.97 (dd, 1H), 7.73 (d, 1H), 7.61 (s (br), 1H), 7.53-7.49 (m, 1H), 7.45-7.38 (m, 2H), 7.38-7.36 (m, 2H), 7.24-7.17 (m, 1H), 6.27 (dd, 2H), 5.02 (qd, 1H), 4.60 (s, 2H), 4.27 (s, 2H), 3.99- 3.74 (m, 3H), 3.43- 3.35 (m, 2H), 1.94- 1.73 (m, 2H), 1.60- 1.44 (m, 2H), 1.42 (d, 3H) 571 513 [01596] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [4-(1H-imidazol-1 yl)phenyl]ethyl} acetamide 1H NMR (DMSO-d6) δ: 8.66 (d, 1H), 8.44 (s, 1H), 8.22 (dd, 1H), 8.02 (d, 1H), 7.97 (dd, 1H), 7.74 (d, 1H), 7.72 (dd, 1H), 7.67-7.57 (m, 3H), 7.46 (d, 2H), 7.10 (dd, 1H), 5.00 (qd, 1H), 4.59 (s, 2H), 4.26 (s, 2H), 4.00- 3.79 (m, 3H), 3.42- 3.35 (m, 2H), 1.90- 1.78 (m, 2H), 1.60- 1.45 (m, 2H), 1.41 (d, 3H). 572 514 [01597] A 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[2- hydroxy-1-(4- methylphenyl)ethyl] acetamide 1H NMR (DMSO, 400 MHz) δ 8.51 (1H, d), 8.44(1H, s), 8.02 (1H, d), 7.97 (1H, dd), 7.73 (1H, d), 7.61 (1H, s), 7.20 (2H, d), 7.12 (2H, d), 4.89 (1H, t), 4.83 (1H, q), 4.58 (2H, s), 4.29 (2H, dd), 3.99- 3.80 (3H, m), 3.54 (2H, t), 3.38 (2H, d), 2.27 (3H, s), 1.84 (2H, d), 1.59-1.43 (2H, m) 536 515 [01598] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [4-(1H-pyrrol-1- yl)phenyl]ethyl}acetamide 1H NMR (DMSO, 400 MHz) δ 8.63 (1H, d), 8.44 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.74 (1H, d), 7.61 (1H, s), 7.55-7.49 (2H, m), 7.42-7.36 (2H, m), 7.33 (2H, t), 6.25 (2H, t), 4.98 (1H, p), 4.59 (2H, s), 4.26 (2H, dd), 3.99-3.79 (3H, m), 3.42-3.35 (2H, m), 1.84 (2H, d), 1.59- 1.45(2H, m), 1.40 (3H, d) 571 516 [01599] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(2- fluorophenyl)methyl] acetamide 1H NMR (DMSO, 400 MHz) δ 8.65 (1H, t), 8.44 (1H, s), 8.04- 8.01 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.62 (1H, s), 7.39- 7.28 (2H, m), 7.22- 7.13 (2H, m), 4.61 (2H, s), 4.34 (2H, d), 4.27 (2H, s), 3.99- 3.79 (3H, m), 3.43- 3.36 (2H, m), 1.84 (2H, d), 1.60-1.45 (2H, m) 510 517 [01600] B 2-(6-{5-chloro-2- [(oxan-4 yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (2,4-dimethylphenyl)- 2- hydroxyethyl]acetamide 1H NMR (DMSO, 400 MHz) δ 8.55 (1H, d), 8.44 (1H, s), 8.04- 7.99 (1H, m), 7.96 (1H, dd), 7.73 (1H, d), 7.62 (1H, s), 7.19 (1H, d), 6.97 (1H, d), 6.94 (1H, s), 5.03 (1H, q), 4.92 (1H, t), 4.56 (2H, s), 4.26 (2H, q), 3.97- 3.78 (3H, m), 3.48 (2H, t), 3.42-3.34 (2H, m), 2.28 (3H, s), 2.22 (3H, s), 1.84 (2H, d), 1.59-1.43 (2H, m) 550 518 [01601] A 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (4- methanesulfonylphenyl) ethyl]acetamide 1H NMR (DMSO, 400 MHz) δ 8.75 (1H, d), 8.44 (1H, s), 8.04- 8.00 (1H, m), 7.97 (1H, dd), 7.92-7.86 (2H, m), 7.73 (1H, d), 7.66-7.55 (3H, m), 5.02 (1H, p), 4.58 (2H, s), 4.27 (2H, s), 3.99- 3.78 (3H, m), 3.44- 3.35 (2H, m), 3.20 (3H, s), 1.84 (2H, d), 1.60-1.44 (2H, m), 1.40 (3H, d) 584 519 [01602] A 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(quinoxalin-6- yl)methyl]acetamide 1H NMR (DMSO, 400 MHz) δ 8.96-8.89 (2H, m), 8.86 (1H, t), 8.44 (1H, s), 8.10- 8.02 (2H, m), 8.00- 7.94 (2H, m), 7.82- 7.72 (2H, m), 7.62 (1H, s), 4.64 (2H, s), 4.58 (2H, d), 4.33 (2H, s), 3.99-3.80 (3H, m), 3.41-3.35 (2H, m), 1.84 (2H, d), 1.59- 1.43(2H, m) 544 520 [01603] C 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [4-(2- methylpropyl)phenyl] ethyl}acetamide 1H NMR (DMSO, 400 MHz) δ 8.56 (1H, d), 8.44 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, s), 7.23 (2H, d), 7.11 (2H, d), 4.94 (1H, p), 4.49 (2H, s), 4.29- 4.17 (2H, m), 3.99- 3.79 (3H, m), 3.43- 3.35 (2H, m), 2.41 (2H, d), 1.91-1.72 (3H, m), 1.59-1.43 (2H, m), 1.37 (3H, d), 0.85 (6H, dd) 562 521 [01604] B N-[1-(4-tert- butylphenyl)ethyl]-2- (6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2- yl)acetamide 1H NMR (DMSO, 400 MHz) δ 8.56 (1H, d), 8.44 (1H, s), 8.01 (1H, d), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, s), 7.34 (2H, d), 7.24 (2H, d), 4.92 (1H, p), 4.59 (2H, s), 4.23 (2H, s), 3.98-3.80 (3H, m), 3.42-3.35 (2H, m), 1.84 (2H, d), 1.59- 1.44 (2H, m), 1.36 (3H, d), 1.26 (9H, s) 562 522 [01605] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[2- (3- methoxyphenyl)propan- 2-yl]acetamide 1H NMR (DMSO, 400 MHz) δ 8.44 (1H, s), 8.38 (1H, s), 8.00 (1H, dd), 7.95 (1H, dd), 7.72 (1H, d), 7.62 (1H, s), 7.20 (1H, t), 6.92 (1H, ddd), 6.87 (1H, t), 6.74 (1H, ddd), 4.56 (2H, s), 4.25 (2H, s), 3.98-3.80 (3H, m), 3.73 (3H, s), 3.42- 3.34 (2H, m), 1.84 (2H, d), 1.58-1.45 (8H, m) 550 523 [01606] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (2,4- difluorophenyl)ethyl] acetamide 1H NMR (DMSO, 400 MHz) δ 8.70 (1H, d), 8.44 (1H, s), 8.04- 7.99 (1H, m), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, s), 7.49- 7.40 (1H, m), 7.24- 7.16 (1H, m), 7.14- 7.05 (1H, m), 5.13 (1H, p), 4.57 (2H, s), 4.25 (2H, s), 3.99- 3.80 (3H, m), 3.44- 3.35 (2H, m), 1.84 (2H, d), 1.63-1.44 (2H, m), 1.37(3H, d) 542 524 [01607] A 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [4-(1H-1,2,4-triazol-1- yl)phenyl]ethyl} acetamide 1H NMR (DMSO, 400 MHz) δ 9.26 (1H, s), 8.68 (1H, d), 8.44 (1H, s), 8.22 (1H, s), 8.05- 8.00 (1H, m), 7.97 (1H, dd), 7.85-7.78 (2H, m), 7.74 (1H, d), 7.62 (1H, s), 7.54- 7.48 (2H, m), 5.01 (1H, p), 4.59 (2H, s), 4.27 (2H, s), 3.99- 3.80 (3H, m), 3.43- 3.34 (2H, m), 1.84 (2H, d), 1.58-1.44 (2H, m), 1.41 (3H, d) 573 525 [01608] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (3- cyanophenyl)ethyl] acetamide 1H NMR (DMSO, 400 MHz) δ 8.68 (1H, d), 8.44 (1H, s), 8.04- 8.00 (1H, m), 7.97 (1H, dd), 7.79 (1H, d), 7.76-7.65 (3H, m), 7.62 (1H, s), 7.55 (1H, t), 4.99 (1H, p), 4.58 (2H, s), 4.27 (2H, s), 4.00-3.79 (3H, m), 3.43-3.34 (2H, m), 1.84 (2H, d), 1.59- 1.43 (2H, m), 1.39 (3H, d) 531 526 [01609] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (2,3-dihydro-1,4- benzodioxin-6- yl)ethyl]acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.56- 8.40 (2H, m), 8.02 (1H, d), 7.97 (1H, dd), 7.73 (1H, d), 7.61 (1H, s), 6.86-6.73 (3H, m), 4.84 (1H, p), 4.58 (2H, s), 4.29-4.14 (6H, m), 4.00-3.79 (3H, m), 3.43-3.33 (2H, m), 1.84 (2H, d), 1.61-1.44 (2H, m), 1.32 (3H, d) 564 528 [01610] A 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- {[4- (hydroxymethyl)phenyl] methyl}acetamide 1H NMR (DMSO, 400 MHz) δ 8.62 (1H, t), 8.44 (1H, s), 8.04- 8.00 (1H, m), 7.97 (1H, dd), 7.75 (1H, d), 7.62 (1H, s), 7.29- 7.18 (4H, m), 5.15 (1H, t), 4.61 (2H, s), 4.46 (2H, d), 4.33- 4.22 (4H, m), 3.89 (3H, dd), 3.40-3.36 (2H, m), 1.84 (2H, d), 1.60-1.42 (2H, m) 522 529 [01611] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (3,4-dihydro-2H-1,5- benzodioxepin-7- yl)ethyl]acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.53 (1H, d), 8.44 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.74 (1H, d), 7.62 (1H, s), 6.97-6.84 (3H, m), 4.87 (1H, p), 4.58 (2H, s), 4.23 (2H, s), 4.16-4.03 (4H, m), 4.00-3.80 (3H, m), 3.38 (2H, d), 2.16- 2.04 (2H, m), 1.84 (2H, d), 1.52 (2H, qd), 1.33 (3H, d) 578 530 [01612] B N-(1-{[1,1′-biphenyl]- 4-yl}ethyl)-2-(6- chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2- yl)acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.66 (1H, d), 8.44 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.74 (1H, d), 7.69- 7.56 (5H, m), 7.52- 7.39 (4H, m), 7.39- 7.31 (1H, m), 5.00 (1H, p), 4.60 (2H, s), 4.27 (2H, d), 4.00- 3.78 (3H, m), 3.43- 3.34(2H, m), 1.84 (2H, d), 1.52 (2H, qd), 1.42 (3H, d) 582 531 [01613] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (3,4- difluorophenyl)ethyl] acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.62 (1H, d), 8.44 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.74 (1H, d), 7.62 (1H, s), 7.44-7.34 (2H, m), 7.15-7.21 542 (1H, m), 4.95 (1H, p), 4.58 (2H, s), 4.25 (2H, s), 4.02-3.79 (3H, m), 3.44-3.33 (2H, 1.84 (2H, d), 1.52 (2H, qd), 1.36 (3H, d) 542 532 [01614] A 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [4-(morpholin-4- yl)phenyl]ethyl}acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.49 (1H, d), 8.44 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.79-7.69 (1H, m), 7.62 (1H, s), 7.25- 7.13 (2H, m), 6.96- 6.85 (2H, m), 4.88 (1H, p), 4.58 (2H, s), 4.22 (2H, d), 4.00- 3.80 (3H, m), 3.80- 3.67 (4H, m), 3.48- 3.34 (2H, m), 3.14- 2.98 (4H, m), 1.84 (2H, d), 1.59-1.45 (2H, m), 1.34 (3H, d) 591 533 [01615] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(3- fluorophenyl)methyl] acetamide 1H NMR (DMSO, 400 MHz) δ 8.68 (1H, t), 8.44 (1H, s), 8.06- 8.01 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.62 (1H, s), 7.41- 7.33 (1H, m), 7.14- 7.03 (3H, m), 4.61 (2H, s), 4.32 (2H, d), 4.28 (2H, s), 3.98- 3.78 (3H, m), 3.43- 3.35 (2H, m), 1.84 (2H, d), 1.58-1.45 (2H, m) 510 534 [01616] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{1- [4-(piperidin-1- yl)phenyl]ethyl}acetamide 1H NMR (DMSO, 400 MHz) δ 8.50-8.42 (2H, m), 8.03-8.00 (1H, m), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, s), 7.15 (2H, d), 6.87 (2H, d), 4.87 (1H, p), 4.58 (2H, s), 4.29- 4.15 (2H, m), 3.99- 3.79 (3H, m), 3.43- 3.34 (4H, m), 3.14- 3.01 (3H, m), 1.84 (2H, d), 1.65-1.43 (7H, m), 1.34 (3H, d) 589 535 [01617] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[1- (2,5- difluorophenyl)ethyl] acetamide 1H NMR (DMSO, 400 MHz) δ 8.69 (1H, d), 8.44 (1H, s), 8.05- 8.00 (1H, m), 7.97 (1H, dd), 7.73 (1H, d), 7.61 (1H, s), 7.28- 7.18 (2H, m), 7.18- 7.07 (1H, m), 5.14 (1H, p), 4.58 (2H, s), 4.27 (2H, s), 4.00- 3.77 (3H, m), 3.43- 3.35 (2H, m), 1.84 (2H, d), 1.62-1.42 (2H, m), 1.37 (3H, d) 542 536 [01618] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(4- propoxyphenyl)methyl] acetamide 1H NMR (DMSO, 400 MHz) δ 8.57 (1H, t), 8.44 (1H, s), 8.05- 8.00 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.62 (1H, s), 7.20- 7.14 (2H, m), 6.90- 6.83 (2H, m), 4.60 (2H, s), 4.27-4.18 (4H, m), 3.99-3.80 (5H, m), 3.38 (2H, d), 1.84 (2H, d), 1.77- 1.63 (2H, m), 1.60- 1.45 (2H, m), 0.96 (3H, t) 550 537 [01619] B 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(3- methoxyphenyl)methyl] acetamide 1H NMR (DMSO, 400 MHz) δ 8.63 (1H, t), 8.45 (1H, s), 8.05- 8.00 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.62 (1H, s), 7.24 (1H, t), 6.87-6.77 (3H, m), 4.61 (2H, s), 4.32- 4.22 (4H, m), 3.97- 3.81 (3H, m), 3.74 (3H, s), 3.44-3.34 (2H, m), 1.84 (2H, d), 1.52 (2H, qd) 522

Example 538: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-{2-[3-(hydroxymethyl)phenyl]propan-2-yl}acetamide

[1698] ##STR01620##

[1699] Triethylamine (208 μl, 1.489 mmol) was added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 150 mg, 0.372 mmol), (3-(2-aminopropan-2-yl)phenyl)methanol, HCl (83 mg, 0.410 mmol) and HATU (156 mg, 0.410 mmol) in DMF (5 mL) and the mixture was stirred for 1h. Water (15 mL) was added, and the resulting precipitate filtered, washed with water (15 mL). Purification by preparative HPLC (acidic) gave the title compound (60 mg, 29.0%) as a colourless powder. 1H NMR (DMSO, 400 MHz) δ 8.44 (1H, s), 8.40 (1H, s), 8.00 (1H, d), 7.95 (1H, dd), 7.71 (1H, d), 7.62 (1H, s), 7.31 (1H, d), 7.26-7.18 (2H, m), 7.12 (1H, dt), 5.16 (1H, s), 4.55 (2H, s), 4.48 (2H, s), 4.25 (2H, s), 3.97-3.80 (3H, m), 3.39-3.35 (2H, m), 1.87-1.79 (2H, m), 1.57 (6H, s), 1.56-1.45 (2H, m). LC-MS: [M+H].sup.+=550.

Example 539: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[3-(2-hydroxyethoxy)phenyl]ethyl]acetamide

[1700] ##STR01621##

[1701] Triethylamine (277 μl, 1.986 mmol) was added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 200 mg, 0.496 mmol), (R)-2-(3-(1-aminoethyl)phenoxy)ethanol, HCl (99 mg, 0.455 mmol) and HATU (208 mg, 0.546 mmol) in DMF (2 mL) and the mixture was stirred for 1h. Water (15 mL) was added, and the resulting precipitate filtered, washed with water (15 mL). Purification by chromatography (SiO.sub.2, 0-5% MeOH in iso-hexane) gave the title compound (98 mg, 33.5%) as a colourless powder. 1H NMR (DMSO, 400 MHz) δ 8.58 (1H, d), 8.44 (1H, s), 8.02 (1H, s), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, bs), 7.22 (1H, dd), 6.91-6.86 (2H, m), 6.80 (1H, ddd), 4.97-4.89 (1H, m), 4.86 (1H, t), 4.59 (2H, s), 4.25 (2H, d), 3.97 (2H, t), 3.94-3.81 (3H, m), 3.71 (2H, q), 3.38 (2H, m), 1.84 (2H, m), 1.52 (2H, m), 1.36 (3H, d). LC-MS: [M+H].sup.+=566.

Example 540: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-1-(3-hydroxyphenyl)ethyl]acetamide

[1702] ##STR01622##

[1703] Triethylamine (277 μl, 1.986 mmol) was added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 200 mg, 0.496 mmol), (R)-3-(1-aminoethyl)phenol (79 mg, 0.546 mmol) and HATU (208 mg, 0.546 mmol) in DMF (2 mL) and the mixture was stirred for 1h. Water (15 mL) was added, and the resulting precipitate filtered, washed with water (15 mL), dried, to give the title compound (211 mg, 80%) as a colourless powder. 1H NMR (DMSO, 400 MHz) δ 9.37 (1H, s), 8.57 (1H, d), 8.44 (1H, s), 8.02 (1H, s), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, bs), 7.10 (1H, dd), 6.76-6.70 (2H, m), 6.62 (1H, ddd), 4.90-4.81 (1H, m), 4.58 (2H, s), 4.23 (2H, d), 3.99-3.78 (3H, m), 3.42-3.35 (2H, m), 1.84 (2H, m), 1.52 (2H, m), 1.34 (3H, d). LC-MS: [M+H].sup.+=522.

Example 541: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-1-{3-[(dimethylamino)methyl]phenyl}ethyl]acetamide

[1704] ##STR01623##

[1705] A microwave tube was charged with (R)—N-(1-(3-bromophenyl)ethyl)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetamide (Preparation 306, 50 mg, 0.081 mmol), potassium ((dimethylamino)methyl)trifluoroborate (20.10 mg, 0.122 mmol), Pd(OAc).sub.2 (0.912 mg, 4.06 μmol), XPhos and Cs.sub.2CO.sub.3 (79 mg, 0.244 mmol). The tube was evacuated and backfilled with nitrogen (3×). 1,4-dioxane (0.8 mL, 9.35 mmol) and water (0.2 mL, 11.10 mmol) were added and the reaction was heated to 100° C. for 1.5h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with NaHCO.sub.3 (10 mL), brine (10 mL), dried (MgSO.sub.4) and concentrated. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-10% (0.7 M Ammonia/MeOH) in DCM) to afford the title compound (16 mg, 33.2%) as a pale yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.62 (1H, d), 8.45 (1H, s), 8.03 (1H, d), 7.98 (1H, dd), 7.74 (1H, d), 7.63 (1H, br. s), 7.31-7.24 (2H, m), 7.24-7.19 (1H, m), 7.17-7.13 (1H, m), 5.02-4.91 (1H, m), 4.64-4.53 (2H, m), 4.25 (2H, s), 4.04-3.81 (3H, m), 3.41-3.36 (3H, m), 2.14 (6H, s), 1.89-1.80 (2H, m), 1.58-1.47 (3H, m), 1.38 (3H, d). LCMS: [M+H].sup.+=563.

Example 542: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[3-(2,3-dihydroxypropoxy)phenyl]ethyl]acetamide

[1706] ##STR01624##

[1707] A solution of potassium osmate dihydrate (0.656 mg, 1.779 μmol) in water (50 μL) was added to a solution of (R)—N-(1-(3-(allyloxy)phenyl)ethyl)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetamide (Preparation 308, 50 mg, 0.089 mmol) and NMO (15.63 mg, 0.133 mmol) in tBuOH/H.sub.2O (2:1, 1 mL). The reaction mixture was stirred at room temperature for 2 days. An aqueous solution of sodium sulfite (3 mL) was added, and the aqueous layer was extracted with EtOAc (2×3 mL). The combined organic layers were dried (MgSO.sub.4) and concentrated in vacuo. Purification by chromatography (SiO.sub.2, 0-10% MeOH in DCM) gave the title compound (31 mg, 0.051 mmol, 57.9% yield) as a colourless powder. 1H NMR (DMSO-d6, 400 MHz) δ 8.59 (1H, d), 8.44 (1H, s), 8.02 (1H, dd), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, s), 7.22 (1H, t), 6.92-6.86 (2H, m), 6.79 (1H, dd), 4.98-4.87 (2H, m), 4.68 (1H, td), 4.59 (2H, s), 4.25 (2H, m), 3.99 (1H, ddd), 3.94-3.82 (2H, m), 3.79 (1H, m), 3.45 (2H, t), 3.40-3.36 (2H, m), 2.54 (2H, s), 1.88-1.80 (2H, m), 1.52 (2H, m), 1.36 (3H, d). LCMS: [M+H].sup.+=596.

Example 543: N-[(1R)-1-[3-(2-aminoethoxy)phenyl]ethyl]-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamide

[1708] ##STR01625##

[1709] Hydrazine hydrate (60% in water, 106 μl, 1.295 mmol) was added to a stirred solution of (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-(1-(3-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)phenyl)ethyl)acetamide (Preparation 309, 90 mg, 0.129 mmol) in THF (2.5 mL) under nitrogen and the mixture was heated to 65° C. and stirred for 2 h. The mixture was cooled to room temperature. The resulting suspension was filtered via a hydrophobic phase separator, washed with EtOAc (1 mL) and the filtrate was concentrated in vacuo. Trituration with Et.sub.2O (3 mL) gave the title compound (31 mg, 41.1%) as a pale tan powder. 1H NMR (DMSO-d6, 400 MHz) δ 8.58 (1H, d), 8.44 (1H, s), 8.02 (1H, d), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, s), 7.22 (1H, dd), 6.92-6.84 (2H, m), 6.79 (1H, d), 4.92 (1H, dq), 4.59 (2H, s), 4.25 (2H, s), 3.98-3.82 (4H, m), 3.43-3.35 (3H, m), 2.87 (2H, t), 1.89-1.78 (2H, m), 1.60-1.44 (2H, m), 1.36 (3H, d). (2 protons signals overlapped with water peak) LCMS: [M+H].sup.+=565.

Example 544: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[3-(difluoromethoxy)phenyl]-2-hydroxyethyl]propanamide

[1710] ##STR01626##

[1711] DIPEA (111 μl, 0.637 mmol) and HATU (121 mg, 0.318 mmol) were added to a stirred solution of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)propanoic acid (Preparation 99), 90 mg, 0.216 mmol), and (S)-2-amino-2-(3-(difluoromethoxy)phenyl)ethanol hydrochloride (51.7 mg, 0.216 mmol) in acetonitrile (8.86 mg, 0.216 mmol) and the mixture was stirred for 1h. The solution was concentrated and the residue dissolved in a small quantity of DCM, then purified by chromatography (SiO.sub.2, 12 g column, 100% EtOAc). Pure fractions were collected and concentrated to afford a colourless solid (75 mg). The solid was dissolved in methanol (2 ml) and the solution loaded on column packed with SCX. The column was washed with methanol and the product eluted with 1% ammonia in methanol. Concentration of the resulting solution afforded a glass which upon stirring overnight in ether (4 ml) afforded the title compound (50 mg, 38.5%), which was collected by filtration. 1H NMR (DMSO-d6, 400 MHz) δ 8.63 (1H, d), 8.45 (1H, s), 8.04 (1H, s), 7.98 (1H, d), 7.75 (1H, d), 7.63 (1H, s), 7.46-6.96 (5H, m), 5.06-4.9 (2H, m), 4.85 (1H, q), 4.76 (1H, d), 4.61 (1H, d), 3.99-3.8 (3H, d), 3.62-3.50 (2H, m), 3.44-3.28 (2H, m), 1.85 (2H, m), 1.6-1.46 (2H, m), 1.45 (3H, d). LCMS: [M+H].sup.+=602.

Example 545: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S,2S)-2-hydroxy-1-(3-methoxyphenyl)propyl]acetamide

[1712] ##STR01627##

[1713] Triethylamine (0.111 mL, 0.794 mmol) was added to a suspension of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Preparation 1, 80 mg, 0.199 mmol) and (1S,2S)-1-amino-1-(3-methoxyphenyl)propan-2-ol hydrochloride (47.6 mg, 0.218 mmol) in DCM (1 mL, 15.54 mmol). After 15 minutes, HATU (83 mg, 0.218 mmol) was added and the mixture was stirred for 2 h at room temperature. The reaction was diluted with EtOAc (10 mL) and water (10 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with 1 M HCl (20 mL), brine (2×20 mL), dried (MgSO.sub.4) and concentrated. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-10% MeOH/DCM). The product was dissolved in MeOH and loaded onto a column packed with SCX (2 g). The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to afford a colourless glass (50 mg). The product was further purified by chromatography (SiO.sub.2, 12 g column, 0-10% MeOH/DCM) to afford the title compound (50 mg, 43.6%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.52-8.41 (2H, m), 8.03-8.01 (1H, m), 7.97 (1H, dd), 7.74 (1H, d), 7.63 (1H, br. s), 7.25-7.19 (1H, m), 6.94-6.88 (2H, m), 6.83-6.78 (1H, m), 4.81 (1H, d), 4.70 (1H, dd), 4.58 (2H, s), 4.36 (1H, d), 4.29 (1H, d), 3.98-3.82 (4H, m), 3.75 (3H, s), 3.40-3.36 (2H, m), 1.90-1.79 (2H, m), 1.58-1.46 (2H, m), 1.00 (3H, d). LCMS: [M+H].sup.+=566.

Example 546: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-{4-[(dimethylamino)methyl]phenyl}-2-hydroxyethyl]acetamide hydrochloride

[1714] ##STR01628##

[1715] A mixture of (S)—N-(1-(4-bromophenyl)-2-hydroxyethyl)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetamide (Preparation 313, 130 mg, 0.216 mmol), potassium ((dimethylamino)methyl)trifluoroborate (54 mg, 0.327 mmol), XPhos Pd G3 (11 mg, 0.023 mmol), cesium carbonate (211 mg, 0.649 mmol) and palladium (II) acetate (3 mg, 0.013 mmol) was sealed in a microwave vial, evacuated and purged with nitrogen (3×), treated with 1,4-dioxane (0.8 mL) and water (0.2 mL) and stirred at 100° C. (bath) for 4h. The mixture was allowed to cool, diluted with water (5 ml) and extracted with ethyl acetate (3×5 ml). The combined extracts were washed with brine (5 ml), dried (Na.sub.2SO.sub.4) and evaporated to give a gum (55 mg). The aqueous layers were combined and extracted with 2-methyl-THF (3×10 ml) and the combined extracts were dried (Na.sub.2SO.sub.4), combined with the ethyl acetate extract and evaporated to give a white solid (115 mg). The solid was purified by reversed phase preparative HPLC on a Waters XBridge BEH C18 OBD, 130 Å, 5 μm, 19 mm×50 mm column, using a gradient of 15 to 35% of acetonitrile in 10 mM aqueous ammonium bicarbonate solution at 28 ml/min as eluent. The clean fractions were pooled and concentrated to remove most of the acetonitrile. The residue was freeze-dried, then taken up in a mixture of methanol (1 ml) and acetic acid (0.1 ml) and loaded on a column packed with SCX. The solution was allowed to soak-in for 1 h and then washed with methanol (6 ml). The resin was eluted with 3M methanolic ammonia solution (6 ml) and the eluents were evaporated to give a glass. The glass was triturated with ether (3 ml) to give a solid, which was collected by filtration, washed with ether (1 ml) and dried to a cream powder (27 mg). The product was further purified by reversed phase preparative HPLC on a Waters XSelect CSH C18 OBD, 130 Å, 5 μm, 19 mm×50 mm column, using a gradient of 5 to 20% of acetonitrile in water with 0.1% formic acid in both at 28 ml/min as eluent. The clean fractions were pooled and evaporated. The residue was taken up in methanol (5 ml), treated with a drop of concentrated hydrochloric acid and evaporated (3×) and the residue was taken up in water (5 ml) and freeze-dried to give the title compound (19 mg, 13.84%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.70 (1H, s), 8.71 (1H, d), 8.44 (1H, s), 8.04-8.00 (1H, m), 7.97 (1H, dd), 7.74 (1H, d), 7.64 (1H, s), 7.52 (2H, d), 7.41 (2H, d), 4.97-4.85 (1H, m), 4.59 (2H, s), 4.37-4.26 (2H, m), 4.23 (2H, d), 3.97-3.86 (3H, m), 3.59 (2H, d), 3.36 (2H, t), 2.67 (6H, d), 1.89-1.77 (2H, m), 1.59-1.43 (2H, m). LCMS: [M+H].sup.+=579.

Example 547: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-1-(2-methoxyphenyl)ethyl]acetamide

[1716] ##STR01629##

[1717] T3P (50 wt % in EtOAc) (0.177 mL, 0.298 mmol) was added to a solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 80 mg, 0.199 mmol), (R)-1-(2-methoxyphenyl)ethanamine (33.0 mg, 0.218 mmol) and triethylamine (0.083 mL, 0.596 mmol) in DMF (2 mL, 25.8 mmol). The reaction was stirred at room temperature for 2 h. The reaction was diluted with 1 M HCl (3 mL) and water (10 mL). The resulting precipitate was isolated by filtration and washed with water (10 mL). The solid was dissolved in DCM (3 mL) and washed with brine (5 mL) and passed through a phase separating cartridge, then concentrated in vacuo to give the title compound product as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.52 (1H, d), 8.45 (1H, s), 8.03 (1H, dd), 7.97 (1H, dd), 7.74 (1H, d), 7.61 (1H, br. s), 7.30 (1H, dd), 7.22 (1H, ddd), 7.00-6.91 (2H, m), 5.24 (1H, dq), 4.59 (2H, s), 4.26 (2H, s), 3.99-3.83 (3H, m), 3.80 (3H, s), 3.44-3.35 (2H, m), 1.85 (2H, br. d), 1.53 (2H, qd), 1.30 (3H, d). LC-MS: [M+H].sup.+=536.

Example 548: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-1-phenylpropyl]acetamide

[1718] ##STR01630##

[1719] Prepared using a similar procedure to Example 547. 1H NMR (DMSO-d6, 400 MHz) δ 8.54 (1H, d), 8.45 (1H, s), 8.05-8.01 (1H, m), 7.98 (1H, dd), 7.74 (1H, d), 7.61 (1H, br. s), 7.37-7.29 (4H, m), 7.27-7.20 (1H, m), 4.73 (1H, q?), 4.59 (2H, s), 4.30 (1H, d), 4.24 (1H, d), 3.99-3.81 (3H, m), 3.42-3.34 (2H, m), 1.89-1.81 (2H, m), 1.72 (2H, qd), 1.53 (2H, qd), 0.86 (3H, t). LC-MS: [M+H].sup.+=520.

Example 549: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-1-(2-methylphenyl)ethyl]acetamide

[1720] ##STR01631##

[1721] Prepared using a similar procedure to Example 547. 1H NMR (DMSO-d6, 400 MHz) δ 8.61 (1H, d), 8.44 (1H, s), 8.01 (1H, dd), 7.96 (1H, dd), 7.81-7.67 (1H, m), 7.61 (1H, s), 7.35 (1H, d), 7.23-7.16 (1H, m), 7.14-7.11 (2H, m), 5.10 (1H, dq), 4.59 (1H, d), 4.54 (1H, d), 4.24 (1H, d), 4.19 (1H, d), 4.00-3.79 (3H, m), 3.44-3.35 (2H, m), 2.30 (3H, s), 1.94-1.75 (2H, m), 1.59-1.45 (2H, m), 1.34 (3H, d). LC-MS: [M+H].sup.+=520

Example 550: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)acetamide

[1722] ##STR01632##

[1723] 5-fluoro-2,3-dihydro-1H-inden-1-amine hydrochloride (43.1 mg, 0.218 mmol) was added to an ice-cooled stirred solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 80 mg, 0.199 mmol), T3P (50% wt in EtOAc) (176 μl, 0.298 mmol) and triethylamine (111 μl, 0.794 mmol) in DMF (3.0 mL) under nitrogen. The reaction was allowed to warm to room temperature and stirred for 20 h. The reaction mixture was diluted with 1 M HCl (10 mL) and the resulting precipitate filtered and washed with water (10 mL), NaHCO.sub.3 (10 mL) and water (10 mL). The collected solid was re-dissolved in DCM (20 mL) and washed with brine (20 mL). The organic extracts were combined and then dried (MgSO.sub.4), filtered and concentrated in vacuo to afford the title compound (77 mg, 71.6%) as an off white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.53 (1H, d), 8.44 (1H, s), 8.03 (1H, dd), 7.98 (1H, dd), 7.83-7.70 (1H, m), 7.61 (1H, s), 7.23 (1H, ddd), 7.08 (1H, dd), 7.05-6.97 (1H, m), 5.28 (1H, dd), 4.63 (2H, s), 4.26 (2H, s), 4.01-3.78 (3H, m), 3.43-3.32 (2H, m), 2.94 (1H, ddd), 2.81 (1H, dt), 2.41 (1H, dtd), 1.95-1.77 (3H, m), 1.62-1.45 (2H, m). LC-MS: [M+H].sup.+=536.

Example 551: N-(5-chloro-2,3-dihydro-1H-inden-1-yl)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamide

[1724] ##STR01633##

[1725] Prepared using a similar procedure to Example 547. 1H NMR (DMSO-d6, 400 MHz) δ 8.55 (1H, d), 8.44 (1H, s), 8.03 (1H, dd), 7.98 (1H, dd), 7.75 (1H, dd), 7.61 (1H, s), 7.32 (1H, d), 7.28-7.20 (2H, m), 5.29 (1H, q), 4.63 (2H, s), 4.26 (2H, s), 3.89 (3H, dd), 3.44-3.32 (2H, m), 2.93 (1H, ddd), 2.81 (1H, dt), 2.40 (1H, dtd), 1.86 (3H, m), 1.52 (2H, m). LC-MS: [M+H].sup.+=552.

Example 552: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]acetamide

[1726] ##STR01634##

[1727] 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% wt in EtOAc) (150 μL, 0.252 mmol) was added to a stirred mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 70 mg, 0.170 mmol), (S)-2,3-dihydro-1H-inden-1-amine (24.95 mg, 0.187 mmol) and triethylamine (71.2 μL, 0.511 mmol) in DMF (1 mL) and the reaction mixture was stirred at room temperature for 3 h. Water (10 mL) was added, and the resulting precipitate was filtered, dried to give the title compound (S)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-(2,3-dihydro-1H-inden-1-yl)acetamide (75 mg, 0.140 mmol, 82% yield) as a colourless powder. 1H NMR (DMSO, 400 MHz) δ 8.54 (1H, d), 8.44 (1H, s), 8.03 (1H, d), 7.98 (1H, dd), 7.75 (1H, d), 7.62 (1H, bs), 7.28-7.16 (4H, m), 5.33 (1H, q), 4.63 (2H, s), 4.26 (2H, s), 3.97-3.81 (3H, m), 2.93 (1H, ddd), 2.81 (1H, dt), 2.44-2.33 (1H, m), 1.84 (3H, qd), 1.60-1.41 (3H, m), 1.15-1.08 (0.5H, m), 0.93-0.91 (0.5H, m). LC-MS: [M+H].sup.+=518.

Example 553-562

[1728] Prepared using an analogous procedure to Example 552, from 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) and the corresponding amine.

TABLE-US-00040 Example Structure Name .sup.1H NMR (400 MHz) MS: [M + H].sup.+ 553 [01635] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H-isoindol- 2-yl)-N-(5-cyano- 2,3-dihydro-1H- inden-1- yl)acetamide 1H NMR (DMSO, 400 MHz) δ 8.63 (1H, d), 8.45 (1H, s), 8.06- 8.01 (1H, m), 7.98 (1H, dd), 7.78-7.64 (3H, m), 7.61 (1H, bs), 7.39 (1H, d), 5.38 (1H, q), 4.63 (2H, s), 4.28 (2H, s), 3.98- 3.81 (3H, m), 3.39-3.35 (2H, m), 2.98 (1H, ddd), 2.86 (1H, dt), 2.47-2.38 (1H, m), 1.92- 1.79 (3H, m), 1.52 (2H, qd). 543 554 [01636] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H-isoindol- 2-yl)-N-[(1R)-1-(3- methoxyphenyl)- ethyl]acetamide 1H NMR (DMSO-d6) δ: 8.59 (d, 1H), 8.45 (s, 1H), 8.03 (dd, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.62 (s, 1H), 7.25 (t, 1H), 6.93-6.86 (m, 2H), 6.81 (m, 1H), 4.94 (dq, 1H), 4.60 (s, 2H), 4.26 (s, 2H), 3.87 (m, 3H), 3.76 (s, 3H), 3.34- 344 (m, 2H), 1.85 (m, 2H), 1.53 (m, 2H), 1.37 (d, 3H). 536 555 [01637] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H-isoindol- 2-yl)-N-[(1R)-1-(4- methoxyphenyl)- ethyl]acetamide 1H NMR (DMSO-d6) δ: 8.53 (d, 1H), 8.45 (s, 1H), 8.03 (dd, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.62 (s, 1H), 7.25 (d, 2H), 6.90 (d, 2H), 4.92 (dq, 1H), 4.59 (s, 2H), 4.26 (d, 1H), 4.21 (d, 1H), 3.82- 3.98 (m, 3H), 3.74 (s, 3H), 3.34-3.42 (m, 2H), 1.85 (m, 2H), 1.53 (m, 2H), 1.36 (d, 3H). 536 556 [01638] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H-isoindol- 2-yl)-N-({4- [(thiophen-2- yl)methyl]phenyl} methyl)acetamide 1H NMR (DMSO-d6) δ: 8.62 (t, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.63 (s (br), 1H), 7.32 (dd, 1H), 7.22 (s, 4H), 6.94 (dd, 1H), 6.92- 6.85 (m, 1H), 4.61 (s, 2H), 4.28 (d, 2H), 4.25 (s, 2H), 4.12 (d, 2H), 4.00-3.80 (m, 3H), 3.44- 3.37 (m, 2H), 1.93-1.78 (m, 2H), 1.62-1.45 (m, 2H). 588 557 [01639] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H-isoindol- 2-yl)-N-(1- phenylpyrrolidin-3- yl)acetamide 1H NMR (DMSO-d6) δ: 8.49 (d, 1H), 8.45 (s (br), 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.63 (s (br), 1H), 7.17 (dd, 2H), 6.66-6.58 (m, 1H), 6.58-6.49 (m, 2H), 4.61 (s, 2H), 4.49- 4.37 (m, 1H), 4.22 (s, 2H), 3.99- 3.81 (m, 3H), 3.49 (dd, 1H), 3.45-3.35 (m, 3H), 3.31-3.22 (m, 1H), 3.10 (dd, 1H), 2.26- 2.15 (m, 1H), 1.99-1.89 (m, 1H), 1.89-1.79 (m, 2H), 1.63- 1.46 (m, 2H). 547 558 [01640] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H-isoindol- 2-yl)-N-[1-(3,5- difluorophenyl)ethyl] acetamide 1H NMR (DMSO-d6) δ: 8.65 (d, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.62 (s (br), 1H), 7.13-7.03 (m, 3H), 4.97 (dq, 1H), 4.60 (s, 2H), 4.28 (s, 2H), 4.01-3.80 (m, 3H), 3.44-3.35 (m, 2H), 1.85 (m 2H), 1.53 (m 2H), 1.38 (d, 3H). 542 559 [01641] N-[(1,3- benzothiazol-5- yl)methyl]-2-(6-{5- chloro-2-[(oxan-4- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H-isoindol- 2-yl)acetamide 1H NMR (DMSO-d6) δ: 9.37 (s, 1H), 8.75 (t, 1H), 8.45 (s (br), 1H), 8.09-8.01 (m, 3H), 7.98 (dd, 1H), 7.76 (d, 1H), 7.63 (s (br), 1H), 7.47 (dd, 1H), 4.63 (s, 2H), 4.47 (d, 2H), 4.30 (s, 2H), 3.98-3.81 (m, 3H), 3.43-3.35 (m, 2H), 1.90-1.79 (m, 2H), 1.58-1.46 (m, 2H). 549 560 [01642] 2-(2-{10- azatricyclo[6.3.1.02, 7]dodeca-2,4,6- trien-10-yl}-2- oxoethyl)-6-{5- chloro-2-[(oxan-4- yl)amino]pyrimidin- 4-yl}-2,3-dihydro-1H- isoindol-1-one 1H NMR (DMSO-d6) δ: 8.44 (s, 1H), 8.00-7.97 (m, 1H), 7.95 (dd, 1H), 7.66 (d, 1H), 7.62 (s (br), 1H), 7.22 (d, 1H), 7.19- 7.11 (m, 2H), 7.05-6.96 (m, 1H), 4.28-3.98 (m, 5H), 3.97- 3.81 (m, 3H), 3.78-3.72 (m, 1H), 3.58-3.50 (m, 1H), 3.44- 3.35 (m, 2H), 3.26-3.19 (m, 2H), 3.03 (dd, 1H), 2.27-2.16 (m, 1H), 1.94 (d, 1H), 1.88- 1.79 (m, 2H), 1.59-1.45 (m, 2H) 544 561 [01643] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H-isoindol- 2-yl)-N-[1-(2,3- difluorophenyl)ethyl] acetamide 1H NMR (DMSO-d6) δ: 8.77 (d, 1H), 8.45 (s, 1H), 8.02 (dd, 1H), 7.97 (d, 1H), 7.74 (d, 1H), 7.62 (s (br), 1H), 7.38-7.16 (m, 3H), 5.18 (qd, 1H), 4.58 (s, 2H), 4.26 (s, 2H), 3.95-3.83 (m, 3H), 3.39 (m, 2H), 1.84 (d, 2H), 1.60-1.48 (m, 2H), 1.40 (d, 3H). 542 562 [01644] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H-isoindol- 2-yl)-N-[(1R)-1-(2- fluoro-5- methoxyphenyl)- ethyl]acetamide 1H NMR (DMSO-d6) δ: 8.68 (d, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.62 (s (br), 1H), 7.08 (dd, 1H), 6.95 (dd, 1H), 6.86-6.79 (m, 1H), 5.22-5.08 (m, 1H), 4.59 (s, 2H), 4.27 (s, 1H), 4.27 (d, 1H), 3.99-3.81 (m, 3H), 3.75 (s, 3H), 3.46-3.35 (m, 2H), 1.91- 1.78 (m, 2H), 1.60-1.46 (m, 2H), 1.37 (d, 3H). 554

Example 563-564

[1729] Prepared using an analogous procedure to Example 547, from 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) and the corresponding amine. The products were further purified by preparative HPLC (acidic) in these cases.

TABLE-US-00041 Example Structure Name .sup.1H NMR (400 MHz) MS: [M + H].sup.+ 563 [01645] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H-isoindol- 2-yl)-N-[(2R)-3,3- dimethylbutan-2- yl]acetamide 1H NMR (400 MHz, DMSO-d6) δ: 8.44 (s, 1H), 8.02-8.01 (m, 1H), 7.97 (dd, 1H), 7.82 (d, 1H), 7.74 (d, 1H), 7.61 (s (br), 1H), 4.59 (s, 2H), 4.26-4.17 (m, 2H), 3.97-3.85 (m, 3H), 3.75-3.67 (m, 1H), 3.37 (t, 2H), 1.86-1.83 (br m, 2H), 1.57-1.47 (m, 2H), 1.00 (d, 3H), 0.85 (s, 9H). 486 564 [01646] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin- 4-yl}-1-oxo-2,3- dihydro-1H-isoindol- 2-yl)-N-(2-methyl-4- phenylbutan-2- yl)acetamide 1H NMR (CDCl3, 400 MHz) δ 8.36-8.32 (2H, m), 8.03 (1H, dd), 7.60 (1H, dd), 7.25 (2H, dt), 7.20-7.13 (3H, m), 6.04 (1H, s), 5.18 (1H, d), 4.63 (2H, s), 4.17 (2H, s), 4.14-3.97 (3H, m), 3.61-3.52 (2H, m), 2.60- 2.53 (2H, m), 2.12-2.00 (4H, m), 1.39 (6H, s). (2 protons overlapped with water peak) 548

Example 565-568

[1730] Prepared using an analogous procedure to Example 547, from 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) and the corresponding amine. The products were further purified by chromatography (SiO.sub.2, gradients of MeOH in DCM) in these cases.

TABLE-US-00042 Example Structure Name .sup.1H NMR (400 MHz) MS: [M+ H].sup.+ 565 [01647] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-[2-(7-methoxy- 2,3,4,5-tetrahydro-1H- 3-benzazepin-3-yl)-2- oxoethyl]-2,3-dihydro- 1H-isoindol-1-one 1H NMR (DMSO-d6) δ: 8.46 (s, 1H), 8.08-8.01 (m, 1H), 7.99 (dd, 1H), 7.75 (d, 1H), 7.63 (s, 1H), 7.08 (t, 1H), 6.78 (dd, 1H), 6.69 (ddd, 1H), 4.61- 4.50 (m, 4H), 3.85-3.98 (m, 3H), 3.72 (s, 3H), 3.67-3.52 (m, 4H), 3.43-3.35 (m, 2H), 2.90-2.95 (m, 2H), 2.76-2.84 (m, 2H), 1.81-1.88 (m, 2H), 1.53 (m, 2H). 562 566 [01648] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[2- (4-propoxyphenyl)propan- 2-yl]acetamide 1H NMR (DMSO) δ: 8.45 (s, 1H), 8.31 (s, 1H), 8.02 (d, 1H), 7.96 (dd, 1H), 7.72 (d, 1H), 7.62 (s (br), 1H), 7.25 (d, 2H), 6.83 (d, 2H), 4.55 (s, 2H), 4.24 (s, 2H), 3.82-3.98 (m, 5H), 3.44-3.35 (m, 2H), 1.79-1.89 (m, 2H), 1.77-1.64 (m, 2H), 1.56 (s, 6H), 1.57- 1.47 (m, 2H), 0.97 (t, 3H). 578 567 [01649] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[2- (2,3-dihydro-1,4- benzodioxin-6- yl)propan-2- yl]acetamide 1H NMR (DMSO-d6) δ: 8.45 (s, 1H), 8.29 (s, 1H), 8.01 (d, 1H), 7.96 (dd, 1H), 7.73 (d, 1H), 7.62 (s (br), 1H), 6.83- 6.70 (m, 3H), 4.56 (s, 2H), 4.26-4.17 (m, 6H), 3.98- 3.82 (m, 3H), 3.45-3.34 (m, 2H), 1.85 (m, 2H), 1.53 (s, 6H), 1.56-1.48 (m, 2H). 578 568 [01650] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1-methyl-1H-indol-6- yl)methyl]acetamide 1H NMR (DMSO-d6) δ: 8.64 (t, 1H), 8.45 (s, 1H), 8.04 (d, 1H), 7.99 (dd, 1H), 7.76 (d, 1H), 7.62 (s (br), 1H), 7.49 (d, 1H), 7.34 (s, 1H), 7.29 (d, 1H), 6.97 (dd, 1H), 6.39 (dd, 1H), 4.64 (s, 2H), 4.42 (d, 2H), 4.27 (s, 2H), 4.01-3.82 (m, 3H), 3.78 (s, 3H), 3.45- 3.37 (m, 2H), 1.94-1.78 (m, 2H), 1.63-1.43 (m, 2H). 545

Example 569-572

[1731] Prepared using an analogous procedure to Example 194, from 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) and the corresponding amine. The products were further purified by chromatography (SiO.sub.2, gradients of MeOH in DCM) in these cases.

TABLE-US-00043 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 569 [01651] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)- N-[1-(4- propoxyphenyl)ethyl] acetamide 1H NMR (DMSO-d6) δ: 8.53 (d, 1H), 8.45 (s, 1H), 8.02 (s, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.62 (s (br), 1H), 7.23 (d, 2H), 6.88 (d, 2H), 4.96-4.85 (m, 1H), 4.59 (s, 2H), 4.25 (d, 1H), 4.20 (s, 1H), 3.90 (t, 2H), 4.00-3.80 (m, 3H), 3.44- 3.36 (m, 2H), 1.91-1.80 (m, 2H), 1.72 (qt, 2H), 1.60-1.46 (m, 2H), 1.36 (d, 3H), 0.97 (t, 3H). 564 570 [01652] (2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-[2- (pyridin-2-yl)propan-2- yl]acetamide 1H NMR (DMSO-d6) δ: 8.55- 8.39 (m, 3H), 8.02 (d, 1H), 7.96 (dd, 1H), 7.77-7.70 (m, 2H), 7.62 (s (br), 1H), 7.46- 7.38 (m, 1H), 7.20 (ddd, 1H), 4.57 (d, 2H), 4.28 (d, 2H), 4.02-3.79 (m, 3H), 3.45- 3.36 (m, 2H), 1.91-1.79 (m, 2H), 1.59 (s, 6H), 1.57-1.46 (m, 2H). 521 571 [01653] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N-{2- [4-(pyrimidin-2- yl)phenyl]propan-2- yl}acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.88 (2H, d), 8.50 (1H, s), 8.43 (1H, s), 8.35- 8.25 (2H, m), 8.01 (1H, dd), 7.94 (1H, dd), 7.75-7.68 (1H, m), 7.60 (1H, s), 7.54-7.47 (2H, m), 7.41 (1H, t), 4.55 (2H, s), 4.28 (2H, s), 4.00- 3.77 (3H, m), 3.43-3.34 (2H, m), 1.90-1.77 (2H, m), 1.62 (6H, s), 1.58-1.43 (2H, m). 598 572 [01654] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-2-(2-oxo-2- {5H,6H,7H,8H,9H- pyrimido[4,5-d]azepin- 7-yl}ethyl)-2,3-dihydro- 1H-isoindol-1-one 1H NMR (DMSO-d6) δ: 8.93 (d, 1H), 8.59 (d, 1H), 8.46 (s, 1H), 8.04 (d, 1H), 8.00 (dd, 1H), 7.76 (d, 1H), 7.63 (s (br), 1H), 4.64-4.52 (m, 4H), 4.01- 3.82 (m, 3H), 3.81-3.62 (m, 4H), 3.44-3.37 (m, 2H), 3.25-3.15 (m, 1H), 3.10- 2.98 (m, 2H), 2.94-2.85 (m, 1H), 1.92-1.76 (m, 2H), 1.60- 1.45 (m, 2H). 534

Example 573: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-{[3-(pyrimidin-2-yl)phenyl]methyl}acetamide

[1732] ##STR01655##

[1733] A stirred mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 80 mg, 0.195 mmol), (3-(pyrimidin-2-yl)phenyl)methanamine (32.6 mg, 0.176 mmol) and triethylamine (73.6 μL, 0.528 mmol) in DMF (1 mL) was cooled in an ice bath. T3P (50% wt in EtOAc) (175 μL, 0.294 mmol) was added, the ice bath was removed and the reaction mixture allowed to warm to room temperature and stirred for 2 h. Water (5 mL) was added, and the resulting white precipitate was filtered, washed with water (5 mL). Trituration with MeOH and Et.sub.2O afforded the title compound (79 mg, 77%) as a colourless powder. 1H NMR (DMSO, 400 MHz) δ 8.92 (1H, s), 8.91 (1H, s), 8.76 (1H, t), 8.44 (1H, s), 8.34 (1H, d), 8.28 (1H, dt), 8.03 (1H, d), 7.98 (1H, dd), 7.75 (1H, d), 7.62 (1H, bs), 7.53-7.42 (3H, m), 4.63 (2H, s), 4.41 (2H, d), 4.28 (2H, s), 3.88-3.84 (3H, m), 3.39-3.35 (2H, m), 1.89-1.79 (2H, m), 1.62-1.45 (2H, m). LC-MS: [M+H].sup.+=570.

Example 574: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[2-(4-methyl-1,3-thiazol-2-yl)propan-2-yl]acetamide

[1734] ##STR01656##

[1735] Prepared using a similar procedure to Example 573. 1H NMR (DMSO, 400 MHz) δ 8.71 (1H, s), 8.44 (1H, s), 8.01 (1H, d), 7.96 (1H, dd), 7.73 (1H, d), 7.61 (1H, s), 7.08 (1H, s), 4.56 (2H, s), 4.24 (2H, s), 3.98-3.81 (3H, m), 3.38 (2H, m), 2.29 (3H, d), 1.90-1.80 (2H, m), 1.64 (6H, s), 1.58-1.44 (2H, m). LC-MS: [M+H].sup.+=541.

Example 575: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(naphthalen-2-yl)methyl]acetamide

[1736] ##STR01657##

[1737] Prepared using a similar procedure to Example 573. 1H NMR (DMSO, 400 MHz) δ 8.75 (1H, t), 8.44 (1H, s), 8.04 (1H, d), 7.98 (1H, dd), 7.88 (3H, td), 7.79-7.73 (2H, m), 7.62 (1H, bs), 7.54-7.46 (2H, m), 7.44 (1H, dd), 4.64 (2H, s), 4.48 (2H, d), 4.30 (2H, s), 3.89-3.87 (3H, m), 3.39-3.35 (2H, m), 1.86-1.82 (2H, m), 1.57-1.47 (2H, m). LC-MS: [M+H].sup.+=542.

Example 576: 4-{[2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamido]methyl}-N-cyclopropylbenzamide

[1738] ##STR01658##

[1739] T3P (50% in EtOAc) (0.177 ml, 0.298 mmol) was added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 0.08 g, 0.199 mmol), 4-(aminomethyl)-N-cyclopropylbenzamide hydrochloride (0.045 g, 0.199 mmol) and triethylamine (0.111 ml, 0.794 mmol)) in DMF (1 mL) and the mixture was stirred for 3h. Further 4-(aminomethyl)-N-cyclopropylbenzamide hydrochloride (0.019 g, 0.099 mmol), triethylamine (0.028 ml, 0.199 mmol) and T3P (50% in EtOAc) (0.059 ml, 0.099 mmol) were added and the mixture was stirred overnight. Water was added and the resulting precipitate was filtered, washed with water and dried under suction. The resulting solid was dissolved in DCM:MeOH and the mixture was concentrated under vacuum. The residue was triturated with EtOAc and the resulting precipitate was filtered, washed with EtOAc and Et.sub.2O. The product was dried in a vacuum oven at 40° C. overnight to afford the title compound (0.072 g, 61.8%) as a white solid. 1H NMR (DMSO-d6) δ: 8.70 (t, 1H), 8.45 (s, 1H), 8.40 (d, 1H), 8.04 (d, 1H), 7.98 (dd, 1H), 7.77 (m, 3H), 7.63 (s (br), 1H), 7.34 (d, 2H), 4.62 (s, 2H), 4.35 (d, 2H), 4.28 (s, 2H), 3.99-3.82 (m, 3H), 3.35-3.45 (m, 2H), 2.87-2.80 (m, 1H), 1.90-1.78 (m, 2H), 1.60-1.45 (m, 2H), 0.72-0.67 (m, 2H), 0.58-0.54 (m, 2H). LC-MS: [M+H].sup.+=575.

Example 577: N-{[4-(azetidine-1-carbonyl)phenyl]methyl}-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamide

[1740] ##STR01659##

[1741] T3P (50% in EtOAc) (0.177 ml, 0.298 mmol) was added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 0.08 g, 0.199 mmol), (4-(aminomethyl)phenyl)(azetidin-1-yl)methanone (0.038 g, 0.199 mmol) and triethylamine (0.111 ml, 0.794 mmol) in DMF (1 mL) and the mixture was stirred for 4.5 h. (4-(aminomethyl)phenyl)(azetidin-1-yl)methanone (0.038 g, 0.199 mmol), triethylamine (0.083 ml, 0.596 mmol) and T3P (50% in EtOAc) (0.118 ml, 0.199 mmol) were added and the mixture was stirred overnight. Water followed by DCM were added and the layers were separated through a phase separating cartridge. The organic extract was dried (MgSO.sub.4), filtered, and adsorbed on to silica. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-5% MeOH in DCM) to afford the title compound (0.015 g, 12.87%) as a white solid after trituration and evaporation from Et.sub.2O. 1H NMR (DMSO-d6) δ: 8.71 (t, 1H), 8.45 (s, 1H), 8.07-8.02 (m, 1H), 7.99 (dd, 1H), 7.76 (d, 1H), 7.63 (s (br), 1H), 7.59 (d, 2H), 7.34 (d, 2H), 4.62 (s, 2H), 4.35 (d, 2H), 4.33-4.23 (m, 4H), 4.04 (t, 2H), 3.98-3.83 (m, 3H), 3.42-3.34 (m, 2H), 2.25 (quint, 2H), 1.89-1.80 (m, 2H), 1.60-1.47 (m, 2H). LCMS: [M+H].sup.+=575.

Example 578: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-(3,3,3-trifluoro-1-phenylpropyl)acetamide

[1742] ##STR01660##

[1743] A stirred mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 75 mg, 0.182 mmol), 3,3,3-trifluoro-1-phenylpropan-1-amine (34.5 mg, 0.182 mmol) and triethylamine (76 μl, 0.547 mmol) in DMF (1 mL) was cooled with an ice bath. T3P (50% in EtOAc, 163 μl, 0.274 mmol) was added, the ice bath was removed and the reaction mixture allowed to warm to room temperature and stirred overnight. Water was added and the mixture was extracted with EtOAc (20 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried (MgSO.sub.4), filtered, and concentrated in vacuo to give the crude product. Purification by chromatography (SiO.sub.2, 24 g column, 0-10% MeOH in EtOAc) afforded the title compound (48 mg, 44.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, 1H), 8.44 (s, 1H), 8.03 (dd, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.62 (s (br), 1H), 7.43-7.33 (m, 4H), 7.33-7.25 (m, 1H), 5.27-5.21 (m, 1H), 4.57 (s, 2H), 4.28-4.20 (m, 2H), 3.98-3.80 (m, 3H), 3.36 (t, 2H), 2.91-2.71 (m, 2H), 1.85-1.82 (m (br), 2H), 1.52 (qd, 2H). LCMS: [M+H].sup.+=574.

Example 579: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2,2,2-trifluoro-1-phenylethyl]acetamide

[1744] ##STR01661##

[1745] A stirred mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 75 mg, 0.182 mmol), (S)-2,2,2-trifluoro-1-phenylethanamine (26.1 μl, 0.182 mmol) and triethylamine (76 μl, 0.547 mmol) in DMF (1 mL) was cooled in an ice bath. T3P (163 μl, 0.274 mmol) was added, the ice bath was removed and the reaction mixture allowed to warm to rt overnight. Water was added and the resulting precipitate collected by filtration and washed with water. The solid was triturated with diethyl ether/isohexane (1:1), filtered and dried to afford the title compound (70 mg, 67.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.48 (d, 1H), 8.44 (s, 1H), 8.02 (dd, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.70-7.53 (m, 3H), 7.51-7.38 (m, 3H), 5.81 (p, 1H), 4.60 (s, 2H), 4.46-4.32 (m, 2H), 3.98-3.80 (m, 3H), 3.37 (t, 2H), 1.85-1.82 (m (br), 2H), 1.57-1.47 (m, 2H). LCMS: [M+H].sup.+=560.

Example 580: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[2-(pyridin-3-yl)propan-2-yl]acetamide

[1746] ##STR01662##

[1747] Triethylamine (0.090 mL, 0.646 mmol) followed by T3P (50 wt % in EtOAc) (0.200 mL, 0.336 mmol) were added to a stirred solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 0.085 g, 0.209 mmol) and 2-(pyridin-3-yl)propan-2-amine (0.043 g, 0.316 mmol) in DMF (2.5 mL, 32.3 mmol). The resulting pale yellow solution was stirred at room temperature for 75 minutes, then diluted with water (5 mL). The mixture was partitioned between saturated aqueous NH.sub.4Cl (10 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with water (10 mL), saturated aqueous NaHCO.sub.3 (10 mL) and brine (3×10 mL), then dried (MgSO.sub.4), filtered, and concentrated under reduced pressure to afford a white solid (63 mg). The solid was dissolved in EtOAc (20 mL) and washed with brine (5×20 mL), dried (MgSO.sub.4), filtered, concentrated under reduced pressure and then dried in a desiccator at 50° C. overnight to afford the title compound (0.053 g, 46.8%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.60-8.55 (m, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.38 (dd, 1H), 8.00 (dd, 1H), 7.95 (dd, 1H), 7.72 (dq, 2H), 7.61 (s (br), 1H), 7.31 (ddd, 1H), 4.55 (s, 2H), 4.27 (s, 2H), 3.95-3.83 (m, 3H), 3.39-3.33 (m, 2H), 1.84 (d (br), 2H), 1.59 (s, 6H), 1.51 (qd, 2H). LCMS: [M+H].sup.+=521.

Example 581: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-(2-oxo-2-{4-oxo-3H,4H,5H,6H,7H,8H,9H-pyrimido[4,5-d]azepin-7-yl}ethyl)-2,3-dihydro-1H-isoindol-1-one

[1748] ##STR01663##

[1749] Prepared using a similar procedure to Example 580. The product was purified by chromatography (SiO.sub.2, 24 g column, 0-10% MeOH in DCM) in this case. 1H NMR (DMSO-d6, 400 MHz) δ 12.42 (s (br), 1H), 8.45 (s, 1H), 8.03 (d, 1H), 8.00-7.95 (m, 2H), 7.74 (d, 1H), 7.62 (s, 1H), 4.58 (s, 2H), 4.53 (d, 2H), 3.93-3.81 (m, 3H), 3.77-3.56 (m, 4H), 3.38-3.35 (m, 2H), 3.02-2.72 (m, 4H), 1.84 (d, 2H), 1.52 (qd, 2H). LCMS: [M+H].sup.+=550.

Example 582: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[2-(1-methyl-1H-pyrazol-4-yl)propan-2-yl]acetamide

[1750] ##STR01664##

[1751] Prepared using a similar procedure to Example 580. The product was further purified by chromatography (SiO.sub.2, 4 g column, 0-5% MeOH in DCM) in this case. 1H NMR (DMSO-d6) δ: 8.45 (s, 1H), 8.08 (s, 1H), 8.02 (dd, 1H), 7.97 (dd, 1H), 7.74 (d, 1H), 7.62 (s (br), 1H), 7.56 (d, 1H), 7.33 (d, 1H), 4.57 (s, 2H), 4.17 (s, 2H), 3.82-3.98 (m, 3H), 3.77 (s, 3H), 3.42-3.33 (m, 2H), 1.90-1.80 (m, 2H), 1.57 (s, 6H), 1.57-1.47 (m, 2H). LCMS: [M+H].sup.+=524.

Example 583: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S,2S)-2-hydroxy-1-(3-methylphenyl)propyl]acetamide

[1752] ##STR01665##

[1753] TBTU (96 mg, 0.298 mmol) was added to an ice-cooled stirred solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 80 mg, 0.199 mmol), (1S,2S)-1-amino-1-(m-tolyl)propan-2-ol hydrochloride (44.1 mg, 0.218 mmol) and triethylamine (111 μl, 0.794 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 1 h, then diluted with EtOAc (30 mL). The organic phase was washed with water (30 mL) 1 M HCl (aq.) (30 mL) and brine (3×30 mL), dried (MgSO.sub.4), filtered, and concentrated in vacuo to give a white semi-solid (150 mg). The crude product was purified by chromatography (SiO.sub.2, 24 g column, 0-10% MeOH in DCM) to afford the title compound (95 mg, 86%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.54-8.35 (m, 2H), 8.02 (d, 1H), 7.96 (dd, 1H), 7.73 (d, 1H), 7.62 (s, 1H), 7.19 (t, 1H), 7.15-7.08 (m, 2H), 7.03 (d, 1H), 4.80 (d, 1H), 4.67 (dd, 1H), 4.57 (s, 2H), 4.35 (d, 1H), 4.28 (d, 1H), 4.01-3.77 (m, 4H), 3.42-3.31 (m, 2H), 2.29 (s, 3H), 1.93-1.77 (m, 2H), 1.62-1.44 (m, 2H), 0.98 (d, 3H). LCMS: [M+H].sup.+=550.

Example 584-589

[1754] Prepared using an analogous procedure to Example 583, from 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1) and the corresponding amine.

TABLE-US-00044 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 584 [01666] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-(3-ethoxy-5- fluorophenyl)-2- hydroxyethyl]acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.54 (d, 1H), 8.45 (s, 1H), 8.07-8.02 (m, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.63 (s (br), 1H), 6.76-6.65 (m, 3H), 4.96 (t, 1H), 4.89-4.82 (m, 1H), 4.60 (s, 2H), 4.35-4.26 (m, 2H), 4.03 (q, 2H), 3.98- 3.83 (m, 3H), 3.59-3.54 (m, 2H), 3.42-3.36 (m, 2H), 1.90- 1.82 (m, 2H), 1.61-1.47 (m, 2H), 1.32 (t, 3H). 584 585 [01667] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-[3-(1,1- difluoroethyl)phenyl]- 2- hydroxyethyl]acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.65 (d, 1H), 8.45 (s, 1H), 8.05-8.01 (m, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.63 (s (br), 1H), 7.57-7.51 (m, 1H), 7.47-7.42 (m, 3H), 5.01- 4.90 (m, 2H), 4.59 (s, 2H), 4.36-4.24 (m, 2H), 3.98- 3.82 (m, 3H), 3.60 (t, 2H), 3.42-3.35 (m, 2H), 1.97 (t, 3H), 1.89-1.80 (m, 2H), 1.60- 1.46 (m, 2H). 586 586 [01668] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl{-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S,2S)-1-(3- ethoxyphenyl)-2- hydroxypropyl] acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.54-8.37 (2H, m), 8.02 (1H, dd), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, s), 7.20 (1H, dd), 6.94-6.84 (2H, m), 6.77 (1H, ddd), 4.80 (1H, d), 4.68 (1H, dd), 4.57 (2H, s), 4.35 (1H, d), 4.28 (1H, d), 4.00 (2H, q), 3.96-3.78 (4H, m), 3.45-3.35 (2H, m), 1.92- 1.76 (2H, m), 1.61-1.44 (2H, m), 1.32 (3H, t), 0.98 (3H, d). 580 587 [01669] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S,2S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxypropyl] acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.54-8.36 (m, 2H), 8.02 (dd, 1H), 7.97 (dd, 1H), 7.73 (d, 1H), 7.61 (s, 1H), 6.83-6.72 (m, 2H), 6.68 (dt, 1H), 4.85 (d, 1H), 4.72 (dd, 1H), 4.58 (s, 2H), 4.37 (d, 1H), 4.31 (d, 1H), 3.98-3.81 (m, 4H), 3.76 (s, 3H), 3.43- 3.32 (m, 2H), 1.89-1.78 (m, 2H), 1.59-1.44 (m, 2H), 1.02 (d, 3H). 584 588 [01670] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S,2S)-1-(3-fluoro-5- methylphenyl)-2- hydroxypropyl] acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.54-8.38 (2H, m), 8.03 (1H, dd), 7.97 (1H, dd), 7.74 (1H, d), 7.62 (1H, s (br)), 7.05-6.94 (2H, m), 6.93- 6.85 (1H, m), 4.86 (1H, d), 4.72 (1H, dd), 4.59 (2H, s), 4.37 (1H, d), 4.31 (1H, d), 4.04-3.80 (4H, m), 3.47- 3.34 (2H, m), 2.31 (3H, s), 1.89-1.80 (2H, m), 1.62- 1.45 (2H, m), 1.02 (3H, d). 568 589 [01671] 2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro- 1H-isoindol-2-yl)-N- [(1S)-1-(4- cyclopropoxyphenyl)- 2- hydroxyethyl] acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.50 (1H, d), 8.44 (1H, s), 8.02 (1H, d), 7.97 (1H, dd), 7.73 (1H, d), 7.62 (1H, s (br)), 7.31-7.14 (2H, m), 7.06-6.91 (2H, m), 4.88 (1H, s), 4.82 (1H, ddd), 4.58 (2H, s), 4.30 (1H, d), 4.24 (1H, d), 3.97-3.82 (3H, m), 3.83-3.75 (1H, m), 3.54 (2H, d), 3.46-3.35 (2H, m), 1.89- 1.77 (2H, m), 1.60-1.43 (2H, m), 0.83-0.72 (2H, m), 0.67- 0.58 (2H, m). 578

Example 590: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[2-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl]acetamide (relative cis stereochemistry)

[1755] ##STR01672##

[1756] TBTU (0.067 g, 0.209 mmol) was added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 0.08 g, 0.199 mmol), (trans-1-amino-2,3-dihydro-1H-inden-2-yl)methanol (0.034 g, 0.209 mmol), and DIPEA (0.036 ml, 0.209 mmol) in DMF (1 mL) and the mixture was stirred for 1 h. The mixture was diluted with EtOAc and transferred into a separating funnel. 1 N aq. HCl was added and the product was extracted with EtOAc. The combined organic extracts were washed with water, saturated aqueous NaHCO.sub.3, brine, dried (MgSO.sub.4), filtered, and adsorbed on to silica. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-6% MeOH in DCM) to afford the title compound (0.07 g, 62.4%) as a white solid, after trituration and evaporation from Et.sub.2O. 1H NMR (DMSO-d6) δ: 8.46 (s, 1H), 8.36 (d, 1H), 8.04 (d, 1H), 7.99 (dd, 1H), 7.76 (d, 1H), 7.63 (s (br), 1H), 7.30-7.16 (m, 4H), 5.38 (t, 1H), 4.65 (d, 1H), 4.60 (s, 1H), 4.46 (dd, 1H), 4.27 (s, 2H), 3.98-3.81 (m, 3H), 3.58-3.49 (m, 1H), 3.44-3.35 (m, 2H), 3.29 (ddd, 1H), 2.88 (ddd, 2H), 2.70-2.59 (m, 1H), 1.90-1.79 (m, 2H), 1.59-1.47 (m, 2H). LCMS: [M+H].sup.+=548.

Example 591: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(4-fluoro-3-methylphenyl)-2-hydroxyethyl]acetamide

[1757] ##STR01673##

[1758] Prepared using a similar procedure to Example 590. 1H NMR (DMSO-d6) δ: 8.54 (d, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.63 (s (br), 1H), 7.23 (dd, 1H), 7.17 (ddd, 1H), 7.08 (dd, 1H), 4.94 (t, 1H), 4.84 (td, 1H), 4.59 (s, 2H), 4.31 (d, 1H), 4.26 (d, 1H), 4.00-3.80 (m, 3H), 3.56 (dd, 2H), 3.42-3.35 (m, 2H), 2.23 (d, 3H), 1.89-1.79 (m, 2H), 1.60-1.46 (m, 2H). LCMS: [M+H].sup.+=554.

Example 592: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S,2S)-2-hydroxy-1-[3-(trifluoromethyl)phenyl]propyl]acetamide

[1759] ##STR01674##

[1760] A stirred solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 70 mg, 0.170 mmol), (1S,2S)-1-amino-1-(3-(trifluoromethyl)phenyl)propan-2-ol, HCl (48 mg, 0.188 mmol), and triethylamine (95 μl, 0.681 mmol) in DMF (1 ml) was treated with TBTU (66 mg, 0.206 mmol) and stirred at room temperature overnight. The mixture was diluted with EtOAc (20 ml), washed with 1 M aq. KHSO.sub.4 (10 ml) followed by saturated aqueous NaHCO.sub.3 (10 ml), brine (2×10 ml), then dried (MgSO.sub.4), filtered, and evaporated. The residue was purified by chromatography (SiO.sub.2, 12 g column, 0-6% EtOH in EtOAc), to give a glassy semi-solid. the product was purified by reversed phase preparative HPLC on a Waters XBridge BEH C18 OBD, 130 Å, 5 μm, 19 mm×50 mm column, using a gradient of 20 to 50% of acetonitrile in 10 mM aqueous ammonium bicarbonate solution at 28 ml/min as eluent. The clean fractions were pooled and concentrated to remove most of the acetonitrile. The residue was freeze-dried to give the title compound (41 mg, 39.5%) as a white powder. 1H NMR (DMSO-d6, 400 MHz) δ 8.62 (d, 1H), 8.44 (s, 1H), 8.04-8.00 (m, 1H), 7.96 (dd, 1H), 7.76-7.67 (m, 2H), 7.69-7.50 (m, 4H), 5.01-4.82 (m, 2H), 4.57 (s, 2H), 4.44-4.25 (m, 2H), 3.99-3.78 (m, 4H), 3.42-3.36 (m, 2H), 1.91-1.77 (m, 2H), 1.61-1.43 (m, 2H), 1.04 (d, 3H). LCMS: [M+H].sup.+=604.

Example 593: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(2-fluoro-3-methylphenyl)-2-hydroxyethyl]acetamide

[1761] ##STR01675##

[1762] Prepared using a similar procedure to Example 590. 1H NMR (DMSO-d6) δ: 8.68 (d, 1H), 8.50 (s, 1H), 8.08 (d, 1H), 8.03 (dd, 1H), 7.79 (d, 1H), 7.67 (s (br), 1H), 7.32-7.19 (m, 2H), 7.13 (dd, 1H), 5.23 (td, 1H), 5.09 (t, 1H), 4.64 (s, 2H), 4.38 (d, 1H), 4.32 (d, 1H), 4.06-3.87 (m, 3H), 3.69-3.56 (m, 2H), 3.48-3.41 (m, 2H), 2.28 (d, 3H), 1.98-1.84 (m, 2H), 1.68-1.50 (m, 2H). LCMS: [M+H].sup.+=554.

Example 594: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-{2-[3-(hydroxymethyl)-3-methylazetidin-1-yl]-2-oxoethyl}-2,3-dihydro-1H-isoindol-1-one

[1763] ##STR01676##

[1764] DIPEA (0.073 ml, 0.417 mmol) was added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 0.08 g, 0.199 mmol), (3-methylazetidin-3-yl)methanol hydrochloride (0.029 g, 0.209 mmol), and TBTU (0.032 g, 0.099 mmol) in DMF (1 mL) and the mixture was stirred for 45 minutes at room temperature. TBTU (0.067 g, 0.209 mmol), DIPEA (0.017 ml, 0.099 mmol) and (3-methylazetidin-3-yl)methanol hydrochloride (0.014 g, 0.099 mmol) were added and the mixture was stirred for 1.75 h. The mixture was diluted with EtOAc (vol?) and transferred into a separating funnel. 1 N aq. HCl was added and the product was extracted with EtOAc. The acidic aqueous layer was neutralized by the addition of 2 N aq. NaOH and was extracted with DCM. The combined organic extracts were dried (MgSO.sub.4), adsorbed on to silica and purified by chromatography (SiO.sub.2, 12 g column, 0-100% MeOH in DCM) to the title compound (0.034 g, 34.5%) as a white solid after trituration and evaporation from Et.sub.2O. 1H NMR (DMSO-d6) δ: 8.45 (s, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.63 (s (br), 1H), 5.00 (s (br), 1H), 4.57 (s, 2H), 4.23 (s, 2H), 4.02 (d, 1H), 3.99-3.81 (m, 3H), 3.79 (d, 1H), 3.74 (d, 1H), 3.46 (d, 1H), 3.43-3.31 (m, 4H), 1.85 (d, 2H), 1.61-1.45 (m, 2H), 1.21 (s, 3H). LCMS: [M+H].sup.+=486.

Example 595: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-phenylethyl]-N-methylacetamide

[1765] ##STR01677##

[1766] TBTU (67.0 mg, 0.209 mmol) was added to a mixture of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 80 mg, 0.199 mmol), (S)-2-(methylamino)-2-phenylethanol, HCl (41.0 mg, 0.218 mmol), and DIPEA (72.8 μl, 0.417 mmol) in DMF (2 mL) and the reaction was stirred at room temperature overnight. An aqueous solution of KHSO.sub.4 (1 M, 10 mL) was added, and the crude product was extracted with EtOAc (15 mL). The organic extracts was successively washed with saturated aq. NaHCO.sub.3 (10 mL) and brine (10 mL), dried (MgSO.sub.4), filtered, and concentrated in vacuo. Purification by chromatography (SiO.sub.2, 0-100% EtOAc in iso-hexanes) followed by preparative HPLC (acidic) gave the title compound (20 mg, 18.6%) as a colourless powder. 1H NMR (DMSO, 400 MHz) δ 8.46 (s, 1H), 8.06-7.96 (m, 2H), 7.76 (dd, 1H), 7.63 (s (br), 1H), 7.44-7.26 (m, 5H), 5.61 (t, 0.6H), 5.24 (s (br), 0.4H), 5.12 (t, 0.4H), 4.97 (s (br), 0.6H), 4.69-4.52 (m, 4H), 3.99-3.83 (m, 5H), 3.41 (m, 2H), 2.89 (s, 1.8H), 2.65 (s, 1.2H), 1.85 (m, 2H), 1.61-1.46 (m, 2H). LCMS: [M+H].sup.+=536.

Example 596: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S,2S)-2-hydroxy-1-phenylbutyl]acetamide

[1767] ##STR01678##

[1768] Prepared using a similar procedure to Example 583. In this case, the product was further purified by preparative HPLC (Waters, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 35-65% MeCN in Water). The fractions were combined and the organics removed in vacuo. The aqueous was extracted with EtOAc (3×50 mL) and the combined organic phases were washed with brine (100 mL), dried (MgSO.sub.4), filtered, and concentrated to give the title compound (78 mg, 44.5%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.55-8.49 (2H, m), 8.10-8.05 (1H, m), 8.03 (1H, dd), 7.79 (1H, d), 7.68 (1H, br. s), 7.43-7.34 (4H, m), 7.32-7.25 (1H, m), 4.88 (1H, dd), 4.85 (1H, d), 4.63 (2H, s), 4.43 (1H, d), 4.35 (1H, d), 4.04-3.87 (3H, m), 3.70-3.57 (1H, m), 3.47-3.41 (2H, m), 1.97-1.76 (2H, m), 1.65-1.52 (2H, m), 1.47-1.28 (2H, m), 0.93 (3H, t). LCMS: [M+H].sup.+=550.

Example 597: 2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-((1S,2S)-1-(3-ethoxy-5-fluorophenyl)-2-hydroxypropyl)acetamide

[1769] ##STR01679##

[1770] A stirred solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Example 1, 70 mg, 0.170 mmol), (1S,2S)-1-amino-1-(3-ethoxy-5-fluorophenyl)propan-2-ol hydrochloride (47 mg, 0.188 mmol), and triethylamine (95 μl, 0.681 mmol) in DMF (1 ml) was treated with TBTU (66 mg, 0.206 mmol) and stirred at rt overnight. The mixture was diluted with EtOAc (20 ml), was washed successively with 1 M aq. KHSO.sub.4 (10 ml), saturated aq. NaHCO.sub.3 (10 ml), brine (2×10 ml), and then water (4×10 ml), dried (MgSO.sub.4), filtered, and evaporated. The residue was purified on a 12 g graceresolv silica cartridge, using a gradient of 0-5% of EtOH/EtOAc as the eluent to give a glass, which was triturated with ether (2 ml) to give a solid. The solid was collected by filtration, washed with ether (2×1 ml) and dried under vacuum at 50° C. overnight to give a white powder (61 mg). LCMS showed this material to contain 5.7% of the dimeric ester product, so it was further purified by reversed phase preparative HPLC on a Waters XSelect CSH C18 OBD, 130 Å, 5 μm, 19 mm×50 mm column, using a gradient of 20-50% of acetonitrile in water with 0.1% formic acid in both at 28 ml/min as the eluent. The clean fractions were pooled and concentrated to remove most of the acetonitrile. The residue was freeze-dried to give the title compound (34 mg, 33.0%) as a cream solid. 1H NMR (DMSO, 400 MHz) δ 8.51-8.40 (m, 2H), 8.04-8.00 (m, 1H), 8.00-7.93 (m, 1H), 7.73 (d, 1H), 7.62 (s, 1H), 6.79-6.70 (m, 2H), 6.70-6.61 (m, 1H), 4.88 (s, 1H), 4.76-4.65 (m, 1H), 4.58 (s, 2H), 4.42-4.27 (m, 2H), 4.01 (q, 2H), 3.97-3.76 (m, 4H), 3.44-3.37 (m, 2H), 1.84 (d, 2H), 1.59-1.43 (m, 2H), 1.31 (t, 3H), 1.01 (d, 3H). LCMS: [M+H].sup.+=598.

Example 598: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-[3-(methoxymethyl)phenyl]ethyl]acetamide

[1771] ##STR01680##

[1772] Prepared using a similar procedure to Example 583. In this case, the product was further purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water). 1H NMR (DMSO-d6, 400 MHz) δ 8.61 (d, 1H), 8.44 (s, 1H), 8.06-7.99 (m, 1H), 7.97 (dd, 1H), 7.73 (d, 1H), 7.64 (s, 1H), 7.33-7.22 (m, 3H), 7.20-7.16 (m, 1H), 5.04-4.93 (m, 1H), 4.87 (ddd, 1H), 4.58 (s, 2H), 4.39 (s, 2H), 4.31 (d, 1H), 4.26 (d, 1H), 4.00-3.79 (m, 3H), 3.64-3.51 (m, 2H), 3.44-3.35 (m, 2H), 3.29 (s, 3H), 1.92-1.77 (m, 2H), 1.60-1.44 (m, 2H). LCMS: [M+H].sup.+=566.

Example 599: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2,3-bis(2-methoxyethyl)-2,3-dihydro-1H-isoindol-1-one

[1773] ##STR01681##

[1774] Prepared from 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1H-isoindol-1-one (Example 128) using a similar procedure to Preparation 48. The product was separated from 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-(2-methoxyethyl)-2,3-dihydro-1H-isoindol-1-one (Example 103) by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water). The product (36 mg, 25.8%) was obtained as a white solid. 1H NMR (400 MHz, CDCl.sub.3) δ 8.38-8.23 (m, 2H), 7.98 (dd, 1H), 7.55 (dt, 1H), 5.17 (d, 1H), 4.93 (dd, 1H), 4.21 (dt, 1H), 4.12-4.02 (m, 1H), 3.99 (dt, 2H), 3.70-3.59 (m, 2H), 3.54 (td, 2H), 3.39 (ddd, 1H), 3.34 (s, 3H), 3.27-3.15 (m, 2H), 3.23 (s, 3H), 2.37 (dtd, 1H), 2.26-2.14 (m, 1H), 2.10-2.00 (m, 2H), 1.56 (dtd, 2H). LCMS: [M+H].sup.+=461.

Example 600: N-tert-butyl-2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-(2-hydroxyethyl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-methylacetamide

[1775] ##STR01682##

[1776] Ethyl chloroformate (15.9 μl, 0.166 mmol) followed by isobutyl chloroformate (19.6 μl, 0.151 mmol) were added to a stirred solution of 2-(2-(2-(tert-butyl(methyl)amino)-2-oxoethyl)-5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-3-oxoisoindolin-1-yl)acetic acid (Preparation 331, 80 mg, 0.151 mmol) and N-methyl morpholine (17.4 μL, 0.158 mmL) in THF (5 mL). After 1 h the reaction mixture was filtered and the solid was washed with additional THF (10 mL). The combined filtrate and washings were cooled to 0° C. in an ice bath and then MeOH (5 mL) was added followed by addition of NaBH.sub.4 (6.00 mg, 0.158 mmol). The resulting mixture was stirred at 0° C. for 2 h. The reaction mixture was concentrated, diluted with EtOAc (50 ml) and transferred into a separating funnel. The mixture was washed with NH.sub.4Cl (20 ml), brine (20 ml), dried (MgSO.sub.4), and concentrated to give a colourless oil. The crude product was purified by chromatography (SiO.sub.2, 24 g column, 0-10% MeOH in DCM) to afford the title compound (56 mg, 71.2%) as a colourless solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.06-7.94 (2H, m), 7.78 (1H, d), 7.60 (1H, s), 4.81 (1H, t), 4.68-4.54 (2H, m), 4.10 (1H, d), 4.00-3.81 (3H, m), 3.39 (3H, dd), 2.95 (3H, s), 2.20 (1H, ddd), 1.99 (1H, dq), 1.85 (2H, d), 1.53 (2H, qd), 1.35 (9H, s). LC-MS: [M+H]+=516

Example 601: 2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-(2-hydroxyethyl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-(1-phenylcyclopropyl)acetamide

[1777] ##STR01683##

[1778] Isobutyl chloroformate (0.108 mL, 0.825 mmol) was added to a stirred solution of 2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-3-oxo-2-(2-oxo-2-((1-phenylcyclopropyl)amino)ethyl)isoindolin-1-yl)acetic acid (Preparation 332, 480 mg, 0.750 mmol) and 4-methylmorpholine (0.091 mL, 0.825 mmol) in THF (25 mL) under nitrogen. The reaction was stirred at room temperature for 2.5 h. The reaction mixture was filtered and the solids were washed with THF (30 mL). MeOH (25 mL) was added to the filtrate, the solution was ice-cooled and sodium borohydride (31.2 mg, 0.825 mmol) was added. The reaction was allowed to warm slowly to room temperature and stirred overnight. A further portion of sodium borohydride (31.2 mg, 0.825 mmol) was added and the mixture stirred for a further 1 h. The reaction mixture was concentrated and diluted with EtOAc (100 ml). The organic phase was washed with NH.sub.4Cl (100 ml), brine (100 ml) and dried (MgSO.sub.4), and concentrated to give a yellow solid (470 mg). The crude product was purified by chromatography (40 g column, 0-5% MeOH in EtOAc) to afford the title compound (224 mg, 51.0%) as an off white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.88 (1H, s), 8.44 (1H, s), 8.03 (1H, dd), 7.99 (1H, dd), 7.77 (1H, d), 7.60 (1H, d), 7.31-7.22 (2H, m), 7.21-7.11 (3H, m), 4.86 (1H, dd), 4.67 (1H, t), 4.43 (1H, d), 3.99 (1H, d), 3.96-3.79 (3H, m), 3.46-3.33 (4H, m), 2.29-2.14 (1H, m), 2.06-1.94 (1H, m), 1.92-1.78 (2H, m), 1.59-1.45 (2H, m), 1.26-1.12 (4H, m). LC-MS: [M+H].sup.+=562.

Example 602-604

[1779] Prepared using an analogous procedure to Example 601, from the appropriate carboxylic acid

TABLE-US-00045 MS: Example Structure Name .sup.1H NMR (400 MHz) [M +H].sup.+ 602 [01684] 6-{5-chloro-2-[(oxan- 4- yl)amino]pyrimidin- 4-yl}-3-(2- hydroxyethyl)-2-[2- oxo-2-(2,3,4,5- tetrahydro-1H-3- benzazepin-3- yl)ethyl]-2,3-dihydro- 1H-isoindol-1-one 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.06- 7.96 (2H, m), 7.78 (1H, d, J = 7.9 Hz), 7.60 (1H, d, J = 7.7 Hz), 7.25-7.10 (4H, m), 4.88-4.76 (2H, m), 4.62 (1H, t, J = 4.8, 4.8 Hz), 4.23 (1H, d, J = 16.8 Hz), 4.00-3.80 (3H, m), 3.75- 3.54 (4H, m), 3.44-3.34 (3H, m), 3.09-2.90 (2H, m), 2.84 (2H, q, J = 4.2, 4.0, 4.0 Hz), 2.19 (1H, ddd, J = 14.0, 11.2, 6.7 Hz), 2.09- 1.95 (1H, m), 1.85 (2H, d, J = 12.6 Hz), 1.61-1.45 (2H, m). 576 603 [01685] 2-(5-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin- 4-yl}-1-(2- hydroxyethyl)-3-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N- methyl-N-(2- phenylethyl)acetamide 1H NMR (DMSO-d6, 400 MHz, 373 K) δ 8.40 (1H, s), 8.07 (1H, d), 8.02 (1H, dd), 7.79-7.71 (1H, m), 7.36- 7.19 (5H, m), 7.11 (1H, d), 4.87-4.82 (1H, m), 4.67 (1H, d), 4.25-4.19 (1H, m), 4.12-3.93 (2H, m), 3.93- 3.86 (2H, m), 3.67-3.56 (2H, m), 3.48-3.39 (4H, m), 2.24-2.11 (1H, m), 2.04-1.86 (4H, m), 1.66- 1.54 (2H, m) (4 protons obscured by solvent peak). 564 604 [01686] 2-(5-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin- 4-yl}-1-(2- hydroxyethyl)-3-oxo- 2,3-dihydro-1H- isoindol-2-yl)-N-(2- phenylpropan-2- yl)acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.44 (1H, s), 8.37 (1H, s), 8.01 (1H, dd), 7.98 (1H, dd), 7.75 (1H, d), 7.58 (1H, d), 7.37 (2H, dd), 7.29 (2H, dd), 7.22-7.12 (1H, m), 4.78 (1H, dd), 4.64 (1H, t), 4.50 (1H, d), 3.98 (1H, d), 3.90 (3H, dd), 3.46- 3.34 (4H, m), 2.22 (1H, ddd), 1.99 (1H, dq), 1.85 (2H, d), 1.58 (6H, d), 1.57- 1.47 (2H, m). 564

Example 605: 2[1-(2-aminoethyl)-5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-tert-butyl-N-methylacetamide

[1780] ##STR01687##

[1781] A stirred solution of N-(tert-butyl)-2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-3-oxoisoindolin-2-yl)-N-methylacetamide (Preparation 340, 20 mg, 0.031 mmol) in ethanol (1 ml) was treated with hydrazine hydrate (6.08 μl, 0.124 mmol) and the resulting white suspension was refluxed 1 h. The reaction mixture was cooled to room temperature and diluted with DCM (0.5 ml). The resulting homogenous solution was refluxed 5h and the resulting white suspension was cooled to room temperature, then diluted further with DCM (0.5 ml). Further hydrazine hydrate (6.08 μl, 0.124 mmol) was added and the resulting homogenous solution refluxed overnight. The reaction mixture was concentrated under vacuum and the residue was purified by chromatography (SiO.sub.2, 12 g column, 0 to 10% of MeOH in DCM) to afford the title compound (8 mg, 49.6%) as a colourless solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.41 (1H, s), 8.06 (1H, dd), 8.02 (1H, dd), 7.75 (1H, dt), 7.22 (1H, d), 4.88 (1H, t), 4.67 (1H, d), 4.06 (1H, d), 4.02-3.93 (1H, m), 3.89 (2H, dt), 3.42 (2H, td), 2.98 (3H, s), 2.44-2.38 (1H, m), 2.20-2.08 (1H, m), 2.04-1.94 (1H, m), 1.90 (2H, d), 1.59 (2H, qd), 1.39 (9H, s). (3 protons overlapped with water peak). LC-MS: [M+H].sup.+=515

Example 606: 3-(2-aminoethyl)-6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[2-oxo-2-(2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1782] ##STR01688##

[1783] Hydrazine hydrate (60.1 μl, 0.741 mmol) was added to a stirred solution of 2-(2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-2-(2-(4,5-dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-oxoethyl)-3-oxoisoindolin-1-yl)ethyl)isoindoline-1,3-dione (Preparation 341, 55 mg, 0.074 mmol) in THF (1.5 mL) under nitrogen and the mixture heated to 65° C. and stirred overnight. The solvent was removed in vacuo and the crude product was adsorbed onto silica and purified by chromatography (SiO.sub.2, 12 g column, 0-10% (0.7 M Ammonia/MeOH) in DCM) to afford the title compound (40 mg, 92%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.05-7.97 (2H, m), 7.76 (1H, d), 7.61 (1H, d), 7.24-7.10 (4H, m), 4.91-4.73 (2H, m), 4.19 (1H, d), 3.91 (3H, dddd), 3.75-3.51 (4H, m), 3.43-3.35 (2H, m), 3.07-2.90 (2H, m), 2.89-2.77 (2H, m), 2.46 (1H, s), 2.27 (1H, s), 2.16-2.05 (1H, m), 2.04-1.91 (1H, m), 1.91-1.78 (2H, m), 1.60-1.45 (2H, m). LC-MS: [M+H]+=575.

Example 607-608

[1784] Prepared using an analogous procedure to Example 606, from the appropriate carboxylic acid

TABLE-US-00046 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 607 [01689] 2-[1-(2-aminoethyl)-5- {5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-3-oxo-2,3-dihydro- 1H-isoindol-2-yl]-N-(2- phenylpropan-2- yl)acetamide 1H NMR (DMSO-d6) δ: 8.43 (2H, d), 8.00 (1H, d), 7.97 (1H, dd), 7.74 (1H, d), 7.61 (1H, brs), 7.43-7.34 (2H, m), 7.33-7.24 (2H. m), 7.22-7.12 (1H, m), 4.84-4.72 (1H, m), 4.51 (1H, d), 4.02-3.80 (5H, m), 3.43-3.38 (1H, m), 2.47- 2.42 (2H, m), 2.36-2.25 (2H, m), 2.17-2.08 (1H, m), 2.02-1.90 (1H, m), 1.90-1.78 (2H, m), 1.58 (6H, s), 1.56-1.46 (2H, m 563 608 [01690] 2[1-(2-aminoethyl)-5- {5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4- yl}-3-oxo-2,3-dihydro- 1H-isoindol-2-yl]-N- [(1S,2R)-2-hydroxy- 2,3-dihydro-1H-inden- 1-yl]acetamide 1H NMR (DMSO-d6, 400 MHz) δ 8.46 (1H, s), 8.37- 8.25 (1H, m), 8.12-7.94 (2H, m), 7.88-7.73 (1H, m), 7.62 (1H, s), 7.33-7.13 (4H, m), 5.29-5.14 (1H, m), 5.03-4.91 (1H, m), 4.60 (1H, d), 4.53-4.35 (1H, m), 4.23-4.03 (1H, m), 4.01-3.79 (3H, m), 3.45-3.38 (3H, m), 3.07 (1H, dd), 2.92-2.76 (1H, m), 2.42-2.15 (2H, m), 2.14-1.99(1H, m), 1.94- 1.79 (2H, m), 1.62-1.43 (2H, m). 3 protons not observed, probably OH and NH2 under water or DMSO peak. 577

Example 609 and 610: 2-[(1S)-1-(2-aminoethyl)-5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1R)-1-(3-methoxyphenyl)ethyl]acetamide and 2-[(1R)-1-(2-aminoethyl)-5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1R)-1-(3-methoxyphenyl)ethyl]acetamide

[1785] ##STR01691##

[1786] The racemic mixture was prepared using a similar procedure to Example 606.

[1787] The diastereoisomers were separated by chiral preparative HPLC (Gilson, Diacel Chiralpak IA, 5 um, 20×250 mm 72:10:18 iso-hexane+0.2% TFA/EtOH/DCM) and each set of fractions (peak A and peak B) were combined separately and neutralised with NaHCO.sub.3 (˜40 mL). Most of the organic solvent was removed in vacuo and the residues were diluted with water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine (100 ml), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. Each diastereoisomers were then further purified by chromatography (4 g column, 0-10% (0.7 M Ammonia/MeOH) in DCM) to afford 2-[(1S)-1-(2-aminoethyl)-5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1R)-1-(3-methoxyphenyl)ethyl]acetamide (17 mg, 4.34%) (A) and 2-[(1R)-1-(2-aminoethyl)-5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1R)-1-(3-methoxyphenyl)ethyl]acetamide (20 mg, 5.10%) (B) as white solids. (A): 1H NMR (DMSO-d6, 400 MHz) δ 8.60 (1H, d), 8.44 (1H, s), 8.06-7.92 (2H, m), 7.74 (1H, d), 7.61 (1H, s (br)), 7.24 (1H, t), 6.98-6.85 (2H, m), 6.80 (1H, ddd), 5.01-4.86 (1H, m), 4.82 (1H, dd), 4.48 (1H, d), 4.02-3.80 (4H, m), 3.76 (3H, s), 3.43-3.33 (2H, m), 2.46-2.35 (1H, m), 2.27 (1H, s), 2.17-2.02 (1H, m), 1.94 (1H, dt), 1.89-1.77 (2H, m), 1.63-1.43 (2H, m), 1.36 (3H, d) (NH.sub.2 signal was not observed and assumed to overlap with water or DMSO peaks). LCMS: [M+H]+=579. (B): 1H NMR (DMSO-d6, 400 MHz) δ 8.60 (1H, d), 8.44 (1H, s), 8.09-7.92 (2H, m), 7.75 (1H, d), 7.60 (1H, s (br)), 7.23 (1H, t), 6.97-6.84 (2H, m), 6.79 (1H, ddd), 5.00-4.81 (2H, m), 4.46 (1H, d), 4.03-3.80 (4H, m), 3.74 (3H, s), 3.48-3.34 (2H, m), 2.47-2.37 (1H, m), 2.36-2.21 (1H, m), 2.19-2.05 (1H, m), 2.03-1.89 (1H, m), 1.90-1.74 (2H, m), 1.61-1.43 (2H, m), 1.37 (3H, d) (NH.sub.2 signal was not observed and assumed to overlap with water or DMSO peaks). LCMS: [M+H]+=579.

Example 611, 612 and 613: 2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide

[1788] ##STR01692##

[1789] Prepared using a similar procedure to Example 590. 1H NMR (DMSO-d6) δ: 8.53 (d, 0.5H), 8.51 (d, 0.5H), 8.45 (s, 1H), 8.05-7.95 (m, 2H), 7.82-7.72 (m, 1H), 7.62 (s (br), 0.5H), 7.61 (s (br), 0.5H), 7.24 (m, 1H), 6.92-6.83 (m, 2H), 6.84-6.77 (m, 1H), 4.94-4.90 (m, 1H), 4.88-4.80 (m, 1H), 4.78 (q, 0.5H), 4.73 (q, 0.5H), 4.49 (d, 0.5H), 4.46 (d, 0.5H), 4.04 (d, 0.5H), 4.03 (d, 0.5H), 3.97-3.82 (m, 3H), 3.76 (s, 1.5H), 3.75 (s, 1.5H), 3.63-3.52 (m, 2H), 3.44-3.36 (m, 2H), 1.90-1.80 (m, 2H), 1.5-1.47 (m, 2H), 1.46 (d, 1.5H), 1.44 (d, 1.5H). LCMS: [M+H]+=566. The diastereoisomers were separated by preparative HPLC (Acquity, Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 25% MeCN in 10 mM NH.sub.4HCO.sub.3). The fractions containing each stereoisomers were separately pooled and concentrated under vacuum. The residues were dissolved in DCM and water was added. The layers were separated through a phase separating cartridge and the organic layer was dried (MgSO.sub.4) and concentrated under vacuum to afford:

[1790] 2-((S)-5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-methyl-3-oxoisoindolin-2-yl)-N—((S)-2-hydroxy-1-(3-methoxyphenyl)ethyl)acetamide (0.0073 g, 0.013 mmol, 6.72% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.51 (d, 1H), 8.45 (s, 1H), 8.03-7.96 (m, 2H), 7.78 (d, 1H), 7.61 (s (br), 1H), 7.23 (dd, 1H), 6.94-6.86 (m, 2H), 6.80 (ddd, 1H), 4.90 (t, 1H), 4.87-4.81 (m, 1H), 4.78 (q, 1H), 4.46 (d, 1H), 4.04 (d, 1H), 3.98-3.81 (m, 3H), 3.75 (s, 3H), 3.61-3.53 (m, 2H), 3.41-3.35 (m, 2H), 1.90-1.79 (m, 2H), 1.59-1.47 (m, 2H), 1.45 (d, 3H). LCMS: [M+H]+=566

and 2-((R)-5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-methyl-3-oxoisoindolin-2-yl)-N—((S)-2-hydroxy-1-(3-methoxyphenyl)ethyl)acetamide (0.0082 g, 0.014 mmol, 7.55% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.54 (d, 1H), 8.45 (s, 1H), 8.03-8.01 (m, 1H), 7.99 (dd, 1H), 7.76 (d, 1H), 7.62 (s, 1H), 7.24 (dd, 1H), 6.94-6.87 (m, 2H), 6.86-6.78 (m, 1H), 4.92 (t, 1H), 4.90-4.79 (m, 1H), 4.72 (q, 1H), 4.49 (d, 1H), 4.03 (d, 1H), 3.97-3.83 (m, 3H), 3.76 (s, 3H), 3.62-3.53 (m, 2H), 3.44-3.35 (m, 2H), 1.90-1.77 (m, 2H), 1.60-1.47 (m, 2H), 1.44 (d, 3H). LCMS: [M+H]+=566

Example 614, 615 and 616: 2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(6-methoxypyridin-2-yl)ethyl]acetamide

[1791] ##STR01693##

[1792] Prepared using a similar procedure to Example 590. 1H NMR (DMF-d7) δ: 8.47-8.35 (m, 2H), 8.04-7.95 (m, 2H), 7.77 (d, 0.5H), 7.76 (d, 0.5H), 7.66 (dd, 0.5H), 7.65 (dd, 0.5H), 7.61 (s (br), 0.5H), 7.60 (s (br), 0.5H), 6.95 (d, 0.5H), 6.94 (d, 0.5H), 6.68 (d, 0.5H), 6.67 (d, 0.5H), 4.91-4.70 (m, 3H), 4.52 (d, 0.5H), 4.49 (d, 0.5H), 4.13-4.05 (m, 1H), 3.97-3.83 (m, 3H), 3.82 (s, 1.5H), 3.81 (s, 1.5H), 3.78-3.62 (m, 2H), 3.42-3.33 (m, 2H), 1.88-1.79 (m, 2H), 1.58-1.42 (m, 5H). LCMS: [M+H]+=567.

[1793] The diastereoisomers were separated by preparative HPLC (Acquity, Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 25% MeCN in 10 mM NH.sub.4HCO.sub.3). The fractions containing each stereoisomers were separately pooled and concentrated under vacuum. The residues were dissolved in DCM and water was added. The layers were separated through a phase separating cartridge and the organic layer was dried (MgSO.sub.4) and concentrated under vacuum to afford:

[1794] 2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(6-methoxypyridin-2-yl)ethyl]acetamide (0.0089 g, 0.016 mmol, 7.79% yield). 1H NMR (DMSO-d6) δ: 8.45 (s, 1H), 8.41 (d, 1H), 8.03-7.97 (m, 2H), 7.79 (d, 1H), 7.66 (dd, 1H), 7.62 (s (br), 1H), 6.95 (d, 1H), 6.68 (d, 1H), 4.91-4.77 (m, 3H), 4.50 (d, 1H), 4.10 (d, 1H), 3.98-3.84 (m, 3H), 3.82 (s, 3H), 3.80-3.65 (m, 2H), 3.43-3.35 (m, 2H), 1.89-1.80 (m, 2H), 1.58-1.49 (m, 2H), 1.47 (d, 3H). LCMS: [M+H]+=567.

[1795] And 2-(5-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(6-methoxypyridin-2-yl)ethyl]acetamide

[1796] (0.0108 g, 0.019 mmol, 9.45% yield). 1H NMR (DMSO-d6) δ: 8.45 (s, 1H), 8.43 (d, 1H), 8.02 (s, 1H), 7.99 (dd, 1H), 7.77 (d, 1H), 7.67 (dd, 1H), 7.62 (s, 1H), 6.97 (d, 1H), 6.69 (d, 1H), 4.90 (t, 1H), 4.88-4.82 (m, 1H), 4.76 (q, 1H), 4.52 (d, 1H), 4.10 (d, 1H), 3.98-3.84 (m, 3H), 3.83 (s, 3H), 3.79-3.62 (m, 2H), 3.42-3.34 (m, 2H), 1.92-1.78 (m, 2H), 1.60-1.47 (m, 2H), 1.45 (d, 3H). LCMS: [M+H]+=567.

Example 617: 6-(5-chloro-2-{[4-(dimethylamino)cyclohexyl]amino}pyrimidin-4-yl)-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1797] ##STR01694##

[1798] A mixture of 6-(2,5-dichloropyrimidin-4-yl)-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Preparation 128, 0.1 g, 0.221 mmol), N1,N1-dimethylcyclohexane-1,4-diamine (0.047 g, 0.331 mmol) and DIPEA (0.077 ml, 0.441 mmol) in 1:1 dioxane:EtOH (1.5 mL) was heated at 80° C. overnight. The mixture was allowed to cool to room temperature and was concentrated under vacuum. The residue was diluted with EtOAc and transferred into a separating funnel. NaHCO.sub.3 was added and the crude product was extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO.sub.4) and absorbed on silica. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-10% of 1% NH.sub.3:MeOH in DCM) to afford the title compound (0.048 g, 38.5%) as a pale tan solid. 1H NMR (400 MHz, DMSO-d6, VT T=350K) δ: 8.39 (m, 1H), 8.08 (m, 1H), 8.01 (ddd, 1H), 7.73 (d, 1H), 7.21 (m, 4H), 7.13 (m, 1H), 4.69 (s (br), 2H), 4.61 (s, 2H), 4.57 (s, 2H), 3.95 (m, 0.7H), 3.63-3.81 (m, 2.5H), 2.91 (m (br), 2H), 2.23 (s, 3H), 2.22 (s, 3H), 2.13-2.21 (m, 1H), 2.00-2.07 (m, 1H), 1.72-1.89 (m, 3.5H), 1.48-1.66 (m, 2.5H), 1.24-1.39 (m, 2H). (note: rotamers were only partially resolved by VT as well as presence of stereoisomers, which made the assignment difficult: some signals may have been overintegrated/or overlapped with H.sub.2O/HDO signal resulting in higher hydrogen count.). LC-MS: [M+H]+=559.1.

Example 618: 6-(5-chloro-2-{([3-(hydroxymethyl)cyclohexyl]amino}pyrimidin-4-yl)-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1799] ##STR01695##

[1800] A mixture of 6-(2,5-dichloropyrimidin-4-yl)-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Preparation 128, 0.2 g, 0.441 mmol), (3-aminocyclohexyl)methanol (0.086 g, 0.662 mmol) and DIPEA (0.154 ml, 0.882 mmol) in 1:1 dioxane:EtOH (2 mL) was heated at 80° C. overnight. The mixture was allowed to cool to room temperature, then concentrated under vacuum. The residue was diluted with EtOAc and transferred into a separating funnel. Water was added and the crude product was extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO.sub.4). The crude product obtained in experiment 1360-53 was combined and the mixture was absorbed on silica. The crude product was purified by chromatography on the Companion (24g Grace column, DCM:MeOH gradient 100%-95%) to afford the title compound (0.078 g, 25.1%) as a pale tan solid. 1H NMR (400 MHz, DMSO-d6, VT T=350K) δ: 8.39 (s, 1H), 8.08 (d, 1H), 8.01 (dd, 1H), 7.73 (dd, 1H), 7.20 (m, 4H), 7.12 (d (br), 1H), 4.69 (m (br), 2H), 4.61 (s, 2H), 4.57 (s, 2H), 4.11 (t, 1H), 3.69-3.82 (m, 3H), 3.21-3.34 (m, 2H), 3.06 (s, 6H), 3.06 (m (br), 1H), 2.91 (m, (br), 2H), 1.93-2.08 (m, 2H), 1.67-1.82 (m, 2H), 1.45-1.56 (m, 1H), 1.16-1.39 (m, 3H), 0.93-1.04 (dd, 1H), 0.86 (ddd, 1H) (note: rotamers were only partially resolved by VT as well as presence of stereoisomers made the assignment difficult and some signals may have been overintegrated/or overlapped with H2O/HDO signal resulting in higher hydrogen count). LC-MS: [M+H]+=546

Example 619: (Trans) 6-(5-chloro-2-{[(3R,4S)-3-hydroxyoxan-4-yl]amino}pyrimidin-4-yl)-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1801] ##STR01696##

[1802] DIPEA (128 μl, 0.731 mmol) was added to a stirred suspension of 6-(2,5-dichloropyrimidin-4-yl)-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one (Preparation 128, 120 mg, 0.244 mmol) and (trans)-4-aminooxan-3-ol (racemic) (73.5 mg, 0.609 mmol) in dioxane/EtOH (1:1) (2.7 mL, 0.1 M). The reaction was heated to 80° C. and the resulting brown solution stirred overnight. A further portion of (trans)-4-aminooxan-3-ol (racemic) (14.26 mg, 0.122 mmol) was added and the reaction re-heated to 80° C. for 4h. After cooling to room temperature, the solvent was removed in vacuo. The crude residue was partitioned between EtOAc (20 ml) and water (20 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×20 mL). The organic extracts were combined and washed with The 1M HCl (1×100 mL), brine (1×100 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford a yellow/brown gum. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-5% MeOH in DCM) to afford the title compound (79 mg, 58.9%) as a pale yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.43 (1H, s), 8.07-8.02 (1H, m), 7.99 (1H, dd), 7.75 (1H, d), 7.50 (1H, s (br)), 7.26-7.17 (4H, m), 4.93 (1H, d), 4.76 (1H, s), 4.62 (1H, s), 4.59 (4H, m), 3.79 (4H, dq), 3.69 (1H, t), 3.49 (1H, tt), 3.29 (1H, s (br)), 3.04 (1H, dd), 2.93 (1H, t), 2.81 (1H, t), 1.94 (1H, br d), 1.49 (1H, qd). LC-MS: [M+H]+=534.

Example 620: (Cis) 6-(5-chloro-2-{[(3S,4S)-3-hydroxyoxan-4-yl]amino}pyrimidin-4-yl)-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one

[1803] ##STR01697##

[1804] Prepared using a similar procedure to Example 619 (HCl). 1H NMR (DMSO-d6, 400 MHz) δ 8.46 (1H, s), 8.08-8.01 (1H, m), 7.99 (1H, dd), 7.75 (1H, d), 7.29-7.13 (4H, m), 7.00 (1H, s), 4.89 (1H, d), 4.76 (1H, s), 4.64-4.55 (5H, m), 3.99 (1H, dddd), 3.85-3.65 (5H, m), 3.51-3.35 (2H, m), 2.93 (1H, t), 2.81 (1H, t), 1.98-1.84 (1H, m), 1.67-1.55 (1H, m). LC-MS: [M+H]+=534.

Example 621: (2R)-2-[6-(5-chloro-2-{[(2S)-1-hydroxypropan-2-yl]amino}pyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]propanamide

[1805] ##STR01698##

[1806] A mixture of (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-2-hydroxy-1-(3-methoxyphenyl)ethyl)propanamide (Preparation 352, 120 mg, 0.215 mmol), DIPEA (94 μl, 0.539 mmol) and (S)-2-aminopropan-1-ol (24.27 mg, 0.323 mmol), in 1,4-dioxane (2 ml) was stirred and heated at 70° C. for 24 h, and then left at ambient temperature for 4 days. The solvent was removed under reduced pressure and the residue purified by chromatography (SiO.sub.2, 4 g column, 100% EtOAc). Pure fractions were collected and the residue triturated diethyl ether affording a solid, which was collected by filtration (90 mg). The solid was dissolved in MeOH and loaded on a column packed with SCX. The column was washed with MeOH and the compound eluted with 1% NH.sub.3/MeOH. The resulting solution was concentrated under vacuum and the residue again triturated with ether. The resulting precipitate was filtered, dried, to afford the title compound (69 mg, 59.3%) as a colourless solid. 1H NMR (DMSO-d6) δ: 8.18 (1H, s), 8.06 (1H, s), 7.84 (1H, d), 7.7 (1H, d), 7.33 (1H, d), 7.15 (1H, d), 6.83 (2H, m), 6.72 (1H, d), 5.69 (1H, s), 5.06 (1H, m), 4.99 (1H, m), 4.72 (1H, d), 4.42 (1H, d), 4.09 (1H, m), 3.75-3.55 (7H, m), 1.44 (3H, d), 1.19 (3H, d). LC-MS: [M+H]+=540

Example 622: 2-[6-(5-chloro-2-{[(2S)-1-hydroxypropan-2-yl]amino}pyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(3-methylphenyl)ethyl]acetamide

[1807] ##STR01699##

[1808] A mixture of (S)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-(2-hydroxy-1-(m-tolyl)ethyl)acetamide (Preparation 353, 0.18 g, 0.382 mmol), DIPEA (0.133 ml, 0.764 mmol), and (S)-2-aminopropan-1-ol (0.041 g, 0.542 mmol) in 1:1 EtOH:dioxane (3 mL) was heated at 80° C. under nitrogen overnight. The mixture was allowed to cool to room temperature and was concentrated under vacuum. The residue was partioned between DCM and water and the layers were separated through a phase separating cartridge. The organic layer was dried (MgSO.sub.4) and absorbed on silica. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-7% MeOH in DCM) to afford the title compound (0.016 g, 8.05%) as a white solid after trituration and evaporation from Et.sub.2O. 1H NMR (DMSO-d6) δ: 8.53 (d, 1H), 8.43 (s, 1H), 8.04 (s, 1H), 7.99 (d, 1H), 7.74 (d, 1H), 7.29 (s, 1H), 7.21 (t, 1H), 7.16-7.02 (m, 3H), 4.91 (t, 1H), 4.84 (q, 1H), 4.69 (t, 1H), 4.59 (s, 2H), 4.32 (d, 1H), 4.26 (d, 1H), 3.98 (p, 1H), 3.56 (t, 2H), 3.52-3.43 (m, 1H), 3.34-3.29 (m, 1H), 2.30 (s, 3H), 1.14 (d, 3H). LC-MS: [M+H]+=510.

Example 623: 2-[6-(5-chloro-2-{[(2S)-1-hydroxypropan-2-yl]amino}pyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S)-1-(2-fluoro-5-methoxyphenyl)-2-hydroxyethyl]acetamide

[1809] ##STR01700##

[1810] Prepared using a similar procedure to Example 617. 1H NMR (DMSO-d6) δ: 8.61 (d, 1H), 8.43 (s, 1H), 8.04 (s, 1H), 7.99 (d, 1H), 7.74 (d, 1H), 7.29 (s (br), 1H), 7.08 (dd, 1H), 6.97 (dd, 1H), 6.89-6.79 (m, 1H), 5.15 (td, 1H), 5.05 (t, 1H), 4.69 (t, 1H), 4.60 (s, 2H), 4.31 (s, 2H), 4.02-3.91 (m, 1H), 3.75 (s, 3H), 3.62-3.44 (m, 3H), 3.34-3.28 (m, 1H), 1.14 (d, 3H). LC-MS: [M+H]+=544.

Example 624: 2-(6-{5-chloro-2-[(oxetan-3-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(3-methylphenyl)ethyl]acetamide

[1811] ##STR01701##

[1812] A mixture of (S)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-(2-hydroxy-1-(m-tolyl)ethyl)acetamide (Preparation 353, 0.17 g, 0.361 mmol), DIPEA (0.133 ml, 0.764 mmol), oxetan-3-amine (0.038 ml, 0.382 mmol) and DMF (0.2 mL) in 1:1 EtOH:dioxane (3 mL) was heated at 80° C. under nitrogen overnight. oxetan-3-amine (0.038 ml, 0.382 mmol) and DIPEA (0.067 ml, 0.382 mmol) were added and the mixture was stirred at 80° C. under nitrogen overnight. The mixture was diluted with EtOAc and transferred into a separating funnel. 1N HCl was added and the crude product was extracted with EtOAc, then DCM. Both extracts were washed with NaHCO.sub.3, brine, then combined and concentrated under vacuum. The residue was suspended in DCM:MeOH and absorbed on silica. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-5% MeOH in DCM) to afford a white solid. The product was suspended in DCM and transferred into a separating funnel. 1N HCl was added and the product was extracted with DCM. The combined organic extracts were washed with NaHCO.sub.3, then brine. The resulting fine suspension was heated, dried (MgSO.sub.4) and concentrated under vacuum to afford the title compound (0.026 g, 13.27%) as a white solid. 1H NMR (DMSO-d6) δ: 8.53 (d, 1H), 8.48 (s, 1H), 8.34 (s (br), 1H), 8.04 (d, 1H), 7.98 (dd, 1H), 7.74 (d, 1H), 7.21 (dd, 1H), 7.15-7.01 (m, 3H), 4.97-4.88 (m, 2H), 4.83 (td, 1H), 4.76 (dd, 2H), 4.59 (s, 2H), 4.54 (dd, 2H), 4.32 (d, 1H), 4.26 (d, 1H), 3.61-3.51 (m, 2H), 2.29 (s, 3H). LC-MS: [M+H]+=508.

Example 625: (2R)-2-[6-(5-chloro-2-{[trans-4-methoxycyclohexyl]amino}pyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]propanamide

[1813] ##STR01702##

[1814] A mixture of (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-2-hydroxy-1-(3-methoxyphenyl)ethyl)propanamide (Preparation 352, 0.1 g, 0.199 mmol), DIPEA (0.070 ml, 0.399 mmol) and trans 4-methoxycyclohexanamine (0.039 g, 0.299 mmol) (0.024 ml, 0.232 mmol) in 1:1 EtOH:dioxane (1 mL) was heated at 80° C. under nitrogen overnight. The mixture was allowed to cool to room temperature and was concentrated under vacuum. The residue was dissolved in EtOAc and transferred into a separating funnel. 1N HCl was added and the crude product was extracted with EtOAc. The combined organic extracts were washed with NaHCO3, brine, dried (MgSO.sub.4) and absorbed on silica. The crude product was purified by chromatography on the Companion (12 g column, 0-5% MeOH in DCM) to afford the title compound (0.06 g, 050.1%) as a white solid after trituration and evaporation from Et.sub.2O. 1H NMR (DMSO-d6) δ: 8.56 (d, 1H), 8.44 (s (br), 1H), 8.07-8.01 (m, 1H), 7.97 (d, 1H), 7.75 (d, 1H), 7.52 (s (br), 1H), 7.28-7.19 (m, 1H), 6.93-6.85 (m, 2H), 6.83-6.76 (m, 1H), 5.06-4.96 (m, 1H), 4.89 (t, 1H), 4.85-4.80 (m, 1H), 4.77 (d, 1H), 4.60 (d, 1H), 3.75 (s, 3H), 3.73-3.63 (m, 1H), 3.57-3.52 (m, 2H), 3.23 (s, 3H), 3.16-3.06 (m, 1H), 2.05-1.91 (m, 4H), 1.45 (d, 3H), 1.39-1.13 (m, 4H). LCMS: [M+H]+=594.

[1815] Prepared using an analogous procedure to Example 625, from the appropriate dichloropyrimidine

TABLE-US-00047 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 626 [01703] (2R)-2-[6-(5-chloro- 2-{[(2S)-1- hydroxypropan-2- yl]amino}pyrimidin- 4-yl)-1-oxo-2,3- dihydro-1H-isoindol- 2-yl]-N-[(S)-2- hydroxy-1-(3- methylphenyl)ethyl] propanamide 1H NMR (DMSO-d6) δ: 8.55 (d, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 7.99 (d, 1H), 7.75 (d, 1H), 7.29 (s (br), 1H), 7.21 (dd, 1H), 7.14-7.00 (m, 3H), 5.01 (td, 1H), 4.88 (t, 1H), 4.84-4.67 (m, 3H), 4.60 (d, 1H), 4.04- 3.92 (m, 1H), 3.58- 3.44 (m, 3H), 3.35-3.29 (m, 1H-overlapped with water peak), 2.30 (s, 3H), 1.43 (d, 3H), 1.14 (d, 3H). 524 627 a) [01704] (2R)-2-{6-[5-chloro- 2- (methylamino) pyrimidin-4-yl]-1- oxo-2,3-dihydro-1H- isoindol-2-yl}- N-[(1S)-2-hydroxy- 1-(3-methoxyphenyl) ethyl]propanamide 1H NMR (DMSO-d6) δ: 8.57 (d, 1H), 8.44 (s (br), 1H), 8.05 (s (br), 1H), 7.99 (s (br), 1H), 7.75 (d, 1H), 7.51 (s (br), 1H), 7.30-7.19 (m, 1H), 6.92-6.85 (m, 2H), 6.84-6.76 (m, 1H), 5.01 (td, 1H), 4.89 (t, 1H), 4.85- 4.80 (m, 1H), 4.78 (d, 1H), 4.61 (d, 1H), 3.75 (s, 3H), 3.61- 3.49 (m, 2H), 2.84 (d, 3H), 1.45 (d, 3H). 496 628 [01705] 2-[6-(5-chloro-2- {[(2S)-1- hydroxypropan-2- yl]amino}pyrimidin- 4-yl)-1-oxo-2,3- dihydro-1H-isoindol- 2-yl]-N-[(R)-1-(2- fluoro-5- methoxyphenyl)ethyl] acetamide 1H NMR (400 MHz, DMSO- d6) δ 8.67 (d, 1H), 8.43 (s, 1H), 8.06-7.98 (m, 2H), 7.74 (d, 1H), 7.29 (br. s, 1H), 7.09 (t, 1H), 6.95 (dd, 1H), 6.87- 6.77 (m, 1H), 5.15 (p, 1H), 4.69 (t, 1H), 4.60 (s, 2H), 4.27 (s, 2H), 3.99 (td, 1H), 3.75 (s, 3H), 3.48 (dt, 1H), 3.34-3.30 (m, 1H), 1.36 (d, 3H), 1.14 (d, 3H). 528 629 b) [01706] (2R)-2-[6-(5-chloro- 2-{[trans-4- methoxycyclohexyl] amino}pyrimidin-4-yl)- 1-oxo-2,3-dihydro- 1H-isoindol-2-yl]-N- [(1S)-2-hydroxy-1-(3- methylphenyl)ethyl] propanamide 1H NMR (DMSO, 400 MHz) δ 8.55 (1H, d), 8.44 (1H, s), 8.09- 8.02 (1H, m), 7.74 (1H, d), 7.52 (1H, s), 7.21 (1H, t), 7.14- 6.99 (3H, m), 5.00 (1H, q), 4.88 (1H, t), 4.84-4.72 (3H, m), 4.60 (1H, d), 3.77-3.60 (1H, m), 3.58-3.49 (2H, m), 3.23 (3H, s), 3.16-3.03 (1H, m), 2.30 (3H, s), 2.06-1.88 (4H, m), 1.43 (3H, d), 1.39- 1.26 (2H, m), 1.26-1.13 (2H, m). 578 a) a sealed Biotage microwave tube was used in this case b) The reaction was carried out in dioxane at 80° C. in this case

Example 630: (2R)-2-{6-[5-chloro-2-(methylamino)pyrimidin-4-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}-N-[(1S)-2-hydroxy-1-(3-methylphenyl)ethyl]propanamide

[1816] ##STR01707##

[1817] A mixture of (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-2-hydroxy-1-(m-tolyl)ethyl)propanamide (2:1 mixture with (R)-2-(6-(2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-5-chloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-2-hydroxy-1-(m-tolyl)ethyl)propanamid) (Preparation 355, 0.147 g, 0.284 mmol), DIPEA (0.198 ml, 1.136 mmol) and methylamine hydrochloride (38 mg, 0.568 mmol) in 1:1 EtOH:dioxane (1 mL) was heated at 80° C. in a sealed Biotage microwave vial for 3 days. The mixture were allowed to cool to room temperature and concentrated under vacuum. The residue was partioned between DCM and water and the layers were separated through a phase separating cartridge. The organic layer was dried (MgSO.sub.4) and absorbed on silica. The crude products were purified by chromatography (SiO.sub.2, 4 g column, 0-4% MeOH in DCM to afford the title compound (0.039 g, 28.3%) as a white solid after trituration and evaporation from Et.sub.2O. 1H NMR (DMSO-d6) δ: 8.55 (d, 1H), 8.45 (s (br), 1H), 8.05 (s (br), 1H), 7.99 (s (br), 1H), 7.75 (d, 1H), 7.51 (s (br), 1H), 7.21 (dd, 1H), 7.14-7.01 (m, 3H), 5.01 (td, 1H), 4.88 (t, 1H), 4.83-4.76 (m, 1H), 4.77 (d, 1H), 4.60 (d, 1H), 3.66-3.47 (m, 2H), 2.84 (d, 3H), 2.30 (s, 3H), 1.43 (d, 3H). LC-MS: [M+H]+=480.

Example 631: (2R)-2-{6-[5-chloro-2-(methylamino)pyrimidin-4-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}-N-[(1S)-1-(3-fluoro-5-methylphenyl)-2-hydroxyethyl]propanamide

[1818] ##STR01708##

[1819] Prepared using a similar procedure to Example 630. 1H NMR (DMSO-d6) δ: 8.57 (d, 1H), 8.45 (s (br), 1H), 8.05 (s (br), 1H), 7.99 (s (br), 1H), 7.75 (d, 1H), 7.51 (s (br), 1H), 6.93 (dd, 3H), 5.00 (td, 1H), 4.94 (t, 1H), 4.86-4.79 (m, 1H), 4.76 (d, 1H), 4.61 (d, 1H), 3.61-3.51 (m, 2H), 2.84 (d, 3H), 2.31 (s, 3H), 1.44 (d, 3H). LC-MS: [M+H]+=498.

Example 632: 2-{6-[5-chloro-2-(methylamino)pyrimidin-4-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}-N-[(1S)-2-hydroxy-1-(3-methylphenyl)ethyl]acetamide

[1820] ##STR01709##

[1821] TBTU (96 mg, 0.300 mmol) was added to an ice-cooled stirred solution of 2-(6-(5-chloro-2-(methylamino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)acetic acid (Preparation 351, 70 mg, 0.200 mmol), (S)-2-amino-2-(m-tolyl)ethanol hydrochloride (41.3 mg, 0.220 mmol) and triethylamine (111 μl, 0.799 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 16 h, then diluted with EtOAc (30 mL). The organic phase was washed with water (30 mL), NH.sub.4Cl (30 mL) and brine (3×30 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to give a white solid (100 mg). The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-6% MeOH in DCM) to afford the title compound (31 mg, 32.1%) as a white solid. 1H NMR (DMSO-d6) δ 8.52 (1H, d), 8.44 (1H, s (br)), 8.12-7.88 (2H, m), 7.73 (1H, d), 7.50 (1H, s (br)), 7.20 (1H, t), 7.16-7.08 (2H, m), 7.08-7.02 (1H, m), 4.90 (1H, dd), 4.83 (1H, ddd), 4.59 (2H, s), 4.31 (1H, d), 4.26 (1H, d), 3.62-3.50 (2H, m), 2.83 (3H, d), 2.29 (3H, s). LC-MS: [M+H]+=466.

Example 633: 2-{6-[5-chloro-2-(methylamino)pyrimidin-4-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}-N-[(1S)-1-(3-fluoro-5-methylphenyl)-2-hydroxyethyl]acetamide

[1822] ##STR01710##

[1823] Prepared using a similar procedure to Example 632. 1H NMR (DMSO-d6) δ: 8.54 (1H, d), 8.44 (1H, s (br)), 8.11-7.91 (2H, m), 7.74 (1H, d), 7.50 (1H, s (br)), 7.05-6.81 (3H, m), 4.95 (1H, dd), 4.85 (1H, ddd), 4.59 (2H, s), 4.32 (1H, d), 4.27 (1H, d), 3.63-3.48 (2H, m), 2.83 (3H, d), 2.30 (3H, s). LC-MS: [M+H]+=484.

Example 634: (2R)-2-(6-{5-chloro-2-[(1-hydroxy-2-methyl propan-2-yl)amino]pyri m id in-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(3-methylphenyl)ethyl]propanamide

[1824] ##STR01711##

[1825] A mixture of (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-2-hydroxy-1-(m-tolyl)ethyl)propanamide compound with (R)-2-(6-(2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-5-chloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-2-hydroxy-1-(m-tolyl)ethyl)propanamide (5:1) (Preparation 355, 0.1 g, 0.206 mmol), DIPEA (0.108 ml, 0.618 mmol), and 2-amino-2-methylpropan-1-ol (0.037 g, 0.412 mmol) in 1:1 EtOH:dioxane (2 mL) was heated at 80° C. under nitrogen overnight. A further portion of 2-amino-2-methylpropan-1-ol (0.037 g, 0.412 mmol) and DIPEA (0.144 ml, 0.824 mmol) were added and the mixture was stirred at 80° C. overnight. The mixture was allowed to cool to room temperature and was concentrated under vacuum. The residue was partioned between EtOAc and NH.sub.4Cl and the layers were separated. The crude product was extracted with EtOAc and the combined organic extracts were washed with water, NaHCO.sub.3, brine, dried (MgSO.sub.4) and absorbed on silica. The crude product was purified by chromatography on the Companion (12 g column, DCM:MeOH gradient 100%-95%) to afford the title compound (0.036 g, 32.5%) as a colourless solid after trituration and evaporation from Et.sub.2O. 1H NMR (DMSO-d6) δ: 8.56 (d, 1H), 8.44 (s, 1H), 8.06 (d, 1H), 7.99 (dd, 1H), 7.76 (d, 1H), 7.21 (dd, 1H), 7.14-7.01 (m, 3H), 6.86 (s, 1H), 5.01 (q, 1H), 4.92-4.72 (m, 4H), 4.60 (d, 1H), 3.59-3.48 (m, 4H), 2.30 (s, 3H), 1.43 (d, 3H), 1.33 (s, 6H). LC-MS: [M+H]+=538.

Example 635: (2R)-2-[6-(5-chloro-2-{[trans-3-(hydroxymethyl)cyclobutyl]amino}pyrimidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(3-methylphenyl)ethyl]propanamide

[1826] ##STR01712##

[1827] A mixture of (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-2-hydroxy-1-(m-tolyl)ethyl)propanamide compound with (R)-2-(6-(2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-5-chloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-2-hydroxy-1-(m-tolyl)ethyl)propanamide (5:1) (Preparation 355, 0.1 g, 0.206 mmol), DIPEA (0.108 ml, 0.618 mmol), and trans-3-aminocyclobutyl)methanol hydrochloride (0.057 g, 0.412 mmol) in 1:1 EtOH:dioxane (2 mL) was heated at 80° C. under nitrogen overnight. The mixture was allowed to cool to room temperature and was concentrated under vacuum. The residue was partioned between EtOAc and NH.sub.4Cl and the layers were separated. The crude product was extracted with EtOAc and the combined organic extracts were washed with water, NaHCO.sub.3, brine, dried (MgSO.sub.4) and absorbed on silica. The crude product was purified by chromatography on the Companion (12 g column, DCM:MeOH gradient 100%-95%) to afford the title compound (0.061 g, 0.111 mmol, 53.8% yield) as a colourless solid after trituration and evaporation from Et.sub.2O. 1H NMR (DMSO-d6) δ: 8.56 (d, 1H), 8.43 (s, 1H), 8.04 (d, 1H), 7.97 (d, 1H), 7.91 (s (br), 1H), 7.75 (d, 1H), 7.21 (dd, 1H), 7.14-7.01 (m, 3H), 5.01 (q, 1H), 4.89 (t, 1H), 4.85-4.70 (m, 2H), 4.64-4.54 (m, 2H), 4.35 (m (br), 1H), 3.58-3.49 (m, 2H), 3.50-3.39 (m, 2H), 2.30 (s, 3H), 2.29-2.18 (m, 1H), 2.17-2.00 (m, 4H), 1.43 (d, 3H). LC-MS: [M+H]+=550.

Example 636: 6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-{2-[(2-phenylpropan-2-yl)oxy]ethyl}-2,3-dihydro-1H-isoindol-1-one

[1828] ##STR01713##

[1829] Prepared according to the procedure for Example 102. The reaction was carried out in refluxing EtOH:dioxane at 90° C. overnight. Further oxan-4-amine (0.050 mL, 0.483 mmol) and DIPEA (0.100 mL, 0.573 mmol) were added and the mixture was refluxed overnight. 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (1H, s), 8.02-7.93 (2H, m), 7.74 (1H, d), 7.65-7.57 (1H, m), 7.35-7.27 (2H, m), 7.22-7.16 (3H, m), 4.61 (2H, s), 3.99-3.90 (1H, m), 3.86 (2H, d), 3.66 (2H, t), 3.42-3.33 (4H, m), 1.85 (2H, d), 1.58-1.49 (2H, m), 1.45 (6H, s). LC-MS: [M+H]+=507.

Example 637: 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-N-(2-phenylpropan-2-yl)acetamide

[1830] ##STR01714##

[1831] Triethylamine (0.075 mL, 0.538 mmol), 2-phenylpropan-2-amine (0.030 mL, 0.209 mmol) and T3P (50 wt % in EtOAc) (0.160 mL, 0.269 mmol) were added to a stirred solution of 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)acetic acid (Preparation 9, 0.080 g, 0.178 mmol) in DMF (2.0 mL, 25.8 mmol) at room temperature. After 4.5 h further 2-phenylpropan-2-amine (15 μL), Triethylamine (35 μL) and T3P (50 wt % in EtOAc) (80 μL) were added. After a total of 6 h 45 min the reaction mixture was partitioned between DCM (20 mL) and water (20 mL). The layers were separated. NaHCO.sub.3 (c.a. 5 mL) was added to the aqueous fraction and then the aqueous fraction was extracted with DCM (2×20 mL). The combined organic extracts were filtered through a phase separating cartridge and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, 0-5% MeOH in DCM) to afford the crude product. The crude product was dissolved in DCM (5 mL) and washed with NH.sub.4Cl (2×5 mL) and brine (2×5 mL). The organic fraction was filtered through a phase separating cartridge and concentrated under reduced pressure to afford the title compound as a white solid (13 mg, 13%). 1H NMR (DMSO-d6, 400 MHz) δ 9.10-9.02 (1H, m), 8.48 (1H, s), 8.42-8.36 (2H, m), 7.70 (1H, s (br)), 7.38-7.33 (2H, m), 7.29 (2H, dd), 7.22-7.11 (1H, m), 4.60 (2H, s), 4.29 (2H, s), 3.98-3.80 (3H, m), 3.38 (2H, t), 1.84 (2H, br. d), 1.58 (6H, s), 1.55-1.44 (2H, m). LC-MS: [M+H]+=521.

Example 638: 3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-6-[2-oxo-2-(2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)ethyl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-5-one

[1832] ##STR01715##

[1833] Triethylamine (0.080 mL, 0.574 mmol) followed by T3P (50 wt % in EtOAc) (0.180 mL, 0.302 mmol) were added to a stirred solution of 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)acetic acid (Preparation 9, 0.081 g, 0.181 mmol) and 2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.041 g, 0.279 mmol) in DMF (2.0 mL, 25.8 mmol) and the mixture was stirred for 1h. Water (5 mL) was added and the mixture stirred at room temperature for 10 minutes. The resulting solid was filtered and washed with water (3×10 mL). The solid was dissolved in DCM (30 mL) and then washed with NH.sub.4Cl (10 mL) and brine (3×10 mL). The organic fraction was filtered through a phase separating cartridge and concentrated under reduced pressure. The residue was dissolved in EtOAc (20 mL) and washed with brine (4×20 mL). The organic fraction was dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the title compound one (0.052 g, 51.9%) as a beige solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.10 (1H, d), 8.49 (1H, s), 8.42 (1H, d), 7.72 (1H, br. s), 7.23-7.10 (4H, m), 4.60 (4H, d), 3.99-3.81 (3H, m), 3.70-3.55 (4H, m), 3.39 (2H, t), 3.02-2.93 (2H, m), 2.90-2.82 (2H, m), 1.85 (2H, br. d), 1.53 (2H, qd). LC-MS: [M+H]+=533

Example 639: 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-N-[(1R)-1-(3-methoxyphenyl)ethyl]acetamide

[1834] ##STR01716##

[1835] Prepared using a similar procedure to Example 638.

[1836] 1H NMR (DMSO-d6, 400 MHz) δ 9.09 (1H, s), 8.58 (1H, d), 8.49 (1H, s), 8.40 (1H, d), 7.70 (1H, s), 7.27-7.20 (1H, m), 6.92-6.85 (2H, m), 6.83-6.74 (1H, m), 4.94 (1H, p), 4.64 (2H, s), 4.28 (2H, s), 3.93 (1H, br. s), 3.86 (2H, br. d), 3.75 (3H, s), 3.39-3.32 (2H, m), 1.84 (2H, br. d), 1.52 (2H, qd), 1.37 (3H, d).). LC-MS: [M+H]+=537.

Example 640: 3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-6-[2-(1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)-2-oxoethyl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-5-one

[1837] ##STR01717##

[1838] Triethylamine (0.080 mL, 0.574 mmol) followed by T3P (50 wt % in EtOAc) (0.180 mL, 0.302 mmol) were added to a stirred solution of 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)acetic acid (Preparation 9, 0.085 g, 0.189 mmol) and 1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.056 g, 0.278 mmol) in DMF (2.0 mL, 25.8 mmol) and the mixture was stirred for 2h. Water (5 mL) was added and the mixture was stirred at room temperature for 5 minutes and then filtered and washed with water (3×10 mL). The filtrate was acidified with NH.sub.4Cl and extracted with DCM (3×50 mL). The solid was dissolved with DCM and combined with the other DCM extracts. The combined DCM fractions were washed with brine (3×50 mL), filtered through a phase separating cartridge and then concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with brine (5×20 mL) then dried (MgSO.sub.4), filtered and concentrated under reduced pressure to leave a yellow gum (78 mg). The product was purified by chromatography (SiO.sub.2, 12 g column, 0-100% (3% MeOH in DCM) in DCM), then further purified by reversed phase preparative HPLC (Waters XSelect CSH C18 OBD, 130 Å, 5 μm, 19 mm×50 mm column, using a gradient of 25 to 55% of acetonitrile in water with 0.1% fomic acid in both at 28 ml/min as eluent). The clean fractions were pooled and concentrated to remove most of the acetonitrile. The residue was freeze-dried to give the title compound (32.3 mg, 70.3%) as a white solid. 1H NMR (DMSO-d6, 400 MHz, 90° C.) δ 9.12 (1H, d), 8.44 (1H, s), 8.40 (1H, d), 7.29 (1H, d), 7.19-7.08 (4H, m), 4.60-4.40 (4H, m), 4.03-3.48 (8H, m), 3.42 (2H, td), 3.24 (2H, s (br)), 1.93-1.86 (2H, m), 1.67-1.53 (2H, m), 1.29 (3H, s (br)). LC-MS: [M+H]+=547.

Example 641: 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide

[1839] ##STR01718##

[1840] Prepared using a similar procedure to Example 95. 1H NMR (DMSO-d6, 400 MHz) δ 9.09 (1H, s), 8.55 (1H, d), 8.49 (1H, s), 8.41 (1H, d), 7.71 (1H, s (br)), 7.23 (1H, t), 6.93-6.85 (2H, m), 6.81 (1H, ddd), 4.92 (1H, t), 4.86 (1H, q), 4.64 (2H, s), 4.39-4.23 (2H, m), 3.99-3.80 (3H, m), 3.74 (3H, s), 3.62-3.51 (2H, m), 3.39-3.34 (2H, m), 1.84 (2H, d), 1.52 (2H, qd). LC-MS: [M+H]+=553.

Example 642: 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-N-[(1S)-1-[3-(difluoromethoxy)phenyl]-2-hydroxyethyl]acetamide

[1841] ##STR01719##

[1842] Prepared using a similar procedure to Example 95. 1H NMR (DMSO-d6, 400 MHz) δ 9.09 (1H, s), 8.61 (1H, d), 8.49 (1H, s), 8.41 (1H, d), 7.71 (1H, br. s), 7.43-7.33 (1H, m), 7.26-7.16 (2H, m), 7.14 (1H, d), 7.08-7.01 (1H, m), 4.98 (1H, t), 4.90 (1H, q), 4.64 (2H, s), 4.40-4.22 (2H, m), 3.99-3.80 (3H, m), 3.64-3.53 (2H, m), 3.39-3.34 (2H, m), 1.84 (2H, br d), 1.52 (2H, qd). LCMS: [M+H]+=589.

Example 643: 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-N-[(1S,2R)-2-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl]acetamide

[1843] ##STR01720##

[1844] Prepared using a similar procedure to Example 407. 1H NMR (DMSO, 400 MHz) δ 9.11 (1H, d), 8.50 (1H, s), 8.43 (1H, d), 8.29 (1H, d), 7.72 (1H, s), 7.14 (1H, d), 6.81-6.75 (2H, m), 5.19 (1H, dd), 5.04 (1H, d), 4.72 (2H, s), 4.47-4.40 (3H, m), 3.99-3.83 (3H, m), 3.74 (3H, s), 3.43-3.35 (2H, m), 2.98 (1H, dd), 2.74 (1H, d), 1.90-1.80 (2H, m), 1.60-1.47 (2H, m). LCMS: [M+H]+=603.

Example 644: 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-N-[(1S)-2-hydroxy-1-(3-methylphenyl)ethyl]acetamide

[1845] ##STR01721##

[1846] HATU (77 mg, 0.202 mmol) was added to an ice-cooled solution of 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)acetic acid (Preparation 9, 68 mg, 0.135 mmol), (S)-2-amino-2-(m-tolyl)ethanol hydrochloride (27.8 mg, 0.148 mmol) and triethylamine (56.3 μl, 0.404 mmol) in DMF (1.4 mL) under nitrogen. The mixture was stirred at room temperature for 1.5 h, then diluted with EtOAc (30 mL). The organic phase was washed with water (30 mL) and brine (3×30 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to give a yellow residue. The crude product was purified by chromatography (SiO.sub.2, 24 g column, 0-10% MeOH in DCM) to afford a beige solid (58 mg). The product was loaded onto a column packed with SCX (0.5 g) in MeOH/DCM. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to afford the title compound (50 mg, 68.4%) as a beige solid (1458-13-5c). 1H NMR (DMSO-d6, 400 MHz) δ 9.09 (1H, s), 8.54 (1H, d), 8.49 (1H, s), 8.41 (1H, d), 7.71 (1H, s (br)), 7.21 (1H, t), 7.15-7.08 (2H, m), 7.08-7.03 (1H, m), 4.91 (1H, t), 4.88-4.80 (1H, m), 4.64 (2H, s), 4.34 (1H, d), 4.29 (1H, d), 4.02-3.77 (3H, m), 3.63-3.49 (2H, m), 3.44-3.33 (2H, m), 2.29 (3H, s), 1.90-1.78 (2H, m), 1.61-1.45 (2H, m). LCMS: [M+H]+=537.

Example 645: (2R)-2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-N-[(1S)-1-(3-ethylphenyl)-2-hydroxyethyl]propanamide

[1847] ##STR01722##

[1848] TBTU (0.056 g, 0.176 mmol) was added to a mixture of (R)-2-(3-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)propanoic acid (Preparation 416, 0.07 g, 0.168 mmol), (S)-2-amino-2-(3-ethylphenyl)ethanol hydrochloride (0.035 g, 0.176 mmol) and DIPEA (0.091 ml, 0.519 mmol) in DMF (1 mL) and the mixture was stirred for 45 minutes. The mixture was diluted with EtOAc and transferred into a separating funnel. NH.sub.4Cl was added and the product was extracted with EtOAc. The combined organic extracts were washed with water, NaHCO.sub.3, brine, dried (MgSO.sub.4) and absorbed on silica. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-5% MeOH in DCM) to afford the title compound (0.046 g, 0.078 mmol, 46.6%) as a white solid after trituration and evaporation from Et.sub.2O. 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 8.56 (d, 1H), 8.49 (s (br), 1H), 8.41 (d, 1H), 7.71 (s (br), 1H), 7.22 (dd, 1H), 7.17-7.03 (m, 3H), 5.04 (td, 1H), 4.89 (t, 1H), 4.86-4.79 (m, 1H), 4.79 (d, 1H), 4.67 (d, 1H), 4.01-3.80 (m, 3H), 3.61-3.47 (m, 2H), 3.42-3.35 (m, 2H), 2.59 (q, 2H), 1.92-1.77 (m, 2H), 1.64-1.49 (m, 2H), 1.46 (d, 3H), 1.18 (t, 3H). LCMS: [M+H]+=565.

Examples 646-649

[1849] Prepared using an analogous procedure to Example 645

TABLE-US-00048 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 646 [01723] (2R)-2-(3-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-5-oxo-5H,6H,7H- pyrrolo[3,4-b]pyridin-6- yl)-N-[(1R)-1-(3- methylphenyl)ethyl] propanamide 1H NMR (400 MHz, DMSO- d6) δ 9.10 (s, 1H), 8.60 (d, 1H), 8.50 (s, 1H), 8.41 (d, 1H), 7.72 (br. s, 1H), 7.22 (t, 1H), 7.14-6.98 (m, 3H), 4.96 (q, 1H), 4.88 (t, 1H), 4.78-4.67 (m, 2H), 4.04- 3.75 (m, 3H), 3.43-3.35 (m, 2H), 2.30 (s, 3H), 1.85 (d, 2H), 1.61-1.43 (d, 4H), 1.35 (d, 3H) (1 proton was not observed and was possibly overlapped with water or DMSO peaks). 535 647 [01724] (2R)-2-(3-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-5-oxo-5H,6H,7H- pyrrolo[3,4-b]pyridin-6- yl)-N-[(1S)-1-(2-fluoro- 5-methylphenyl)-2- hydroxyethyl] propanamide 1H NMR (400 MHz, DMSO- d6) δ 9.10 (s, 1H), 8.62 (d, 1H), 8.50 (s, 1H), 8.42 (d, 1H), 7.72 (br. s, 1H), 7.17 (d, 1H), 7.14-6.98 (m, 2H), 5.17-4.97 (m, 3H), 4.73 (q, 2H), 4.03-3.79 (m, 3H), 3.62-3.44 (m, 2H), 3.44- 3.34 (m, 2H), 2.28 (s, 3H), 1.85 (d, 2H), 1.62-1.39 (m, 5H). LCMS: [M + H].sup.+ = 569. 569 648 [01725] (2R)-2-(3-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-5-oxo-5H,6H,7H- pyrrolo[3,4-b]pyridin-6- yl)-N-[(1S)-1-(3-fluoro- 5-methylphenyl)-2- hydroxyethyl] propanamide 1H NMR (400 MHz, DMSO- d6) δ 9.10 (s, 1H), 8.56 (d, 1H), 8.50 (s, 1H), 8.42 (d, 1H), 7.72 (br. s, 1H), 7.01- 6.84 (m, 3H), 5.03 (q, 1H), 4.94 (t, 1H), 4.89-4.61 (m, 3H), 3.96-3.86 (m, 3H), 3.58-3.53 (m, 2H), 3.41- 3.35 (m, 2H), 2.31 (s, 3H), 1.85 (d, 2H), 1.63-1.39 (m, 5H). 569 649 [01726] (2R)-2-(3-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-5-oxo-5H,6H,7H- pyrrolo[3,4-b]pyridin-6- yl)-N-[(1S)-1-(3- ethoxyphenyl)-2- hydroxyethyl] propanamide 1H NMR (400 MHz, DMSO- d6) δ 9.10 (s, 1H), 8.55 (d, 1H), 8.50 (s, 1H), 8.42 (d, 1H), 7.72 (br. s, 1H), 7.22 (t, 1H), 6.90 -6.82 (m, 2H), 6.82-6.76 (m, 1H), 5.04 (q, 1H), 4.90 (t, 1H), 4.87-4.62 (m, 3H), 4.01 (q, 2H), 3.97- 3.81 (m, 3H), 3.61-3.47 (m, 2H), 3.41-3.34 (m, 2H), 1.85 (d, 2H), 1.62-1.43 (m, 5H), 1.33 (t, 3H). 581

Example 650: (2R)-2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-N-[(1S)-1-(2-fluoro-3-methylphenyl)-2-hydroxyethyl]propanamide

[1850] ##STR01727##

[1851] Prepared using an analogous procedure to Example 645. In this case, the product was further purified by preparative HPLC (Varian, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water) 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.64 (d, 1H), 8.49 (s, 1H), 8.41 (d, 1H), 7.71 (br. s, 1H), 7.17 (q, 2H), 7.06 (t, 1H), 5.14 (q, 1H), 5.09-4.96 (m, 2H), 4.72 (q, 2H), 3.95-3.85 (m, 3H), 3.61-3.44 (m, 2H), 3.40-3.34 (m, 2H), 2.22 (s, 3H), 1.84 (d, 2H), 1.53 (qd, 2H), 1.44 (d, 3H). LCMS: [M+H]+=569.

Example 651: (2R)-2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-N-[(1S)-2-hydroxy-1-(6-methoxypyridin-2-yl)ethyl]propanamide

[1852] ##STR01728##

[1853] TBTU (67.6 mg, 0.211 mmol) was added to a mixture of (R)-2-(3-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)propanoic acid (Preparation 416, 80 mg, 0.191 mmol), (S)-2-amino-2-(6-methoxypyridin-2-yl)ethanol, HCl (43.1 mg, 0.211 mmol) and triethylamine (107 μl, 0.766 mmol) in DMF (1 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (10 mL), washed successively with KHSO.sub.4 (1M, 10 mL), NaHCO.sub.3 (10 mL) and brine (10 mL), dried (MgSO.sub.4) and concentrated in vacuo. Purification by chromatography (SiO.sub.2, 0-100% EtOAc in iso-hexanes) gave the title compound (56 mg, 50.5%) as a colourless glass. 1H NMR (DMSO-D6, 400 MHz) δ 9.06 (1H, s), 8.50-8.44 (2H, m), 8.38 (1H, s), 7.69 (1H, s), 7.63 (1H, dd), 6.88 (1H, d), 6.64 (1H, d), 5.07 (1H, dt), 4.86 (1H, t), 4.83-4.77 (1H, m), 4.74 (1H, d), 4.66 (1H, d), 3.95-3.80 (3H, m), 3.80 (3H, s), 3.74-3.67 (1H, m), 3.63-3.56 (1H, m), 3.39-3.32 (2H, m), 1.86-1.76 (2H, m), 1.55-1.43 (5H, m). LCMS: [M+H]+=568.

Example 652: (2R)-2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]propanamide

[1854] ##STR01729##

[1855] A mixture of (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N—((S)-2-hydroxy-1-(3-methoxyphenyl)ethyl)propanamide (0.08 g, 0.159 mmol), DIPEA (0.056 ml, 0.319 mmol) and oxan-4-amine (0.025 ml, 0.239 mmol) in 1:1 EtOH:dioxane (1 mL) was heated at 80° C. under nitrogen overnight. The mixture was allowed to cool to room temperature was diluted with EtOAc, then transferred into a separating funnel. Saturated aqueous NH.sub.4Cl was added and the crude product was extracted with EtOAc. The combined organic extracts were washed with NaHCO.sub.3, brine, dried (MgSO.sub.4) and absorbed on silica. The crude product was purified by chromatography (12 g column, 0-6% MeOH in DCM), then re-purified by chromatography (12 g column, 5-10% EtOAc in MeOH) to afford the title compound (0.033 g, 35.8%) as a pale yellow solid after trituration and evaporation from Et.sub.2O. 1H NMR (DMSO-d6) δ: 9.10 (s, 1H), 8.58 (d, 1H), 8.50 (s, 1H), 8.42 (d, 1H), 7.72 (s (br), 1H), 7.29-7.18 (m, 1H), 6.92-6.84 (m, 2H), 6.81 (dd, 1H), 5.11-4.98 (m, 1H), 4.92 (t, 1H), 4.87-4.74 (m, 2H), 4.68 (d, 1H), 4.01-3.82 (m, 3H), 3.75 (s, 3H), 3.61-3.48 (m, 2H), 3.44-3.36 (m, 2H), 1.92-1.77 (m, 2H), 1.60-1.50 (m, 2H), 1.48 (d, 3H). LCMS: [M+H]+=567.

Examples 653-657

[1856] Prepared using an analogous procedure to Example 652.

TABLE-US-00049 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 653 [01730] ((2R)-2-(3-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-5-oxo-5H,6H,7H- pyrrolo[3,4-b]pyridin-6- yl)-N-[(1S)-2-hydroxy- 1-(3- methylphenyl)ethyl] propanamide 1H NMR (DMSO-d6) δ: 9.10 (s, 1H), 8.55 (d, 1H), 8.50 (s, 1H), 8.42 (d, 1H), 7.72 (s (br), 1H), 7.21 (dd, 1H), 7.15-6.99 (m, 3H), 5.09-4.99 (m, 1H), 4.89 (t, 1H), 4.86-4.73 (m, 2H), 4.67 (d, 1H), 4.01-3.82 (m, 3H), 3.61-3.49 (m, 2H), 3.44-3.35 (m, 2H), 2.30 (s, 3H), 1.91-1.80 (m, 2H), 1.61- 1.48 (m, 2H), 1.46 (d, 3H). 551 654 [01731] (2R)-2-(3-{5-chloro-2- [(oxetan-3- yl)amino]pyrimidin-4- yl}-5-oxo-5H,6H,7H- pyrrolo[3,4-b]pyridin-6- yl)-N-[(1S)-2-hydroxy- 1-(3- methylphenyl)ethyl] propanamide 1H NMR (DMSO-d6) δ: 9.11 (d, 1H), 8.59-8.50 (m, 2H), 8.43 (d, 1H), 8.43 (s (br), 1H), 7.21 (dd, 1H), 7.15-7.01 (m, 3H), 5.04 (td, 1H), 4.98-4.86 (m, 2H), 4.86-4.73 (m, 4H), 4.68 (d, 1H), 4.56 (t, 2H), 3.60-3.48 (m, 2H), 2.30 (s, 3H) 1.46 (d, 3H). 523 655 [01732] (2R)-2-[3-(5-chloro-2- {[(2S)-1- hydroxypropan-2- yl]amino}pyrimidin-4- yl)-5-oxo-5H,6H,7H- pyrrolo[3,4-b]pyridin-6- yl]-N-[(1S)-2-hydroxy- 1-(3- methylphenyl)ethyl] propanamide 1H NMR (DMSO-d6) δ: 9.11 (s (br), 1H), 8.55 (d, 1H), 8.48 (s (br), 1H), 8.42 (d, 1H), 7.39 (s (br), 1H), 7.21 (dd, 1H), 7.15-7.01 (m, 3H), 5.04 (td, 1H), 4.89 (t, 1H), 4.86-4.74 (m, 2H), 4.74-4.62 (m, 2H), 4.04-3.93 (m, 1H), 3.60- 3.44 (m, 3H), 2.30 (s, 3H), 1.46 (d, 3H), 1.15 (d, 3H) (One proton overlapped with water peak). 525 656 [01733] (2R)-2-(3-{5-chloro-2- [(oxetan-3- yl)amino]pyrimidin-4- yl}-5-oxo-5H,6H,7H- pyrrolo[3,4-b]pyridin-6- yl)-N-[(1S)-2-hydroxy- 1-(3- methoxyphenyl)ethyl] propanamide 1H NMR (DMSO-d6) δ: 9.11 (d, 1H), 8.57 (d, 1H), 8.53 (s, 1H), 8.43 (d, 1H), 8.43 (s (br), 1H), 7.24 (dd, 1H), 6.92-6.85 (m, 2H), 6.81 (ddd, 1H), 5.04 (td, 1H), 4.98-4.88 (m, 2H), 4.88-4.73 (m, 4H), 4.69 (d, 1H), 4.56 (t, 2H), 3.75 (s, 3H), 3.61-3.49 (m, 2H), 1.48 (d, 3H). 539 657 [01734] (2R)-2-[3-(5-chloro-2- {[(2S)-1- hydroxypropan-2- yl]amino}pyrimidin-4- yl)-5-oxo-5H,6H,7H- pyrrolo[3,4-b]pyridin-6- yl]-N-[(1S)-2-hydroxy- 1-(3- methoxyphenyl)ethyl] propanamide 1H NMR (DMSO-d6) δ: 9.11 (s (br), 1H), 8.56 (d, 1H), 8.51- 8.35 (m, 2H), 7.39 (s (br), 1H), 7.24 (dd, 1H), 6.92-6.84 (m, 2H), 6.84-6.76 (m, 1H), 5.04 (td, 1H), 4.90 (t, 1H), 4.87-4.61 (m, 4H), 4.05- 3.91 (m, 1H), 3.75 (s, 3H), 3.61-3.42 (m, 3H), 1.48 (d, 3H), 1.15 (d, 3H). One proton overlapped with water peak. 541

Example 658: (2R)-2-(3-{5-chloro-2-[(propan-2-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]propanamide

[1857] ##STR01735##

[1858] A mixture of (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N—((S)-2-hydroxy-1-(3-methoxyphenyl)ethyl)propanamide (Preparation 370, 0.08 g, 0.159 mmol), DIPEA (0.056 ml, 0.319 mmol) and propan-2-amine (0.041 ml, 0.478 mmol) in 1:1 EtOH:dioxane (1 mL) was heated at 80° C. in a sealed Biotage microwave vial overnight. The mixture was allowed to cool to room temperature was diluted with EtOAc, then transferred into a separating funnel. Saturated aqueous NH.sub.4Cl was added and the crude product was extracted with EtOAc. The combined organic extracts were washed with NaHCO.sub.3, brine, dried (MgSO.sub.4) and absorbed on silica. The crude product was purified by chromatography (SiO.sub.2, 4 g column, 0-4% MeOH in DCM) to afford the title compound (0.01 g, 11.84%) as a pale yellow solid after trituration and evaporation from Et.sub.2O. 1H NMR (DMSO-d6) δ: 9.11 (s (br), 1H), 8.56 (d, 1H), 8.48 (s (br), 1H), 8.42 (d, 1H), 7.57 (d, 1H), 7.24 (dd, 1H), 6.93-6.84 (m, 2H), 6.81 (ddd, 1H), 5.11-4.98 (m, 1H), 4.91 (t, 1H), 4.87-4.73 (m, 2H), 4.68 (d, 1H), 4.09-3.97 (m, 1H), 3.75 (s, 3H), 3.59-3.49 (m, 2H), 1.47 (d, 3H), 1.18 (d, 6H). LCMS: [M+H]+=525.

Example 659: (2R)-2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-N-[(1S)-1-[3-(difluoromethoxy)phenyl]-2-hydroxyethyl]propanamide

[1859] ##STR01736##

[1860] DIPEA (0.060 mL, 0.344 mmol) followed by oxan-4-amine (0.020 mL, 0.193 mmol) were added to a stirred solution of (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N—((S)-1-(3-(difluoromethoxy)phenyl)-2-hydroxyethyl)propanamide (0.057 g, 0.093 mmol) in 1,4-dioxane (1.0 mL, 11.69 mmol) and the mixture was heated to 90° C. for 3.5h. After 4 h, further oxan-4-amine (0.020 mL, 0.193 mmol), DIPEA (0.060 mL, 0.344 mmol) and EtOH (1 mL) were added and the reaction mixture was left to heat for a further 2 h then cooled to room temperature and stirred overnight. The mixture was partitioned between EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous layer extracted with EtOAc (50 mL). The combined organic extracts were washed with brine (3×50 mL), dried (MgSO.sub.4), filtered and concentrated. Purification by chromatography (SiO.sub.2, 12 g column, 0-100% (10% MeOH in DCM) in DCM) afforded the title compound (16 mg, 27.9%) as a pale yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.10 (1H, d), 8.61 (1H, d), 8.49 (1H, s), 8.41 (1H, d), 7.71 (1H, br. s), 7.44-7.32 (1H, m), 7.24-7.14 (2H, m), 7.11 (1H, t), 7.07-7.01 (1H, m), 5.03 (1H, q), 4.95 (1H, t), 4.86 (1H, q), 4.81-4.60 (2H, m), 3.96-3.85 (3H, m), 3.63-3.49 (2H, m), 3.43-3.33 (2H, m), 1.89-1.78 (2H, m), 1.54 (2H, td), 1.47 (3H, d). LCMS: [M+H]+=603.

Example 660: 2-[3-(5-chloro-2-{[trans-4-methoxycyclohexyl]amino}pyrimidin-4-yl)-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-N-[(1S)-2-hydroxy-1-(3-methylphenyl)ethyl]acetamide

[1861] ##STR01737##

DIPEA (59.9 μl, 0.343 mmol) was added to a stirred solution of (S)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N-(2-hydroxy-1-(m-tolyl)ethyl)acetamide (80 mg, 0.137 mmol) and (1r,4r)-4-methoxycyclohexanamine (26.6 mg, 0.206 mmol) in dioxane (1 mL) under nitrogen. The mixture was heated to 90° C. and stirred for 16 h. The mixture was allowed to cool to room temperature and was diluted with EtOAc (20 mL) and water (20 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (60 mL), dried (MgSO.sub.4) and concentrated. The crude product was purified by chromatography (SiO.sub.2, 24 g column, 0-10% MeOH in DCM) to afford a beige solid. The product was loaded onto a column packed with SCX (0.5 g) in MeOH. The column was washed with MeOH and the product eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to afford the title compound (52 mg, 66.4%) as a beige solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.09 (1H, s), 8.54 (1H, d), 8.48 (1H, s (br)), 8.40 (1H, d), 7.62 (1H, s (br)), 7.21 (1H, t), 7.15-7.08 (2H, m), 7.07-7.03 (1H, m), 4.91 (1H, t), 4.88-4.80 (1H, m), 4.64 (2H, s), 4.34 (1H, d), 4.29 (1H, d), 3.77-3.62 (1H, m), 3.61-3.50 (2H, m), 3.22 (3H, s), 3.17-3.05 (1H, m), 2.29 (3H, s), 2.10-1.84 (4H, m), 1.41-1.24 (2H, m), 1.24-1.11 (2H, m). LCMS: [M+H]+=565.

Example 661: 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-N-[(1R)-1-(6-methoxypyridin-2-yl)ethyl]acetamide

[1862] ##STR01738##

[1863] A mixture of (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N-(1-(6-methoxypyridin-2-yl)ethyl)acetamide (0.115 g, 0.243 mmol), DIPEA (0.085 ml, 0.486 mmol) and oxan-4-amine (0.038 ml, 0.364 mmol) in 1:1 EtOH:dioxane (1.5 mL) was heated at 80° C. under nitrogen overnight. The mixture was allowed to cool to room temperature was diluted with EtOAc, then transferred into a separating funnel. Water was added and the crude product was extracted with EtOAc. The combined organic extracts were washed with NaHCO.sub.3, brine, dried (MgSO.sub.4) and absorbed on silica. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-5% MOH in DCM) to afford the title compound (0.085 g, 64.4%) as a pale yellow solid after trituration and evaporation from Et.sub.2O. 1H NMR (DMSO-d6) δ: 9.10 (d, 1H), 8.57 (d, 1H), 8.49 (s, 1H), 8.42 (d, 1H), 7.72 (s (br), 1H), 7.67 (dd, 1H), 6.95 (d, 1H), 6.68 (d, 1H), 4.92 (dq, 1H), 4.70 (d, 1H), 4.64 (d, 1H), 4.34 (s, 2H), 3.98-3.86 (m, 3H), 3.86 (s, 3H), 3.43-3.35 (m, 2H), 1.91-1.78 (m, 2H), 1.61-1.46 (m, 2H), 1.42 (d, 3H). LCMS: [M+H]+=538.

Example 5260: 2-(3-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-N-[(1R)-1-(3-methylphenyl)ethyl]acetamide

[1864] ##STR01739##

[1865] Oxan-4-amine (108 mg, 1.063 mmol) was added to a solution of crude (R)-2-(3-(2,5-dichloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N-(1-(m-tolyl)ethyl)acetamide (97 mg, 0.213 mmol) (containing (R)-2-(3-(2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-5-chloropyrimidin-4-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N-(1-(m-tolyl)ethyl)acetamide as impurity) in dioxane (2 ml) and the mixture heated at 90° C. overnight. The reaction mixture was cooled to room temperature and partitioned between water (50 ml) and 1N HCl (50 ml) and the organic phase collected. The DCM solution was washed with aq 10% NaHCO.sub.3 (50 ml) and dried (MgSO.sub.4). Concentration of the extract afforded a glass which was purified by chromatography (SiO.sub.2, 4 g column, 100% EtOAc). The pure fractions were concentrated to dryness and the residue crystallised using diethyl ether to afford the title compound (70 mg, 63.2%) as a cream coloured solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.10 (1H, d), 8.58 (1H, d), 8.50 (1H, s), 8.41 (1H, d), 7.72 (1H, s), 7.26-6.90 (4H, m), 5.02-4.85 (1H, m), 4.64 (2H, s), 4.28 (2H, s), 3.98-3.80 (3H, m), 3.41-3.36 (2H, m), 2.30 (3H, s), 1.90-1.79 (2H, m), 1.62-1.42 (2H, m), 1.37 (3H, d). LCMS: [M+H]+=521.

Example 663: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide

[1866] ##STR01740##

[1867] HATU (115 mg, 0.303 mmol) was added to a suspension of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (118 mg, 0.275 mmol), (S)-2-amino-2-(3-methoxyphenyl)ethanol hydrochloride (61.6 mg, 0.303 mmol) and triethylamine (0.153 mL, 1.100 mmol) in DMF (1.5 mL, 19.37 mmol) at room temperature. The reaction was stirred for 1 h, then diluted with water (10 mL) and 1 M HCl (5 mL). The resulting precipitate was isolated by filtration, then dissolved in EtOAc (10 mL), dried (MgSO.sub.4) and concentrated to give a pale yellow solid, which was redissolved in EtOAc (15 mL) and washed with 1 M HCl (2×15 mL), brine (2×15 mL), dried (MgSO.sub.4) and concentrated to give a pale yellow solid. The crude product was loaded onto a column of SCX (5 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to afford the title compound (49 mg, 30.0%) as a white powder. 1H NMR (DMSO-d6, 400 MHz) δ 8.55 (1H, d), 8.48 (1H, s), 7.96-7.89 (1H, m), 7.83 (1H, dd), 7.68 (1H, br. s), 7.27-7.20 (1H, m), 6.92-6.88 (2H, m), 6.85-6.79 (1H, m), 4.93 (1H, t), 4.89-4.83 (1H, m), 4.68 (2H, s), 4.33 (1H, d), 4.28 (1H, d), 3.98-3.82 (3H, m), 3.75 (3H, s), 3.62-3.53 (2H, m), 3.42-3.35 (2H, m), 1.84 (2H, d), 1.59-1.47 (2H, m). LCMS: [M+H]+=570.

Example 664: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S,2S)-2-hydroxy-1-phenylpropyl]acetamide

[1868] ##STR01741##

[1869] DIPEA (0.110 ml, 0.631 mmol) and HATU (120 mg, 0.315 mmol) were added to a stirred solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Preparation 16, 90 mg, 0.214 mmol), and (1S,2S)-1-amino-1-phenylpropan-2-ol hydrochloride (40.1 mg, 0.214 mmol) in acetonitrile (2 ml, 0.214 mmol) and the resulting solution was stirred at room temperature for 48h. The solution was concentrated and the residue dissolved in a small quantity of DCM purified by chromatography (SiO.sub.2, 12 g column, 100% EtOAc) to give a colourless solid (75 mg). The solid was dissolved in methanol (2 ml) and the solution loaded on a column packed with SCX. The column was washed with MeOH and the product eluted with 1% ammonia in methanol. The resulting solution was concentrated to dryness and the residual glass triturated with Et.sub.2O (2 ml). The resulting precipitate was filtered to afford the title compound (53 mg, 44.2%) as a colourless solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.53 (1H, d), 8.48 (1H, s), 7.91 (1H, d), 7.82 (1H, dd), 7.68 (1H, s), 7.36-7.21 (5H, m), 4.83 (1H, d), 4.72 (1H, dd), 4.66 (2H, s), 4.38 (1H, d), 4.30 (1H, d), 3.99-3.80 (3H, m), 3.42-3.35 (2H, m), 1.84 (2H, d), 1.58-1.46 (2H, m), 1.00 (3H, d). (One exchangeable proton was not observed and may have overlapped with DMSO or water peaks). LCMS: [M+H]+=554.

Example 665: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[3-(difluoromethoxy)phenyl]-2-hydroxyethyl]acetamide

[1870] ##STR01742##

[1871] DIPEA (110 μl, 0.631 mmol) and HATU (120 mg, 0.315 mmol) were added to a stirred solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Preparation 16, 90 mg, 0.214 mmol), and (S)-2-amino-2-(3-(difluoromethoxy)phenyl)ethanol hydrochloride (51.3 mg, 0.214 mmol) in acetonitrile (8.78 mg, 0.214 mmol). The resulting solution was stirred at room temperature for 48 h. The solution was concentrated to dryness and the residue dissolved in a small quantity of DCM, then purified by chromatography (SiO.sub.2, 12 g column, 100% EtOAc) to afford a colourless solid (89 mg). The solid was dissolved in methanol (2 ml) and the solution loaded on a column packed with SCX. The column was washed with MeOH and the product eluted with 1% ammonia in methanol. The resulting solution was concentrated to dryness and the residual glass triturated with Et.sub.2O (2 ml). The resulting precipitate was filtered to afford afford a colourless solid (60 mg). The solid was dissolved in DCM (30 ml) and the solution washed with 1N HCl (20 ml). The organic phase was dried (MgSO.sub.4) and concentrated to dryness, then purified by preparative HPLC (acidic) to afford the title compound acetamide (15 mg, 11.57%) as a colourless solid. 1H NMR (DMSO, 400 MHz) δ 8.62 (1H, d), 8.48 (1H, s), 7.92 (1H, s), 7.83 (1H, d), 7.68 (1H, s (br)), 7.45-6.97 (5H, m), 4.99 (1H, t), 4.96-4.80 (1H, m), 4.67 (2H, s), 4.42-4.20 (2H, m), 4.06-3.72 (3H, m), 3.41-3.47 (2H, m), 3.69-3.49 (2H, m), 1.93-1.72 (2H, m), 1.64-1.42 (2H, m). LCMS: [M+H]+=606.

Example 666: 2-[6-(5-chloro-2-{[(2S)-1-hydroxypropan-2-yl]amino}pyrimidin-4-yl)-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1R)-1-(3-methoxyphenyl)ethyl]acetamide

[1872] ##STR01743##

[1873] Prepared using a similar procedure to Example 102. 1H NMR (DMSO, 400 MHz) δ 8.58 (1H, d), 8.45 (1H, s), 7.92 (1H, d), 7.83 (1H, d), 7.34 (1H, s), 7.24 (1H, t), 6.92-6.86 (2H, m), 6.83-6.76 (1H, m), 4.93 (1H, p), 4.73-4.61 (3H, m), 4.25 (2H, s), 4.00-3.90 (1H, m), 3.75 (3H, s), 3.53-3.44 (1H, m), 3.32-3.26 (1H, m), 1.36 (3H, d), 1.13 (3H, d). LCMS: [M+H]+=528.

Example 667: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(3-methylphenyl)ethyl]acetamide

[1874] ##STR01744##

[1875] Prepared using a similar procedure to Example 583. 1H NMR (DMSO-d6, 400 MHz) δ 8.54 (1H, d), 8.47 (1H, s), 7.91 (1H, d), 7.82 (1H, dd), 7.67 (1H, s), 7.21 (1H, t), 7.17-7.08 (2H, m), 7.07-7.02 (1H, m), 4.92 (1H, t), 4.88-4.79 (1H, m), 4.66 (2H, s), 4.32 (1H, d), 4.26 (1H, d), 4.00-3.80 (3H, m), 3.66-3.49 (2H, m), 3.38 (2H, d), 2.29 (3H, s), 1.90-1.78 (2H, m), 1.58-1.46 (2H, m). LCMS: [M+H]+=554.

Example 668: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(6-methoxypyridin-2-yl)ethyl]acetamide

[1876] ##STR01745##

[1877] TBTU (47.8 mg, 0.149 mmol) was added to an ice-cooled stirred solution of 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetic acid (Preparation 16, 44 mg, 0.099 mmol), (S)-2-amino-2-(6-methoxypyridin-2-yl)ethanol hydrochloride (22.36 mg, 0.109 mmol) and triethylamine (55.4 μl, 0.397 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 16 h, then diluted with EtOAc (30 mL). The organic phase was washed with water (30 mL), NH.sub.4Cl (30 mL), brine (3×30 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-6% MeOH in DCM) to afford the title compound (39 mg, 68.1%) as an off white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.58-8.40 (2H, m), 7.91 (1H, d), 7.82 (1H, dd), 7.75-7.59 (2H, m), 7.03-6.88 (1H, m), 6.68 (1H, d), 4.95-4.81 (2H, m), 4.69 (2H, s), 4.34 (2H, s), 4.00-3.85 (3H, m), 3.84 (3H, s), 3.81-3.73 (1H, m), 3.72-3.63 (1H, m), 3.42-3.36 (2H, m), 1.88-1.78 (2H, m), 1.60-1.45 (2H, m). LCMS: [M+H]+=571.

Examples 669-670

[1878] Prepared using an analogous procedure to Example 668

TABLE-US-00050 MS: Example Structure Name .sup.1H NMR (400 MHz) [M + H].sup.+ 669 [01746] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-4-fluoro-1-oxo-2,3- dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy- 1-(3- methoxyphenyl)ethyl] propanamide 1H NMR (DMSO-d6, 400 MHz) δ 8.58 (1H, d), 8.48 (1H, s), 7.95-7.90 (1H, m), 7.82 (1H, dd), 7.68 (1H, br. s), 7.24 (1H, t), 6.91-6.84 (2H, m), 6.81 (1H, ddd), 4.99 (1H, q), 4.91 (1H, t), 4.87-4.67 (3H, m), 3.97-3.85 (3H, m), 3.75 (3H, s), 3.61-3.49 (2H, m), 3.41-3.36 (2H, m), 1.85 (2H, br. d), 1.54 (2H, tt), 1.46 (3H, d). 584 670 [01747] (2R)-2-(6-{5-chloro-2- [(oxan-4- yl)amino]pyrimidin-4- yl}-4-fluoro-1-oxo-2,3- dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy- 1-(3- methylphenyl)ethyl] propanamide 1H NMR (DMSO-d6, 400 MHz) δ 8.56 (1H, d), 8.48 (1H, s), 7.93 (1H, d), 7.82 (1H, dd), 7.68 (1H, br. s), 7.21 (1H, t), 7.12-7.01 (3H, m), 4.99 (1H, q), 4.89 (1H, t), 4.86- 4.67 (3H, m), 4.01-3.81 (3H, m), 3.59-3.49 (2H, m), 3.40-3.34 (2H, m), 2.30 (3H, s), 1.85 (2H, br. d), 1.53 (2H, qd), 1.45 (3H, d). 568

Example 671: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(6-methylpyridin-2-yl)ethyl]propanamide

[1879] ##STR01748##

[1880] Prepared using an analogous procedure to Example 668. In this case, the product was further purified by preparative HPLC (Varian, Acidic, 15-35%, 10 min run), then freeze-dried. 1H NMR (DMSO-d6, 400 MHz) δ 8.55 (1H, d), 8.48 (1H, s), 7.93 (1H, s), 7.83 (1H, dd), 7.72-7.63 (2H, m), 7.13 (2H, dd), 5.03 (1H, q), 4.93-4.69 (4H, m), 3.97-3.85 (3H, m), 3.74-3.68 (1H, m), 3.67-3.57 (1H, m), 3.41-3.34 (2H, m), 2.43 (3H, s), 1.85 (2H, br. d), 1.57-1.47 (5H, m). LCMS: [M+H]+=569.

Example 672: (2R)-2-[6-(5-chloro-2-{[(2S)-1-hydroxypropan-2-yl]amino}pyrimidin-4-yl)-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(3-methylphenyl)ethyl]propanamide

[1881] ##STR01749##

[1882] A stirred solution of (S)-2-amino-2-(m-tolyl)ethanol, HCl (32 mg, 0.171 mmol), (R)-2-(6-(5-chloro-2-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)propanoic acid (91 mg, 0.140 mmol) and triethylamine (78 μl, 0.561 mmol) in DMF (2 ml) was treated with TBTU (50 mg, 0.156 mmol) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate (10 ml), was washed successively with 1M KHSO.sub.4 (5 ml), NaHCO.sub.3 (5 ml), brine (2×5 ml), water (4×5 ml), then dried (MgSO.sub.4) and evaporated. The residue was purified on a 12 g graceresolv silica cartridge, using a gradient of 0 to 5% of ethanol in ethyl acetate as a eluent to give a colourless glass which was further purified by reversed phase preparative HPLC (Waters XSelect CSH C18 OBD, 130 Å, 5 μm, 19 mm×50 mm column, using a gradient of 20 to 50% of acetonitrile in water with 0.1% formic acid in both at 28 ml/min as eluent). The clean fractions were pooled and concentrated to remove most of the acetonitrile. The residue was freeze-dried to the title compound (21 mg, 27.4%) as a fluffy white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.56 (1H, d), 8.45 (1H, s), 7.97-7.88 (1H, m), 7.83 (1H, d), 7.34 (1H, s), 7.20 (1H, t), 7.13-7.00 (3H, m), 4.98 (1H, q), 4.89 (1H, t), 4.85-4.76 (2H, m), 4.74-4.67 (2H, m), 4.05-3.90 (1H, m), 3.59-3.41 (3H, m), 2.29 (3H, s), 1.44 (3H, d), 1.13 (3H, d). (One proton was not observed and overlapped with water peak). LCMS: [M+H]+=542.

Example 673: 2-(6-{5-chloro-2-[(propan-2-yl)amino]pyrimidin-4-yl}-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]acetamide

[1883] ##STR01750##

[1884] A solution of (S)-2-(6-(2-((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)-5-chloropyrimidin-4-yl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(2-hydroxy-1-(3-methoxyphenyl)ethyl)acetamide (62 mg, 0.102 mmol), isopropylamine (0.018 ml, 0.205 mmol) and DIPEA (0.054 ml, 0.307 mmol) in dioxane (2 mL) was sealed in a microwave vial and stirred at 85° C. (bath) overnight. The mixture was combined with the reaction mixture from a separate experiment (37 mg scale), diluted with ethyl acetate (20 ml), was washed with water (10 ml) followed by brine (20 ml), dried (Na.sub.2SO.sub.4) and evaporated. The residue was purified by chromatography (SiO.sub.2, 24 g column, 0 to 5% EtOH in EtOAc) to afford the title compound (42 mg, 44.5%) as a white powder. 1H NMR (DMSO-d6, 400 MHz) δ 8.54 (1H, d), 8.45 (1H, s), 7.92 (1H, s), 7.83 (1H, d), 7.53 (1H, d), 7.23 (1H, t), 6.92-6.85 (2H, m), 6.84-6.77 (1H, m), 4.92 (1H, t), 4.89-4.79 (1H, m), 4.67 (2H, s), 4.37-4.23 (2H, m), 4.08-3.95 (1H, m), 3.74 (3H, s), 3.64-3.48 (2H, m), 1.16 (6H, d). LCMS: [M+H]+=528.

Example 674: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-phenylethyl]propanamide

[1885] ##STR01751##

[1886] Prepared using a similar procedure to Example 406. 1H NMR (DMSO-d6) δ: 8.59 (d, 1H), 8.45 (s, 1H), 8.04 (d, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.62 (s (br), 1H), 7.36-7.28 (m, 4H), 7.28-7.20 (m, 1H), 5.01 (q, 1H), 4.90 (t, 1H), 4.84 (td, 1H), 4.76 (d, 1H), 4.60 (d, 1H), 4.01-3.81 (m, 3H), 3.61-3.50 (m, 2H), 3.45-3.36 (m, 2H), 1.91-1.79 (m, 2H), 1.62-1.47 (m, 2H), 1.44 (d, 3H). LC-MS: [M+H]+=536.

Example 675: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]propanamide

[1887] ##STR01752##

[1888] Prepared using a similar procedure to Example 451. 1H NMR (DMSO-d6, 400 MHz) δ 8.56 (1H, d), 8.45 (1H, s), 8.05-8.03 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.63 (1H, br. S), 7.27-7.20 (1H, m), 6.90-6.86 (2H, m), 6.85-6.76 (1H, m), 5.01 (1H, q), 4.89 (1H, t), 4.84-4.80 (1H, m), 4.77 (1H, d), 4.60 (1H, d), 3.99-3.83 (3H, m), 3.75 (3H, s), 3.57-3.52 (2H, m), 3.42-3.35 (2H, m), 1.88-1.80 (2H, m), 1.59-1.48 (2H, m), 1.45 (3H, d). LC-MS: [M+H]+=566.

Example 676: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[1-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl]propanamide

[1889] ##STR01753##

[1890] Prepared using a similar procedure to Example 95. 1H NMR (DMSO-d6) δ: 8.45 (s, 1H), 8.15-8.00 (m, 2H), 7.99-7.88 (m, 1H), 7.73 (dd, 1H), 7.63 (s, 1H), 7.26-7.05 (m, 4H), 5.05-4.91 (m, 2H), 4.70 (dd, 1H), 4.58 (dd, 1H), 3.96-3.83 (m, 3H), 3.61 (dt, 1H), 3.54-3.45 (m, 1H), 3.43-3.35 (m, 2H), 2.95-2.79 (m, 2H), 2.42-2.19 (m, 2H), 1.89-1.81 (m, 2H), 1.60-1.48 (m, 2H), 1.51-1.34 (m, 3H). LCMS: [M+H]+=562.

Example 677 (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(3-methylphenyl)ethyl]butanamide

[1891] ##STR01754##

[1892] Prepared using a similar procedure to Example 406. 1H NMR (DMSO, 400 MHz) δ 8.69 (1H, d), 8.45 (1H, s), 8.04 (1H, d), 7.97 (1H, dd), 7.74 (1H, d), 7.62 (1H, s), 7.20 (1H, dd), 7.12-7.07 (2H, m), 7.04 (1H, d), 4.90-4.81 (3H, m), 4.78 (1H, dt), 4.54 (1H, d), 3.97-3.82 (3H, m), 3.52 (2H, dd), 3.41-3.35 (2H, m), 2.29 (3H, s), 1.96-1.88 (1H, m), 1.88-1.80 (2H, m), 1.78-1.68 (1H, m), 1.58-1.46 (2H, m), 0.80 (3H, t). LCMS: [M+H]+=564.

Example 678 ((2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S,2S)-2-hydroxy-1-phenylpropyl]butanamide

[1893] ##STR01755##

[1894] Prepared using a similar procedure to Example 406. 1H NMR (DMSO, 400 MHz) δ 8.62 (1H, d), 8.45 (1H, s), 8.05 (1H, d), 7.97 (1H, dd), 7.74 (1H, d), 7.62 (1H, s), 7.34-7.28 (4H, m), 7.24-7.19 (1H, m), 4.95 (1H, dd), 4.85 (1H, d), 4.75 (1H, d), 4.67 (1H, dd), 4.54 (1H, d), 3.97-3.80 (4H, m), 3.41-3.36 (2H, m), 1.95-1.81 (3H, m), 1.77-1.67 (1H, m), 1.58-1.47 (2H, m), 0.93 (3H, d), 0.80 (3H, t). LCMS: [M+H]+=564.

Example 679: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]propanamide

[1895] ##STR01756##

[1896] Prepared using a similar procedure to Example 95. In this case, the product was further purified by preparative HPLC (acidic). 1H NMR (DMSO-d6) δ: 8.42 (s, 1H), 8.15 (d, 1H), 8.03 (d, 1H), 7.97 (dd, 1H), 7.77 (d, 1H), 7.55 (s, 1H), 7.25-7.10 (m, 4H), 5.19 (dd, 1H), 5.11-4.99 (m, 1H), 4.85 (d, 1H), 4.67 (d, 1H), 4.46-4.36 (m, 1H), 3.95-3.77 (m, 3H), 3.45-3.28 (m, 2H), 3.03 (dd, 1H), 2.79 (d, 1H), 1.94-1.74 (m, 2H), 1.56 (d, 4H), 1.55-1.43 (m, 2H). LC-MS: [M+H]+=548.

Example 680: (2S)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-phenylethyl]propanamide

[1897] ##STR01757##

[1898] DIPEA (0.075 ml, 0.427 mmol) and HATU (121 mg, 0.318 mmol) were added to a stirred solution of (S)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (90 mg, 0.216 mmol), and (S)-2-amino-2-phenylethanol (29.6 mg, 0.216 mmol) in DCM (2 ml, 0.216 mmol). The resulting suspension was treated with MeCN (2 ml) and the resulting solution was stirred for 1h, then concentrated under vacuum. The residue was dissolved in DCM and purified by chromatography (SiO.sub.2, 12 g column, 0-10% MeCN in EtOAc) to afford the title compound (90 mg, 78%) as a cream coloured solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.5 (d, 1H), 8.44 (s, 1H), 8.02 (s, 1H), 7.97 (d, 1H) 7.73 (d, 1H), 7.61 (s (br),1H),7.3-.7.18 (m, 5H), 4.98 (q, 1H) 4.89 (t, 1H), 4.83 (q, 1H), 4.63 (q, 2H), 4-3.8 (m, 3H), 3.57 (t, 2H), 3.4-3.3 (m, 2H), 1.87-1.83 (m, 2H), 1.56-1.5 (m, 5H). LCMS: [M+H]+=534.

Example 681: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[3-(hydroxymethyl)phenyl]ethyl]propanamide

[1899] ##STR01758##

[1900] DIPEA (0.079 ml, 0.452 mmol) and HATU (127 mg, 0.333 mmol) were added to a stirred solution of (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid. TFA (120 mg, 0.226 mmol), and (R)-(3-(1-aminoethyl)phenyl)methanol (68.4 mg, 0.452 mmol) in acetonitrile (5 ml, 0.226 mmol) and the resulting solution was stirred at ambient temperature for 1 h. The solution was concentrated and the residue was dissolved in a small quantity of DCM, then purified by chromatography (SiO.sub.2, 4 g column, 100% EtOAc). Concentration of the pure fractions gave a colourless solid (107 mg), which was dissolved in MeOH and loaded on a column packed with SCX. The SCX was washed with methanol until no longer acidic to test paper, then the product was eluted with 1% ammonia in methanol. The resulting solution was concentrated to dryness under vacuum and the residue triturated with diethyl ether (1 ml) to afford the title compound (60 mg, 0.106 mmol, 46.8% yield) as a colourless solid. 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, 1H), 8.45 (s, 1H), 8.03 (s, 1H), 7.97 (d, 1H), 7.75 (d, 1H), 7.62 (s (br), 1H), 7.27 (m, 2H), 7.17 (d, 2H), 5.19 (t, 1H), 4.93 (m, 2H), 4.75 (d, 1H), 4.61 (d, 1H), 4.49 (d, 2H), 3.99-3.82 (m, 3H), 3.43-3.34 (m, 2H), 1.85 (d, 2H), 1.52 (m, 2H), 1.45 (d, 3H), 1.36 (d, 3H). LCMS: [M+H]+=550.

Example 682: (2R)-(2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S,2S)-2-hydroxy-1-phenylpropyl]propanamide

[1901] ##STR01759##

[1902] Prepared using a similar procedure to Example 539. 1H NMR (DMSO-d6, 400 MHz) δ 8.49 (1H, d), 8.45 (1H, s), 8.05 (1H, s), 8.00-7.95 (1H, d), 7.74 (1H, d), 7.63 (1H, s), 7.37-7.19 (5H, m), 5.07 (1H, q), 4.78 (1H, d), 4.69 (1H, m), 4.61 (1H, d), 3.99-3.80 (4H, m), 3.35 (2H, m+water) 1.92-1.78 (2H, m), 1.53 (2H, m), 1.42 (3H, d), 0.96 (3H, d) (note: exchangeable OH signal was not observed and may have been overlapped with water or DMSO peaks). LCMS: [M+H]+=550.

Example 683: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(3-methylphenyl)ethyl]propanamide

[1903] ##STR01760##

[1904] Method A: A mixture of (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-2-hydroxy-1-(m-tolyl)ethyl)propanamide (200 mg, 0.330 mmol), oxan-4-amine (50.0 mg, 0.494 mmol) and N-ethyl-N-isopropylpropan-2-amine (144 μl, 0.824 mmol) in dry Dioxane (3 ml) was stirred and heated at 85° C. overnight. The reaction mixture was cooled to room temperature and partitioned between 1M HCl (50 ml) and dichloromethane (100 ml). The organic phase was collected and washed with NaHCO.sub.3 (25 ml), dried (MgSO.sub.4), filtered and concentrating to dryness. The residual oil was purified by chromatography (SiO.sub.2, 4 g column, 100% EtOAc). The pure fractions were combined and concentrated to give a foam (95 mg) which upon trituration with diethyl ether (15 ml) afforded the title compound (75 mg, 41.4%) as a cream coloured solid.

[1905] Method B: triethylamine (2.060 mL, 14.78 mmol) was added to a suspension of (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (1.54 g, 3.69 mmol) and (S)-2-amino-2-(m-tolyl)ethanol hydrochloride (0.763 g, 4.06 mmol) in DMF (15 mL, 194 mmol). After 15 minutes, TBTU (1.305 g, 4.06 mmol) was added and the mixture was stirred for 2 h at room temperature. The reaction was diluted with EtOAc (30 mL) and water (100 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with NH.sub.4Cl (100 mL), NaHCO.sub.3 (100 mL), brine (2×100 mL), dried (MgSO.sub.4) and concentrated. The crude product was purified by chromatography (SiO.sub.2, 40 g column, 0-7% MeOH in DCM) to afford the product as a colourless gum. The gum was triturated with diethyl ether (100 mL) to give the title compound (1.409 g, 68.0%) as a white solid. 1H NMR (DMSO, 400 MHz) δ 8.56 (1H, d), 8.45 (1H, s), 8.08-8.02 (1H, m), 7.98 (1H, dd), 7.75 (1H, d), 7.63 (1H, s), 7.21 (1H, t), 7.13-6.96 (3H, m), 5.01 (1H, q), 4.93-4.84 (1H, m), 4.83-4.72 (2H, m), 4.60 (1H, d), 4.01-3.80 (3H, m), 3.59-3.50 (2H, m), 3.43-3.36 (2H, m), 2.30 (3H, s), 1.90-1.79 (2H, m), 1.60-1.46 (2H, m), 1.43 (3H, d). LCMS: [M+H]+=550.

Example 684: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-ethoxyphenyl)-2-hydroxyethyl]propanamide

[1906] ##STR01761##

[1907] Prepared using a similar procedure to Example 592. 1H NMR (DMSO, 400 MHz) δ 8.57 (1H, d), 8.44 (1H, s), 8.06-8.01 (1H, m), 7.97 (1H, dd), 7.74 (1H, d), 7.61 (1H, s), 7.25-7.16 (1H, m), 6.89-6.82 (2H, m), 6.81-6.74 (1H, m), 5.05-4.85 (2H, m), 4.85-4.71 (2H, m), 4.59 (1H, d), 4.07-3.80 (5H, m), 3.60-3.48 (2H, m), 3.43-3.36 (2H, m), 1.91-1.77 (2H, m), 1.60-1.37 (5H, m), 1.32 (3H, t). LCMS: [M+H]+=580.

Example 685: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide

[1908] ##STR01762##

[1909] A stirred solution of (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (70 mg, 0.168 mmol), (S)-2-amino-2-(3-fluoro-5-methoxyphenyl)ethanol, HCl (41 mg, 0.185 mmol) and triethylamine (0.094 ml, 0.672 mmol) in DMF (1 ml) was treated with TBTU (65 mg, 0.202 mmol) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 ml), was washed successively with 1M KHSO.sub.4 (10 ml), NaHCO.sub.3 (10 ml), brine (2×10 ml) and then water (4×10 ml), was dried (MgSO.sub.4) and evaporated. The residue was purified by chromatography (SiO.sub.2, 12 g column, 0-5% EtOOH in EtOAc) to give a glass, which was triturated with ether (2 ml) to give a solid. The solid was collected by filtration, washed with ether (2×1 ml) and dried under vacuum at 50° C. overnight to give the title compound (64.3 mg, 64.3%) as a cream solid. 1H NMR (DMSO, 400 MHz) δ 8.56 (1H, d), 8.44 (1H, s), 8.07-8.00 (1H, m), 7.97 (1H, dd), 7.74 (1H, d), 7.61 (1H, s), 6.76-6.64 (3H, m), 4.99 (1H, q), 4.91 (1H, t), 4.86-4.70 (2H, m), 4.60 (1H, d), 4.00-3.80 (3H, m), 3.76 (3H, s), 3.60-3.47 (2H, m), 3.40-3.33 (2H, m), 1.84 (2H, d), 1.59-1.39 (5H, m).). LCMS: [M+H]+=584.

Example 686: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methylphenyl)-2-hydroxyethyl]propanamide

[1910] ##STR01763##

[1911] Prepared using a similar procedure to Example 685. 1H NMR (DMSO, 400 MHz) δ 8.55 (1H, d), 8.44 (1H, s), 8.06-8.01 (1H, m), 7.97 (1H, dd), 7.74 (1H, d), 7.61 (1H, s), 6.99-6.84 (3H, m), 4.99 (1H, q), 4.91 (1H, t), 4.86-4.74 (1H, m), 4.72 (1H, s), 4.60 (1H, d), 4.00-3.79 (3H, m), 3.60-3.46 (2H, m), 3.41-3.34 (2H, m), 2.35-2.24 (3H, m), 1.84 (2H, d), 1.61-1.37 (5H, m). LCMS: [M+H]+=568.

Example 687: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(4-fluoro-3-methylphenyl)-2-hydroxyethyl]propanamide

[1912] ##STR01764##

[1913] Prepared using a similar procedure to Example 590. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, 1H), 8.45 (s, 1H), 8.03 (s, 1H), 7.97 (dd, 1H), 7.74 (d, 1H), 7.61 (br. S, 1H), 7.19 (d, 1H), 7.14 (td, 1H), 7.07 (dd, 1H), 4.98 (q, 1H), 4.89 (t, 1H), 4.83-4.53 (m, 3H), 3.92-3.85 (m, 3H), 3.52 (t, 2H), 3.33-3.40 (m, 2H), 2.22 (d, 3H), 1.84 (d, 2H), 1.52 (qd, 2H), 1.42 (d, 3H). LCMS: [M+H]+=568.

Example 688: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(6-methoxypyridin-2-yl)ethyl]propanamide

[1914] ##STR01765##

[1915] TBTU (0.057 g, 0.176 mmol) was added to a mixture of (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (0.07 g, 0.168 mmol), (S)-2-amino-2-(6-methoxypyridin-2-yl)ethanol hydrochloride (0.036 g, 0.176 mmol) and DIPEA (0.062 ml, 0.353 mmol) in DMF (1 mL) and the mixture was stirred for 45 minutes. DIPEA (0.032 ml, 0.185 mmol) was added and the mixture was stirred for a further 45 minutes. The mixture was diluted with EtOAc and transferred into a separating funnel. NH.sub.4Cl was added and the product was extracted with EtOAc. The combined organic extracts were washed with water, NaHCO.sub.3, brine, dried (MgSO.sub.4) and absorbed on silica. The crude product was purified by chromatography (SiO.sub.2, 12 g column, 0-5% MeOH in DCM) to afford a colourless glass (64 mg). The product was re-purified by chromatography (SiO.sub.2, 12 g column, 0-2% MeOH in EtOAc), then by preparative HPLC (Varian, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water). Fractions were pooled and reduced to a small volume under vacuum. The residue was partitioned between EtOAc and NaHCO.sub.3 and the product was extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO.sub.4) and concentrated under vacuum to the title compound (0.028 g, 28.8%) as a white solid after trituration and evaporation from Et.sub.2O. 1H NMR (DMSO-d6) δ: 8.55-8.47 (m, 2H), 8.10 (d, 1H), 8.04 (dd, 1H), 7.81 (d, 1H), 7.72 (dd, 1H), 7.69 (s (br), 1H), 6.98 (d, 1H), 6.74 (d, 1H), 5.13 (td, 1H), 4.93 (t, 1H), 4.90-4.87 (m, 1H), 4.84 (d, 1H), 4.68 (d, 1H), 4.04-3.89 (m, 3H), 3.88 (s, 3H), 3.84-3.75 (m, 1H), 3.74-3.66 (m, 1H), 3.48-3.41 (m, 2H), 1.96-1.85 (m, 2H), 1.65-1.57 (m, 2H), 1.55 (d, 3H). LCMS: [M+H]+=567.

Example 689: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(2-fluoro-3-methylphenyl)-2-hydroxyethyl]propanamide

[1916] ##STR01766##

[1917] Prepared using a similar procedure to Example 685. 1H NMR (DMSO-d6, 400 MHz) δ 8.64 (1H, d), 8.45 (1H, s), 8.05-8.00 (1H, m), 7.97 (1H, dd), 7.74 (1H, d), 7.62 (1H, s), 7.23-7.11 (2H, m), 7.06 (1H, t), 5.18-5.06 (1H, m), 5.06-4.94 (2H, m), 4.80-4.52 (2H, m), 3.98-3.80 (3H, m), 3.59-3.45 (2H, m), 3.43-3.33 (2H, m), 2.22 (3H, d), 1.84 (2H, d), 1.60-1.46 (2H, m), 1.41 (3H, d). LCMS: [M+H]+=568.

Example 690: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(2-fluoro-5-methylphenyl)-2-hydroxyethyl]propanamide

[1918] ##STR01767##

[1919] Prepared using a similar procedure to Example 590. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, 1H), 8.45 (s, 1H), 8.04 (s, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.62 (br. S, 1H), 7.18 (d, 1H), 7.13-6.98 (m, 2H), 5.09 (q, 1H), 5.05-4.99 (m, 2H), 4.81-4.54 (m, 2H), 4.01-3.80 (m, 3H), 3.54 (q, 2H), 3.39 (t, 2H), 2.28 (s, 3H), 1.85 (d, 2H), 1.61-1.47 (m, 2H), 1.43 (d, 3H). LCMS: [M+H]+=568.

Example 691: (2R,3S)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-3-hydroxy-N-[(1R)-1-(3-methoxyphenyl)ethyl]butanamide

[1920] ##STR01768##

[1921] A solution of (2R,3S)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-3-hydroxy-N—((R)-1-(3-methoxyphenyl)ethyl)butanamide (150 mg, 0.239 mmol), oxan-4-amine (49.4 μl, 0.477 mmol) and DIPEA (108 μl, 0.621 mmol) in 1,4-dioxane (5 mL) was stirred at 80 C overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc (10 mL), washed successively with KHSO.sub.4 (1M, 10 mL), NaHCO.sub.3(10 mL) and brine (10 mL), dried (MgSO.sub.4) and concentrated in vacuo. Purification by chromatography (SiO.sub.2, 0-100% EtOAc in iso-hexanes) gave the title compound (58 mg, 40.6%) as a colourless glass. 1H NMR (DMSO, 400 MHz) δ 8.88 (1H, d), 8.45 (1H, s), 8.07-8.03 (1H, m), 7.97 (1H, dd), 7.77 (1H, d), 7.62 (1H, s), 7.22 (1H, dd), 6.95-6.88 (2H, m), 6.78 (1H, ddd), 5.03 (1H, d), 4.96-4.84 (2H, m), 4.77-4.69 (2H, m), 4.14 (1H, q), 3.97-3.83 (3H, m), 3.74 (3H, s), 3.42-3.35 (2H, m), 1.89-1.81 (2H, m), 1.60-1.49 (2H, m), 1.34 (3H, d), 1.03 (3H, d). LCMS: [M+H]+=580.

Example 692: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(6-methylpyridin-2-yl)ethyl]propanamide

[1922] ##STR01769##

[1923] TBTU (0.065 g, 0.202 mmol) was added to a mixture of (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (0.08 g, 0.192 mmol), ((S)-2-amino-2-(6-methylpyridin-2-yl)ethanol dihydrochloride (0.045 g, 0.202 mmol) and DIPEA (0.134 ml, 0.768 mmol) in DMF (1 mL) and the mixture was stirred for 45 minutes. The mixture was diluted with EtOAc and transferred into a separating funnel. NH.sub.4Cl was added and the product was extracted with EtOAc. The combined organic extracts were washed with water, NaHCO.sub.3, brine, dried (MgSO.sub.4) and absorbed on silica. The crude product was purified by chromatography (SiO.sub.2, 12 g column, DCM:MeOH gradient 100%-95%) to afford (R)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-2-hydroxy-1-(6-methylpyridin-2-yl)ethyl)propanamidea white solid (32 mg). The product was repurified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 10-40% MeCN in Water). The fractions were pooled, concentrated under vacuum and the residue was diluted with EtOAc and NaHCO.sub.3. The product was extracted with EtOAc and the combined organic extracts were washed with brine, dried (MgSO.sub.4) and concentrated under vacuum to afford the title compound (0.032 g, 30.0%) as a white solid after trituration and evaporation from Et.sub.2O. 1H NMR (DMSO-d6) δ: 8.52 (d, 1H), 8.45 (s, 1H), 8.04 (s (br), 1H), 7.98 (dd, 1H), 7.79-7.58 (m, 3H), 7.13 (dd, 2H), 5.05 (td, 1H), 4.91-4.80 (m, 2H), 4.77 (d, 1H), 4.62 (d, 1H), 4.00-3.82 (m, 3H), 3.77-3.58 (m, 2H), 3.44-3.36 (m, 2H), 2.43 (s, 3H), 1.89-1.80 (m, 2H), 1.59-1.50 (m, 2H), 1.48 (d, 3H). LCMS: [M+H]+=551.

Example 693: 2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-3-hydroxy-N-[(1R)-1-phenylethyl]propanamide

[1924] ##STR01770##

[1925] Prepared using a similar procedure to Example 120. In this case, the product was purified by preparative HPLC (acidic). The product was obtained as a 3:2 mixture of diastereoisomers. 1H NMR (CDCl3, 400 MHz) δ 8.33 (1H, s), 8.28 (1H, d), 8.00 (1H, m), 7.58 (0.6H, d), 7.51 (0.4H, d), 7.36-7.28 (2H, m), 7.16-7.09 (2.6H, m), 7.04 (0.4H, d), 5.23 (1H, d), 5.05 (1H, p), 4.93 (0.4H, t), 4.90 (0.6H, t), 4.84-4.66 (1.6H, m), 4.42 (0.4H, d), 4.29-4.18 (1H, m), 4.11-3.95 (4H, m), 3.77 (1H, bs), 3.54 (2H, td), 2.04 (2H, m), 1.57 (2H, m), 1.47 (1H, d), 1.43 (2H, d). (exchangeable OH not observed). LC-MS: [M+H]+=536.

Examples 694 and 695: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-3-hydroxy-N-[(1R)-1-(3-methoxyphenyl)ethyl]propanamide and (2S)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-3-hydroxy-N-[(1R)-1-(3-methoxyphenyl)ethyl]propanamide

[1926] ##STR01771##

[1927] 3-((tert-butyldimethylsilyl)oxy)-2-(6-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((R)-1-(3-methoxyphenyl)ethyl)propanamide (Preparation 413, 260 mg, 0.382 mmol) was taken up in TFA (2 ml), allowed to stand for 2 minutes and evaporated. The residue was basified with NaHCO.sub.3 (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (10 ml), dried (Na.sub.2SO.sub.4) and evaporated to give a viscous yellow oil. Purification by chromatography (SiO.sub.2, 12 g column, 50-100% EtOAc in isohexane) afforded (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-3-hydroxy-N-[(1R)-1-(3-methoxyphenyl)ethyl]propanamide (55 mg, 25.4%) (A) and (2S)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-3-hydroxy-N-[(1R)-1-(3-methoxyphenyl)ethyl]propanamide (19 mg, 8.78%) (B) as white powders. A: 1H NMR (DMSO-d6) δ: 8.69 (d, 1H), 8.45 (s, 1H), 8.03 (d, 1H), 7.97 (dd, 1H), 7.76 (d, 1H), 7.62 (s (br), 1H), 7.23 (dd, 1H), 6.91-6.83 (m, 2H), 6.78 (ddd, 1H), 5.13 (t, 1H), 4.98-4.86 (m, 2H), 4.81 (d, 1H), 4.64 (d, 1H), 3.97-3.77 (m, 5H), 3.75 (s, 3H), 3.41-3.34 (m, 2H), 1.91-1.77 (m, 2H), 1.60-1.43 (m, 2H), 1.34 (d, 3H). LCMS: [M+H]+=566. B: 1H NMR (DMSO-d6) δ: 8.68 (d, 1H), 8.44 (s, 1H), 8.01 (d, 1H), 7.96 (dd, 1H), 7.74 (d, 1H), 7.61 (s (br), 1H), 7.18 (dd, 1H), 6.88-6.82 (m, 2H), 6.75 (ddd, 1H), 5.13 (s (br), 1H), 4.96-4.83 (m, 2H), 4.75 (d, 1H), 4.64 (d, 1H), 3.98-3.78 (m, 5H), 3.68 (s, 3H), 3.49-3.38 (m, 2H), 1.90-1.76 (m, 2H), 1.60-1.43 (m, 2H), 1.34 (d, 3H). LCMS: [M+H]+=566.

Example 696: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-4-hydroxy-N-[(1R)-1-(3-methoxyphenyl)ethyl]butanamide

[1928] ##STR01772##

[1929] A mixture of (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)-4-hydroxy-N—((R)-1-(3-methoxyphenyl)ethyl)butanamide (Preparation 403, 0.023 g, 0.043 mmol), oxan-4-amine (0.010 mL, 0.097 mmol) and DIPEA (0.020 mL, 0.115 mmol) in 1,4-dioxane (2.0 mL, 23.38 mmol) was heated to 90° C. overnight. After 16.5 h further oxan-4-amine (0.010 mL, 0.097 mmol) and DIPEA (0.020 mL, 0.115 mmol) were added and the mixture was heated to 90° C. for 41h. The reaction mixture was cooled to room temperature and then partitioned between EtOAc (30 mL) and NH.sub.4Cl (20 mL), The layers were separated and the organic fraction was washed with NH.sub.4Cl (20 mL), water (20 mL) and brine (3×20 mL), then dried (MgSO.sub.4), filtered and concentrated under reduced pressure to afford the crude product (26 mg) as a pale yellow solid. The crude product was purified by chromatography (SiO.sub.2, 4 g column, 0-10% MeOH in DCM) to afford the title compound butanamide (0.015 g, 58.5%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.70 (1H, d), 8.45 (1H, s), 8.03 (1H, t), 7.97 (1H, dd), 7.75 (1H, d), 7.62 (1H, br. s), 7.24 (1H, t), 6.91-6.87 (2H, m), 6.80 (1H, ddd), 4.99 (1H, dd), 4.88 (1H, p), 4.81 (1H, d), 4.65-4.51 (2H, m), 3.90 (3H, dd), 3.96-3.85 (3H, m), 3.44-3.34 (4H, m), 2.06 (1H, dq), 2.01-1.88 (1H, m), 1.85 (2H, br. d), 1.53 (2H, qd), 1.34 (3H, d). LCMS: [M+H]+=580.

Example 697: (2R)-2-(6-{5-chloro-2-[(2-methyl-2H-1,2,3-triazol-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide

[1930] ##STR01773##

Method A:

[1931] A stirred solution of (R)-2-(6-(5-chloro-2-((2-methyl-2H-1,2,3-triazol-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (Preparation 417, 2.2 g, 4.78 mmol), (S)-2-amino-2-(3-fluoro-5-methoxyphenyl)ethanol hydrochloride (1.167 g, 5.26 mmol) and DIPEA (2.76 ml, 15.79 mmol) in dry DMF (5 ml) was treated with TBTU (1.997 g, 6.22 mmol). The solution was stirred at room temperature for 30 minutes and the resulting yellow solution was partitioned between DCM ((200 ml) and water (200 ml). The organic phase was collected and was successively washed with 10% aqueous NaHCO.sub.3 (100 ml), 1M HCl (100 ml) and water (2×100 ml), dried (MgSO.sub.4) and concentrated under vacuum. The residue was dissolved in DCM and purified by chromatography (SiO.sub.2, 80 g column, 0-100% EtOAc in heptane). The product was then triturated with diethyl ether/heptane and the resulting precipitate was filtered, then dried in a dessicator at 56° C. overnight. The solid was dissolved in a mixture of DCM, ethyl acetate and acetonitrile and the solution concentrated to dryness. The residue was triturated with diethyl ether and the resulting precipitate was filtered and dried under vacuum at 60° C. to afford the title compound (2.2 g, 79%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.69 (s, 1H), 8.58 (d, 1H), 8.16-8.09 (m, 1H), 8.07 (dd, 1H), 7.92 (s, 1H), 7.81 (d, 1H), 6.78-6.66 (m, 3H), 5.02 (q, 1H), 4.93 (t, 1H), 4.88-4.74 (m, 2H), 4.64 (d, 1H), 4.07 (s, 3H), 3.77 (s, 3H), 3.59-3.51 (m, 2H), 1.46 (d, 3H). LCMS: [M+H]+=581.

Procedure B:

[1932] A mixture of (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (Preparation 349) (185 mg, 0.525 mmol), 2-methyl-2H-1,2,3-triazol-4-amine hydrochloride (85 mg, 0.630 mmol) and cesium carbonate (455 mg, 1.397 mmol) was suspended in dry DMF and the suspension degassed by bubbling a stream of nitrogen through for 5 minutes. t-BuBrettPhos Allyl (Pd-175) (24.62 mg, 0.032 mmol) was added and the mixture heated at 70° C. under microwave radiation for 2 h. The mixture was cooled to room temperature and treated with DIPEA (0.212 ml, 1.211 mmol) and (S)-2-amino-2-(3-fluoro-5-methoxyphenyl)ethanol hydrochloride (163 mg, 0.734 mmol). After stirring for 5 minutes at room temperature, TBTU (177 mg, 0.551 mmol) was added and the mixture stirred a further 1.5 h. The suspension was diluted with DCM (50 ml) and the mixture washed with 2M NaHCO.sub.3 (20 ml), 10% aqueous citric acid (20 ml) and water (20 ml). The organic phase was collected, dried (MgSO.sub.4) and concentrated under vacuum. The crude product was purified purified by chromatography (SiO.sub.2, 12 g column, 0-100% EtOAc in isohexane) to afford the title compound (55 mg, 25.8%) as a cream coloured solid.

Example 698: (2R)-2-(6-{5-Chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(2-methoxypyridin-4-yl)ethyl]propanamide

[1933] ##STR01774##

[1934] TBTU (0.095 g, 0.29 mmol) was added to a mixture of (2S)-2-amino-2-(2-methoxypyridin-4-yl)ethanol HCl (0.047 g, 0.23 mmol), (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)propanoic acid (Preparation 99, 0.080 g, 0.19 mmol) and DIPEA (0.0101 mL, 0.58 mmol) in DCM (1.9 mL). The mixture was stirred for 2 hours. The reaction was quenched by diluting with water and extracting with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered, and concentrated to dryness. The residue was purified by biotage (EtOAc/0-15% MeOH) to yield the title compound as a colourless solid. 1H NMR (400 MHz, Me-d3-OD): 8.67-8.51 (1H, m), 8.36 (1H, s), 8.24 (1H, s), 8.12-8.03 (2H, m), 7.73 (1H, d), 6.96 (1H, dd), 6.80 (1H, s), 5.11 (1H, q), 4.98-4.91 (1H, m), 4.85 (1H, d), 4.71 (1H, d), 4.11-4.03 (1H, m), 4.02-3.96 (2H, m), 3.92 (3H, s), 3.84-3.72 (2H, m), 3.55 (2H, td), 2.02 (3H, d), 1.72-1.55 (5H, m). [M+H]+=567.

Example 699: (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[6-(4-methylpiperazin-1-yl)pyridin-2-yl]ethyl]propanamide

[1935] ##STR01775##

[1936] Prepared from (1R)-1-[6-(4-Methylpiperazin-1-yl)pyridin-2-yl]ethan-1-amine (Preparation 418) and (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)propanoic acid (Preparation 99) using a similar procedure to Example 2. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (1H, s), 8.36 (1H, d), 8.05 (1H, s), 7.99 (1H, dd), 7.76 (1H, d), 7.58 (1H, d), 7.49 (1H, dd), 6.66 (1H, d), 6.59 (1H, d), 4.98 (1H, q), 4.84-4.70 (2H, m), 4.63 (1H, d), 3.99-3.83 (3H, m), 3.46 (4H, t), 2.39-2.33 (4H, m), 2.20 (3H, s), 1.85 (2H, d), 1.61-1.43 (5H, m), 1.34 (3H, d).. LCMS: [M+H]+=619.

Example 700: 2-(5-(5-chloro-2-((oxan-4-yl)amino)pyrimidin-4-yl)-1-(2-hydroxyethyl)-3-oxoisoindolin-2-yl)-N—((R)-1-(3-methoxyphenyl)ethyl)acetamide

[1937] ##STR01776##

[1938] Prepared using a similar procedure to Example 601. LC-MS: [M+H]+=580 (see also Preparation 338).

Example 701: (R)-2-(6-(5-chloro-2-((2-methoxypyridin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propanamide

[1939] ##STR01777##

[1940] Procedure A:

[1941] TBTU (3.19 g, 9.95 mmol) was added to a solution of (R)-2-(6-(5-chloro-2-((2-methoxypyridin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (3.4 g, 7.65 mmol), (S)-2-amino-2-(3-fluoro-5-methoxyphenyl)ethanol hydrochloride (2.035 g, 9.18 mmol), and DIPEA (4.14 ml, 23.72 mmol) in anhydrous DMF (30 mL) at room temperature and the mixture was stirred for 1h. Saturated aqueous NH.sub.4Cl (200 mL) was added and the mixture was stirred until formation of a cream coloured precipitate. The resulting suspension was diluted with water (100 mL) and the precipitate filtered, washed with water and semi-dried in a vacuum oven to give a cream coloured solid. The solid was taken up in EtOAc and the mixture washed with NaHCO.sub.3 (200 mL). The phases were separated and the aqueous layer extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (3×100 mL), dried (MgSO.sub.4), filtered and evaporated to give a pale yellow foam, which was dried in a vacuum oven at 50° C. overnight. The solid was triturated with Et.sub.2O and the resulting precipitate was collected by filtration to give a light brown solid which was dried in the desiccator at 45° C. overnight to give 4.5g of a light brown solid (93%). A second batch (3 g) prepared following the same procedure was combined and the mixture was taken up in EtOAc (600 mL), washed with brine (4×200 mL), dried (MgSO.sub.4), filtered and evaporated at 45° C. to give a solid (7.75 g). The solid was triturated with Et.sub.2O (200 mL) and the resulting precipitate was filtered, washed with excess Et.sub.2O and left to dry under reduced pressure to give a wet solid, which was further dried in the desiccator at 45° C. overnight. The product was then suspended in MeCN (3×50 mL) and the mixture was concentrated under vacuum. The resulting solid was then left to dry in the desiccator at 45° C. to give the title compound (6.55 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ 10.40 (br s, 1H), 8.79 (s, 1H), 8.58 (d, 1H), 8.13 (dd, 1H), 8.05 (dd, 1H), 7.97 (d, 1H), 7.82 (dd, 1H), 7.40-7.34 (m, 1H), 7.26 (dd, 1H), 6.78-6.65 (m, 3H), 5.01 (q, 1H), 4.93 (t, 1H), 4.87-4.78 (m, 1H), 4.79 (d, 1H), 4.64 (d, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.59-3.52 (m, 2H), 1.46 (d, 3H). LCMS: [M+H]+=607.

Procedure B:

[1942] Pd(PPh.sub.3).sub.4 (48.9 mg, 0.042 mmol) was added to a degassed (3×using nitrogen) suspension of (R)—N—((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)-2-(1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)propanamide (422 mg, 0.847 mmol), 4,5-dichloro-N-(2-methoxypyridin-4-yl)pyrimidin-2-amine (270 mg, 0.847 mmol) and 2M Na.sub.2CO.sub.3 (0.847 mL, 1.693 mmol) in 1,4-dioxane (5 mL, 58.5 mmol). The reaction was further degassed, then stirred at 85° C. for 1.5 h under nitrogen. The mixture was allowed to cool to room temperature and was diluted with water (30 mL). The crude product was extracted with EtOAc (2×30 mL) and the combined organic extracts were washed with 1: 1 water: brine (40 mL), brine (30 mL), dried (MgSO.sub.4), filtered then concentrated in vacuo to leave a brown foam (505 mg). The crude product was purified by chromatography (SiO.sub.2, 10-100% EtOAc in iso-hexane) to afford a pale yellow solid (195 mg). The product was re-purified by chromatography (SiO.sub.2, 0-4% MeOH in DCM), then re-purified by chromatography (SiO.sub.2, 0-100% THF in DCM) to afford a white solid (39 mg). The mixed fractions were further purified by chromatography (RP Flash C18, 10-80% solution of 0.1% formic acid in MeCN: 0.1% formic acid in water) to afford a pale brown solid. The batches were combined and re-purified by chromatography (SiO.sub.2, 0-50% (10% MeOH in DCM) in DCM) to afford the tile compound (72 mg, 13.59%) as a white solid.

Example 702: (R)-2-(6-(5-chloro-2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-1-(6-(dimethylamino)pyridin-2-yl)-2-hydroxyethyl)propanamide

[1943] ##STR01778##

Procedure A:

[1944] DMF (109 mL) was added to a 500 mL round bottom flask containing (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-1-oxoisoindolin-2-yl)propanoic acid (4.4 g, 10.87 mmol), 2-methylpyrimidin-4-amine (1.542 g, 14.13 mmol) and cesium carbonate (7.44 g, 22.83 mmol). The system was evacuated and back-filled with nitrogen (×3), heated to 75° C. and stirred for 10 minutes. XantPhos Allyl (Pd-177) (0.414 g, 0.543 mmol) was added and the system evacuated and back-filled with nitrogen (×3), The mixture was stirred at 75° C. for 2.5 h. After cooling to room temperature, (S)-2-amino-2-(6-(dimethylamino)pyridin-2-yl)ethanol (2.257 g, 11.96 mmol) was added in DMF (27 mL) followed by N-methylmorpholine (5.38 ml, 48.9 mmol). The mixture was ice-cooled and TBTU (5.76 g, 17.93 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with Et.sub.2O (350 mL) and the resulting precipitate filtered in vacuo, washed with Et.sub.2O (4×100 mL) to give a dark yellow solid (16.5 g). The solid was suspended in water (50 mL) and filtered in vacuo, then washed with water (4×50 mL) and dried to give a lighter yellow solid (14.05 g). The solid was partially dissolved in 10% MeOH/DCM (150 mL) and the resulting suspension filtered and washed with 10% MeOH/DCM (2×100 mL). The filtrate was adsorbed onto silica and purified by chromatography (SiO.sub.2, 0-10% (0.7 M NH.sub.3/MeOH) in DCM) to afford the title compound (3.63 g, 56.2% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.77 (br s, 1H), 8.83 (s, 1H), 8.47 (d, 1H), 8.38 (d, 1H), 8.19-8.10 (m, 1H), 8.12-8.00 (m, 2H), 7.82 (d, 1H), 7.51-7.39 (m, 1H), 6.50 (dd, 2H), 5.06 (q, 1H), 4.95-4.58 (m, 4H), 3.77-3.64 (m, 1H), 3.64-3.54 (m, 1H), 2.97 (s, 6H), 2.51 (s, 3H), 1.49 (d, 3H). LCMS: [M+H]+=588.

[1945] Note: Alternative catalysts systems (Xanpthos/Pd(OAc).sub.2, Xantphos Pd G3) can be used in first step.

Procedure B:

[1946] A microwave tube was charged with 4,5-dichloro-N-(2-methylpyrimidin-4-yl)pyrimidin-2-amine (124 mg, 0.485 mmol) and (R)—N—((S)-1-(6-(dimethylamino)pyridin-2-yl)-2-hydroxyethyl)-2-(1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)propanamide (200 mg, 0.405 mmol). 1,4-dioxane (2 mL) and sodium carbonate (2 M aqueous) (0.405 mL, 0.809 mmol) were added and the mixture was degassed for 5 minutes before addition of Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (16.52 mg, 0.020 mmol). The mixture was heated to 80° C. for 1.5 h under nitrogen, then cooled to room temperature and diluted with water (10 mL). The precipitate was isolated by filtration and washed with water (30 mL). The solid was dissolved in DCM/MeOH (9:1, 100 mL) and passed through a phase separator then absorbed on silica gel. The crude product was purified by chromatography (SiO.sub.2, 0-10% (0.7 M Ammonia/MeOH) in DCM) to afford the title compound (168 mg, 68.5%) as an off-white solid.

Example 702a: (R)-2-(6-(5-chloro-2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-1-(6-(dimethylamino)pyridin-2-yl)-2-hydroxyethyl)propanamide hydrochloride salt

[1947] ##STR01779##

[1948] To a stirred solution of the product from Example 702 (154 mg) in THF (8 mL), was added HCl (2N in Et.sub.2O, 127 μL, 1 mol. eq.). The resulting precipitate was collected by filtration and washed successively with THF and EtOAc. The title compound was obtained as a white solid (55 mg). 1H NMR (400 MHz, DMSO-d6): 11.72 (1H, br s), 8.95 (1H, s), 8.64 (1H, d), 8.48 (1H, br s), 8.24 (1H, d), 8.17 (1H, s), 8.10 (1H, dd), 7.84 (1H, d), 7.58 (1H, br s), 6.63 (2H, m), 5.06 (1H, q), 4.94-4.75 (2H, m), 4.68 (1H, d), 3.76-3.58 (3H, m), 3.05 (6H, s), 2.63 (3H, s), 1.51 (3H, d). LCMS: [M+H]+=588.

Example 702b: (R)-2-(6-(5-chloro-2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-1-(6-(dimethylamino)pyridin-2-yl)-2-hydroxyethyl)propanamide methanesulfonate salt

[1949] ##STR01780##

[1950] To a stirred solution of the product from Example 702 (152 mg) in THF (8 mL), was added methanesulfonic acid (24.8 mg, 1 mol. eq.). The resulting precipitate was collected by filtration and washed successively with THF and EtOAc. The title compound was obtained as a white solid (106 mg). 1H NMR (400 MHz, DMSO-d6): 12.06 (1H, br s), 9.00 (1H, s), 8.71 (1H, d), 8.59 (1H, br s), 8.31 (1H, d), 8.18 (1H, s), 8.11 (1H, dd), 7.85 (1H, d), 7.72 (1H, br s), 6.83 (1H, br s), 6.70 (1H, d), 5.11-4.94 (2H, m), 4.79 (1H, d), 4.68 (1H, d), 3.79-3.63 (2H, m), 3.12 (6H, s), 2.66 (3H, s), 2.33 (5H, s), 1.51 (3H, d). LCMS: [M+H]+=588.

Examples 703-1123

[1951] The following Examples were prepared using procedures analogous to those described herein for Examples 1-702.

TABLE-US-00051 MS Data [M + H].sup.+ unless Example Structure Name specified 703 [01781] (2R)-2-[3-(5-chloro-2-{[trans-4- hydroxycyclohexyl]amino}pyrimidin-4- yl)-5-oxo-5H,6H,7H-pyrrolo[3,4- b]pyridin-6-yl]-N-[(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 565 No Example 704 705 [01782] (2R)-2-[6-(5-chloro-2-{[(1S,3S)-3- hydroxycyclopentyl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1S)-2-hydroxy-1-(3- methoxyphenyl)ethyl]propanamide 566 706 [01783] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-2-{1-[(1S)-2- hydroxy-1-phenylethyl]-2- oxopyrrolidin-3-yl}-2,3-dihydro-1H- isoindol-1-one 548 707 [01784] (2R)-2-[6-(5-chloro-2-{[(2S)-1- hydroxypropan-2-yl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-3-hydroxy-N-[1-(3- methylphenyl)cyclopropyl]propanamide 536 708 [01785] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-3-hydroxy- N-[1-(3-methylphenyl)cyclopropyl]- propanamide 562 709 [01786] 2-(1-benzyl-2-oxopyrrolidin-3-yl)-6-{5- chloro-2-[(oxan-4-yl)amino]pyrimidin- 4-yl}-2,3-dihydro-1H-isoindol-1-one 518 710 There is no Example 710 711 [01787] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-4-methoxy-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]acetamide 566 712 [01788] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-4- (dimethylamino)-N-[(1R)-1-(3- methoxyphenyl)ethyl]butanamide 607 713 [01789] 2-[6-(5-chloro-2-{[(2S)-1- hydroxypropan-2-yl]amino}pyrimidin- 4-yl)-4-methoxy-1-oxo-2,3-dihydro- 1H-isoindol-2-yl]-N-[(1S)-2-hydroxy-1- (3-methylphenyl)ethyl]acetamide 540 714 [01790] N-[(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]-2-(6-{5-methyl-2- [(oxan-4-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2- yl)acetamide 530 715 [01791] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(6- cyclopropylpyridin-2-yl)-2- hydroxyethyl]acetamide 563 716 [01792] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(6- cyclopropylpyridin-3-yl)-2- hydroxyethyl]acetamide 561 [M − H].sup.− 717 [01793] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(5- cyclopropylpyridin-2-yl)-2- hydroxyethyl]acetamide 563 718 [01794] N-[1-(1-benzyl-1H-pyrazol-4-yl)ethyl]- 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)acetamide 586 719 [01795] (2R)-N-[(1S)-2-hydroxy-1-(3- methoxyphenyl)ethyl]-2-(6-{2-[(1- methyl-1H-pyrazol-5- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)propanamide 528 720 [01796] (2R)-N-[(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]-2-(6-{2-[(1- methyl-1H-pyrazol-5- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)propanamide 510 [M − H].sup.− 721 [01797] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(quinolin-7- yl)ethyl]acetamide 573 722 [01798] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(2-methoxypyridin-4- yl)ethyl]acetamide 553 723 [01799] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[1-(1- phenyl-1H-pyrazol-4- yl)ethyl]acetamide 572 724 [01800] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-{1-[5- (trifluoromethyl)-1,2,4-oxadiazol-3- yl]ethyl}acetamide 566 725 [01801] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-(3,3- difluoro-1-phenylpropyl)acetamide 556 726 [01802] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-[4-(pyrimidin-5- yl)phenyl]ethyl]acetamide 600 727 [01803] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[4- (pyrimidin-2-yl)phenyl]ethyl]acetamide 584 728 [01804] (2R)-2-(6-{5-chloro-2-[(1,5-dimethyl- 1H-pyrazol-4-yl)amino]pyrimid in-4-yl}- 1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 560 729 No Example 729 730 [01805] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-[4-(1-methylpiperidin-4- yl)phenyl]ethyl]acetamide 619 731 [01806] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[4- (5-cyclopropylpyrimidin-2- yl)phenyl]ethyl]acetamide 624 732 [01807] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {4[4-(hydroxymethyl)pyrimidin-2- yl]phenyl}ethyl]acetamide 614 733 [01808] 2-(6-{5-chloro-2-[(3-methyloxetan-3- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]acetamide 521 [M − H].sup.− 734 [01809] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-4-methoxy-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1R)-1-(3- methoxyphenyl)ethyl]propanamide 580 735 [01810] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- pyrazol-5-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(3- methoxyphenyl)ethyl]propanamide 562 736 No Example 736 737 [01811] (2R)-2-(6-{5-chloro-2-[(1-methyl-2- oxopiperidin-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 577 738 [01812] (2R)-2-(6-{5-chloro-2-[(1-methyl-6- oxopiperidin-3-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 577 739 No Example 739 740 [01813] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- pyrazol-4-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 546 741 [01814] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[1- (pyridin-2-yl)cyclopropyl]acetamide 519 742 [01815] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-[6-(pyrrolidin-1-yl)pyridin-2- yl]ethyl]acetamide 592 743 [01816] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]acetamide 621 744 [01817] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N- cyclopentylpropanamide 484 745 [01818] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-(1- methylcyclopentyl)propanamide 498 746 [01819] (2R)-2-(6-{5-chloro-2-[(1-methyl-5- oxopyrrolidin-3-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 563 747 [01820] (2R)-2-(6-{5-chloro-2-[(1,3,5-trimethyl- 1H-pyrazol-4-yl)amino]pyrimidin-4-yl}- 1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 574 748 [01821] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-(1- phenylpiperidin-3-yl)acetamide 561 749 [01822] (2R)-N-benzyl-2-(6-{5-chloro-2- [(oxan-4-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2- yl)propanamide 506 750 [01823] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3-methylphenyl)ethyl]-2- methylpropanamide 564 751 [01824] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-(3,3- difluoro-1-phenylpropyl)acetamide Stereoisomer 1 556 752 [01825] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-(3,3- difluoro-1-phenylpropyl)acetamide Stereoisomer 2 556 753 [01826] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 547 754 [01827] 2-(5-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-[2- (dimethylamino)ethyl]-3-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- (3-methoxyphenyl)ethyl]acetamide 607 755 [01828] (2R)-2-{6-[5-chloro-2- (phenylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-[(1S)- 2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 542 756 [01829] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3-methylphenyl)ethyl]-3- (1H-imidazol-4-yl)propanamide 616 757 [01830] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S,2S)- 2-hydroxy-1-(3- methoxyphenyl)propyl]propanamide 580 758 [01831] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-{3- [(dimethylamino)methyl]phenyl}-2- hydroxyethyl]acetamide 579 759 [01832] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- (3-methylphenyl)ethyl]propanamide 534 760 No Example 760 761 [01833] 1-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]cyclopropane-1- carboxamide 562 762 [01834] 1-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- (3- methoxyphenyl)ethyl]cyclopropane-1- carboxamide 562 763 [01835] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-{[6- (dimethylamino)pyridin-2- yl]methyl}acetamide 550 764 [01836] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(6- methoxypyridin-2-yl)methyl]acetamide 537 765 [01837] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyridin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]propanamide 549 766 [01838] (2R)-2-[6-(5-chloro-2-{[1- (dimethylamino)-3-hydroxypropan-2- yl]amino}pyrimidin-4-yl)-1-oxo-2,3- dihydro-1H-isoindol-2-yl]-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]propanamide 567 767 [01839] 2-(5-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1[2- (methylamino)ethyl]-3-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- (3-methoxyphenyl)ethyl]acetamide 593 768 [01840] (2R)-2-(6-{5-chloro-2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 558 769 [01841] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S,2S)- 2-hydroxy-1-(3- methylphenyl)propyl]propanamide 564 770 [01842] (2R)-2-(6-{5-chloro-2-[(1,3-dimethyl- 1H-pyrazol-4-yl)amino]pyrimidin-4-yl}- 1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 560 771 [01843] (2R)-2-(6-{5-chloro-2-[(1,4-oxazepan- 6-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]propanamide 565 772 No Example 772 773 [01844] (2R)-2-[6-(5-chloro-2- acetamidopyrimidin-4-yl)-1-oxo-2,3- dihydro-1H-isoindol-2-yl]-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]propanamide 508 774 [01845] (2R)-2-(6-{5-chloro-2-[(1,1-dioxo-1λ.sup.6- thian-4-yl)amino]pyrimidin-4-yl}-1-oxo- 2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)- 2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 598 775 [01846] 2-(6-}5-chloro-2-[(1-oxo-1λ.sup.4-thian-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]acetamide 568 776 [01847] 2-(6-{5-chloro-2-[(1-methyl-6-oxo-1,6- dihydropyridin-3-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]acetamide 559 777 [01848] (2R)-2-(3-{5-chloro-2-[(oxan-4- yl)amino]pyridin-4-yl}-5-oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)- N-[(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 550 778 [01849] 2-(5-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-[2- (dimethylamino)ethyl]-3-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- (3-methoxyphenyl)ethyl]acetamide Stereoisomer 1 607 779 [01850] 2-(5-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-[2- (dimethylamino)ethyl]-3-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- (3-methoxyphenyl)ethyl]acetamide Stereoisomer 2 607 780 [01851] 2-(5-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1,1-dimethyl- 3-oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]acetamide 564 781 [01852] (2R)-2-(6-}5-chloro-2-[(1-methyl-1H- pyrazol-5-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 546 782 [01853] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1[6- (dimethylamino)pyridin-2-yl]-2- hydroxyethyl]propanamide 580 783 [01854] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[6- (dimethylamino)pyridin-2- yl]ethyl]propanamide 564 784 [01855] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[6- (dimethylamino)pyridin-2- yl]ethyl]acetamide 550 [M − H].sup.+ 785 [01856] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- (3-methoxyphenyl)ethyl]-4- (methylamino)butanamide 593 786 [01857] 2-(6-{5-chloro-2-[(5-methyl-1,3,4- thiadiazol-2-yl)amino]pyrimidin-4-yl}- 1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]acetamide 550 787 [01858] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyridin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(6-methylpyridin-2- yl)ethyl]propanamide 550 788 [01859] 2-(6-{5-chloro-2-[(2-methylpyridin-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]acetamide 543 789 [01860] 2-(6-{5-chloro-2-[(6-methylpyrimidin- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]acetamide 544 790 [01861] (2R)-2-{6-[5-chloro-2- (phenylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-[(1S)- 2-hydroxy-1-(6-methylpyridin-2- yl)ethyl]propanamide 543 791 [01862] (2R)-2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-[(1S)- 2-hydroxy-1-(6-methylpyridin-2- yl)ethyl]propanamide 481 792 [01863] (2R)-2-(6-{5-chloro-2-[(propan-2- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2 hydroxy-1-(6-methylpyridin-2- yl)ethyl]propanamide 509 793 [01864] 2-(6-{5-chloro-2-[(1-methyl-1H- imidazol-2-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]acetamide 532 794 [01865] (2S)-2-(6-{5-chloro-2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 558 795 [01866] (2S)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 547 796 [01867] (2R)-2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-[(1S)- 2-hydroxy-1-(6-methoxypyridin-2- yl)ethyl]propanamide 497 797 [01868] (2R)-2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-[(1R)- 1-(6-methylpyridin-2- yl)ethyl]propanamide 465 798 [01869] (2R)-2-(6-{5-chloro-2-[(propan-2- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(6-methoxypyridin-2- yl)ethyl]propanamide 525 799 [01870] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- pyrazol-4-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-(3-fluoro-5-methylphenyl)-2- hydroxyethyl]propanamide 564 800 [01871] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- pyrazol-4-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(6-methylpyridin-2- yl)ethyl]propanamide 547 801 [01872] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- pyrazol-4-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1R)-1-(6-methylpyridin-2- yl)ethyl]propanamide 531 802 [01873] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3-methoxyphenyl)-2- methylpropyl]acetamide 580 803 [01874] (2R)-2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-[(1S)- 1-[6-(dimethylamino)pyridin-2-yl]-2- hydroxyethyl]propanamide 510 804 [01875] (2R)-2-(6-{5-chloro-2-[(2-ethyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]propanamide 561 805 [01876] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(3-fluoro-5- methylphenyl)-2- hydroxyethyl]propanamide 565 806 [01877] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-[3- (trifluoromethyl)phenyl]ethyl]propanamide 599 807 No Example 807 808 [01878] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- pyrazol-4-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-[6-(dimethylamino)pyridin-2- yl]-2-hydroxyethyl]propanamide 576 809 [01879] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- pyrazol-4-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-(3-fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 580 810 [01880] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- pyrazol-5-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-(3-fluoro-5-methylphenyl)-2- hydroxyethyl]propanamide 564 811 [01881] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- pyrazol-5-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-(3-fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 580 812 [01882] (2R)-2-(6-{5-chloro-2-[(1,5-dimethyl- 1H-pyrazol-4-yl)amino]pyrimidin-4-yl}- 1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-[6-(dimethylamino)pyridin-2- yl]-2-hydroxyethyl]propanamide 590 813 [01883] (2R)-2-[6-(5-chloro-2-{[(1R,3R)-3- hydroxycyclopentyl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]N-[(1R)-1-(6-methylpyridin-2- yl)ethyl]propanamide 535 814 [01884] (2R)-2-[6-(5-chloro-2-{[(1R,3R)-3- hydroxycyclopentyl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-(1S)-2-hydroxy-1-(6- methylpyridin-2-yl)ethyl]propanamide 551 815 [01885] (2R)-2-[6-(5-chloro-2-{[(1R,3R)-3- hydroxycyclopentyl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1S)-1[6- (dimethylamino)pyridin-2-yl]-2- hydroxyethyl]propanamide 580 816 [01886] (2R)-2-{6[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-[(1R)- 1-[6-(dimethylamino)pyridin-2- yl]ethyl]propanamide 494 817 [01887] (2R)-2-{6-[5-chloro-2- (methylamino)pyrimid in-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N- [(1S,2S)-1-(2-fluoro-5-methylphenyl)- 2-hydroxybutyl]propanamide 526 818 [01888] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-2-methyl-1-(3- methylphenyl)propyl]propanamide 578 819 [01889] (2R)-2-[6-(5-chloro-2-{[(1R,3R)-3- hydroxycyclopentyl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1R)-1-[6- (dimethylamino)pyridin-2- yl]ethyl]propanamide 564 820 [01890] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[2- (dimethylamino)pyrimidin-4- yl]ethyl]propanamide 565 821 [01891] 2-(5-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-[2- (methylamino)ethyl]-3-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- (3-methoxyphenyl)ethyl]acetamide Stereoisomer 1 593 822 [01892] 2-(5-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-[2- (methylamino)ethyl]-3-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- (3-methoxyphenyl)ethyl]acetamide Stereoisomer 2 593 823 [01893] (2R)-2-(6-{5-chloro-2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(3-fluoro-5- methylphenyl)-2- hydroxyethyl]propanamide 576 824 [01894] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- pyrazol-5-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-[6-(dimethylamino)pyridin-2- yl]-2-hydroxyethyl]propanamide 576 825 [01895] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- pyrazol-4-yl)amino]pyrimidin-4-yl|-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1R)-1-[6-(dimethylamino)pyridin-2- yl]ethyl]propanamide 560 826 [01896] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3-methoxyphenyl)-2- methylpropyl]propanamide 594 827 [01897] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-2-methyl-1-(3- methylphenyl)propyl]acetamide 564 828 [01898] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[2- (dimethylamino)pyridin-4-yl]-2- hydroxyethyl]propanamide 580 829 [01899] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- (5-chloropyridin-2-yl)-2- hydroxyethyl]propanamide 571 830 [01900] (2R)-2-(6-{5-chloro-2-[(2-rnethyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-(6- methylpyridin-2-yl)ethyl]propanamide 548 831 [01901] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-[6- (dimethylamino)pyridin-2- yl]ethyl]propanamide 561 832 [01902] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-(6-methylpyridin-2- yl)ethyl]propanamide 532 833 [01903] (2R)-2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-[(1S)- 2-hydroxy-1-[3- (trifluoromethyl)phenyl]ethyl]propanamide 534 834 [01904] (2R)-2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-[(1S)- 1-(3-fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 514 835 [01905] (2R)-2-(6-{5-chloro-2-[(propan-2- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[6- (dimethylamino)pyridin-2-yl]-2- hydroxyethyl]propanamide 538 836 [01906] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- pyrazol-5-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1R)-1-(6-methylpyridin-2- yl)ethyl]propanamide 531 837 [01907] (2R)-2-[6-(5-chloro-2-{[(2S)-1- hydroxypropan-2-yl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1R)-1-[6- (dimethylamino)pyridin-2- yl]ethyl]propanamide 538 838 [01908] (2R)-2-(6-{5-chloro-2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide 592 839 [01909] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S,2S)- 1-(5-fluoro-6-methylpyridin-2-yl)-2- hydroxypropyl]propanamide 583 840 [01910] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1- (3,5-difluoropyridin-2-yl)-2- hydroxyethyl]propanamide 573 841 [01911] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(4- chloro-3-methoxyphenyl)-2- hydroxyethyl]propanamide 600 842 [01912] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimid in-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S,2S)- 1-(5-fluoropyridin-2-yl)-2- hydroxypropyl]propanamide 567 [M −H].sup.− 843 [01913] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[3- (morpholin-4- yl)phenyl]ethyl]propanamide 605 844 [01914] (2R)-2-(6-{5-chloro-2-[(3-fluorooxan- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]propanamide 568 845 No Example 845 846 [01915] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(5- chloropyridin-2-yl)-2- hydroxyethyl]propanamide 569 [M − H].sup.− 847 [01916] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S,2S)- 2-hydroxy-1-(2-methoxypyridin-4- yl)propyl]propanamide 581 848 [01917] (2R)-2-{6-[5-chloro-2- (cyclobutylamino)pyrimidin-4-yl]-1- oxo-2,3-dihydro-1H-isoindol-2-yl}-N- [(1S)-2-hydroxy-1-(6-methoxypyridin- 2-yl)ethyl]propanamide 537 849 [01918] (2R)-2-(6-{5-chloro-2-[(3,3- difluorocyclobutyl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-(6- methoxypyridin-2- yl)ethyl]propanamide 573 850 [01919] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1- (3,5-difluorophenyl)-2- hydroxyethyl]propanamide 572 851 [01920] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3- fluorophenyl)-2- hydroxyethyl]propanamide 554 852 [01921] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- pyrazol-5-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1R)-1-[6-(dimethylamino)pyridin-2- yl]ethyl]propanamide 560 853 [01922] (2R)-2-(6-{5-chloro-2-[(oxetan-3- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-[3- (trifluoromethyl)phenyl]ethyl]propanamide 576 854 [01923] 2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-[(1S)- 1-(2-ethylphenyl)-2- hydroxyethyl]acetamide 480 855 [01924] (2R)-2-(6-{5-chloro-2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-(6-methylpyridin-2- yl)ethyl]propanamide 543 856 [01925] (2R)-2-(6-{5-chloro-2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-[6- (dimethylamino)pyridin-2- yl]ethyl]propanamide 572 857 [01926] (2R)-2-[6-(5-chloro-2-{[trans-3- hydroxycyclobutyl]amino}pyrimidin-4- yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1S)-1-(3-fluoro-5- methylphenyl)-2- hydroxyethyl]propanamide 554 858 [01927] (2R)-2-[6-(5-chloro-2-{[trans-3- hydroxycyclobutyl]amino}pyrimidin-4- yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide 570 859 [01928] (2R)-2-[6-(5-chloro-2-{[(2S)-1- hydroxypropan-2-yl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]N-[(1S)-1-[6- (dimethylamino)pyridin-2-yl]-2- hydroxyethyl]propanamide 554 860 [01929] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-[2-(pyrrolidin-1-yl)pyridin-4- yl]ethyl]propanamide 606 861 [01930] (2R)-2-(6-{5-chloro-2-[(3-fluorooxan- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]propanamide Stereoisomer 1 568 862 [01931] (2R)-2-(6-{5-chloro-2-[(3-fluorooxan- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]propanamide Stereoisomer 2 568 863 [01932] (2R)-2-(6-{5-chloro-2-[(3-fluorooxan- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]propanamide Stereoisomer 3 568 864 [01933] 2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N- [(1S,2S)-2-hydroxy-1-(3- methylphenyl)butyl]acetamide 494 865 [01934] 2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N- [(1S,2S)-2-hydroxy-1-(3- methoxyphenyl)butyl]acetamide 510 866 [01935] 2-(6-{5-chloro-2-[(2,2,2- trifluoroethyl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]acetamide 534 867 [01936] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- pyrazol-5-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(6-methylpyridin-2- yl)ethyl]propanamide 547 868 [01937] (2R)-2-(6-{5-chloro-2-[(morpholin-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]propanamide 551 869 [01938] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[6- (piperazin-1-yl)pyridin-2- yl]ethyl]propanamide 605 870 [01939] (2R)-2-(6-{5-chloro-2-[(3-fluorooxan- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]propanamide Stereoisomer 1 566 [M − H].sup.− 871 [01940] (2R)-2-(6-{5-chloro-2-[(3-fluorooxan- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]propanamide Stereoisomer 2 566 [M − H].sup.− 872 [01941] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(5-methylthiophen-3- yl)ethyl]propanamide 554 [M − H].sup.− 873 [01942] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-[2-(morpholin-4-yl)pyridin- 4-yl]ethyl]propanamide 622 874 [01943] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- (1-oxo-1λ.sup.5-pyridin-2- yl)ethyl]acetamide 523 875 [01944] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- (6-fluoropyridin-2- yl)ethyl]propanamide 539 876 [01945] (2R)-2-(6-{5-chloro-2-[(1,5-dimethyl- 1H-pyrazol-4-yl)amino]pyrimidin-4-yl}- 1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(6-methylpyridin-2- yl)ethyl]propanamide 561 877 [01946] 2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N- [(1S,2S)-2-hydroxy-1- phenylbutyl]acetamide 480 878 [01947] 2-(5-{5-chloro-2-[(2-methyl-2H-1,2,3- triazol-4-yl)amino]pyrimidin-4-yl}-1- methyl-3-oxo-2,3-dihydro-1H-isoindol- 2-yl)-N-[(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]acetamide Stereoisomer 1 547 879 [01948] 2-(5-{5-chloro-2-[(2-methyl-2H-1,2,3- triazol-4-yl)amino]pyrimidin-4-yl}-1- methyl-3-oxo-2,3-dihydro-1H-isoindol- 2-yl)-N-[(1S)-2-hydroxy-1-(3- methylphenyl)ethyl]acetamide Stereoisomer 2 547 880 [01949] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[6- (morpholin-4-yl)pyridin-2- yl]ethyl]propanamide 606 881 [01950] 2-[(1R)-5-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-methoxy-3- oxo-2,3-dihydro-1H-isoindol-2-yl]-N- [(1S)-2-hydroxy-1-(3- methoxyphenyl)ethyl]acetamide 580 [M − H].sup.− 882 [01951] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(5- chloro-6-methylpyridin-2-yl)-2- hydroxyethyl]propanamide 585 883 [01952] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-[2-(methylamino)pyridin-4- yl]ethyl]propanamide 566 884 [01953] (2S)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[6- (morpholin-4-yl)pyridin-2- yl]ethyl]propanamide 606 885 [01954] (2S)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-[2-(methylamino)pyridin-4- yl]ethyl]propanamide 566 886 [01955] (2R)-2-{6-[5-chloro-2 (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N- [(1S,2S)-2-hydroxy-1- phenylbutyl]propanamide 494 887 [01956] (2R)-2-(6-{5-chloro-2-[(1H-pyrazol-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3- fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 566 888 [01957] (2R)-2-(6-{5-chloro-2-[(1H-pyrazol-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- (3-methoxyphenyl)ethyl]propanamide 532 889 [01958] (2R)-2-(6-{5-chloro-2-[(2-methyloxan- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(6-methoxypyridin-2- yl)ethyl]propanamide 581 890 [01959] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-[2- (dimethylamino)pyridin-4-yl]-2- hydroxyethyl]propanamide 577 891 [01960] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-[6-(methylamino)pyridin-2- yl]ethyl]propanamide 566 892 [01961] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(2- fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 584 893 [01962] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[2- (hydroxymethyl)pyridin-4- yl]ethyl]propanamide 551 894 [01963] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1[6- (difluoromethyl)pyridin-2-yl]-2- hydroxyethyl]propanamide 587 895 [01964] (2R)-N-[(1R)-1-[5-chloro-2- (dimethylamino)pyridin-4-yl]ethyl]-2- (6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)propanamide 598 896 [01965] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1- (2,5-difluorophenyl)-2- hydroxyethyl]propanamide 572 897 [01966] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(5- fluoro-2-methylphenyl)-2- hydroxyethyl]propanamide 568 898 [01967] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(5- fluoro-2-methoxyphenyl)-2- hydroxyethyl]propanamide 584 899 [01968] (2S)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[2- (dimethylamino)-5-fluoropyridin-4- yl]ethyl]propanamide 582 900 [01969] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[2- (dimethylamino)-5-fluoropyridin-4- yl]ethyl]propanamide 582 901 [01970] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[2- (dimethylamino)-6-methylpyridin-4- yl]ethyl]propanamide 578 902 [01971] (2R)-N-[(1S)-1-[5-chloro-2- (dimethylamino)pyridin-4-yl]-2- hydroxyethyl]-2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)propanamide 614 903 [01972] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[2- (dimethylamino)-5-fluoropyridin-4-yl] 2-hydroxyethyl]propanamide 598 904 [01973] 2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N- [(1S,2S)-2-hydroxy-1- phenylpentyl]acetamide 494 905 [01974] (2R)-2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N- [(1S,2S)-2-hydroxy-1- phenylpentyl]propanamide 508 906 [01975] 2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N- [(1S,2R)-2,3-dihydroxy-1- phenylpropyl]acetamide 482 907 [01976] 2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N- [(1S,2S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxybutyl]acetamide 528 908 [01977] (2R)-2-(6-}5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(3-fluorophenyl)-2- hydroxyethyl]propanamide 551 909 [01978] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(2-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide 581 910 [01979] (2R)-2-(6-{5-chloro-2-[(3-fluorooxan- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3- fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 600 [M − H].sup.− 911 [01980] (2R)-2-(6-{5-chloro-2-[(3-fluorooxan- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3- fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide Stereoisomer 1 602 [M + H]+ 912 [01981] (2R)-2-(6-{5-chloro-2-[(3-fluorooxan- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3- fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide Stereoisomer 2 600 [M − H].sup.− 913 [01982] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(2- cyano-5-fluorophenyl)-2- hydroxyethyl]propanamide 577 [M − H].sup.− 914 [01983] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-{2- [ethyl(methyl)amino]pyridin-4-yl{-2- hydroxyethyl]propanamide 594 915 [01984] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(4- chloro-3-fluorophenyl)-2- hydroxyethyl]propanamide 588 916 [01985] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[1-(1- phenylazetidin-3-yl)ethyl]acetamide 561 917 [01986] 2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N- [(1S,2S)-2-cyclopropyl-2-hydroxy-1- phenylethyl]acetamide 492 There is no Example 918 919 [01987] (2R)-2-[6-(5-chloro-2-{[(3R,4R)-3,4- dihydroxycyclopentyl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1R)-1-(3-fluoro-5- methoxyphenyl)ethyl]propanamide 584 920 [01988] (2R)-2-[6-(5-chloro-2-{[(3R,4R)-3,4- dihydroxycyclopentyl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide 598 [M − H].sup.− 921 [01989] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyridin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1[2- (dimethylamino)pyridin-4-yl]-2- hydroxyethyl]propanamide 579 922 [01990] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyridin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(2-methoxypyridin-4- yl)ethyl]propanamide 566 923 No Example 923 924 [01991] (2R)-2-(6-{5-chloro-2-[(morpholin-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3- fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 585 925 [01992] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[2- (morpholin-4-yl)pyrimidin-4- yl]ethyl]propanamide 607 There is no Example 926 927 [01993] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[2- (4-methylpiperazin-1-yl)pyrimidin-4- yl]ethyl]propanamide 620 928 [01994] (2R)-2-(6-{5-chloro-2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-[2- (dimethylamino)pyridin-4-yl]-2- hydroxyethyl]propanamide 588 929 [01995] (2R)-2-(6-{5-chloro-2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-(2- methoxypyridin-4- yl)ethyl]propanamide 575 930 [01996] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S,2S)- 1-(3-fluoro-5-methoxyphenyl)-2- hydroxybutyl]acetamide 598 931 [01997] (2R)-2-(6-{5-chloro-2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(3-fluorophenyl)-2- hydroxyethyl]propanamide 562 932 [01998] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- 1,2,4-triazol-3-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide 581 933 [01999] 2-(6-{5-chloro-2-[(1,4-oxazepan-6- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(3- methylphenyl)ethyl]acetamide 551 934 [02000] 2-[(1R)-5-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-methyl-3- oxo-2,3-dihydro-1H-isoindol-2-yl]-N- [(1S)-1-(3-fluoro-5-methoxyphenyl)-2- hydroxyethyl]acetamide 584 935 [02001] 2-[(1R)-5-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-methyl-3- oxo-2,3-dihydro-1H-isoindol-2-yl]-N- [(1S)-1[2-(dimethylamino)pyridin-4- yl]-2-hydroxyethyl]acetamide 580 936 [02002] 2-[(1R)-5-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-methyl-3-oxo-2,3-dihydro-1H- isoindol-2-yl]N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]acetamide 581 937 [02003] 2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-(3,3,3- trifluoro-2-hydroxy-1- phenylpropyl)acetamide 520 938 [02004] (2R)-2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N- [(1S,2R)-3,3,3-trifluoro-2-hydroxy-1- phenylpropyl]propanamide 534 939 [02005] (2R)-2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N- [(1R,2S)-3,3,3-trifluoro-2-hydroxy-1- phenylpropyl]propanamide 534 940 [02006] (2R)-2-(6-{5-chloro-2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-(2-methoxypyridin-4- yl)ethyl]propanamide 559 941 [02007] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyridin-4-yl}- 1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-(3-fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 580 942 [02008] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {6-[(3S)-3-(dimethylamino)pyrrolidin- 1-yl]pyridin-2-yl}ethyl]propanamide 633 943 [02009] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {6-[4-(dimethylamino)piperidin-1- yl]pyridin-2-yl}ethyl]propanamide 647 944 [02010] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[6- (3,3-difluoropyrrolidin-1-yl)pyridin-2- yl]ethyl]propanamide 626 945 [02011] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(2,3,5- trifluorophenyl)ethyl]propanamide 590 946 [02012] (2R)-2-(6-{5-chloro-2-[(morpholin-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[6- (4-methylpiperazin-1-yl)pyridin-2- yl]ethyl]propanamide 620 947 [02013] 2-[(1R)-5-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-methoxy-3- oxo-2,3-dihydro-1H-isoindol-2-yl]-N- [(1S)-1-(3-fluoro-5-methoxyphenyl)-2- hydroxyethyl]acetamide 598 [M − H]+ 948 [02014] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- methoxy-1-phenylethyl]acetamide 536 949 [02015] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[6- (4-methylpiperazin-1-yl)pyridin-2- yl]ethyl]acetamide 605 950 [02016] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[2- (4-methylpiperazin-1-yl)pyridin-4- yl]ethyl]propanamide 617 [M − H].sup.+ 951 [02017] (2R)-2-(6-}5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1[6- (dimethylamino)-3-fluoropyridin-2-yl]- 2-hydroxyethyl]propanamide 596 [M − H].sup.− 952 [02018] 2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-[1-(3- fluoro-5-methylphenyl)-2- hydroxybutyl]acetamide 512 953 [02019] 2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-[1-(3- fluoro-5-methylphenyl)-2- hydroxybutyl]acetamide 512 954 [02020] (2R)-2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-[1-(3- fluoro-5-methylphenyl)-2- hydroxybutyl]propanamide 526 955 [02021] (2R)-2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-[1-(3- fluoro-5-methylphenyl)-2- hydroxybutyl]propanamide 526 956 [02022] (2R)-2-{6-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1-oxo- 2,3-dihydro-1H-isoindol-2-yl}-N-[(1R)- 1-[6-(4-methylpiperazin-1-yl)pyridin-2- yl]ethyl]propanamide 607 957 [02023] 2-(6-{5-chloro-2-[(2-methylpyrimidin- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[6- (dimethylamino)pyridin-2- yl]ethyl]acetamide 558 958 [02024] (2R)-2-(6-{5-chloro-2-[(6- methoxypyridin-3-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide 607 959 [02025] 2-(6-{5-chloro-2-[(2-methyl-2H-1,2,3- triazol-4-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-(3-fluoro-5-methoxyphenyl)-2- hydroxyethyl]acetamide 567 960 [02026] 2-[(1R)-5-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-methyl-3-oxo-2,3-dihydro-1H- isoindol-2-yl]-N-(1S)-1-[2- (dimethylamino)pyridin-4-yl]-2- hydroxyethyl]acetamide 577 961 [02027] 2-[(1R)-5-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-methyl-3-oxo-2,3-dihydro-1H- isoindol-2-yl]-N-[(1S)-2-hydroxy-1-(2- methoxypyridin-4-yl)ethyl]acetamide 564 962 [02028] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-{imidazo[1,2-a]pyridin-7- yl}ethyl]propanamide 574 [M − H].sup.− 963 [02029] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(5- chloro-3-fluoropyridin-2-yl)-2- hydroxyethyl]propanamide 587 [M − H].sup.+ 964 [02030] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {6-[(3R)-3-(dimethylamino)pyrrolidin- 1-yl]pyridin-2-yl}ethyl]propanamide 633 965 [02031] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[3- fluoro-6-(4-methylpiperazin-1- yl)pyridin-2-yl]-2- hydroxyethyl]propanamide 651 [M − H].sup.− 966 [02032] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {6-[3-(dimethylamino)azetidin-1- yl]pyridin-2-yl}ethyl]propanamide 619 967 [02033] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-2-[(2R)-1-(4- methyl-1,4-diazepan-1-yl)-1- oxopropan-2-yl]-2,3-dihydro-1H- isoindol-1-one 513 968 [02034] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[6- (4-methyl-1,4-diazepan-1-l)pyridin-2- yl]ethyl]propanamide 633 969 [02035] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[6- (4-methyl-1,4-diazepan-1-yl)pyridin-2- yl]ethyl]propanamide 633 970 [02036] (2R)-N-[(1R)-1-[5-chloro-2- (methylamino)pyridin-4-yl]ethyl]-2-(6- {5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)propanamide 584 971 [02037] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[6- (dimethylamino)-3-fluoropyridin-2- yl]ethyl]propanamide 582 972 [02038] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[3- fluoro-6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 637 973 [02039] (2R)-N-[(1S)-1-[5-chloro-2- (methylamino)pyridin-4-yl]-2- hydroxyethyl]-2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)propanamide- 598 [M − H].sup.− 974 [02040] (2R)-N-[(1R)-1-[5-chloro-2-(4- methylpiperazin-1-yl)pyridin-4- yl]ethyl]-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)propanamide 651 [M − H].sup.− 975 [02041] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl{-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {2[(2- hydroxyethyl)(methyl)amino]pyridin-4- yl}ethyl]propanamide 592 [M − H].sup.− 976 [02042] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-(5- methylthiophen-3- yl)ethyl]propanamide 553 977 [02043] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide Stereoisomer 1 616 978 [02044] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide Stereoisomer 2 616 979 [02045] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[6- (thiomorpholin-4-yl)pyridin-2- yl]ethyl]propanamide 622 980 [02046] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyridin-4-yl}- 1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-2-hydroxy-1-(2-methoxypyridin- 4-yl)ethyl]propanamide 561 [M − H].sup.+ 981 [02047] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {2-[(3R)-3-(dimethylamino)pyrrolidin- 1-yl]pyridin-4-yl}ethyl]propanamide 633 982 [02048] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[2- (dimethylamino)pyridin-4- yl]ethyl]propanamide 564 983 [02049] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {2-[ethyl(methyl)amino]pyridin-4- yl}ethyl]propanamide 578 984 [02050] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-{5- chloro-2-[ethyl(methyl)amino]pyridin- 4-yl}-2-hydroxyethyl]propanamide 626 [M − H].sup.− 985 [02051] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {2-[(3S)-3-(dimethylamino)pyrrolidin- 1-yl]pyridin-4-yl}ethyl]propanamide 633 986 [02052] (2R)-2-(3-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-5-oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)- N-[(1R)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 620 987 [02053] 2-[(1R)-5-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1- methyl-3-oxo-2,3-dihydro-1H-isoindol- 2-yl]-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]acetamide 514 988 [02054] (2R)-2-(3-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-5-oxo-5H,6H,7H-pyrrolo[3,4- b]pyridin-6-yl)-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide 582 989 [02055] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide 581 990 [02056] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-(3-fluoro-5- methoxyphenyl)ethyl]-3- hydroxypropanamide 581 991 [02057] 2-[(1R)-5-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-methyl-3- oxo-2,3-dihydro-1H-isoindol-2-yl]-N- [(1S)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]acetamide 619 992 [02058] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 635 993 [02059] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-(oxan-4- yl)propanamide 499 994 [02060] 6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-2-[(2R)-1-(4- methylpiperazin-1-yl)-1-oxopropan-2- yl]-2,3-dihydro-1H-isoindol-1-one 500 995 [02061] (2R)-N-[(1S)-1-[5-chloro-2-(4- methylpiperazin-1-yl)pyridin-4-yl]-2- hydroxyethyl]-2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)propanamide 669 996 [02062] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl{-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[5- fluoro-2-(4-methylpiperazin-1- yl)pyridin-4-yl]-2- hydroxyethyl]propanamide 653 997 [02063] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[3- chloro-6-(4-methylpiperazin-1- yl)pyridin-2-yl]-2- hydroxyethyl]propanamide 669 998 [02064] (2R)-2-(6-{5-chloro-2-[(3-methyl-1,2,4- oxadiazol-5-yl)amino]pyrimidin-4-yl}- 1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-(3-fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 582 999 [02065] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[3- chloro-6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 653 1000 [02066] (2R)-N-[(1S)-1-[5-chloro-2- (ethylamino)pyridin-4-yl]-2- hydroxyethyl]-2-(6-{5-chloro-2-[(oxan- 4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)propanamide 612 [M − H].sup.− 1001 [02067] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[5- fluoro-2-(4-methylpiperazin-1- yl)pyridin-4-yl]ethyl]propanamide 637 1002 [02068] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl{-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-{6-[(3R)-3- (dimethylamino)pyrrolidin-1-yl]pyridin- 2-yl}ethyl]propanamide 630 1003 [02069] (2R)-2-(6-{5-chloro-2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 627 1004 [02070] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-[2-(4-methylpiperazin-1- yl)pyridin-4-yl]ethyl]propanamide 635 1005 [02071] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-{6-[(3S)-3- (dimethylamino)pyrrolidin-1-yl]pyridin- 2-yl}ethyl]propanamide 630 1006 [02072] 2-[(1R)-5-[5-chloro-2- (methylamino)pyrimidin-4-yl]-1- methyl-3-oxo-2,3-dihydro-1H-isoindol- 2-yl]-N-[(1S,2S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxybutyl]acetamide 542 1007 [02073] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S,2S)- 2-hydroxy-1-(2-methoxypyridin-4- yl)butyl]propanamide 595 1008 [02074] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyridin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[6- (4-methylpiperazin-1-yl)pyridin-2- yl]ethyl]propanamide 618 1009 [02075] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-4-fluoro-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 637 1010 [02076] 2-[(1R)-5-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-methyl-3- oxo-2,3-dihydro-1H-isoindol-2-yl]-N- [(1S)-2-hydroxy-1-[2-(4- methylpiperazin-1-yl)pyridin-4- yl]ethyl]acetamide 635 1011 [02077] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[2- (methylamino)pyridin-4- yl]ethyl]propanamide 550 1012 [02078] (2S)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[3- fluoro-6-(4-methylpiperazin-1- yl)pyridin-2-yl]-2- hydroxyethyl]propanamide 651 [M − H].sup.+ 1013 [02079] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-{2- [4-(dimethylamino)piperidin-1- yl]pyridin-4-yl}ethyl]propanamide 647 1014 [02080] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {2-[4-(dimethylamino)piperidin-1- yl]pyridin-4-yl}ethyl]propanamide 647 1015 [02081] 2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[3- fluoro-5-(4-methylpiperazin-1- yl)phenyl]ethyl]acetamide 622 1016 [02082] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[3- fluoro-5-(4-methylpiperazin-1- yl)phenyl]ethyl]propanamide 634 [M − H].sup.+ 1017 [02083] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1[3- chloro-6-(methylamino)pyridin-2-yl]-2- hydroxyethyl]propanamide 600 1018 [02084] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyridin-4-yl}- 1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1R)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 615 1019 [02085] (2R)-2-(6-{5-chloro-2-[(3-methyl-1,2- oxazol-5-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-(3-fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 579 [M − H].sup.− 1020 [02086] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {3-[2-(dimethylamino)ethoxy]-5- fluorophenyl}ethyl]propanamide 625 1021 [02087] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3- chlorophenyl)-2- hydroxyethyl]propanamide 570 1022 [02088] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3- chloro-5-fluorophenyl)-2- hydroxyethyl]propanamide 588 1023 [02089] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[5- fluoro-2-(methylamino)pyridin-4-yl]-2- hydroxyethyl]propanamide 582 [M − H].sup.− 1024 [02090] (2R)-2-(6-{5-chloro-2-[(5-methyl-1,2- oxazol-3-l)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-(3-fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 579 [M − H].sup.− 1025 [02091] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[5- fluoro-2-(methylamino)pyridin-4- yl]ethyl]propanamide 568 1026 [02092] (2R)-N-[(1R)-1-[5-chloro-2- (ethylamino)pyridin-4-yl]ethyl]-2-(6-{5- chloro-2-[(oxan-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)propanamide 598 1027 [02093] 2-[(1R)-5-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-methyl-3- oxo-2,3-dihydro-1H-isoindol-2-yl]-N- [(1R)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]acetamide 619 1028 [02094] (2R)-2-(3-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-5-oxo-5H,6H,7H-pyrrolo[3,4- b]pyridin-6-yl)-N-[(1R)-1-[6-(4- methylpiperazin-1-yl)pyridin-2- yl]ethyl]propanamide 617 1029 [02095] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[3- (4-methylpiperazin-1- yl)phenyl]ethyl]propanamide 618 1030 [02096] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-[3-(4-methylpiperazin-1- yl)phenyl]ethyl]propanamide 634 1031 [02097] 2-[(1R)-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-methyl-3- oxo-2,3-dihydro-1H-isoindol-2-ylFN- [(1S)-2-hydroxy-1-[6-(4- methyl piperazin-1-yl)pyridin-2- yl]ethyl]acetamide 635 1032 [02098] (2S)-N-[(1R)-1-[5-chloro-2- (ethylamino)pyridin-4-yl]ethyl]-2-(6-{5- chloro-2-[(oxan-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)propanamide 598 1033 [02099] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl{-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {6-[4-(2-hydroxyethyl)piperazin-1- yl]pyridin-2-yl}ethyl]propanamide 649 1034 [02100] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-[6- (dimethylamino)pyridin-2-yl]-2- hydroxyethyl]propanamide 575 [M − H].sup.+ 1035 [02101] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- (5-fluoro-2-methoxypyridin-4- yl)ethyl]propanamide 569 1036 [02102] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[2- (morpholin-4-yl)pyridin-4- yl]ethyl]propanamide 606 1037 [02103] (2R)-N-[(1R)-1-[5-chloro-2- (morpholin-4-yl)pyridin-4-yl]ethyl]-2- (6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)propanamide 638 [M − H].sup.− 1038 [02104] (2R)-2-(6-{5-chloro-2-[(6- methoxypyridin-3-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 642 1039 [02105] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {6-[(3R)-3-methylpiperazin-1- yl]pyridin-2-yl}ethyl]propanamide 619 1040 [02106] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-[6-(4- methylpiperazin-1-yl)pyridin-2- yl]ethyl]propanamide 632 1041 [02107] 2-(3-{5-chloro-2-[(2-methyl-2H-1 2,3- triazol-4-yl)amino]pyrimidin-4-yl}-5- oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6- yl)-N-[(1S,2S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxybutyl]acetamide 596 1042 [02108] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 616 1043 [02109] (2R)-2-(6-{5-chloro-2-[(2- methoxypyridin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 642 1044 [02110] (2R)-2-(6-{5-chloro-2-[(2- methoxypyridin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-[6-(4- methylpiperazin-1-yl)pyridin-2- yl]ethyl]propanamide 658 1045 [02111] (2R)-2-(3-{5-chloro-2-[(1-methyl-1H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-5-oxo-5H,6H,7H-pyrrolo[3,4- b]pyridin-6-yl)-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide 582 1046 [02112] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- 1,2,3-triazol-4-yl)amino]pyridin-4-yl}- 1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1R)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 613 [M − H].sup.+ 1047 [02113] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- 1,2,3-triazol-5-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide 581 1048 [02114] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- 1,2,3-triazol-5-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 616 1049 [02115] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1[6- (4-ethylpiperazin-1-yl)pyridin-2-yl]-2- hydroxyethyl]propanamide 649 1050 [02116] 2-(3-{5-chloro-2-[(2-methyl-2H-1,2,3- triazol-4-yl)amino]pyrimidin-4-yl}-5- oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6- yl)-N-[(1S)-1-(3-ethoxy-5- fluorophenyl)-2- hydroxyethyl]acetamide 582 1051 [02117] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {6-[(3S)-3-methylpiperazin-1- yl]pyridin-2-yl}ethyl]propanamide 619 1052 [02118] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-4-fluoro-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1R)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 637 1053 [02119] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {6-[2-(dimethylamino)ethoxy]pyridin-2- yl}ethyl]propanamide 608 1054 [02120] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[3- fluoro-5-(4-methylpiperazin-1- yl)phenyl]-2- hydroxyethyl]propanamide 650 1055 [02121] (2R)-2-(6-{5-chloro-2-[(1-methyl-1H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(3-ethoxy-5- fluorophenyl)-2- hydroxyethyl]propanamide 595 1056 [02122] 2-(6-{5-chloro-2-[(2-methyl-2H-1,2,3- triazol-4-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-[6-(dimethylamino)pyridin-2- yl]-2-hydroxyethyl]acetamide 561 [M − H].sup.+ 1057 [02123] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {3-fluoro-5-[4-(2- hydroxyethyl)piperazin-1- yl]phenyl}ethyl]propanamide 664 [M − H].sup.+ 1058 [02124] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-146-(dimethylamino)-3- fluoropyridin-2-yl]-2- hydroxyethyl]propanamide [M − H].sup.+ 593 1059 [02125] (2S)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[2- (morpholin-4-yl)pyridin-4- yl]ethyl]propanamide 606 1060 [02126] (2R)-2-(6-{5-chloro-2-[(5-methyl-1-2- oxazol-4-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-(3-fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 581 1061 [02127] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(2- chloro-5-methoxyphenyl)-2- hydroxyethyl]propanamide M − H ion 598 1062 [02128] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3- chloro-6-methoxypyridin-2-yl)-2- hydroxyethyl]propanamide M − H ion 599 1063 [02129] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[3- chloro-6-(morpholin-4-yl)pyridin-2-yl]- 2-hydroxyethyl]propanamide M − H ion 654 1064 [02130] (2R)-N-[(1S)-1-[5-chloro-2-(morpholin- 4-yl)pyridin-4-yl]-2-hydroxyethyl]-2-(6- {5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl{-1-oxo-2,3- dihydro-1H-isoindol-2-yl)propanamide M − H 645 1065 [02131] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-{3- [2-(dimethylamino)ethoxy]-5- fluorophenyl}-2- hydroxyethyl]propanamide M − H 639 1066 [02132] (2R)-2-(6-{5-chloro-2-[(2- methoxypyridin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2 yl)-N-[(1S)-1-[3-chloro-6- (dimethylamino)pyridin-2-yl]-2- hydroxyethyl]propanamide M − H ion 635 1067 [02133] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(2- chloro-5-fluorophenyl)-2- hydroxyethyl]propanamide 588 1068 [02134] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-(2- methoxypyridin-4- yl)ethyl]propanamide 564 1069 [02135] (2R)-2-(3-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-5-oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)- N-[(1S)-1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl]propanamide 589 1070 [02136] (2R)-2-(6-{5-chloro-2-[(2- methoxypyridin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1[6- (dimethylamino)pyridin-2-yl]-2- hydroxyethyl]propanamide 603 1071 [02137] (2R)-2-(6-{5-chloro-2-[(2- methoxypyridin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-(2- methoxypyridin-4- yl)ethyl]propanamide 590 1072 [02138] (2R)-2-[6-(5-chloro-2-{[(2S)-1- hydroxypropan-2-yl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide 558 1073 [02139] (2R)-2-[6-(5-chloro-2-{[(2R)-1- hydroxypropan-2-yl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide M − H ion 556 1074 [02140] (2R)-2-(6-{5-chloro-2-[(2- methoxypyridin-4-yl)amino]pyrimidin- 4-yl{-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-[6-(ethylamino)pyridin-2- yl]ethyl]propanamide 587 1075 [02141] (2R)-2-(6-{5-chloro-2-[(2- methoxypyridin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-[6-(ethylamino)pyridin-2- yl]-2-hydroxyethyl]propanamide 603 1076 [02142] (2R)-2-[6-(5-chloro-2-{[trans-4- hydroxycyclohexyl]amino}pyrimidin-4- yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide M − H ion 596 1077 [02143] (2R)-2-(6-{5-chloro-2-[(3-methyl-1,2- oxazol-5-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1R)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 616 1078 [02144] (2R)-2-(6-{5-chloro-2-[(3-methyl-1,2,4- thiadiazol-5-yl)amino]pyrimidin-4-yl}- 1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-(3-fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide M − H 596 1079 [02145] (2R)-2-(6-{5-chloro-2-[(oxetan-3- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3- fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 556 1080 [02146] (2R)-2-[6-(5-chloro-2-{[(2S)-1- hydroxypropan-2-yl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1S)-1-[3-fluoro-5- trideuteromethoxyphenyl]-2- hydroxyethyl]propanamide 561 1081 [02147] (2R)-2-[6-(5-chloro-2-{[trans-4- methoxycyclohexyl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide M − H 610 1082 [02148] (2R)-2-(6-{5-chloro-2-[(3-methyl-1,2- thiazol-5-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2-yl)-N- [(1S)-1-(3-fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 597 1083 [02149] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[3- fluoro-5-trideuteromethoxyphenyl]-2- hydroxyethyl]propanamide M − H ion 585 1084 [02150] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- (5-chloro-2-methoxypyridin-4- yl)ethyl]propanamide 585 1085 [02151] (2R)-2-(6-{5-chloro-2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-2-hydroxy-1-[6-(4- methylpiperazin-1-yl)pyridin-2- yl]ethyl]propanamide 643 1086 [02152] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(3-ethoxy-5- fluorophenyl)-2- hydroxyethyl]propanamide 595 1087 [02153] (2R)-2-(6-{5-chloro-2-[(2- methoxypyridin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(3-ethoxy-5- fluorophenyl)-2- hydroxyethyl]propanamide 621 1088 [02154] (2R)-2-(6-{5-chloro-2-[(1-methyl-6- oxopiperidin-3-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide 609 [M − H].sup.− 1089 [02155] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3- chloro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 598 1090 [02156] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(5- fluoro-2-methoxypyridin-4-yl)-2- hydroxyethyl]propanamide 585 1091 [02157] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(5- chloro-2-methoxypyridin-4-yl)-2- hydroxyethyl]propanamide M − H 599 1092 [02158] (2R)-2-[6-(5-chloro-2-{[(1R,3S)-3- hydroxycyclopentyl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide M − H ion 582 1093 [02159] (2R)-2-[6-(5-chloro-2-{[(1S,3S)-3- hydroxycyclopentyl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide 582 1094 [02160] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-[3-chloro-6- (ethylamino)pyridin-2-yl]-2- hydroxyethyl]propanamide 611 1095 [02161] (2R)-2-(6-{5-chloro-2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl-N-[(1R)-1-[6-(ethylamino)pyridin-2- yl]ethyl]propanamide 572 1096 [02162] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {3-[4-(2-hydroxyethyl)piperazin-1- yl]phenyl}ethyl]propanamide 648 1097 [02163] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-{6- [(3S)-3,4-dimethylpiperazin-1- yl]pyridin-2-yl}-2- hydroxyethyl]propanamide M + H 649 1098 [02164] (2R)-2-[6-(5-chloro-2-{[(3R)-1-methyl- 6-oxopiperidin-3-yl]amino}pyrimidin-4- yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide M − H 609 1099 [02165] (2R)-2-[6-(5-chloro-2-{[(3S)-1-methyl- 6-oxopiperidin-3-yl]amino}pyrimidin-4- yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide M − H 609 1100 [02166] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-[3-chloro-6- (methylamino)pyridin-2- yl]ethyl]propanamide 581 1101 [02167] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-[3-chloro-6- (methylamino)pyridin-2-yl]-2- hydroxyethyl]propanamide 597 1102 [02168] (2R)-2-(6-{5-chloro-2-[(6- methoxypyrimidin-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3- fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 608 1103 [02169] (2R)-2-(6-{5-chloro-2-[(2- methoxypyrimidin-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3- fluoro-5-methoxyphenyl)-2- hydroxyethyl]propanamide 608 1104 [02170] (2R)-2-(6-}5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-{6- [(3R)-3,4-dimethylpiperazin-1- yl]pyridin-2-yl}-2- hydroxyethyl]propanamide M − H 647 1105 [02171] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3- fluoro-5-hydroxyphenyl)-2- hydroxyethyl]propanamide M − H 568 1106 [02172] (2R)-2-(6-{5-chloro-2-[(2- methoxypyridin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-[3-fluoro-5-(4- methylpiperazin-1- yl)phenyl]ethyl]propanamide 659 1107 [02173] (2R)-2-(6-{5-chloro-2-[(2-methyl-2H- 1,2,3-triazol-4-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-[3-chloro-6- (ethylamino)pyridin-2- yl]ethyl]propanamide 595 1108 [02174] (2R)-2-(6-}5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-{6-[4-(propan-2- yl)piperazin-1-yl]pyridin-2- yl}ethyl]propanamide M + H 663 1109 [02175] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(2- ethoxypyridin-4-yl)-2- hydroxyethyl]propanamide 579 1110 [02176] (2R)-2-(6-{5-chloro-2-[(6- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide 592 1111 [02177] (2R)-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2-hydroxyethyl]-2-(6- {2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2- yl)propanamide 550 1112 [02178] (2R)-2-(6-{5-chloro-2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-[6-(ethylamino)pyridin-2- yl]-2-hydroxyethyl]propanamide 588 1113 [02179] (2R)-N-[(1S)-2-hydroxy-1-(2- methoxypyridin-4-yl)ethyl]-2-(6-{2- [(oxan-4-yl)amino]pyrimidin-4-yl}-1- oxo-2,3-dihydro-1H-isoindol-2- yl)propanamide 533 1114 [02180] (2R)-2-(6-}5-chloro-2-[(oxetan-3- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[3- fluoro-5-(4-methylpiperazin-1- yl)phenyl]ethyl]propanamide 608 1115 [02181] (2R)-2-[6-(5-chloro-2-{[cis-3- methoxycyclobutyl]amino}pyrimidin-4- yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide [M − H]+ 582 1116 [02182] (2R)-2-(6-{5-chloro-2-[(oxetan-3- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[6- (4-methylpiperazin-1-yl)pyridin-2- yl]ethyl]propanamide 591 1117 [02183] (2R)-2-[6-(5-chloro-2-{[trans-4- hydroxycyclohexyl]amino}pyrimidin-4- yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1R)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 633 1118 [02184] (2R)-2-[6-(5-chloro-2-{[(2S)-1- hydroxypropan-2-yl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1R)-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 593 1119 [02185] (2R)-2-(6-{5-chloro-2-[(oxetan-3- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-[6-(4-methylpiperazin-1- yl)pyridin-2-yl]ethyl]propanamide 607 1120 [02186] (2R)-2-[6-(5-chloro-2-{[trans-4- methoxycyclohexyl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1S)-2-hydroxy-1-[6-(4- methylpiperazin-1-yl)pyridin-2- yl]ethyl]propanamide 663 1121 [02187] (2R)-2-[6-(5-chloro-2-{[trans-4- hydroxycyclohexyl]amino}pyrimidin-4- yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1R)-1-[3-fluoro-5-(4- methylpiperazin-1- yl)phenyl]ethyl]propanamide 650 1122 [02188] (2R)-2-[6-(5-chloro-2-{[(2S)-1- hydroxypropan-2-yl]amino}pyrimidin- 4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2- yl]-N-[(1R)-1-[3-fluoro-5-(4- methylpiperazin-1- yl)phenyl]ethyl]propanamide 610 1123 [02189] (2R)-2-(6-{5-chloro-2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1R)-1-[3-fluoro-5-(4- methylpiperazin-1- yl)phenyl]ethyl]propanamide 644 1124 [02190] (2R)-2-(6-{5-chloro-2-[(1,2-dimethyl- 1H-imidazol-5-yl)amino]pyrimidin-4- yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2- hydroxyethyl]propanamide 594 1125 [02191] (2R)-2-(6-{5-chloro-2-[(oxetan-3- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-1[6- (dimethylamino)pyridin-2-yl]-2- hydroxyethyl]propanamide 552 1126 [02192] (2R)-2-(3-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-5-oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)- N-[(1S)-1-(3-fluoro-5-methoxyphenyl)- 2-hydroxyethyl]propanamide 585 1127 [02193] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1[6- (ethylamino)pyridin-2- yl]ethyl]propanamide 564 1128 [02194] (2R)-N-[(1S)-1-(3-fluoro-5- methoxyphenyl)-2-hydroxyethyl]-2-(6- {2-[(2-methoxypyridin-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)propanamide 573 1129 [02195] (2R)-N-[(1S)-1-[6- (dimethylamino)pyridin-2-yl]-2- hydroxyethyl]-2-(6-{2-[(2- methylpyrimidin-4-yl)amino]pyrimidin- 4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2- yl)propanamide 554 1130 [02196] (2R)-2-(6-{5-chloro-2-[(oxetan-3- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[6- ethylamino)pyridin-2- yl]ethyl]propanamide 536 1131 [02197] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1S)-2- hydroxy-1-(1-methyl-6-oxo-1,6- dihydropyridin-2-yl)ethyl]propanamide 567 1132 [02198] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[3- fluoro-5-(4-methyl-2-oxopiperazin-1- yl)phenyl]ethyl]propanamide 648 [M − H]+ 1133 [02199] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1- {6-[(methylamino)methyl]pyridin-2- yl}ethyl]propanamide 564 1134 [02200] (2R)-2-(6-{5-chloro-2-[(oxan-4- yl)amino]pyrimidin-4-yl}-1-oxo-2,3- dihydro-1H-isoindol-2-yl)-N-[(1R)-1-[6- (hydroxymethyl)pyridin-2- yl]ethyl]propanamide 551

Biological Activity

Example A

ERK2 In Vitro Inhibition Assay

[1952] The inhibitory activity of the compounds of the invention was determined using the protocol set out below.

[1953] Activity of ERK2 enzyme (Life Technologies) was determined using a time-resolved fluorescence format measuring the phosphorylation of a truncated version of Activating transcription factor 2 labelled with green fluorescent protein (ATF2-GFP) (Life Technologies). Assay reactions containing 50 mM Tris pH 7.5, 10 mM MgCl.sub.2, 1 mM EGTA, 0.01% Triton X-100, 1 mM DTT, 2.5% DMSO, 0.4 μM ATF2-GFP, 20 μM ATP and 0.25 nM ERK2 were set up in the presence of compound and allowed to proceed for 30 min at room temperature. Reactions were then stopped using TR-FRET dilution buffer (Life Technologies), 25 mM EDTA and 2 nM Tb-Anti-pATF2 (Thr71) (Life Technologies). After a further incubation period of at least 30 minutes, fluorescence was read on a Pherastar reader (Lanthascreen optic module; excitation 340 nm, emission 520 nm (channel A), 495 nm (channel B)). The ratio between A and B counts was used to calculate signal. IC.sub.50 values were calculated using a sigmoidal dose response equation (Prism GraphPad software, La Jolla, Calif., USA).

[1954] In the assays using ERK2, the compounds of Examples 125,127, 162, 181, 183, 289, 299, 310 and 939 have IC.sub.50 values in the range from 1 μM to 10 μM, provide at least 50% inhibition of the activity at a concentration of 10 μM in the assay against ERK2 or would be expected to provide at least 50% inhibition of the activity at a concentration of 10 μM (based on the level of inhibition of the activity at concentrations of 3 μM) in the assay against ERK2.

[1955] The compounds of Examples 1, 12, 24, 28, 30, 36, 37, 44, 45, 51, 61, 65, 69, 71, 73, 89, 92, 106, 109, 111, 113, 114, 118, 119, 121, 124, 126, 129, 133, 135, 138, 139, 140, 143, 156, 158, 159, 160, 161, 166, 167, 169, 170, 171, 172, 173, 174, 178, 180, 182, 184, 185, 187, 189, 191, 198, 199, 204, 215, 222, 223, 243, 251, 255, 258, 279, 285, 296, 297, 301, 302, 305, 306, 307, 308, 309, 314, 331, 363, 378, 382, 404, 411, 414, 483, 486, 492, 494, 496, 501, 503, 513, 515, 520, 521, 528, 530, 532, 534, 536, 541, 546, 551, 553, 556, 572, 576, 577, 581, 594, 617, 618, 620, 680, 706, 709, 719, 724, 737, 749, 750, 752, 762, 766, 793, 794, 821, 874, 893, 917, 937, 938, 967, 978, 991, 993, 994, 1006, 1013, 1014, 1059 and 1113 have IC.sub.50 values in the range from 0.1 μM to 1 μM, provide at least 50% inhibition of the activity at a concentration of 1 μM or would be expected to provide at least 50% inhibition of the activity at a concentration of 1 μM (based on the level of inhibition of the activity at concentrations of 0.10 μM) in the assay against ERK2.

[1956] The compounds of Examples 5, 6, 8, 9, 10, 13, 14, 15, 17, 18, 20, 23, 29, 31, 32, 33, 39, 41, 43, 46, 47, 49, 50, 52, 53, 54, 58, 60, 62, 63, 64, 66, 68, 70, 75, 77, 81, 83, 88, 90, 91, 97, 98, 99, 100, 102, 104, 105, 107, 108, 110, 112, 115, 116, 117, 120, 122, 123, 128, 130, 131, 132, 134, 136, 142, 144, 145, 146, 147, 148, 149, 153, 154, 155, 157, 163, 164, 165, 168, 175, 176, 177, 179, 186, 188, 190, 200, 202, 203, 205, 206, 208, 211, 212, 213, 216, 217, 218, 220, 224, 225, 226, 227, 228, 229, 231, 233, 236, 238, 245, 246, 247, 248, 249, 250, 252, 253, 254, 256, 257, 259, 265, 267, 268, 269, 270, 272, 273, 274, 275, 276, 277, 278, 281, 286, 288, 292, 293, 295, 300, 304, 311, 312, 313, 315, 320, 329, 330, 334, 338, 339, 340, 343, 345, 346, 350, 353, 361, 362, 364, 368, 373, 374, 375, 376, 377, 379, 380, 387, 388, 389, 394, 401, 405, 407, 408, 409, 410, 412, 413, 416, 417, 418, 419, 420, 424, 426, 427, 438, 439, 440, 441, 446, 449, 464, 467, 470, 472, 473, 474, 479, 484, 485, 487, 489, 490, 491, 493, 497, 502, 505, 506, 507, 508, 516, 518, 519, 523, 524, 531, 533, 535, 537, 539, 544, 547, 550, 552, 557, 559, 561, 562, 564, 566, 568, 569, 570, 573, 578, 579, 580, 582, 584, 585, 586, 587, 589, 590, 592, 595, 599, 605, 607, 610, 611, 619, 622, 632, 636, 637, 638, 645, 646, 647, 648, 649, 655, 659, 662, 664, 667, 668, 670, 679, 682, 690, 691, 695, 714, 718, 723, 725, 726, 731, 733, 734, 741, 744, 745, 748, 751, 755, 758, 761, 764, 770, 771, 773, 775, 778, 790, 791, 792, 796, 797, 813, 829, 832, 833, 839, 842, 854, 866, 879, 884, 885, 889, 899, 901, 904, 905, 906, 916, 933, 946, 948, 955, 969, 998, 1009, 1012, 1028, 1032, 1055, 1082, 1084 and 1091 have IC.sub.50 values in the range from 0.01 μM to 0.1 μM provide at least 50% inhibition of the activity at a concentration of 0.1 μM or would be expected to provide at least 50% inhibition of the activity at a concentration of 0.1 μM (based on the level of inhibition of the activity at concentrations of 0.0030 μM or 0.010 μM) in the assay against ERK2.

[1957] The compounds of Examples 2, 3, 4, 7, 11, 16, 19, 21, 22, 25, 26, 27, 34, 35, 38, 40, 42, 48, 55, 56, 57, 59, 67, 72, 74, 76, 78, 79, 80, 82, 84, 85, 86, 87, 93, 94, 95, 96, 101, 103, 137, 141, 150, 151, 152, 192, 193, 194, 195, 196, 197, 201, 207, 209, 210, 214, 219, 221, 230, 232, 234, 235, 237, 239, 240, 241, 242, 244, 260, 261, 262, 263, 264, 266, 271, 280, 282, 283, 284, 287, 289, 290, 291, 294, 303, 316, 317, 318, 319, 321, 322, 323, 324, 325, 326, 327, 328, 333, 335, 336, 337, 341, 342, 344, 347, 348, 349, 351, 352, 354, 355, 356, 357, 358, 359, 360, 365, 367, 369, 370, 371, 372, 381, 383, 384, 372, 386, 390, 391, 392, 393, 395, 396, 397, 398, 399, 400, 402, 403, 406, 415, 421, 422, 423, 425, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 442, 443, 444, 445, 448, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 465, 466, 469, 471, 475, 476, 477, 478, 480, 481, 482, 488, 495, 498, 499, 500, 504, 509, 510, 511, 512, 514, 517, 522, 525, 526, 529, 538, 540, 542, 543, 545, 548, 549, 554, 555, 558, 560, 563, 565, 567, 571, 574, 575, 583, 588, 591, 593, 596, 597, 598, 600, 601, 602, 603, 604, 606, 608, 609, 612, 613, 614, 615, 616, 621, 623, 624, 625, 626, 627, 628, 629, 630, 631, 633, 634, 635, 639, 640, 641, 642, 643, 644, 650, 651, 652, 653, 654, 656, 657, 658, 660, 661, 663, 665, 666, 669, 671, 672, 673, 674, 675, 676, 677, 678, 681, 683, 684, 685, 686, 687, 688, 689, 692, 693, 694, 696, 697, 698, 699, 701, 702, 703, 705, 707, 708, 711, 712, 713, 715, 716, 717, 719, 720, 721, 722, 727, 728, 730, 732, 735, 737, 738, 740, 742, 743, 746, 747, 753, 754, 756, 757, 759, 763, 765, 767, 768, 769, 774, 776, 777, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 798, 799, 800, 801, 802, 803, 804, 805, 806, 808, 809, 810, 811, 812, 814, 815, 816, 817, 818, 819, 820, 822, 823, 824, 825, 826, 827, 828, 830, 831, 834, 835, 836, 837, 838, 840, 841, 843, 844, 846, 847, 848, 849, 850, 851, 852, 853, 855, 856, 857, 858, 859, 864, 865, 867, 868, 869, 870, 871, 872, 873, 875, 876, 877, 878, 880, 881, 882, 883, 886, 887, 888, 890, 891, 892, 894, 895, 896, 897, 986, 900, 902, 903, 907, 908, 909, 910, 911, 912, 913, 914, 915, 918, 919, 920, 921, 922, 924, 925, 926, 927, 928, 929, 930, 931, 932, 934, 935, 936, 940, 941, 942, 943, 944, 945, 947, 949, 950, 951, 952, 953, 954, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 968, 970, 971, 972, 973, 974, 975, 976, 977, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 992, 995, 996, 997, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1007, 1008, 1010, 1011, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1029, 1030, 1031, 1033, 1034, 1035, 1036, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1056, 1057, 1058, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1083, 1085, 1086, 1087, 1088, 1089, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 598, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 609, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134 have IC.sub.50 values in the range from 0.001 μM to 0.01 μM, provide at least 50% inhibition of the activity at a concentration of 0.01 μM or would be expected to provide at least 50% inhibition of the activity at a concentration of 0.01 μM (based on the level of inhibition of the activity at concentrations of 0.00050 μM, 0.0010 μM or 0.0030 μM) in the assay against ERK2.

Example B

Anti-Proliferative Activity

[1958] The anti-proliferative activities of compounds of the invention were determined by measuring the ability of the compounds to inhibit growth in the Human melanoma cell line A375.

[1959] Cell proliferation was determined by measuring the conversion of rezasurin (Alamar Blue) to resorufin in response to mitochondrial activity (Nociari, M. M, Shalev, A., Benias, P., Russo, C. Journal of Immunological Methods 1998, 213, 157-167). A375 cells (American Type Culture Collection, Teddington, UK) were grown in Dulbecco's Modified Eagle Medium+10% FBS. Each well of a black 96-well flat-bottomed plate was seeded with 2×10.sup.3 cells in 200 μl of complete culture medium one day before the compound treatment. Cells were incubated with compound in 0.1% (v/v) dimethyl sulfoxide (DMSO) for 4 days before addition of 20 μl Alamar blue. After a further 6 h incubation at 37° C. the plate was read on a Spectramax Gemini reader (Molecular Devices; excitation 535 nm, emission 590 nm). GI.sub.50 values were calculated using a sigmoidal dose response equation (Prism GraphPad software, La Jolla, Calif., USA).

[1960] In the assays using A375, the compounds of Examples 5, 6, 7, 8, 9, 10, 15, 18, 20, 25, 29, 41, 42, 46, 49, 50, 51, 53, 58, 60, 62, 68, 78, 81, 88, 97, 98, 100, 102, 108, 110, 112, 115, 116, 120, 122, 124, 128, 130, 134, 137, 144, 145, 146, 147, 149, 154, 155, 157, 158, 163, 165, 168, 170, 174, 176, 177, 179, 184, 368, 405, 407, 410, 412, 417, 418, 426, 438, 439, 445, 449, 471, 481, 483, 485, 553, 564, 566, 569, 578, 582, 599, 619, 632, 636, 771, 776, 913, 920, 932 and 1055 have GI.sub.50 values in the range from 1 μM to 10 μM, provide at least 50% inhibition of growth at a concentration of 10 μM or would be expected to provide at least 50% inhibition of the activity at a concentration of 10 μM (based on the level of inhibition of the activity at concentrations of 1 μM) in the assay against A375.

[1961] In the assays using A375, the compounds of Examples 2, 3, 4, 11, 13, 16, 17, 19, 21, 22, 23, 26, 27, 31, 33, 34, 35, 38, 39, 40, 43, 47, 48, 54, 55, 56, 57, 59, 63, 64, 66, 67, 70, 72, 74, 75, 76, 82, 83, 84, 85, 87, 90, 91, 93, 94, 95, 96, 101, 103, 107, 117, 141, 148, 150, 151, 152, 153, 164, 175, 186, 190, 193, 194, 195, 196, 197, 201, 221, 237, 287, 294, 317, 318, 319, 320, 322, 323, 328, 337, 369, 371, 381, 383, 386, 389, 398, 401, 406, 413, 415, 416, 419, 421, 423, 424, 426, 427, 428, 429, 430, 437, 440, 441, 442, 447, 453, 455, 469, 470, 473, 476, 477, 479, 480, 487, 488, 495, 497, 498, 500, 511, 538, 540, 547, 548, 549, 550, 552, 555, 558, 559, 560, 561, 563, 565, 567, 568, 570, 571, 573, 574, 575, 580, 600, 601, 602, 603, 605, 606, 607, 630, 637, 638, 639, 640, 643, 654, 655, 656, 657, 666, 693, 703, 712, 716, 717, 719, 720, 727, 731, 737, 738, 746, 747, 756, 774, 785, 786, 787, 790, 798, 800, 801, 813, 816, 830, 834, 836, 839, 840, 846, 848, 849, 855, 867, 875, 876, 883, 886, 889, 901, 918, 919, 921, 926, 927, 928, 929, 940, 946, 949, 950, 956, 960, 961, 962, 968, 975, 977, 981, 983, 985, 986, 987, 996, 1001, 1002, 1003, 1004, 1008, 1011, 1014, 1015, 1018, 1020, 1027, 1038, 1039, 1042, 1045, 1046, 1047, 1048, 1050, 1051, 1053, 1065, 1073, 1077, 1078, 1113, 1117, 1118, 1121, 1123, 1124, 1132 and 1134 have GI.sub.50 values in the range from 0.1 μM to 1 μM or provide at least 50% inhibition of growth at a concentration of 1 μM or would be expected to provide at least 50% inhibition of the activity at a concentration of 1 μM (based on the level of inhibition of the activity at concentrations of 0.30 μM) in the assay against A375.

[1962] In the assays using A375, the compounds of Examples 52, 77, 79, 80, 86, 192, 209, 232, 240, 261, 264, 265, 271, 282, 283, 291, 292, 316, 324, 325, 326, 327, 334, 335, 336, 342, 347, 348, 349, 351, 354, 355, 356, 357, 359, 360, 367, 370, 372, 385, 390, 392, 393, 395, 399, 400, 402, 403, 422, 425, 431, 432, 444, 448, 451, 452, 459, 460, 467, 475, 478, 482, 499, 504, 508, 510, 517, 525, 539, 554, 562, 579, 591, 593, 598, 609, 611, 612, 613, 614, 616, 621, 622, 623, 624, 625, 626, 627, 628, 629, 631, 633, 634, 635, 641, 642, 644, 645, 648, 650, 653, 658, 659, 663, 664, 665, 668, 669, 670, 671, 672, 673, 674, 681, 682, 687, 688, 689, 692, 696, 697, 698, 699, 701, 702, 705, 708, 711, 713, 715, 721, 722, 728, 734, 735, 740, 743, 753, 754, 755, 759, 763, 765, 767, 768, 770, 777, 780, 781, 783, 784, 788, 789, 799, 802, 803, 804, 805, 806, 809, 810, 811, 817, 818, 819, 820, 822, 823, 824, 825, 826, 827, 828, 831, 835, 837, 838, 841, 843, 847, 850, 851, 852, 853, 856, 857, 858, 860, 861, 864, 865, 868, 869, 870, 871, 872, 873, 877, 878, 882, 887, 888, 890, 894, 895, 896, 897, 898, 900, 902, 903, 907, 908, 912, 914, 915, 922, 924, 925, 931, 935, 936, 941, 942, 943, 944, 945, 952, 953, 954, 957, 958, 959, 963, 964, 965, 966, 970, 971, 972, 973, 974, 976, 979, 980, 982, 984, 988, 989, 990, 992, 995, 999, 1000, 1005, 1007, 1016, 1019, 1023, 1024, 1025, 1026, 1029, 1030, 1031, 1033, 1034, 1035, 1036, 1037, 1040, 1041, 1043, 1044, 1049, 1052, 1054, 1056, 1057, 1058, 1060, 1064, 1066, 1067, 1068, 1069, 1071, 1072, 1074, 1075, 1076, 1079, 1080, 1081, 1082, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1114, 1115, 1116, 1119, 1120, 1122 and 1126 have GI.sub.50 values in the range from 0.01 μM to 0.1 μM or provide at least 50% inhibition of growth at a concentration of 0.1 μM.

[1963] In the assays using A375, the compounds of Examples 262, 284, 303, 333, 345, 346, 434, 443, 446, 450, 456, 457, 458, 461, 462, 463, 465, 544, 545, 583, 584, 585, 586, 587, 588, 592, 596, 597, 598, 609, 647, 649, 652, 667, 675, 683, 684, 685, 686, 690, 694, 742, 757, 769, 782, 808, 812, 815, 859, 862, 880, 881, 891, 892, 909, 910, 911, 923, 930, 934, 947, 951, 997, 1017, 1021, 1022, 1061, 1062, 1063, 1070, 1083, 1125, 1127, 1128, 1129 and 1130 have GI.sub.50 values in the range from 0.001 μM to 0.01 μM or provide at least 50% inhibition of growth at a concentration of 0.01 μM.

[1964] The individual IC.sub.50 values for the compounds tested in Example A are set out in the table below.

TABLE-US-00052 Example ERK2 IC.sub.50 (μM) 1 0.21 2 0.0030 3 0.0039 4 0.0053 5 0.027 6 0.027 7 46% @ 0.0030 8 0.063 9 0.067 10 0.057 11 0.0019 12 0.27 13 0.014 14 0.016 15 0.023 16 0.0059 17 0.061 18 0.038 19 0.0068 20 0.035 21 0.0050 22 0.0028 23 0.025 24 0.11 25 0.0069 26 0.010 27 0.0039 28 0.29 29 0.014 30 0.19 31 0.044 32 0.10 33 0.031 34 0.0063 35 0.0079 36 0.77 37 0.13 38 0.0035 39 0.038 40 0.0064 41 0.035 42 0.0058 43 0.014 44 0.13 45 0.11 46 0.094 47 0.027 48 0.0088 49 0.045 50 0.020 51 0.17 52 0.062 53 0.027 54 0.027 55 0.0048 56 0.010 57 0.010 58 0.020 59 0.0034 60 0.083 61 0.160 62 0.032 63 0.019 64 0.015 65 0.15 66 0.034 67 48% @ 0.0030 68 0.061 69 0.11 70 0.041 71 0.18 72 0.0068 73 0.50 74 0.0065 75 0.02 76 0.0040 77 0.021 78 0.0052 79 49% @ 0.0010 80 0.0043 81 0.012 82 0.0099 83 0.032 84 0.0097 85 0.0060 86 0.0028 87 0.0040 88 0.016 89 0.20 90 0.043 91 0.056 92 0.14 93 53% @ 0.0030 94 0.0072 95 0.0065 96 0.0028 97 0.04 98 0.012 99 0.057 100 0.020 101 0.0046 102 0.074 103 0.0039 104 0.012 105 0.038 106 0.12 107 0.051 108 0.023 109 0.12 110 0.016 111 0.34 112 0.019 113 1.0 114 0.36 115 0.012 116 0.024 117 0.072 118 0.87 119 0.12 120 0.091 121 0.62 122 0.018 123 0.072 124 0.12 125 1.2 126 0.36 127 5.2 128 0.011 129 0.11 130 0.035 131 0.025 132 0.023 133 0.17 134 0.057 135 0.14 136 0.069 137 0.0087 138 0.16 139 0.16 140 0.12 141 0.009 142 0.033 143 0.17 144 0.023 145 0.032 146 0.034 147 0.09 148 0.029 149 0.032 150 0.010 151 0.0023 152 0.0044 153 0.011 154 0.014 155 0.098 156 0.11 157 0.030 158 0.13 159 40% @ 0.30 160 0.49 161 0.21 162 2.0 163 0.048 164 0.059 165 0.083 166 0.14 167 0.69 168 0.048 169 0.47 170 0.11 171 0.12 172 0.24 173 1.0 174 0.14 175 0.09 176 0.081 177 0.082 178 0.22 179 0.084 180 0.19 181 1.2 182 0.39 183 1.4 184 0.17 185 0.22 186 0.030 187 54% @ 1.0 188 41% @ 0.030 189 0.45 190 0.036 191 0.32 192 0.0068 193 0.0051 194 0.0094 195 0.0051 196 0.0034 197 0.004 198 0.11 199 0.3 200 0.053 201 0.01 202 0.041 203 0.014 204 0.21 205 0.012 206 0.014 207 0.0062 208 0.015 209 0.0033 210 0.01 211 0.019 212 0.013 213 0.095 214 0.01 215 0.33 216 0.022 217 0.042 218 0.014 219 0.01 220 0.021 221 0.0047 222 0.11 223 0.16 224 0.023 225 0.024 226 0.023 227 0.013 228 0.045 229 0.033 230 0.01 231 0.048 232 0.0018 233 0.033 234 0.01 235 0.0085 236 0.022 237 0.0069 238 0.015 239 0.0097 240 0.0061 241 0.0093 242 0.0086 243 0.65 244 0.0078 245 0.038 246 0.033 247 0.054 248 0.038 249 0.078 250 0.074 251 0.27 252 0.031 253 0.023 254 0.016 255 0.31 256 0.06 257 0.026 258 0.25 259 0.06 260 0.0065 261 54% @ 0.0010 μM 262 0.0021 263 0.0057 264 0.0025 265 57% @ 0.0030 μM 266 0.008 267 0.058 268 0.1 269 0.028 270 0.036 271 0.0054 272 0.012 273 0.036 274 0.061 275 0.039 276 0.1 277 0.079 278 0.031 279 0.38 280 0.0048 281 0.044 282 0.0024 283 0.0026 284 39% @ 0.0010 μM 285 0.2 286 0.032 287 0.004 288 0.016 289 0.0063 290 0.0085 291 0.0031 292 48% @ 0.0030 μM 293 0.019 294 0.002 295 0.018 296 0.16 297 0.2 298 1.8 299 1.2 300 0.053 301 0.18 302 0.14 303 0.002 304 0.015 305 0.45 306 0.72 307 0.21 308 0.36 309 0.12 310 1.3 311 0.023 312 0.035 313 0.088 314 0.42 315 0.014 316 71% @ 0.0010 μM 317 0.0037 318 0.0049 319 0.0059 320 0.011 321 0.0078 322 0.0026 323 0.0021 324 0.0019 325 48% @ 0.0010 μM 326 40% @ 0.0010 μM 327 40% @ 0.0010 μM 328 0.0046 329 0.029 330 0.092 331 0.23 332 59% @ 3.0 μM 333 51% @ 0.00050 μM, 51% @ 0.0010 μM 334 62% @ 0.0030 μM 335 0.0029 336 0.0016 337 0.0071 338 0.022 339 0.021 340 0.1 341 0.0038 342 0.0028 343 0.013 344 0.0098 345 57% @ 0.0030 μM 346 45% @ 0.0030 μM 347 0.0032 348 0.0031 349 0.0047 350 0.054 351 0.0035 352 0.0067 353 0.031 354 0.0052 355 0.0047 356 0.0044 357 0.0038 358 0.0056 359 0.0042 360 0.0039 361 0.035 362 0.016 363 0.22 364 0.08 365 0.0079 367 0.0043 368 0.011 369 0.0056 370 0.0026 371 45% @ 0.0010 μM 372 44% @ 0.0010 μM 373 0.015 374 0.035 375 0.025 376 0.053 377 0.05 378 0.14 379 0.027 380 0.011 381 0.0052 382 0.13 383 0.0017 384 0.0084 385 41% @ 0.0010 μM 386 0.00363 387 0.018 388 0.011 389 55% @ 0.0030 μM 390 0.0036 391 0.009 392 0.003 393 0.0042 394 0.034 395 0.0029 396 0.0089 397 0.0069 398 0.0034 399 0.0026 400 0.0024 401 51% @ 0.0030 μM 402 0.0036 403 49% @ 0.0030 μM 404 0.32 405 0.033 406 0.0085 407 0.027 408 0.1 409 0.032 410 0.059 411 0.35 412 0.026 413 0.017 414 0.11 415 0.007 416 0.03 417 0.024 418 0.022 419 0.011 420 0.062 421 0.0079 422 0.0042 423 0.0053 424 0.013 425 0.0029 426 0.036 427 0.027 428 0.0055 429 0.0045 430 0.0035 431 0.0037 432 42% @ 0.0010 μM 433 0.0069 434 57% @ 0.0010 μM 435 0.0064 436 0.0076 437 0.01 438 0.053 439 0.052 440 0.042 441 0.016 442 0.0069 443 0.0019 444 0.0023 445 48% @ 0.0010 μM 446 0.09 448 0.0051 449 0.055 450 0.0016 451 0.0017 452 37% @ 0.0010 μM 453 0.0064 454 0.009 455 0.0033 456 43% @ 0.0010 μM 457 54% @ 0.0010 μM 458 55% @ 0.0010 μM 459 51% @ 0.0010 μM 460 0.0025 461 43% @ 0.0010 μM 462 0.0021 463 0.002 464 0.087 465 0.0032 466 0.007 467 52% @ 0.0030 μM 469 0.0054 470 0.04 471 0.01 472 0.036 473 0.012 474 0.078 475 0.0033 476 0.0052 477 0.01 478 0.0024 479 0.016 480 0.0028 481 0.0082 482 0.003 483 0.19 484 0.082 485 0.021 486 0.15 487 0.021 488 0.0047 489 0.066 490 0.033 491 0.062 492 0.15 493 0.03 494 0.11 495 0.0094 496 0.18 497 0.012 498 0.0022 499 0.0035 500 0.0073 501 0.24 502 0.052 503 0.17 504 0.0024 505 0.027 506 0.06 507 0.028 508 61% @ 0.0030 μM 509 0.0029 510 0.0028 511 0.0036 512 0.0082 513 0.2 514 0.0065 515 0.25 516 0.014 517 0.0034 518 0.051 519 0.016 520 0.38 521 0.66 522 0.0054 523 0.023 524 0.049 525 0.0051 526 0.0069 528 0.15 529 0.0078 530 0.48 531 0.029 532 0.23 533 0.046 534 0.29 535 0.014 536 0.14 537 0.02 538 0.01 539 53% @ 0.0030 μM 540 0.0028 541 0.15 542 0.0025 543 0.009 544 60% @ 0.0030 μM 545 0.0017 546 0.2 547 0.035 548 0.005 549 0.0084 550 0.055 551 0.14 552 0.031 553 0.12 554 0.0021 555 0.0066 556 0.11 557 0.1 558 0.0085 559 0.017 560 0.0046 561 0.018 562 61% @ 0.0030 μM 563 0.01 564 0.016 565 0.0048 566 0.03 567 0.005 568 0.031 569 0.045 570 0.021 571 0.006 572 0.32 573 0.015 574 0.008 575 0.0086 576 0.27 577 0.15 578 0.046 579 0.051 580 0.015 581 0.17 582 0.041 583 40% @ 0.0010 μM, 55% @ 0.0030 μM 584 48% @ 0.0030 μM 585 65% @ 0.0030 μM 586 57% @ 0.0030 μM 587 35% @ 0.0010 μM 588 0.002 589 0.011 590 0.035 591 0.0033 592 38% @ 0.0030 μM 593 0.0029 594 0.39 595 0.097 596 0.0019 597 0.0029 598 43% @ 0.0010 μM 599 0.015 600 0.0085 601 0.0089 602 0.0036 603 0.0043 604 0.008 605 0.011 606 0.0048 607 32% @ 0.0030 μM 608 0.005 609 47% @ 0.0010 μM, 50% @0.0030 μM 610 0.057 611 62% @ 0.0030 μM 612 0.0034 613 0.0025 614 0.004 615 0.0013 616 0.0023 617 0.38 618 0.13 619 0.087 620 0.52 621 0.0017 622 60% @ 0.0030 μM 623 41% @ 0.0010μM 624 43% @ 0.0010 μM 625 0.0027 626 41% @ 0.0010 μM 627 0.0059 628 0.004 629 0.0037 630 0.0075 631 0.0067 632 0.013 633 0.006 634 0.0034 635 0.0021 636 0.021 637 0.021 638 42% @ 0.0030 μM 639 0.0055 640 0.0038 641 42% @ 0.0010 μM 642 0.0017 643 0.0065 644 0.0021 645 55% @ 0.0030 μM 646 0.016 647 47% @ 0.0030 μM 648 45% @ 0.0030 μM 649 50% @ 0.0030 μM 650 0.0051 651 0.0061 652 0.0032 653 0.0026 654 0.0026 655 54% @ 0.0030 μM 656 0.0024 657 0.0023 658 0.0044 659 46% @ 0.0030 μM 660 0.0064 661 0.0099 662 0.015 663 0.0024 664 62% @ 0.0030 μM 665 0.003 666 0.0094 667 0.029 668 0.035 669 0.0028 670 42% @ 0.0030 μM 671 0.0046 672 42% @ 0.0010 μM 673 0.0051 674 0.0025 675 0.0013 676 0.0083 677 0.0062 678 0.0092 679 0.015 680 44% @ 0.10 μM 681 0.0034 682 60% @ 0.0030 μM 683 0.003 684 0.003 685 0.0025 686 0.0027 687 0.0028 688 0.0026 689 0.0026 690 63% @ 0.0030 μM 691 0.031 692 0.0032 693 0.0046 694 0.0025 695 0.03 696 0.0035 697 0.0020 698 0.0023 699 37% @ 0.0010 μM 701 44% @ 0.0030 μM 702 65% @ 0.0030 μM 703 0.0074 705 37% @ 0.0010 μM 706 0.77 707 0.01 708 61% @ 0.0030 μM 709 0.37 711 0.0024 712 0.009 713 55% @ 0.0030 μM 714 36% @ 0.010 μM 715 60% @ 0.0010 μM 716 0.003 717 0.0051 718 0.086 719 0.005 720 0.0067 721 43% @ 0.0010 μM 722 56% @ 0.0030 μM 723 0.029 724 0.16 725 0.036 726 0.011 727 64% @ 0.010 μM 728 0.0038 730 59% @ 0.030 μM 731 45% @ 0.010 μM 732 72% @ 0.030 μM 733 0.015 734 0.012 735 0.0023 737 0.0064 738 45% @ 0.0030 μM 740 0.0021 741 0.035 742 64% @ 0.0030 μM 743 49% @ 0.0030 μM 744 0.04 745 0.022 746 0.0067 747 0.0082 748 0.055 749 0.15 750 0.18 751 0.025 752 0.11 753 66% @ 0.0030 μM 754 0.0076 755 0.021 756 0.0028 757 0.0028 758 0.051 759 0.0055 761 0.037 762 0.2 763 0.0029 764 0.013 765 0.0031 766 0.2 767 0.006 768 56% @ 0.0030 μM 769 40% @ 0.0030 μM 770 33% @ 0.0030 μM 771 53% @ 0.030 μM 773 0.03 774 0.0029 775 0.016 776 0.0026 777 0.0076 778 0.062 779 0.0062 780 0.0044 781 0.0026 782 0.0036 783 0.0038 784 0.002 785 0.0039 786 58% @ 0.0030 μM 787 0.0054 788 54% @ 0.0010 μM 789 42% @ 0.0010 μM 790 0.012 791 0.062 792 0.017 793 0.5 794 0.18 796 0.031 797 0.098 798 0.0061 799 33% @ 0.0010 μM 800 0.0027 801 0.0054 802 0.002 803 0.0017 804 0.002 805 0.0018 806 0.0033 808 71% @ 0.0030 μM 809 37% @ 0.0010 μM 810 64% @ 0.0030 μM 811 68% @ 0.0030 μM 812 60% @ 0.0030 μM 813 0.013 814 0.01 815 71% @ 0.0030 μM 816 0.0043 817 52% @ 0.0030 μM 818 0.0035 819 0.0019 820 0.0024 821 0.37 822 0.0032 823 0.0019 824 0.0026 825 0.0026 826 0.0035 827 60% @ 0.0030 μM 828 0.0017 829 0.083 830 0.0086 831 0.0077 832 0.024 833 0.027 834 0.0073 835 0.0074 836 0.0097 837 64% @ 0.0030 μM 838 0.0028 839 0.014 840 0.0099 841 0.0043 842 0.064 843 49% @ 0.0030 μM 844 0.0026 846 0.0088 847 0.0046 848 0.0069 849 0.0091 850 43% @ 0.0010 μM 851 40% @ 0.0010 μM 852 57% @ 0.0030 μM 853 39% @ 0.0010 μM 854 0.052 855 0.0065 856 0.0028 857 47% @ 0.0010 μM 858 71% @ 0.0030 μM 859 35% @ 0.0010 μM 864 0.0031 865 0.0024 866 54% @ 0.030 μM 867 0.0069 868 0.0055 869 0.0025 870 54% @ 0.0030 μM 871 0.0095 872 0.0016 873 64% @ 0.0030 μM 874 0.26 875 0.0045 876 0.0067 877 0.004 878 0.0023 879 36% @ 0.010 μM 880 0.0033 881 56% @ 0.0030 μM 882 0.0038 883 55% @ 0.0030 μM 884 0.019 885 0.054 886 0.01 887 0.0018 888 63% @ 0.0030 μM 889 0.011 890 0.0023 891 0.0018 892 67% @ 0.0030 μM 893 0.21 894 0.002 895 0.005 896 42% @ 0.0010 μM 897 47% @ 0.0010 μM 898 55% @ 0.0030 μM 899 0.07 900 0.0036 901 0.012 902 0.0033 903 56% @ 0.0030 μM 904 0.024 905 0.1 906 0.047 907 0.002 908 0.0039 909 0.0018 910 0.0024 911 42% @ 0.0030 μM 912 0.0058 913 0.0028 914 0.0033 915 0.0041 916 0.068 917 0.31 918 0.0023 919 0.0021 920 64% @ 0.0030 μM 921 0.0027 922 57% @ 0.0030 μM 924 0.0035 925 43% @ 0.0010 μM 926 42% @ 0.0030 μM 927 0.0037 928 40% @ 0.0030 μM 929 0.0018 930 35% @ 0.0010 μM 931 0.0025 932 0.009 933 0.054 934 0.0011 935 47% @ 0.0030 μM 936 0.0017 937 0.15 938 0.3 939 40% @ 3.0 μM 940 0.0073 941 0.0041 942 0.0021 943 0.0025 944 0.0057 945 0.0021 946 0.011 947 0.0013 948 0.057 949 0.0034 950 0.0055 951 65% @ 0.0030 μM 952 0.0017 953 0.0015 954 0.0044 955 0.03 956 0.0061 957 38% @ 0.0010 μM 958 0.0052 959 44% @ 0.0010 μM 960 0.0052 961 0.0039 962 0.0016 963 0.004 964 0.0021 965 0.0024 966 0.0047 967 0.57 968 0.003 969 0.071 970 0.0031 971 0.004 972 0.0029 973 40% @ 0.0010 μM 974 0.0029 975 0.0051 976 0.0021 977 0.0023 978 62% @ 0.30 μM 979 52% @ 0.0030 μM 980 0.0051 981 0.0073 982 0.0034 983 0.0074 984 0.0026 985 0.0035 986 0.0056 987 0.0041 988 0.0014 989 48% @ 0.0010 μM 990 0.003 991 0.19 992 0.0031 993 0.43 994 0.12 995 66% @ 0.0030 μM 996 0.0015 997 0.0014 998 0.027 999 0.0023 1000 70% @ 0.0050 μM 1001 0.0026 1002 0.0035 1003 0.0028 1004 0.0037 1005 0.0019 1006 54% @ 1.0 μM 1007 0.0021 1008 0.0028 1009 0.07 1010 0.0055 1011 0.0028 1012 0.038 1013 0.2 1014 0.0071 1015 42% @ 0.0010 μM 1016 0.0021 1017 38% @ 0.0010 μM 1018 0.0056 1019 43% @ 0.0010 μM 1020 0.0044 1021 60% @ 0.0030 μM 1022 0.0027 1023 35% @ 0.0010 μM 1024 0.0028 1025 0.0026 1026 0.0037 1027 0.0047 1029 0.0035 1030 0.0034 1031 0.0023 1032 0.07 1033 0.003 1034 35% @ 0.0010 μM 1035 0.0039 1036 0.0035 1038 0.0027 1039 0.0026 1040 69% @ 0.0030 μM 1041 38% @ 0.0010 μM 1042 52% @ 0.0030 μM 1043 65% @ 0.0030 μM 1044 41% @ 0.0010 μM 1045 0.0017 1046 0.0037 1047 44% @ 0.0010 μM 1048 0.0015 1049 50% @ 0.0030 μM 1050 42% @ 0.0010 μM 1051 0.0026 1052 0.0044 1053 0.0083 1054 0.0018 1055 0.041 1056 54% @ 0.0010 μM 1057 0.0022 1058 0.0017 1059 0.11 1060 51% @ 0.0030 μM 1061 68% @ 0.0030 μM 1062 0.0022 1063 0.0016 1064 0.0024 1065 63% @ 0.0030 μM 1066 0.0031 1067 38% @ 0.0010 μM 1068 0.0037 1069 0.004 1070 51% @ 0.0030 μM 1071 65% @ 0.0030 μM 1072 0.0012 1073 0.0021 1074 0.01 1075 0.0027 1076 0.0028 1077 0.004 1078 0.003 1079 48% @ 0.0010 μM 1080 45% @ 0.0010 μM 1081 0.0054 1082 0.017 1083 0.0023 1084 0.012 1085 0.003 1086 0.0023 1087 56% @ 0.010 μM 1088 0.0094 1089 0.0029 1090 0.0044 1091 0.059 1092 32% @ 0.0010 μM 1093 45% @ 0.0010 μM 1094 38% @ 0.0010 μM 1095 0.0016 1096 65% @ 0.0030 μM 1097 0.0026 1098 71% @ 0.0030 μM 1099 36% @ 0.0010 μM 1100 70% @ 0.010 μM 1101 35% @ 0.0010 μM 1102 61% @ 0.0030 μM 1103 67% @ 0.0030 μM 1104 37% @ 0.0030 μM 1105 0.0016 1106 0.0022 1107 0.0043 1108 0.0032 1109 0.0031 1110 46% @ 0.0010 μM 1111 51% @ 0.0030 μM 1112 0.0015 1113 0.0075 1114 0.0015 1115 0.0016 1116 59% @ 0.0030 μM 1117 0.0028 1118 0.0029 1119 41% @ 0.0010 μM 1120 0.003 1121 45% @ 0.0030 μM 1122 0.0024 1123 0.0033 1124 0.0025 1125 50% @ 0.0010 μM 1126 0.0028 1127 60% @ 0.0030 μM 1128 43% @ 0.0030 μM 1129 0.0024 1130 51% @ 0.0010 μM 1131 0.0059 1132 0.0060 1133 0.071 1134 47% @ 0.0030 μM

Combination Protocol for Cell Proliferation

[1965] The effect of a compound of formula (0) (Compound I) in combination with an anticancer agent (Compound II) can be assessed using the following technique. Human cancer cell lines (e.g. A375) were seeded onto 96-well tissue culture plates at a concentration of 2×10.sup.3-4×10.sup.3 cells/well. Cells were allowed to recover for 16-24 hours prior to addition of compound(s) or DMSO control (0.1-0.5% DMSO). Cells were incubated with compound in 0.1%-0.5% (v/v) dimethyl sulfoxide (DMSO) for 72-96 hours, before addition of 20 μl Alamar blue. After a further 6 h incubation at 37° C. the plate was read on a Spectramax Gemini reader (Molecular Devices; excitation 535 nm, emission 590 nm). GI.sub.50 values were calculated using a sigmoidal dose response equation (Prism GraphPad software, La Jolla, Calif., USA). The GI.sub.50 for Compound II in the presence of varying doses of Compound I was determined. Synergy was determined when the GI.sub.50 shifted down in the presence of sub-effective doses of Compound I. Additivity was determined when the response to Compound II and Compound I together resulted in an effect equivalent to the sum of the two compounds individually. Antagonistic effects were defined as those causing the GI.sub.50 to shift upwards, i.e. those where the response to the two compounds was less than the sum of the effect of the two compounds

Pharmaceutical Formulations

(i) Tablet Formulation

[1966] A tablet composition containing a compound of formulae (0), (1) and subformulae thereof as defined herein is prepared by mixing an appropriate amount of the compound (for example 50-250 mg) with an appropriate diluent, disintegrant, compression agent and/or glidant. One possible tablet comprises 50 mg of the compound with 197 mg of lactose (BP) as diluent, and 3 mg magnesium stearate as a lubricant and compressing to form a tablet in known manner. The compressed tablet may be optionally film coated.

(ii) Capsule Formulation

[1967] A capsule formulation is prepared by mixing 100-250 mg (e.g 100 mg) of a compound of formulae (0), (1) and subformulae thereof as defined herein with an equivalent amount of lactose (e.g. 100 mg) and filling the resulting mixture into standard opaque hard gelatin capsules. An appropriate disintegrant and/or glidant can be included in appropriate amounts as required.

(iii) Injectable Formulation I

[1968] A parenteral composition for administration by injection can be prepared by dissolving a compound of formulae (0), (1) and subformulae thereof as defined herein (e.g. in a salt form) in water containing 10% propylene glycol to give a concentration of active compound of 1.5% by weight. The solution is then sterilised by filtration, filled into an ampoule and sealed. Optionally the solution can be made isotonic before sterilisation.

(iv) Injectable Formulation II

[1969] A parenteral composition for injection is prepared by dissolving in water a compound of formulae (0), (1) and subformulae thereof as defined herein (e.g. in salt form) (2 mg/ml) and mannitol (50 mg/ml), sterile filtering the solution and filling into sealable 1 ml vials or ampoules or pre-filled syringe.

(v) Injectable Formulation III

[1970] A formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of formulae (0), (1) and subformulae thereof (e.g. in a salt form) in water at 20 mg/ml and optionally then adjusted for isotonicity. The vial is then sealed and sterilised by autoclaving. Alternatively it may be filled into an ampoule or vial or pre-filled syringe, sterilised by filtration and sealed.

(vi) Injectable Formulation IV

[1971] A formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of formulae (0), (1) and subformulae thereof (e.g. in a salt form) in water containing a buffer (e.g. 0.2 M acetate pH 4.6) at 20 mg/ml. The vial is then sealed and sterilised by autoclaving. Alternatively a pre-filled syringe is then sealed and sterilised by autoclaving or sterilized by filtration and sealed.

(vii) Subcutaneous or Intramuscular Injection Formulation

[1972] A composition for sub-cutaneous (or intramuscular) administration is prepared by mixing a compound of formulae (0), (1) and subformulae thereof as defined herein with pharmaceutical grade corn oil to give a concentration of 5-50 mg/ml (e.g. 5 mg/ml). The composition is sterilised and filled into a suitable container.

(viii) Lyophilised Formulation

[1973] Aliquots of formulated compound of formulae (0), (1) and subformulae thereof are put into 50 ml vials and lyophilized. During lyophilisation, the compositions are frozen using a one-step freezing protocol at (−45° C.). The temperature is raised to −10° C. for annealing, then lowered to freezing at −45° C., followed by primary drying at +25° C. for approximately 3400 minutes, followed by a secondary drying with increased steps if temperature to 50° C. The pressure during primary and secondary drying is set at 80 millitor.

(ix) Lyophilised Formulation II

[1974] Aliquots of formulated compound of formulae (0), (1) and subformulae thereof or a salt thereof as defined herein are put into 50 mL vials and lyophilized. During lyophilisation, the compositions are frozen using a one-step freezing protocol at (−45° C.). The temperature is raised to −10° C. for annealing, then lowered to freezing at −45° C., followed by primary drying at +25° C. for approximately 3400 minutes, followed by a secondary drying with increased steps if temperature to 50° C. The pressure during primary and secondary drying is set at 80 millitor.

(x) Lyophilised Formulation for Use in i.v. Administration III

[1975] An aqueous buffered solution is prepared by dissolving a compound of formulae (0), (1) and subformulae thereof in a buffer. The buffered solution is filled, with filtration to remove particulate matter, into a container (such as a Type 1 glass vial) which is then partially sealed (e.g. by means of a Fluorotec stopper). If the compound and formulation are sufficiently stable, the formulation is sterilised by autoclaving at 121° C. for a suitable period of time. If the formulation is not stable to autoclaving, it can be sterilised using a suitable filter and filled under sterile conditions into sterile vials. The solution is freeze dried using a suitable cycle. On completion of the freeze drying cycle the vials are back filled with nitrogen to atmospheric pressure, stoppered and secured (e.g. with an aluminium crimp). For intravenous administration, the freeze dried solid can be reconstituted with a pharmaceutically acceptable diluent, such as 0.9% saline or 5% dextrose. The solution can be dosed as is, or can be diluted further into an infusion bag (containing a pharmaceutically acceptable diluent, such as 0.9% saline or 5% dextrose), before administration.

(xii) Powder in a Bottle

[1976] A composition for oral administration is prepared by filling a bottle or vial with a compound of formulae (0), (1) and subformulae thereof. The composition is then reconstituted with a suitable diluent for example water, fruit juice, or commercially available vehicle such as OraSweet or Syrspend. The reconstituted solution may be dispensed into dosing cups or oral syringes for administration.