WO2009007748A2 - Trisubstituted pyrimidine derivatives for the treatment of proliferative diseases - Google Patents

Trisubstituted pyrimidine derivatives for the treatment of proliferative diseases Download PDF

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WO2009007748A2
WO2009007748A2 PCT/GB2008/050546 GB2008050546W WO2009007748A2 WO 2009007748 A2 WO2009007748 A2 WO 2009007748A2 GB 2008050546 W GB2008050546 W GB 2008050546W WO 2009007748 A2 WO2009007748 A2 WO 2009007748A2
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alkyl
6alkyl
bis
amino
phenyl
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PCT/GB2008/050546
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French (fr)
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WO2009007748A3 (en
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Jeffrey James Morris
Kurt Gordon Pike
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Astrazeneca Ab
Astrazeneca Uk Limited
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Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Priority to AU2008273889A priority Critical patent/AU2008273889B2/en
Priority to CN200880106248A priority patent/CN101801962A/en
Priority to BRPI0814818A priority patent/BRPI0814818A2/en
Priority to EP08776181A priority patent/EP2074118A2/en
Priority to EA201000092A priority patent/EA201000092A1/en
Priority to JP2010515600A priority patent/JP2010533158A/en
Priority to CA 2692945 priority patent/CA2692945A1/en
Publication of WO2009007748A2 publication Critical patent/WO2009007748A2/en
Publication of WO2009007748A3 publication Critical patent/WO2009007748A3/en
Priority to ZA2010/00106A priority patent/ZA201000106B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to morpholino pyrimidine compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of proliferative disease such as cancer and particularly in disease mediated by an mTOR kinase and/or one or more PBK enzyme.
  • tumour-suppressor genes contributes to the formation of malignant tumours, for example by way of increased cell proliferation or increased cell survival. It is also known that signalling pathways mediated by the PBK/mTOR families have a central role in a number of cell processes including proliferation and survival, and deregulation of these pathways is a causative factor in a wide spectrum of human cancers and other diseases.
  • the mammalian target of the macrolide antibiotic Rapamycin is the enzyme mTOR.
  • This enzymes belongs to the phosphatidylinositol (PI) kinase-related kinase (PIKK) family of protein kinases, which also includes ATM, ATR, DNA-PK and hSMG-1.
  • PIKK phosphatidylinositol
  • mTOR like other PIKK family members, does not possess detectable lipid kinase activity, but instead functions as a serine/threonine kinase. Much of the knowledge of mTOR signalling is based upon the use of Rapamycin.
  • Rapamycin first binds to the 12 kDa immunophilin FK506- binding protein (FKBP 12) and this complex inhibits mTOR signalling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37).
  • the mTOR protein consists of a catalytic kinase domain, an FKBP12-Rapamycin binding (FRB) domain, a putative repressor domain near the C-terminus and up to 20 tandemly-repeated HEAT motifs at the TV- terminus, as well as FRAP -ATM-TRRAP (FAT) and FAT C-terminus domain (Huang and Houghton, Current Opinion in Pharmacology, 2003, 3, 371-377).
  • mTOR kinase is a key regulator of cell growth and has been shown to regulate a wide range of cellular functions including translation, transcription, mRNA turnover, protein stability, actin cytoskeleton reorganisation and autophagy (Jacinto and Hall, Nature Reviews Molecular and Cell Biology, 2005, 4, 117-126).
  • mTOR kinase integrates signals from growth factors (such as insulin or insulin-like growth factor) and nutrients (such as amino acids and glucose) to regulate cell growth.
  • growth factors such as insulin or insulin-like growth factor
  • nutrients such as amino acids and glucose
  • mTOR kinase The most well characterised function of mTOR kinase in mammalian cells is regulation of translation through two pathways, namely activation of ribosomal S6K1 to enhance translation of mRNAs that bear a 5 '-terminal oligopyrimidine tract (TOP) and suppression of 4E-BP1 to allow CAP-dependent mRNA translation.
  • TOP 5 '-terminal oligopyrimidine tract
  • PI3K pathway the pathways upstream of mTOR, such as the PI3K pathway, are frequently activated in cancer.
  • components of the PI3K pathway that are mutated in different human tumours include activating mutations of growth factor receptors and the amplification and/or overexpression of PI3K and Akt.
  • endothelial cell proliferation may also be dependent upon mTOR signalling.
  • Endothelial cell proliferation is stimulated by vascular endothelial cell growth factor (VEGF) activation of the PI3K-Akt-mTOR signalling pathway (Dancey, Expert Opinion on Investigational Drugs, 2005, 14, 313-328).
  • VEGF vascular endothelial cell growth factor
  • mTOR kinase signalling is believed to partially control VEGF synthesis through effects on the expression of hypoxia- inducible factor- l ⁇ (HIF- l ⁇ ) (Hudson et al, Molecular and Cellular Biology, 2002, 22, 7004- 7014).
  • tumour angiogenesis may depend on mTOR kinase signalling in two ways, through hypoxia-induced synthesis of VEGF by tumour and stromal cells, and through VEGF stimulation of endothelial proliferation and survival through PI3K-Akt-mTOR signalling.
  • pharmacological inhibitors of mTOR kinase should be of therapeutic value for treatment of the various forms of cancer comprising solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies.
  • inhibitors of mTOR kinase should be of therapeutic value for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
  • cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva,
  • tumour suppressor proteins such as TSCl, TSC2, PTEN and LKBl tightly control mTOR kinase signalling. Loss of these tumour suppressor proteins leads to a range of hamartoma conditions as a result of elevated mTOR kinase signalling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37).
  • mTOR kinase Syndromes with an established molecular link to dysregulation of mTOR kinase include Peutz-Jeghers syndrome (PJS), Cowden disease, Bannayan-Riley- Ruvalcaba syndrome (BRRS), Proteus syndrome, Lhermitte-Duclos disease and Tuberous Sclerosis (TSC) (Inoki et ah, Nature Genetics, 2005, 37, 19-24). Patients with these syndromes characteristically develop benign hamartomatous tumours in multiple organs. Recent studies have revealed a role for mTOR kinase in other diseases (Easton & Houghton, Expert Opinion on Therapeutic Targets, 2004, 8, 551-564).
  • Rapamycin has been demonstrated to be a potent immunosuppressant by inhibiting antigen-induced proliferation of T cells, B cells and antibody production (Sehgal, Transplantation Proceedings, 2003, 35, 7S- 14S) and thus mTOR kinase inhibitors may also be useful immunosuppressives. Inhibition of the kinase activity of mTOR may also be useful in the prevention of restenosis, that is the control of undesired proliferation of normal cells in the vasculature in response to the introduction of stents in the treatment of vasculature disease (Morice et ah, New England Journal of Medicine, 2002, 346, 1773-1780).
  • mTOR kinase inhibitors are expected to be of value in the prevention and treatment of a wide variety of diseases in addition to cancer.
  • PI phosphatidylinositol
  • PI 3-kinases Phosphatidylinositol 3-kinases
  • All PBKs are dual-specificity enzymes with a lipid kinase activity that phosphorylates phosphoinositides at the 3 -hydroxy position, and a less well characterised protein kinase activity.
  • PI(3)P phosphatidylinositol 3,4,5-trisphosphate
  • PI(3,4)P 2 phosphatidylinositol 3,4- bisphosphate
  • PI(3)P phosphatidylinositol 3 -monophosphate
  • PI(3)P is constitutively present in all cells and its levels do not change dramatically following agonist stimulation.
  • PI(3,4)P 2 and PI(3,4,5)P 3 are nominally absent in most cells but they rapidly accumulate on agonist stimulation.
  • PBK-produced 3-phosphoinositide second messengers are mediated by target molecules containing 3-phosphoinositide binding domains such as the pleckstrin homology (PH) domain and the recently identified FYVE and phox domains.
  • target molecules containing 3-phosphoinositide binding domains such as the pleckstrin homology (PH) domain and the recently identified FYVE and phox domains.
  • Well-characterised protein targets for PBK include PDKl and protein kinase B (PKB).
  • PKA protein kinase B
  • tyrosine kinases like Btk and Itk are dependent on PBK activity.
  • the PBK family of lipid kinases can be classified into three groups according to their physiological substrate specificity (Vanhaesebroeck et al, Trends in Biol. ScL, 1997, 22, 267).
  • Class III PBK enzymes phosphorylate PI alone.
  • Class II PBK enzymes phosphorylate both PI and PI 4-phosphate [PI(4)P].
  • Class I PBK enzymes phosphorylate PI, PI(4)P and PI 4,5-bisphosphate [PI(4,5)P 2 ], although only PI(4,5)P 2 is believed to be the physiological cellular substrate. Phosphorylation of PI(4,5)P 2 produces the lipid second messenger PI(3,4,5)P3.
  • Class IV kinases such as mTOR (discussed above) and DNA-dependent kinase that phosphorylate serine/threonine residues within protein substrates.
  • mTOR DNA-dependent kinase that phosphorylate serine/threonine residues within protein substrates.
  • PBK lipid kinases
  • Class I PBKs are heterodimers consisting of a pi 10 catalytic subunit and a regulatory subunit.
  • the family is further divided into Class Ia and Class Ib enzymes on the basis of regulatory partners and the mechanism of regulation.
  • Class Ia enzymes consist of three distinct catalytic subunits (pi 10a, pi lO ⁇ and pi lO ⁇ ) that dimerise with five distinct regulatory subunits (p85 ⁇ , p55 ⁇ , p50 ⁇ , p85 ⁇ and p55 ⁇ ), with all catalytic subunits being able to interact with all regulatory subunits to form a variety of heterodimers.
  • Class Ia PBKs are generally activated in response to growth factor-stimulation of receptor tyrosine kinases via interaction of their regulatory subunit SH2 domains with specific phospho-tyrosine residues of activated receptor or adaptor proteins such as IRS-I .
  • Both pi 10 ⁇ and pi lO ⁇ are constitutively expressed in all cell types, whereas pi lO ⁇ expression is more restricted to leukocyte populations and some epithelial cells.
  • the single Class Ib enzyme consists of a pi lO ⁇ catalytic subunit that interacts with a plOl regulatory subunit.
  • GPCRs G-protein coupled receptor systems
  • Class Ia PBKs contributes to tumourigenic events that occur upstream in signalling pathways, for example by way of ligand-dependent or ligand-independent activation of receptor tyrosine kinases, GPCR systems or integrins (Vara et al., Cancer Treatment Reviews, 2004, 30, 193-204).
  • upstream signalling pathways include over- expression of the receptor tyrosine kinase erbB2 in a variety of tumours leading to activation of PBK-mediated pathways (Harari et al., Oncogene, 2000, 19, 6102-6114) and over-expression of the ras oncogene (Kauffmann-Zeh et al., Nature, 1997, 385, 544-548).
  • Class Ia PBKs may contribute indirectly to tumourigenesis caused by various downstream signalling events.
  • loss of the effect of the PTEN tumour-suppressor phosphatase that catalyses conversion of PI(3,4,5)P3 back to PI(4,5)P 2 is associated with a very broad range of tumours via deregulation of PBK-mediated production of PI(3,4,5)P3 (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41).
  • augmentation of the effects of other PBK- mediated signalling events is believed to contribute to a variety of cancers, for example by activation of Akt (Nicholson and Anderson, Cellular Signalling, 2002, 14, 381-395).
  • Class Ia PI3K enzymes contribute to tumourigenesis in tumour- associated stromal cells.
  • PI3K signalling is known to play an important role in mediating angiogenic events in endothelial cells in response to pro-angiogenic factors such as VEGF (Abid et al, Arterioscler. Thromb. Vase. Biol, 2004, 24, 294-300).
  • VEGF vascular endothelial growth factor
  • Class I PI3K enzymes are also involved in motility and migration (Sawyer, Expert Opinion Investig. Drugs, 2004, 13, 1-19), PI3K enzyme inhibitors should provide therapeutic benefit via inhibition of tumour cell invasion and metastasis.
  • Class I PI3K enzymes play an important role in the regulation of immune cells contributing to pro-tumourigenic effects of inflammatory cells (Coussens and Werb, Nature, 2002, 420, 860-867).
  • inhibitors of Class I PI3K enzymes should be of therapeutic value for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
  • cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva,
  • PI3K ⁇ the Class Ib PI3K
  • GPCRs GPCRs
  • neutrophils and macrophages derived from PI3K ⁇ -deficient animals failed to produce PI(3,4,5)P3 in response to stimulation with various chemotactic substances (such as IL-8, C5a, fMLP and MIP-Ia), whereas signalling through protein tyrosine kinase- coupled receptors to Class Ia PBKs was intact (Hirsch et al., Science, 2000, 287(5455), 1049- 1053; Li et al, Science, 2002, 287(5455), 1046-1049; Sasaki et al., Science 2002, 287(5455), 1040-1046).
  • PI(3,4,5)P3-mediated phosphorylation of PKB was not initiated by these GPCR ligands in PI3K ⁇ -null cells.
  • murine bone marrow-derived neutrophils and peritoneal macrophages from wild- type and PBKy "7" mice were tested in vitro, a reduced, but not completely abrogated, performance in chemotaxis and adherence assays was observed.
  • PBK phosphatidylinositol
  • PBKKs phosphatidylinositol
  • arylamino- and heteroarylamino-substituted pyrimidines which differ from the compounds of the present invention by virtue of their arylamino- and heteroarylamino substituents.
  • WO 2004/048365 does not disclose compounds with the -XR 1 substituents of the present invention.
  • Inhibitors of PBK activity useful in the treatment of cancer are also disclosed in European Patent Application 1 277 738 which mentions 4-morpholino-substituted bicyclic heteroaryl compounds such as quinazoline and pyrido[3,2-J]pyrimidine derivatives and A- morpholino-substituted tricyclic heteroaryl compounds but not monocyclic pyrimidine derivatives.
  • WO2007/080382, WO2008/023180 and WO2008/023159 disclose compounds that possess mTOR and/or PBK enzyme inhibitory activity and are useful in the treatment of cancer.
  • WO2007/080382, WO2008/023180 and WO2008/023159 do not disclose compounds comprising a cyclic moiety in the linker group X in the group -XR 1 .
  • morpholino pyrimidine derivatives possess useful therapeutic properties. Without wishing to be bound by theoretical constraints, it is believed that the therapeutic usefulness of the derivatives is derived from their inhibitory activity against mTOR kinase and/or one or more PBK enzyme (such as the Class Ia enzyme and/or the Class Ib enzyme). Because signalling pathways mediated by the PBK/mTOR families have a central role in a number of cell processes including proliferation and survival, and because deregulation of these pathways is a causative factor in a wide spectrum of human cancers and other diseases, it is expected that the derivatives will be therapeutically useful.
  • PBK enzyme such as the Class Ia enzyme and/or the Class Ib enzyme
  • the derivatives will have anti-proliferative and/or apoptotic properties which means that they will be useful in the treatement of proliferative disease such as cancer.
  • the compounds of the present invention may also be useful in inhibiting the uncontrolled cellular proliferation which arises from various non-malignant diseases such as inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases.
  • the compounds of the present invention possess potent inhibitory activity against mTOR kinase but the compound may also possess potent inhibitory activity against one or more PBK enzyme (such as the Class Ia enzyme and/or the Class Ib enzyme).
  • PBK enzyme such as the Class Ia enzyme and/or the Class Ib enzyme.
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • R 1 is a group selected from hydrogen, Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl and heterocyclylCi- ⁇ alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -SR 9 , -
  • R 2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , -
  • each R 3 when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -SR 13 , -SOR 13 , -SO 2 R 13 , -COR 13 , -CO 2 R 13 , -CONR 13 R 14 , -NR 13 R 14 , -NR 13 COR 14 , -NR 13 CO 2 R 14 and -NR 13 SO 2 R 14 ;
  • R 4 and R 5 are independently hydrogen or Ci_ 6 alkyl; or R 1 and R 4 together with the atom or atoms to which they are attached form a 4- to
  • Ci-6alkyl hydroxyCi-6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci- 6 alkyl)amino, aminoCi- 6 alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi -6 alkyl, Ci -6 alkylsulfonyl, Ci -6 alkylsulfonylamino, Ci-ealkylsulfony ⁇ d-ealkyFjamino, sulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, C 1- OaIk-UiOyI(C 1- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(
  • R 11 , R 12 , R 17 and R 18 are independently hydrogen or a group selected from C 1-6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is 5 optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi.
  • R 13 , R 14 , R 15 and R 16 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi_ 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi.
  • R 19 is hydrogen, cyano or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, Ci_6alkoxy, haloCi.
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • R 1 is a group selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, carbocyclylCi- 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -SR 9 , -
  • R 2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -
  • each R 3 when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -SR 13 , -SOR 13 , -SO 2 R 13 , -COR 13 , -CO 2 R 13 , -CONR 13 R 14 , -NR 13 R 14 , -NR 13 COR 14 , -NR 13 CO 2 R 14 and -NR 13 SO 2 R 14 ;
  • R 4 and R 5 are independently hydrogen or Ci_ 6 alkyl; or R 1 and R 4 together with the atom or atoms to which they are attached form a 4- to
  • Ci-6alkyl hydroxyCi-6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci- 6 alkyl)amino, aminoCi- 6 alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi -6 alkyl, Ci -6 alkylsulfonyl, Ci -6 alkylsulfonylamino, Ci-ealkylsulfony ⁇ d-ealkyFjamino, sulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, C 1- OaIk-UiOyI(C 1- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(
  • R 11 , R 12 , R 17 and R 18 are independently hydrogen or a group selected from C 1-6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi.
  • R 13 , R 14 , R 15 , R 16 and R 19 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi_ 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi. 6 alkoxy, amino, bis(Ci.
  • 10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi.
  • 5 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • R 1 is a group selected from C ⁇ aHcyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, carbocyclylCi- 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -SR 9 , - SOR 9 , -SO 2 R 9 , -COR 9 , -CO 2 R 9 , -CONR 9 R 10 , -NR 9 R 10 , -NR 9 COR 10 , -NR 9 CO 2 R 10 , s -NR 9 CONR 10 R 15 , -NR 9 COCONR 10 R 15 and -NR 9 SO 2 R 10 ; or X-R 1 is -CR 6 R 7 OH;
  • R 2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , -o NR 11 COCONR 12 R 16 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 ; each R 3 , when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -SR 13 ,
  • R 4 and R 5 are independently hydrogen or Ci_ 6 alkyl; 5 or R 1 and R 4 together with the atom or atoms to which they are attached form a 4- to
  • 10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C 1-6 alkyl, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi. 6 alkoxy, amino, bis(Ci. 6 alkyl)amino, aminoCi.
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi.
  • R 8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi- 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- 6 alkyl, Ci -6 alkoxy, haloCi -6 alkyl, haloCi -6 alkoxy, hydroxyCi -6 alkyl, hydroxyCi -6 alkoxy, C 1- 6alkoxyCi_6alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi.
  • ⁇ alkyl (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, Ci- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, C 1- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
  • R 11 , R 12 , R 17 and R 18 are independently hydrogen or a group selected from carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloCi-6alkoxy, hydroxyC 1-6 alkyl, hydroxyCi.
  • Ci-6alkylamino IUs(C 1- 6alkyl)amino, aminoC 1-6 alkyl, (C 1-6 alkyl)aminoC 1-6 alkyl, bis(C 1-6 alkyl)aminoC 1-6 alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci-6alkanoylamino, d-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
  • R 13 , R 14 , R 15 , R 16 and R 19 are independently hydrogen or a group selected from carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi- 6 alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci- 6 alkyl)amino, aminoCi- 6 alkyl, (Ci- 6 alkyl)aminoCi- 6 alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi -6 alkyl, Ci -6 alkylsul
  • formula (I) or a pharmaceutically acceptable salt thereof wherein m is 0, 1, 2, 3 or 4; 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • R 1 is a group selected from C ⁇ aUcyl, C 2 - 6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl and heterocyclylCi- ⁇ alkyl, which group is optionally substituted by one or more substituent group selected from
  • R 2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , -s NR 11 COCONR 12 R 16 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 ; each R 3 , when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -SR 13 ,
  • R 4 and R 5 are independently hydrogen or o or R 1 and R 4 together with the atom or atoms to which they are attached form a 4- to
  • R 8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi -6 alkyl, heterocyclyl and heterocyclylCi -6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- ⁇ alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi.
  • R , R , R and R are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi. 6 alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, Ci -6 alkylamino, bis(Ci.
  • R 13 , R 14 , R 15 , R 16 and R 19 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi_ 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloCi-6alkoxy, hydroxyC 1-6 alkyl, hydroxyCi.
  • Ci-6alkylamino bis(Ci_ 6alkyl)amino, aminoC 1-6 alkyl, (C 1-6 alkyl)aminoC 1-6 alkyl, bis(C 1-6 alkyl)aminoC 1-6 alkyl, cyanoC 1-6 alkyl, C 1-6 alkylsulfonyl, Ci-6alkylsulfonylamino, C 1-6 alkylsulfonyl(C 1-6 alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkylamino, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, carbamoyl
  • formula (I) or a pharmaceutically acceptable salt thereof wherein m is 0, 1, 2, 3 or 4; 1Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • R 1 is a group selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, carbocyclylC
  • R 2 is a group selected from Ci. 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R 11 , -OR 11 , - SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , -NR 11 COCONR 12 R 16 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 ; each R 3 , when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -SR 13 , - SOR 13 , -SO 2 R 13 , -COR 13 , -CO 2 R 13 , -CONR 13 R 14 , -
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, haloCi_6alkoxy, hydroxyCi.
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi- 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is
  • alkyl bis(Ci -6 alkyl)aminoCi -6 alkyl, C 1- 6 alkylsulfonyl, Ci.6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, C 1- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci.6alkanoylammo, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
  • R , R , R and R are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi.
  • R 13 , R 14 , R 15 and R 16 are independently hydrogen or a group selected from C 1-6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from
  • R 19 is hydrogen, cyano or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocycl
  • Ci- 6alkoxyCi_6alkoxy amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (C 1- 6 alkyl)aminoC 1-6 alkyl, bis(C 1-6 alkyl)aminoC 1-6 alkyl, cyanoC 1-6 alkyl, C 1-6 alkylsulfonyl, C 1- 6alkylsulfonylamino, C 1-6 alkylsulfonyl(C 1-6 alkyl)amino, sulfamoyl, C 1-6 alkylsulfamoyl, bis(Ci_ 6 alkyl)sulfamoyl, Ci-6alkanoylamino, C 1-6 alkanoyl(C 1-6 alkyl)amino, carbamoyl, C 1- 6alkylcarbamoyl and bis(C 1-6 alkyl)carbamoyl;
  • 6alkyl hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, 6alkyl)amino, carbamoyl, and bis(Ci. 6 alkyl)carbamoyl in the manufacture of a medicament for use in the treatment of prolifer
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • R 1 is a group selected from hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, carbocyclylCi -6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R 9 , -OR 9 , -SR 9 ,
  • R 2 is a group selected from C ⁇ aUcyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R 11 , -OR 11 , - SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , -NR 11 COCONR 12 R 16 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 ; 5 each R 3 , when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -SR 13 , - SOR 13 ,
  • R 4 and R 5 are independently hydrogen or Ci_ 6 alkyl; or R 1 and R 4 together with the atom or atoms to which they are attached form a 4- too 10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C 1-6 alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi.
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi- 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally 0 substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- 6alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi.
  • R , R , R and R are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi.
  • Ci -6 alkoxyCi -6 alkyl Ci -6 alkoxyCi -6 alkoxy, amino, Ci -6 alkylamino, bis(Ci. 6alkyl)amino, aminoCi- 6 alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkanoylamino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
  • R 13 , R 14 , R 15 , R 16 and R 19 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi_ 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi.
  • Ci-6alkylamino bis(Ci_ 6alkyl)amino, aminoCi- 6 alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, 6alkyl)amino, carbamoyl, Ci.
  • R 18 and R 19 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi.
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • R 1 is a group selected from C ⁇ aUcyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, carbocyclylCi_ 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R 9 , -OR 9 , -SR 9 ,
  • R 2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -
  • each R 3 when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -SR 13 , -
  • R 4 and R 5 are independently hydrogen or C h alky!; or R 1 and R 4 together with the atom or atoms to which they are attached form a 4- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd.
  • Ci-6alkylamino bis(Ci-6alkyl)amino, aminoCi-6alkyl, 6alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi_ 6 alkyl, Ci- 6 alkylsulfonyl, Ci- 6 alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealky ⁇ amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci- 6 alkanoylamino, carbamoyl, and bis(Ci. 6alkyl)carbamoyl;
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, haloCi_6alkoxy, hydroxyCi.
  • R 8 is selected from hydrogen, halo, cyano and
  • R 9 and R 10 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl, carbocyclylCi_ 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- ⁇ alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, C 1- 6alkoxyCi_6alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi.
  • R , R , R and R are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C
  • Ci- ⁇ alkoxyCi- ⁇ alkyl Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci.6alkylammo, bis(Ci_ 6alkyl)amino, aminoCi. 6 alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci.6alkanoylammo, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
  • R 13 , R 14 , R 15 , R 16 and R 19 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci -6 alkoxy, haloCi -6 alkyl, haloCi -6 alkoxy, hydroxyCi -6 alkyl, hydroxyCi.
  • 10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi.
  • 5 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • io R 1 is a group selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, carbocyclylCi_ 6 alkyl, heterocyclyl and heterocyclylCi_ 6 alkyl, which group is optionally substitute
  • R 2 is a group selected from C 1-6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R 11 , -OR 11 , - SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , and -NR 11 COCONR 12 R 16 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 ;
  • each R 3 when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -SR 13 , - SOR 13 , -SO 2 R 13 , -COR 13 , -CO 2 R 13 , -CONR 13 R 14 , -NR 13 R 14 , -NR 13 COR 14 , -R 13 CO 2 R 14 and - NR 13 SO 2 R 14 ;
  • R 4 and R 5 are independently hydrogen or Ci -6 alkyl; or R 1 and R 4 together with the atom or atoms to which they are attached form a 4- to
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi.
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi- 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1- 6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloCi-6alkoxy, hydroxyC 1-6 alkyl, hydroxyCi-6alkoxy, C 1- 6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, Ci -6 alkylamino, bis(Ci -6 alkyl)amino, aminoCi.
  • R 11 , R 12 , R 17 and R 18 are independently hydrogen or a group selected from C 1-6 alkyl, carbocyclyl, carbocyclylC 1-6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloCi-6alkoxy, hydroxyC 1-6 alkyl, hydroxyCi.
  • Ci-6alkylamino bis(Ci_ 6alkyl)amino, aminoC 1-6 alkyl, (C 1-6 alkyl)aminoC 1-6 alkyl, bis(C 1-6 alkyl)aminoC 1-6 alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci-6alkanoylamino, d-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
  • R 13 , R 14 , R 15 , R 16 and R 19 are independently hydrogen or a group selected from carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi- 6 alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci- 6 alkyl)amino, aminoCi- 6 alkyl, (Ci- 6 alkyl)aminoCi- 6 alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi -6 alkyl, Ci -6 alkylsul
  • formula (I) or a pharmaceutically acceptable salt thereof wherein m is 0, 1, 2, 3 or 4; 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • R 1 is a group selected from hydrogen, Ci. 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl and heterocyclylCi- ⁇ alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R 9 , -OR 9 , -SR 9 ,o -SOR 9 , -O 2 R 9 , -COR 9 , -CO 2 R 9 , -CONR 9 R 10 , -NR 9 R 10 , -NR 9 COR 10 , -NR 9 CO 2 R 10 , -NR 9 CONR 10 R 15 , -NR 9 COCONR 10 R 15 and NR 9 SO 2 R 10 ;
  • R 2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , -s NR 11 COCONR 12 R 16 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 ; each R 3 , when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -R 13 ,
  • R 4 and R 5 are independently hydrogen or o or R 1 and R 4 together with the atom or atoms to which they are attached form a 4- to
  • R 8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi -6 alkyl, heterocyclyl and heterocyclylCi -6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- ⁇ alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi.
  • R , R , R and R are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi. 6 alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, Ci -6 alkylamino, bis(Ci.
  • R 13 , R 14 , R 15 and R 16 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi_ 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloCi-6alkoxy, hydroxyC 1-6 alkyl, hydroxyCi.
  • Ci-6alkylamino bis(Ci_ 6alkyl)amino, aminoC 1-6 alkyl, (C 1-6 alkyl)aminoC 1-6 alkyl, bis(C 1-6 alkyl)aminoC 1-6 alkyl, cyanoC 1-6 alkyl, C 1-6 alkylsulfonyl, Ci-6alkylsulfonylamino, C 1-6 alkylsulfonyl(C 1-6 alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkylamino, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, carbamoyl
  • formula (I) or a pharmaceutically acceptable salt thereof wherein m is 0, 1, 2, 3 or 4; 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • R 1 is a group selected from hydrogen, Ci. 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl and heterocyclylCi- ⁇ alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R 9 , -OR 9 , -SR 9 ,o -SOR 9 , -O 2 R 9 , -COR 9 , -CO 2 R 9 , -CONR 9 R 10 , -NR 9 R 10 , -NR 9 COR 10 , -NR 9 CO 2 R 10 , -NR 9 CONR 10 R 15 , -NR 9 COCONR 10 R 15 and NR 9 SO 2 R 10 ;
  • R 2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , -s NR 11 COCONR 12 R 16 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 ; each R 3 , when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -R 13 ,
  • R 4 and R 5 are independently hydrogen or o or R 1 and R 4 together with the atom or atoms to which they are attached form a 4- to
  • R 8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi -6 alkyl, heterocyclyl and heterocyclylCi -6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- ⁇ alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi.
  • R , R , R and R are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi. 6 alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, Ci -6 alkylamino, bis(Ci.
  • R 13 , R 14 , R 15 , R 16 and R 19 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi_ 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloCi-6alkoxy, hydroxyC 1-6 alkyl, hydroxyCi.
  • Ci-6alkylamino bis(Ci_ 6alkyl)amino, aminoC 1-6 alkyl, (C 1-6 alkyl)aminoC 1-6 alkyl, bis(C 1-6 alkyl)aminoC 1-6 alkyl, cyanoC 1-6 alkyl, C 1-6 alkylsulfonyl, Ci-6alkylsulfonylamino, C 1-6 alkylsulfonyl(C 1-6 alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkylamino, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, carbamoyl
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • R 1 is a group selected from Ci-6alkyl, C 2- 6alkenyl, C 2- 6alkynyl, carbocyclyl, carbocyclylCi -6 alkyl, heterocyclyl and heterocyclylCi -6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R 9 , -OR 9 , -SR 9 , -SOR 9 , -O 2 R 9 , -COR 9 , -CO 2 R 9 , -CONR 9 R 10 , -NR 9 R 10 , -NR 9 COR 10 , -NR 9 CO 2 R 10 , -NR 9 CONR 10 R 15 , -NR 9 COCONR 10 R 15 and NR 9 SO 2 R 10 ; or X-R 1 is -CR 6 R 7 OH;
  • R 2 is a group selected from C ⁇ aUcyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , - NR 11 COCONR 12 R 16 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 ; each R 3 , when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -R 13 , " SOR 13 , -SO 2 R 13 , -COR 13 , -CO 2 R 13 , -CONR 13 R 14 , -
  • R 4 and R 5 are independently hydrogen or Ci_ 6 alkyl; or R 1 and R 4 together with the atom or atoms to which they are attached form a 4- to 10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd.
  • Ci-6alkylamino bis(Ci-6alkyl)amino, aminoCi-6alkyl, 6alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi_ 6 alkyl, Ci- 6 alkylsulfonyl, Ci- 6 alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealky ⁇ amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci_ 6 alkyl)carbamoyl;
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, haloCi_6alkoxy, hydroxyCi. ⁇ alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci. 6 alkyl)amino, aminoCi.
  • R 8 is selected from hydrogen, halo, cyano and Chalky!;
  • R 9 and R 10 are independently hydrogen or a group selected from C ⁇ aUcyl, carbocyclyl, carbocyclylCi- 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent
  • R 11 , R 12 , R 17 and R 18 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi_ 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi- ⁇ alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci- 6 alkyl)amino, aminoCi.
  • R 13 , R 14 , R 15 , R 16 and R 19 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci -6 alkoxy, haloCi -6 alkyl, haloCi -6 alkoxy, hydroxyCi -6 alkyl, hydroxyCi.
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • R 1 is a group selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, carbocyclyl, carbocyclylCi- 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R 9 , -OR 9 , -SR 9 , -
  • R 2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , 5 and -NR 11 COCONR 12 R 16 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 ; each R 3 , when present, is independently selected from halo, cyano, nitro, -R 13 , -OR 13 , -R 13 ,
  • R 4 and R 5 are independently hydrogen or Ci_ 6 alkyl; or R 1 and R 4 together with the atom or atoms to which they are attached form a 4- to
  • Ci-6alkyl hydroxyCi-6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci- 6 alkyl)amino, aminoCi- 6 alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi -6 alkyl, Ci -6 alkylsulfonyl, Ci -6 alkylsulfonylamino, Ci-ealkylsulfony ⁇ d-ealkyFjamino, sulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, C 1- OaIk-UiOyI(C 1- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(
  • R 11 , R 12 , R 17 and R 18 are independently hydrogen or a group selected from C 1-6 alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi.
  • R 13 , R 14 , R 15 , R 16 and R 19 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl, carbocyclylCi_ 6 alkyl, heterocyclyl and heterocyclylCi- ⁇ alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi. 6 alkoxy, amino, bis(Ci.
  • 10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention. Solvates and mixtures thereof also form an aspect of the present invention.
  • a suitable solvate of a compound of formula (I) is, for example, a hydrate such as a hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate or an alternative quantity thereof.
  • the present invention relates to the compounds of formula (I) as herein defined as well as to salts thereof.
  • Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I) and their pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of compounds of formula (I) as herein defined which are sufficiently basic to form such salts.
  • acid addition salts include but are not limited to furmarate, methanesulfonate, hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulfuric acid.
  • salts are base salts and examples include but are not limited to, an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylpiperidine, N- ethylpiperidine, dibenzylamine or amino acids such as lysine.
  • an alkali metal salt for example sodium or potassium
  • an alkaline earth metal salt for example calcium or magnesium
  • organic amine salt for example triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylpiperidine, N- ethylpiperidine, dibenzylamine or amino acids such as lysine.
  • the compounds of formula (I) may also be provided as in vivo hydrolysable esters.
  • An in vivo hydrolysable ester of a compound of formula (I) containing carboxy or hydroxy group is, for example a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid or alcohol.
  • esters can be identified by administering, for example, intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluid.
  • Suitable pharmaceutically acceptable esters for carboxy include Ci-6alkoxymethyl esters for example methoxymethyl, Ci- 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, Cs-scycloalkoxycarbonyloxyCi- ⁇ alkyl esters for example 1-cyclohexylcarbonyloxyethyl, l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl, and Ci. 6 alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in the compounds of this invention.
  • Suitable pharmaceutically acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include Ci-ioalkanoyl, for example formyl, acetyl, benzoyl, phenylacetyl, substituted benzoyl and phenylacetyl; C ⁇ oalkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-Ci- 4 alkylcarbamoyl and 7V-(di-Ci- 4 alkylaminoethyl)-7V- Ci-4alkylcarbamoyl (to give carbamates); di-Ci-4alkylaminoacetyl and carboxyacetyl.
  • ring substituents on phenylacetyl and benzoyl include aminomethyl, Ci- 4 alkylaminomethyl and di-(Ci- 4 alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position of the benzoyl ring.
  • Other interesting in vivo hydrolysable esters include, for example, R A C(O)OCi. 6 alkyl-CO-, wherein R A is for example, benzyloxy-Ci- 4 alkyl, or phenyl.
  • Suitable substituents on a phenyl group in such esters include, for example, 4-Ci- 4 piperazino-Ci- 4 alkyl, piperazino-Ci- 4 alkyl and morpholino-Ci- 4 alkyl.
  • the compounds of the formula (I) may be also be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the formula (I).
  • a prodrug derivatives are known in the art.
  • prodrug derivatives see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191
  • C p-q alkyl includes both straight-chain and branched-chain alkyl groups.
  • references to individual alkyl groups such as "propyl” are specific for the straight chain version only (i.e. n-propyl and isopropyl) and references to individual branched-chain alkyl groups such as "tert-butyl” are specific for the branched chain version only.
  • C p-q in C p-q alkyl and other terms indicates the range of carbon atoms that are present in the group, for example includes Cialkyl (methyl), C 2 alkyl (ethyl), C ⁇ alkyl (propyl as n-propyl and isopropyl) and C 4 alkyl (n-butyl, sec- butyl, isobutyl and tert-butyl).
  • C p-q alkoxy comprises -O-C p-q alkyl groups.
  • C p-q alkanoyl comprises -C(O)alkyl groups.
  • halo includes fluoro, chloro, bromo and iodo.
  • Carbocyclyl includes “aryl”, “C p-q cycloalkyl” and “C p - q cycloalkenyl”.
  • aryl is an aromatic monocyclic, bicyclic or tricyclic carbcyclyl ring system.
  • Heterocyclyl includes “heteroaryl", “cycloheteroalkyl” and “cycloheteroalkenyl” .
  • Heteroaryl is an aromatic monocyclic, bicyclic or tricyclic heterocyclyl, particularly having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulfur or oxygen where a ring nitrogen or sulfur may be oxidised.
  • carbocyclylC p-q alkyl comprises C p-q alkyl substituted by carbocyclyl
  • heterocyclylC p-q alkyl comprises C p-q alkyl substituted by heterocyclyl
  • bis(C p-q alkyl)amino comprises amino substituted by 2 C p-q alkyl groups which may be the same or different.
  • HaloC p-q alkyl is a C p-q alkyl group that is substituted by 1 or more halo substituents and particuarly 1, 2 or 3 halo substituents.
  • other generic terms containing halo such as haloC p-q alkoxy may contain 1 or more halo substituents and particluarly 1 , 2 or 3 halo substituents.
  • HydroxyC p-q alkyl is a C p-q alkyl group that is substituted by 1 or more hydroxyl substituents and particularly by 1, 2 or 3 hydroxy substituents.
  • other generic terms containing hydroxy such as hydroxyC p-q alkoxy may contain 1 or more and particularly 1, 2 or 3 hydroxy substituents.
  • C p-q alkoxyC p-q alkyl is a C p-q alkyl group that is substituted by 1 or more C p-q alkoxy substituents and particularly 1, 2 or 3 C p-q alkoxy substituents.
  • other generic terms containing C p-q alkoxy such as C p-q alkoxyC p-q alkoxy may contain 1 or more C p-q alkoxy substituents and particularly 1, 2 or 3 C p-q alkoxy substituents.
  • substituents are chosen from “1 or 2", from “1, 2, or 3” or from “1, 2, 3 or 4" groups or substituents it is to be understood that this definition includes all substituents being chosen from one of the specified groups i.e. all substitutents being the same or the substituents being chosen from two or more of the specified groups i.e. the substitutents not being the same.
  • Proliferative disease(s) includes malignant disease(s) such as cancer as well as non- malignant disease(s) such as inflammatory diseases, obstracutive airways diseases, immune diseases or cardiovascular diseases.
  • Suitable values for any R group or any part or substituted for such groups include: for methyl, ethyl, propyl, butyl, 2-methylpropyl and tert-butyl; for Ci_ 6 alkyl: Ci_ 4 alkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl and hexyl; for C 3 . 6 cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; for C 3 - 6 cycloalkylCi.
  • R 11 , R 12 , R 13 , R 14 , R 17 , R 18 and R 19 are as follows. Such values may be used idividually or in combination where appropriate, in connection with any aspect of the invention, or part thereof, and with any of the definitions, claims or embodiments defined herein. m
  • n is 0, 1, 2 or 3. In another aspect m is 0, 1 or 2.
  • m is 0 or 1.
  • m is 0 so that R 3 is absent.
  • m is 1 and R 3 is methyl.
  • m is 1 and R 3 is hydroxymethyl. In yet another aspect m is 1 and R 3 is ethyl.
  • m is 1 and R 3 is dimethylcarbamoyl.
  • m is 1 and R 3 is carbamoyl.
  • m is 2 and each R 3 is methyl.
  • 1 Y and Y 2 In one aspect of the invention 1 Y is N and Y 2 is CR 8 .
  • Y is N and Y 2 is CH.
  • Y is CR 8 and Y 2 is N.
  • Y is CH or CF and Y 2 is N.
  • Y is CH and Y 2 is N.
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -, -S(O) 2 CR 6 R 7 -, -C(O)NR 4 CR 6 R 7 -, -NR 4 C(O)CR 6 R 7 -, -NR 4 C(O)NR 5 CR 6 R 7 - and -S(O) 2 NR 4 CR 6 R 7 -.
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -, -S(O) 2 CR 6 R 7 -, -C(O)NR 4 CR 6 R 7 -, -NR 4 C(O)CR 6 R 7 -, -NR 4 C(O)NR 5 CR 6 R 7 - and -S(O) 2 NR 4 CR 6 R 7 .
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -,
  • X is a linker group selected from -NR 4 CR 6 6 ⁇ R-> 7-,
  • X is a linker group selected from -SCR 6 T R-) 7-, - oS( / ⁇ OW) ⁇ CTR) 6T R-> 7 - and
  • X is -SCR 6 R 7 - or -S(O) 2 CR 6 R 7 -. In another aspect X is -S(O) 2 CR 6 R 7 -.
  • R 1 is a group selected from C 1-4 alkyl, C 3 -iocycloalkyl, aryl, cycloheteroalkyl, heteroaryl, cycloheteroalkylCi. 4 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -COR 9 , -CONR 9 R 10 , -NR 9 R 10 and -NR 9 COR 10 .
  • R 1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thiadiazolyl, thiazolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, furanylmethyl, furanylethyl, thiadiazolylmethyl, thiadiazolylethyl, thiazolyl
  • R 1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, pyridinylethyl, pyridin
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH 3 , -CONH 2 and -CONHCH 3 .
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH 2 and -CONHCH3.
  • R 1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 C(OH)(CH 3 ) 2 , -CH 2 CH 2 CH 2 OCHF 2 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NHC(O)CH 3 , -CH 2 C(O)NH 2 , -CH 2 C(O)NHMe, -CH 2 CH 2 NHMe, phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2-fiuoro-4-methylaminophenyl, 4-fluoro-2-methylphenyl, 5-fiuoro-2-methylphenyl, 3-fiuoro-4-(2-hydroxyethyla
  • R 1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NHC(O)CH 3 , -CH 2 C(O)NH 2 , -CH 2 C(O)NHMe, phenyl, 4-fluorophenyl, 4- chlorophenyl, 2-chlorophenyl, 3,5-difluorophenyl, 2-(trifiuoromethyl)phenyl, 2- methoxyphenyl, 2-methylphenyl, 4-(2-hydroxyethylamino)phenyl, lH-imidazol-2-yl, 2-(dimethylcarbamoyl)pyridin-3 -yl, 5 -(dimethylcarbamoy
  • R 1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH 2 CH 2 OH, -CH 2 CH 2 NHC(O)CH 3 , phenyl, 4-fluorophenyl, 2-chlorophenyl, 2- trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, 2-oxopyrolidin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, and 3- 5 methyl- 1, 3, 4-thiadiazol-2-yl.
  • R 1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NHC(O)CH 3 , -CH 2 C(O)NH 2 , -CH 2 C(O)NHMe, phenyl, 4-fluorophenyl, 4- chlorophenyl, 3,5-difiuorophenyl, 2-(trifluoromethyl)phenyl, 4-(2-hydroxyethylamino)phenyl,o lH-imidazol-2-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, pyridin-4-yl, pyridin-2-
  • R 1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 C(OH)(CH 3 ) 2 , -CH 2 CH 2 CH 2 OCHF 2 ,s -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NHC(O)CH 3 , -CH 2 CH 2 NHMe, phenyl, 2-fluorophenyl,
  • R 1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NHC(O)CH 3 , phenyl, 4-fluorophenyl, 4-chlorophenyl, 3,5-difiuorophenyl, lH-imidazol-2-yl, o 2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, pyridin-4-yl, pyridin- 2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl, 4-methylthiazol-2-yl and 5-methyl-l,3,4-thiadiazol-2- yi.
  • R 1 is a group selected from methyl, ethyl, cyclopropyl, -CH 2 CH 2 CH 2 OH, phenyl, 2-fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-chlorophenyl, 2-methylphenyl, 5-fluoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl.
  • R 1 is a group selected from -CH 2 CH 2 CH 2 OH, phenyl, 4-fiuorophenyl, pyridin- 2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl.
  • R 1 is methyl
  • R 1 is ethyl
  • R 1 is cyclopropyl
  • R 1 is -CH 2 CH 2 CH 2 OH. In yet another aspect R 1 is phenyl.
  • R 1 is 2-fluorophenyl
  • R 1 is 3 -fluorophenyl.
  • R 1 is 4-fluorophenyl.
  • R 1 is 2-chlorophenyl. In yet another aspect R 1 is 2-methylphenyl.
  • R 1 is 5-fluoropyridin-2-yl
  • R 1 is pyridin-2-yl.
  • R 1 is thiazol-2-yl.
  • R 1 is 4-methylthiazol-2-yl.
  • X-R 1 is -CR 6 R 7 OH.
  • R 2 is a group selected from carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , -NR 11 COCONR 12 R 16 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 .
  • R 2 is selected from carbocyclyl or heterocyclyl which group is substituted by -NR 17 CONR 18 R 19 or -NR 17 CSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , - COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R 2 is selected from carbocyclyl or heterocyclyl which group is substituted by -NHCONR 18 R 19 or -NHCSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , - CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R 2 is selected from carbocyclyl or heterocyclyl which group is substituted by -NHCONHR 19 or -NHCSNHR 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , - CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R 2 is a group selected from 5 or 6 membered carbocyclyl or heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , - CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , -NR 11 COCONR 12 R 16 , -NR 11 SO 2 R 12 , - NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 .
  • R 2 is selected from 5 or 6 membered carbocyclyl or heterocyclyl which group is substituted by -NR 17 CONR 18 R 19 or -NR 17 CSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R 2 is selected from 5 or 6 membered carbocyclyl or heterocyclyl which group is substituted by -NHCONR 18 R 19 or -NHCSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R 2 is selected from 5 or 6 membered carbocyclyl or heterocyclyl which group is substituted by -NHCONHR 19 or -NHCSNHR 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R 2 is selected from a 6 membered aryl and 5 or 6 membered heteroaryl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , - CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , -NR 11 COCONR 12 R 16 , -NR 11 SO 2 R 12 , - NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 .
  • substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , - CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12
  • R 2 is selected from a 6 membered aryl and 5 or 6 membered heteroaryl which group is substituted by -NR 17 CONR 18 R 19 or -NR 17 CSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R 2 is selected from a 6 membered aryl and 5 or 6 membered heteroaryl which group is substituted by -NHCONR 18 R 19 or -NHCSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R 2 is selected from a 6 membered aryl and 5 or 6 membered heteroaryl which group is substituted by -NHCONHR 19 or -NHCSNHR 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R 2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , -NR 11 COCONR 12 R 16 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 .
  • R 2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, , which group is substituted by - NR 17 CONR 18 R 19 or -NR 17 CSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R 2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by - NHCONR 18 R 19 or -NHCSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by - NHCONHR 19 or -NHCSNHR 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 .
  • R 2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is optionally substituted by one or more substituent group independently selected from fiuoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 , -NR 11 COR 12 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 .
  • R 2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, 5 thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by - NR 17 CONR 18 R 19 or -NR 17 CSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from fiuoro, methyl, methoxy, hydroxymethyl, cyanomethyl, - CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 .
  • R 2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl,o thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -
  • NHCONR 18 R 19 or -NHCSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from fiuoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 .
  • R is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl,s thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -
  • NHCONHR 19 or -NHCSNHR 19 and optionally substituted by one or more substituent group independently selected from fiuoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 .
  • R 2 is selected from phenyl, pyridinyl or pyrimidinylo which group is optionally substituted by one or more substituent group independently selected from fiuoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 , -NR 11 COR 12 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 .
  • R 2 is selected from phenyl or pyridinyl which group is optionally substituted by one or more substituent group independently selected from fiuoro,5 methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 , -NR 11 COR 12 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 .
  • R is phenyl, pyridinyl or pyrimidinyl substituted by - NR 17 CONR 18 R 19 or -NR 17 CSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from fiuoro, methyl, methoxy, hydroxymethyl, cyanomethyl,o -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 .
  • R 2 is phenyl or pyridinyl substituted by -NR 17 CONR 18 R 19 or -NR 17 CSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 .
  • R 2 is phenyl or pyridinyl substituted by -NHCONR 18 R 19 or -NHCSNR 18 R 19 and optionally substituted by one or more substituent group independently 5 selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 .
  • R 2 is phenyl or pyridinyl substituted by -NHCONHR 19 or -NHCSNHR 19 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 0 and -CON(CH 3 ) 2 .
  • R is phenyl or pyridinyl optionally substituted by -NR CONR R or -NR 17 CSNR 18 R 19 .
  • R 2 is phenyl or pyridinyl optionally substituted by -NHCONR 18 R 19 or -NHCSNR 18 R 19 .
  • R 2 is phenyl or pyridinyl optionally substituted by -NHCONHR 19 or
  • R 2 is
  • a 1 and A 2 are selected from CH or N provided that at least one of A 1 or A 2 iso CH.
  • R 2 is
  • a 2 and A 3 are selected from CH or N.
  • R 2 is wherein A 1 and A 2 are selected from CH or N provided that at least one of A 1 or A 2 is CH.
  • R is
  • a 2 and A 3 are selected from CH or N.
  • R 2 is
  • a 1 and A 2 are selected from CH or N provided that at least one of A 1 or A 2 is CH.
  • R is
  • a 2 and A 3 are selected from CH or N.
  • R is 3-(hydroxymethyl)phenyl, 4-(hydroxymethyl)phenyl, 4-(cyanomethyl)phenyl, 3,4-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-phenoxyphenyl, 3-pyrrolidin-lylphenyl, 3-(aminocarbonyl)phenyl, 4-(dimethylaminocarbonyl)phenyl, furan-3- yl, thien-3-yl, 5-(hydroxymethyl)thien-2-yl, pyridin-2-yl, pyridin-4-yl, 2-methoxypyridin-5-yl, 2-methoxypyrimidin-5-yl, 2-methoxynaphth-6-yl, 5,7-diazabicyclo[4.3.0]nona-2,4,8,10- tetraenyl, azaindolyl, indol-5-yl, l-methylindol-5-yl, quinolin-6
  • R is azaindolyl, indol-5-yl, benzimidazolyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl or 4-hydroxymethylphenyl
  • R 2 is pyridin-2-yl.
  • R 2 is 3-hydroxyphenyl or 4-hydroxyphenyl. In yet another aspect R 2 is 3-hydroxymethylphenyl or 4-hydroxymethylphenyl. In yet a further aspect R 2 is indol-5-yl. In one aspect R 2 is morpholinyl. In another aspect R is morpholino.
  • Each R 3 is independently selected from cyano, R 13 , and -CONR 13 R 14 , wherein R 13 and R 14 are independently hydrogen or a which is optionally substituted by one or more substituent groups selected from halo, cyano, hydroxy and Each R 3 is independently selected from hydrogen, C 1-3 alkyl, and
  • R 13 and R 14 are independently hydrogen or a C 1-3 alkyl.
  • Each R 3 is independently selected from hydrogen, methyl, ethyl, hydroxymethyl, carbamoyl and dimethylcarbamoyl.
  • R 4 is hydrogen or methyl.
  • R 4 is hydrogen.
  • R 1 and R 4 together with the atom or atoms to which they are attached form a 4- to 10-membered heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C 1-6 alkyl, C 1- 6 alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd.
  • Ci-ealkoxyd- ⁇ alkoxy amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (C 1- 6 alkyl)aminoC i - ⁇ alkyl, bis(C i -6 alkyl)aminoC i - ⁇ alkyl, cyanoC i - ⁇ alkyl, C i _6alkylsulfonyl, C i .
  • R 1 and R 4 together with the atom or atoms to which they are attached form a 5-, 6- or 7-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi- 6 alkyl, haloCi- 6 alkoxy, hydroxyCi- 6 alkyl, hydroxyCi_ 6 alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci- 6 alkoxyCi -6 alkoxy, amino, Ci -6 alkylamin
  • R 1 and R 4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi- 6 alkyl, haloCi- 6 alkoxy, hydroxyCi- 6 alkyl, hydroxyCi_ 6 alkoxy, Ci-ealkoxyd- ⁇ alkyl, C 1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(
  • R 1 and R 4 together with the atom or atoms to which they are attached form a morpholine or piperazine ring which ring is optionally substituted by one or more methyl groups.
  • R 5 In one aspect of the invention R 5 is hydrogen or methyl.
  • R 5 is hydrogen
  • R 5 is methyl
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi -6 alkyl, haloCi -6 alkoxy, hydroxyCi -6 alkyl, hydroxyCi -6 alkoxy, Ci -6 alkoxyCi -6 alkyl, C 1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (C 1- 6 alkyl)aminoCi- 6 alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, Ci-
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 6-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi- 6 alkyl, haloCi- 6 alkoxy, hydroxyCi- 6 alkyl, hydroxyCi_ 6 alkoxy, Ci-ealkoxyd- ⁇ alkyl, C 1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (C 1- 6 alkyl)aminoCi -6 alkyl, bis(C 1-6 alkyl)aminoC 1-6 alkyl, cyanoC 1-6 alkyl, C
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 5-membered carbocyclic ring.
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 4-membered carbocyclic ring.
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3-membered carbocyclic ring. In another aspect R 6 and R 7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring.
  • R 8 is hydrogen or halo. 5 In another aspect R 8 is hydrogen or fluoro.
  • R 8 is hydrogen
  • R 9 is hydrogen or optionally substituted by 1, 2 or 3 substituent groups selected from halo, cyano, nitro, hydroxy, Ci -4 alkoxy, amino, C 1- i o 4alkylamino and bis(C i .4alkyl)amino .
  • R 9 is hydrogen or optionally substituted by 1, 2 or 3 halo substituents.
  • R 9 is hydrogen, methyl or trifluoromethyl.
  • R ⁇ is In one aspect of the invention R 10 is hydrogen.
  • R 11 is hydrogen or a group selected from C 1-4 alkyl, aryl and cycloheteroalkyl which group is optionally substituted by 1 , 2 or 3 groups selected from halo, hydroxy and cyano.
  • R 11 is hydrogen, methyl optionally substituted with hydroxy or cyano, phenyl or pyrrolidinyl.
  • R 11 is hydrogen or methyl.
  • R 12 is hydrogen or methyl.
  • R 17 is hydrogen or a group selected from C 1-4 alkyl, aryl and cycloheteroalkyl which group is optionally substituted by 1 , 2 or 3 groups selected from halo, hydroxy and cyano.
  • R 17 is hydrogen, methyl optionally substituted with hydroxy or cyano, 30 phenyl or pyrrolidinyl.
  • R 17 is hydrogen or methyl.
  • R 17 is hydrogen.
  • R 18 is hydrogen or methyl. In one aspect of the invention R 18 is hydrogen
  • R 19 is hydrogen or a group selected from Ci_ 6 alkyl, C 3- ⁇ Cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- 6alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, Ci -6 alkylamino, bis(Ci -6 alkyl)amino, aminoCi.o 6 alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, Ci-
  • R 19 is hydrogen or a group selected from Ci_ 6 alkyl, C 3- 5 6 cycloakyl, phenyl, naphthyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl, indolyl, quinolinyl, benzimidazolyl, benzofuranyl, dibenzofuranyl, benzothienyl, pyrrolidinyl, pyrazinyl, oxetanyl, dioxothiolanyl, thiazolyl, thiadiazolyl, phenylCi- 6 alkyl, naphthylCi- 6 alkyl, pyrrolylCi- 6 alkyl, imidazolylCi.
  • 6alkyl isoxazolylCi- 6 alkyl, pyrazolylCi- 6 alkyl, furanylCi- 6 alkyl, thienylCi- 6 alkyl, pyridinylCi.0 6 alkyl, pyrimidinylCi- 6 alkyl, pyridazinylCi- 6 alkyl, azaindolylCi- 6 alkyl, indolylCi- 6 alkyl, quinolinylCi -6 alkyl, benzimidazolylCi -6 alkyl, benzofuranylCi -6 alkyl, dibenzofuranylCi -6 alkyl, benzothienylCi- 6 alkyl, pyrrolidinylCi-oalkyl, pyrazinylCi- 6 alkyl, oxetanylCi- 6 alkyl, dioxothiolanylCi- 6
  • R 19 is hydrogen or a group selected from Ci_ 6 alkyl, C 3- ⁇ Cycloakyl, phenyl, naphthyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl, indolyl, quinolinyl, benzimidazolyl, benzofuranyl, dibenzofuranyl, benzothienyl, phenylCi- 6 alkyl, naphthylCi- ⁇ alkyl, pyrro IyIC 1 .
  • R 19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, dioxothiolanyl, imidazoylmethyl, isoxazolyl, oxazolyl, oxetanyl, pyrazinyl, pyrazolyl, pyrazolylmethyl, pyridinyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl, thiazolyl and triazolyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi
  • R 19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyrazolylmethyl, pyridinyl and pyrimidinyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, haloCi- ⁇ alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyd-6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd- ⁇ alkoxy, amino, Ci- 6 alkylamino, bis(C
  • Ci- sulfamoyl Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci- 6 alkanoylamino, carbamoyl, Ci. 6 alkylcarbamoyl and bis(Ci. 6alkyl)carbamoyl.
  • R 19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 (cyclopropyl), -CH 2 CH 2 NMe 2 , -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 SO 2 Me, -CH 2 CH(OH)CF 3 , -CH 2 CH 2
  • R 19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH 2 (cyclopropyl), -CH 2 CH 2 NMe 2 , -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 C(CH 3 ) 2 CH 2 OH, -CH 2 C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 SO 2 Me, -CH 2 CH(OH)CF 3 , -CH 2 CH 2 CN, -CH 2 CN, -CH 2
  • R 19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 (cyclopropyl), -CH 2 CH 2 NMe 2 , -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CHF 2 , 5 -CH 2 CH 2 SO 2 Me, -CH 2 CH(OH)CF 3 , -CH 2 CH 2 CN, -CH 2 CN, -CH 2 CONMe 2 , 1-
  • R 19 is hydrogen or a group selected from methyl, ethyl,s propyl, i-propyl, cyclopropyl, cyclobutyl, -CH 2 (cyclopropyl), -CH 2 CH 2 NMe 2 ,
  • R 19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, 5 cyclohexyl, -CH 2 (cyclopropyl), -CH 2 CH 2 NMe 2 , -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH,
  • R 19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH 2 (cyclopropyl), -CH 2 CH 2 NMe 2 , -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CHF 2 , -CH 2 CH 2 SO 2 Me, -CH 2 CH(OH)CF 3 , -CH 2 CH 2 CN, -CH 2 CN, -CH 2 CONMe 2 , l-(methyl)cyclopropyl, l-(hydroxymethyl)cyclopropyl, phenyl,
  • R 19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, -CH 2 (cyclopropyl), -CH 2 CH 2 NMe 2 , -C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CN, l-(hydroxymethyl)cyclopropyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, -CH 2 CH 2 (pyrrolidin-l-yl), -CH 2 (imidazol-2-yl), oxazolyl-2-yl, isoxazolyl- 3-yl, oxetan-3-yl, 5-methylisoxazol-3-yl, 1 -methylpyrazol-4-yl
  • R 19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl, -CH(CH 3 )CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CH 2 CN, (lR)-2-hydroxy-l-methylethyl, (lS)-2-hydroxy-l-methylethyl, -CH 2 (imidazol-2- yl), oxazolyl-2-yl, isoxazolyl-3-yl, 1 -methylpyrazol-4-yl, 5 -methylpyrazin-2-yl, thiazol-2-yl and l,2,4-thiadiazol-5-yl.
  • R 19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CN, -CH 2 (imidazol-2-yl), oxazolyl-2-yl, isoxazolyl-3-yl, 1 -methylpyrazol-4-yl, 5 -methylpyrazin-2-yl, thiazol-2-yl and 1,2,4-thiadiazol- 5-yl.
  • R 19 is hydrogen or a group selected from methyl, ethyl, cyclopropyl, 1 -methylpyrazol-4-yl, and -CH 2 (I -methylpyrazol-4-yl).
  • R 19 is methyl
  • R 19 is ethyl. In one aspect of the invention R 19 is cyclopropyl.
  • R 19 is cyclobutyl
  • R 19 is -CH(CH 3 )CH 2 OH. In one aspect of the invention R 19 is -CH 2 CH 2 OH.
  • R 19 is -CH 2 CH 2 CH 2 OH.
  • R 19 is -CH 2 CHF 2
  • R 19 is -CH 2 CH 2 F. 5 In one aspect of the invention R 19 is -CH 2 CH 2 CN.
  • R 19 is (lR)-2-hydroxy-l-methylethyl.
  • R 19 is (lS)-2-hydroxy-l-methylethyl.
  • R 19 is -CH 2 (imidazol-2-yl).
  • R 19 is oxazolyl-2-yl. o In one aspect of the invention R 19 is isoxazolyl-3-yl.
  • R 19 is l-methylpyrazol-4-yl.
  • R 19 is 5-methylpyrazin-2-yl.
  • R 19 is thiazol-2-yl.
  • R 19 is l,2,4-thiadiazol-5-yl. s R 18 and R 19
  • R 18 and R 19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, o haloC i - ⁇ alkyl, haloC i -6 alkoxy , hydroxyC i - ⁇ alkyl, hydroxyC i -6 alkoxy , C i -6 alkoxyC i - ⁇ alkyl, C i .
  • Ci-6 alkylamino bis(Ci -6 alkyl)amino, aminoCi -6 alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, Ci- 6 alkylsulfonyl, Ci- 6alkylsulfonylamino, bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino, carbamoyl, 5 Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
  • R 18 and R 19 together with the nitrogen atom to which they are attached form a morpholine ring.
  • R 18 and R 19 together with the nitrogen atom to which they are attached form a 3-hydroxypyrrolidin-l-yl group.
  • m is 0, 1 or 2
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -, -S(O) 2 CR 6 R 7 -, -C(O)NR 4 CR 6 R 7 -, -NR 4 C(O)CR 6 R 7 -, -NR 4 C(O)NR 5 CR 6 R 7 - and -S(O) 2 NR 4 CR 6 R 7 ;
  • R 1 is a group selected from C ⁇ aHcyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylC i_ 6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -COR 9 , -CONR 9 R 10 , -NR 9 R 10 and -NR 9 COR 10 ; or X-R 1 is -CR 6 R 7 OH; R 2 is a group selected from carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , - SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11
  • ⁇ alkyl (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, Ci- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi.
  • 6alkyl hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd- ⁇ alkoxy, amino, Ci- 6alkylamino and bis(Ci-6alkyl)amino;
  • R , R , R and R are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi.
  • R 13 and R 14 are independently hydrogen or a which is optionally substituted by one or more substituent groups selected from halo, cyano, hydroxy and C ⁇ alkoxy;
  • R 19 is hydrogen, cyano or a group selected from Ci_ 6 alkyl, C ⁇ - ⁇ Cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi- 6 alkyl, haloCi- 6 alkoxy, hydroxyCi- 6 alkyl, hydroxyCi_ 6 alkoxy, Ci-ealkoxyd- ⁇ alkyl, C 1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
  • 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloCi-6alkoxy, hydroxyC 1-6 alkyl, hydroxyCi_6alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkoxy, amino, Ci-6alkylamino, IUs(C 1- 6alkyl)amino, aminoC 1-6 alkyl, (C 1-6 alkyl)aminoC 1-6 alkyl, bis(C 1-6 alkyl)aminoC 1-6 alkyl, cyanoC 1-6 alkyl, C 1-6 alkylsulfonyl, Ci-6alkylsulfonylamino, C 1-6 alkylsulfon
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -,
  • R 1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylC i_ 6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -COR 9 , -CONR 9 R 10 , -NR 9 R 10 and -NR 9 COR 10 ; or X-R 1 is -CR 6 R 7 OH; s R 2 is a group selected from carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , - SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR
  • 6alkyl bis(Ci -6 alkyl)aminoCi -6 alkyl, C 1- 6 alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, 0 carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi.
  • R 8 is selected from hydrogen, halo, cyano and Ci_6alkyl
  • R 9 and R 10 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-
  • R 11 , R 12 , R 17 and R 18 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi. ⁇ alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino;
  • R 13 and R 14 are independently hydrogen or a C 1-3 alkyl; and R 19 is hydrogen, cyano or a group selected from Ci_ 6 alkyl, C ⁇ - ⁇ Cycloakyl, aryl, heteroaryl, and heteroarylCi. 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, Ci_6alkoxy, haloCi- 6 alkyl, haloCi_ 6 alkoxy, hydroxyCi_ 6 alkyl, hydroxyCi_ 6 alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-
  • Ci-6alkylamino bis(Ci-6alkyl)amino, aminoCi-6alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, Ci- 6 alkylsulfonyl, Ci-
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -,
  • R 1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylC 1-6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -COR 9 , -CONR 9 R 10 , -NR 9 R 10 and -NR 9 COR 10 ; or X-R 1 is -CR 6 R 7 OH;
  • R 2 is a group selected from carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , - SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , -
  • each R 3 when present, is methyl or ethyl;
  • R 4 and R 5 are independently hydrogen or Ci_ 6 alkyl; or, when X is -NR 4 CR 6 R 7 -, -NR 4 C(O)CR 6 R 7 - or -NR 4 C(O)NR 5 CR 6 R 7 -, R 1 and R 4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
  • Ci-ealkoxyCi_6alkyl Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. 6 alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi_ 6 alkyl, Ci-
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi- 6 alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci- ⁇ alkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci- 6 alkyl)amino, aminoCi- 6 alkyl, (Ci- 6 alkyl)aminoCi- 6 alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi -6 alkyl, Ci -6 alkylsulfon
  • R 9 and R 10 are independently hydrogen or a group selected from Ci- 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, hydroxyd-6alkyl, hydroxyd-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci- ⁇ alkoxyCi- ⁇ alkoxy, amino, Ci- 6alkylamino and bis(Ci-6alkyl)amino;
  • R , R , R and R are independently hydrogen or a group selected from Ci- 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi- 6 alkoxy, hydroxyd -6 alkyl, hydroxyCi -6 alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and
  • R 19 is hydrogen, cyano or a group selected from Ci- 6 alkyl, d- ⁇ Cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, d-6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-6alkoxyCi-6alkyl, Ci- 6 alkoxyCi. 6 alkoxy, amino, bis(Ci. 6 alkyl)amino, aminoCi.
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -, -S(O) 2 CR 6 R 7 -, -C(O)NR 4 CR 6 R 7 -, -NR 4 C(O)CR 6 R 7 -, -NR 4 C(O)NR 5 CR 6 R 7 - and -S(O) 2 NR 4 CR 6 R 7 ;
  • R 1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylC i_ 6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -COR 9 , -CONR 9 R 10 , -NR 9 R 10 and -NR 9 COR 10 ; or X-R 1 is -CR 6 R 7 OH;
  • R 2 is a group selected from carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , - SR 11 , -SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , - NR 11 COCONR 12 R 16 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 ; each R 3 , when present, is methyl; R 4 and R 5 are independently hydrogen or or, when X is -NR 4 CR 6 R 7 -, -NR 4 C(O)CR 6 R 7 - or -NR 4 C(O)NR 5 CR 6 R 7 -, R 1 and R 4 together with the atom or atoms to which
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci -6 alkoxy, haloCi -6 alkyl, haloCi -6 alkoxy, hydroxyCi.
  • Ci-6alkyl hydroxyCi_6alkoxy, Ci-6alkoxyCi-6alkyl, Ci- ⁇ alkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci- 6 alkyl)amino, aminoCi- 6 alkyl, (Ci- 6 alkyl)aminoCi- 6 alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, d-6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci- ⁇ alkoxyCi- ⁇ alkoxy, amino, C 1- 6alkylamino and bis(Ci-6alkyl)amino;
  • R , R , R and R are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi- ⁇ alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-6alkoxyCi-6alkyl, Ci- ⁇ alkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and
  • R 19 is hydrogen, cyano or a group selected from Ci_ 6 alkyl, C 3 _ 6 Cycloakyl, aryl, heteroaryl, and heteroarylCi. 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi- 6 alkyl, haloCi- 6 alkoxy, hydroxyCi- 6 alkyl, hydroxyCi_ 6 alkoxy, Ci-ealkoxyd- ⁇ alkyl, C 1- 6alkoxyCi_6alkoxy, amino, d-ealkylamino, bis(Ci-6alkyl)amino, aminoC 1-6 alkyl,
  • 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci_
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -,
  • R 1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylC i -6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -COR 9 , -CONR 9 R 10 , -NR 9 R 10 and -NR 9 COR 10 ; or X-R 1 is -CR 6 R 7 OH;
  • R 2 is a group selected from carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -
  • R 4 and R 5 are independently hydrogen or Ci_ 6 alkyl; or, when X is -NR 4 CR 6 R 7 -, -NR 4 C(O)CR 6 R 7 - or -NR 4 C(O)NR 5 CR 6 R 7 -, R 1 and R 4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- 6 alkoxyCi.
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi.
  • R 8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi -6 alkyl, hydroxyCi -6 alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, C 1- 6alkylamino and bis(Ci-6alkyl)amino;
  • R 11 , R 12 , R 17 and R 18 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloCi. ⁇ alkoxy, hydroxyC 1-6 alkyl, hydroxyCi_6alkoxy, C 1-6 alkoxyC 1-6 alkyl, Ci- ⁇ alkoxyCi- ⁇ alkoxy, amino, and bis(Ci. 6 alkyl)amino; and
  • R 19 is hydrogen or a group selected from C 1-6 alkyl, C 3-6 cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, Ci_6alkoxy, haloC 1-6 alkyl, haloCi-6alkoxy, hydroxyC 1-6 alkyl, hydroxyCi_6alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoC 1-6 alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi_ 6 alkyl, Ci- 6 alkylsulfonyl, Ci- 6alkylsulfonyla
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -, -S(O) 2 CR 6 R 7 -, -C(O)NR 4 CR 6 R 7 -, -NR 4 C(O)CR 6 R 7 -, -NR 4 C(O)NR 5 CR 6 R 7 - and -S(O) 2 NR 4 CR 6 R 7 ;
  • R 1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylC i_ 6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -COR 9 , -CONR 9 R 10 , -NR 9 R 10 and -NR 9 COR 10 ; Or X-R 1 Is -CR 6 R 7 OH;
  • R 2 is a group selected from aryl and heteroaryl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -SR 11 , - SOR 11 , -SO 2 R 11 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -NR 11 R 12 , -NR 11 COR 12 , -NR 11 COCONR 12 R 16 , -NR 11 SO 2 R 12 , -NR 17 CONR 18 R 19 and -NR 17 CSNR 18 R 19 ; each R 3 , when present, is methyl;
  • R 4 and R 5 are independently hydrogen or C h alky!; or, when X is -NR 4 CR 6 R 7 -, -NR 4 C(O)CR 6 R 7 - or -NR 4 C(O)NR 5 CR 6 R 7 -, R 1 and R 4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amin
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi.
  • R 8 is selected from hydrogen, halo, cyano and Ci_ 6 alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, C 1- 6alkylamino and bis(Ci-6alkyl)amino;
  • R 11 , R 12 , R 17 and R 18 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, ImIoC 1- ⁇ alkoxy, hydroxyC 1-6 alkyl, hydroxyCi_6alkoxy, C 1-6 alkoxyC 1-6 alkyl, Ci- ⁇ alkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and
  • R 19 is hydrogen or a group selected from C 1-6 alkyl, C 3-6 cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C ⁇ aUcyl, Ci_6alkoxy, haloCi_ 6 alkyl, haloCi_ 6 alkoxy, hydroxyCi_ 6 alkyl, hydroxyCi_ 6 alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci- 6 alkoxyCi. 6 alkoxy, amino, bis(Ci.
  • m is 0, 1 or 2; 1Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -, -S(O) 2 CR 6 R 7 -, -C(O)NR 4 CR 6 R 7 -, -NR 4 C(O)CR 6 R 7 -, -NR 4 C(O)NR 5 CR 6 R 7 - and -S(O) 2 NR 4 CR 6 R 7 ;
  • R 1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylC i_ 6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -COR 9 , -CONR 9 R 10 , -NR 9 R 10 and -NR 9
  • R 4 and R 5 are independently hydrogen or Ci_ 6 alkyl; or, when X is -NR 4 CR 6 R 7 -, -NR 4 C(O)CR 6 R 7 - or -NR 4 C(O)NR 5 CR 6 R 7 -, R 1 and R 4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
  • 6alkylsulfamoyl bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi.
  • Ci-6alkylamino bis(Ci- 6 alkyl)amino, aminoCi- 6 alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
  • R 8 is selected from hydrogen, halo, cyano and C 1-6 alkyl
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-
  • R , R , R and R are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, ImIoC 1- ⁇ alkoxy, hydroxyC 1-6 alkyl, hydroxyCi_6alkoxy, C 1-6 alkoxyC 1-6 alkyl, Ci- ⁇ alkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and R 19 is hydrogen or a group selected from C ⁇ aUcyl, C 3 _ 6 Cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro
  • R 18 and R 19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, IUS(C 1- 6 alkyl)amino, aminoCi.
  • 6 alkyl bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 - and -S(O) 2 CR 6 R 7 -;
  • R 1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thiadiazolyl, thiazolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, furanylmethyl, furanylethyl, thiadiazolylmethyl, thiadiazolylethyl, thiazolylmethyl, thiazolylmethyl, thiazo
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi.
  • R 8 is selected from hydrogen, halo, cyano and Ci_ 6 alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci- 6 alkylamino and bis(Ci. 6 alkyl)amino;
  • R 11 , R 12 and R 18 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd- ⁇ alkoxy, amino, Ci- 6alkylamino and bis(Ci-6alkyl)amino; and R 19 is hydrogen, cyano or a group selected from Ci -6 alkyl, C 3-6 cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6
  • m is 0, 1 or 2; 1Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 - and -S(O) 2 CR 6 R 7 -;
  • R 1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinyl
  • R 2 is selected from 5 or 6 membered aryl and heteroaryl which group is substituted by -NHCONR 18 R 19 or -NHCSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 ; each R 3 , when present, is methyl; R 4 is hydrogen or Ci_ 6 alkyl; or, when X is -NR 4 CR 6 R 7 -, R 1 and R 4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci -6 alkoxy, haloCi
  • Ci-6alkylamino bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci_ 6 alkyl)aminoCi- 6 alkyl, Ci- 6 alkylsulfonyl, Ci- 6 alkylsulfonylamino, C 1- 6alkylsulfonyl(Ci.6alkyl)amino, sulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci_ 6 alkyl)carbamoyl;
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6 alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci- 6 alkyl)ammo, aminoCi.
  • R 8 is selected from hydrogen, halo, cyano and Ci_ 6 alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi -6 alkyl, hydroxyCi -6 alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, C 1- 6alkylamino and bis(Ci-6alkyl)amino;
  • R 11 , R 12 and R 18 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, C 1- 6 alkylamino and bis(Ci. 6 alkyl)amino; and
  • R 19 is hydrogen or a group selected from C 1-6 alkyl, C 3-6 cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, Ci_6alkoxy, haloC 1-6 alkyl, haloCi-6alkoxy, hydroxyC 1-6 alkyl, hydroxyCi_6alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoC 1-6 alkyl,
  • X is a -S(O) 2 CR 6 R 7 - linker group
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl,o thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH 3 , -CONH 2 and -CONHCH 3 ; or -XR 1 is -C(CH 3 ) 2 OH or -CH 2 OH
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, haloCi_6alkoxy, hydroxyCi.5 6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci- 6 alkyl)amino, aminoCi- 6 alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, sulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamin
  • R 19 is hydrogen, cyano or a group selected from C 1-6 alkyl, C 3 . 6 cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more 5 substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi- 6 alkyl, haloCi- 6 alkoxy, hydroxyCi- 6 alkyl, hydroxyCi_ 6 alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-
  • Ci-6alkylamino bis(Ci-6alkyl)amino, aminoCi-6alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi_ 6 alkyl, Ci- 6 alkylsulfonyl, Ci- 6 alkylsulfonylamino, Ci-ealkylsulfony ⁇ d-ealky ⁇ amino, sulfamoyl, Ci -6 alkylsulfamoyl, IUs(C 1- o 6alkyl)sulfamoyl, Ci-6alkanoylamino, carbamoyl,
  • X is a -S(O) 2 CR 6 R 7 - linker group
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is 0 optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH 3 , -CONH 2 and -CONHCH 3 ; or -XR 1 is -C(CH 3 ) 2 OH or -CH 2 OH;
  • R 2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NHCONHR 19 or 5 -NHCSNHR 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and
  • R 3 when present, is methyl
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-memberedo carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N,
  • R 11 , R 12 and R 18 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi -6 alkyl, hydroxyCi -6 alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, C 1- 6alkylamino and bis(Ci-6alkyl)amino; and
  • R 19 is hydrogen or a group selected from Ci_ 6 alkyl, C 3 _ 6 Cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, Ci_6alkoxy, haloCi- 6 alkyl, haloCi_ 6 alkoxy, hydroxyCi_ 6 alkyl, hydroxyCi_ 6 alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, C 1- 6 alkoxyCi. 6 alkoxy, amino, C 1-6 alkylamino, bis(Ci. 6 alkyl)amino, aminoC 1-6 alkyl,
  • X is a -S(O) 2 CR 6 R 7 - linker group selected; 1Y is CH and Y 2 is N.
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH 3 , -CON
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi.
  • X is a -S(O) 2 CR 6 R 7 - linker group selected; 1Y is CH and Y 2 is N.
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH 3 , -CON
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N,o O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi.
  • R 19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, dioxothiolanyl, imidazoylmethyl, isoxazolyl, oxazolyl, oxetanyl, pyrazinyl, pyrazolyl,0 pyrazolylmethyl, pyridinyl, pyrimidinyl, pyrroli
  • X is a -S(O) 2 CR 6 R 7 - linker group selected; 1Y is CH and Y 2 is N.
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH 3 , -CONH 2 and -CONHCH 3 ; R 2 is phenyl or pyridinyl substituted by -
  • R 19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thien
  • R 1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH 2 CH 2 OH, -CH 2 CH 2 NHC(O)CH 3 , phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin- 2-yl, 2-oxopyrolidin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, and 3-methyl-l,3,4-thiadiazol-2- yi;
  • a 1 and A 2 are selected from CH or N provided that at least one of A 1 or A 2 is CH; R 17 is hydrogen; R 18 is hydrogen;
  • R 19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 (cyclopropyl), -CH 2 CH 2 NMe 2 , -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, 4-methylphenyl, 4- chlorophenyl, 4-trifiuoromethylphenyl, 4-flurophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CH 2 (imidazol-2-yl), -CH 2 (imidazol-3-yl), isoxazolyl-3-yl, 6-ox
  • R 3 is methyl
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci -6 alkoxy, haloCi -6 alkyl, haloCi -6 alkoxy, hydroxyCi.
  • X is a -S(O) 2 CR 6 R 7 - linker group; 1Y is CH and Y 2 is N.
  • R 1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 C(OH)(CH 3 ) 2 , -CH 2 CH 2 CH 2 OCHF 2 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NHC(O)CH 3 , -CH 2 C(O)NH 2 , -CH 2 C(O)NHMe, -CH 2 CH 2 NHMe, phenyl, 2-fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-fluoro-4-methylaminophenyl, 4-fiu
  • a 1 and A 2 are selected from CH or N provided that at least one of A 1 or
  • a , 2 z is CH
  • R 19 is is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH 2 (cyclopropyl), -CH 2 CH 2 NMe 2 , -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, 5 -CH 2 C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CF 3 ,
  • R 1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NHC(O)CH 3 , -CH 2 C(O)NH 2 , -CH 2 C(O)NHMe, phenyl, 4-fluorophenyl, 4-chlorophenyl, 3,5-difluorophenyl, 2-(trifiuoromethyl)phenyl, 4-(2-hydroxyethylamino)phenyl, lH-imidazol-2-yl,
  • a 1 and A 2 are selected from CH or N provided that at least one of A 1 or
  • 6alkyl hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, 6alkyl)amino, carbamoyl, and bis(Ci. 6 alkyl)carbamoyl.
  • Ci-6alkylamino bis(Ci-6al
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -,
  • R 1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylC i_ 6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -COR 9 , -CONR 9 R 10 , -NR 9 R 10 and -NR 9 COR 10 ; or X-R 1 is -C(CH 3 ) 2 OH or -CH 2 OH;
  • R 2 is selected from aryl and heteroaryl which group is substituted by -NR 17 CONR 18 R 19 or -NR 17 CSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -
  • R 4 and R 5 are independently hydrogen or or, when X is -NR 4 CR 6 R 7 -, -NR 4 C(O)CR 6 R 7 - or -NR 4 C(O)NR 5 CR 6 R 7 -, R 1 and R 4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amin
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, hydroxyCi.
  • Ci-6alkyl hydroxyCi-6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci- 6 alkyl)amino, aminoCi- 6 alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, C 1- OaIk-UiOyI(C 1- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloCi_6alkoxy, hydroxyC 1-6 alkyl, hydroxyCi_6alkoxy, C 1-6 alkoxyC 1-6 alkyl, Ci- ⁇ alkoxyCi- ⁇ alkoxy, amino, C 1- 6alkylamino and bis(Ci-6alkyl)amino;
  • R 11 , R 12 , R 17 and R 18 are independently hydrogen or a group selected from C 1-6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, ImIoC 1- ⁇ alkoxy, hydroxyC 1-6 alkyl, hydroxyCi_6alkoxy, C 1-6 alkoxyC 1-6 alkyl, Ci- ⁇ alkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino;
  • R 19 is hydrogen or a group selected from C ⁇ aUcyl, C 3 _ 6 Cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo,
  • R 18 and R 19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, IUS(C 1- 6 alkyl)amino, aminoCi.
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -, -S(O) 2 CR 6 R 7 -, -C(O)NR 4 CR 6 R 7 -, -NR 4 C(O)CR 6 R 7 -, -NR 4 C(O)NR 5 CR 6 R 7 - and -S(O) 2 NR 4 CR 6 R 7 ;
  • R 1 is a group selected from C ⁇ aHcyl, carbocyclyl, carbocyclylCi- ⁇ alkyl, heterocyclyl and heterocyclylC i_ 6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -COR 9 , -CONR 9 R 10 , -NR 9 R 10 and -NR 9 COR 10 ; or X-R 1 is -C(CH 3 ) 2 OH or -CH 2 OH; R 2 is selected from aryl and heteroaryl which group is substituted by -NR 17 CONR 18 R 19 or -NR 17 CSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and - NR 11 COR
  • ⁇ alkyl (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, Ci- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi.
  • 6alkyl hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd- ⁇ alkoxy, amino, Ci- 6alkylamino and bis(Ci-6alkyl)amino;
  • R , R , R and R are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi.
  • R 19 is hydrogen or a group selected from Ci_ 6 alkyl, C 3 _ 6 Cycloakyl, aryl, heteroaryl, arylCi- ⁇ alkyl and heteroarylCi.
  • 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi- 6 alkyl, haloCi- 6 alkoxy, hydroxyCi- 6 alkyl, hydroxyCi_ 6 alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi_ 6 alkyl, Ci- 6 alkylsulfonyl, C 1- 6alkylsulfonylamino, bis(Ci_ 6 alkyl)sulfamoyl, Ci.
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -,
  • R 1 is a group selected from Ci. 6 alkyl, carbocyclyl, carbocyclylCi. 6 alkyl, heterocyclyl and heterocyclylC 1-6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -COR 9 , -CONR 9 R 10 , -NR 9 R 10 and -NR 9 COR 10 ; or X-R 1 is -C(CH 3 ) 2 OH or -CH 2 OH; R 2 is selected from aryl and heteroaryl which group is substituted by -NR 17 CONR 18 R 19 or -NR 17 CSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and - NR 11 COR 12 ;
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi- 6 alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci- ⁇ alkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci -6 alkyl)amino, aminoCi -6 alkyl, (Ci- 6 alkyl)aminoCi- 6 alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl
  • R , R , R and R are independently hydrogen or a group selected from Ci- 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, d -6 alkoxy, haloCi -6 alkyl, haloCi- ⁇ alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and
  • R 19 is hydrogen or a group selected from Ci- 6 alkyl, d- ⁇ Cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, d-6alkyl, Ci_6alkoxy, 6alkoxyCi_6alkoxy, amino, Ci-oalkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi- 6 alkyl, Ci- ⁇ alkylsulfonyl, C 1- 6alkylsulfonylamino, bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino, carbamoyl, Ci-6alkylcarbamoyl and bis(
  • 1Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 -,
  • R 1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylC i_ 6 alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R 9 , -OR 9 , -COR 9 , -CONR 9 R 10 , -NR 9 R 10 and -NR 9 COR 10 ; or X-R 1 is -C(CH 3 ) 2 OH or -CH 2 OH;
  • R 2 is selected from aryl and heteroaryl which group is substituted by -NR 17 CONR 18 R 19 or -NR 17 CSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -
  • R 3 is methyl
  • R 4 and R 5 are independently hydrogen or or, when X is -NR 4 CR 6 R 7 -, -NR 4 C(O)CR 6 R 7 - or -NR 4 C(O)NR 5 CR 6 R 7 -, R 1 and R 4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
  • 6alkylsulfamoyl bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi.
  • Ci-6alkylamino bis(Ci- 6 alkyl)amino, aminoCi- 6 alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
  • R 8 is selected from hydrogen, halo, cyano and C 1-6 alkyl
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-
  • R , R , R and R are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, ImIoC 1- ⁇ alkoxy, hydroxyC 1-6 alkyl, hydroxyCi_6alkoxy, C 1-6 alkoxyC 1-6 alkyl, Ci- ⁇ alkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and R 19 is hydrogen or a group selected from C ⁇ aUcyl, C 3 _ 6 Cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro
  • R 18 and R 19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, IUS(C 1- 6 alkyl)amino, aminoCi.
  • 6 alkyl bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 - and -S(O) 2 CR 6 R 7 -;
  • R 1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thiadiazolyl, thiazolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethy
  • R 2 is selected from 5 or 6 membered aryl and heteroaryl which group is substituted by -NHCONR 18 R 19 or -NHCSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 ;
  • R 3 is methyl;
  • R 4 is hydrogen or Ci_ 6 alkyl; or, when X is -NR 4 CR 6 R 7 -, R 1 and R 4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci -6 alkyl, Ci -6 alkoxy, haloCi -6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi.
  • Ci-6alkylamino bis(Ci-6alkyl)amino, aminoCi-6alkyl, ⁇ alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, Ci- 6 alkylsulfonyl, Ci- 6 alkylsulfonylamino, bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci_ 6 alkyl)carbamoyl;
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6 alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci- 6 alkyl)ammo, aminoCi.
  • R 8 is selected from hydrogen, halo, cyano and Ci_ 6 alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi -6 alkyl, hydroxyCi -6 alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, C 1- 6alkylamino and bis(Ci-6alkyl)amino;
  • R 11 , R 12 and R 18 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, C 1- 6 alkylamino and bis(Ci. 6 alkyl)amino; and
  • R 19 is hydrogen, cyano or a group selected from C 1-6 alkyl, C 3-6 cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, Ci_6alkoxy, haloC 1-6 alkyl, haloCi-6alkoxy, hydroxyC 1-6 alkyl, hydroxyCi_6alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoC 1-6 alkyl,
  • 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloCi-6alkoxy, hydroxyC 1-6 alkyl, hydroxyCi_6alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkoxy, amino, Ci-6alkylamino, Ms(C 1- 6alkyl)amino, aminoC 1-6 alkyl, (C 1-6 alkyl)aminoC 1-6 alkyl, bis(C 1-6 alkyl)aminoC 1-6 alkyl, cyanoC 1-6 alkyl, C 1-6 alkylsulfonyl, Ci-6alkylsulfonylamino, C 1-6 alkylsulfony
  • 1 Y and Y 2 are independently N or CR 8 provided that one of 1 Y and Y 2 is N and the other is CR 8 ;
  • X is a linker group selected from -NR 4 CR 6 R 7 -, -OCR 6 R 7 -, -SCR 6 R 7 -, -S(O)CR 6 R 7 - and -S(O) 2 CR 6 R 7 -;
  • R 1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinyl
  • R 2 is selected from 5 or 6 membered aryl and heteroaryl which group is substituted by -NHCONR 18 R 19 or -NHCSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -NR 11 COR 12 ;
  • R 3 is methyl;
  • R 4 is hydrogen or C h alky!; or, when X is -NR 4 CR 6 R 7 -, R 1 and R 4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd.
  • Ci-6alkylamino bis(Ci-6alkyl)amino, aminoCi-6alkyl, 6alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi_ 6 alkyl, Ci- 6 alkylsulfonyl, Ci- 6 alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealky ⁇ amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci- 6 alkanoylamino, carbamoyl, and bis(Ci. 6alkyl)carbamoyl;
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi.
  • R 8 is selected from hydrogen, halo, cyano and C 1-6 alkyl;
  • R 9 and R 10 are independently hydrogen or a group selected from Ci -6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, C 1- 6alkylamino and bis(Ci-6alkyl)amino;
  • R 11 , R 12 and R 18 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloCi-6alkoxy, hydroxyC 1-6 alkyl, hydroxyCi-6alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkoxy, amino, C 1- 6alkylamino and bis(Ci-6alkyl)amino; and
  • R 19 is hydrogen or a group selected from C 1-6 alkyl, C 3-6 cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C ⁇ aUcyl, Ci_6alkoxy, haloCi_ 6 alkyl, haloCi_ 6 alkoxy, hydroxyCi_ 6 alkyl, hydroxyCi_ 6 alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci- 6 alkoxyCi. 6 alkoxy, amino, bis(Ci.
  • X is a -S(O) 2 CR 6 R 7 - linker group
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH 3 , -CONH 2 and -CONHCH 3 ; or -XR 1 is -C(CH 3 ) 2 OH or -CH 2 OH;
  • R 2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NHCONHR 19 or
  • R 3 is methyl; R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi.
  • R 11 , R 12 and R 18 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci -6 alkyl, Ci -6 alkoxy, haloCi -6 alkyl,
  • R 19 is hydrogen, cyano or a group selected from Ci_ 6 alkyl, C 3-6 Cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi_ 6 alkyl, Ci- 6 alkylsulfonyl, C 1- 6alkylsulfonylamino, bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino, carbamoyl, Ci-6alkylcarbamoyl and bis(
  • X is a -S(O) 2 CR 6 R 7 - linker group
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group iso optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifiuoromethyl, trifluoromethoxy, -NHCOCH 3 , -CONH 2 and -CONHCH 3 ; or -XR 1 is -C(CH 3 ) 2 OH or -CH 2 OH;
  • R 2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NHCONHR 19 or s -NR 17 CSNR 18 R 19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R 11 , -OR 11 , -COR 11 , -CONR 11 R 12 , -NR 11 R 12 and -
  • R 3 is methyl
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-memberedo carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N,
  • R 11 , R 12 and R 18 are independently hydrogen or a group selected from Ci_ 6 alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyd- ⁇ alkoxy, amino, C 1- 6alkylamino and bis(Ci-6alkyl)amino; and
  • R 19 is hydrogen or a group selected from Ci_ 6 alkyl, C 3-6 Cycloakyl, aryl, heteroaryl, arylCi- 6 alkyl and heteroarylCi- 6 alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi -6 alkyl, haloCi -6 alkoxy, hydroxyCi -6 alkyl, hydroxyCi -6 alkoxy, Ci -6 alkoxyCi -6 alkyl, C 1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, Ci- 6 alkylsulfonyl, Ci- 6alkylsulfonylamino, bis(Ci_
  • X is a -S(O) 2 CR 6 R 7 - linker group; 1Y is CH and Y 2 is N.
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH 3 , -CONH 2 and -CONHCH 3 ; R 2 is phenyl or pyridinyl substituted by -NHCONHR 19 or -
  • Ci-6 alkyl hydroxyCi -6 alkoxy, Ci -6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, Ci -6 alkylamino, bis(Ci- 6 alkyl)amino, aminoCi- 6 alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH 3 , -CONH 2 and -CONHCH 3 ; R 2 is phenyl or pyridinyl substituted by -NHCONHR 19 or -
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkoxy, haloCi_6alkoxy, hydroxyCi.
  • 6alkyl hydroxyCi_6alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkyl, Ci-ealkoxyCi- ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci- 6 alkyl)amino, aminoCi- 6 alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, bis(Ci.
  • R 19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i- butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, dioxothiolanyl, imidazoylmethyl, isoxazolyl, oxazolyl, oxetanyl, pyrazinyl, pyrazolyl, pyrazolylmethyl, pyridinyl, pyrimidinyl, pyrrolidin
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH 3
  • R 2 is phenyl or pyridinyl substituted by -NHCONHR 19 or -NHCSNHR 19 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH 2 , -CONHCH 3 and -CON(CH 3 ) 2 ;
  • R 3 is methyl;
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi.
  • R 19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopen
  • X is a -S(O) 2 CR 6 R 7 - linker group
  • Y is CH and Y 2 is N.
  • R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifiuoromethyl, trifluoromethoxy, -NHCOCH 3 , -CONH 2 and -CONHCH 3 ; R 2 is phenyl or pyridinyl substituted by -NHCONHR 19 or -NHCSNHR 19 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, me
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1-6 alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi.
  • R 19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyrazolylmethyl, pyridinyl and pyrimidinyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C 1- 6alkyl, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6 alkoxyCi -6 alkyl, Ci -6 alkoxyCi -6 alkoxy, amino, Ci -6 alkylamino, bis(Ci -6 al
  • ⁇ alkyl (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, Ci- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
  • R 1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NHC(O)CH 3 , -CH 2 C(O)NH 2 , -CH 2 C(O)NHMe, phenyl, 4-fiuorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3,5-difiuorophenyl, 2-(trifiuoromethyl)phenyl, 4-(2-hydroxyethylamino)phenyl,
  • a 1 and A 2 are selected from CH or N provided that at least one of A 1 or
  • a , 2 z is CH
  • R 17 is hydrogen
  • R 18 is hydrogen
  • R 19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i- propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 (cyclopropyl), -CH 2 CH 2 NMe 2 ,
  • -CH 2 CH 2 (pyrrolidin-l-yl),-CH 2 (imidazol-2-yl), -CH 2 (imidazol-3-yl), oxazolyl-2-yl, isoxazolyl-3-yl, 6-oxo-lH-pryrdin-2-yl, oxetan-3-yl, 1,1- dioxothiolan-3-yl, 5-methylisoxazol-3-yl, -CH 2 (I -methylpyrazol-4-yl), l-methylpyrazol-4-yl, -CH 2 (I -methylpyrazol-4-yl), 5-methylpyrazin-2- yl, -CH 2 (2H-l,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl,
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi.
  • Ci-6alkyl hydroxyCi-6alkoxy, Ci-ealkoxyd- ⁇ alkyl, Ci-ealkoxyC ⁇ alkoxy, amino, Ci-6alkylamino, bis(Ci- 6 alkyl)amino, aminoCi- 6 alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci -6 alkyl)aminoCi -6 alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony ⁇ Ci-ealkyFjamino, sulfamoyl, Ci -6 alkylsulfamoyl, bis(Ci -6 alkyl)sulfamoyl, Ci -6 alkanoylamino, Ci -6 alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-6alky
  • R 1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH 2 CH 2 OH, -CH 2 CH 2 NHC(O)CH 3 , phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifiuoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin- 2-yl, 2-oxopyrolidin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, and 3-methyl-l,3,4-thiadiazol-2- yi;
  • a 1 and A 2 are selected from CH or N provided that at least one of A 1 or A 2 is CH; R 17 is hydrogen; R 18 is hydrogen; and
  • R 19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 (cyclopropyl), -CH 2 CH 2 NMe 2 , -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, 4-methylphenyl, 4- chlorophenyl, 4-trifiuoromethylphenyl, 4-flurophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CH 2 (imidazol-2-yl), -CH 2 (imidazol-3-yl), isoxazolyl-3-yl, 6-ox
  • R 3 is methyl; and R 6 and R 7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, haloCi_6alkoxy, hydroxyCi.
  • m is 1;
  • X is a -S(O) 2 CR 6 R 7 - linker group;
  • Y is CH and Y 2 is N.
  • R 1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NHC(O)CH 3 ,
  • a 1 and A 2 are selected from CH or N provided that at least one of A 1 or
  • a 2 is CH; R 17 is hydrogen; R 18 is hydrogen; and R 19 is is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH ⁇ cyclopropyl), -CH 2 CH 2 NMe 2 , -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CHF 2 , -CH 2 CH 2 SO 2 Me, -CH 2 CH(OH)CF 3 , -CH 2 CH 2 CN, -CH 2 CN, -CH 2 CN, -CH 2 CN, -CH 2 CN, -CH 2 CN,
  • CH 2 CONMe 2 l-(methyl)cyclopropyl, l-(hydroxymethyl)cyclopropyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, -CH 2 CH 2 (pyrrolidin-l-yl),-CH 2 (imidazol-2-yl), oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, l,l-dioxothiolan-3-yl, 5-methylisoxazol-3- yl, -CH 2 (I -methylpyrazol-4-yl), l-methylpyrazol-4-yl, 5-methylpyrazin- 2-yl, -CH 2 (2H-l,2,4-triazol-3-yl), 6-methoxypryridin-3--
  • R 6 and R 7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring.
  • X is a -S(O) 2 CR 6 R 7 - linker group
  • R 1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 C(OH)(CH 3 ) 2 , -CH 2 CH 2 CH 2 OCHF 2 ,
  • a 1 and A 2 are selected from CH or N provided that at least one of A 1 or
  • a 2 is CH
  • R .17 is hydrogen
  • R ,18 is hydrogen
  • R .19 is is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH 2 (cyclopropyl), -CH 2 CH 2 NMe 2 , -CH(CH 3 )CH 2 OH, -C(CHs) 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 SO 2 Me, -CH 2 CH(OH)CF 3 , -CH 2 CH 2 CN, -CH 2 CN, -CH 2 CONMe 2 , -CH 2 CO 2 H,
  • R 6 and R 7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R 3A is hydrogen, R 3B is hydrogen, methyl, ethyl, hydroxymethyl, dimethylcarbamoyl or carbamoyl; or when R 3A is methyl, R 3B is methyl.
  • X is a -S(O) 2 CR 6 R 7 - linker group; 1Y is CH and Y 2 is N;
  • R 1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, -CH 2 CH 2 OH, - CH 2 CH 2 CH 2 OH, -CH 2 CH 2 C(OH)(CH 3 )2, -CH 2 CH 2 CH 2 OCHF 2 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NHC(O)CH 3 , -CH 2 CH 2 NHMe, phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-fluoro-4-methylaminophenyl, 4-fluoro-2-methylphenyl, 5-fiuoro-2- methylphenyl, 3 -fluoro-4-(2-hydroxyethylamino)phenyl, 4-(difluoromethoxy)phenyl, 4-carbamoyl-2-chlorophenyl, 4-chloropheny
  • a 1 and A 2 are selected from CH or N provided that at least one of A 1 or
  • a , 2 z is CH
  • R 17 is hydrogen
  • R 18 is hydrogen
  • R 19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, -CH 2 (cyclopropyl), -CH 2 CH 2 NMe 2 ,
  • R 6 and R 7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R 3A is hydrogen, R 3B is hydrogen, methyl or ethyl; or when R 3A is methyl, R 3B is methyl.
  • R 1 is a group selected from methyl, ethyl, cyclopropyl, -CH 2 CH 2 CH 2 OH, phenyl, 2-fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-chlorophenyl, 2-methylphenyl, 5-fiuoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl; R 2 is
  • a 1 and A 2 are selected from CH or N provided that at least one of A 1 or
  • a 2 is CH; R 17 is hydrogen; R 18 is hydrogen; and
  • R 19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl, -CH(CH 3 )CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CH 2 CN, (lR)-2-hydroxy-l-methylethyl, (lS)-2- hydroxy-1-methylethyl, -CH 2 (imidazol-2-yl), oxazolyl-2-yl, isoxazolyl- 3-yl, l-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, thiazol-2-yl and l,2,4-thiadiazol-5-yl;
  • R 6 and R 7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R 3A is hydrogen, R 3B is hydrogen, methyl or ethyl; or when R 3A is methyl, R 3B is methyl.
  • R 3A is hydrogen
  • R 3B is hydrogen, methyl or ethyl
  • R 3B is methyl.
  • X is a -S(O) 2 CR 6 R 7 - linker group; 1Y is CH and Y 2 is N;
  • R 1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 C(OH)(CH 3 ) 2 , -CH 2 CH 2 CH 2 OCHF 2 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NHC(O)CH 3 , -CH 2 C(O)NH 2 , -CH 2 C(O)NHMe, -CH 2 CH 2 NHMe, phenyl, 2-fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-fluoro-4-methylaminophenyl, 4-fiuoro-2-methylphenyl, 5-fiuoro-2-methylphenyl, 3-fiuoro-4-(2-hydroxyethy
  • a 1 and A 2 are CH;
  • R 17 is hydrogen; R 18 is hydrogen; and
  • R 19 is is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH 2 (cyclopropyl),
  • R 6 and R 7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R 3A is hydrogen, R 3B is hydrogen, methyl, ethyl, hydroxymethyl, dimethylcarbamoyl or carbamoyl; or when R 3 is methyl, R 3 is methyl.
  • R 1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, -CH 2 CH 2 OH, - CH 2 CH 2 CH 2 OH, -CH 2 CH 2 C(OH)(CH 3 ) 2 , -CH 2 CH 2 CH 2 OCHF 2 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NHC(O)CH 3 , -CH 2 CH 2 NHMe, phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-fluoro-4-methylaminophenyl, 4-fluoro-2-methylphenyl, 5-fiuoro-2-o methylphenyl, 3-fluoro-4-(2-hydroxyethylamino)phenyl, 4-(difluoromethoxy)phenyl, 4-carbamoyl-2-chlorophenyl, 4-chlorophen
  • a 1 and A 2 are CH;
  • R 17 is hydrogen
  • R 18 is hydrogen; and R 19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, -CH ⁇ cyclopropyl), -CH 2 CH 2 NMe 2 , -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CN, 5 -CH 2 (I -hydroxycyclopropyl), l-(hydroxymethyl)cyclopropyl,
  • R 6 and R 7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R 3A is hydrogen, R 3B is hydrogen, methyl or ethyl; or s when R 3A is methyl, R 3B is methyl.
  • R 1 is a group selected from methyl, ethyl, cyclopropyl, -CH 2 CH 2 CH 2 OH, phenyl, 2-fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-chlorophenyl, 2-methylphenyl, 5-fiuoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl; 5 R 2 is wherein A 1 and A 2 are CH;
  • R 17 is hydrogen; R 18 is hydrogen; and
  • R 19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl, -CH(CH 3 )CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CH 2 CN, (lR)-2-hydroxy-l-methylethyl, (lS)-2- hydroxy-1-methylethyl, -CH 2 (imidazol-2-yl), oxazolyl-2-yl, isoxazolyl- 3-yl, l-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, thiazol-2-yl and l,2,4-thiadiazol-5-yl;
  • R 6 and R 7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R 3A is hydrogen, R 3B is hydrogen, methyl or ethyl; or when R 3A is methyl, R 3B is methyl.
  • X is a -S(O) 2 CR 6 R 7 - linker group; 1Y is CH and Y 2 is N;
  • R 1 is a group selected from methyl, ethyl, cyclopropyl, -CH 2 CH 2 CH 2 OH, phenyl, 2-fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-chlorophenyl, 2-methylphenyl, 5-fiuoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl;
  • R 2 is wherein A 1 and A 2 are CH;
  • R .17 is hydrogen
  • R ,18 is hydrogen
  • R .19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl, -CH(CH 3 )CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CH 2 CN, (lR)-2-hydroxy-l-methylethyl, (lS)-2- hydroxy-1-methylethyl, -CH 2 (imidazol-2-yl), oxazolyl-2-yl, isoxazolyl- 3-yl, l-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, thiazol-2-yl and l,2,4-thiadiazol-5-yl;
  • R 6 and R 7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R 3A is hydrogen, R 3B is methyl or ethyl; or when R 3A is methyl, R 3B is methyl.
  • Another aspect of the invention provides a compound, or a combination of compounds, selected from any one of the Examples or a pharmaceutically acceptable salt thereof.

Abstract

A compound of formula (I) or a pharamaceutically acceptable salt thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of proliferative disease such as cancer and particularly in disease mediated by an mTOR kinase and/or one or more PI3K enzyme.

Description

Compounds - 945
The present invention relates to morpholino pyrimidine compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of proliferative disease such as cancer and particularly in disease mediated by an mTOR kinase and/or one or more PBK enzyme.
It is now well understood that deregulation of oncogenes and tumour-suppressor genes contributes to the formation of malignant tumours, for example by way of increased cell proliferation or increased cell survival. It is also known that signalling pathways mediated by the PBK/mTOR families have a central role in a number of cell processes including proliferation and survival, and deregulation of these pathways is a causative factor in a wide spectrum of human cancers and other diseases.
The mammalian target of the macrolide antibiotic Rapamycin (sirolimus) is the enzyme mTOR. This enzymes belongs to the phosphatidylinositol (PI) kinase-related kinase (PIKK) family of protein kinases, which also includes ATM, ATR, DNA-PK and hSMG-1. mTOR, like other PIKK family members, does not possess detectable lipid kinase activity, but instead functions as a serine/threonine kinase. Much of the knowledge of mTOR signalling is based upon the use of Rapamycin. Rapamycin first binds to the 12 kDa immunophilin FK506- binding protein (FKBP 12) and this complex inhibits mTOR signalling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37). The mTOR protein consists of a catalytic kinase domain, an FKBP12-Rapamycin binding (FRB) domain, a putative repressor domain near the C-terminus and up to 20 tandemly-repeated HEAT motifs at the TV- terminus, as well as FRAP -ATM-TRRAP (FAT) and FAT C-terminus domain (Huang and Houghton, Current Opinion in Pharmacology, 2003, 3, 371-377). mTOR kinase is a key regulator of cell growth and has been shown to regulate a wide range of cellular functions including translation, transcription, mRNA turnover, protein stability, actin cytoskeleton reorganisation and autophagy (Jacinto and Hall, Nature Reviews Molecular and Cell Biology, 2005, 4, 117-126). mTOR kinase integrates signals from growth factors (such as insulin or insulin-like growth factor) and nutrients (such as amino acids and glucose) to regulate cell growth. mTOR kinase is activated by growth factors through the PI3K-Akt pathway. The most well characterised function of mTOR kinase in mammalian cells is regulation of translation through two pathways, namely activation of ribosomal S6K1 to enhance translation of mRNAs that bear a 5 '-terminal oligopyrimidine tract (TOP) and suppression of 4E-BP1 to allow CAP-dependent mRNA translation.
Generally, investigators have explored the physiological and pathological roles of mTOR using inhibition with Rapamycin and related Rapamycin analogues based on their specificity for mTOR as an intracellular target. However, recent data suggests that Rapamycin displays variable inhibitory actions on mTOR signalling functions and suggest that direct inhibition of the mTOR kinase domain may display substantially broader anti-cancer activities than that achieved by Rapamycin (Edinger et ah, Cancer Research, 2003, 63, 8451-8460). For this reason, potent and selective inhibitors of mTOR kinase activity would be useful to allow a more complete understanding of mTOR kinase function and to provide useful therapeutic agents.
There is now considerable evidence indicating that the pathways upstream of mTOR, such as the PI3K pathway, are frequently activated in cancer (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501; Bjornsti and Houghton, Nature Reviews Cancer, 2004, 4, 335-348; Inoki et ah, Nature Genetics, 2005, 37, 19-24). For example, components of the PI3K pathway that are mutated in different human tumours include activating mutations of growth factor receptors and the amplification and/or overexpression of PI3K and Akt.
In addition there is evidence that endothelial cell proliferation may also be dependent upon mTOR signalling. Endothelial cell proliferation is stimulated by vascular endothelial cell growth factor (VEGF) activation of the PI3K-Akt-mTOR signalling pathway (Dancey, Expert Opinion on Investigational Drugs, 2005, 14, 313-328). Moreover, mTOR kinase signalling is believed to partially control VEGF synthesis through effects on the expression of hypoxia- inducible factor- lα (HIF- lα) (Hudson et al, Molecular and Cellular Biology, 2002, 22, 7004- 7014). Therefore, tumour angiogenesis may depend on mTOR kinase signalling in two ways, through hypoxia-induced synthesis of VEGF by tumour and stromal cells, and through VEGF stimulation of endothelial proliferation and survival through PI3K-Akt-mTOR signalling.
These findings suggest that pharmacological inhibitors of mTOR kinase should be of therapeutic value for treatment of the various forms of cancer comprising solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies. In particular, inhibitors of mTOR kinase should be of therapeutic value for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
In addition to tumourigenesis, there is evidence that mTOR kinase plays a role in an array of hamartoma syndromes. Recent studies have shown that the tumour suppressor proteins such as TSCl, TSC2, PTEN and LKBl tightly control mTOR kinase signalling. Loss of these tumour suppressor proteins leads to a range of hamartoma conditions as a result of elevated mTOR kinase signalling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37). Syndromes with an established molecular link to dysregulation of mTOR kinase include Peutz-Jeghers syndrome (PJS), Cowden disease, Bannayan-Riley- Ruvalcaba syndrome (BRRS), Proteus syndrome, Lhermitte-Duclos disease and Tuberous Sclerosis (TSC) (Inoki et ah, Nature Genetics, 2005, 37, 19-24). Patients with these syndromes characteristically develop benign hamartomatous tumours in multiple organs. Recent studies have revealed a role for mTOR kinase in other diseases (Easton & Houghton, Expert Opinion on Therapeutic Targets, 2004, 8, 551-564). Rapamycin has been demonstrated to be a potent immunosuppressant by inhibiting antigen-induced proliferation of T cells, B cells and antibody production (Sehgal, Transplantation Proceedings, 2003, 35, 7S- 14S) and thus mTOR kinase inhibitors may also be useful immunosuppressives. Inhibition of the kinase activity of mTOR may also be useful in the prevention of restenosis, that is the control of undesired proliferation of normal cells in the vasculature in response to the introduction of stents in the treatment of vasculature disease (Morice et ah, New England Journal of Medicine, 2002, 346, 1773-1780). Furthermore, the Rapamycin analogue, everolimus, can reduce the severity and incidence of cardiac allograft vasculopathy (Eisen et ah, New England Journal of Medicine, 2003, 349, 847-858). Elevated mTOR kinase activity has been associated with cardiac hypertrophy, which is of clinical importance as a major risk factor for heart failure and is a consequence of increased cellular size of cardiomyocytes (Tee & Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37). Thus mTOR kinase inhibitors are expected to be of value in the prevention and treatment of a wide variety of diseases in addition to cancer. It is also believed that a number of these morpholino pyrimidine derivatives may have inhibitory activity against the phosphatidylinositol (PI) 3-kinases family of kinases. Phosphatidylinositol (PI) 3-kinases (PBKs) are ubiquitous lipid kinases that function both as signal transducers downstream of cell-surface receptors and in constitutive intracellular membrane and protein trafficking pathways. All PBKs are dual-specificity enzymes with a lipid kinase activity that phosphorylates phosphoinositides at the 3 -hydroxy position, and a less well characterised protein kinase activity. The lipid products of PBK-catalysed reactions comprising phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], phosphatidylinositol 3,4- bisphosphate [PI(3,4)P2] and phosphatidylinositol 3 -monophosphate [PI(3)P] constitute second messengers in a variety of signal transduction pathways, including those essential to cell proliferation, adhesion, survival, cytoskeletal rearrangement and vesicle trafficking. PI(3)P is constitutively present in all cells and its levels do not change dramatically following agonist stimulation. Conversely, PI(3,4)P2 and PI(3,4,5)P3 are nominally absent in most cells but they rapidly accumulate on agonist stimulation.
The downstream effects of PBK-produced 3-phosphoinositide second messengers are mediated by target molecules containing 3-phosphoinositide binding domains such as the pleckstrin homology (PH) domain and the recently identified FYVE and phox domains. Well-characterised protein targets for PBK include PDKl and protein kinase B (PKB). In addition, tyrosine kinases like Btk and Itk are dependent on PBK activity.
The PBK family of lipid kinases can be classified into three groups according to their physiological substrate specificity (Vanhaesebroeck et al, Trends in Biol. ScL, 1997, 22, 267). Class III PBK enzymes phosphorylate PI alone. In contrast, Class II PBK enzymes phosphorylate both PI and PI 4-phosphate [PI(4)P]. Class I PBK enzymes phosphorylate PI, PI(4)P and PI 4,5-bisphosphate [PI(4,5)P2], although only PI(4,5)P2 is believed to be the physiological cellular substrate. Phosphorylation of PI(4,5)P2 produces the lipid second messenger PI(3,4,5)P3. More distantly related members of the lipid kinase superfamily are Class IV kinases such as mTOR (discussed above) and DNA-dependent kinase that phosphorylate serine/threonine residues within protein substrates. The most studied and understood of the PBK lipid kinases are the Class I PBK enzymes.
Class I PBKs are heterodimers consisting of a pi 10 catalytic subunit and a regulatory subunit. The family is further divided into Class Ia and Class Ib enzymes on the basis of regulatory partners and the mechanism of regulation. Class Ia enzymes consist of three distinct catalytic subunits (pi 10a, pi lOβ and pi lOδ) that dimerise with five distinct regulatory subunits (p85α, p55α, p50α, p85β and p55γ), with all catalytic subunits being able to interact with all regulatory subunits to form a variety of heterodimers. Class Ia PBKs are generally activated in response to growth factor-stimulation of receptor tyrosine kinases via interaction of their regulatory subunit SH2 domains with specific phospho-tyrosine residues of activated receptor or adaptor proteins such as IRS-I . Both pi 10α and pi lOβ are constitutively expressed in all cell types, whereas pi lOδ expression is more restricted to leukocyte populations and some epithelial cells. In contrast, the single Class Ib enzyme consists of a pi lOγ catalytic subunit that interacts with a plOl regulatory subunit. Furthermore, the Class Ib enzyme is activated in response to G-protein coupled receptor systems (GPCRs) and its expression appears to be limited to leukocytes and cardiomyocytes. There is now considerable evidence indicating that Class Ia PBK enzymes contribute to tumourigenesis in a wide variety of human cancers, either directly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501). For example, the pi 10a subunit is amplified in some tumours such as those of the ovary (Shayesteh et al., Nature Genetics, 1999, 21, 99-102) and cervix (Ma et al, Oncogene, 2000, 19, 2739-2744). More recently, activating mutations within the catalytic site of the pi 10a catalytic subunit have been associated with various other tumours such as those of the colorectal region and of the breast and lung (Samuels et al, Science, 2004, 304, 554). Tumour-related mutations in the p85α regulatory subunit have also been identified in cancers such as those of the ovary and colon (Philp et al., Cancer Research, 2001, 61, 7426-7429). In addition to direct effects, it is believed that activation of Class Ia PBKs contributes to tumourigenic events that occur upstream in signalling pathways, for example by way of ligand-dependent or ligand-independent activation of receptor tyrosine kinases, GPCR systems or integrins (Vara et al., Cancer Treatment Reviews, 2004, 30, 193-204). Examples of such upstream signalling pathways include over- expression of the receptor tyrosine kinase erbB2 in a variety of tumours leading to activation of PBK-mediated pathways (Harari et al., Oncogene, 2000, 19, 6102-6114) and over-expression of the ras oncogene (Kauffmann-Zeh et al., Nature, 1997, 385, 544-548). In addition, Class Ia PBKs may contribute indirectly to tumourigenesis caused by various downstream signalling events. For example, loss of the effect of the PTEN tumour-suppressor phosphatase that catalyses conversion of PI(3,4,5)P3 back to PI(4,5)P2 is associated with a very broad range of tumours via deregulation of PBK-mediated production of PI(3,4,5)P3 (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41). Furthermore, augmentation of the effects of other PBK- mediated signalling events is believed to contribute to a variety of cancers, for example by activation of Akt (Nicholson and Anderson, Cellular Signalling, 2002, 14, 381-395).
In addition to a role in mediating proliferative and survival signalling in tumour cells, there is evidence that Class Ia PI3K enzymes contribute to tumourigenesis in tumour- associated stromal cells. For example, PI3K signalling is known to play an important role in mediating angiogenic events in endothelial cells in response to pro-angiogenic factors such as VEGF (Abid et al, Arterioscler. Thromb. Vase. Biol, 2004, 24, 294-300). As Class I PI3K enzymes are also involved in motility and migration (Sawyer, Expert Opinion Investig. Drugs, 2004, 13, 1-19), PI3K enzyme inhibitors should provide therapeutic benefit via inhibition of tumour cell invasion and metastasis. In addition, Class I PI3K enzymes play an important role in the regulation of immune cells contributing to pro-tumourigenic effects of inflammatory cells (Coussens and Werb, Nature, 2002, 420, 860-867).
These findings suggest that pharmacological inhibitors of Class I PI3K enzymes will be of therapeutic value for the treatment of various diseases including different forms of the disease of cancer comprising solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies. In particular, inhibitors of Class I PI3K enzymes should be of therapeutic value for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
PI3Kγ, the Class Ib PI3K, is activated by GPCRs, as was finally demonstrated in mice lacking the enzyme. Thus, neutrophils and macrophages derived from PI3Kγ-deficient animals failed to produce PI(3,4,5)P3 in response to stimulation with various chemotactic substances (such as IL-8, C5a, fMLP and MIP-Ia), whereas signalling through protein tyrosine kinase- coupled receptors to Class Ia PBKs was intact (Hirsch et al., Science, 2000, 287(5455), 1049- 1053; Li et al, Science, 2002, 287(5455), 1046-1049; Sasaki et al., Science 2002, 287(5455), 1040-1046). Furthermore, PI(3,4,5)P3-mediated phosphorylation of PKB was not initiated by these GPCR ligands in PI3Kγ-null cells. Taken together, the results demonstrated that, at least in resting haematopoietic cells, PI3Kγ is the sole PI3K isoform that is activated by GPCRs in vivo. When murine bone marrow-derived neutrophils and peritoneal macrophages from wild- type and PBKy"7" mice were tested in vitro, a reduced, but not completely abrogated, performance in chemotaxis and adherence assays was observed. However, this translated into a drastic impairment of IL-8 driven neutrophil infiltration into tissues (Hirsch et ah, Science, 2000, 287(5455), 1049-1053.). Recent data suggest that PBKγ is involved in the path finding process rather than in the generation of mechanical force for motility, as random migration was not impaired in cells that lacked PBKγ (Hannigan et ah, Proc. Nat. Acad, of Sciences of U.S.A., 2002, 99(6), 3603-8). Data linking PBKγ to respiratory disease pathology came with the demonstration that PBKγ has a central role in regulating endotoxin-induced lung infiltration and activation of neutrophils leading to acute lung injury (Yum et ah, J. Immunology, 2001, 167(11), 6601-8). The fact that although PBKγ is highly expressed in leucocytes, its loss seems not to interfere with haematopoiesis, and the fact that PBKγ-null mice are viable and fertile further implicates this PBK isoform as a potential drug target. Work with knockout mice also established that PBKγ is an essential amplifier of mast cell activation (Laffargue et ah, Immunity, 2002, 16(3), 441-451).
Thus, in addition to tumourigenesis, there is evidence that Class I PBK enzymes play a role in other diseases (Wymann et ah, Trends in Pharmacological Science, 2003, 24, 366-376). Both Class Ia PBK enzymes and the single Class Ib enzyme have important roles in cells of the immune system (Koyasu, Nature Immunology, 2003, 4, 313-319) and thus they are therapeutic targets for inflammatory and allergic indications. Recent reports demonstrate that mice deficient in PBKγ and PBKδ are viable, but have attenuated inflammatory and allergic responses (AIi et ah, Nature, 2004, 431(7011), 1007-11). Inhibition of PBK is also useful to treat cardiovascular disease via anti-inflammatory effects or directly by affecting cardiac myocytes (Prasad et ah, Trends in Cardiovascular Medicine, 2003, 13, 206-212). Thus, inhibitors of Class I PBK enzymes are expected to be of value in the prevention and treatment of a wide variety of diseases in addition to cancer. Several compounds that inhibit PBKs and phosphatidylinositol (PI) kinase-related kinase (PBKKs) have been identified, including wortmannin and the quercetin derivative LY294002. These compounds are reasonably specific inhibitors of PBKs and PBKKs over other kinases but they lack potency and display little selectivity within the PBK families. Accordingly, it would be desirable to provide further effective mTOR and/or PBK inhibitors for use in the treatment of cancer, inflammatory or obstructive airways diseases, immune or cardiovascular diseases. Morpholino pyrimidine derivatives and PBK inhibitors are known in the art. International Patent Application WO 2004/048365 discloses compounds that possess PBK enzyme inhibitory activity and are useful in the treatment of cancer. These compounds are arylamino- and heteroarylamino-substituted pyrimidines which differ from the compounds of the present invention by virtue of their arylamino- and heteroarylamino substituents. WO 2004/048365 does not disclose compounds with the -XR1 substituents of the present invention. Inhibitors of PBK activity useful in the treatment of cancer are also disclosed in European Patent Application 1 277 738 which mentions 4-morpholino-substituted bicyclic heteroaryl compounds such as quinazoline and pyrido[3,2-J]pyrimidine derivatives and A- morpholino-substituted tricyclic heteroaryl compounds but not monocyclic pyrimidine derivatives.
WO2007/080382, WO2008/023180 and WO2008/023159 disclose compounds that possess mTOR and/or PBK enzyme inhibitory activity and are useful in the treatment of cancer. WO2007/080382, WO2008/023180 and WO2008/023159 do not disclose compounds comprising a cyclic moiety in the linker group X in the group -XR1.
A number of compounds such as 4-morpholin-4-yl-6-(phenylsulfonylmethyl)-2- pyridin-4-yl-pyrimidine and 4- {6-[(phenylsulfonyl)methyl]-2-pyridin-2-ylpyrimidin-4- yl}morpholine have been registered in the Chemical Abstracts database but no utility has been indicated and there is no suggestion that these compounds have mTOR and/or PBK inhibitory activity or useful therapeutic properties.
Surprisingly, we have found that certain morpholino pyrimidine derivatives possess useful therapeutic properties. Without wishing to be bound by theoretical constraints, it is believed that the therapeutic usefulness of the derivatives is derived from their inhibitory activity against mTOR kinase and/or one or more PBK enzyme (such as the Class Ia enzyme and/or the Class Ib enzyme). Because signalling pathways mediated by the PBK/mTOR families have a central role in a number of cell processes including proliferation and survival, and because deregulation of these pathways is a causative factor in a wide spectrum of human cancers and other diseases, it is expected that the derivatives will be therapeutically useful. In particular, it is expected that the derivatives will have anti-proliferative and/or apoptotic properties which means that they will be useful in the treatement of proliferative disease such as cancer. The compounds of the present invention may also be useful in inhibiting the uncontrolled cellular proliferation which arises from various non-malignant diseases such as inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases.
Generally, the compounds of the present invention possess potent inhibitory activity against mTOR kinase but the compound may also possess potent inhibitory activity against one or more PBK enzyme (such as the Class Ia enzyme and/or the Class Ib enzyme).
In accordance with an aspect of the present invention, there is provided a compound of formula (I)
Figure imgf000010_0001
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8;
X is a linker group selected from -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C≡CCR6R7-, -CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-, -NR4S(O)2CR6R7-, and -S(O)2NR4CR6R7-;
R1 is a group selected from hydrogen, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl,
Figure imgf000010_0002
heterocyclyl and heterocyclylCi-όalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -SR9, -
SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10,
-NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10;
R2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -
NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR13SO2R14;
R4 and R5 are independently hydrogen or Ci_6alkyl; or R1 and R4 together with the atom or atoms to which they are attached form a 4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, C1-OaIkOXyC1- βalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000011_0001
βalkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000011_0002
Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino,
Figure imgf000011_0003
bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino,
Figure imgf000011_0004
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci_ 6alkyl)carbamoyl; R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000011_0005
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^d-ealkyFjamino, sulfamoyl,
Figure imgf000011_0006
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-OaIk-UiOyI(C1- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and C1-6alkyl; R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- 6alkyl,
Figure imgf000011_0007
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. 6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-
6alkylsulfonyl, Ci-oalkylsulfonylamino, d-ealkylsulfony^Ci-ealky^amino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci.6alkanoylammo,
Figure imgf000012_0001
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R11, R12, R17 and R18 are independently hydrogen or a group selected from C1-6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is 5 optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000012_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi. 6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci-6alkyl)amino, io carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R13, R14, R15 and R16 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000012_0003
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi.
15 6alkoxy,
Figure imgf000012_0004
amino,
Figure imgf000012_0005
bis(Ci. 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000012_0006
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000012_0007
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
20 R19 is hydrogen, cyano or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloCi. βalkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (C1-
25 6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000012_0008
Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino,
Figure imgf000012_0009
bis(Ci_ 6alkyl)sulfamoyl, Ci.6alkanoylamino,
Figure imgf000012_0010
carbamoyl, Ci- 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 3- to
30 10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloCi-6alkoxy, hydroxyCi. βalkyl, hydroxyCi-6alkoxy, Ci-ealkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci.6alkylammo, bis(Ci-6alkyl)ammo, aminoCi.6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000013_0001
sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-OaIk-UiOyI(C1- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl for use as a medicament in the treatment of proliferative disease.
In accordance with an aspect of the present invention, there is provided a compound of formula (I)
Figure imgf000013_0002
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8; X is a linker group selected from -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C≡CCR6R7-,
-CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-, -NR4S(O)2CR6R7-, and -S(O)2NR4CR6R7-;
R1 is a group selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-όalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -SR9, -
SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10,
-NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10;
R2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -
R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -
NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, -SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR13SO2R14;
R4 and R5 are independently hydrogen or Ci_6alkyl; or R1 and R4 together with the atom or atoms to which they are attached form a 4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, C1-OaIkOXyC1- βalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000014_0001
βalkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000014_0002
Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino,
Figure imgf000014_0003
bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino,
Figure imgf000014_0004
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci_ 6alkyl)carbamoyl; R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000014_0005
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^d-ealkyFjamino, sulfamoyl,
Figure imgf000014_0006
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-OaIk-UiOyI(C1- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and C1-6alkyl; R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- 6alkyl,
Figure imgf000014_0007
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. 6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-
6alkylsulfonyl, Ci-oalkylsulfonylamino, d-ealkylsulfony^Ci-ealky^amino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci.6alkanoylammo,
Figure imgf000015_0001
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R11, R12, R17 and R18 are independently hydrogen or a group selected from C1-6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000015_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi. 6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R13, R14, R15, R16 and R19 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000015_0003
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi. 6alkoxy,
Figure imgf000015_0004
amino,
Figure imgf000015_0005
bis(Ci. 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000015_0006
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000015_0007
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000015_0008
haloCi_6alkoxy, hydroxyCi. βalkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000015_0009
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealky^amino, sulfamoyl,
Figure imgf000015_0010
bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci.6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl for use as a medicament in the treatment of proliferative disease. In accordance with another aspect of the present invention, there is provided a compound of formula (I)
Figure imgf000016_0001
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4;
5 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8;
X is a linker group selected from -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C≡CCR6R7-, -CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-, -NR4S(O)2CR6R7-o and -S(O)2NR4CR6R7-;
R1 is a group selected from C^aHcyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-όalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -SR9, - SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, s -NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10; or X-R1 is -CR6R7OH;
R2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -o NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13,
-SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and
-NR13SO2R14;
R4 and R5 are independently hydrogen or Ci_6alkyl; 5 or R1 and R4 together with the atom or atoms to which they are attached form a 4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6alkyl,
Figure imgf000017_0001
haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi. 6alkoxy, amino,
Figure imgf000017_0002
bis(Ci.6alkyl)amino, aminoCi.6alkyl,
Figure imgf000017_0003
6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci.6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealky^amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino,
Figure imgf000017_0004
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci_ 6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000017_0005
haloCi_6alkoxy, hydroxyCi. βalkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000017_0006
bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci.6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- 6alkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, C1- 6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. βalkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000017_0007
Ci- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, C1- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000017_0008
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R11, R12, R17 and R18 are independently hydrogen or a group selected from
Figure imgf000017_0009
carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloCi-6alkoxy, hydroxyC1-6alkyl, hydroxyCi. 6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, Ci-6alkylamino, IUs(C1- 6alkyl)amino, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci-6alkanoylamino, d-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R13, R14, R15, R16 and R19 are independently hydrogen or a group selected from
Figure imgf000018_0001
carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000018_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi- 6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci- 6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, d-6alkylsulfonyl(d-6alkyl)amino, sulfamoyl,
Figure imgf000018_0003
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000018_0004
hydroxyCi- 6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-όalkyi, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-oalkylsulfonylamino, Ci-ealkylsulfony^d-ealky^amino, sulfamoyl,
Figure imgf000018_0005
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000018_0006
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl for use as a medicament in the treatment of proliferative disease.
In accordance with another aspect of the present invention, there is provided a compound of formula (I)
Figure imgf000018_0007
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4; 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8;
X is a linker group selected from -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C≡CCR6R7-, -CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, 5 -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NR5CR6R7- and -S(O)2NR4CR6R7-; R1 is a group selected from C^aUcyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl,
Figure imgf000019_0001
heterocyclyl and heterocyclylCi-όalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -SR9, - SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, o -NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10; or X-R1 is -CR6R7OH;
R2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -s NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13,
-SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -
NR13SO2R14;
R4 and R5 are independently hydrogen or
Figure imgf000019_0002
o or R1 and R4 together with the atom or atoms to which they are attached form a 4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
Figure imgf000019_0003
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, d-βalkoxyd.5 6alkoxy, amino,
Figure imgf000019_0004
bis(Ci.6alkyl)amino, aminoCi.6alkyl, (Ci-6alkyl)aminoCi- 6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, d-6alkylsulfonyl, d-6alkylsulfonylamino, d-6alkylsulfonyl(d-6alkyl)amino, sulfamoyl,
Figure imgf000019_0005
bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino, d-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci- 6alkyl)carbamoyl; 0 R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000020_0001
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. βalkyl, hydroxyCi-6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, d-ealkylamino, bis(Ci.6alkyl)amino, aminoCi.6alkyl,
Figure imgf000020_0002
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, d-ealkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000020_0003
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;; R8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- βalkyl,
Figure imgf000020_0004
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. βalkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000020_0005
Ci- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, C1- 6alkylsulfamoyl, bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino,
Figure imgf000020_0006
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R , R , R and R are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000020_0007
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi. 6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci. 6alkyl)amino, aminoCi-6alkyl,
Figure imgf000020_0008
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkanoylamino,
Figure imgf000020_0009
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R13, R14, R15, R16 and R19 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloCi-6alkoxy, hydroxyC1-6alkyl, hydroxyCi. 6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, Ci-6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi- 6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, d-6alkylsulfonyl(d-6alkyl)amino, sulfamoyl,
Figure imgf000021_0001
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl for use as a medicament in the treatment of proliferative disease.
In accordance with another aspect of the present invention, there is provided the use of a compound of formula (I)
Figure imgf000021_0002
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4; 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8;
X is a linker group selected from -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C≡CCR6R7-, -CR6R7C≡d, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-, -NR4S(O)2CR6R7- and -S(O)2NR4CR6R7-; R1 is a group selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9, -SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10;
R2 is a group selected from Ci.6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R11, -OR11, - SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, - SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and - NR13SO2R14; R4 and R5 are independently hydrogen or Ci_6alkyl; or R1 and R4 together with the atom or atoms to which they are attached form a 4- to 10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
Figure imgf000022_0001
Ci_6alkoxy,
Figure imgf000022_0002
Figure imgf000022_0003
Ci.6alkoxyCi. βalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000022_0004
6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealky^amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino,
Figure imgf000022_0005
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci_ 6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000022_0006
haloCi_6alkoxy, hydroxyCi. 6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000022_0007
sulfamoyl,
Figure imgf000022_0008
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000022_0009
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- βalkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci.6alkylammo, bis(Ci.6alkyl)amino, aminoCi. 6alkyl,
Figure imgf000023_0001
bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000023_0002
C1- 6alkylsulfonyl, Ci.6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, C1- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci.6alkanoylammo,
Figure imgf000023_0003
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R , R , R and R are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000023_0004
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi. βalkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkanoylamino,
Figure imgf000023_0005
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R13, R14, R15 and R16 are independently hydrogen or a group selected from C1-6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000023_0006
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi. 6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl,
Figure imgf000023_0007
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^d-ealky^amino, sulfamoyl,
Figure imgf000023_0008
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000023_0009
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R19 is hydrogen, cyano or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000023_0010
Ci_6alkoxy, haloCi. 6alkyl,
Figure imgf000023_0011
Ci- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (C1- 6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, C1- 6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1-6alkylsulfamoyl, bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-6alkanoyl(C1-6alkyl)amino, carbamoyl, C1- 6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000024_0001
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000024_0002
6alkyl)amino, carbamoyl,
Figure imgf000024_0003
and bis(Ci.6alkyl)carbamoyl in the manufacture of a medicament for use in the treatment of proliferative disease.
In accordance with another aspect of the present invention, there is provided the use of a compound of formula (I)
Figure imgf000024_0004
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8;
X is a linker group selected from -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C≡CCR6R7-, -CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-, -NR4S(O)2CR6R7- and -S(O)2NR4CR6R7-;
R1 is a group selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-όalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9,
-SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10,
-NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10; R2 is a group selected from C^aUcyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R11, -OR11, - SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; 5 each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, - SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and - NR13SO2R14;
R4 and R5 are independently hydrogen or Ci_6alkyl; or R1 and R4 together with the atom or atoms to which they are attached form a 4- too 10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi. βalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000025_0001
5
Figure imgf000025_0002
Ci.6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealky^amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino,
Figure imgf000025_0003
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci_ 6alkyl)carbamoyl; R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-memberedo carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000025_0004
haloCi_6alkoxy, hydroxyCi. βalkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,5 cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealky^amino, sulfamoyl,
Figure imgf000025_0005
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000025_0006
6alkyl)amino, carbamoyl, Ci.6alkylcarbamoyl and bis(Ci.6alkyl)carbamoyl; R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally 0 substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- 6alkyl,
Figure imgf000025_0007
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. βalkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci- 6alkylsulfonyl, Ci.6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino,
Figure imgf000026_0001
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R , R , R and R are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000026_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi. 6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci. 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkanoylamino,
Figure imgf000026_0003
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R13, R14, R15, R16 and R19 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000026_0004
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi. 6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000026_0005
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000026_0006
6alkyl)amino, carbamoyl, Ci.6alkylcarbamoyl and bis(Ci.6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000026_0007
haloCi_6alkoxy, hydroxyCi. βalkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci.6alkyl)amino, aminoCi.6alkyl,
Figure imgf000026_0008
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealky^amino, sulfamoyl,
Figure imgf000026_0009
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000026_0010
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl in the manufacture of a medicament for use in the treatment of proliferative disease. In accordance with another aspect of the present invention, there is provided the use of a compound of formula (I)
Figure imgf000027_0001
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8;
X is a linker group selected from -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C≡CCR6R7-, -CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-, -NR4S(O)2CR6R7- and -S(O)2NR4CR6R7-;
R1 is a group selected from C^aUcyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9,
-SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10,
-NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10; or X-R1 is -CR6R7OH;
R2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -
R11, -OR11, - SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12,
-NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, -
SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and - NR13SO2R14;
R4 and R5 are independently hydrogen or Chalky!; or R1 and R4 together with the atom or atoms to which they are attached form a 4- to 10- membered carbocyclic or heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd. βalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000028_0001
6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealky^amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino,
Figure imgf000028_0002
carbamoyl,
Figure imgf000028_0003
and bis(Ci. 6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000028_0004
haloCi_6alkoxy, hydroxyCi.
Figure imgf000028_0005
amino,
Figure imgf000028_0006
bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000028_0007
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000028_0008
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and
Figure imgf000028_0009
R9 and R10 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- βalkyl,
Figure imgf000028_0010
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, C1- 6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. βalkyl,
Figure imgf000028_0011
bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000028_0012
Ci- 6alkylsulfonyl, Ci.6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealky^amino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000028_0013
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R , R , R and R are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000029_0001
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi. βalkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci.6alkylammo, bis(Ci_ 6alkyl)amino, aminoCi.6alkyl,
Figure imgf000029_0002
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci.6alkanoylammo,
Figure imgf000029_0003
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R13, R14, R15, R16 and R19 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi. βalkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000029_0004
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000029_0005
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000029_0006
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^d-ealky^amino, sulfamoyl,
Figure imgf000029_0007
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000029_0008
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl in the manufacture of a medicament for use in the treatment of proliferative disease. In accordance with another aspect of the present invention, there is provided the use of a compound of formula (I)
Figure imgf000030_0001
formula (I) or a pharmaceutically acceptable salt; wherein m is 0, 1, 2, 3 or 4;
5 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8;
X is a linker group selected from -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C≡CCR6R7-, -CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NR5CR6R7- and -S(O)2NR4CR6R7-; io R1 is a group selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi_6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9, -SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10; is Or X-R1 Is -CR6R7OH
R2 is a group selected from C1-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R11, -OR11, - SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, and -NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19;
2o each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13, - SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -R13CO2R14 and - NR13SO2R14;
R4 and R5 are independently hydrogen or Ci-6alkyl; or R1 and R4 together with the atom or atoms to which they are attached form a 4- to
25 10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6alkyl,
Figure imgf000030_0002
haloCi^alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi. βalkoxy, amino, Ci.6alkylammo, bis(Ci.6alkyl)amino, aminoCi.6alkyl,
Figure imgf000031_0001
6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000031_0002
Ci.6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealky^amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, C1- 6alkanoylamino,
Figure imgf000031_0003
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci_ 6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000031_0004
haloCi_6alkoxy, hydroxyCi. βalkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000031_0005
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-OaIk-UiOyI(C1- 6alkyl)amino, carbamoyl,
Figure imgf000031_0006
and bis(Ci.6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1- 6alkyl, C1-6alkoxy, haloC1-6alkyl, haloCi-6alkoxy, hydroxyC1-6alkyl, hydroxyCi-6alkoxy, C1- 6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. 6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1- 6alkylsulfonyl, Ci-6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1- 6alkylsulfamoyl, bis(C1-6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-6alkanoyl(C1-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl;
R11, R12, R17 and R18 are independently hydrogen or a group selected from C1-6alkyl, carbocyclyl, carbocyclylC1-6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloCi-6alkoxy, hydroxyC1-6alkyl, hydroxyCi. 6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci-6alkanoylamino, d-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R13, R14, R15, R16 and R19 are independently hydrogen or a group selected from
Figure imgf000032_0001
carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000032_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi- 6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci- 6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, d-6alkylsulfonyl(d-6alkyl)amino, sulfamoyl,
Figure imgf000032_0003
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000032_0004
hydroxyCi- 6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-όalkyi, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^d-ealky^amino, sulfamoyl,
Figure imgf000032_0005
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000032_0006
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl in the manufacture of a medicament for use in the treatment of proliferative disease.
In accordance with a further aspect of the present invention, there is also provided a compound of formula (I)
Figure imgf000032_0007
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4; 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8;
X is a linker group selected from -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C≡CCR6R7-, -CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
5 -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-, -NR4S(O)2CR6R7- and -S(O)2NR4CR6R7-;
R1 is a group selected from hydrogen, Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl,
Figure imgf000033_0001
heterocyclyl and heterocyclylCi-όalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9,o -SOR9, -O2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 and NR9SO2R10;
R2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -s NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -R13,
"SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -
NR13SO2R14;
R4 and R5 are independently hydrogen or
Figure imgf000033_0002
o or R1 and R4 together with the atom or atoms to which they are attached form a 4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
Figure imgf000033_0003
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, d-βalkoxyd.5 6alkoxy, amino,
Figure imgf000033_0004
bis(Ci.6alkyl)amino, aminoCi.6alkyl, (Ci-6alkyl)aminoCi- 6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, d-6alkylsulfonyl, d-6alkylsulfonylamino, d-6alkylsulfonyl(d-6alkyl)amino, sulfamoyl,
Figure imgf000033_0005
bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino, d-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci- 6alkyl)carbamoyl; 0 R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000034_0001
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. βalkyl, hydroxyCi-6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, d-ealkylamino, bis(Ci.6alkyl)amino, aminoCi.6alkyl,
Figure imgf000034_0002
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, d-ealkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000034_0003
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- βalkyl,
Figure imgf000034_0004
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. βalkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000034_0005
Ci- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, C1- 6alkylsulfamoyl, bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino,
Figure imgf000034_0006
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R , R , R and R are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000034_0007
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi. 6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci. 6alkyl)amino, aminoCi-6alkyl,
Figure imgf000034_0008
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkanoylamino,
Figure imgf000034_0009
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R13, R14, R15 and R16 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloCi-6alkoxy, hydroxyC1-6alkyl, hydroxyCi. 6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, Ci-6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R19 is hydrogen, cyano or a group selected from
Figure imgf000035_0001
carbocyclyl,
Figure imgf000035_0002
heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi- 6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (C1- 6alkyl)aminoCi.6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino, Ci-ealkylsulfony^d-ealky^amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(d. 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000035_0003
carbamoyl, Ci- 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000035_0004
hydroxyCi. 6alkyl, hydroxyCi-6alkoxy, Ci-όalkoxyd-ealkyl, Ci-ealkoxyd-όalkoxy, amino, d-όalkylamino, bis(Ci-6alkyl)amino, aminoCi-oalkyl,
Figure imgf000035_0005
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-όalkylsulfonyl, Ci-oalkylsulfonylamino, Ci-ealkylsulfony^d-ealky^amino, sulfamoyl,
Figure imgf000035_0006
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-OaIk-UiOyI(C1- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In accordance with a further aspect of the present invention, there is also provided a compound of formula (I)
Figure imgf000035_0007
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4; 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8;
X is a linker group selected from -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C≡CCR6R7-, -CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
5 -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-, -NR4S(O)2CR6R7- and -S(O)2NR4CR6R7-;
R1 is a group selected from hydrogen, Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl,
Figure imgf000036_0001
heterocyclyl and heterocyclylCi-όalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9,o -SOR9, -O2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 and NR9SO2R10;
R2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -s NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -R13,
"SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -
NR13SO2R14;
R4 and R5 are independently hydrogen or
Figure imgf000036_0002
o or R1 and R4 together with the atom or atoms to which they are attached form a 4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
Figure imgf000036_0003
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, d-βalkoxyd.5 6alkoxy, amino,
Figure imgf000036_0004
bis(Ci.6alkyl)amino, aminoCi.6alkyl, (Ci-6alkyl)aminoCi- 6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, d-6alkylsulfonyl, d-6alkylsulfonylamino, d-6alkylsulfonyl(d-6alkyl)amino, sulfamoyl,
Figure imgf000036_0005
bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino, d-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci- 6alkyl)carbamoyl; 0 R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000037_0001
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. βalkyl, hydroxyCi-6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, d-ealkylamino, bis(Ci.6alkyl)amino, aminoCi.6alkyl,
Figure imgf000037_0002
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, d-ealkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000037_0003
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- βalkyl,
Figure imgf000037_0004
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. βalkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000037_0005
Ci- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, C1- 6alkylsulfamoyl, bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino,
Figure imgf000037_0006
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R , R , R and R are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000037_0007
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi. 6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci. 6alkyl)amino, aminoCi-6alkyl,
Figure imgf000037_0008
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkanoylamino,
Figure imgf000037_0009
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R13, R14, R15, R16 and R19 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloCi-6alkoxy, hydroxyC1-6alkyl, hydroxyCi. 6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, Ci-6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi- 6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, d-6alkylsulfonyl(d-6alkyl)amino, sulfamoyl,
Figure imgf000038_0001
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In accordance with a further aspect of the present invention, there is also provided a compound of formula (I)
Figure imgf000038_0002
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8; X is a linker group selected from -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C≡CCR6R7-,
-CR6R7C≡d, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-, -NR4S(O)2CR6R7- and -S(O)2NR4CR6R7-;
R1 is a group selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9, -SOR9, -O2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 and NR9SO2R10; or X-R1 is -CR6R7OH;
R2 is a group selected from C^aUcyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, - NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -R13, "SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and - NR13SO2R14;
R4 and R5 are independently hydrogen or Ci_6alkyl; or R1 and R4 together with the atom or atoms to which they are attached form a 4- to 10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
Figure imgf000039_0001
haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd. βalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000039_0002
6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealky^amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino,
Figure imgf000039_0003
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci_ 6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000039_0004
haloCi_6alkoxy, hydroxyCi. βalkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci.6alkyl)amino, aminoCi.6alkyl,
Figure imgf000039_0005
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000039_0006
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000039_0007
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;; R8 is selected from hydrogen, halo, cyano and Chalky!; R9 and R10 are independently hydrogen or a group selected from C^aUcyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- 6alkyl,
Figure imgf000040_0001
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, C1- 6alkoxyCi_6alkyl, Ci-όalkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi- 6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci- 6alkylsulfonyl, Ci-6alkylsulfonylamino, d-6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, d-6alkanoyl(Ci-6alkyl)amino, carbamoyl,
Figure imgf000040_0002
and bis(Ci.6alkyl)carbamoyl; R11, R12, R17 and R18 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000040_0003
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi- βalkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci- 6alkyl)amino, aminoCi.6alkyl, (Ci-oalkyFjammoCi.ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkanoylamino, d-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R13, R14, R15, R16 and R19 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi. βalkoxy, Ci-6alkoxyCi-6alkyl, Ci-όalkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci- 6alkyl)amino, aminoCi-6alkyl,
Figure imgf000040_0004
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealky^amino, sulfamoyl,
Figure imgf000040_0005
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000040_0006
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000040_0007
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000040_0008
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci.6alkylsulfonylammo, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000041_0001
6alkyl)amino, carbamoyl, Ci.6alkylcarbamoyl and bis(Ci.6alkyl)carbamoyl..
In accordance with a further aspect of the present invention, there is also provided a 5 compound of formula (I)
Figure imgf000041_0002
formula (I) or a pharmaceutically acceptable salt thereof; wherein o m is 0, 1, 2, 3 or 4;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8;
X is a linker group selected from -CR4=CR5CR6R7-, -CR6R7CR5=CR4-,
-C≡CCR6R7-, -CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, s -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)NR5CR6R7- and -S(O)2NR4CR6R7-; R1 is a group selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylCi-6alkyl, heterocyclyl and heterocyclylCi-όalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, -R9, -OR9, -SR9, -SOR9, -O2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, o -NR9CONR10R15, -NR9COCONR10R15 and NR9SO2R10; or X-R1 is -CR6R7OH;
R2 is a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12,5 and -NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -R13,
"SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -
NR13SO2R14;
R4 and R5 are independently hydrogen or Ci_6alkyl; or R1 and R4 together with the atom or atoms to which they are attached form a 4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, C1-OaIkOXyC1- βalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000042_0001
βalkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000042_0002
Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino,
Figure imgf000042_0003
bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino,
Figure imgf000042_0004
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci_ 6alkyl)carbamoyl; R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000042_0005
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^d-ealkyFjamino, sulfamoyl,
Figure imgf000042_0006
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-OaIk-UiOyI(C1- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and C1-6alkyl; R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- 6alkyl,
Figure imgf000042_0007
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. 6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-
6alkylsulfonyl, Ci-oalkylsulfonylamino, d-ealkylsulfony^Ci-ealky^amino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci.6alkanoylammo,
Figure imgf000043_0001
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R11, R12, R17 and R18 are independently hydrogen or a group selected from C1-6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000043_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi. 6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R13, R14, R15, R16 and R19 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000043_0003
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi. 6alkoxy,
Figure imgf000043_0004
amino,
Figure imgf000043_0005
bis(Ci. 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000043_0006
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000043_0007
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000043_0008
haloCi_6alkoxy, hydroxyCi. βalkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealky^amino, sulfamoyl,
Figure imgf000043_0009
bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci.6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention. Solvates and mixtures thereof also form an aspect of the present invention. For example, a suitable solvate of a compound of formula (I) is, for example, a hydrate such as a hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate or an alternative quantity thereof.
The present invention relates to the compounds of formula (I) as herein defined as well as to salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I) and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of compounds of formula (I) as herein defined which are sufficiently basic to form such salts. Such acid addition salts include but are not limited to furmarate, methanesulfonate, hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulfuric acid. In addition where compounds of formula (I) are sufficiently acidic, salts are base salts and examples include but are not limited to, an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylpiperidine, N- ethylpiperidine, dibenzylamine or amino acids such as lysine.
The compounds of formula (I) may also be provided as in vivo hydrolysable esters. An in vivo hydrolysable ester of a compound of formula (I) containing carboxy or hydroxy group is, for example a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid or alcohol. Such esters can be identified by administering, for example, intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluid.
Suitable pharmaceutically acceptable esters for carboxy include Ci-6alkoxymethyl esters for example methoxymethyl, Ci-6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, Cs-scycloalkoxycarbonyloxyCi-όalkyl esters for example 1-cyclohexylcarbonyloxyethyl, l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl, and Ci.6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in the compounds of this invention. Suitable pharmaceutically acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include Ci-ioalkanoyl, for example formyl, acetyl, benzoyl, phenylacetyl, substituted benzoyl and phenylacetyl; Cπoalkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-Ci-4alkylcarbamoyl and 7V-(di-Ci-4alkylaminoethyl)-7V- Ci-4alkylcarbamoyl (to give carbamates); di-Ci-4alkylaminoacetyl and carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, Ci- 4alkylaminomethyl and di-(Ci-4alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position of the benzoyl ring. Other interesting in vivo hydrolysable esters include, for example, RAC(O)OCi.6alkyl-CO-, wherein RA is for example, benzyloxy-Ci-4alkyl, or phenyl. Suitable substituents on a phenyl group in such esters include, for example, 4-Ci-4piperazino-Ci-4alkyl, piperazino-Ci-4alkyl and morpholino-Ci-4alkyl.
The compounds of the formula (I) may be also be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the formula (I). Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191
(1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984). In this specification the generic term "Cp-qalkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight chain version only (i.e. n-propyl and isopropyl) and references to individual branched-chain alkyl groups such as "tert-butyl" are specific for the branched chain version only. The prefix Cp-q in Cp-qalkyl and other terms (where p and q are integers) indicates the range of carbon atoms that are present in the group, for example
Figure imgf000045_0001
includes Cialkyl (methyl), C2alkyl (ethyl), Cβalkyl (propyl as n-propyl and isopropyl) and C4alkyl (n-butyl, sec- butyl, isobutyl and tert-butyl).
The term Cp-qalkoxy comprises -O-Cp-qalkyl groups.
The term Cp-qalkanoyl comprises -C(O)alkyl groups. The term halo includes fluoro, chloro, bromo and iodo.
"Carbocyclyl" is a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 14 ring atoms, wherein a ring CH2 group may be replaced with a C=O group. "Carbocyclyl" includes "aryl", "Cp-qcycloalkyl" and "Cp-qcycloalkenyl". "aryl" is an aromatic monocyclic, bicyclic or tricyclic carbcyclyl ring system.
"Cp-qCycloalkenyl" is an unsaturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclyl ring system containing at least 1 C=C bond and wherein a ring CH2 group may be replaced with a C=O group.
"Cp-qcycloalkyl" is a saturated monocyclic, bicyclic or tricyclic carbocyclyl ring system and wherein a ring CH2 group may be replaced with a C=O group.
"Heterocyclyl" is a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 14 ring atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulfur or oxygen, which ring may be carbon or nitrogen linked and wherein a ring nitrogen or sulfur atom may be oxidised and wherein a ring CH2 group may be replaced with a C=O group. "Heterocyclyl" includes "heteroaryl", "cycloheteroalkyl" and "cycloheteroalkenyl" .
"Heteroaryl" is an aromatic monocyclic, bicyclic or tricyclic heterocyclyl, particularly having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulfur or oxygen where a ring nitrogen or sulfur may be oxidised. "Cycloheteroalkenyl" is an unsaturated or partially saturated monocyclic, bicyclic or tricyclic heterocyclyl ring system, particularly having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulfur or oxygen, which ring may be carbon or nitrogen linked and wherein a ring nitrogen or sulfur atom may be oxidised and wherein a ring CH2 group may be replaced with a C=O group. "Cycloheteroalkyl" is a saturated monocyclic, bicyclic or tricyclic heterocyclic ring system, particularly having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulfur or oxygen, which ring may be carbon or nitrogen linked and wherein a ring nitrogen or sulfur atom may be oxidised and wherein a ring CH2 group may be replaced with a C=O group.
This specification may make use of composite terms to describe groups comprising more than one functionality. Unless otherwise described herein, such terms are to be interpreted as is understood in the art. For example carbocyclylCp-qalkyl comprises Cp-qalkyl substituted by carbocyclyl, heterocyclylCp-qalkyl comprises Cp-qalkyl substituted by heterocyclyl, and bis(Cp-qalkyl)amino comprises amino substituted by 2 Cp-qalkyl groups which may be the same or different.
HaloCp-qalkyl is a Cp-qalkyl group that is substituted by 1 or more halo substituents and particuarly 1, 2 or 3 halo substituents. Similarly, other generic terms containing halo such as haloCp-qalkoxy may contain 1 or more halo substituents and particluarly 1 , 2 or 3 halo substituents.
HydroxyCp-qalkyl is a Cp-qalkyl group that is substituted by 1 or more hydroxyl substituents and particularly by 1, 2 or 3 hydroxy substituents. Similarly other generic terms containing hydroxy such as hydroxyCp-qalkoxy may contain 1 or more and particularly 1, 2 or 3 hydroxy substituents.
Cp-qalkoxyCp-qalkyl is a Cp-qalkyl group that is substituted by 1 or more Cp-qalkoxy substituents and particularly 1, 2 or 3 Cp-qalkoxy substituents. Similarly other generic terms containing Cp-qalkoxy such as Cp-qalkoxyCp-qalkoxy may contain 1 or more Cp-qalkoxy substituents and particularly 1, 2 or 3 Cp-qalkoxy substituents.
Where optional substituents are chosen from "1 or 2", from "1, 2, or 3" or from "1, 2, 3 or 4" groups or substituents it is to be understood that this definition includes all substituents being chosen from one of the specified groups i.e. all substitutents being the same or the substituents being chosen from two or more of the specified groups i.e. the substitutents not being the same.
Compounds of the present invention have been named with the aid of computer software (ACD/Name version 8.0).
"Proliferative disease(s)" includes malignant disease(s) such as cancer as well as non- malignant disease(s) such as inflammatory diseases, obstracutive airways diseases, immune diseases or cardiovascular diseases.
Suitable values for any R group or any part or substituted for such groups include: for methyl, ethyl, propyl, butyl, 2-methylpropyl and tert-butyl; for Ci_6alkyl: Ci_4alkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl and hexyl; for C3.6cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; for C3-6cycloalkylCi.4alkyl: cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl; for aryl: phenyl and naphthyl; for
Figure imgf000048_0001
benzyl, phenethyl, naphthylmethyl and naphthylethyl; for carbocylyl: aryl, cyclohexenyl and Cβ-όCycloalkyl; for halo: fluoro, chloro, bromo and iodo; for
Figure imgf000048_0002
methoxy, ethoxy, propoxy and isopropoxy; for Ci_6alkoxy:
Figure imgf000048_0003
pentyloxy, 1-ethylpropoxy and hexyloxy; for Ci_6alkanoyl: acetyl, propanoyl and 2-methylpropanoyl; for heteroaryl: pyridinyl, imidazolyl, quinolinyl, cinnolyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, thiazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, dibenzofuranyl and benzothienyl; for
Figure imgf000048_0004
pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, theinylethyl, pyridinylmethyl, pyridinylethyl, pyrazinylmethyl, pyrazinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrimidinylpropyl, pyrimidinylbutyl, imidazolylpropyl, imidazolylbutyl, quinolinylpropyl, 1,3,4-triazolylpropyl and oxazolylmethyl; for heterocyclyl: heteroaryl, pyrrolidinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, dihydro-2H-pyranyl and tetrahydro furanyl.
It should be noted that examples given for terms used in the description are not limiting. Particular values of m, X, 1Y and Y2, X, R1, X-R1, R2, R3, R4, R5, R6, R7, R8, R9, R10,
R11, R12, R13, R14, R17, R18 and R19are as follows. Such values may be used idividually or in combination where appropriate, in connection with any aspect of the invention, or part thereof, and with any of the definitions, claims or embodiments defined herein. m
In one aspect of the invention m is 0, 1, 2 or 3. In another aspect m is 0, 1 or 2.
In a further aspect m is 0 or 1.
In yet another aspect m is 0 so that R3 is absent.
In yet another aspect m is 1 and R3 is methyl.
In yet another aspect m is 1 and R3 is hydroxymethyl. In yet another aspect m is 1 and R3 is ethyl.
In yet another aspect m is 1 and R3 is dimethylcarbamoyl.
In yet another aspect m is 1 and R3 is carbamoyl.
In yet another aspect m is 2 and each R3 is methyl.
1Y and Y2 In one aspect of the invention 1Y is N and Y2 is CR8.
In another aspect 1Y is N and Y2 is CH.
In yet another aspect 1Y is CR8 and Y2 is N.
In a further aspect 1Y is CH or CF and Y2 is N.
In yet a further aspect 1Y is CH and Y2 is N. X
In one aspect of the invention X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- and -S(O)2NR4CR6R7-.
In another aspect X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- and -S(O)2NR4CR6R7.
In a further aspect X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-,
-S(O)CR6R7- and -S(O)2CR6R7-.
In a further aspect X is a linker group selected from -NR4CR 66τR-> 7-,
Figure imgf000049_0001
-S(O)CR6R7- and -S(O)2CR6R7-.
In yet another aspect X is a linker group selected from -SCR 6 T R-) 7-, - oS( /ΓOW)ΓCTR) 6T R-> 7 - and
-S(O)2CR6R7-. In another aspect X is -SCR6R7- or -S(O)2CR6R7-. In another aspect X is -S(O)2CR6R7-.
R±
In one aspect of the invention R1 is a group selected from C1-4alkyl, C3-iocycloalkyl, aryl,
Figure imgf000050_0001
cycloheteroalkyl, heteroaryl, cycloheteroalkylCi. 4alkyl,
Figure imgf000050_0002
which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10.
In another aspect, R1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thiadiazolyl, thiazolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thiadiazolylmethyl, thiadiazolylethyl, thiazolylmethyl, thiazolylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl and pyrazinylethyl, which group is optionally substituted by 1, 2 or 3 substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, - NR9R10 and -NR9COR10.
In another aspect, R1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl and pyrazinylethyl, which group is optionally substituted by 1 , 2 or 3 substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10.
In a further aspect, R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3. In a further aspect, R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3.
In yet another aspect R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2C(OH)(CH3)2, -CH2CH2CH2OCHF2, -CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2C(O)NH2, -CH2C(O)NHMe, -CH2CH2NHMe, phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2-fiuoro-4-methylaminophenyl, 4-fluoro-2-methylphenyl, 5-fiuoro-2-methylphenyl, 3-fiuoro-4-(2-hydroxyethylamino)phenyl, 4-(difluoromethoxy)phenyl, 4-carbamoyl-2- chlorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methylaminophenyl, 3-chloro-4-ethylaminophenyl, 3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-hydroxyethylamino)phenyl, 2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-(trifluoromethyl)phenyl, 2-methylphenyl, 4-methylphenyl, 4-(2-hydroxyethylamino)phenyl, lH-imidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin- 2-yl, l-(difluoromethyl)pyrazol-4-yl, l-(difluoromethyl)-3,5-dimethylpyrazol-4-yl, l,3-dimethylpyrazol-4-yl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, 5-fiuoropyridin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 2,4-dimethylthiazol-5-yl, 5-methyl-l,3,4-thiadiazol-2-yl, terahydrofuran-3-yl and terahydropyran-4-yl.
In yet another aspect R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2C(O)NH2, -CH2C(O)NHMe, phenyl, 4-fluorophenyl, 4- chlorophenyl, 2-chlorophenyl, 3,5-difluorophenyl, 2-(trifiuoromethyl)phenyl, 2- methoxyphenyl, 2-methylphenyl, 4-(2-hydroxyethylamino)phenyl, lH-imidazol-2-yl, 2-(dimethylcarbamoyl)pyridin-3 -yl, 5 -(dimethylcarbamoyl)pyridin-2-yl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 2-oxopyrolidin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, 5-methyl-l,3,4-thiadiazol-2-yl and 3-methyl-l ,3,4-thiadiazol-2-yl. In yet another aspect R1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH, -CH2CH2NHC(O)CH3, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2- trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, 2-oxopyrolidin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, and 3- 5 methyl- 1, 3, 4-thiadiazol-2-yl.
In yet another aspect R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2C(O)NH2, -CH2C(O)NHMe, phenyl, 4-fluorophenyl, 4- chlorophenyl, 3,5-difiuorophenyl, 2-(trifluoromethyl)phenyl, 4-(2-hydroxyethylamino)phenyl,o lH-imidazol-2-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, 5-fiuoropyridin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl and 5-methyl-l,3,4-thiadiazol-2-yl.
In yet another aspect R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2C(OH)(CH3)2, -CH2CH2CH2OCHF2,s -CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2CH2NHMe, phenyl, 2-fluorophenyl,
3 -fluorophenyl, 4-fluorophenyl, 2-fluoro-4-methylaminophenyl, 4-fluoro-2-methylphenyl, 5 -fluoro-2-methylphenyl, 3 -fluoro-4-(2-hydroxyethylamino)phenyl,
4-(difluoromethoxy)phenyl, 4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methylaminophenyl, 3-chloro-4-ethylaminophenyl,o 3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-hydroxyethylamino)phenyl, 2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difiuorophenyl, 2-methylphenyl, 4-methylphenyl, lH-imidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, 1 -(difluoromethyl)pyrazol-4-yl, 1 ,3-dimethylpyrazol-4-yl,5 pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl, 4-methylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 2,4-dimethylthiazol-5-yl and 5-methyl-l,3,4-thiadiazol-2-yl.
In yet another aspect R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2OCH3, -CH2CH2NHC(O)CH3, phenyl, 4-fluorophenyl, 4-chlorophenyl, 3,5-difiuorophenyl, lH-imidazol-2-yl, o 2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, pyridin-4-yl, pyridin- 2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl, 4-methylthiazol-2-yl and 5-methyl-l,3,4-thiadiazol-2- yi. In yet another aspect R1 is a group selected from methyl, ethyl, cyclopropyl, -CH2CH2CH2OH, phenyl, 2-fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-chlorophenyl, 2-methylphenyl, 5-fluoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl.In yet another aspect R1 is a group selected from -CH2CH2CH2OH, phenyl, 4-fiuorophenyl, pyridin- 2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl.
In yet another aspect R1 is methyl.
In yet another aspect R1 is ethyl.
In yet another aspect R1 is cyclopropyl.
In yet another aspect R1 is -CH2CH2CH2OH. In yet another aspect R1 is phenyl.
In yet another aspect R1 is 2-fluorophenyl.
In yet another aspect R1 is 3 -fluorophenyl.
In yet another aspect R1 is 4-fluorophenyl.
In yet another aspect R1 is 2-chlorophenyl. In yet another aspect R1 is 2-methylphenyl.
In yet another aspect R1 is 5-fluoropyridin-2-yl
In yet another aspect R1 is pyridin-2-yl.
In yet another aspect R1 is thiazol-2-yl.
In yet another aspect R1 is 4-methylthiazol-2-yl. X-R1
In one embodiment X-R1 is -CR6R7OH.
In one aspect of the invention R2 is a group selected from carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19.
In one aspect of the invention R2 is selected from carbocyclyl or heterocyclyl which group is substituted by -NR17CONR18R19 or -NR17CSNR18R19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, - COR11, -CONR11R12, -NR11R12 and -NR11COR12. In one aspect of the invention R2 is selected from carbocyclyl or heterocyclyl which group is substituted by -NHCONR18R19 or -NHCSNR18R19and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, - CONR11R12, -NR11R12 and -NR11COR12. In one aspect of the invention R2 is selected from carbocyclyl or heterocyclyl which group is substituted by -NHCONHR19 or -NHCSNHR19and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, - CONR11R12, -NR11R12 and -NR11COR12.
In one aspect of the invention R2 is a group selected from 5 or 6 membered carbocyclyl or heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, - CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -NR11COCONR12R16, -NR11SO2R12, - NR17CONR18R19 and -NR17CSNR18R19.
In one aspect of the invention R2 is selected from 5 or 6 membered carbocyclyl or heterocyclyl which group is substituted by -NR17CONR18R19 or -NR17CSNR18R19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12.
In one aspect of the invention R2 is selected from 5 or 6 membered carbocyclyl or heterocyclyl which group is substituted by -NHCONR18R19 or -NHCSNR18R19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12.
In one aspect of the invention R2 is selected from 5 or 6 membered carbocyclyl or heterocyclyl which group is substituted by -NHCONHR19 or -NHCSNHR19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, - R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12.
In one aspect of the invention R2 is selected from a 6 membered aryl and 5 or 6 membered heteroaryl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, - CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -NR11COCONR12R16, -NR11SO2R12, - NR17CONR18R19 and -NR17CSNR18R19.
In one aspect of the invention R2 is selected from a 6 membered aryl and 5 or 6 membered heteroaryl which group is substituted by -NR17CONR18R19 or -NR17CSNR18R19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12.
In one aspect of the invention R2 is selected from a 6 membered aryl and 5 or 6 membered heteroaryl which group is substituted by -NHCONR18R19 or -NHCSNR18R19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12.
In one aspect of the invention R2 is selected from a 6 membered aryl and 5 or 6 membered heteroaryl which group is substituted by -NHCONHR19 or -NHCSNHR19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12.
In one aspect of the invention R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19.
In another aspect R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, , which group is substituted by - NR17CONR18R19 or -NR17CSNR18R19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12.
In another aspect R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by - NHCONR18R19 or -NHCSNR18R19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12.
In another aspect R is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by - NHCONHR19 or -NHCSNHR19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12.
In one aspect of the invention R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is optionally substituted by one or more substituent group independently selected from fiuoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2, -NR11COR12, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19.
In another aspect R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, 5 thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by - NR17CONR18R19 or -NR17CSNR18R19 and optionally substituted by one or more substituent group independently selected from fiuoro, methyl, methoxy, hydroxymethyl, cyanomethyl, - CONH2, -CONHCH3 and -CON(CH3)2.
In another aspect R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl,o thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -
NHCONR18R19 or -NHCSNR18R19 and optionally substituted by one or more substituent group independently selected from fiuoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2.
In another aspect R is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl,s thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -
NHCONHR19 or -NHCSNHR19and optionally substituted by one or more substituent group independently selected from fiuoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2.
In one aspect of the invention R2 is selected from phenyl, pyridinyl or pyrimidinylo which group is optionally substituted by one or more substituent group independently selected from fiuoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2, -NR11COR12, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19.
In one aspect of the invention R2 is selected from phenyl or pyridinyl which group is optionally substituted by one or more substituent group independently selected from fiuoro,5 methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2, -NR11COR12, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19.
In another aspect R is phenyl, pyridinyl or pyrimidinyl substituted by - NR17CONR18R19 or -NR17CSNR18R19 and optionally substituted by one or more substituent group independently selected from fiuoro, methyl, methoxy, hydroxymethyl, cyanomethyl,o -CONH2, -CONHCH3 and -CON(CH3)2.
In another aspect R2 is phenyl or pyridinyl substituted by -NR17CONR18R19 or -NR17CSNR18R19 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2.
In another aspect R2 is phenyl or pyridinyl substituted by -NHCONR18R19 or -NHCSNR18R19 and optionally substituted by one or more substituent group independently 5 selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2.
In another aspect R2 is phenyl or pyridinyl substituted by -NHCONHR19 or -NHCSNHR19 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH30 and -CON(CH3)2.
In another aspect R is phenyl or pyridinyl optionally substituted by -NR CONR R or -NR17CSNR18R19.
In another aspect R2 is phenyl or pyridinyl optionally substituted by -NHCONR18R19 or -NHCSNR18R19. s In another aspect R2 is phenyl or pyridinyl optionally substituted by -NHCONHR19 or
-NHCSNHR19.
In another aspect R2 is
Figure imgf000057_0001
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or A2 iso CH.
In another aspect R2 is
Figure imgf000057_0002
wherein A2 and A3 are selected from CH or N. In another aspect R2 is
Figure imgf000058_0001
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or A2 is CH.
In another aspect R is
Figure imgf000058_0002
wherein A2 and A3 are selected from CH or N. In another aspect R2 is
Figure imgf000058_0003
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or A2 is CH.
In another aspect R is
Figure imgf000058_0004
wherein A2 and A3 are selected from CH or N.
In yet another aspect R is 3-(hydroxymethyl)phenyl, 4-(hydroxymethyl)phenyl, 4-(cyanomethyl)phenyl, 3,4-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-phenoxyphenyl, 3-pyrrolidin-lylphenyl, 3-(aminocarbonyl)phenyl, 4-(dimethylaminocarbonyl)phenyl, furan-3- yl, thien-3-yl, 5-(hydroxymethyl)thien-2-yl, pyridin-2-yl, pyridin-4-yl, 2-methoxypyridin-5-yl, 2-methoxypyrimidin-5-yl, 2-methoxynaphth-6-yl, 5,7-diazabicyclo[4.3.0]nona-2,4,8,10- tetraenyl, azaindolyl, indol-5-yl, l-methylindol-5-yl, quinolin-6-yl, benzimidazolyl, benzofuran-2-yl, dibenzofuran-1-yl and benzothien-3-yl. In yet a further aspect R is pyridin-2-yl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl or indol-5-yl.
In yet a further aspect R is azaindolyl, indol-5-yl, benzimidazolyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl or 4-hydroxymethylphenyl In another aspect R2 is pyridin-2-yl.
In a further aspect R2 is 3-hydroxyphenyl or 4-hydroxyphenyl. In yet another aspect R2 is 3-hydroxymethylphenyl or 4-hydroxymethylphenyl. In yet a further aspect R2 is indol-5-yl. In one aspect R2 is morpholinyl. In another aspect R is morpholino.
Each R3 is independently selected from cyano, R13, and -CONR13R14, wherein R13 and R14 are independently hydrogen or a
Figure imgf000059_0001
which is optionally substituted by one or more substituent groups selected from halo, cyano, hydroxy and
Figure imgf000059_0002
Each R3 is independently selected from hydrogen, C1-3alkyl,
Figure imgf000059_0003
and
-CONR13R14, wherein R13 and R14 are independently hydrogen or a C1-3alkyl.
Each R3 is independently selected from hydrogen, methyl, ethyl, hydroxymethyl, carbamoyl and dimethylcarbamoyl.
E! In one aspect of the invention R4 is hydrogen or methyl.
In another aspect R4 is hydrogen. R4. and R^
In another aspect of the invention, when X is -NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- or -NR4S(O)2CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 4- to 10-membered heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6alkyl, C1- 6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd. 6alkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (C1- 6alkyl)aminoC i -βalkyl, bis(C i -6alkyl)aminoC i -βalkyl, cyanoC i -βalkyl, C i _6alkylsulfonyl, C i . 6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000060_0001
carbamoyl, Ci- 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In another aspect of the invention, when X is -NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- or -NR4S(O)2CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5-, 6- or 7-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, Ci- 6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (C1- 6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000060_0002
Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino,
Figure imgf000060_0003
bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000060_0004
carbamoyl, Ci- 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In another aspect of the invention, when X is -NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- or -NR4S(O)2CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, C1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (C1- 6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, C1- 6alkylsulfonylamino,
Figure imgf000060_0005
bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000060_0006
carbamoyl, Ci- 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl. In another aspect of the invention, when X is -NR4CR6R7-, -NR4C(O)CR6R7-,
-NR4C(O)NR5CR6R7- or -NR4S(O)2CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a morpholine or piperazine ring which ring is optionally substituted by one or more methyl groups.
In another aspect of the invention, when X is -NR4C(O)CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a morpholine or piperazine ring which ring is optionally substituted by one or more methyl groups. R5 In one aspect of the invention R5 is hydrogen or methyl.
In another aspect R5 is hydrogen.
In another aspect R5 is methyl.
R6 and R7 In one aspect of the invention R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, C1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (C1- 6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000061_0001
Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino,
Figure imgf000061_0002
bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000061_0003
carbamoyl, Ci- 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl. In one aspect of the invention R6 and R7 together with the carbon atom to which they are attached form a 3- to 6-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, C1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (C1- 6alkyl)aminoCi-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, C1- 6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1-6alkylsulfamoyl, Ms(C1- 6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-6alkanoyl(C1-6alkyl)amino, carbamoyl, C1- 6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl. In another aspect R6 and R7 together with the carbon atom to which they are attached form a 3- to 6-membered carbocyclic ring.
In another aspect R6 and R7 together with the carbon atom to which they are attached form a 3- to 5-membered carbocyclic ring.
In another aspect R6 and R7 together with the carbon atom to which they are attached form a 3- to 4-membered carbocyclic ring.
In another aspect R6 and R7 together with the carbon atom to which they are attached form a 3-membered carbocyclic ring. In another aspect R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring.
In one aspect of the invention R8 is hydrogen or halo. 5 In another aspect R8 is hydrogen or fluoro.
In a further aspect R8 is hydrogen.
E!
In one aspect of the invention R9 is hydrogen or
Figure imgf000062_0001
optionally substituted by 1, 2 or 3 substituent groups selected from halo, cyano, nitro, hydroxy, Ci-4alkoxy, amino, C1- i o 4alkylamino and bis(C i .4alkyl)amino .
In another aspect R9 is hydrogen or
Figure imgf000062_0002
optionally substituted by 1, 2 or 3 halo substituents.
In a further aspect R9 is hydrogen, methyl or trifluoromethyl. R^ is In one aspect of the invention R10 is hydrogen.
In one aspect of the invention R11 is hydrogen or a group selected from C1-4alkyl, aryl and cycloheteroalkyl which group is optionally substituted by 1 , 2 or 3 groups selected from halo, hydroxy and cyano.
20 In another aspect R11 is hydrogen, methyl optionally substituted with hydroxy or cyano, phenyl or pyrrolidinyl.
In another aspect R11 is hydrogen or methyl.
R^
In one aspect of the invention R12 is hydrogen or methyl.
In one aspect of the invention R17 is hydrogen or a group selected from C1-4alkyl, aryl and cycloheteroalkyl which group is optionally substituted by 1 , 2 or 3 groups selected from halo, hydroxy and cyano.
In another aspect R17 is hydrogen, methyl optionally substituted with hydroxy or cyano, 30 phenyl or pyrrolidinyl.
In another aspect R17 is hydrogen or methyl.
In another aspect R17 is hydrogen. In one aspect of the invention R18 is hydrogen or methyl. In one aspect of the invention R18 is hydrogen
5 In one aspect of the invention R19 is hydrogen or a group selected from Ci_6alkyl, C3- όCycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- 6alkyl,
Figure imgf000063_0001
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi.o 6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000063_0002
Ci-
6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000063_0003
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In one aspect of the invention R19 is hydrogen or a group selected from Ci_6alkyl, C3-5 6cycloakyl, phenyl, naphthyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl, indolyl, quinolinyl, benzimidazolyl, benzofuranyl, dibenzofuranyl, benzothienyl, pyrrolidinyl, pyrazinyl, oxetanyl, dioxothiolanyl, thiazolyl, thiadiazolyl, phenylCi-6alkyl, naphthylCi-6alkyl, pyrrolylCi-6alkyl, imidazolylCi. 6alkyl, isoxazolylCi-6alkyl, pyrazolylCi-6alkyl, furanylCi-6alkyl, thienylCi-6alkyl, pyridinylCi.0 6alkyl, pyrimidinylCi-6alkyl, pyridazinylCi-6alkyl, azaindolylCi-6alkyl, indolylCi-6alkyl, quinolinylCi-6alkyl, benzimidazolylCi-6alkyl, benzofuranylCi-6alkyl, dibenzofuranylCi-6alkyl, benzothienylCi-6alkyl, pyrrolidinylCi-oalkyl, pyrazinylCi-6alkyl, oxetanylCi-6alkyl, dioxothiolanylCi-6alkyl, thiazolylCi_6alkyl and thiadiazolylCi_6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-5 6alkyl,
Figure imgf000063_0004
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi.6alkyl,
Figure imgf000063_0005
bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000063_0006
C1- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealky^amino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, o carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In one aspect of the invention R19 is hydrogen or a group selected from Ci_6alkyl, C3- όCycloakyl, phenyl, naphthyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl, indolyl, quinolinyl, benzimidazolyl, benzofuranyl, dibenzofuranyl, benzothienyl, phenylCi-6alkyl, naphthylCi-όalkyl, pyrro IyIC1. 6alkyl, imidazolylCi.6alkyl,
Figure imgf000064_0001
pyrazolylCi.6alkyl, furanylCi-όalkyl, thienylCi- 6alkyl, pyridinylCi-6alkyl, pyrimidinylCi-όalkyl, pyridazinylCi-6alkyl, azaindolylCi-6alkyl, indolylC i -6alkyl, quinolinylC i -6alkyl, benzimidazolylC i -6alkyl, benzofuranylC i -6alkyl, dibenzofuranylCi-6alkyl, benzothienylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-6alkoxyCi-6alkyl, Ci- 6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci- 6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000064_0002
Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino, d-6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl,
Figure imgf000064_0003
bis(Ci- 6alkyl)sulfamoyl, Ci-6alkanoylamino, d-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci- 6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In one aspect of the invention R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, dioxothiolanyl, imidazoylmethyl, isoxazolyl, oxazolyl, oxetanyl, pyrazinyl, pyrazolyl, pyrazolylmethyl, pyridinyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl, thiazolyl and triazolyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000064_0004
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci- 6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi-6alkyl, Ms(Ci- 6alkyl)aminoCi-6alkyl,
Figure imgf000064_0005
Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci- 6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl,
Figure imgf000064_0006
bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino,
Figure imgf000064_0007
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci- 6alkyl)carbamoyl.
In one aspect of the invention R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyrazolylmethyl, pyridinyl and pyrimidinyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000064_0008
haloCi-όalkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyd-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci- 6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci_ 6alkyl)ammoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci.6alkylsulfonylammo, Ci-
Figure imgf000065_0001
sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino,
Figure imgf000065_0002
carbamoyl, Ci.6alkylcarbamoyl and bis(Ci. 6alkyl)carbamoyl.
5 In one aspect of the invention R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)2OH, -CH2C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CH2SO2Me, -CH2CH(OH)CF3, -CH2CH2CN,o -CH2CN, -CH2CONMe2, -CH2CO2H, l-(methyl)cyclopropyl, -CH2(I -hydroxy cyclopropyl), 1 -(hydroxymethyl)cyclopropyl, ( 1 R)-2-hydroxy- 1 -methylethyl, ( 1 S)-2-hydroxy- 1 -methylethyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-(trifiuoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2- yl), -CH2(imidazol-3-yl), l-methylimidazol-4-yl, oxazolyl-2-yl, isoxazolyl-3-yl, s 6-oxo-lH-pryrdin-2-yl, oxetan-3-yl, l,l-dioxothiolan-3-yl, 5-methylisoxazol-3-yl, -CH2( 1 -methylpyrazol-4-yl), 1 -methylpyrazol-4-yl, -CH2( 1 -methylpyrazol-4-yl), 5-methylpyrazin-2-yl, -CH2(2H-l,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl, 5- fluoropyridin-2-yl, pyrimidin-2-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl, l-methylpyrazol-3-yl and lH-pyrazol-3-yl. o In one aspect of the invention R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)2OH, -CH2C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CH2SO2Me, -CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, -CH2CONMe2, -CH2CO2H,5 l-(methyl)cyclopropyl, -CH2(I -hydroxycyclopropyl), l-(hydroxymethyl)cyclopropyl, (lR)-2-hydroxy-l -methylethyl, (lS)-2-hydroxy-l -methylethyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-(trifiuoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, -CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2-yl), l-methylimidazol-4-yl, oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, l,l-dioxothiolan-3-yl, 5-methylisoxazol-3-yl,o -CH2(I -methylpyrazol-4-yl), 1 -methylpyrazol-4-yl, -CH2(I -methylpyrazol-4-yl),
5-methylpyrazin-2-yl, -CH2(2H-l,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl, 5- fluoropyridin-2-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl and l-methylpyrazol-3-yl. In one aspect of the invention R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)2OH, -CH2C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CHF2, 5 -CH2CH2SO2Me, -CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, -CH2CONMe2, 1-
(methyl)cyclopropyl, l-(hydroxymethyl)cyclopropyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2-yl), -CH2(imidazol-3-yl), oxazolyl-2-yl, isoxazolyl-3-yl, 6-oxo-lH-pryrdin-2-yl, oxetan-3-yl, l,l-dioxothiolan-3-yl, 5-methylisoxazol-o 3-yl, -CH2(I -methylpyrazol-4-yl), l-methylpyrazol-4-yl, -CH2(I -methylpyrazol-4-yl),
5-methylpyrazin-2-yl, -CH2(2H-l,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl, 5- fluoropyridin-2-yl, pyrimidin-2-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl, l-methylpyrazol-3-yl and lH-pyrazol-3-yl.
In one aspect of the invention R19 is hydrogen or a group selected from methyl, ethyl,s propyl, i-propyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2CH2NMe2,
-CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CH2CN, -CH2(I -hydroxycyclopropyl),
1 -(hydroxymethyl)cyclopropyl, ( 1 R)-2-hydroxy- 1 -methylethyl, ( 1 S)-2-hydroxy- 1 -methylethyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, o -CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2-yl), l-methylimidazol-4-yl, oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, 5-methylisoxazol-3-yl, l-methylpyrazol-4-yl, 5-methylpyrazin-2- yl, 6-methoxypryridin-3-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl and l-methylpyrazol-3-yl.
In one aspect of the invention R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, 5 cyclohexyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH,
-CH2CH2OH, -CH2CH2CH2OH, 4-methylphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4- fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CH2(imidazol-2-yl), -CH2(imidazol-3-yl), isoxazolyl-3-yl, 6-oxo-lH-pryrdin-2-yl, 5-methylisoxazol-3-yl, -CH2( 1 -methylpyrazol-4-yl), 1 -methylpyrazol-4-yl, -CH2( 1 -methylpyrazol-4-yl), o 6-methoxypryridin-3-yl, 5-fluoropyridin-2-yl, pyrimidin-2-yl, and lH-pyrazol-3-yl.
In one aspect of the invention R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)2OH, -CH2C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CHF2, -CH2CH2SO2Me, -CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, -CH2CONMe2, l-(methyl)cyclopropyl, l-(hydroxymethyl)cyclopropyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, -CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2-yl), oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, l,l-dioxothiolan-3-yl, 5-methylisoxazol-3-yl, -CH2( 1 -methylpyrazol-4-yl), 1 -methylpyrazol-4-yl, 5 -methylpyrazin-2-yl, -CH2(2H-l,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl, and l-methylpyrazol-3-yl. In one aspect of the invention R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2CH2NMe2, -C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CN, l-(hydroxymethyl)cyclopropyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, -CH2CH2(pyrrolidin-l-yl), -CH2(imidazol-2-yl), oxazolyl-2-yl, isoxazolyl- 3-yl, oxetan-3-yl, 5-methylisoxazol-3-yl, 1 -methylpyrazol-4-yl, 5 -methylpyrazin-2-yl, 6-methoxypryridin-3-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl, and l-methylpyrazol-3-yl.
In one aspect of the invention R19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl, -CH(CH3)CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CHF2, -CH2CH2F, -CH2CH2CN, (lR)-2-hydroxy-l-methylethyl, (lS)-2-hydroxy-l-methylethyl, -CH2(imidazol-2- yl), oxazolyl-2-yl, isoxazolyl-3-yl, 1 -methylpyrazol-4-yl, 5 -methylpyrazin-2-yl, thiazol-2-yl and l,2,4-thiadiazol-5-yl.
In one aspect of the invention R19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CN, -CH2(imidazol-2-yl), oxazolyl-2-yl, isoxazolyl-3-yl, 1 -methylpyrazol-4-yl, 5 -methylpyrazin-2-yl, thiazol-2-yl and 1,2,4-thiadiazol- 5-yl.
In one aspect of the invention R19 is hydrogen or a group selected from methyl, ethyl, cyclopropyl, 1 -methylpyrazol-4-yl, and -CH2(I -methylpyrazol-4-yl).
In one aspect of the invention R19 is methyl.
In one aspect of the invention R19 is ethyl. In one aspect of the invention R19 is cyclopropyl.
In one aspect of the invention R19 is cyclobutyl.
In one aspect of the invention R19 is -CH(CH3)CH2OH. In one aspect of the invention R19 is -CH2CH2OH.
In one aspect of the invention R19 is -CH2CH2CH2OH.
In one aspect of the invention R19 is -CH2CHF2
In one aspect of the invention R19 is -CH2CH2F. 5 In one aspect of the invention R19 is -CH2CH2CN.
In one aspect of the invention R19 is (lR)-2-hydroxy-l-methylethyl.
In one aspect of the invention R19 is (lS)-2-hydroxy-l-methylethyl.
In one aspect of the invention R19 is -CH2(imidazol-2-yl).
In one aspect of the invention R19 is oxazolyl-2-yl. o In one aspect of the invention R19 is isoxazolyl-3-yl.
In one aspect of the invention R19 is l-methylpyrazol-4-yl.
In one aspect of the invention R19 is 5-methylpyrazin-2-yl.
In one aspect of the invention R19 is thiazol-2-yl.
In one aspect of the invention R19 is l,2,4-thiadiazol-5-yl. s R18 and R19
In one aspect of the invention, R18 and R19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, o haloC i -βalkyl, haloC i -6alkoxy , hydroxyC i -βalkyl, hydroxyC i -6alkoxy , C i -6alkoxyC i -βalkyl, C i . 6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000068_0001
bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000068_0002
Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino,
Figure imgf000068_0003
bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000068_0004
carbamoyl, 5 Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In one aspect of the invention, R18 and R19 together with the nitrogen atom to which they are attached form a morpholine ring.
In one aspect of the invention, R18 and R19 together with the nitrogen atom to which they are attached form a 3-hydroxypyrrolidin-l-yl group. 0 In one aspect of the invention there is provided a subset of compounds of formula (I), or a pharmaceutically acceptable salt thereof; m is 0, 1 or 2; 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8;
X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- and -S(O)2NR4CR6R7;
R1 is a group selected from C^aHcyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylC i_6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; or X-R1 is -CR6R7OH; R2 is a group selected from carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, - SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, - NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is selected from cyano, R13, and -CONR13R14; R4 and R5 are independently hydrogen or
Figure imgf000069_0001
or, when X is -NR4CR6R7-, -NR4C(O)CR6R7- or -NR4C(O)NR5CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
Figure imgf000069_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. βalkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000069_0003
Ci- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000069_0004
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000069_0005
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000070_0001
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and C1-6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000070_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci- 6alkylamino and bis(Ci-6alkyl)amino;
R , R , R and R are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000070_0003
haloCi. βalkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; R13 and R14 are independently hydrogen or a
Figure imgf000070_0004
which is optionally substituted by one or more substituent groups selected from halo, cyano, hydroxy and C^alkoxy; and
R19 is hydrogen, cyano or a group selected from Ci_6alkyl, Cβ-όCycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, C1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
(Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, C1- 6alkylsulfonylamino,
Figure imgf000070_0005
bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000070_0006
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a
6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloCi-6alkoxy, hydroxyC1-6alkyl, hydroxyCi_6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, Ci-6alkylamino, IUs(C1- 6alkyl)amino, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, Ci-6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000071_0001
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In another aspect of the invention there is provided a subset of compounds of formula (I), or a pharmaceutically acceptable salt thereof; 5 m is 0, 1 or 2;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8;
X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- and o -S(O)2NR4CR6R7;
R1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylC i_6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; or X-R1 is -CR6R7OH; s R2 is a group selected from carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, - SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, - NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is selected from C1-3alkyl, and -CONR13R14; o R4 and R5 are independently hydrogen or Ci_6alkyl; or, when X is -NR4CR6R7-, -NR4C(O)CR6R7- or -NR4C(O)NR5CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,5 C1-6alkyl,
Figure imgf000071_0003
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. 6alkyl,
Figure imgf000071_0004
bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000071_0005
C1- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000071_0006
0 carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi.
6alkyl,
Figure imgf000072_0001
amino,
Figure imgf000072_0002
bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000072_0003
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000072_0004
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000072_0005
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-
6alkylamino and bis(Ci-6alkyl)amino;
R11, R12, R17 and R18 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000072_0006
haloCi-6alkyl, haloCi. βalkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino;
R13 and R14 are independently hydrogen or a C1-3alkyl; and R19 is hydrogen, cyano or a group selected from Ci_6alkyl, Cβ-όCycloakyl, aryl, heteroaryl,
Figure imgf000072_0007
and heteroarylCi.6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-
6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000072_0008
bis(Ci-6alkyl)aminoCi-6alkyl, Ci-6alkylsulfonyl, Ci-
6alkylsulfonylamino,
Figure imgf000072_0010
bis(Ci_
6alkyl)sulfamoyl, Ci.6alkanoylamino,
Figure imgf000072_0011
carbamoyl,
Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000072_0012
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci.6alkylammo, bis(Ci_
6alkyl)amino, aminoCi.6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000073_0001
sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-OaIk-UiOyI(C1- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.In another aspect of the invention there is provided a subset of compounds of formula (I), or a pharmaceutically acceptable salt thereof; m is 0, 1 or 2;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8;
X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- and
-S(O)2NR4CR6R7;
R1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylC 1-6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; or X-R1 is -CR6R7OH;
R2 is a group selected from carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, - SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -
NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is methyl or ethyl;
R4 and R5 are independently hydrogen or Ci_6alkyl; or, when X is -NR4CR6R7-, -NR4C(O)CR6R7- or -NR4C(O)NR5CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
C1-6alkyl,
Figure imgf000073_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-
6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. 6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-
6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, d-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000074_0001
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi- 6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-όalkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, d-6alkylsulfonyl(d-6alkyl)amino, sulfamoyl,
Figure imgf000074_0002
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and d-6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000074_0003
hydroxyd-6alkyl, hydroxyd-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-όalkoxyCi-όalkoxy, amino, Ci- 6alkylamino and bis(Ci-6alkyl)amino;
R , R , R and R are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000074_0004
haloCi-6alkyl, haloCi- 6alkoxy, hydroxyd-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and
R19 is hydrogen, cyano or a group selected from Ci-6alkyl, d-όCycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, d-6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-6alkoxyCi-6alkyl, Ci- 6alkoxyCi.6alkoxy, amino,
Figure imgf000074_0005
bis(Ci.6alkyl)amino, aminoCi.6alkyl,
Figure imgf000074_0006
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-όalkylsulfonyl, Ci- 6alkylsulfonylamino, d-ealkylsulfony^Ci-ealky^amino, sulfamoyl, d-6alkylsulfamoyl, bis(d. 6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-6alkanoyl(C1-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000075_0001
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000075_0002
6alkyl)amino, carbamoyl,
Figure imgf000075_0003
and bis(Ci.6alkyl)carbamoyl. In another aspect of the invention there is provided a subset of compounds of formula
(I), or a pharmaceutically acceptable salt thereof; m is 0, 1 or 2;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8; X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- and -S(O)2NR4CR6R7;
R1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylC i_6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; or X-R1 is -CR6R7OH;
R2 is a group selected from carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, - SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, - NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is methyl; R4 and R5 are independently hydrogen or
Figure imgf000075_0004
or, when X is -NR4CR6R7-, -NR4C(O)CR6R7- or -NR4C(O)NR5CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
Figure imgf000075_0005
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-όalkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci.6alkyl)amino, aminoCi- βalkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci- 6alkylsulfonyl, Ci.6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, d-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6alkyl, hydroxyCi_6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-όalkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, d-6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl,
Figure imgf000076_0001
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and C1-6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000076_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-όalkoxyCi-όalkoxy, amino, C1- 6alkylamino and bis(Ci-6alkyl)amino;
R , R , R and R are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000076_0003
haloCi- βalkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-όalkoxyCi-όalkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and
R19 is hydrogen, cyano or a group selected from Ci_6alkyl, C3_6Cycloakyl, aryl, heteroaryl,
Figure imgf000076_0004
and heteroarylCi.6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, C1- 6alkoxyCi_6alkoxy, amino, d-ealkylamino, bis(Ci-6alkyl)amino, aminoC1-6alkyl,
(C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, C1- 6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1-6alkylsulfamoyl, bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000077_0001
carbamoyl,
Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a
6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci_
6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^d-ealky^amino, sulfamoyl,
Figure imgf000077_0002
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000077_0003
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In one aspect of the invention there is provided a subset of compounds of formula (I), or a pharmaceutically acceptable salt thereof; m is 0, 1 or 2; 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8;
X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- and
-S(O)2NR4CR6R7; R1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylC i-6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; or X-R1 is -CR6R7OH;
R2 is a group selected from carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -
SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -
NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is methyl;
R4 and R5 are independently hydrogen or Ci_6alkyl; or, when X is -NR4CR6R7-, -NR4C(O)CR6R7- or -NR4C(O)NR5CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- 6alkoxyCi.6alkyl,
Figure imgf000078_0001
amino,
Figure imgf000078_0002
bis(Ci.6alkyl)amino, aminoCi. 6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, C1- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci.6alkanoylamino,
Figure imgf000078_0003
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000078_0004
haloCi_6alkoxy, hydroxyCi. βalkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000078_0005
bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci.6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000078_0006
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, C1- 6alkylamino and bis(Ci-6alkyl)amino;
R11, R12, R17 and R18 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloCi. βalkoxy, hydroxyC1-6alkyl, hydroxyCi_6alkoxy, C1-6alkoxyC1-6alkyl, Ci-όalkoxyCi-όalkoxy, amino,
Figure imgf000078_0007
and bis(Ci.6alkyl)amino; and
R19 is hydrogen or a group selected from C1-6alkyl, C3-6cycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloC1-6alkyl, haloCi-6alkoxy, hydroxyC1-6alkyl, hydroxyCi_6alkoxy, C1-6alkoxyC1-6alkyl, C1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoC1-6alkyl,
Figure imgf000079_0001
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci_ 6alkyl)sulfamoyl, Ci.6alkanoylamino,
Figure imgf000079_0002
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000079_0003
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci. 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000079_0004
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000079_0005
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In one aspect of the invention there is provided a subset of compounds of formula (I), or a pharmaceutically acceptable saltthereof; m is 0, 1 or 2;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8; X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- and -S(O)2NR4CR6R7;
R1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylC i_6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; Or X-R1 Is -CR6R7OH;
R2 is a group selected from aryl and heteroaryl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, - SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is methyl;
R4 and R5 are independently hydrogen or Chalky!; or, when X is -NR4CR6R7-, -NR4C(O)CR6R7- or -NR4C(O)NR5CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. 6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000080_0001
haloCi_6alkoxy, hydroxyCi.
Figure imgf000080_0002
amino,
Figure imgf000080_0003
bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000080_0004
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000080_0005
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000080_0006
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, C1- 6alkylamino and bis(Ci-6alkyl)amino;
R11, R12, R17 and R18 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, ImIoC1- βalkoxy, hydroxyC1-6alkyl, hydroxyCi_6alkoxy, C1-6alkoxyC1-6alkyl, Ci-όalkoxyCi-όalkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and
R19 is hydrogen or a group selected from C1-6alkyl, C3-6cycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C^aUcyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci- 6alkoxyCi.6alkoxy, amino,
Figure imgf000081_0001
bis(Ci.6alkyl)amino, aminoCi.6alkyl,
Figure imgf000081_0002
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, C1- 6alkylsulfonylamino,
Figure imgf000081_0003
bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000081_0004
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000081_0005
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000081_0006
bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci.6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In one aspect of the invention there is provided a subset of compounds of formula (I), or a pharmaceutically acceptable saltthereof; m is 0, 1 or 2; 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8;
X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- and -S(O)2NR4CR6R7; R1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylC i_6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; or X-R1 is -CR6R7OH; R2 is selected from aryl and heteroaryl which group is substituted by -NR17CONR18R19 or - NR17CSNR18R19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and - NR11COR12; each R3, when present, is methyl;
R4 and R5 are independently hydrogen or Ci_6alkyl; or, when X is -NR4CR6R7-, -NR4C(O)CR6R7- or -NR4C(O)NR5CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-
6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi.
6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, C1- βalkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-
6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000082_0001
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000082_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi.
6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000082_0003
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000082_0004
6alkyl)amino, carbamoyl, Ci.6alkylcarbamoyl and bis(Ci.6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1-6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000082_0005
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-
6alkylamino and bis(Ci.6alkyl)amino;
R , R , R and R are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, ImIoC1- βalkoxy, hydroxyC1-6alkyl, hydroxyCi_6alkoxy, C1-6alkoxyC1-6alkyl, Ci-όalkoxyCi-όalkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and R19 is hydrogen or a group selected from C^aUcyl, C3_6Cycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000083_0001
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, C1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000083_0002
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000083_0003
carbamoyl,
Figure imgf000083_0004
and bis(Ci.6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000083_0005
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, IUS(C1- 6alkyl)amino, aminoCi.6alkyl,
Figure imgf000083_0006
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000083_0007
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000083_0008
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In another aspect of the invention there is provided a subset of compounds of formula (I), or a pharmaceutically acceptable salt thereof; m is 0, 1 or 2;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8; X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7- and -S(O)2CR6R7-;
R1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thiadiazolyl, thiazolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thiadiazolylmethyl, thiadiazolylethyl, thiazolylmethyl, thiazolylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl and pyrazinylethyl, which group is optionally substituted by 1 , 2 or 3 substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; or X-R1 is -C(CH3)2OH or -CH2OH; R2 is selected from 5 or 6 membered aryl and heteroaryl which group is substituted by -NHCONR18R19 or -NHCSNR18R19and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12; each R3, when present, is methyl; R4 is hydrogen or Ci_6alkyl; or, when X is -NR4CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi. 6alkoxy,
Figure imgf000084_0001
amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci_ 6alkyl)aminoCi.6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-
Figure imgf000084_0002
sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino,
Figure imgf000084_0003
carbamoyl, Ci-6alkylcarbamoyl and IUS(C1- 6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000084_0004
haloCi_6alkoxy, hydroxyCi. 6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000084_0005
sulfamoyl,
Figure imgf000084_0006
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000084_0007
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000085_0001
haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci- 6alkylamino and bis(Ci.6alkyl)amino;
R11, R12 and R18 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000085_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci- 6alkylamino and bis(Ci-6alkyl)amino; and R19 is hydrogen, cyano or a group selected from Ci-6alkyl, C3-6cycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000085_0003
Ci_6alkoxy, haloCi-6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000085_0004
bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000085_0005
Ci-6alkylsulfonyl, C1- 6alkylsulfonylamino,
Figure imgf000085_0006
bis(Ci. 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000085_0007
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000085_0008
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000085_0009
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In another aspect of the invention there is provided a subset of compounds of formula (I), or a pharmaceutically acceptable salt thereof; m is 0, 1 or 2; 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8; X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7- and -S(O)2CR6R7-;
R1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl and pyrazinylethyl, which group is optionally substituted by 1 , 2 or 3 substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; or X-R1 is -C(CH3)2OH or -CH2OH;
R2 is selected from 5 or 6 membered aryl and heteroaryl which group is substituted by -NHCONR18R19 or -NHCSNR18R19and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12; each R3, when present, is methyl; R4 is hydrogen or Ci_6alkyl; or, when X is -NR4CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi. βalkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci_ 6alkyl)aminoCi-6alkyl,
Figure imgf000086_0001
Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, C1- 6alkylsulfonyl(Ci.6alkyl)amino, sulfamoyl,
Figure imgf000086_0002
bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino,
Figure imgf000086_0003
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci_ 6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000086_0004
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)ammo, aminoCi.6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci.6alkylsulfonylammo, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000087_0001
bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci.6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000087_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, C1- 6alkylamino and bis(Ci-6alkyl)amino;
R11, R12 and R18 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000087_0003
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, C1- 6alkylamino and bis(Ci.6alkyl)amino; and
R19 is hydrogen or a group selected from C1-6alkyl, C3-6cycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloC1-6alkyl, haloCi-6alkoxy, hydroxyC1-6alkyl, hydroxyCi_6alkoxy, C1-6alkoxyC1-6alkyl, C1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoC1-6alkyl,
(C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, C1- 6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1-6alkylsulfamoyl, Ms(C1- 6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-6alkanoyl(C1-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloCi-6alkoxy, hydroxyC1-6alkyl, hydroxyCi_6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, Ci-6alkylamino, Ms(Ci- 6alkyl)amino, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, Ci-6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000088_0001
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In another particular class of compound of formula (I), or a pharmaceutically acceptable salt thereof; 5 m is O orl;
1Y is CH and Y2 is N;
X is a -S(O)2CR6R7- linker group;
R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl,o thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3; or -XR1 is -C(CH3)2OH or -CH2OH; s R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NHCONHR19 or -NHCSNHR19and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12; 0 R3, when present, is methyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000088_0002
haloCi_6alkoxy, hydroxyCi.5 6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000088_0003
sulfamoyl,
Figure imgf000088_0004
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000088_0005
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; o R11, R12 and R18 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Chalky!,
Figure imgf000088_0006
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-
6alkylamino and bis(Ci-6alkyl)amino; and
R19 is hydrogen, cyano or a group selected from C1-6alkyl, C3.6cycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more 5 substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, Ci-
6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000089_0001
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino, Ci-ealkylsulfony^d-ealky^amino, sulfamoyl, Ci-6alkylsulfamoyl, IUs(C1-o 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000089_0002
carbamoyl,
Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In another particular class of compound of formula (I), or a pharmaceutically acceptable salt thereof; m is 0 orl; s 1Y is CH and Y2 is N;
X is a -S(O)2CR6R7- linker group;
R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is 0 optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3; or -XR1 is -C(CH3)2OH or -CH2OH;
R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NHCONHR19 or 5 -NHCSNHR19and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and
-NR11COR12;
R3, when present, is methyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-memberedo carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N,
O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000089_0003
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. βalkyl, hydroxyCi-6alkoxy, Ci-ealkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci.6alkylammo, bis(Ci-6alkyl)ammo, aminoCi.6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000090_0001
sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-OaIk-UiOyI(C1- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R11, R12 and R18 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000090_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, C1- 6alkylamino and bis(Ci-6alkyl)amino; and
R19 is hydrogen or a group selected from Ci_6alkyl, C3_6Cycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, C1- 6alkoxyCi.6alkoxy, amino, C1-6alkylamino, bis(Ci.6alkyl)amino, aminoC1-6alkyl,
(C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, C1- 6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1-6alkylsulfamoyl, bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-6alkanoyl(C1-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl. In a further particular class of compound of formula (I), or a pharmaceutically acceptable salt thereof; m is 0, 1 or 2;
X is a -S(O)2CR6R7- linker group selected; 1Y is CH and Y2 is N. R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3; R2 is phenyl or pyridinyl substituted by -NHCONHR19 or -NHCSNHR19and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2; R3, when present, is methyl or ethyl;
5 R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino,o bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000091_0001
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000091_0002
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; and R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,s t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, dioxothiolanyl, imidazoylmethyl, isoxazolyl, oxazolyl, oxetanyl, pyrazinyl, pyrazolyl, pyrazolylmethyl, pyridinyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl, thiazolyl and triazolyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000091_0003
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl,0 hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000091_0004
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000091_0005
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl. 5 In a further particular class of compound of formula (I), or a pharmaceutically acceptable salt thereof; m is 1;
X is a -S(O)2CR6R7- linker group selected; 1Y is CH and Y2 is N. o R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3; R2 is phenyl or pyridinyl substituted by -NHCONHR19 or -NHCSNHR19and optionally 5 substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2; R3 is methyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N,o O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi. βalkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino,s sulfamoyl,
Figure imgf000092_0001
bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci.6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; and R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, dioxothiolanyl, imidazoylmethyl, isoxazolyl, oxazolyl, oxetanyl, pyrazinyl, pyrazolyl,0 pyrazolylmethyl, pyridinyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl, thiazolyl and triazolyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000092_0002
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,5 cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000092_0003
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000092_0004
6alkyl)amino, carbamoyl,
Figure imgf000092_0005
and bis(Ci.6alkyl)carbamoyl.
In a further particular class of compound of formula (I), or a pharmaceutically acceptable salt thereof; o m is 1;
X is a -S(O)2CR6R7- linker group selected; 1Y is CH and Y2 is N. R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3; R2 is phenyl or pyridinyl substituted by -NHCONHR19 or -NHCSNHR19and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2; R3 is methyl; R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi. βalkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci.6alkyl)amino, aminoCi.6alkyl,
Figure imgf000093_0001
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000093_0002
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000093_0003
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; and R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyrazolylmethyl, pyridinyl and pyrimidinyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci- βalkyl,
Figure imgf000093_0004
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. 6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000093_0005
Ci-
6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino,
Figure imgf000093_0006
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In a further particular class of compound of formula (I), or a pharmaceutically acceptable salt thereof; m is 1; X is a -S(O)2CR6R7- linker group; 1Y is CH and Y2 is N.
R1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH, -CH2CH2NHC(O)CH3, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin- 2-yl, 2-oxopyrolidin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, and 3-methyl-l,3,4-thiadiazol-2- yi;
R2 is
Figure imgf000094_0001
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or A2 is CH; R17 is hydrogen; R18 is hydrogen;
R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, 4-methylphenyl, 4- chlorophenyl, 4-trifiuoromethylphenyl, 4-flurophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CH2(imidazol-2-yl), -CH2(imidazol-3-yl), isoxazolyl-3-yl, 6-oxo-lH-pryrdin-2-yl, 5-methylisoxazol-3-yl, l-methylpyrazol-4-yl, -CH2(I -methylpyrazol-4- yl), -CH2( l-methylpyrazol-4-yl), 6-methoxypryridin-3-yl, 5-fluoropyridin-2-yl, pyrimidin-2-yl, and lH-pyrazol-3-yl;
R3 is methyl; and
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. βalkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci.6alkylsulfonylammo, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000095_0001
6alkyl)amino, carbamoyl, Ci.6alkylcarbamoyl and bis(Ci.6alkyl)carbamoyl.
In a further particular class of compound of formula (I), or a pharmaceutically acceptable salt thereof; m is 0, 1 or 2;
X is a -S(O)2CR6R7- linker group; 1Y is CH and Y2 is N. R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2C(OH)(CH3)2, -CH2CH2CH2OCHF2, -CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2C(O)NH2, -CH2C(O)NHMe, -CH2CH2NHMe, phenyl, 2-fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-fluoro-4-methylaminophenyl, 4-fiuoro-2-methylphenyl, 5-fiuoro-2-methylphenyl, 3-fiuoro-4-(2-hydroxyethylamino)phenyl, 4-(difluoromethoxy)phenyl, 4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methylaminophenyl, 3-chloro-4-ethylaminophenyl, 3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-hydroxyethylamino)phenyl, 2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-(trifiuoromethyl)phenyl, 2-methylphenyl, 4-methylphenyl, 4-(2-hydroxyethylamino)phenyl, lH-imidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin- 2-yl, l-(difiuoromethyl)pyrazol-4-yl, l-(difluoromethyl)-3,5-dimethylpyrazol-4-yl, l,3-dimethylpyrazol-4-yl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 2,4-dimethylthiazol-5-yl, 5-methyl-l,3,4-thiadiazol-2-yl, terahydrofuran-3-yl and terahydropyran-4-yl; R2 is
Figure imgf000095_0002
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or
A , 2z is CH;
R17 is hydrogen; R18 is hydrogen;
R19 is is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)2OH, 5 -CH2C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CF3,
-CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CH2SO2Me, -CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, -CH2CONMe2, -CH2CO2H, 1 -(methyl)cyclopropyl, -CH2( 1 -hydroxy cyclopropyl), 1 -(hydroxymethyl)cyclopropyl, ( 1 R)-2-hydroxy- 1 -methylethyl, ( 1 S)-2-o hydroxy- 1 -methylethyl, phenyl, 4-methylphenyl, 4-chlorophenyl,
4-(trifluoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, -CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2-yl), l-methylimidazol-4-yl, oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, 1,1- dioxothiolan-3-yl, 5-methylisoxazol-3-yl, -CH2(I -methylpyrazol-4-yl),s 1 -methylpyrazol-4-yl, -CH2(I -methylpyrazol-4-yl), 5-methylpyrazin-2- yl, -CH2(2H-l,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl, 5- fluoropyridin-2-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl and 1 -methylpyrazol-3 -yl; R3, when present, is methyl or ethyl; and o R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi. βalkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino,5 bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000096_0001
bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci.6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In a further particular class of compound of formula (I), or a pharmaceutically 0 acceptable salt thereof; m is 1; X is a -S(O)2CR6R7- linker group; 1Y is CH and Y2 is N.
R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2C(O)NH2, -CH2C(O)NHMe, phenyl, 4-fluorophenyl, 4-chlorophenyl, 3,5-difluorophenyl, 2-(trifiuoromethyl)phenyl, 4-(2-hydroxyethylamino)phenyl, lH-imidazol-2-yl,
2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, pyridin-4-yl, pyridin- 2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl and 5-methyl-l ,3,4-thiadiazol-2-yl;
R2 is
Figure imgf000097_0001
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or
A2 is CH; R17 is hydrogen; R18 is hydrogen; R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i- propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)2OH, -CH2C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CHF2, -CH2CH2SO2Me, -CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, - CH2CONMe2, l-(methyl)cyclopropyl, l-(hydroxymethyl)cyclopropyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, -CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2-yl), oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, l,l-dioxothiolan-3-yl, 5-methylisoxazol-3- yl, -CH2(I -methylpyrazol-4-yl), l-methylpyrazol-4-yl, 5-methylpyrazin-
2-yl, -CH2(2H-l,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl, 5-fiuoropyridin-2-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl, and 1 -methylpyrazol-3 -yl; R3 is methyl; and R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000098_0001
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000098_0002
6alkyl)amino, carbamoyl,
Figure imgf000098_0003
and bis(Ci.6alkyl)carbamoyl. In one aspect of the invention there is provided a subset of compounds of formula (IA),
(IB) or (IC)
Figure imgf000098_0004
(IA) (IB) (IC) or a pharmaceutically acceptable salt thereof; 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8;
X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- and
-S(O)2NR4CR6R7; R1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylC i_6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; or X-R1 is -C(CH3)2OH or -CH2OH;
R2 is selected from aryl and heteroaryl which group is substituted by -NR17CONR18R19 or -NR17CSNR18R19and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -
NR11COR12; R4 and R5 are independently hydrogen or or, when X is -NR4CR6R7-, -NR4C(O)CR6R7- or -NR4C(O)NR5CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. 6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^d-ealky^amino, sulfamoyl, C1- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000099_0001
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000099_0002
hydroxyCi. 6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000099_0003
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-OaIk-UiOyI(C1- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and Ci-6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloCi_6alkoxy, hydroxyC1-6alkyl, hydroxyCi_6alkoxy, C1-6alkoxyC1-6alkyl, Ci-όalkoxyCi-όalkoxy, amino, C1- 6alkylamino and bis(Ci-6alkyl)amino;
R11, R12, R17 and R18 are independently hydrogen or a group selected from C1-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, ImIoC1- βalkoxy, hydroxyC1-6alkyl, hydroxyCi_6alkoxy, C1-6alkoxyC1-6alkyl, Ci-όalkoxyCi-όalkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; R19 is hydrogen or a group selected from C^aUcyl, C3_6Cycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000100_0001
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, C1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000100_0002
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000100_0003
carbamoyl,
Figure imgf000100_0004
and bis(Ci.6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000100_0005
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, IUS(C1- 6alkyl)amino, aminoCi.6alkyl,
Figure imgf000100_0006
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000100_0007
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000100_0008
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; and when R3A is hydrogen, R3B is hydrogen, methyl, ethyl, hydroxymethyl, dimethylcarbamoyl or carbamoyl; or when R3A is methyl, R3B is methyl.
In one aspect of the invention there is provided a subset of compounds of formula (IA), (IB) or (IC)
Figure imgf000100_0009
(IA) (IB) (IC) or a pharmaceutically acceptable salt thereof; 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8;
X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- and -S(O)2NR4CR6R7;
R1 is a group selected from C^aHcyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylC i_6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; or X-R1 is -C(CH3)2OH or -CH2OH; R2 is selected from aryl and heteroaryl which group is substituted by -NR17CONR18R19 or -NR17CSNR18R19and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and - NR11COR12; R3A and R3B independently is hydrogen, methyl or ethyl; R4 and R5 are independently hydrogen or
Figure imgf000101_0001
or, when X is -NR4CR6R7-, -NR4C(O)CR6R7- or -NR4C(O)NR5CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
Figure imgf000101_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. βalkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000101_0003
Ci- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000101_0004
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000101_0005
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000102_0001
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and C1-6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000102_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci- 6alkylamino and bis(Ci-6alkyl)amino;
R , R , R and R are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000102_0003
haloCi. βalkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and R19 is hydrogen or a group selected from Ci_6alkyl, C3_6Cycloakyl, aryl, heteroaryl, arylCi-βalkyl and heteroarylCi.6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, Ci- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000102_0004
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, C1- 6alkylsulfonylamino,
Figure imgf000102_0005
bis(Ci_ 6alkyl)sulfamoyl, Ci.6alkanoylamino,
Figure imgf000102_0006
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloCi_6alkoxy, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, C1-6alkylamino, Ms(C1- 6alkyl)amino, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, Ci-6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1-6alkylsulfamoyl, bis(C1-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000102_0007
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl. In one aspect of the invention there is provided a subset of compounds of formula (Ia) or (Ib)
Figure imgf000103_0001
or a pharmaceutically acceptable salt thereof;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8;
X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- and -S(O)2NR4CR6R7;
R1 is a group selected from Ci.6alkyl, carbocyclyl, carbocyclylCi.6alkyl, heterocyclyl and heterocyclylC 1-6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; or X-R1 is -C(CH3)2OH or -CH2OH; R2 is selected from aryl and heteroaryl which group is substituted by -NR17CONR18R19 or -NR17CSNR18R19and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and - NR11COR12; R3 is hydrogen, methyl or ethyl; R4 and R5 are independently hydrogen or Ci_6alkyl or, when X is -NR4CR6R7-, -NR4C(O)CR6R7- or -NR4C(O)NR5CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6alkyl,
Figure imgf000103_0002
C1- 6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. 6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci- 6alkylsulfonyl, Ci.6alkylsulfonylamino, d-6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, d-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci.6alkylcarbamoyl and bis(Ci.6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000104_0001
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi- 6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-όalkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, d-6alkylsulfonyl(Ci-6alkyl)amino, sulfamoyl,
Figure imgf000104_0002
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci- 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and
Figure imgf000104_0003
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000104_0004
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-όalkoxyCi-όalkoxy, amino, Ci- 6alkylamino and bis(Ci-6alkyl)amino;
R , R , R and R are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, d-6alkoxy, haloCi-6alkyl, haloCi- βalkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and
R19 is hydrogen or a group selected from Ci-6alkyl, d-όCycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, d-6alkyl, Ci_6alkoxy,
Figure imgf000104_0005
6alkoxyCi_6alkoxy, amino, Ci-oalkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000104_0006
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-όalkylsulfonyl, C1- 6alkylsulfonylamino,
Figure imgf000104_0007
bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000104_0008
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000105_0001
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000105_0002
6alkyl)amino, carbamoyl,
Figure imgf000105_0003
and bis(Ci.6alkyl)carbamoyl. In one aspect of the invention there is provided a subset of compounds of formula (Ia) or (Ib)
Figure imgf000105_0004
or a pharmaceutically acceptable salt thereof; 1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8;
X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- and
-S(O)2NR4CR6R7; R1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylC i_6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; or X-R1 is -C(CH3)2OH or -CH2OH;
R2 is selected from aryl and heteroaryl which group is substituted by -NR17CONR18R19 or -NR17CSNR18R19and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -
NR11COR12; R3 is methyl;
R4 and R5 are independently hydrogen or
Figure imgf000106_0001
or, when X is -NR4CR6R7-, -NR4C(O)CR6R7- or -NR4C(O)NR5CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-
6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi.
6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, C1- βalkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-
6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000106_0002
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000106_0003
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi.
6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000106_0004
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000106_0005
6alkyl)amino, carbamoyl, Ci.6alkylcarbamoyl and bis(Ci.6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1-6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000106_0006
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-
6alkylamino and bis(Ci.6alkyl)amino;
R , R , R and R are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, ImIoC1- βalkoxy, hydroxyC1-6alkyl, hydroxyCi_6alkoxy, C1-6alkoxyC1-6alkyl, Ci-όalkoxyCi-όalkoxy, amino, Ci-6alkylamino and bis(Ci-6alkyl)amino; and R19 is hydrogen or a group selected from C^aUcyl, C3_6Cycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000107_0001
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, C1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000107_0002
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000107_0003
carbamoyl,
Figure imgf000107_0004
and bis(Ci.6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000107_0005
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, IUS(C1- 6alkyl)amino, aminoCi.6alkyl,
Figure imgf000107_0006
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000107_0007
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000107_0008
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In another aspect of the invention there is provided a subset of compounds of formula (Ia) or (Ib)
Figure imgf000107_0009
(Ia) (Ib) or a pharmaceutically acceptable salt thereof;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8;
X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7- and -S(O)2CR6R7-; R1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thiadiazolyl, thiazolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thiadiazolylmethyl, thiadiazolylethyl, thiazolylmethyl, thiazolylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl and pyrazinylethyl, which group is optionally substituted by 1 , 2 or 3 substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; or X-R1 is -C(CH3)2OH or -CH2OH;
R2 is selected from 5 or 6 membered aryl and heteroaryl which group is substituted by -NHCONR18R19 or -NHCSNR18R19and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12; R3 is methyl;
R4 is hydrogen or Ci_6alkyl; or, when X is -NR4CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci-6alkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi. βalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000108_0001
βalkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000108_0002
Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino,
Figure imgf000108_0003
bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino,
Figure imgf000108_0004
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci_ 6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000108_0005
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)ammo, aminoCi.6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci.6alkylsulfonylammo, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000109_0001
bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci.6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and Ci_6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000109_0002
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, C1- 6alkylamino and bis(Ci-6alkyl)amino;
R11, R12 and R18 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000109_0003
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, C1- 6alkylamino and bis(Ci.6alkyl)amino; and
R19 is hydrogen, cyano or a group selected from C1-6alkyl, C3-6cycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloC1-6alkyl, haloCi-6alkoxy, hydroxyC1-6alkyl, hydroxyCi_6alkoxy, C1-6alkoxyC1-6alkyl, C1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoC1-6alkyl,
(C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, C1- 6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1-6alkylsulfamoyl, Ms(C1- 6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-6alkanoyl(C1-6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a
6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloCi-6alkoxy, hydroxyC1-6alkyl, hydroxyCi_6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, Ci-6alkylamino, Ms(C1- 6alkyl)amino, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, Ci-6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000110_0001
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In another aspect of the invention there is provided a subset of compounds of formula (Ia) or (Ib)
Figure imgf000110_0002
(Ia) (Ib) or a pharmaceutically acceptable salt thereof;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8; X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7- and -S(O)2CR6R7-;
R1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl and pyrazinylethyl, which group is optionally substituted by 1 , 2 or 3 substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10; or X-R1 is -C(CH3)2OH or -CH2OH;
R2 is selected from 5 or 6 membered aryl and heteroaryl which group is substituted by -NHCONR18R19 or -NHCSNR18R19and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12; R3 is methyl;
R4 is hydrogen or Chalky!; or, when X is -NR4CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd. βalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000111_0001
6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealky^amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci- 6alkanoylamino,
Figure imgf000111_0002
carbamoyl,
Figure imgf000111_0003
and bis(Ci. 6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000111_0004
haloCi_6alkoxy, hydroxyCi.
Figure imgf000111_0005
amino,
Figure imgf000111_0006
bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000111_0007
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000111_0008
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R8 is selected from hydrogen, halo, cyano and C1-6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000111_0009
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, C1- 6alkylamino and bis(Ci-6alkyl)amino;
R11, R12 and R18 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloCi-6alkoxy, hydroxyC1-6alkyl, hydroxyCi-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, C1- 6alkylamino and bis(Ci-6alkyl)amino; and
R19 is hydrogen or a group selected from C1-6alkyl, C3-6cycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C^aUcyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci- 6alkoxyCi.6alkoxy, amino,
Figure imgf000112_0001
bis(Ci.6alkyl)amino, aminoCi.6alkyl,
Figure imgf000112_0002
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, C1- 6alkylsulfonylamino,
Figure imgf000112_0003
bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000112_0004
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000112_0005
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000112_0006
bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci.6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl. In another particular class of compound of formula (Ia) or (Ib),
Figure imgf000112_0007
or a pharmaceutically acceptable salt thereof;
1Y is CH and Y2 is N;
X is a -S(O)2CR6R7- linker group;
R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3; or -XR1 is -C(CH3)2OH or -CH2OH;
R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NHCONHR19 or
-NR17CSNR18R19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and - NR11COR12; R3 is methyl; R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi. βalkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci.6alkyl)amino, aminoCi.6alkyl,
Figure imgf000113_0001
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000113_0002
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000113_0003
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R11, R12 and R18 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci-6alkyl, Ci-6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci- 6alkylamino and bis(Ci-6alkyl)amino; and
R19 is hydrogen, cyano or a group selected from Ci_6alkyl, C3-6Cycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy,
Figure imgf000113_0004
6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000113_0005
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, C1- 6alkylsulfonylamino,
Figure imgf000113_0006
bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000113_0007
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl. In another particular class of compound of formula (Ia) or (Ib),
Figure imgf000114_0001
or a pharmaceutically acceptable salt thereof; 5 1Y is CH and Y2 is N;
X is a -S(O)2CR6R7- linker group;
R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group iso optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifiuoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3; or -XR1 is -C(CH3)2OH or -CH2OH;
R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NHCONHR19 or s -NR17CSNR18R19 and optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -
NR11COR12;
R3 is methyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-memberedo carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N,
O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000114_0002
Ci_6alkoxy,
Figure imgf000114_0003
haloCi_6alkoxy, hydroxyCi.
6alkyl,
Figure imgf000114_0004
amino,
Figure imgf000114_0005
bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,5
Figure imgf000114_0006
sulfamoyl,
Figure imgf000114_0007
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R11, R12 and R18 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000115_0001
hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, C1- 6alkylamino and bis(Ci-6alkyl)amino; and
R19 is hydrogen or a group selected from Ci_6alkyl, C3-6Cycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, C1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000115_0002
bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000115_0003
Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino,
Figure imgf000115_0004
bis(Ci_ 6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000115_0005
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl. In a further particular class of compound of formula (IA), (IB) or (IC)
Figure imgf000115_0006
or a pharmaceutically acceptable salt thereof; X is a -S(O)2CR6R7- linker group; 1Y is CH and Y2 is N.
R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3; R2 is phenyl or pyridinyl substituted by -NHCONHR19 or -NHCSNHR19 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2; R3A and R3B each independently is hydrogen, methyl or ethyl; R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6alkyl, hydroxyCi-6alkoxy, Ci-6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000116_0001
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000116_0002
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, dioxothiolanyl, imidazoylmethyl, isoxazolyl, oxazolyl, oxetanyl, pyrazinyl, pyrazolyl, pyrazolylmethyl, pyridinyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl, thiazolyl and triazolyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000116_0003
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000116_0004
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000116_0005
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; and when R3A is hydrogen, R3B is hydrogen, methyl, ethyl, hydroxymethyl, dimethylcarbamoyl or carbamoyl; or when R L33AA iiss m methyl, R3B is methyl. In a further particular class of compound of formula (Ia) or (Ib)
Figure imgf000117_0001
or a pharmaceutically acceptable salt thereof; X is a -S(O)2CR6R7- linker group; 1Y is CH and Y2 is N.
R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3; R2 is phenyl or pyridinyl substituted by -NHCONHR19 or -NHCSNHR19 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2; R3A and R3B each independently is hydrogen, methyl or ethyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000117_0002
Ci_6alkoxy,
Figure imgf000117_0003
haloCi_6alkoxy, hydroxyCi. 6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000117_0004
bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci.6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; and R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i- butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, dioxothiolanyl, imidazoylmethyl, isoxazolyl, oxazolyl, oxetanyl, pyrazinyl, pyrazolyl, pyrazolylmethyl, pyridinyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl, thiazolyl and triazolyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000118_0001
hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000118_0002
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000118_0003
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl. In a further particular class of compound of formula (Ia) or (Ib)
Figure imgf000118_0004
or a pharmaceutically acceptable salt thereof; X is a -S(O)2CR6R7- linker group; 1Y is CH and Y2 is N. R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3;
R2 is phenyl or pyridinyl substituted by -NHCONHR19 or -NHCSNHR19 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2; R3 is methyl; R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000119_0001
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. βalkyl, hydroxyCi-6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, d-ealkylamino, bis(Ci.6alkyl)amino, aminoCi.6alkyl,
Figure imgf000119_0002
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, d-ealkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000119_0003
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; and R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, dioxothiolanyl, imidazoylmethyl, isoxazolyl, oxazolyl, oxetanyl, pyrazinyl, pyrazolyl, pyrazolylmethyl, pyridinyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl, thiazolyl and triazolyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000119_0004
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000119_0005
sulfamoyl,
Figure imgf000119_0006
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000119_0007
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl. In a further particular class of compound of formula (Ia) or (Ib)
Figure imgf000119_0008
or a pharmaceutically acceptable salt thereof;
X is a -S(O)2CR6R7- linker group;
1Y is CH and Y2 is N.
R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, methyl, methoxy, trifiuoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3; R2 is phenyl or pyridinyl substituted by -NHCONHR19 or -NHCSNHR19 and optionally substituted by one or more substituent group independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2; R3 is methyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi. βalkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000120_0001
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-OaIk-UiOyI(C1- 6alkyl)amino, carbamoyl,
Figure imgf000120_0002
and bis(Ci.6alkyl)carbamoyl; and
R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyrazolylmethyl, pyridinyl and pyrimidinyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1- 6alkyl,
Figure imgf000120_0003
haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci- 6alkoxyCi-6alkyl, Ci-6alkoxyCi-6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi. βalkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000120_0004
Ci- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000120_0005
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
In a further particular class of compound of formula (Ia) or (Ib)
Figure imgf000121_0001
(Ia) (Ib) or a pharmaceutically acceptable salt thereof; m is 1; X is a -S(O)2CR6R7- linker group; 1Y is CH and Y2 is N.
R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2C(O)NH2, -CH2C(O)NHMe, phenyl, 4-fiuorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3,5-difiuorophenyl, 2-(trifiuoromethyl)phenyl, 4-(2-hydroxyethylamino)phenyl,
2-methoxyphenyl, 2-methylphenyl, lH-imidazol-2-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5- (dimethylcarbamoyl)pyridin-2-yl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2- yl, 5-fiuoropyridin-2-yl, 5-fluoropyridin-3-yl, 2-oxopyrolidin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, 5-methyl-l,3,4-thiadiazol-2-yl and 3-methyl-l,3,4-thiadiazol-2-yl; R2 is
Figure imgf000121_0002
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or
A , 2z is CH;
R17 is hydrogen;
R18 is hydrogen; and
R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i- propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2CH2NMe2,
-CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)2OH, -CH2C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CHF2, -CH2CH2SO2Me, -CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, -CH2CONMe2, 1 -(methyl)cyclopropyl, 1 -(hydroxymethyl)cyclopropyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, A- fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl,
-CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2-yl), -CH2(imidazol-3-yl), oxazolyl-2-yl, isoxazolyl-3-yl, 6-oxo-lH-pryrdin-2-yl, oxetan-3-yl, 1,1- dioxothiolan-3-yl, 5-methylisoxazol-3-yl, -CH2(I -methylpyrazol-4-yl), l-methylpyrazol-4-yl, -CH2(I -methylpyrazol-4-yl), 5-methylpyrazin-2- yl, -CH2(2H-l,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl,
5-fluoropyridin-2-yl, pyrimidin-2-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl, l-methylpyrazol-3-yl and lH-pyrazol-3-yl; R3 is methyl; and
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi. 6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyCόalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl. In a further particular class of compound of formula (Ia) or (Ib)
Figure imgf000122_0001
(Ia) (Ib) or a pharmaceutically acceptable salt thereof; m is 1; X is a -S(O)2CR »6π R7- linker group; 1Y is CH and Y2 is N.
R1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH, -CH2CH2NHC(O)CH3, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifiuoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin- 2-yl, 2-oxopyrolidin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, and 3-methyl-l,3,4-thiadiazol-2- yi;
R2 is
Figure imgf000123_0001
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or A2 is CH; R17 is hydrogen; R18 is hydrogen; and
R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, 4-methylphenyl, 4- chlorophenyl, 4-trifiuoromethylphenyl, 4-flurophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CH2(imidazol-2-yl), -CH2(imidazol-3-yl), isoxazolyl-3-yl, 6-oxo-lH-pryrdin-2-yl, 5-methylisoxazol-3-yl, l-methylpyrazol-4-yl, -CH2(I -methylpyrazol-4- yl), -CH2( l-methylpyrazol-4-yl), 6-methoxypryridin-3-yl, 5-fluoropyridin-2-yl, pyrimidin-2-yl, and lH-pyrazol-3-yl;
R3 is methyl; and R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy,
Figure imgf000123_0002
haloCi_6alkoxy, hydroxyCi. βalkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCόalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)ammo, aminoCi.6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci.6alkylsulfonylammo, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000124_0001
bis(Ci.6alkyl)sulfamoyl, Ci.6alkanoylamino, Ci.6alkanoyl(Ci. 6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl. In a further particular class of compound of formula (Ia) or (Ib)
Figure imgf000124_0002
or a pharmaceutically acceptable salt thereof; m is 1; X is a -S(O)2CR6R7- linker group;
1Y is CH and Y2 is N.
R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2OCH3, -CH2CH2NHC(O)CH3,
-CH2C(O)NH2, -CH2C(O)NHMe, phenyl, 4-fluorophenyl, 4-chlorophenyl, 3,5-difluorophenyl, 2-(trifiuoromethyl)phenyl, 4-(2-hydroxyethylamino)phenyl, lH-imidazol-2-yl,
2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, pyridin-4-yl, pyridin-
2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl and
5 -methyl- 1 ,3,4-thiadiazol-2-yl;
R2 is
Figure imgf000124_0003
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or
A2 is CH; R17 is hydrogen; R18 is hydrogen; and R19 is is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH^cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)2OH, -CH2C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CHF2, -CH2CH2SO2Me, -CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, -
CH2CONMe2, l-(methyl)cyclopropyl, l-(hydroxymethyl)cyclopropyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, -CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2-yl), oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, l,l-dioxothiolan-3-yl, 5-methylisoxazol-3- yl, -CH2(I -methylpyrazol-4-yl), l-methylpyrazol-4-yl, 5-methylpyrazin- 2-yl, -CH2(2H-l,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl, and 1 -methylpyrazol-3 -yl; R3 is methyl; and
R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring.
In a further particular class of compound of formula (IA), (IB) or (IC)
Figure imgf000125_0001
or a pharmaceutically acceptable salt thereof;
X is a -S(O)2CR6R7- linker group;
1Y is CH and Y2 is N;
R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2C(OH)(CH3)2, -CH2CH2CH2OCHF2,
-CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2C(O)NH2, -CH2C(O)NHMe, -CH2CH2NHMe, phenyl, 2-fiuorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2-fluoro-4-methylaminophenyl, 4-fluoro-2-methylphenyl, 5-fluoro-2-methylphenyl, 3-fluoro-4-(2-hydroxyethylamino)phenyl, 4-(difluoromethoxy)phenyl, 4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methylaminophenyl, 3-chloro-4-ethylaminophenyl, 3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-hydroxyethylamino)phenyl, 2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-(trifluoromethyl)phenyl, 2-methylphenyl, 4-methylphenyl, 4-(2-hydroxyethylamino)phenyl, lH-imidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin- 2-yl, l-(difluoromethyl)pyrazol-4-yl, l-(difluoromethyl)-3,5-dimethylpyrazol-4-yl, l,3-dimethylpyrazol-4-yl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 2,4-dimethylthiazol-5-yl, 5-methyl-l,3,4-thiadiazol-2-yl, terahydrofuran-3-yl and terahydropyran-4-yl; R2 is
Figure imgf000126_0001
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or
A2 is CH;
R .17 is hydrogen;
R ,18 is hydrogen; and
R .19 is is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CHs)2CH2OH, -CH2C(CH3)2OH, -CH2C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CH2SO2Me, -CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, -CH2CONMe2, -CH2CO2H, 1 -(methyl)cyclopropyl, -CH2( 1 -hydroxy cyclopropyl), 1 -(hydroxymethyl)cyclopropyl, ( 1 R)-2-hydroxy- 1 -methylethyl, ( 1 S)-2- hydroxy-1-methylethyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-(trifiuoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, -CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2-yl), l-methylimidazol-4-yl, oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, 1,1- dioxothiolan-3-yl, 5-methylisoxazol-3-yl, -CH2(I -methylpyrazol-4-yl), l-methylpyrazol-4-yl, -CH2(I -methylpyrazol-4-yl), 5-methylpyrazin-2- yl, -CH2(2H-l,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl, 5- fluoropyridin-2-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl and
1 -methylpyrazol-3 -yl;
R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R3A is hydrogen, R3B is hydrogen, methyl, ethyl, hydroxymethyl, dimethylcarbamoyl or carbamoyl; or when R3A is methyl, R3B is methyl.
In a further particular class of compound of formula (IA), (IB) or (IC)
Figure imgf000127_0001
or a pharmaceutically acceptable salt thereof; X is a -S(O)2CR6R7- linker group; 1Y is CH and Y2 is N;
R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, -CH2CH2OH, - CH2CH2CH2OH, -CH2CH2C(OH)(CH3)2, -CH2CH2CH2OCHF2, -CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2CH2NHMe, phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-fluoro-4-methylaminophenyl, 4-fluoro-2-methylphenyl, 5-fiuoro-2- methylphenyl, 3 -fluoro-4-(2-hydroxyethylamino)phenyl, 4-(difluoromethoxy)phenyl, 4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methylaminophenyl, 3-chloro-4-ethylaminophenyl, 3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-hydroxyethylamino)phenyl, 2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-methylphenyl, 4-methylphenyl, lH-imidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, 1 -(difluoromethyl)pyrazol-4-yl, 1 ,3-dimethylpyrazol-4-yl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl, 4-methylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 2,4-dimethylthiazol-5-yl and 5-methyl-l,3,4-thiadiazol-2-yl; R2 is
Figure imgf000128_0001
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or
A , 2z is CH;
R17 is hydrogen;
R18 is hydrogen; and
R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2CH2NMe2,
-CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH,
-CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CH2CN,
-CH2( 1 -hydroxycyclopropyl), 1 -(hydroxymethyl)cyclopropyl,
( 1 R)-2-hydroxy- 1 -methylethyl, ( 1 S)-2-hydroxy- 1 -methylethyl, phenyl,
4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl,
-CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2-yl), l-methylimidazol-4-yl, oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, 5-methylisoxazol-3-yl,
1 -methylpyrazol-4-yl, 5-methylpyrazin-2-yl, 6-methoxypryridin-3-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl and l-methylpyrazol-3-yl;
R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R3A is hydrogen, R3B is hydrogen, methyl or ethyl; or when R3A is methyl, R3B is methyl.
In a further particular class of compound of formula (IA), (IB) or (IC)
Figure imgf000129_0001
(IA) (IB) (IC) or a pharmaceutically acceptable salt thereof; X is a -S(O)2CR6R7- linker group; 1Y is CH and Y2 is N;
R1 is a group selected from methyl, ethyl, cyclopropyl, -CH2CH2CH2OH, phenyl, 2-fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-chlorophenyl, 2-methylphenyl, 5-fiuoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl; R2 is
Figure imgf000129_0002
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or
A2 is CH; R17 is hydrogen; R18 is hydrogen; and
R19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl, -CH(CH3)CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CHF2, -CH2CH2F, -CH2CH2CN, (lR)-2-hydroxy-l-methylethyl, (lS)-2- hydroxy-1-methylethyl, -CH2(imidazol-2-yl), oxazolyl-2-yl, isoxazolyl- 3-yl, l-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, thiazol-2-yl and l,2,4-thiadiazol-5-yl;
R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R3A is hydrogen, R3B is hydrogen, methyl or ethyl; or when R3A is methyl, R3B is methyl. In a further particular class of compound of formula (IA), (IB) or (IC)
Figure imgf000130_0001
or a pharmaceutically acceptable salt thereof; X is a -S(O)2CR6R7- linker group; 1Y is CH and Y2 is N;
R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2C(OH)(CH3)2, -CH2CH2CH2OCHF2, -CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2C(O)NH2, -CH2C(O)NHMe, -CH2CH2NHMe, phenyl, 2-fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-fluoro-4-methylaminophenyl, 4-fiuoro-2-methylphenyl, 5-fiuoro-2-methylphenyl, 3-fiuoro-4-(2-hydroxyethylamino)phenyl, 4-(difluoromethoxy)phenyl, 4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chloro-4-fiuorophenyl, 3-chloro-4-methylaminophenyl, 3-chloro-4-ethylaminophenyl, 3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-hydroxyethylamino)phenyl, 2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-(trifluoromethyl)phenyl, 2-methylphenyl, 4-methylphenyl, 4-(2-hydroxyethylamino)phenyl, lH-imidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin- 2-yl, l-(difluoromethyl)pyrazol-4-yl, l-(difluoromethyl)-3,5-dimethylpyrazol-4-yl, l,3-dimethylpyrazol-4-yl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 2,4-dimethylthiazol-5-yl, 5-methyl-l,3,4-thiadiazol-2-yl, terahydrofuran-3-yl and terahydropyran-4-yl; R2 is
Figure imgf000130_0002
wherein A1 and A2 are CH;
R17 is hydrogen; R18 is hydrogen; and
R19 is is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl),
-CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)2OH, -CH2C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CH2SO2Me, -CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, -CH2CONMe2, -CH2CO2H, l-(methyl)cyclopropyl, -CH2(I -hydroxy cyclopropyl),
1 -(hydroxymethyl)cyclopropyl, ( 1 R)-2-hydroxy- 1 -methylethyl, ( 1 S)-2- hydroxy-1-methylethyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-(trifiuoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, -CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2-yl), l-methylimidazol-4-yl, oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, 1,1- dioxothiolan-3-yl, 5-methylisoxazol-3-yl, -CH2(I -methylpyrazol-4-yl), l-methylpyrazol-4-yl, -CH2(I -methylpyrazol-4-yl), 5-methylpyrazin-2- yl, -CH2(2H-l,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl, 5- fluoropyridin-2-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl and 1 -methylpyrazol-3 -yl;
R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R3A is hydrogen, R3B is hydrogen, methyl, ethyl, hydroxymethyl, dimethylcarbamoyl or carbamoyl; or when R3 is methyl, R3 is methyl.
In a further particular class of compound of formula (IA), (IB) or (IC)
Figure imgf000132_0001
or a pharmaceutically acceptable salt thereof; X is a -S(O)2CR6R7- linker group; 5 1Y is CH and Y2 is N;
R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, -CH2CH2OH, - CH2CH2CH2OH, -CH2CH2C(OH)(CH3)2, -CH2CH2CH2OCHF2, -CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2CH2NHMe, phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-fluoro-4-methylaminophenyl, 4-fluoro-2-methylphenyl, 5-fiuoro-2-o methylphenyl, 3-fluoro-4-(2-hydroxyethylamino)phenyl, 4-(difluoromethoxy)phenyl, 4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methylaminophenyl, 3-chloro-4-ethylaminophenyl, 3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-hydroxyethylamino)phenyl, 2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, s 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-methylphenyl, 4-methylphenyl, lH-imidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, 1 -(difluoromethyl)pyrazol-4-yl, 1 ,3-dimethylpyrazol-4-yl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl, 4-methylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 2,4-dimethylthiazol-5-yl and 5-methyl-l,3,4-thiadiazol-2-yl; o R2 is
Figure imgf000132_0002
wherein A1 and A2 are CH;
R17 is hydrogen;
] R18 is hydrogen; and R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, -CH^cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CH2CN, 5 -CH2(I -hydroxycyclopropyl), l-(hydroxymethyl)cyclopropyl,
( 1 R)-2-hydroxy- 1 -methylethyl, ( 1 S)-2-hydroxy- 1 -methylethyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, -CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2-yl), l-methylimidazol-4-yl, oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, 5-methylisoxazol-3-yl,o l-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, 6-methoxypryridin-3-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl and l-methylpyrazol-3-yl;
R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R3A is hydrogen, R3B is hydrogen, methyl or ethyl; or s when R3A is methyl, R3B is methyl.
In a further particular class of compound of formula (IA), (IB) or (IC)
Figure imgf000133_0001
(IA) (IB) (IC) or a pharmaceutically acceptable salt thereof; o X is a -S(O)2CR6R7- linker group; 1Y is CH and Y2 is N;
R1 is a group selected from methyl, ethyl, cyclopropyl, -CH2CH2CH2OH, phenyl, 2-fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-chlorophenyl, 2-methylphenyl, 5-fiuoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl; 5 R2 is
Figure imgf000134_0001
wherein A1 and A2 are CH;
R17 is hydrogen; R18 is hydrogen; and
R19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl, -CH(CH3)CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CHF2, -CH2CH2F, -CH2CH2CN, (lR)-2-hydroxy-l-methylethyl, (lS)-2- hydroxy-1-methylethyl, -CH2(imidazol-2-yl), oxazolyl-2-yl, isoxazolyl- 3-yl, l-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, thiazol-2-yl and l,2,4-thiadiazol-5-yl;
R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R3A is hydrogen, R3B is hydrogen, methyl or ethyl; or when R3A is methyl, R3B is methyl.
In a further particular class of compound of formula (IA), (IB) or (IC)
Figure imgf000134_0002
or a pharmaceutically acceptable salt thereof; X is a -S(O)2CR6R7- linker group; 1Y is CH and Y2 is N;
R1 is a group selected from methyl, ethyl, cyclopropyl, -CH2CH2CH2OH, phenyl, 2-fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-chlorophenyl, 2-methylphenyl, 5-fiuoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl; R2 is
Figure imgf000135_0001
wherein A1 and A2 are CH;
R .17 is hydrogen;
R ,18 is hydrogen; and
R .19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl, -CH(CH3)CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CHF2, -CH2CH2F, -CH2CH2CN, (lR)-2-hydroxy-l-methylethyl, (lS)-2- hydroxy-1-methylethyl, -CH2(imidazol-2-yl), oxazolyl-2-yl, isoxazolyl- 3-yl, l-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, thiazol-2-yl and l,2,4-thiadiazol-5-yl;
R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R3A is hydrogen, R3B is methyl or ethyl; or when R3A is methyl, R3B is methyl.
Another aspect of the invention provides a compound, or a combination of compounds, selected from any one of the Examples or a pharmaceutically acceptable salt thereof.
In another aspect of the invention there is provided a compound, or a combination of compounds, selected from any one of
3 -Ethyl- 1 -[4-[4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]urea,
3 -methyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]urea,
3-Cyclopropyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-[(l-methylpyrazol-4-yl)methyl]urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, 3-cyclobutyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3 -( 1 H-imidazol-2-ylmethyl)- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl]-6-( 1 - methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, 3-(2-dimethylaminoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(l-hydroxy-2-methyl-propan-2-yl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfbnylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(l ,2-oxazol-3-yl)urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfbnylcyclopropyl)pyrimidin-2- yl]phenyl]-3-phenyl-urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-propan-2-yl-urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl] -3 -propyl-urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(2-methylpropyl)urea,
3 -(cyclopropylmethyl)- 1 -[4-[4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 - methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(l-hydroxypropan-2-yl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, 3 -(6-methoxypyridin-3 -yl)- 1 - [4- [4-[(3 S)-3 -methylmorpholin-4-yl] -6-( 1 - methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(4-fluorophenyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(3,4-difluorophenyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(4-methylphenyl)urea, 3 -(4-chlorophenyl)- 1 -[4- [4- [(3 S)-3 -methylmorpholin-4-yl]-6-( 1 - methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(4-methoxyphenyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, 5 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfbnylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(5-methyl-l,2-oxazol-3-yl)urea,
3 -(5 -fluoropyridin-2-yl)- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl]-6-( 1 - methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxy-2,2-dimethylpropyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- i o methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfbnylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(2-pyrrolidin- 1 -ylethyl)urea, is 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(3,3,3-trifluoro-2-hydroxypropyl)urea,
3-(2-hydroxy-2-methylpropyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-[l-(hydroxymethyl)cyclopropyl]-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- 20 methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(oxetan-3-yl)urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-3-yl)urea, 25 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(l,2,4-thiadiazol-5-yl)urea,
3-(cyanomethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- 30 yl]phenyl]-3-(2H- 1 ,2,4-triazol-3-ylmethyl)urea,
3-cyclopropyl-l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, 3-cyclobutyl-l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-pyridin-2-yl-urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-methylpropyl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-propan-2-yl-urea,
3 - [4- [4-( 1 -cyclopropylsulfonylcyclopropy^-ό- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-l -ethyl-urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-dimethylaminoethyl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, 3 - [4- [4-( 1 -cyclopropylsulfonylcyclopropy^-ό- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- y l]phenyl] - 1 -propy 1-urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl] -3 -methyl-urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-hydroxy-2-methyl-propan-2-yl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl] -3 -(3 -hydroxy-2,2-dimethylpropyl)urea,
3-(2-cyanoethyl)-l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-pyrrolidin- 1 -ylethyl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3,3,3-trifluoro-2-hydroxypropyl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl] -3 -(2-hydroxy-2-methylpropyl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[l-(hydroxymethyl)cyclopropyl]urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(oxetan-3-yl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l -methylpyrazol-3-yl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l,2,4-thiadiazol-5-yl)urea,
3 -methyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopentyl)pyrimidin-2- yl]phenyl]urea, 3-ethyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopentyl)pyrimidin-2- yl]phenyl]urea,
3 -cyclopropyl- 1 -[4- [4- [(3 S)-3 -methylmorpholin-4-yl]-6-( 1 - methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopentyl)pyrimidin-2- yl]phenyl]-3-propan-2-yl-urea,
3-cyclobutyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea, 3-(l-hydroxy-2-methyl-propan-2-yl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
3-(2-dimethylaminoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopentyl)pyrimidin-2- yl]phenyl]-3-propyl-urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopentyl)pyrimidin-2- yl]phenyl]-3-(2-methylpropyl)urea, 3-(3-hydroxypropyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopentyl)pyrimidin-2- yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea, 5 l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopentyl)pyrimidin-2- yl]phenyl]-3-pyridin-2-yl-urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopentyl)pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea,
3-(lH-imidazol-2-ylmethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- i o methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
3 -methyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclobutyl)pyrimidin-2- yl]phenyl]urea,
3 -ethyl- 1 - [4- [4-[(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -me thylsulfonylcyclobutyl)pyrimidin-2- yl]phenyl]urea, 15 3 -cyclopropyl- 1 -[4- [4- [(3 S)-3 -methylmorpholin-4-yl]-6-( 1 - methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]-
3-propan-2-yl-urea,
3-cyclobutyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclobutyl)pyrimidin- 20 2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3-(l-hydroxy-2-methyl-propan-2-yl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea, 25 3-(2-dimethylaminoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]-
3-propyl-urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]- 30 3-(2-methylpropyl)urea,
3-(3-hydroxypropyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]-
3 - [4-(trifluoromethyl)phenyl]urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]-
3 -pyridin-2-yl-urea, 5 l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]-
3 -( 1 -methylpyrazol-4-yl)urea,
3-(lH-imidazol-2-ylmethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3 -cyclobutyl- 1 - [4-[4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-4- i o ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-pyridin-2-yl-urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(2-methylpropyl)urea, is 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-propan-2-yl-urea,
3 -ethyl- 1 - [4- [4-[(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-dimethylaminoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- 20 ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl] -3 -propyl-urea, 25 3-methyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea,
3-(l-hydroxy-2-methyl-propan-2-yl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- 30 ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3 -(3 -hydroxypropyl)-l- [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-(l-pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea,
3 -cyclopropyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, 3-methyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-propan-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1 -ethyl-3 - [4- [4-[(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -propan-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1- [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-(l -propan-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-propan-2-yl-urea,
3-cyclobutyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-propan-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3 -cyclopropyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -propan-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, 3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-propan-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(l-hydroxy-2-methyl-propan-2-yl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-propan-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-dimethylaminoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-propan-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -propan-2-ylsulfonylcyclopropyl)pyrimidin-2- y l]phenyl] - 1 -propy 1-urea,
1- [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-(l -propan-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(2-methylpropyl)urea, 3-(3-hydroxypropyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-propan-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1- [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-(l -propan-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea,
1- [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-(l -propan-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-pyridin-2-yl-urea,
1- [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-(l -propan-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl] -3 -methyl-urea,
1 -ethyl-3 -[4-[4-[I -(4-fluorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, 3-cyclopropyl- 1 -[4-[4-[ 1 -(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-propan-2-yl-urea,
3-cyclobutyl- 1 -[4-[4-[ 1 -(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-hydroxy-2-methyl-propan-2-yl)urea, 3-(2-dimethylaminoethyl)-l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- y l]phenyl] - 1 -propy 1-urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-methylpropyl)urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-pyridin-2-yl-urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-(l-cyclopentylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropyl-urea,
3-cyclobutyl-l-[4-[4-(l-cyclopentylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-(l-cyclopentylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-pyridin-2-yl-urea, l-[4-[4-(l-cyclopentylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-methylpropyl)urea, l-[4-[4-(l-cyclopentylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-propan-2-yl-urea,
3 - [4- [4-( 1 -cyclopentylsulfonylcyclopropy^-ό- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]- 1 -ethyl-urea, l-[4-[4-(l-cyclopentylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-dimethylaminoethyl)urea, l-[4-[4-(l-cyclopentylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea,
3 - [4- [4-( 1 -cyclopentylsulfonylcyclopropy^-ό- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- y l]phenyl] - 1 -propy 1-urea, l-[4-[4-(l -cyclopentylsulfonylcyclopropy^-ό- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl] -3 -methyl-urea, l-[4-[4-(l-cyclopentylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea, l-[4-[4-(l-cyclopentylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l -hydroxy-2-methyl-propan-2-yl)urea, l-[4-[4-(l-cyclopentylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, l-[4-[4-(l-cyclopentylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, 3 -cyclopropyl- 1 -[4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-[ 1 - [2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-cyclobutyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[2- (trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]-3-pyridin-2-yl-urea, l.[4.[4.[(3S)-3-methylmorpholin-4-yl]-6-[l-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]-3-(2-methylpropyl)urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[2-
(trifluoromethyl)phenyl] sulfonylcyclopropyl]pyrimidin-2-yl]phenyl] -3 -propan-2-yl-urea, l-ethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea, 3-(2-dimethylaminoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[2- (trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]- 1 -propyl-urea,
3-methyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]-3-[4- (trifluoromethyl)phenyl]urea,
3-(l-hydroxy-2-methyl-propan-2-yl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxypropyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[2-
(trifluoromethyl)phenyl] sulfonylcyclopropyl]pyrimidin-2-yl]phenyl] -3 -( 1 -methylpyrazol-4- yl)urea,
3-cyclopropyl-l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-
3 -methyl-urea, l-ethyl-3-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]urea, l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]- 3 -propan-2-yl-urea,
3-cyclobutyl-l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]urea, l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-
3 -(2-hydroxyethyl)urea, l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-
3 -( 1 -hydroxy-2-methyl-propan-2-yl)urea, 3-(2-dimethylaminoethyl)-l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-
1-propyl-urea, l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]- 3-(2-methylpropyl)urea, l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-
3 -(3 -hydroxypropyl)urea, l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-
3 - [4-(trifluoromethyl)phenyl]urea, l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-
3 -pyridin-2-yl-urea, l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-
3 -( 1 -methylpyrazol-4-yl)urea,
3 -cyclopropyl- 1 - [4- [4-( 1 -methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea,
3 -methyl- 1 - [4- [4-( 1 -methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]urea,
3-ethyl-l-[4-[4-(l-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]urea,
3 -cyclobutyl- 1 - [4- [4-( 1 -methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea, 3-(2-hydroxyethyl)-l-[4-[4-(l-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea,
3-(l -hydroxy-2-methylpropan-2-yl)- 1 -[4-[4-(I -methylsulfonylcyclopropyl)-6-morpholin-4- ylpyrimidin-2-yl]phenyl]urea,
3-(2-dimethylaminoethyl)-l-[4-[4-(l-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin- 2-yl]phenyl]urea, l-[4-[4-(l-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3-propylurea, 3 -(3 -hydroxypropyl)- 1 - [4- [4-( 1 -methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea,
3-(l-methylpyrazol-4-yl)-l-[4-[4-(l-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea, 3-cyclopropyl-l-[4-[4-(l-methylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea,
3 -methyl- 1 - [4- [4-( 1 -methylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]urea,
3 -(2-hydroxyethyl)- 1 -[4- [4-( 1 -methylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea, 3-(l-hydroxy-2-methylpropan-2-yl)-l-[4-[4-(l-methylsulfonylcyclopentyl)-6-morpholin-4- ylpyrimidin-2-yl]phenyl]urea,
3-(2-dimethylaminoethyl)-l-[4-[4-(l-methylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-
2-yl]phenyl]urea,
3 -(3 -hydroxypropyl)- 1 - [4- [4-( 1 -me thylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea,
3-cyclopropyl-l-[4-[4-(l-methylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea,
3-methyl-l-[4-[4-(l-methylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-(l-methylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea,
3-(2-dimethylaminoethyl)-l-[4-[4-(l-methylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea,
3-(3-hydroxypropyl)-l-[4-[4-(l-methylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea, 3 -cyclopropyl- 1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropyl)-6-morpholm-4-ylpyrimidin-2- yl]phenyl]urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropyl)-6-morpholm-4-ylpyrimidin-2-yl]phenyl]-3 - methylurea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3 - ethylurea,
3 -cyclobutyl- 1 - [4-[4-( 1 -cyclopropylsulfonylcyclopropyl)-6-morpholm-4-ylpyrimidin-2- yl]phenyl]urea, 1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3 -(2- hydroxyethyl)urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3 -( 1 - hydroxy-2-methylpropan-2-yl)urea, 1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3 -(2- dimethylaminoethyl)urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3 - propylurea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3 -(3 - hydroxypropyl)urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3 -( 1 - methylpyrazol-4-yl)urea,
3 -cyclopropyl- 1 - [4- [4-( 1 -cyclopropylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea, l-[4-[4-(l-cyclopropylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3- methylurea, l-[4-[4-(l-cyclopropylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3-(2- hydroxyethyl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3-(l- hydroxy-2-methylpropan-2-yl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3-(2- dimethylaminoethyl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3-(3- hydroxypropyl)urea, 3 -cyclopropyl- 1 - [4- [4-( 1 -cyclopropylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea, l-[4-[4-(l-cyclopropylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3- methylurea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl] -3 -(2- hydroxyethyl)urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl] -3 -( 1 - hydroxy-2-methylpropan-2-yl)urea, 1 - [4- [4-( 1 -cyclopropylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl] -3 -(2- dimethylaminoethyl)urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl] -3 -(3 - hydroxypropyl)urea, 3 -cyclopropyl- l-[5-[4-(l -cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]pyridin-2-yl]urea,
1 - [5 - [4-( 1 -cyclopropylsulfonylcyclopropyl)-6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]pyridin-2-yl] -3 -methylurea,
1 - [5 - [4-( 1 -cyclopropylsulfonylcyclopropyl)-6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]pyridin-2-yl]-3-(2-dimethylaminoethyl)urea,
1 - [5 - [4-( 1 -cyclopropylsulfonylcyclopropyl)-6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]pyridin-2-yl] -3 -(2-hydroxyethyl)urea,
1 - [5 - [4-( 1 -cyclopropylsulfonylcyclopropyl)-6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]pyridin-2-yl] -3 -( 1 -methylpyrazol-4-yl)urea, 3 -cyclopropyl- 1 - [5 - [4-[ 1 -(4-fluorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]pyrimidin-2-yl]urea, l-[5-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]pyrimidin-2-yl]-3-methylurea, l-[5-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]pyrimidin-2-yl] -3 -(2-hydroxyethyl)urea, l-[5-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]pyrimidin-2-yl]-3-(l-methylpyrazol-4-yl)urea,
3 -cyclopropyl- 1 - [5 - [4-[ 1 -(4-fluorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]pyridin-2-yl]urea, l-[5-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]pyridin-2-yl] -3 -methylurea,
3-(2-dimethylaminoethyl)-l-[5-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2-yl]urea, l-[5-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]pyridin-2-yl]-3-(2-hydroxyethyl)urea, l-[5-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]pyridin-2-yl]-3-(l-methylpyrazol-4-yl)urea, 3 -cyclopropyl- 1 -[5 - [4- [(3 S)-3 -methylmorpholin-4-yl]-6-( 1 - methylsulfonylcyclopentyl)pyrimidin-2-yl]pyridin-2-yl]urea,
3 -methyl- 1 - [5 - [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfbnylcyclopentyl)pyrimidin-2- yl]pyridin-2-yl]urea, 3-(2-dimethylaminoethyl)-l-[5-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopentyl)pyrimidin-2-yl]pyridin-2-yl]urea,
3-(2-hydroxyethyl)-l-[5-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopentyl)pyrimidin-2-yl]pyridin-2-yl]urea,
1 - [5 - [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopentyl)pyrimidin-2- yl]pyridin-2-yl]-3-(l -methylpyrazol-4-yl)urea,
3 -cyclopropyl- 1 -[5 - [4- [(3 S)-3 -methylmorpholin-4-yl]-6-( 1 - methylsulfonylcyclopentyl)pyrimidin-2-yl]pyrimidin-2-yl]urea,
3 -methyl- 1 - [5 - [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopentyl)pyrimidin-2- yl]pyrimidin-2-yl]urea, 3-(2-hydroxyethyl)-l-[5-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopentyl)pyrimidin-2-yl]pyrimidin-2-yl]urea,
1 - [5 - [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopentyl)pyrimidin-2- yl]pyrimidin-2-yl]-3-(l-methylpyrazol-4-yl)urea,
3 -cyclopropyl- l-[5-[4-(l -cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]pyrimidin-2-yl]urea,
1 - [5 - [4-( 1 -cyclopropylsulfonylcyclopropyl)-6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]pyrimidin-2-yl]-3-methylurea,
1 - [5 - [4-( 1 -cyclopropylsulfonylcyclopropyl)-6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]pyrimidin-2-yl] -3 -(2-hydroxyethyl)urea, 1 - [5 - [4-( 1 -cyclopropylsulfonylcyclopropyl)-6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]pyrimidin-2-yl]-3-(l-methylpyrazol-4-yl)urea,
3-(2-hydroxyethyl)-l-[5-[4-[l-[4-(2-hydroxyethylamino)phenyl]sulfonylcyclopropyl]-6-[(3S)-
3-methylmorpholin-4-yl]pyrimidin-2-yl]pyrimidin-2-yl]urea,
3 -cyclopropyl- 1 -[4-[4-[ 1 -(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea,
3-ethyl-l-[4-[4-[l-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea,
3-cyclobutyl-l-[4-[4-[l-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, 3-(2-hydroxyethyl)-l-[4-[4-[l-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l,2,4-thiadiazol-5-yl)urea, l-[4-[4-[l-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l -methylpyrazol-4-yl)urea,
3-[4-[4-[l-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]- 1 -propylurea, l-[4-[4-[l-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, 3-(2-cyanoethyl)-l-[4-[4-[l-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(lH-imidazol-2-ylmethyl)urea, l-[4-[4-[l-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[l-(hydroxymethyl)cyclopropyl]urea, l-[4-[4-[l-(5-fluoropyridin-3-yl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea,
3-ethyl-l-[4-[4-[l-(5-fluoropyridin-3-yl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(5-fluoropyridin-3-yl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3 -cyclopropyl- 1 - [4- [4- [ 1 -(5 -fluoropyridin-3 -yl)sulfonylcyclopropyl] -6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-(l-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea, l-[4-[4-(l-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclobutylurea, l-[4-[4-(l-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-pyridin-2-ylurea, l-[4-[4-(l-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-methylpropyl)urea, l-[4-[4-(l-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-propan-2-ylurea, l-[4-[4-(l-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-ethylurea, l-[4-[4-(l-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-dimethylaminoethyl)urea, l-[4-[4-(l-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-(l-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-propylurea, l-[4-[4-(l-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea, l-[4-[4-(l-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea, l-[4-[4-(l-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l -hydroxy-2-methylpropan-2-yl)urea, l-[4-[4-(l-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, l-[4-[4-(l-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, 3 -cyclopropyl- 1 -[4- [4- [ 1 -(3 ,5 -difluoropheny^sulfonylcyclopropyl] -6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3 -cyclobutyl- 1 - [4- [4-[ 1 -(3 ,5 -difluoropheny^sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-pyridin-2-ylurea, l-[4-[4-[l-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-methylpropyl)urea, l-[4-[4-[l-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-propan-2-ylurea, l-[4-[4-[l-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-ethylurea, 5 l-[4-[4-[l-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-dimethylaminoethyl)urea, l-[4-[4-[l-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea, l-[4-[4-[l-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- i o yl]pyrimidin-2-yl]phenyl] -3 -propylurea, l-[4-[4-[l-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-methylurea, l-[4-[4-[l-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea, is l-[4-[4-[l-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(l-hydroxy-2-methylpropan-2-yl)urea, l-[4-[4-[l-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(3 -hydroxypropyl)urea, l-[4-[4-[l-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- 20 yl]pyrimidin-2-yl]phenyl]-3-(l -methylpyrazol-4-yl)urea,
3-cyclopropyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(4-methylsulfonylpiperidin-4- yl)pyrimidin-2-yl]phenyl]urea,
3 -methyl- 1 - [4- [4-[(3 S)-3 -methylmorpholin-4-yl] -6-(4-methylsulfonylpiperidin-4-yl)pyrimidin-
2-yl]phenyl]urea, 25 3-(2-dimethylaminoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(4- methylsulfonylpiperidin-4-yl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(4-methylsulfonylpiperidin-4- yl)pyrimidin-2-yl]phenyl]urea,
1- [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-(4-methylsulfonylpiperidin-4-yl)pyrimidin-2- 30 yl]phenyl]-3-(l -methylpyrazol-4-yl)urea,
3-cyclopropyl-l-[4-[4-(4-cyclopropylsulfonylpiperidin-4-yl)-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-(4-cyclopropylsulfonylpiperidin-4-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea, l-[4-[4-(4-cyclopropylsulfonylpiperidin-4-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, 5 l-[4-[4-(4-cyclopropylsulfonylpiperidin-4-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-[l-Benzyl-4-(3,5-difluorophenyl)sulfonylpiperidin-4-yl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-cyclopropylurea,
3-cyclopropyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(4-methylsulfonyloxan-4- i o yl)pyrimidin-2-yl]phenyl]urea,
3 -methyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-(4-methylsulfonyloxan-4-yl)pyrimidin-2- yl]phenyl]urea,
3-(2-dimethylaminoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(4-methylsulfonyloxan-4- yl)pyrimidin-2-yl]phenyl]urea, is 3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(4-methylsulfonyloxan-4- yl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(4-methylsulfonyloxan-4-yl)pyrimidin-2-yl]phenyl]-
3 -( 1 -methylpyrazol-4-yl)urea,
3-cyclopropyl-l-[4-[4-(4-cyclopropylsulfonyloxan-4-yl)-6-[(3S)-3-methylmorpholin-4- 20 yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-(4-cyclopropylsulfonyloxan-4-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea, l-[4-[4-(4-cyclopropylsulfonyloxan-4-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-dimethylaminoethyl)urea, 25 l-[4-[4-(4-cyclopropylsulfonyloxan-4-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-(4-cyclopropylsulfonyloxan-4-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-[4-(4-chlorophenyl)sulfonyloxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- 30 yl]phenyl]-3-methylurea, l-[4-[4-[4-(4-chlorophenyl)sulfonyloxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-dimethylaminoethyl)urea, l-[4-[4-[4-(4-chlorophenyl)sulfonyloxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[4-(4-chlorophenyl)sulfonyloxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-[4-(4-chlorophenyl)sulfonyloxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea,
3 -cyclopropyl- 1 -[4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6- [ 1 - [(4-methyl- 1 ,3 -thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3 -cyclobutyl- 1 - [4- [4-[(3 S)-3 -methylmorpholin-4-yl] -6- [ 1 - [(4-methyl- 1 ,3 -thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl] cyclopropyl]pyrimidin-2-yl]phenyl] -3 -pyridin-2-ylurea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]-3-(2-methylpropyl)urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]-3-propan-2-ylurea, l-ethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-dimethylaminoethyl)- 1 -[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[ 1 -[(4-methyl- 1 ,3-thiazol- 2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]- 1 -propylurea, 3 -methyl- 1 - [4- [4-[(3 S)-3 -methylmorpholin-4-yl] -6- [ 1 -[(4-methyl- 1 ,3 -thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl] cyclopropyl]pyrimidin-2-yl]phenyl] -3 - [4-(trifluoromethyl)phenyl]urea,
3-(l -hydroxy-2-methylpropan-2-yl)- 1 -[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[ 1 -[(4-methyl- l,3-thiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxypropyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea, l.[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl] cyclopropyl]pyrimidin-2-yl]phenyl] -3 -( 1 -methylpyrazol-4-yl)urea, l-[4-[4-(l-cyclohexylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea, 3 -cyclobutyl- 1 - [4-[4-( 1 -cyclohexylsulfonylcyclopropy^-ό- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-(l-cyclohexylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]- 1 -ethylurea, l-[4-[4-(l-cyclohexylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-dimethylaminoethyl)urea, l-[4-[4-(l-cyclohexylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-(l-cyclohexylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea, l-[4-[4-(l-cyclohexylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-hydroxy-2-methylpropan-2-yl)urea, l-[4-[4-(l-cyclohexylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, l-[4-[4-(l-cyclohexylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l -methylpyrazol-4-yl)urea,
1 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea,
1 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclobutylurea, l-[4-[4-[l -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-pyridin-2-ylurea,
1 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-methylpropyl)urea,
1 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-propan-2-ylurea,
1 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea, 3 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]- 1 -ethylurea,
1 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-dimethylaminoethyl)urea, 5 1 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea,
3 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]- 1 -propylurea,
1 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- i o yljphenyl] -3 -[4-(trifluoromethyl)phenyl]urea,
1 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-hydroxy-2-methylpropan-2-yl)urea,
1 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, is 1 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea,
3 -cyclopropyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3 -cyclobutyl- 1 - [4-[4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-2- 20 ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-pyridin-2-ylurea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(2-methylpropyl)urea, 25 1- [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-(l-pyridin-2 -ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-propan-2-ylurea,
3 -methyl- 1 - [4- [4-[(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-dimethylaminoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- 30 ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, 3 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]- 1 -propylurea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea, 3-(l-hydroxy-2-methylpropan-2-yl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3 -(3 -hydroxypropyl)-l- [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-(l-pyridin-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea
[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]urea,
3 -cyclopropyl- 1 - [4- [4- [4-(3 ,5-difluorophenyl)sulfonylpiperidin-4-yl] -6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-propan-2-ylurea,
3 -cyclopropyl- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea,
3-cyclobutyl- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-pyridin-2-ylurea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-(2-methylpropyl)urea, l-ethyl-3-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin- 2-yl]phenyl]-3-methylurea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea, 3-(3-hydroxypropyl)- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] -3 -( 1 -methylpyrazol-4-yl)urea, 3 - [4- [4- [ 1 -(3 -hydroxypropylsulfonyl)cyclopropyl]-6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] - 1 -propylurea,
3-(2-dimethylaminoethyl)- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea
3-(l -hydroxy-2-methylpropan-2-yl)- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclopropyl]-6- [(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea
N,N-dimethyl-l-[2-[4-(methylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4- yl] cyclopropane- 1-carboxamide
3 -methyl- 1 - [4- [4-[ 1 - [(3 S)-3 -methylmorpholine-4-carbonyl] cyclopropyl] -6-morpholin-4- ylpyrimidin-2-yl]phenyl]urea N-cyclopropyl-l-[2-[4-(methylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4- yl] cyclopropane- 1-carboxamide
N-cyclopropyl-N-methyl-l-[2-[4-(methylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-
4-yl] cyclopropane- 1 -carboxamide
3-methyl- 1 -[4-[4-[ 1 -(4-methylpiperazine-l -carbonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin- 2-yl]phenyl]urea l-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4-yl]-N,N- dimethylcyclopropane- 1 -carboxamide
3 -cyclopropyl- 1 -[4- [4- [ 1 - [(3 S)-3 -methylmorpholine-4-carbonyl] cyclopropyl] -6-morpholin-4- ylpyrimidin-2-yl]phenyl]urea N-cyclopropyl- 1 -[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4- yl] cyclopropane- 1-carboxamide
N-cyclopropyl- 1- [2- [4-(cyclopropylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4- yl]-N-methylcyclopropane- 1 -carboxamide
3 -cyclopropyl- 1 -[4-[4-[ 1 -(4-methylpiperazine- 1 -carbonyl)cyclopropyl]-6-morpholin-4- ylpyrimidin-2-yl]phenyl]urea l-[2-[4-(2-hydroxyethylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4-yl]-N,N- dimethylcyclopropane- 1 -carboxamide 3-(2-hydroxyethyl)-l-[4-[4-[l-[(3S)-3-methylmorpholine-4-carbonyl]cyclopropyl]-6- morpholin-4-ylpyrimidin-2-yl]phenyl]urea
N-cyclopropyl- 1 - [2- [4-(2-hydroxyethylcarbamoylamino)phenyl] -6-morpholin-4-ylpyrimidin-
4-yl] cyclopropane- 1 -carboxamide N-cyclopropyl- 1 -[2-[4-(2-hydroxyethylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-
4-yl]-N-methylcyclopropane- 1 -carboxamide,
3-(2-hydroxyethyl)- 1 -[4-[4-[I -(4-methylpiperazine- 1 -carbonyl)cyclopropyl]-6-morpholin-4- ylpyrimidin-2-yl]phenyl]urea,
3 -methyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]thiourea,
3-ethyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]thiourea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea, 3-(2-dimethylaminoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
3 -cyclopropyl- 1 -[4- [4- [(3 S)-3 -methylmorpholin-4-yl]-6-( 1 - methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
3 - [ 1 -(hydroxymethyl)cyclopropyl] - 1 - [4-[4- [ 1 -(3 -hydroxypropylsulfony^cyclopropyl] -6-[(3 S)- 3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-(l,2,4-thiadiazol-5-yl)urea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-(lH-imidazol-2-ylmethyl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea,
3 -cyclopropyl- 1 -[4- [4-( 1 -cyclopropylsulfonylcyclobuty^-ό- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclobuty^-ό- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea,
3-(2-cyanoethyl)-l-[4-[4-(l-cyclopropylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, 1 - [4- [4-( 1 -cyclopropylsulfonylcyclobuty^-ό- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclobutyl)-6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(lH-imidazol-2-ylmethyl)urea, 3 -cyclopropyl- 1 - [4- [4-( 1 -cyclopropylsulfonylcyclopentyl)-6-[(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-(l-cyclopropylsulfonylcyclopentyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea,
3-(2-cyanoethyl)-l-[4-[4-(l-cyclopropylsulfonylcyclopentyl)-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-(l-cyclopropylsulfonylcyclopentyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea,
3-(lH-imidazol-2-ylmethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3- thiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea, 3-(2-cyanoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea, l.[4.[4.[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]-3-(l,2,4-thiadiazol-5-yl)urea,
3-[l-(hydroxymethyl)cyclopropyl]-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl- l,3-thiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)-l-[4-[4-(l-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea, l-[4-[4-(l-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3-(l,2,4- thiadiazol-5-yl)urea, 3-(lH-imidazol-2-ylmethyl)-l-[4-[4-(l-methylsulfonylcyclopropyl)-6-morpholin-4- ylpyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)-l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]- 3 - [ 1 -(hydroxymethyl)cyclopropyl]urea, l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-
3 -( 1 H-imidazol-2-ylmethyl)urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[l-(hydroxymethyl)cyclopropyl]urea,
3-(2-cyanoethyl)-l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea, 5 l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l,2,4-thiadiazol-5-yl)urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(lH-imidazol-2-ylmethyl)urea,
3 -cyclopropyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-2- i o ylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea, is 3 -(3 -hydroxypropyl)-l- [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-(l-pyridin-2- ylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
3 -cyclopropyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-2- ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3 -methyl- 1 - [4- [4-[(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-2- 20 ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea, 25 l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-2-ylsulfonylcyclobutyl)pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea,
3 -(I H-imidazol-2-ylmethyl)-l- [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-(l-pyridin-2- ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3 -cyclopropyl- 1 -[4-[4-[ 1 -(4-fluorophenyl)sulfonylcyclopropyl]-6-morpholin-4-ylpyrimidin-2- 30 yl]phenyl]urea,
3-(2-cyanoethyl)-l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-morpholin-4-ylpyrimidin-
2-yl]phenyl]urea, 1 -[4-[4-[ 1 -(4-fluorophenyl)sulfonylcyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3-
(1 ,2,4-thiadiazol-5-yl)urea,
1 -ethyl-3-[4-[4-[ 1 -(4-fluorophenyl)sulfonylcyclopropyl]-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea, 3-[4-[4-[ 1 -(4-fluorophenyl)sulfonylcyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]phenyl]- 1 - methylurea,
3-[4-[4-[ 1 -(4-fluorophenyl)sulfonylcyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]phenyl]- 1 -(I - methylpyrazol-4-yl)urea,
3-(2-hydroxyethyl)-l-[4-[4-morpholin-4-yl-6-(l-pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]urea, l-(l-methylpyrazol-4-yl)-3-[4-[4-morpholin-4-yl-6-(l-pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, l-methyl-3-[4-[4-morpholin-4-yl-6-(l-pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]urea, l-ethyl-3-[4-[4-morpholin-4-yl-6-(l-pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]urea,
3 -cyclopropyl- 1 - [4- [4-morpholin-4-yl-6-( 1 -pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]urea,
3-(2-cyanoethyl)-l-[4-[4-morpholin-4-yl-6-(l-pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]urea,
3 -(3 -hydroxypropyl)- 1 - [4- [4-morpholin-4-yl-6-( 1 -pyridin^-ylsulfonylcyclopropy^pyrimidin-
2-yl]phenyl]urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfbnylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(l,3-thiazol-2-yl)urea, 3 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfbnylcyclopropyl)pyrimidin-2- yl]phenyl]- 1 -(5-methylpyrazin-2-yl)urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(l,3-oxazol-2-yl)urea,
3-(3-hydroxypropyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclobutylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3,3,3-trifluoro-2-hydroxypropyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-propan-2-ylurea,
3 - [4- [4-[ 1 -(benzenesulfonyl)cyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]- 1 -ethylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea,
3 - [4- [4-[ 1 -(benzenesulfonyl)cyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]- 1 -propylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-hydroxy-2-methylpropan-2-yl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-cyanoethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(lH-imidazol-2-ylmethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[l-(hydroxymethyl)cyclopropyl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(oxetan-3-yl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l,2,4-thiadiazol-5-yl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l -methylpyrazol-4-yl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopentyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopentyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopentyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopentyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-cyanoethyl)urea, l-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea, l-ethyl-3-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea,
3-cyclopropyl-l-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea,
3-cyclobutyl-l-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)-l-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3S)-3-methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea, 3-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]- 1 -propylurea,
3-(2-hydroxyethyl)-l-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l -methylpyrazol-4-yl)urea, l-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l,3-thiazol-2-yl)urea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-(l,3-thiazol-2-yl)urea, l-cyclopropyl-3-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl] - 1 -methylurea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-(l-methylcyclopropyl)urea,
3-(2,2-difluoroethyl)- 1 -[4-[4-[I -(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-tert-butyl-l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea,
3-cyano-l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea,
3-hydroxy-N-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]pyrrolidine- 1 -carboxamide, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] -3 -(2-methylsulfonylethyl)urea,
3 -( 1 , 1 -dioxothiolan-3 -yl)- 1 -[4- [4- [ 1 -(3 -hydroxypropylsulfonyl)cyclopropyl]-6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
2-[[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamoylamino]-N,N-dimethylacetamide,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(l,2,4-thiadiazol-5-yl)urea,
3 -(lH-imidazol-2-ylmethyl)-l- [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-(l-pyridin-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, 3-[l-(hydroxymethyl)cyclopropyl]-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3 -(I H-imidazol-2-ylmethyl)-l- [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-(l-pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3 - [ 1 -(hydroxymethyl)cyclopropyl] - 1 -[4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[4-(benzenesulfonyl)oxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea, 3-[4-[4-[4-(benzenesulfonyl)oxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]- 1 -ethylurea, l-[4-[4-[4-(benzenesulfonyl)oxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea, l-[4-[4-[4-(benzenesulfonyl)oxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea,
1 -[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3- cyclopropylurea,
3-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]phenyl]- 1 - ethylurea,
1 -[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3-(2- hydroxyethyl)urea,
3-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]phenyl]- 1 - methylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3-(3- hydroxypropyl)urea,
1 -[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3-(2- cyanoethyl)urea,
1 -[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3-(l ,2,4- thiadiazol-5-yl)urea,
3-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]phenyl]- 1 -(I - methylpyrazol-4-yl)urea,
3 -cyclopropyl- 1 -[4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6- [ 1 - [(4-methyl- 1 ,3 -thiazol-2- yl)sulfonyl]cyclopentyl]pyrimidin-2-yl]phenyl]urea, 3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopentyl]pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopentyl]pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxypropyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopentyl]pyrimidin-2-yl]phenyl]urea,
N-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-hydroxypyrrolidine- 1 -carboxamide, 2-[[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamoylamino]acetic acid,
2-[[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamoylamino]-N,N-dimethylacetamide, 3 - [4- [4-[ 1 -(benzenesulfonyl)cyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]- 1 -cyclopropyl- 1 -methylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-fluoroethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-cyanoethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(lH-imidazol-2-ylmethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3 -( 1 -methylpyrazol-3 -yl)urea, 3 - [4- [4-[ 1 -(benzenesulfonyl)cyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-l-(5-methyl-l,2-oxazol-3-yl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2,2-difluoroethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l ,3-oxazol-2-yl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l,2-oxazol-3-yl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2,2,2-trifluoroethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylimidazol-4-yl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2S)-l-hydroxypropan-2-yl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2R)-l-hydroxypropan-2-yl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-chloroethyl)urea, l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-
3 -(2-fluoroethyl)urea,
3-(2,2-difluoroethyl)-l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylthiourea,
3-cyclopropyl-l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]thiourea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)thiourea,
3-cyclobutyl- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]thiourea,
3-(2-cyanoethyl)- 1 -[4-[4-[I -(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea, 3-(3-hydroxypropyl)-l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] -3 -methylthiourea,
3-cyclopropyl- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin- 4-yl]pyrimidin-2-yl]phenyl]thiourea,
3-(2-hydroxyethyl)-l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] -3 -( 1 -methylpyrazol-4-yl)thiourea, l-ethyl-3-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]thiourea,
3 - [4- [4- [ 1 -(3 -hydroxypropylsulfonyl)cyclopropyl]-6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] - 1 -propylthiourea,
3-(3-hydroxypropyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-propylthiourea, 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -methylsulfbnylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)thiourea,
3 -methyl- 1 - [4- [4-[(3 S)-3 -methylmorpholin-4-yl] -6- [ 1 -[(4-methyl- 1 ,3 -thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]thiourea, 3 -cyclopropyl- 1 -[4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6- [ 1 - [(4-methyl- 1 ,3 -thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]thiourea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]thiourea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylthiourea,
3 -cyclopropyl- 1 -[4-[4-[ 1 -(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]thiourea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)thiourea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylthiourea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)thiourea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)thiourea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-cyanoethyl)thiourea,
3 - [4- [4-[ 1 -(benzenesulfonyl)cyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]- 1 -ethylthiourea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)thiourea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylthiourea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(lH-imidazol-2-ylmethyl)thiourea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea, 3 -cyclopropyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
3 -methyl- 1 - [4- [4-[(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-hydroxy-2-methylpropan-2-yl)thiourea,
3 -cyclopropyl- 1 -[4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6- [ 1 -[(5 -methyl- 1 ,3 ,4-thiadiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-methyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(5-methyl-l,3,4-thiadiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3 -cyclopropyl- 1 - [4- [4-[(3 S)-3 -methylmorpholin-4-yl] -6-[ 1 -( 1 ,3 -thiazol-2- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-methyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea, 1 - [4- [4-[ 1 -( 1 H-imidazol-2-ylsulfonyl)cyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] -3 -methylurea,
3 -cyclopropyl- l-[4-[4-[l-(l H-imidazol-2-ylsulfonyl)cyclopropyl] -6- [(3 S)-3 -methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
3 -cyclopropyl- 1 -[4- [4- [ 1 - [(4-methyl- 1 ,3 -thiazol-2-yl)sulfonyl] cyclopropyl] -6-morpholin-4- ylpyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[l -[(4-methyl- l,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-morpholin-
4-ylpyrimidin-2-yl]phenyl]urea, 3-(l -methylpyrazol-4-yl)- 1 -[4-[4-[ 1 -[(4-methyl- 1 ,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6- morpholin-4-ylpyrimidin-2-yl]phenyl]urea,
3-methyl- 1 -[4-[4-[ 1 -[(4-methyl- 1 ,3 -thiazol-2-yl)sulfonyl] cyclopropyl] -6-morpholin-4- ylpyrimidin-2-yl]phenyl]urea, l-ethyl-3-[4-[4-[l-[(4-methyl-l,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-morpholin-4- ylpyrimidin-2-yl]phenyl]urea,
3-cyclobutyl-l -[4-[4-[ 1 -[(4-methyl- 1 ,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-morpholin-4- ylpyrimidin-2-yl]phenyl]urea, 3-(2-cyanoethyl)-l-[4-[4-[l-[(4-methyl-l,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-morpholin-4- ylpyrimidin-2-yl]phenyl]urea,
3-[4-[4-[ 1 -[(4-methyl- 1 ,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-morpholin-4-ylpyrimidin-2- yl]phenyl]- 1 -propylurea, 1 -[4-[4-[ 1 -[(4-methyl- 1 ,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-morpholin-4-ylpyrimidin-2- yl]phenyl]-3-propan-2-ylurea,
3-cyclopropyl- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin- 2-yl]phenyl]-3-methylurea,
3-(2-hydroxyethyl)-l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)- 1 -[4-[4-[I -(3-hydroxypropylsulfbnyl)cyclobutyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] -3 -( 1 -methylpyrazol-4-yl)urea,
1 - [4- [4-[ 1 -(3 -hydroxypropylsulfonyl)cyclobutyl]-6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-(lH-imidazol-2-ylmethyl)urea,
3-cyclopropyl- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclopentyl]-6-[(3S)-3-methylmorpholin- 4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopentyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)- 1 -[4-[4-[I -(3-hydroxypropylsulfbnyl)cyclopentyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, 3-(3-hydroxypropyl)- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfbnyl)cyclopentyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-ethyl-3-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin- 2-yl]phenyl]-l -propylurea,
3-(3-hydroxypropyl)-l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-(l,2-oxazol-3-yl)urea,
3-(2-fluoroethyl)- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, 3-(2,2-difluoroethyl)-l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-(l-hydroxy-2-methylpropan-2-yl)-l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-
3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-[(2S)- 1 -hydroxypropan-2-yl]- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-[(2R)- 1 -hydroxypropan-2-yl]- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-(l,2,4-thiadiazol-5-yl)urea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-(l,3-thiazol-2-yl)urea,
N-[2-[l-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4- y l]pyrimidin-4-y 1] cy clopropy 1] sulfony lethy 1] acetamide ,
N-[2-[l-[2-[4-(ethylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4- y 1] cy clopropy 1] sulfony lethy 1] acetamide ,
2-[l-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4- y 1] cy clopropy 1] sulfony lacetamide ,
2-[l-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4- y 1] cy clopropy 1] sulfony 1-N-methy lacetamide , 3-cyclopropyl- 1 -[4-[4-[ 1 -(2-hydroxyethylsulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea,
1 -[4-[4-[ 1 -(2-hydroxyethylsulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3- methylurea,
3 -ethyl- 1 -[4-[4-[ 1 -(2-hydroxyethylsulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea, l-[4-[4-[l-(5-fiuoropyridin-2-yl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-methylurea, 3 -cyclopropyl- 1 - [4- [4- [ 1 -(5 -fluoropyridin-2-yl)sulfbnylcyclopropyl] -6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
N,N-dimethyl-6-[l-[2-[4-(methylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-4-yl]cyclopropyl]sulfonylpyridine-3-carboxamide, 6-[l-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4- yφyclopropy^sulfonyl-N^-dimethylpyridine-S-carboxamide,
N,N-dimethyl-3 - [ 1 -[2- [4-(methylcarbamoylamino)phenyl]-6- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-4-yl]cyclopropyl]sulfonylpyridine-2-carboxamide,
3-[l-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4- yl]cyclopropyl]sulfonyl-N,N-dimethylpyridine-2-carboxamide, l-[4-[4-[l-(2-methoxyethylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] -3 -methylurea,
3 -cyclopropyl- 1 - [2-fluoro-4- [4- [(3 S)-3 -methylmorpholin-4-yl]-6-( 1 - methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, l-[2-fluoro-4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-methylurea,
3 -ethyl- 1 - [2-fluoro-4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 - methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, l-[2-fluoro-4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[2-fluoro-4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-[l-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea, 3 -cyclopropyl- 1 -[4-[4-[ 1 -(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea,
3-(2-fluoroethyl)-l-[4-[4-[l-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin- 4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)-l-[4-[4-[l-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, 1 -ethyl-3 - [4- [4-[ 1 -(3 -fluoropheny^sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, 3-methyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(2- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3 -cyclopropyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-[ 1 -(2- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(2- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-fluoroethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(2- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(2- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea, l-ethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(2- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6- [ 1 -(2-methylphenyl)sulfonylcyclopropyl]pyrimidin-
2-yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-[l-(l,3-dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3 -cyclopropyl- l-[4-[4-[l-(l ,3 -dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(l,3-dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea, l-[4-[4-[l-(l,3-dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
3-(2,2-difluoroethyl)-l-[4-[4-[l-(l,3-dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-[l-(l,3-dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]- 1 -ethylurea, l-[4-[4-[l-(l,3-dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, 3 -cyclopropyl- 1 - [4- [4-morpholin-4-yl-6-( 1 -pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]urea,
3-methyl-l-[4-[4-morpholin-4-yl-6-(l-pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]urea, 5 3-ethyl-l-[4-[4-morpholin-4-yl-6-(l-pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-morpholin-4-yl-6-(l-pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]urea,
3 -(I -methylpyrazol-4-yl)- 1 -[4-[4-morpholin-4-yl-6-(l -pyridin-2- i o ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(2-fluoro-4-methylaminophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl] -3 -methylurea,
3 -cyclopropyl- 1 -[4- [4- [ 1 -(2,4-difluorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, is l-[4-[4-[l-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea, l-[4-[4-[l-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
3-(2,2-difluoroethyl)-l-[4-[4-[l-(2,4-difluorophenyl)sulfonylcyclop,ropyl]-6-[(3S)-3- 20 methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-[l-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]- 1 -ethylurea, l-[4-[4-[l-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, 25 l-[4-[4-[l-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-[(l-hydroxycyclopropyl)methyl]urea, l-[4-[4-[l-(2-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea,
3 -cyclopropyl- 1 -[4-[4-[ 1 -(2-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- 30 yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(2-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, 3-(2-fluoroethyl)-l-[4-[4-[l-(2-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea,
3 -(2,2-difluoroethyl)- 1 -[4- [4- [ 1 -(2-fluorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, 1 -ethyl-3 -[4-[4-[I -(2-fluorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(2-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-[l-(2-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(l-hydroxycyclopropyl)methyl]urea, l-[4-[4-[l-[(3,5-dimethyl-l,2-oxazol-4-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3 -cyclopropyl- 1 - [4- [4-[ 1 - [(3 ,5 -dimethyl- 1 ,2-oxazol-4-yl)sulfonyl] cyclopropyl] -6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-[(3,5-dimethyl-l,2-oxazol-4-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea, l-[4-[4-[l-[(3,5-dimethyl-l,2-oxazol-4-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
3-(2,2-difluoroethyl)-l-[4-[4-[l-[(3,5-dimethyl-l,2-oxazol-4-yl)sulfonyl]cyclopropyl]-6-[(3S)- 3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-[(3,5-dimethyl-l,2-oxazol-4-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -[( 1 -hydroxy cyclopropyl)methyl]urea,
3-[4-[4-[l-[(3,5-dimethyl-l,2-oxazol-4-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]- 1 -ethylurea, l-[4-[4-[l-[(3,5-dimethyl-l,2-oxazol-4-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(l-methylpyrazol-43-yl)urea, l-[4-[4-[l-(2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3 -cyclopropyl- 1 -[4- [4- [ 1 -(2,5 -difluorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea, l-[4-[4-[l-(2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
3-(2,2-difluoroethyl)-l-[4-[4-[l-(2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, 3-[4-[4-[l-(2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]- 1 -ethylurea, l-[4-[4-[l-(2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3 -( 1 -methylpyrazol-43 -yl)urea l-[4-[4-[l-(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-cyclopropyl-l-[4-[4-[l-(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea, 3-(2-fluoroethyl)-l-[4-[4-[l-(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)-l-[4-[4-[l-(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-ethyl-3-[4-[4-[l-(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin- 4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3 -( 1 -methylpyrazol-43 -yl)urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]thiourea, 3 -( 1 H-imidazol-2-ylmethyl)- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl]-6-( 1 - methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]thiourea,
3-[(2S)- 1 -hydroxypropan-2-yl]- 1 -[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l - methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]thiourea,
3-[(2R)-l-hydroxypropan-2-yl]-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]thiourea,
3-(3-hydroxypropyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]thiourea, 3-(lH-imidazol-2-ylmethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]thiourea,
3 -cyclopropyl- 1 - [4- [4- [ 1 -[4-(difluoromethoxy)phenyl] sulfonylcyclopropyl] -6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-[4-(difluoromethoxy)phenyl]sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3 - [4- [4- [ 1 -[4-(difluoromethoxy)phenyl]sulfonylcyclopropyl]-6- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]- 1 -ethylurea, l-[4-[4-[l-[4-(difluoromethoxy)phenyl]sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-[4-(difluoromethoxy)phenyl]sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-[l-[4-(difluoromethoxy)phenyl]sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea, 3-(2,2-difluoroethyl)-l-[4-[4-[l-[4-(difluoromethoxy)phenyl]sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-[4-[4-[l-(3,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]- 1 -ethylurea,
3 -cyclopropyl- 1 -[4- [4- [ 1 -(3 ,4-difluorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea, l-[4-[4-[l-(3,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-[l-(3,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
3-(2,2-difluoroethyl)-l-[4-[4-[l-(3,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-[3-fluoro-4-(2-hydroxyethylamino)phenyl]sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-hydroxy-2-methylpropan-2-yl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2S)-l-hydroxypropan-2-yl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2R)-l-hydroxypropan-2-yl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-fluoroethyl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-fluoroethyl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2,2-difluoroethyl)urea, 1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropy^-ό- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(lH-imidazol-2-ylmethyl)urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclobuty^-ό- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-hydroxy-2-methylpropan-2-yl)urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclobuty^-ό- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2S)-l-hydroxypropan-2-yl]urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclobuty^-ό- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2R)-l-hydroxypropan-2-yl]urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclobuty^-ό- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, 3-(2-fluoroethyl)-l-[4-[4-[(3S)-3-methylmoipholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-[(2S)-l-hydroxypropan-2-yl]-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3- thiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-[(2R)-l-hydroxypropan-2-yl]-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3- thiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea, 3-(2-fluoroethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(l,2-oxazol-3-yl)urea,
1 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2,2-difluoroethyl)urea,
1 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l ,2-oxazol-3-yl)urea,
3-(2-fluoroethyl)-l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-(l,2-oxazol-3-yl)urea, 1 -[4-[4-[ 1 -[ 1 -(difluoromethyl)pyrazol-4-yl]sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(lH-imidazol-2-ylmethyl)urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-hydroxy-2-methylpropan-2-yl)urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2S)-l-hydroxypropan-2-yl]urea, l-[4-[4-[l-(4-fluorophenyl)sulfonylcyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2R)-l-hydroxypropan-2-yl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxypropyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea, 3-(lH-imidazol-2-ylmethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]thiourea, 3 -cyclopropyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-[ 1 -(4- methylphenyl)sulfonylcyclobutyl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(4-methylphenyl)sulfonylcyclobutyl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea,
1 -[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-ethylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-ethylurea,
1 -[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[3-(hydroxymethyl)morpholin-4-yl]pyrimidin-2- yl]phenyl]-3-ethylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-ethylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-ethylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-fluoroethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2,2-difluoroethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l -methylpyrazol-4-yl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2S)-l-hydroxypropan-2-yl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2R)-l-hydroxypropan-2-yl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(l-hydroxycyclopropyl)methyl]urea,
3-Cyclopropyl- 1 -[4-[4-[ 1 -[ 1 -(difluoromethyl)-3,5-dimethylpyrazol-4-yl]sulfonylcyclopropyl]-
6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1 -[4-[4-[ 1 -[ 1 -(difluoromethyl)-3,5-dimethylpyrazol-4-yl]sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3 - [4- [4- [ 1 -[ 1 -(difluoromethyl)-3 ,5 -dimethylpyrazol-4-yl] sulfonylcyclopropyl] -6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] - 1 -ethylurea,
1 -[4-[4-[ 1 -[ 1 -(difluoromethyl)-3, 5 -dimethylpyrazol-4-yl] sulfonylcyclopropyl] -6- [(3 S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea, 3-(2,2-difluoroethyl)-l-[4-[4-[l-[l-(difluoromethyl)-3,5-dimethylpyrazol-4- yl]sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1 -[4-[4-[ 1 -[ 1 -(difluoromethyl)-3, 5 -dimethylpyrazol-4-yl] sulfonylcyclopropyl] -6- [(3 S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
1 -[4-[4-[ 1 -[ 1 -(difluoromethyl)-3, 5 -dimethylpyrazol-4-yl] sulfonylcyclopropyl] -6- [(3 S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(l-methylpyrazol-4-yl)urea,
1 - [4- [4-[ 1 -(2-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea,
1 - [4- [4-[ 1 -(2-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea, 3-[4-[4-[l -(2-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]- 1 -ethylurea,
1 - [4- [4-[ 1 -(2-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea,
1 - [4- [4-[ 1 -(2-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2,2-difluoroethyl)urea,
1 - [4- [4-[ 1 -(2-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-fluoroethyl)urea, 1 - [4- [4-[ 1 -(2-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-[l-(4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea, l-[4-[4-[l-(4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea,
3-[4-[4-[l-(4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]- 1 -ethylurea, l-[4-[4-[l-(4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2,2-difluoroethyl)urea, l-[4-[4-[l-(4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-fluoroethyl)urea, l-[4-[4-[l-(4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea,
3 -cyclopropyl- 1 - [4- [4-[ 1 - [(2,4-dimethyl- 1 ,3 -thiazol-5 -yl)sulfonyl]cyclopropyl]-6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-[(2,4-dimethyl-l,3-thiazol-5-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-[4-[4-[l-[(2,4-dimethyl-l,3-thiazol-5-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]- 1 -ethylurea, l-[4-[4-[l-[(2,4-dimethyl-l,3-thiazol-5-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea, 3-(2,2-difluoroethyl)-l-[4-[4-[l-[(2,4-dimethyl-l,3-thiazol-5-yl)sulfonyl]cyclopropyl]-6-[(3S)-
3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-[(2,4-dimethyl-l,3-thiazol-5-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea, l-[4-[4-[l-[(2,4-dimethyl-l,3-thiazol-5-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(l -methylpyrazol-4-yl)urea,
3 -cyclopropyl- 1 -[4-[4-[I -(3-hydroxy-3-methylbutyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3-hydroxy-3-methylbutyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-(2-hydroxyethyl)-l-[4-[4-[l-(3-hydroxy-3-methylbutyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, 3-(2,2-difluoroethyl)- 1 -[4-[4-[I -(3-hydroxy-3-methylbutyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2-fluoroethyl)-l-[4-[4-[l-(3-hydroxy-3-methylbutyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3-hydroxy-3-methylbutyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(l -methylpyrazol-4-yl)urea,
1 -ethyl-3 - [4- [4- [ 1 -(3 -hydroxy-3 -methylbuty^sulfonylcyclopropyl] -6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)-l-[4-[4-[l-[(4,5-dimethyl-l,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-[(3S)-
3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-[(4,5-dimethyl-l,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
3 -cyclopropyl- 1 - [4- [4-[ 1 - [(4,5 -dimethyl- 1 ,3 -thiazol-2-yl)sulfonyl]cyclopropyl]-6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-[(4,5-dimethyl-l,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-[(4,5-dimethyl-l,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-[4-[4-[l-[(4,5-dimethyl-l,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]- 1 -ethylurea, l-[4-[4-[l-[(4,5-dimethyl-l,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-[l-(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-cyclopropyl-l-[4-[4-[l-(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea, 3-(2-fluoroethyl)-l-[4-[4-[l-(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)-l-[4-[4-[l-(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, 5 3-ethyl-l-[4-[4-[l-(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(l-methylpyrazol-4-yl)urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- i o ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3-[(2S)-l-hydroxypropan-2-yl]-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3-[(2R)-l-hydroxypropan-2-yl]-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea, is 3-(l-hydroxy-2-methylpropan-2-yl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3-(lH-imidazol-2-ylmethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-ethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]- 20 3-methylurea,
3 -cyclopropyl- 1 - [4- [4-[(3 S)-3 -ethylmorpholin-4-yl]-6-( 1 - methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-ethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]-
3 -(2-hydroxyethyl)urea, 25 l-[4-[4-[(3S)-3-ethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]-
3 -(2-fluoroethyl)urea,
3-(2,2-difluoroethyl)-l-[4-[4-[(3S)-3-ethylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-ethyl-l-[4-[4-[(3S)-3-ethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- 30 yl]phenyl]urea, l-[4-[4-[(3S)-3-ethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]-
3 -( 1 -methylpyrazol-4-yl)urea 3-chloro-4-[l-[2-[4-(methylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-4-yl]cyclopropyl]sulfonylbenzamide
3-chloro-4-[l-[2-[4-(ethylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-4-yl]cyclopropyl]sulfonylbenzamide 3-chloro-4-[l-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-4-yl]cyclopropyl]sulfonylbenzamide
3-chloro-4-[l-[2-[4-(2-fluoroethylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-4-yl]cyclopropyl]sulfonylbenzamide
3-chloro-4-[l-[2-[4-(2-hydroxyethylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-4-yl]cyclopropyl]sulfonylbenzamide l-[4-[4-[l-(2-chloro-4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -methylurea
3-[4-[4-[l-(2-chloro-4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] - 1 -ethylurea l-[4-[4-[l-(2-chloro-4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-cyclopropylurea l-[4-[4-[l-(2-chloro-4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2,2-difluoroethyl)urea l-[4-[4-[l-(2-chloro-4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea l-[4-[4-[l-(2-chloro-4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea l-[4-[4-[l-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -methylurea l-[4-[4-[l-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -ethylurea
3 -cyclopropyl- 1 -[4- [4- [ 1 -(2,6-difluorophenyl)sulfbnylcyclopropyl] -6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea l-[4-[4-[l-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea, 3-(2,2-difluoroethyl)-l-[4-[4-[l-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-(l-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-
(2-hydroxyethyl)urea, l-[4-[4-(l-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-
( 1 H-imidazol-2-ylmethyl)urea, l-[4-[4-(l-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3- (3-hydroxypropyl)urea, l-[4-[4-(l-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3- methylurea, l-[4-[4-(l-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-
( 1 -hydroxy-2-methylpropan-2-yl)urea, l-[4-[4-(l-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-
[(2S)- 1 -hydroxypropan-2-yl]urea, l-[4-[4-(l-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-
[(2R)- 1 -hydroxypropan-2-yl]urea, l-[4-[4-(l-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3- (3 -hydroxypropyl) thiourea, l-[4-[4-(l-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-
(2-hydroxyethyl)thiourea, l-[4-[4-(l-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-
( 1 H-imidazol-2-ylmethyl)thiourea, l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-
3 -(3 -hydroxypropyl)thiourea, l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-
3 -(2-hydroxyethyl)thiourea, l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]- 3-(lH-imidazol-2-ylmethyl)thiourea,
4-[6-[l-(benzenesulfonyl)cyclopropyl]-2-[4-(ethylcarbamoylamino)phenyl]pyrimidin-4- yl]morpholine-3-carboxamide, 4-[6-[l-(benzenesulfonyl)cyclopropyl]-2-[4-(ethylcarbamoylamino)phenyl]pyrimidin-4-yl]-
N,N-dimethylmorpholine-3-carboxamide,
3-cyclopropyl-l-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-methylurea, l-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-ethylurea, l-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(2-fluoroethyl)urea, l-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea,
3 -cyclopropyl- 1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropy^-ό- [(3 S ,5 S)-3 ,5 -dimethylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea, 1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropy^-ό- [(3 S ,5 S)-3 ,5 -dimethylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-(2,2-difluoroethyl)urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropy^-ό- [(3 S ,5 S)-3 ,5 -dimethylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] -3 -( 1 -methylpyrazol-4-yl)urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropyl)-6- [(3 S ,5 S)-3 ,5 -dimethylmorpholin-4-yl]pyrimidin- 2-yl]phenyl]-3-methylurea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropyl)-6- [(3 S ,5 S)-3 ,5 -dimethylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-ethylurea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropyl)-6- [(3 S ,5 S)-3 ,5 -dimethylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-(2-fluoroethyl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] -3 -(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-fluoroethyl)urea l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2,2-difluoroethyl)urea l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea
3-methyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(oxan-4- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea
1 -ethyl-3 - [4- [4-[(3 S)-3 -methylmorpholin-4-yl] -6-[ 1 -(oxan-4- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea
3 -cyclopropyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-[ 1 -(oxan-4- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(oxan-4- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6- [ 1 -(oxan-4-ylsulfbnyl)cyclopropyl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea
3-cyclobutyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(oxan-4- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea
3 -methyl- 1 - [4- [4-[(3 S)-3 -methylmorpholin-4-yl] -6- [ 1 -(oxolan-3 - ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea l-ethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(oxolan-3- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea
3 -cyclopropyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-[ 1 -(oxolan-3 - ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea 3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(oxolan-3- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6- [ 1 -(oxolan-3 -ylsulfonyl)cyclopropyl]pyrimidin-2- yl]phenyl]-3-(l-methylpyrazol-4-yl)urea,
1 - [4- [4- [ 1 -(3 -chloro-4-fluorophenyl)sulfonylcyclopropyl]-6- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-methylurea,
1 - [4- [4- [ 1 -(3 -chloro-4-fluorophenyl)sulfonylcyclopropyl]-6- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-cyclopropylurea, 1 - [4- [4- [ 1 -(3 -chloro-4-fluorophenyl)sulfonylcyclopropyl]-6- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea,
1 - [4- [4- [ 1 -(3 -chloro-4-fluorophenyl)sulfonylcyclopropyl]-6- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea, 1 - [4- [4- [ 1 -(3 -chloro-4-fluorophenyl)sulfonylcyclopropyl]-6- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2,2-difluoroethyl)urea,
3 - [4- [4- [ 1 -(3 -chloro-4-fluorophenyl)sulfonylcyclopropyl]-6- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]- 1 -ethylurea,
1 - [4- [4- [ 1 -(3 -chloro-4-fluorophenyl)sulfonylcyclopropyl]-6- [(3 S)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(l -methylpyrazol-4-yl)urea,
1 - [4- [4- [ 1 -(3 -chloro-4-methylaminophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl] -3 -methylurea, l-[4-[4-[l-[3-chloro-4-(2-hydroxyethylamino)phenyl]sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-[3-chloro-4-(2-fluoroethylamino)phenyl]sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea, l-[4-[4-[l-(3-chloro-4-ethylaminophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-ethylurea,
3-methyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(4- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3 -cyclopropyl- 1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6-[ 1 -(4- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(4- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea, 3-(2-fluoroethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(4- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(4- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea, l-ethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(4- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
1 - [4- [4- [(3 S)-3 -methylmorpholin-4-yl] -6- [ 1 -(4-methylphenyl)sulfonylcyclopropyl]pyrimidin-
2-yl]phenyl]-3-(l-methylpyrazol-4-yl)urea, l-[4-[4-[l-[3-(difluoromethoxy)propylsulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
3 -(2,2-difluoroethyl)- 1 - [4-[4- [ 1 - [3 -(difluoromethoxy)propylsulfonyl]cyclopropyl] -6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-[3-(difluoromethoxy)propylsulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyramidin-2-yl]phenyl]-3-ethylurea, l-[4-[4-[l-[3-(difluoromethoxy)propylsulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(l-methylpyrazol-4-yl)urea,
3 -cyclopropyl- 1 - [4- [4- [ 1 -[3 -(difluoromethoxy)propylsulfonyl] cyclopropyl]-6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3 -methyl- 1 - [4- [4-[ 1 -(2-methylaminoethylsulfonyl)cyclopropyl] -6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea,
3-(l -hydroxy-2-methylpropan-2-yl)- 1 -[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[ 1 -[(4-methyl- l,3-thiazol-2-yl)sulfonyl]cyclobutyl]pyrimidin-2-yl]phenyl]urea, 3-[(2S)-l-hydroxypropan-2-yl]-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3- thiazol-2-yl)sulfonyl]cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-(lH-imidazol-2-ylmethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3- thiazol-2-yl)sulfonyl]cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxypropyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-[(2R)-l-hydroxypropan-2-yl]-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3- thiazol-2-yl)sulfonyl]cyclobutyl]pyrimidin-2-yl]phenyl]urea, 3-(l-hydroxy-2-methylpropan-2-yl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-
2-ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-[(2S)-l-hydroxypropan-2-yl]-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-(lH-imidazol-2-ylmethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxypropyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea, 3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-[(2R)-l-hydroxypropan-2-yl]-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] -3 -methylthiourea,
3-cyclopropyl- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]thiourea,
1 - [4- [4- [ 1 -(3 -hydroxypropylsulfonyl)cyclobutyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin- 2-yl]phenyl]-3-(lH-imidazol-2-ylmethyl)thiourea,
3-(l-hydroxy-2-methylpropan-2-yl)-l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-
3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea, l-ethyl-3-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]thiourea, 3-(2-hydroxyethyl)-l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea,
3-(2,2-difluoroethyl)-l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea,
3 - [4- [4- [ 1 -(3 -hydroxypropylsulfonyl)cyclobutyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin- 2-yl]phenyl] - 1 -propylthiourea,
3-(3-hydroxypropyl)-l-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea, and
3-(2,2-difluoroethyl)- 1 -[4-[4-[I -(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea, or a pharmaceutically acceptable salt thereof.
In another aspect of the invention there is provided a compound, or a combination of compounds, selected from any one of l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-
3 -methyl-urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, 3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
3 -cyclopropyl- 1 - [4- [4-( 1 -methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea, 1 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)thiourea,
3 -cyclopropyl- 1 -[4-[4-[ 1 -(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]thiourea,
3 -cyclopropyl- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]thiourea, l-ethyl-3-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]thiourea, l-[4-[4-(l-cyclopropylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylthiourea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(lH-imidazol-2-ylmethyl)thiourea, 3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-fluoroethyl)urea, l-[4-[4-[l-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea, l-[4-[4-[l-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea,
3-(2-hydroxyethyl)- 1 -[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[ 1 -(2- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-fluoroethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(2- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea, 1 - [4- [4-[ 1 -(2-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2S)-l-hydroxypropan-2-yl]urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclobuty^-ό- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2S)-l-hydroxypropan-2-yl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2R)-l-hydroxypropan-2-yl]urea,
3-(2-fluoroethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea, 3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-fluoroethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2,2-difluoroethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2S)-l-hydroxypropan-2-yl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2R)-l-hydroxypropan-2-yl]urea,
3 -cyclopropyl- 1 - [4- [4-[(3 S)-3 -ethylmorpholin-4-yl]-6-( 1 - methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-ethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]-
3 -(2-hydroxyethyl)urea, l-[4-[4-[l-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropy^-ό- [(3 S ,5 S)-3 ,5 -dimethylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] -3 -(2-hydroxyethyl)urea,
3-cyclopropyl-l-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(2-fluoroethyl)urea, l-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, and l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2S)-l-hydroxypropan-2-yl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(l-hydroxycyclopropyl)methyl]urea, l-[4-[4-(l-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-
(2-hydroxyethyl)thiourea, l-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-ethylurea,
3-[(2S)-l-hydroxypropan-2-yl]-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea, and l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-fluoroethyl)urea, or a pharmaceutically acceptable salt thereof.
The invention also provides processes for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
A compound of formula (I), wherein X = -S(O)2CR6R7-, may be prepared by oxidising a compound of the formula (I), wherein X = SCR6R7-, for example by using Oxone® at room temperature in a mixed solvent system of water and ethanol
Figure imgf000197_0001
O (D
A compound of formula (I), wherein R1X = R1OCR6R7-, may be prepared by the reaction of a compound of formula (I), wherein R1X = HOCR6R7-, with a compound of formula (II), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N, N- dimethy lformamide .
Figure imgf000197_0002
A compound of formula (I), wherein R1X = R1R4NCR6R7-, may be prepared by the reaction of a compound of formula (I), wherein R1X = HR4NCR6R7-, with a compound of formula (II), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N, N- dimethylformamide; or by the reaction of a compound of formula (I), wherein R1X =
HR4NCR6R7-, with a compound of formula (III) in the presence of a suitable reducing agent such as NaCNBH3.
Figure imgf000198_0001
A compound of formula (I), wherein X1 = -S(O)2CR6R7-, -SCR6R7-, -OCR6R7-, -R4NCR6R7-, -S(O)CR6R7-, may be prepared by the reaction of a compound of formula (IV), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with a compound of formula (V) optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or Λ/,Λ/-dimethylformamide.
Figure imgf000198_0002
A compound of formula (I), wherein X = -SCR6R7-, may be prepared by the reaction of a compound of formula (IV), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with thiourea in a suitable solvent such as ethanol to generate a compound of formula (VI) which is then subsequently reacted with a compound of formula (II) in the presence of a suitable base such as sodium hydroxide and a solvent such as Λ/,Λ/-dimethylformamide.
Figure imgf000198_0003
A compound of formula (I), wherein X = -S(O)2CR6R7-, may be prepared by the reaction of a compound of formula (VIII) with a compound of formula (VII), wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in which 1 carbon may be optionally replaced with O, N or S, and wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), in the presence of a suitable base such as sodium hydride or potassium tert-butoxide in a suitable solvent such as tetrahydrofuran or 7V,Λ/-dimethylformamide, or by using aqueous sodium hydroxide solution and DCM as a solvent with a suitable phase transfer agent such as tetrabutylammonium bromide.
Figure imgf000199_0001
A compound of formula (I), wherein X = -S(O)2CR >6π R7 -, may be prepared by the reaction of a compound of formula (VIII) with a compound of formula (IX), wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in which 1 carbon may be optionally replaced with O, N or S, and wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), and L3 is a group which can be transformed to a suitable leaving group (such as halo, tosyl, mesyl) at a later stage, to give a compound of formula (X) in the presence of a suitable base such as sodium hydride or potassium tert-butoxide in a suitable solvent such as tetrahydrofuran or N, N- dimethylformamide, or by using aqueous sodium hydroxide solution and DCM as a solvent with a suitable phase transfer agent such as tetrabutylammonium bromide, and subsequently converting L3 to an appropriate leaving group (such as halo, tosyl, mesyl etc.) and then exposing to a suitable base such as sodium hydride or potassium tert-butoxide in a suitable solvent such as tetrahydrofuran or 7V,Λ/-dimethylformamide, or by using aqueous sodium hydroxide solution and DCM as a solvent with a suitable phase transfer agent such as tetrabutylammonium bromide.
Figure imgf000199_0002
A compound of formula (I), wherein R1X = HOCR6R7-, may be prepared by the reaction of a compound of formula (XI), with suitable organometallic reagent of fomula (XII) wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in which 1 carbon may be optionally replaced with O, N or S, such as the grignard reagent in a suitable solvent.
Figure imgf000200_0001
A compound of formula (I), wherein R1X = HOCR6R7-, may be prepared by the reaction of a compound of formula (XI), with suitable organometallic reagent of fomula (XIII) wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in which 1 carbon may be optionally replaced with O, N or S, and M1 is a group which can be transformed into a suitable organometallic reagent (such as a grignard reagent) at a later date, such as the grignard reagent in a suitable solvent, to give a compound of formula (XIV), and then subsequent conversion of M1 to a suitable organometallic reagent and subsequent reaction.
Figure imgf000200_0002
A compound of formula (I) may be prepared from a compound of formula (XV), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), with a suitable organometallic reagent (such as the boronic acid R2B(OH)2 or the boronic ester R2B(OR)2 etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4-dioxane. Alternatively where R connects to the pyrimidine ring through a nitrogen, oxygen or sulphur atom a compound of formula (I) may be prepared from a compound of formula (XIII), wherein L is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), by reaction with the required amine, alcohol or thiol in the presence of a suitable base such as potassium carbonate in a suitable solvent such as Λ/,Λ/-dimethylformamide.
Figure imgf000201_0001
(XV) (0
It will be appreciated that a compound of formula (XV) may be transformed into another compound of formula (XV) by techniques such as oxidation, alkylation, reductive amination etc., either listed above or otherwise known in the literature.
A compound of formula (XV), wherein X1 = -S(O)2CR6R7-, -SCR6R7-, -OCR6R7-, -R4NCR6R7-, -S(O)CR6R7-, may be prepared by the reaction of a compound of formula (XVI), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with a compound of formula (V) optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or Λ/,Λ/-dimethylformamide.
Figure imgf000201_0002
A compound of formula (XV), wherein X = -SCR6R7-, may be prepared by the reaction of a compound of formula (XVI), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with thiourea in a suitable solvent such as ethanol to generate a compound of formula (XVII) which is then subsequently reacted with a compound of formula (II) in the presence of a suitable base such as sodium hydroxide and a solvent such as N, N- dimethy lformamide .
Figure imgf000201_0003
A compound of formula (XV), wherein X = -S(O)2CR6R7-, may be prepared by the reaction of a compound of formula (XVIII), wherein X = -S(O)2CH2-, with a compound of formula (VII), wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in which 1 carbon may be optionally replaced with O, N or S, and wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), in the presence of a suitable base such as sodium hydride or potassium tert-butoxide in a suitable solvent such as tetrahydrofuran or N, N- dimethylformamide, or by using aqueous sodium hydroxide solution and DCM as a solvent with a suitable phase transfer agent such as tetrabutylammonium bromide.
Figure imgf000202_0001
A compound of formula (XV), wherein X = -S(O)2CR6R7-, may be prepared by the reaction of a compound of formula (XVIII), wherein X = -S(O)2CH2-, with a compound of formula (IX), wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in which 1 carbon may be optionally replaced with O, N or S, and wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), and L3 is a group which can be transformed to a suitable leaving group (such as halo, tosyl, mesyl) at a later stage, to give a compound of formula (XIX) in the presence of a suitable base such as sodium hydride or potassium tert-butoxide in a suitable solvent such as tetrahydrofuran or Λ/,7V-dimethylformamide, or by using aqueous sodium hydroxide solution and DCM as a solvent with a suitable phase transfer agent such as tetrabutylammonium bromide, and subsequently converting L3 to an appropriate leaving group (such as halo, tosyl, mesyl etc.) and then exposing to a suitable base such as sodium hydride or potassium tert-butoxide in a suitable solvent such as tetrahydrofuran or N, N- dimethylformamide, or by using aqueous sodium hydroxide solution and DCM as a solvent with a suitable phase transfer agent such as tetrabutylammonium bromide.
Figure imgf000202_0002
A compound of formula (XV), wherein R1X = HOCR6R7-, may be prepared by the reaction of a compound of formula (XX), with suitable organometallic reagent of fomula (XII) wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in which 1 carbon may be optionally replaced with O, N or S, such as the grignard reagent in a suitable solvent.
Figure imgf000203_0001
A compound of formula (XV), wherein R1X = HOCR6R7-, may be prepared by the reaction of a compound of formula (XX), with suitable organometallic reagent of fomula (XIII) wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in which 1 carbon may be optionally replaced with O, N or S, and M1 is a group which can be transformed into a suitable organometallic reagent (such as a grignard reagent) at a later date, such as the grignard reagent in a suitable solvent, to give a compound of formula (XXI), and then subsequent conversion of M1 to a suitable organometallic reagent and subsequent reaction.
Figure imgf000203_0002
A compound of formula (IV) may be prepared from a compound of formula (XVI), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.) and L1 is a leaving group (such as halo, tosyl, mesyl etc.), with a suitable organometallic reagent (such as the boronic acid R2B(OH)2 or the boronic ester R2B(OR)2 etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4-dioxane. Alternatively where R2 connects to the pyrimidine ring through a nitrogen, oxygen or sulphur atom a compound of formula (IV) may be prepared from a compound of formula (XVI), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), by reaction with the required amine, alcohol or thiol in the presence of a suitable base such as potassium carbonate in a suitable solvent such as Λ/,Λ/-dimethylformamide.
Figure imgf000203_0003
A compound of formula (XI) may be prepared from a compound of formula (XX), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.) and R is a hydrogen or Ci-4 alkyl group, with a suitable organometallic reagent (such as the boronic acid R2B(OH)2 or the boronic ester R2B(OR)2 etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4-dioxane. Alternatively where R2 connects to the pyrimidine ring through a nitrogen, oxygen or sulphur atom a compound of formula (XI) may be prepared from a compound of formula (XX), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), by reaction with the required amine, alcohol or thiol in the presence of a suitable base such as potassium carbonate in a suitable solvent such as Λ/,Λ/-dimethylformamide.
Figure imgf000204_0001
A compound of formula (XXII) may be prepared from a compound of formula (XXIII), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), with a suitable organometallic reagent (such as the boronic acid R2B(OH)2 or the boronic ester R2B(OR)2 etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4-dioxane. Alternatively where R2 connects to the pyrimidine ring through a nitrogen, oxygen or sulphur atom a compound of formula (XXII) may be prepared from a compound of formula (XXIII), wherein L is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), by reaction with the required amine, alcohol or thiol in the presence of a suitable base such as potassium carbonate in a suitable solvent such as Λ/,Λ/-dimethylformamide.
Figure imgf000204_0002
(XXIII) (XXII)
A compound of formula (XXIV) may be prepared from a compound of formula (XXV), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), with a suitable organometallic reagent (such as the boronic acid R2B(OH)2 or the boronic ester R2B(OR)2 etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4-dioxane. Alternatively where R connects to the pyrimidine ring through a nitrogen, oxygen or sulphur atom a compound of formula (XXIV) may be prepared from a compound of formula (XXV), wherein L is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), by reaction with the required amine, alcohol or thiol in the presence of a suitable base such as potassium carbonate in a suitable solvent such as Λ/,Λ/-dimethylformamide.
Figure imgf000205_0001
(XXV) (XXIV)
A compound of formula (I), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), may be prepared by the reaction of a compound of formula (XXVI) with a compound of formula (XXVII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as Λ/,Λ/-dimethylformamide.
C° w>3>m RS RYΛSAR2
Figure imgf000205_0002
(XXVIl) (XXVl) (I)
It will be appreciated that a compound of formula (XXV) may be transformed into another compound of formula (XXV) by techniques such as oxidation, alkylation, reductive amination etc., either listed above or otherwise known in the literature. A compound of formula (IV), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), may be prepared by the reaction of a compound of formula (XXVIII) with a compound of formula (XXVII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as Λ/,Λ/-dimethylformamide.
Figure imgf000205_0003
A compound of formula (XI), wherein R is a hydrogen or a Ci-4 alkyl group, may be prepared by the reaction of a compound of formula (XXIX), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) with a compound of formula (XXVII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N, N- dimethy lformamide .
Figure imgf000206_0002
(XXVIl)
Figure imgf000206_0001
A compound of formula (XXII) may be prepared by the reaction of a compound of formula (XXX), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with a compound of formula (XXVII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as Λ/,Λ/-dimethylformamide.
Figure imgf000206_0003
(XXX) (XXII)
A compound of formula (XXIV), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), may be prepared by the reaction of a compound of formula (XXXI), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) with a compound of formula (XXVII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N,7V-dimethylformamide.
Figure imgf000206_0004
(XXXI) (XXIV) A compound of formula (XV), wherein L is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), may be prepared by the reaction of a compound of formula (XXXII), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) with a compound of formula (XXVII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N,7V-dimethylformamide.
Figure imgf000207_0001
(XXVIi) (XXXIi) (XV)
It will be appreciated that a compound of formula (XXXII) may be transformed into another compound of formula (XXXII) by techniques such as oxidation, alkylation, reductive amination etc., either listed above or otherwise known in the literature.
A compound of formula (XVI), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), may be prepared by the reaction of a compound of formula (XXXIII) with a compound of formula (XXVII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N,7V-dimethylformamide.
Figure imgf000207_0002
A compound of formula (XX), wherein L is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.) and R is a hydrogen or a Ci-4 alkyl group, may be prepared by the reaction of a compound of formula (XXXIV), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) with a compound of formula (XXVII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N,7V-dimethylformamide.
Figure imgf000207_0003
A compound of formula (XXIII), wherein L is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), may be prepared by the reaction of a compound of formula (XXXV), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.) with a compound of formula (XXVII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N,7V-dimethylformamide. ,o.
".L :' NC' ' N' "L2
Figure imgf000208_0001
(XXIIi)
A compound of formula (XXV), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)2Me etc.), may be prepared by the reaction of a compound of formula (XXXVI), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with a compound of formula (XXVII) optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as Λ/,Λ/-dimethylformamide.
Figure imgf000208_0002
(XXXVI) (XXV)
A compound of formula (XXXVII), wherein R1X = H2NC(O)-, may be prepared from a compound of formula (XXII) by hydrolysis with, for example, sodium hydroxide in a suitable solvent such as a water ethanol mix.
Figure imgf000208_0003
(XXIi)
Figure imgf000208_0004
A compound of formula (I), wherein R1X = H2NCR6R7-, may be prepared by the reaction of a compound of formula (XXII), with suitable organometallic reagent of fomula (XII) wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in which 1 carbon may be optionally replaced with O, N or S, such as the grignard reagent or alkyl lithium reagent in a suitable solvent.
Figure imgf000208_0005
A compound of formula (XV), wherein R1X = H2NCR6R7-, may be prepared by the reaction of a compound of formula (XXIII), with suitable organometallic reagent of fomula (XII) wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in which 1 carbon may be optionally replaced with O, N or S, such as the grignard reagent or alkyl lithium reagent in a suitable solvent.
Figure imgf000209_0001
A compound of formula (VIII) may be prepared by the reaction of a compound of formula (XXXVIII), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with a compound of formula (V), wherein X1 = -S-, -SO2-, optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or 7V,7V-dimethylformamide. In the case where X1 = -SH a subsequent oxidation step, for example by using Oxone® at room temperature in a solvent system of water and ethanol, or for example by using 3- chloroperbenzoic acid with dichloromethane as solvent will be required.
Figure imgf000209_0002
(XXXVIII) (VIII) A compound of formula (VIII) may be prepared by the reaction of a compound of formula (XXXVIII), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with thiourea in a suitable solvent such as ethanol to generate a compound of formula (XXXIX) which is then subsequently reacted with a compound of formula (II) in the presence of a suitable base such as sodium hydroxide and a solvent such as Λ/,Λ/-dimethylformamide, and subsequently oxidised, for example by using Oxone® at room temperature in a solvent system of water and ethanol, or for example by using 3-chloroperbenzoic acid with dichloromethane as solvent.
Figure imgf000210_0001
A compound of formula (XVIII), wherein L2 is a leaving group (such as halo, tosyl mesyl, -SMe, -S(O)2Me etc.), may be prepared by the reaction of a compound of formula (XL), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with a compound of formula (V), wherein X1 = -S-, -SO2-, optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or 7V,7V-dimethylformamide. In the case where X1 = -S- a subsequent oxidation step, for example by using Oxone® at room temperature in a solvent system of water and ethanol, or for example by using 3-chloroperbenzoic acid with dichloromethane as solvent will be required.
Figure imgf000210_0002
(XL) (XVIII)
A compound of formula (XVIII), wherein L is a leaving group (such as halo, tosyl mesyl, -SMe, -S(O)2Me etc.), may be prepared by the reaction of a compound of formula (XL), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with thiourea in a suitable solvent such as ethanol to generate a compound of formula (XLI) which is then subsequently reacted with a compound of formula (II) in the presence of a suitable base such as sodium hydroxide and a solvent such as 7V,7V-dimethylformamide, and subsequently oxidised, for example by using Oxone® at room temperature in a solvent system of water and ethanol, or for example by using 3-chloroperbenzoic acid with dichloromethane as solvent.
H2
Figure imgf000210_0003
It will be appreciated that the substituent R1 present in a compound of formula (I) and formula (XV) can be transformed into another substituent R1 by a series of chemical transformations known in the literature, such as oxidation, reduction, nucleophilic or electrophilic reactions, addition and elimination reactions. An example of such a transformation would be the reaction of a compound of formula (XLII), wherein L2 is a leaving group (such as halo, tosyl mesyl, -SMe, -S(O)2Me etc.), with an electrophile such as dimethyl carbonate in the presence of a base such as sodium hydride in a suitable solvent such as tetrahydrofuran, followed by a reduction, such as the conversion to a mixed anhydride followed by treatment with a hydride source, to give a compound of formula (XLIII)
Figure imgf000211_0001
(XLIl) (XLIII)
It will be appreciated that the R2 group may be introduced and subsequently converted to another group of the formula R2 at a subsequent stage in the synthesis using methods known in the literature. For example, but not limited to, an R2 containing an alkyl or aryl amine (which may be suitably protected as, for example, a nitro or t-butoxycarbamate) may be introduced at any stage and then converted, for instance, to a urea by reaction with a suitable isocyanate (or by activation to a suitable group, such as isocyanate or phenoxycarbamate, and subsequent reaction with an amine); or to a thiourea by reaction with a suitable isothiocyanate (or by activation to a suitable group, such as an isothiocyanate, and subsequent reaction with an amine); or to an amide or sulphonamide by reaction with a suitably activated carboxylic acid or sulphonic acid derivative; or by other methods known in the literature.
It will be appreciated that where R6 and R7, together with the carbon to which they are attached, form a 3-10 membered heterocyclic ring containing a nitrogen atom that the nitrogen atom may be suitably protected (for example a t-butoxycarbamate or benzyl group) and that the protecting group may be removed and if necessary a further reaction performed on the nitrogen (for example an alkylation, reductive amination or amidation) at any stage in the synthesis.
A compound of formula (XLV) may be prepared by the reaction of an amine of formula R1R4NH with a compound of formula (XLIV) in the presence of a suitable coupling agent, such as HATU, or following suitable activation of (XLIV), such as the conversion to an acid chloride.
Figure imgf000212_0001
A compound of formula (XLIV) may be prepared from a compound of formula (XLVI) by hydrolysis, for example with sodium hydroxide in a suitable solvent such as an ethanohwater mix.
Figure imgf000212_0002
A compound of formula (XLVII) may be prepared by the reaction of an amine of formula R1R4NH with a compound of formula (XLVIII) in the presence of a suitable coupling agent, such as HATU, or following suitable activation of (XLVIII), such as the conversion to an acid chloride.
Figure imgf000212_0003
(XLVIII)
Figure imgf000212_0004
A compound of formula (XLIX) may be prepared from a compound of formula (XLVIII) by hydrolysis, for example with sodium hydroxide in a suitable solvent such as an ethanohwater mix.
Figure imgf000212_0005
(XLlX) (XLVIII) A compound of formula (L), wherein Y = R1R4NC(O)-, ROC(O)-, NC-, may be prepared by the reaction of a compound of formula (VIII) with a compound of formula (LI), wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in which 1 carbon may be optionally replaced with O, N or S, and wherein L is a leaving group (such as halo, tosyl, mesyl etc.), in the presence of a suitable base such as sodium hydride or potassium tert- butoxide in a suitable solvent such as tetrahydrofuran or 7V,7V-dimethylformamide, or by using aqueous sodium hydroxide solution and DCM as a solvent with a suitable phase transfer agent such as tetrabutylammonium bromide.
Figure imgf000213_0001
A compound of formula (LI), wherein Y = NC-, HOC(O)-, may be prepared by the reaction of a compound of formula (XXXVIII) with a suitable nucleophile, such as for example sodium cyanide or for example tris(phenylthio)methane anion followed by a suitable hydrolysis.
Figure imgf000213_0002
(XXXVIII) (Ll)
A compound of formula (LII), wherein L2 is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)2Me etc.), may be prepared by the reaction of an amine of formula R1R4NH with a compound of formula (LIII) in the presence of a suitable coupling agent, such as HATU, or following suitable activation of (LIII), such as the conversion to an acid chloride.
Figure imgf000213_0003
A compound of formula (LIII), wherein L2 is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)2Me etc.), may be prepared from a compound of formula (LIV) by hydrolysis, for example with sodium hydroxide in a suitable solvent such as an ethanohwater mix.
Figure imgf000214_0001
A compound of formula (LV), wherein L2 is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)2Me etc.), may be prepared by the reaction of an amine of formula R1R4NH with a compound of formula (LVI) in the presence of a suitable coupling agent, such as HATU, or following suitable activation of (LVI), such as the conversion to an acid chloride.
Figure imgf000214_0002
A compound of formula (LVI), wherein L2 is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)2Me etc.), may be prepared from a compound of formula (LVII) by hydrolysis, for example with sodium hydroxide in a suitable solvent such as an ethanohwater mix.
Figure imgf000214_0003
A compound of formula (LVIII), wherein Y = R1R4NC(O)-, ROC(O)-, NC-, and L2 is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)2Me etc.), may be prepared by the reaction of a compound of formula (VIII) with a compound of formula (LIX), wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in which 1 carbon may be optionally replaced with O, N or S, and wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), in the presence of a suitable base such as sodium hydride or potassium tert-butoxide in a suitable solvent such as tetrahydrofuran or 7V,7V-dimethylformamide, or by using aqueous sodium hydroxide solution and DCM as a solvent with a suitable phase transfer agent such as tetrabutylammonium bromide.
Figure imgf000215_0001
A compound of formula (LIX), wherein Y = NC-, HOC(O)-, and L is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)2Me etc.), may be prepared by the reaction of a compound of formula (XL) with a suitable nucleophile, such as for example sodium cyanide or for example tris(phenylthio)methane anion followed by a suitable hydrolysis.
Figure imgf000215_0002
A compound of formula (L), wherein Y = NC-, ROC(O)-, may be prepared by the reaction of a compound of formula (XXVII) with a compound of formula (LX), wherein L2 is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)2Me etc.), optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as Λ/,Λ/-dimethylformamide.
Figure imgf000215_0004
(XXVII)
Figure imgf000215_0003
A compound of formula (LX), wherein Y = NC-, ROC(O)-, and L2 is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)2Me etc.) may be prepared by the reaction of a compound of formula (LXI) with a compound of formula (LXII) and subsequent conversion of the OH group to a suitable leaving group, such as by reaction with N- phenyltrifluoromethanesulfonimide in the presence of a suitable base such as DBU and a suitable solvent such as dichloromethane.
Figure imgf000216_0001
A compound of formula (LI), wherein Y = NC-, ROC(O)-, may be prepared by the reaction of a compound of formula (XXVII) with a compound of formula (LXIII), wherein L2 is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)2Me etc.), optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as Λ/,Λ/-dimethylformamide.
Figure imgf000216_0002
(XXVII)
(LXIII) (Ll)
A compound of formula (LXIII), wherein Y = NC-, ROC(O)-, and L2 is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)2Me etc.) may be prepared by the reaction of a compound of formula (LXIV) with a compound of formula (LXII) and subsequent conversion of the OH group to a suitable leaving group, such as by reaction with N- phenyltrifluoromethanesulfonimide in the presence of a suitable base such as DBU and a suitable solvent such as dichloromethane.
Figure imgf000216_0003
(LXIV) (LXN) (LXIII) A compound of formula (LVIII), wherein Y = NC-, ROC(O)-, and L2 is a leaving group
(such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)2Me etc.) may be prepared by the reaction of a compound of formula (XXVII) with a compound of formula (LXV), wherein L2 is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, - S(O)2Me etc.), optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as Λ/,Λ/-dimethylformamide.
Figure imgf000217_0002
(XXVII)
Figure imgf000217_0001
A compound of formula (LXV), wherein Y = NC-, ROC(O)-, and L2 is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)2Me etc.) may be prepared by the reaction of a compound of formula (LXI) with a compound of formula (LXVI) and subsequent conversion of the OH group to a suitable leaving group, such as by reaction with N- phenyltrifluoromethanesulfonimide in the presence of a suitable base such as DBU and a suitable solvent such as dichloromethane.
Figure imgf000217_0003
A compound of formula (LIX), wherein Y = NC-, ROC(O)-, and L is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)2Me etc.) may be prepared by the reaction of a compound of formula (XXVII) with a compound of formula (LXVII), wherein L2 is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, - S(O)2Me etc.), optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as Λ/,Λ/-dimethylformamide.
C
Figure imgf000217_0004
(XXV") ι (\L wXViInI) (LIX)
A compound of formula (LXVII), wherein Y = NC-, ROC(O)-, and L2 is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)2Me etc.) may be prepared by the reaction of a compound of formula (LXIV) with a compound of formula (LXVI) and subsequent conversion of the OH group to a suitable leaving group, such as by reaction with 7V-phenyltrifluoromethanesulfonimide in the presence of a suitable base such as DBU and a suitable solvent such as dichloromethane.
Figure imgf000218_0001
(LXIV) (LXVI) (LXVII)
It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. For example compounds of formula (I) may be converted into further compounds of formula (I) by standard aromatic substitution reactions or by conventional functional group modifications. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogen group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl. It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tøt-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifiuoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifiuoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
Many of the intermediates defined herein are novel and these are provided as a further feature of the invention. Biological Assays The following assays can be used to measure the effects of the compounds of the present invention as mTOR kinase inhibitors, as PB kinase inhibitors, as inhibitors in vitro of the activation of PB kinase signalling pathways and as inhibitors in vitro of the proliferation of MDA-MB-468 human breast adenocarcinoma cells. (a)(i) In Vitro mTOR Kinase Assay
The assay used AlphaScreen technology (Gray et ah, Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant mTOR.
A C-terminal truncation of mTOR encompassing amino acid residues 1362 to 2549 of mTOR (EMBL Accession No. L34075) was stably expressed as a FLAG-tagged fusion in HEK293 cells as described by Vilella-Bach et al, Journal of Biochemistry, 1999, 274, 4266- 4272. The HEK293 FLAG-tagged mTOR (1362-2549) stable cell line was routinely maintained at 37°C with 5% CO2 up to a confiuency of 70-90% in Dulbecco's modified Eagle's growth medium (DMEM; Invitrogen Limited, Paisley, UK Catalogue No. 41966-029) containing 10% heat-inactivated foetal calf serum (FCS; Sigma, Poole, Dorset, UK, Catalogue No. F0392), 1% L-glutamine (Gibco, Catalogue No. 25030-024) and 2 mg/ml Geneticin (G418 sulfate; Invitrogen Limited, UK Catalogue No. 10131-027). Following expression in the mammalian HEK293 cell line, expressed protein was purified using the FLAG epitope tag using standard purification techniques. Test compounds were prepared as 10 mM stock solutions in DMSO and diluted into water as required to give a range of final assay concentrations. Aliquots (2 μl) of each compound dilution were placed into a well of a Greiner 384-well low volume (LV) white polystyrene plate (Greiner Bio-one). A 30 μl mixture of recombinant purified mTOR enzyme, 1 μM biotinylated peptide substrate (Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe- Thr-Tyr-Val-Ala-Pro-Ser-Val-Leu-Glu-Ser- VaI-LyS-GIu-NH2; Bachem UK Ltd), ATP (20 μM) and a buffer solution [comprising Tris-HCl pH7.4 buffer (50 mM), EGTA (0.1 mM), bovine serum albumin (0.5 mg/mL), DTT (1.25 mM) and manganese chloride (10 mM)] was agitated at room temperature for 90 minutes.
Control wells that produced a maximum signal corresponding to maximum enzyme activity were created by using 5% DMSO instead of test compound. Control wells that produced a minimum signal corresponding to fully inhibited enzyme were created by adding EDTA (83 mM) instead of test compound. These assay solutions were incubated for 2 hours at room temperature.
Each reaction was stopped by the addition of 10 μl of a mixture of EDTA (50 mM), bovine serum albumin (BSA; 0.5 mg/mL) and Tris-HCl pH7.4 buffer (50 mM) containing 5 p70 S6 Kinase (T389) 1A5 Monoclonal Antibody (Cell Signalling Technology, Catalogue No. 9206B) and AlphaScreen Streptavidin donor and Protein A acceptor beads (200 ng; Perkin Elmer, Catalogue No. 6760002B and 6760137R respectively) were added and the assay plates were left for about 20 hours at room temperature in the dark. The resultant signals arising from laser light excitation at 680 nm were read using a Packard Envision instrument. io Phosphorylated biotinylated peptide is formed in situ as a result of mTOR mediated phosphorylation. The phosphorylated biotinylated peptide that is associated with AlphaScreen Streptavidin donor beads forms a complex with the p70 S6 Kinase (T389) 1A5 Monoclonal Antibody that is associated with Alphascreen Protein A acceptor beads. Upon laser light excitation at 680 nm, the donor bead : acceptor bead complex produces a signal that can be is measured. Accordingly, the presence of mTOR kinase activity results in an assay signal. In the presence of an mTOR kinase inhibitor, signal strength is reduced. mTOR enzyme inhibition for a given test compound was expressed as an IC50 value. (a)(ii) In Vitro mTOR Kinase Assay (Echo)
The assay used AlphaScreen technology (Gray et ah, Analytical Biochemistry, 2003,
20 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant mTOR.
A C-terminal truncation of mTOR encompassing amino acid residues 1362 to 2549 of mTOR (EMBL Accession No. L34075) was stably expressed as a FLAG-tagged fusion in HEK293 cells as described by Vilella-Bach et al, Journal of Biochemistry, 1999, 274, 4266-
25 4272. The HEK293 FLAG-tagged mTOR (1362-2549) stable cell line was routinely maintained at 37°C with 5% CO2 up to a confiuency of 70-90% in Dulbecco's modified Eagle's growth medium (DMEM; Invitrogen Limited, Paisley, UK Catalogue No. 41966-029) containing 10% heat-inactivated foetal calf serum (FCS; Sigma, Poole, Dorset, UK, Catalogue No. F0392), 1% L-glutamine (Gibco, Catalogue No. 25030-024) and 2 mg/ml Geneticin (G418
30 sulfate; Invitrogen Limited, UK Catalogue No. 10131-027). Following expression in the mammalian HEK293 cell line, expressed protein was purified using the FLAG epitope tag using standard purification techniques. Test compounds were prepared as 10 mM stock solutions in DMSO and diluted in into waterDMSO as required to give a range of final assay concentrations. Aliquots (120nl2 μl) of each compound dilution were acoustically dispensedplaced using a Labcyte Echo 550 into a well of a Greiner 384-well low volume (LV) white polystyrene plate (Greiner Bio-one). A 5 1230 μl mixture of recombinant purified mTOR enzyme, 1 μM biotinylated peptide substrate (Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe-Thr-Tyr-Val-Ala-Pro-Ser-Val-Leu- Glu-Ser- VaI-LyS-GIu-NH2; Bachem UK Ltd), ATP (20 μM) and a buffer solution [comprising Tris-HCl pH7.4 buffer (50 mM), EGTA (0.1 mM), bovine serum albumin (0.5 mg/mL), DTT (1.25 mM) and manganese chloride (10 mM)] was incubated at room temperature for 12090o minutes.
Control wells that produced a maximum signal corresponding to maximum enzyme activity were created by using 1005% DMSO instead of test compound. Control wells that produced a minimum signal corresponding to fully inhibited enzyme were created by adding LY294002EDTA (100uM83 mM) compound. These assay solutions were incubated for 2s hours at room temperature.
Each reaction was stopped by the addition of 510 μl of a mixture of EDTA (50 mM), bovine serum albumin (BSA; 0.5 mg/mL) and Tris-HCl pH7.4 buffer (50 mM) containing p70 S6 Kinase (T389) 1A5 Monoclonal Antibody (Cell Signalling Technology, Catalogue No. 9206B) and AlphaScreen Streptavidin donor and Protein A acceptor beads (200 ng; Perkin0 Elmer, Catalogue No. 6760002B and 6760137R respectively) were added and the assay plates were left overnight at room temperature in the dark. The resultant signals arising from laser light excitation at 680 nm were read using a Packard Envision instrument.
Phosphorylated biotinylated peptide is formed in situ as a result of mTOR mediated phosphorylation. The phosphorylated biotinylated peptide that is associated with AlphaScreen5 Streptavidin donor beads forms a complex with the p70 S6 Kinase (T389) 1A5 Monoclonal Antibody that is associated with Alphascreen Protein A acceptor beads. Upon laser light excitation at 680 nm, the donor bead : acceptor bead complex produces a signal that can be measured. Accordingly, the presence of mTOR kinase activity results in an assay signal. In the presence of an mTOR kinase inhibitor, signal strength is reduced. 0 mTOR enzyme inhibition for a given test compound was expressed as an IC50 value. (b)(i) In Vitro PI3K Enzyme Assay The assay used AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant Type I PI3K enzymes of the lipid PI(4,5)P2.
DNA fragments encoding human PI3K catalytic and regulatory subunits were isolated from cDNA libraries using standard molecular biology and PCR cloning techniques. The selected DNA fragments were used to generate baculovirus expression vectors. In particular, full length DNA of each of the pi 10a, pi lOβ and pi lOδ Type Ia human PI3K pi 10 isoforms (EMBL Accession Nos. HSU79143, S67334, Y10055 for pi 10a, pi lOβ and pi lOδ respectively) were sub-cloned into a pDESTIO vector (Invitrogen Limited, Fountain Drive, Paisley, UK). The vector is a Gateway-adapted version of Fastbacl containing a 6-His epitope tag. A truncated form of Type Ib human PI3K pi lOγ isoform corresponding to amino acid residues 144-1102 (EMBL Accession No. X8336A) and the full length human p85α regulatory subunit (EMBL Accession No. HSP13KIN) were also sub-cloned into pFastBacl vector containing a 6-His epitope tag. The Type Ia pi 10 constructs were co-expressed with the p85α regulatory subunit. Following expression in the baculovirus system using standard baculovirus expression techniques, expressed proteins were purified using the His epitope tag using standard purification techniques.
DNA corresponding to amino acids 263 to 380 of human general receptor for phosphoinositides (Grpl) PH domain was isolated from a cDNA library using standard molecular biology and PCR cloning techniques. The resultant DNA fragment was sub-cloned into a pGEX 4Tl E. coli expression vector containing a GST epitope tag (Amersham Pharmacia Biotech, Rainham, Essex, UK) as described by Gray et al., Analytical Biochemistry, 2003, 313: 234-245). The GST-tagged Grpl PH domain was expressed and purified using standard techniques. Test compounds were prepared as 10 mM stock solutions in DMSO and diluted into water as required to give a range of final assay concentrations. Aliquots (2 μl) of each compound dilution were placed into a well of a Greiner 384-well low volume (LV) white polystyrene plate (Greiner Bio-one, Brunei Way, Stonehouse, Gloucestershire, UK Catalogue No. 784075). A mixture of each selected recombinant purified PI3K enzyme (15 ng), DiC8- PI(4,5)P2 substrate (40 μM; Cell Signals Inc., Kinnear Road, Columbus, USA, Catalogue No. 901), adenosine triphosphate (ATP; 4 μM) and a buffer solution [comprising Tris-HCl pH7.6 buffer (40 mM, 10 μl), 3-[(3-cholamidopropyl)dimethylammonio]-l-propanesulfonate (CHAPS; 0.04%), dithiothreitol (DTT; 2 mM) and magnesium chloride (10 mM)] was agitated at room temperature for 20 minutes.
Control wells that produced a minimum signal corresponding to maximum enzyme 5 activity were created by using 5% DMSO instead of test compound. Control wells that produced a maximum signal corresponding to fully inhibited enzyme were created by adding wortmannin (6 μM; Calbiochem / Merck Bioscience, Padge Road, Beeston, Nottingham, UK, Catalogue No. 681675) instead of test compound. These assay solutions were also agitated for 20 minutes at room temperature. io Each reaction was stopped by the addition of 10 μl of a mixture of EDTA (100 mM), bovine serum albumin (BSA, 0.045 %) and Tris-HCl pH7.6 buffer (40 mM).
Biotinylated-DiC8-PI(3,4,5)P3 (50 nM; Cell Signals Inc., Catalogue No. 107), recombinant purified GST-Grpl PH protein (2.5 nM) and AlphaScreen Anti-GST donor and acceptor beads (100 ng; Packard Bioscience Limited, Station Road, Pangbourne, Berkshire, is UK, Catalogue No. 6760603M) were added and the assay plates were left for about 5 to 20 hours at room temperature in the dark. The resultant signals arising from laser light excitation at 680 nm were read using a Packard AlphaQuest instrument.
PI(3,4,5)P3 is formed in situ as a result of PI3K mediated phosphorylation of PI(4,5)P2. The GST-Grpl PH domain protein that is associated with AlphaScreen Anti-GST donor beads
20 forms a complex with the biotinylated PI(3,4,5)P3 that is associated with Alphascreen Streptavidn acceptor beads. The enymatically-produced PI(3,4,5)P3 competes with biotinylated PI(3,4,5)P3 for binding to the PH domain protein. Upon laser light excitation at 680 nm, the donor bead : acceptor bead complex produces a signal that can be measured. Accordingly, PI3K enzme activity to form PI(3,4,5)P3 and subsequent competition with
25 biotinylated PI(3,4,5)P3 results in a reduced signal. In the presence of a PI3K enzyme inhibitor, signal strength is recovered.
PI3K enzyme inhibition for a given test compound was expressed as an IC50 value. (b)(ii) In Vitro PI3K Enzyme Assay (Echo)
The assay used AlphaScreen technology (Gray et ah, Analytical Biochemistry, 2003,
30 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant Type I PI3K enzymes of the lipid PI(4,5)P2. DNA fragments encoding human PBK catalytic and regulatory subunits were isolated from cDNA libraries using standard molecular biology and PCR cloning techniques. The selected DNA fragments were used to generate baculovirus expression vectors. In particular, full length DNA of each of the pi 10a, pi lOβ and pi lOδ Type Ia human PBK pi 10 isoforms 5 (EMBL Accession Nos. HSU79143, S67334, Y10055 for pi 10a, pi lOβ and pi lOδ respectively) were sub-cloned into a pDESTIO vector (Invitrogen Limited, Fountain Drive, Paisley, UK). The vector is a Gateway-adapted version of Fastbacl containing a 6-His epitope tag. A truncated form of Type Ib human PBK pi lOγ isoform corresponding to amino acid residues 144-1102 (EMBL Accession No. X8336A) and the full length human p85α regulatory io subunit (EMBL Accession No. HSP13KIN) were also sub-cloned into pFastBacl vector containing a 6-His epitope tag. The Type Ia pi 10 constructs were co-expressed with the p85α regulatory subunit. Following expression in the baculovirus system using standard baculovirus expression techniques, expressed proteins were purified using the His epitope tag using standard purification techniques. is DNA corresponding to amino acids 263 to 380 of human general receptor for phosphoinositides (Grpl) PH domain was isolated from a cDNA library using standard molecular biology and PCR cloning techniques. The resultant DNA fragment was sub-cloned into a pGEX 4Tl E. coli expression vector containing a GST epitope tag (Amersham Pharmacia Biotech, Rainham, Essex, UK) as described by Gray et al, Analytical Biochemistry.
20 2003, 313: 234-245). The GST-tagged Grpl PH domain was expressed and purified using standard techniques.
Test compounds were prepared as 10 mM stock solutions in DMSO and diluted in DMSO to wateras required to give a range of final assay concentrations. Aliquots (120nl2 μl) of each compound dilution were acoustically dispensed using a Labcyte Echo 550 placed into
25 a well of a Greiner 384-well low volume (LV) white polystyrene plate (Greiner Bio-one, Brunei Way, Stonehouse, Gloucestershire, UK Catalogue No. 784075). A mixture of each selected recombinant purified PBK enzyme (15 ng), DiC8-PI(4,5)P2 substrate (40 μM; Cell Signals Inc., Kinnear Road, Columbus, USA, Catalogue No. 901), adenosine triphosphate (ATP; 4 μM) and a buffer solution [comprising Tris-HCl pH7.6 buffer (40 mM, 10 μl), 3-[(3-
30 cholamidopropyl)dimethylammonio]-l-propanesulfonate (CHAPS; 0.04%), dithiothreitol (DTT; 2 mM) and magnesium chloride (10 mM)] was agitatedincubated at room temperature for 20 minutes.
Control wells that produced a minimum signal corresponding to maximum enzyme activity were created by using 1005% DMSO instead of test compound. Control wells that produced a maximum signal corresponding to fully inhibited enzyme were created by adding Wwortmannin (6 μM; Calbiochem / Merck Bioscience, Padge Road, Beeston, Nottingham, UK, Catalogue No. 681675) instead of test compound. These assay solutions were also incubatedagitated for 20 minutes at room temperature.
Each reaction was stopped by the addition of 10 lOμl of a mixture of EDTA (100 mM), bovine serum albumin (BSA, 0.045 %) and Tris-HCl pH7.6 buffer (40 mM).
Biotinylated-DiC8-PI(3,4,5)P3 (50 nM; Cell Signals Inc., Catalogue No. 107), recombinant purified GST-Grpl PH protein (2.5 nM) and AlphaScreen Anti-GST donor and acceptor beads (100 ng; Packard Bioscience Limited, Station Road, Pangbourne, Berkshire, UK, Catalogue No. 6760603M) were added and the assay plates were left for about 5 to overnight
20 hours at room temperature in the dark. The resultant signals arising from laser light excitation at 680 nm were read using a Packard AlphaQuest instrument.
PI(3,4,5)P3 is formed in situ as a result of PI3K mediated phosphorylation of PI(4,5)P2. The GST-Grpl PH domain protein that is associated with AlphaScreen Anti-GST donor beads forms a complex with the biotinylated PI(3,4,5)P3 that is associated with Alphascreen Streptavidn acceptor beads. The enymatically-produced PI(3,4,5)P3 competes with biotinylated PI(3,4,5)P3 for binding to the PH domain protein. Upon laser light excitation at 680 nm, the donor bead : acceptor bead complex produces a signal that can be measured. Accordingly, PI3K enzme activity to form PI(3,4,5)P3 and subsequent competition with biotinylated PI(3,4,5)P3 results in a reduced signal. In the presence of a PI3K enzyme inhibitor, signal strength is recovered.
PI3K enzyme inhibition for a given test compound was expressed as an IC50 value, (c) In Vitro phospho-Ser473 Akt assay
This assay determines the ability of test compounds to inhibit phosphorylation of Serine 473 in Akt as assessed using Acumen Explorer technology (Acumen Bioscience
Limited), a plate reader that can be used to rapidly quantitate features of images generated by laser-scanning. A MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem, Teddington, Middlesex, UK, Catalogue No. HTB-132) was routinely maintained at 37°C with 5% CO2 up to a confluency of 70-90% in DMEM containing 10% heat-inactivated FCS and 1% L-glutamine. For the assay, the cells were detached from the culture flask using 'Accutase'
(Innovative Cell Technologies Inc., San Diego, CA, USA; Catalogue No. AT 104) using standard tissue culture methods and resuspended in media to give 1.7xlO5 cells per mL. Aliquots (90 μl) were seeded into each of the inner 60 wells of a black Packard 96 well plate (PerkinElmer, Boston, MA, USA; Catalogue No. 6005182) to give a density of -15000 cells per well. Aliquots (90 μl) of culture media were placed in the outer wells to prevent edge effects. The cells were incubated overnight at 37°C with 5% CO2 to allow them to adhere.
On day 2, the cells were treated with test compounds and incubated for 2 hours at 37°C with 5% CO2. Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as required with growth media to give a range of concentrations that were 10-fold the required final test concentrations. Aliquots (10 μl) of each compound dilution were placed in a well (in triplicate) to give the final required concentrations. As a minimum reponse control, each plate contained wells having a final concentration of 100 μM LY294002 (Calbiochem, Beeston, UK, Catalogue No. 440202). As a maximum response control, wells contained 1% DMSO instead of test compound. Following incubation, the contents of the plates were fixed by treatment with a 1.6% aqueous formaldehyde solution (Sigma, Poole, Dorset, UK, Catalogue No. F 1635) at room temperature for 1 hour.
All subsequent aspiration and wash steps were carried out using a Tecan 96 well plate washer (aspiration speed 10 mm/sec). The fixing solution was removed and the contents of the plates were washed with phosphate-buffered saline (PBS; 50 μl; Gibco, Catalogue No. 10010015). The contents of the plates were treated for 10 minutes at room temperature with an aliquot (50 μl) of a cell permeabilisation buffer consisting of a mixture of PBS and 0.5% Tween-20. The 'permeabilisation' buffer was removed and non-specific binding sites were blocked by treatment for 1 hour at room temperature of an aliquot (50 μl) of a blocking buffer consisting of 5% dried skimmed milk ['Marvel' (registered trade mark); Premier Beverages, Stafford, GB] in a mixture of PBS and 0.05% Tween-20. The 'blocking' buffer was removed and the cells were incubated for 1 hour at room temperature with rabbit anti phospho-Akt (Ser473) antibody solution (50 μl per well; Cell Signalling, Hitchin, Herts, U.K., Catalogue No 9277) that had been diluted 1:500 in 'blocking' buffer. Cells were washed three times in a mixture of PBS and 0.05% Tween-20. Subsequently, cells were incubated for 1 hour at room temperature with Alexafiuor488 labelled goat anti-rabbit IgG (50 μl per well; Molecular Probes, Invitrogen Limited, Paisley, UK, Catalogue No. Al 1008) that had been diluted 1 :500 in 'blocking' buffer. Cells were washed 3 times with a mixture of PBS and 0.05% Tween-20. An aliquot of PBS (50 μl) was added to each well and the plates were sealed with black plate sealers and the fluorescence signal was detected and analysed.
Fluorescence dose response data obtained with each compound were analysed and the degree of inhibition of Serine 473 in Akt was expressed as an IC50 value.
(d) In Vitro MDA-MB-468 human breast adenocarcinoma Proliferation Assay
This assay determines the ability of test compounds to inhibit cell proliferation as assessed using Cellomics Arrayscan technology. A MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem, Catalogue No. HTB-132) was routinely maintained as described in Biological Assay (b) herein.
For the proliferation assay, the cells were detached from the culture flask using Accutase and seeded into the inner 60 wells of a black Packard 96 well plate at a density of 8000 cells per well in 100 μl of complete growth media. The outer wells contained 100 μl of sterile PBS. The cells were incubated overnight at 37°C with 5% CO2 to allow them to adhere. On day 2, the cells were treated with test compounds and incubated for 48 hours at
37°C with 5% CO2. Test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as required with growth media to give a range of test concentrations. Aliquots (50 μl) of each compound dilution were placed in a well and the cells were incubated for 2 days at 37°C with 5% CO2. Each plate contained control wells without test compound. On day 4, BrdU labelling reagent (Sigma, Catalogue No. B9285) at a final dilution of
1 : 1000 was added and the cells were incubated for 2 hours at 37°C. The medium was removed and the cells in each well were fixed by treatment with 100 μl of a mixture of ethanol and glacial acetic acid (90% ethanol, 5% glacial acetic acid and 5% water) for 30 minutes at room temperature. The cells in each well were washed twice with PBS (100 μl). Aqueous hydrochloric acid (2M, 100 μl) was added to each well. After 20 minutes at room temperature, the cells were washed twice with PBS. Hydrogen peroxide (3%, 50 μl; Sigma, Catalogue No. H 1009) was added to each well. After 10 minutes at room temperature, the wells were washed again with PBS.
BrdU incorporation was detected by incubation for 1 hour at room temperature with mouse anti-BrdU antibody (50 μl; Caltag, Burlingame, CA, US; Catalogue No. MD5200) that was diluted 1:40 in PBS containing 1% BSA and 0.05% Tween-20. Unbound antibody was removed with two washes of PBS. For visualisation of incorporated BrdU, the cells were treated for 1 hour at room temperature with PBS (50 μl) and 0.05% Tween-20 buffer containing a 1:1000 dilution of Alexa fluor 488-labelled goat anti-mouse IgG. For visualisation of the cell nucleus, a 1:1000 dilution of Hoechst stain (Molecular Probes, Catalogue No. H3570) was added. Each plate was washed in turn with PBS. Subsequently, PBS (100 μl) was added to each well and the plates were analysed using a Cellomics array scan to assess total cell number and number of BrdU positive cells.
Fluorescence dose response data obtained with each compound were analysed and the degree of inhibition of MDA-MB-468 cell growth was expressed as an IC50 value. Although the pharmacological properties of the compounds of formula (I) vary with structural change as expected, in general, it is believed that activity possessed by compounds of formula (I) may be demonstrated at the following concentrations or doses in one or more of the above tests (a) to (d) :-
Test (a)(i):- IC50 versus mTOR kinase at less than 10 μM, in particular 0.001 - 0.5 μM for many compounds; for example 2b the IC50 was measured on three occasions, the values were 0.059, 0.005 and 0.023μM.
Test (b)(i):- IC50 versus pi lOγ Type Ib human PBK at less than 10 μM, in particular 0.001 - 0.5 μM for many compounds; and IC50 versus pi 10a Type Ia human PBK at less than 10 μM, in particular 0.001 - 0.5 μM for many compounds; for example 2b the IC50 was measured, the value was 1.044 μM. Test (c):- IC50 versus Serine 473 in Akt at less than 10 μM, in particular 0.1 - 20 μM for many compounds); for example 2b the IC50 was measured on two occasions, the values were 0.052 and 0.025 μM. Test (d):- IC50 at less than 20 μM.
The following examples were tested in enzyme assay Test (a)(ii):
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Compounds may be further selected on the basis of further biological or physical properties which may be measured by techniques known in the art and which may be used in the assessment or selection of compounds for therapeutic or prophylactic application.
The compounds of the present invention are advantageous in that they possess pharmacological activity. In particular, the compounds of the present invention modulate (in particular, inhibit) mTOR kinase and/or phosphatidylinositol-3 -kinase (PI3K) enzymes, such as the Class Ia PI3K enzymes (e.g. PBKalpha, PBKbeta and PBKdelta) and the Class Ib PBK enzyme (PBKgamma). More particularly compounds of the present invention modulate (in particular, inhibit) mTOR kinase. More particularly compounds of the present invention modulate (in particular, inhibit) one or more PBK enzyme. The inhibitory properties of compounds of formula (I) may be demonstrated using the test procedures set out herein and in the experimental section. Accordingly, the compounds of formula (I) may be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and non-human animals which are mediated by mTOR kinase and/or one or more PBK enzyme(s), and in particular by mTOR kinase.
The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically acceptable diluent or carrier.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 1 mg to 1 g of active agent (more suitably from 1 to 250 mg, for example from 1 to 100 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. The size of the dose for therapeutic or prophylactic purposes of a compound of formula
I will naturally vary according to the nature and severity of the disease state, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
In using a compound of formula (I) for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 1 mg/kg to 100 mg/kg body weight is received, given if required in divided doses. In general, lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 1 mg/kg to 25 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 1 mg/kg to 25 mg/kg body weight will be used. Typically, unit dosage forms will contain about 10 mg to 0.5 g of a compound of this invention. As stated herein, it is known that mTOR kinase and the PBK enzymes have roles in tumourigenesis as well as numerous other diseases. We have found that the compounds of formula (I) possess potent anti-tumour activity which it is believed is obtained by way of inhibition of mTOR kinase and/or one or more of the PBK enzymes.
Accordingly, the compounds of the present invention are of value as anti-tumour agents. Particularly, the compounds of the present invention are of value as anti-proliferative, apoptotic and/or anti-invasive agents in the containment and/or treatment of solid and/or liquid tumour disease. Particularly, the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR and/or one or more of the PBK enzymes such as the Class Ia PBK enzymes and the Class Ib PBK enzyme. Further, the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are mediated alone or in part by mTOR and/or one or more of the PBK enzymes such as the Class Ia PBK enzymes and the Class Ib PBK enzyme. The compounds may thus be used to produce an mTOR enzyme inhibitory effect in a warm-blooded animal in need of such treatment. Certain compounds may be used to produce an PBK enzyme inhibitory effect in a warm-blooded animal in need of such treatment.
As stated herein, inhibitors of mTOR kinase and/or one or more PBK enzymes should be of therapeutic value for the treatment of proliferative disease such as cancer and in particular solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies and in particular for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias [including acute lymphoctic leukaemia (ALL) and chronic myelogenous leukaemia (CML)], multiple myeloma and lymphomas.
Anti-cancer effects which are accordingly useful in the treatment of cancer in a patient include, but are not limited to, anti-tumour effects, the response rate, the time to disease progression and the survival rate. Anti-tumour effects of a method of treatment of the present invention include but are not limited to, inhibition of tumour growth, tumour growth delay, regression of tumour, shrinkage of tumour, increased time to regrowth of tumour on cessation of treatment, slowing of disease progression. Anti-cancer effects include prophylactic treatment as well as treatment of existing disease. A mTOR kinase inhibitor, or a pharmaceutically acceptable salt thereof, may also be useful for the treatment patients with cancers, including, but not limited to, haematologic malignancies such as leukaemia, multiple myeloma, lymphomas such as Hodgkin's disease, non-Hodgkin's lymphomas (including mantle cell lymphoma), and myelodysplastic syndromes, and also solid tumours and their metastases such as breast cancer, lung cancer (non-small cell lung cancer (NSCL), small cell lung cancer (SCLC), squamous cell carcinoma), endometrial cancer, tumours of the central nervous system such as gliomas, dysembryoplastic neuroepithelial tumour, glioblastoma multiforme, mixed gliomas, medulloblastoma, retinoblastoma, neuroblastoma, germinoma and teratoma, cancers of the gastrointestinal tract such as gastric cancer, oesophagal cancer, hepatocellular (liver) carcinoma, cholangiocarcinomas, colon and rectal carcinomas, cancers of the small intestine, pancreatic cancers, cancers of the skin such as melanomas (in particular metastatic melanoma), thyroid cancers, cancers of the head and neck and cancers of the salivary glands, prostate, testis, ovary, cervix, uterus, vulva, bladder, kidney (including renal cell carcinoma, clear cell and renal oncocytoma), squamous cell carcinomas, sarcomas such as osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, gastrointestinal stromal tumour (GIST), Kaposi's sarcoma, and paediatric cancers such as rhabdomyosarcomas and neuroblastomas.
The compounds of the present invention and the methods of treatment comprising the administering or use of a mTOR kinase inhibitor, or a pharmaceutically acceptable salt thereof, are expected to be particularly useful for the treatment of patients with lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the central nervous system and their metastases, and also for the treatment of patients with acute myeloid leukaemia.
According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use as a medicament in a warm-blooded animal such as man.
According to a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.
According to a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the production of an apoptotic effect in a warm-blooded animal such as man.
According to a further feature of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and/or treatment of proliferative disease such as cancer.
According to a further aspect of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for the production of an anti-proliferative effect in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.
According to a further aspect of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for the production of an apoptotic effect in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the production of an apoptotic effect in a warmblooded animal such as man. According to a further feature of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in a warm-blooded animal such as man as an anti- invasive agent in the containment and/or treatment of proliferative disease such as cancer.
According to a further feature of this aspect of the invention there is provided a method for producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further feature of this aspect of the invention there is provided a method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the prevention or treatment of proliferative disease such as cancer in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is provided a method for the prevention or treatment of proliferative disease such as cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase and/or one or more PBK enzymes (such as the Class Ia enzymes and/or the Class Ib PBK enzyme) that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
According to a further feature of this aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase and/or one or more PBK enzymes (such as the Class Ia enzymes and/or the Class Ib PBK enzyme) that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
According to a further feature of this aspect of the invention there is provided a method for the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase and/or one or more PBK enzymes (such as the Class Ia enzymes and/or the Class Ib PBK enzyme) that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein. According to a further aspect of the invention there is provided a compound of formula
(I), or a pharmaceutically acceptable salt thereof, as defined herein for use in providing a mTOR kinase inhibitory effect and/or a PBK enzyme inhibitory effect (such as a Class Ia PBK enzyme or Class Ib PBK enzyme inhibitory effect).
According to a further feature of this aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in providing a mTOR kinase inhibitory effect and/or a PBK enzyme inhibitory effect (such as a Class Ia PBK enzyme or Class Ib PBK enzyme inhibitory effect).
According to a further aspect of the invention there is also provided a method for providing a mTOR kinase inhibitory effect and/or a PBK enzyme inhibitory effect (such as a Class Ia PBK enzyme or Class Ib PBK enzyme inhibitory effect) which comprises administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further feature of the invention there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases.
According to a further feature of the invention there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies.
According to a further feature of the invention there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate.
According to a further feature of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
According to a further feature of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, endometrium, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
According to a further feature of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the central nervous system and their metastases, and also for the treatment acute myeloid leukaemia.
According to a further feature of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases.
According to a further feature of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of of solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies.
According to a further feature of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate.
According to a further feature of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas. According to a further feature of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the treatment of lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the central nervous system and their metastases, and also for the treatment acute myeloid leukaemia.
According to a further feature of the invention there is provided a method for treating cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further feature of the invention there is provided a method for treating solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further feature of the invention there is provided a method for treating cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
According to a further feature of the invention there is provided a method for treating cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein. According to a further feature of the invention there is provided a method for treating lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the central nervous system and their metastases, and acute myeloid leukaemia in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
As stated herein, the in vivo effects of a compound of formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of formula (I). The invention further relates to combination therapies wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of formula (I) is administered concurrently or sequentially or as a combined preparation with another treatment of use in the control of oncology disease. In particular, the treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Accordingly, the compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of cancer. Suitable agents to be used in combination include :- (i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like paclitaxel and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecins); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, fiutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride;
(iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-(6-chloro- 2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin- 1 -yl)ethoxy]-5-tetrahydropyran- 4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-l-yl]-2-methylpyrimidin- 4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem.. 2004, 47, 6658- 6661), and metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);
(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™] and the anti-erbBl antibody cetuximab [C225]); such inhibitors also include, for example, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD 1839), Λ/-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-Λ/-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)quinazolin-4-amine (CI 1033) and erbB2 tyrosine kinase inhibitors such as lapatinib), inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006)) and inhibitors of cell signalling through MEK and/or Akt kinases; (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo- 2-fiuoroanilino)-6-methoxy-7-( 1 -methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy- 7-(3-pyrrolidin-l-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SUl 1248 (sunitinib; WO 01/60814), and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin)]; (vi) vascular damaging agents such as combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense agent;
(viii) gene therapy approaches, including approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
(ix) immunotherapeutic approaches, including ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
The invention will now be further explained by reference to the following illustrative examples.
Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received.
In the examples 1H NMR spectra were recorded on a Bruker DPX 300 (300 MHz), Bruker DRX 400 (400 MHz) instrument or a Bruker DRX 500 (500 MHz) instrument. The central peaks of chloroform-d (δH 7.27 ppm), dimethylsulfoxide-d6 (δH 2.50 ppm) or acetone-de (6H 2.05 ppm) were used as internal references. The following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.
Column chromatography was carried out using silica gel (0.04-0.063 mm, Merck). In general, a Kromasil KR- 100-5 -C 18 reversed-phase column (250 x 20 mm, Akzo Nobel) was used for preparative HPLC with mixtures of acetonitrile and water [containing 0.1% trifiuoroacetic acid (TFA)] used as the eluent at a flow rate of 10 mL/min.
The following methods were used for liquid chromatography (LC) / mass spectral (MS) analysis :- HPLC: Agilent 1100 or Waters Alliance HT (2790 & 2795)
Mass Spectrometer: Waters ZQ ESCi HPLC Column
The standard HPLC column used is the Phemonenex Gemini C18 5μm, 50 x 2 mm. Acidic HPLC Methods
The mobile phases used are: Mobile phase A: Water
Mobile Phase B: Acetonitrile
Mobile Phase C: 1 % Formic Acid in 50:50 WateπMeCN (v/v) Each method is followed by a rapid equilibration using a 5 mL flow rate for 0.45 min.
Four generic HPLC methods are available: 5 Minute Monitor Acidic method
Figure imgf000252_0001
Early Acidic method for early eluting compounds
Figure imgf000252_0002
Mid Acidic method for middle eluting compounds
Figure imgf000253_0001
Late Acidic method for late eluting compounds
Figure imgf000253_0002
Basic HPLC methods
In some instances the standard acidic methods may be unsuitable for either the compound ionisation or the chromatography separation required. In such cases four comparable Basic HPLC methods are available.
The mobile phases used are: Mobile phase A: Water Mobile Phase B: Acetonitrile
Mobile Phase D: 0.1% 880 Ammonia in acetonitrile
Each method is followed by a rapid equilibration using a 5 mL flow rate for 0.45 min. Minute Monitor Basic method
Figure imgf000254_0001
Early Basic method for early eluting compounds
Figure imgf000254_0002
Mid Basic method for middle eluting compounds
Figure imgf000254_0003
Late Basic method for late eluting compounds
Figure imgf000254_0004
The following method was used for liquid chromatography (LC) / mass spectral (MS) analysis :- Instrument: Agilent 1100; Column: Waters 'Symmetry' 2.1 x 30 mm; Mass
Spectral analysis using chemical ionisation (APCI); Flow rate: 0.7 mL/min; Absorption Wavelength: 254 nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA ;
Solvent Gradient: 15-95% Solvent B for 2.7 minutes followed by 95% Solvent B for 0.3 minutes.
The following methods were used for LC analysis :-
Method A :- Instrument: Agilent 1100; Column: Kromasil C18 reversed-phase silica, 100 x 3 mm, 5μm particle size; Solvent A: 0.1% TFA/water, Solvent B: 0.08%
TFA/acetonitrile; Flow Rate: 1 mL/min; Solvent Gradient: 10-100% Solvent B for 20 minutes followed by 100% Solvent B for 1 minute; Absorption Wavelengths: 220, 254 and 280 nm. In general, the retention time of the product was noted.
Method B :- Instrument: Agilent 1100; Column: Waters 'Xterra' C8 reversed-phase silica, 100 x 3 mm, 5μm particle size; Solvent A: 0.015M ammonia in water, Solvent B: acetonitrile; Flow Rate: 1 ml/min, Solvent Gradient: 10-100% Solvent B for 20 minutes followed by 100% Solvent B for 1 minute; Absorption Wavelength: 220, 254 and 280 nm. In general, the retention time of the product was noted.
The following abbreviations are used herein or within the following illustrative examples :-
HPLC High Performance Liquid Chromatography
HBTU O-(benzotriazol- 1 -yl)-NJVJf ^'-tetramethyluronium hexafiuorophosphate;
HATU O-(7-azabenzotriazol- 1 -yl)-Λ/,Λ/,Λf\Λ/"-tetramethyluronium hexafiuorophosphate;
HOBT 1-hydroxybenzotriazole; HOAT l-hydroxy-7-azabenzotriazole;
NMP 7V-methylpyrrolidin-2-one;
DMSO dimethylsulfoxide;
DMF 7V,7V-dimethylformamide;
DMA 7V,7V-dimethylacetamide; THF tetrahydrofuran;
DME 1 ,2-dimethoxyethane;
DCCI dicyclohexylcarbodiimide; MeOH methanol;
MeCN acetonitrile;
DCM dichloromethane;
DIPEA 7V,7V-diisopropylethylamine; DBU l,8-diazabicyclo[5.4.0]undec-7-ene;
RT room temperature (approximately 17 to 250C); tR retention time; m/z mass/charge ratio.
The chemical names were generated by software which used the Lexichem Toolkit (v. 1.60) from OpenEye Scientific Software (www.eyesopen.com) to generate IUPAC conforming names.
Example 1: 3-Ethyl-l-[4-[4-[(3SV3-methylmorpholin-4-yll-6-q- methylsulfonylcvclopropyl)pyrimidin-2-yll phenyll urea
Figure imgf000256_0001
To a solution of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidine (200 mg, 0.60 mmol) in ethanol was added toluene (1.00 mL), water (1.00 mL), [4-(3-ethylureido)phenyl]boronic acid, pinacol ester (262 mg, 0.90 mmol), tri-potassium orthophosphate (448 mg, 2.11 mmol) and palladiumbis(tri-tøt- butylphosphine) (18.55 mg, 0.04 mmol). The reaction was degassed then purged with nitrogen and heated at 800C for 2 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (5 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product which was purified by flash silica chromatography, elution gradient 0 to 10% (3.5M ammonia in methanol) in DCM, to give the desired material as a white solid (109 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.07 (3H, m), 1.23 (3H, d), 1.56 (2H, s), 1.67 (2H, s), 3.14 (2H, t), 3.22 (IH, m), 3.30 (3H, s), 3.48 (IH, t), 3.63 (IH, m), 3.76 (IH, d), 3.97 (IH, d), 4.21 (IH, d), 4.57 (IH, s), 6.16 (IH, t), 6.76 (IH, s), 7.50 (2H, d), 8.20 (2H, d), 8.66 (IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 460 ; HPLC tR = 1.83 min mTOR Kinase Assay (Echo): 0.00276μM
The following compound was made in an analogous fashion from the appropriate boronic ester.
Figure imgf000257_0002
Example Ia: 1R NMR (400.132 MHz, DMSO) δ 1.23 (3H, d), 1.31 (3H, s), 1.56 (2H, m), 1.67 (2H, m), 2.66 (3H, d), 3.22 (IH, m), 3.48 (IH, m), 3.63 (IH, m), 3.76 (IH, d), 3.97 (IH, m), 4.21 (IH, d), 4.57 (IH, s), 6.07 (IH, m), 6.76 (IH, s), 7.51 (2H, d), 8.19 (2H, d), 8.75 (IH, s) mTOR Kinase Assay (Echo): 0.00279μM
The preparation of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidine is described below.
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(l-methylsulfonylcvclopropyl)pyrimidine
Figure imgf000257_0001
2-Chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (1.2 g, 3.9 mmol) was dissolved in DMF (20 mL) and sodium tert-butoxide (755 mg, 7.85 mmol) was added to the reaction, followed by dibromoethane (738 mg, 3.9 mmol). The reaction was stirred at RT for 4 hours then at 600C overnight. Further sodium tert-butoxide (378 mg, 3.9 mmol) was added to the reaction, followed by dibromoethane (369 mg, 1.9 mmol) and the reaction stirred at 600C a further 24 hours. DCM (20 mL) was added and the reaction washed with 2M aqueous hydrochloric acid (20 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude solid was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material (400 mg, 31 %).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (d, 3H), 1.51 (m, 2H), 1.64 (m, 2H), 3.18 (s, 3H), 3.22 (m, IH), 3.43 (m, IH), 3.58 (m, IH), 3.72 (d, IH), 3.93 (m, IH), 4.05 (d, IH), 4.41 (s, IH), 6.93 (s, IH) LCMS Spectrum: m/z (ESI+)(M+H)+ 332, HPLC tR = 1.6 min
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(methylsulfonylmethvπpyrimidine
Figure imgf000258_0001
2,4-Dichloro-6-(methylsulfonylmethyl)pyrimidine (30 g, 0.13 mol) was dissolved in dichloromethane and stirred (under nitrogen) at -5°C. Triethylamine (17.4 mL, 0.13 mol) was added to give a clear brown solution. (35)-3-Methylmorpholine was dissolved in dichloromethane and added dropwise keeping the reaction below -5°C. The cooling bath was then removed and the mixture stirred for 1 hour. The reaction mixture was heated at reflux for 2 hours, then the reaction mixture was washed with water, dried then evaporated. The crude material was purified by preparative HPLC to give the desired material as a solid (19.3 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δl.21 - 1.23 (m, 3H), 3.11 (s, 3H), 3.19 - 3.26 (m, IH), 3.42 - 3.49 (m, IH), 3.58 - 3.62 (IH, m), 3.73 (d, IH), 3.92 - 3.96 (m, 2H), 4.27 ■ 4.31 (m, IH), 4.45 (s, 2H), 6.92 (s, IH) LCMS Spectrum: MH+ 306, retention time 1.42 min, Method 5 Min Acid
2,4-Dichloro-6-(methylsulfonylmethvDpyrimidine
Figure imgf000258_0002
6-(Methylsulfonylmethyl)-lH-pyrimidine-2,4-dione (132 g, 0.65 mol) was added to phosphorus oxychloride (1.2 L) and the mixture heated to reflux for 16 hours, then cooled to room temperature. The excess phosphorus oxychloride was removed in vacuo, the residue azeotroped with toluene (2 x 500 mL) and dissolved in dichloromethane. This mixture was then poured slowly onto ice (4 L) and stirred for 20 minutes, then extracted with dichloromethane (3 x 1 L) (the insoluble black material was filtered off and discarded) and ethyl acetate (2 x 1 L). The extracts were combined, dried, then evaporated to leave the desired material as a dark brown solid (51 g). The material was used without further purification. NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) 53.13 (s, 3H), 4.79 (s, 2H), 7.87 (s, IH) LCMS Spectrum: MH+ 239, retention time 1.21 min, Method 5 Min Acid
6-(MethylsulfonylmethyiyiH-pyrimidine-2,,4-dione
Figure imgf000259_0001
6-(Chloromethyl)-lH-pyrimidine-2,4-dione (175 g, 1.09 mol) was dissolved in DMF (2 L) and methanesulphinic acid sodium salt (133.5 g, 1.31 mol) was added. The reaction was heated to 125°C for 2 hours then allowed to cool and the suspension filtered and concentrated in vacuo to give a yellow solid. The crude material was washed with water, filtered, then triturated with toluene. The solid was filtered then triturated with isohexane to leave the desired compound as a yellow solid (250 g). The material was used without further purification.
6-(Chloromethyl)-lH-pyrimidine-2,4-dione is a commercially available material.
2-Chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidine can also be prepared by the method described below.
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(l-methylsulfonylcvclopropyl)pyrimidine
Figure imgf000259_0002
Sodium hydroxide (50%w/w solution) (115 g, 2877.88 mmol) was addedto 2-chloro-4-[(3S>3- methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (16 g, 52.33 mmol), 1,2- dibromoethane (13.53 ml, 156.98 mmol) and tetrabutylammonium bromide (1.687 g, 5.23 mmol) in toluene (128 mL) and the resulting suspension stirred at RT for 4 hours. Water was added and the mixture was extracted twice with toluene. The toluene was dried over MgSO4, filtered and evaporated. The crude product, 15g was purified by flash silicachromatography, elution gradient Oto 20% ethyl acetate in DCM, to give the desired material (13 g) as a white solid which was identical to previous samples.
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(methylsulfonylmethyl)pyrimidine
Figure imgf000260_0001
Methanesulfinic acid, sodium salt (11.75 g, 115.11 mmol) was added in one portion to 2- chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (37 g, 104.64 mmol), in acetonitrile (900 mL) and the resulting solution stirred at 85°Cfor 24 hours. The organic layers were combined and washed with water (3 x 100 mL), dried over MgSO4, filtered, and the solvent was removed by evaporation to give the crude product as a dark brown oil, which solidifed (36 g). The crude solidwas purified by flash silicachromatography, elution gradient 0 to 30% ethyl acetate in DCM, to give the desired material (22 g) as a cream solid which was identical to previous samples.
2-Chloro-4-(iodomethyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000260_0002
Methanesulfonyl chloride (0.245 mL, 3.14 mmol) was added dropwise over a period of 5 minutes to a solution of triethylamine (0.875 mL, 6.28 mmol) and [2-chloro-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-4-yl]methanol (510 mg, 2.09 mmol) in DCM (30 mL) at O0C under nitrogen. The resulting solution was stirred at RT for 45 minutes. The reaction mixture was diluted with water (20 mL). The organic layer was dried (MgSO4) and filtered. Sodium Iodide (1569 mg, 10.46 mmol) was added and the reaction was heated to 5O0C for 20 hours. The reaction mixture was filtered and evaporated to afford the desired material (761 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSO) δ 1.19 - 1.25 (3H, m), 3.18 - 3.22 (IH, m), 3.40 - 3.47 (IH, m), 3.57 - 3.60 (IH, m), 3.71 (IH, d), 3.90 - 3.94 (IH, m), 3.96 - 3.98 (IH, m), 4.28 - 4.32 (3H, m), 6.94 (IH, s).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 354; HPLC tR = 2.10 min.
2-Chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine can also be prepared by the dropwise addition of methanesulfonyl chloride (91 mL, 1169.52 mmol) to [2-chloro-6- [(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methanol (190 g, 779.68 mmol) and triethylamine (163 mL, 1169.52 mmol) in DCM (2293 mL) at O0C under air. The resulting solution was allowed to warm up slowly to RT over a period of 4 hours. The reaction mixture was quenched with water, extracted with DCM and the organic layer dried over MgSO4, filtered and evaporated to afford [2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4- yljmethyl methanesulfonate as a yellow gum (251 g). Sodium iodide (234 g, 1560.07 mmol) was added to this material in acetone (3679 mL) and the resulting suspension stirred at RT for 16 hours. The reaction mixture was evaporated to dryness and redissolved in DCM and washed three times with water then with a saturated aqueous solution of sodium thiosulphate. The organic layer was dried over MgSO4, filtered and evaporated to afford crude desired product (270 g). This was purified by chromatography to give an off white solid which was further triturated with ether to give the desired material which was identical to previous samples.
[2-Chloro-6-[(36f)-3-methylmorpholin-4-yllpyrimidin-4-yllmethanol
Figure imgf000261_0001
Methyl 2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylate (3.15 g) was dissolved in dry THF (20 mL) and cooled to O0C under nitrogen. A solution of lithium borohydride (2.0M in THF, 6.09mL) was added dropwise and the solution allowed to warm to RT and stirred for 1 hour. The reaction was quenched with water (20 mL) then evaporated to dryness, the residue dissolved in ethyl acetate (150 mL) and washed with water (150 mL) followed by brine (50 mL). The organics were evaporated to dryness to give to the desired material as a white solid (2.44 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO) δ 1.20 - 1.21 (3H, m), 3.18 - 3.22 (IH, m), 3.40 - 3.47 (IH, m), 3.56 - 3.60 (IH, m), 3.71 (IH, d), 3.91 - 3.94 (IH, m), 3.98 (IH, d), 4.35 (3H, d), 5.51 (IH, t), 6.74 (IH, s). Mass Spectrum; M+H+ 244.
[2-Chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methanol can also be prepared by the dropwise addition of lithium borohydride (2M in THF) (454 mL, 908.17 mmol) over a period of 15 minutes to a solution of methyl 2-chloro-6-[(35)-3-methylmorpholin-4- yl]pyrimidine-4-carboxylate (235 g, 864.92 mmol) in the THF (4701 mL) at O0C. The mixture was stirred at RT for 2 hours then water (1500 mL) was added slowly. A white solid formed which was decanted off and the THF was removed under vacuum. To the residue was added more water (500 mL), and extracted with ethyl acetate (3 x 700 mL). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to a white solid which was identical to previous samples.
Methyl 2-chloro-6- [(36^-3 -methylmorpholin-4-yllpyrimidine-4-carboxylate
Figure imgf000262_0001
Methyl 2,6-dichloropyrimidine-4-carboxylate (5 g) was dissolved in DCM (120 mL). (35)-3- Methylmorpholine (2.49 g) dissolved in triethylamine (3.70 mL) and DCM (10 mL) was added dropwise to the solution over 10 minute. The reaction was left to stir at room temperature for 1 hour. The reaction was then evaporated to dryness and dissolved in DCM (300 mL). The organics were washed once with water (150 mL) and dried (MgSO4), filtered and evaporated. The crude material was chromatographed on silica, eluting with 2.5% methanol in DCM, to give the desired material as a white solid (3.15 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO) δ 1.22 - 1.24 (3H, m), 3.25 (IH, d), 3.41 - 3.48 (IH, m), 3.57 - 3.61 (IH, m), 3.71 (IH, d), 3.87 (3H, s), 3.91 - 3.95 (IH, m), 4.25 (IH, s), 4.45 (IH, s), 7.29 (IH, s). Mass Spectrum; M+H+ 272.
Methyl 2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylate can also be prepared by the addition of methyl 2,6-dichloropyrimidine-4-carboxylate (250 g, 1207.65 mmol) to the DCM (2500 mL).Triethylamine (185 mL, 1328.41 mmol) was added and the reaction cooled to O0C. (35)-3-Methylmorpholine (128 g, 1268.03 mmol) dissolved in DCM (300 mL), was added dropwise over 30 minutes and the mixture stirred at 5° overnight. Water (800 mL) was added, the phases separated and the aquoeus layer extracted with DCM (300 mL). The combined organics were washed with brine (300 mL), dried over MgSO4, filtered and concentrated to a cream solid. The crude solid was dissolved in hot ethyl acetate (3 volumes) then isohexane (5 volumes) added the mixture left to cool with stirring over the weekend to give the desired material as a solid which was identical to previous samples.
Example 2: 3-Cvclopropyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yll-6-α- methylsulfonylcvclopr()pyl)pyrimidin-2-yll phenyll urea
Figure imgf000263_0001
To a solution of phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]carbamate (200 mg, 0.39 mmol) in DMF (2 mL) was added triethylamine (0.164 mL, 1.18 mmol) followed by cyclopropylamine (0.136 mL, 1.97 mmol) and the reaction heated at 500C for 2 hours.
The solvent was removed under reduced pressure to give the crude product which was purified by flash silica chromatography, elution gradient 0 to 10% (3.5M ammonia in methanol) in
DCM, to give the desired product as a white solid (168 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.42 (2H, m), 0.65 (2H, m), 1.24 (3H, d), 1.56 (2H, m), 1.67 (2H, m), 2.56 (3H, m), 3.21 (IH, m), 3.48 (IH, m), 3.63 (IH, m), 3.78
(IH, d), 3.97 (IH, m), 4.21 (IH, d), 4.57 (IH, s), 6.43 (IH, d), 6.77 (IH, s), 7.51 (2H, d), 8.20
(2H, d), 8.54 (IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 472; HPLC tR = 1.93 min. mTOR Kinase Assay (Echo): 0.0015μM
The compounds below were prepared in an analogous fashion using the appropriate amine.
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Both Example 2 and Example Ia can be prepared in an analogous fashion to that described above but using THF as a solvent. Example Ia can also be prepared in an analogous fashion to that described above but using NMP as a solvent.
Example 2a: 1R NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.56 (2H, s), 1.67 (2H, s), 3.21 (IH, m), 3.48 (IH, t), 3.63 (IH, d), 3.76 (4H, m), 3.80 (3H, s), 3.97 (IH, d), 4.13 (2H, d),
4.20 (IH, s), 4.57 (IH, s), 6.42 (IH, t), 6.77 (IH, s), 7.35 (IH, s), 7.51 (2H, d), 7.59 (IH, s),
8.20 (2H, d), 8.70 (IH, s) mTOR Kinase Assay (Echo): 0.0932μM
Example 2b: 1H NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.55 - 1.58 (2H, m), 1.66 - 1.69 (2H, m), 3.21 (IH, dt), 3.27 - 3.29 (IH, m), 3.29 (3H, s), 3.49 (IH, dt), 3.64 (IH, dd), 3.79
(3H, s), 3.98 (IH, dd), 4.22 (IH, d), 4.58 (IH, s), 6.78 (IH, s), 7.38 (IH, s), 7.55 (2H, d), 7.76
(IH, s), 8.23 (2H, d), 8.38 (IH, s), 8.84 (IH, s) mTOR Kinase Assay (Echo): 0.000169μM
Example 2c: 1U NMR (400.132 MHz, DMSOd6) δ 1.23-1.24 (3H, d), 1.54-1.69 (6H, m), 1.81-1.91 (2H, m), 2.18-2.25 (2H, m), 3.17-3.24 (IH, td), 3.29 (3H, s), 3.45-3.52 (IH, td), 3.62-3.65 (IH, dd), 3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.10-4.23 (2H, m), 4.57 (IH, bs),
6.45-6.47 (IH, d), 6.77 (IH, s), 7.47-7.50 (2H, d), 8.18-8.21 (2H, d), 8.57 (IH, s). mTOR Kinase Assay (Echo): 0.00121μM
Example 2d: 1H NMR (400.132 MHz, DMSOd6) δ 1.23-1.25 (3H, d), 1.55-1.66 (2H, q), 1.67-1.69 (2H, q), 3.17-3.25 (IH, td), 3.30 (3H, s), 3.45-3.52 (IH, td), 3.62-3.65 (IH, dd),
3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.20-4.23 (IH, d), 4.32-4.34 (2H, d), 4.57 (IH, bs), 6.61-
6.64 (IH, t), 6.77 (IH, s), 6.77 (2H, bs), 7.51-7.54 (2H, d), 8.21-8.22 (2H, d), 8.94 (IH, s),
11.84 (IH, bs). mTOR Kinase Assay (Echo): 0.0239μM Example 2e: 1U NMR (400.132 MHz, DMSOd6) δ 1.23-1.24 (3H, d), 1.54-1.58 (2H, q), 1.66-
1.69 (2H, q), 2.19 (6H, s), 2.33-2.36 (2H, t), 3.18-3.22 (2H, t), 3.20-3.25 (IH, td), 3.45-3.52
(IH, td), 3.62-3.65 (IH, dd), 3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.20-4.23 (IH, d), 4.57
(IH, bs), 6.15-6.18 (IH, t), 6.77 (IH, s), 7.49-7.51 (2H, d), 8.19-8.21 (2H, d), 8.90 (IH, s).
Note:methyl signal obscured by water peak at 3.29. mTOR Kinase Assay (Echo): 0.279μM
Example 2f: 1R NMR (400.132 MHz, DMSO-d6) δ 1.23-1.25(9H, d), 1.54-1.58 (2H, q), 1.66-
1.69 (2H, q), 3.17-3.25 (IH, td), 3.39-3.40 (2H, d), 3.45-3.52 (IH, td), 3.62-3.65 (IH, dd), 3.75-3.78 (IH, d), 3.96-4.00 (IH, dd), 4.20-4.23 (IH, d), 4.56 (IH, bs), 4.94-4.97 (IH, t), 6.01 (IH, s), 6.77 (IH, s), 7.45-7.47 (2H, d), 8.18-8.20 (2H, d), 8.74 (IH, s). Note:methyl signal obscured by water peak at 3.29. mTOR Kinase Assay (Echo): 0.00433μM
Example 2g: 1U NMR (400.132 MHz, DMSO-de) δ 1.24-1.25 (3H, d), 1.56-1.59 (2H, q), 1.67-
1.70 (2H, q), 3.19-3.26 (IH, td), 3.46-3.53 (IH, td), 3.62-3.66 (IH, dd), 3.76-3.79 (IH, d), 3.97-4.00 (IH, dd), 4.21-4.24 (IH, d), 4.58 (IH, bs), 6.81 (IH, s), 6.87-6.88 (IH, d), 7.57-7.59 (2H, d), 8.27-8.29 (2H, d), 8.75-8.76 (IH, d), 9.08 (lH,s), 9.62 (IH, s). Note:methyl signal obscured by water peak at 3.29. mTOR Kinase Assay (Echo): 0.000137μM
Example 2h: 1H NMR (400.132 MHz, DMSO-d6) δ 1.24-1.26 (3H, d), 1.56-1.59 (2H, q),
1.67-1.70 (2H, q), 3.18-3.26 (IH, td), 3.31 (3H, s), 3.46-3.53 (IH, td), 3.63-3.66 (IH, dd), 3.76-3.79 (IH, d), 3.96-4.00 (IH, dd), 4.21-4.24 (IH, d), 4.59 (IH, bs), 6.79 (IH, s), 6.98-7.01
(IH, t), 7.28-7.32 (2H, t), 7.46-7.48 (2H, d), 7.57-7.59 (2H, d), 8.25-8.27 (2H, d), 8.71 (IH, s),
8.92 (IH, s). mTOR Kinase Assay (Echo): 0.000272μM
Example 2i: 1H NMR (400.132 MHz, DMSO-d6) δ 1.23-1.24 (3H, d), 1.54-1.58 (2H, q), 1.65-
1.70 (2H, q), 3.16-3.25 (IH, td), 3.16-3.21 (2H, q), 3.45-3.52 (IH, td), 3.45-3.49 (2H, q), 3.62-
3.65 (IH, dd), 3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.20-4.23 (IH, d), 4.57 (IH, bs), 4.72- 4.74 (IH, t), 6.25-6.27 (IH, t), 6.77 (IH, s), 7.49-7.51 (2H, d), 8.19-8.21 (2H, d), 8.82 (IH, s).
Note:methyl signal obscured by water peak at 3.29. mTOR Kinase Assay (Echo): 0.00207μM
Example 2j: 1R NMR (400.132 MHz, DMSOd6) δ 1.11-1.12 (6H, d), 1.23-1.24 (3H, d), 1.54-
1.58 (2H, q), 1.66-1.69 (2H, q), 3.17-3.25 (IH, td), 3.45-3.52 (IH, td), 3.62-3.65 (IH, dd), 3.74-3.82 (2H, m), 3.96-3.99 (IH, dd), 4.20-4.23 (IH, d), 4.57 (IH, bs), 6.06-6.07 (IH, d), 6.77
(IH, s), 7.48-7.50 (2H, d), 8.19-8.21 (2H, d), 8.54 (IH, s). Note:methyl signal obscured by water peak at 3.29. mTOR Kinase Assay (Echo): 0.012μM
Example 2k: 1H NMR (400.132 MHz, DMSOd6) δ 0.87-0.91 (3H, t), 1.23-1.25 (3H, d), 1.42- 1.51 (2H, m), 1.54-1.58 (2H, q), 1.66-1.69 (2H, q), 3.05-3.09 (2H, q), 3.17-3.25 (IH, td), 3.45-
3.52 (IH, td), 3.61-3.65 (IH, dd), 3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.20-4.23 (IH, d),
4.57 (IH, bs), 6.19-6.22 (IH, t), 6.77 (IH, s), 7.49-7.51 (2H, d), 8.19-8.21 (2H, d), 8.66 (IH, s). Note:methyl signal obscured by water peak at 3.29. mTOR Kinase Assay (Echo): 0.00406μM Example 21: 1H NMR (400.132 MHz, DMSO-d6) δ 0.88-0.90 (6H, d), 1.23-1.25 (3H, d), 1.54-
1.58 (2H, q), 1.66-1.68 (2H, q), 1.67-1.76 (IH, m), 2.93-2.96 (2H, t), 3.17-3.25 (IH, td), 3.45- 3.52 (IH, td), 3.62-3.65 (IH, dd), 3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.20-4.23 (IH, d), 4.57 (IH, bs), 6.24-6.27 (IH, t), 6.77 (IH, s), 7.49-7.51 (2H, d), 8.19-8.21 (2H, d), 8.66 (IH, s). Note:methyl signal obscured by water peak at 3.29. mTOR Kinase Assay (Echo): 0.0116μM
Example 2m: 1H NMR (400.132 MHz, DMSO-d6) δ 0.18-0.22 (2H, m), 0.42-0.46 (2H, m), 0.93-1.00 (IH, m), 1.23-1.25 (3H, d), 1.54-1.58 (2H, q), 1.66-1.69 (2H, q), 2.98-3.01 (2H, t), 3.17-3.25 (IH, td), 3.45-3.52 (IH, td), 3.62-3.65 (IH, dd), 3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.20-4.23 (IH, d), 4.57 (IH, bs), 6.25-6.28 (IH, t), 6.77 (IH, s), 7.49-7.51 (2H, d), 8.19- 8.21 (2H, d), 8.70 (IH, s). Note:methyl signal obscured by water peak at 3.29. mTOR Kinase Assay (Echo): 0.00589μM Example 2n: 1H NMR (400.132 MHz, DMSO-d6) δ 1.08-1.10 (3H, d), 1.23-1.25 (3H, d),
1.54-1.57 (2H, q), 1.66-1.69 (2H, q), 2.98-3.01 (2H, t), 3.18-3.25 (IH, td), 3.30 (3H, s), 3.34-
3.43 (2H, m), 3.45-3.52 (IH, td), 3.62-3.65 (IH, dd), 3.69-3.75 (IH, m), 3.75-3.78 (IH, d),
3.96-3.99 (IH, dd), 4.20-4.23 (IH, d), 4.57 (IH, bs), 4.77-4.80 (IH, t), 6.09-6.11 (IH, d), 6.77 (IH, s), 7.48-7.50 (2H, d), 8.19-8.21 (2H, d), 8.72 (IH, s). mTOR Kinase Assay (Echo): 0.00844μM
Example 2o: 1R NMR (400.132 MHz, DMSO-de) δ 1.23-1.25 (3H, d), 1.56-1.59 (2H, q), 1.67-
1.70 (2H, q), 3.18-3.26 (IH, td), 3.30 (3H, s), 3.46-3.53 (IH, td), 3.62-3.66 (IH, dd), 3.76-3.79
(IH, d), 3.83 (3H, s), 3.96-4.00 (IH, dd), 4.21-4.24 (IH, d), 4.58 (IH, bs), 6.79(s, IH), 6.79- 6.81 (IH, d), 7.56-7.58 (2H, d), 7.83-7.86 (IH, dd), 8.21-8.22 (IH, d), 8.25-8.27 (2H, d), 8.62
(IH, s), 8.98 (IH, s). mTOR Kinase Assay (Echo): 0.000851 μM
Example 2p: 1H NMR (400.132 MHz, DMSOd6) δ 1.23-1.25 (3H, d), 1.55-1.58 (2H, q),
1.66-1.69 (2H, q), 3.18-3.25 (IH, td), 3.30 (3H, s), 3.46-3.52 (IH, td), 3.62-3.66 (IH, dd), 3.76-3.78 (IH, d), 3.96-4.00 (IH, dd), 4.21-4.24 (IH, d), 4.58 (IH, bs), 6.79(s, IH), 7.11-7.16
(2H, t), 7.46-7.50 (2H, m), 7.56-7.58 (2H, d), 8.24-8.27 (2H, d), 8.74 (IH, s), 8.92 (IH, s). mTOR Kinase Assay (Echo): 0.0027μM
Example 2q: 1H NMR (400.132 MHz, DMSO-d6) δ 1.24-1.25 (3H, d), 1.56-1.59 (2H, q),
1.67-1.70 (2H, q), 3.18-3.26 (IH, td), 3.30 (3H, s), 3.46-3.53 (IH, td), 3.62-3.66 (IH, dd), 3.76-3.79 (IH, d), 3.96-4.00 (IH, dd), 4.21-4.24 (IH, d), 4.58 (IH, bs), 6.80(s, IH), 7.14-7.17
(IH, m), 7.32-7.39 (IH, q), 7.56-7.59 (2H, d), 7.65-7.71 (IH, qd), 8.26-8.28 (2H, d), 8.93 (IH, s), 9.00 (IH, s). mTOR Kinase Assay (Echo): O.OOlμM
Example 2r: 1U NMR (400.132 MHz, DMSO-de) δ 1.24-1.25 (3H, d), 1.56-1.59 (2H, q), 1.67- 1.70 (2H, q), 2.26 (3H, s), 3.18-3.26 (IH, td), 3.30 (3H, s), 3.46-3.53 (IH, td), 3.62-3.66 (IH, dd), 3.76-3.79 (IH, d), 3.96-4.00 (IH, dd), 4.21-4.24 (IH, d), 4.58 (IH, bs), 6.79(s, IH), 7.09-
7.12 (2H, d), 7.34-7.36 (2H, d), 7.56-7.58 (2H, d), 8.24-8.27 (2H, d), 8.59 (IH, s), 8.87 (IH, s). mTOR Kinase Assay (Echo): 0.00066μM
Example 2s: 1R NMR (400.132 MHz, DMSO-de) δ 1.24-1.25 (3H, d), 1.56-1.59 (2H, q), 1.67- 1.70 (2H, q), 3.18-3.26 (IH, td), 3.46-3.53 (IH, td), 3.62-3.66 (IH, dd), 3.76-3.79 (IH, d),
3.96-4.00 (IH, dd), 4.21-4.24 (IH, d), 4.58 (IH, bs), 6.79(s, IH), 7.33-7.36 (2H, d), 7.50-7.52 (2H, d), 7.56-7.59 (2H, d), 8.25-8.27 (2H, d), 8.87 (IH, s), 8.97 (IH, s). Note:methyl signal obscured by water peak at 3.29 mTOR Kinase Assay (Echo): 0.00138μM
Example 2t: 1R NMR (400.132 MHz, DMSOd6) δ 1.24-1.25 (3H, d), 1.56-1.58 (2H, q), 1.67- 1.69 (2H, q), 3.18-3.25 (IH, td), 3.46-3.53 (IH, td), 3.62-3.66 (IH, dd), 3.73 (3H, s), 3.76-3.79 (IH, d), 3.96-4.00 (IH, dd), 4.21-4.24 (IH, d), 4.58 (IH, bs), 6.79(s, IH), 6.88-6.90 (2H, d), 7.36-7.38 (2H, d), 7.55-7.57 (2H, d), 8.24-8.26 (2H, d), 8.51 (IH, s), 8.84 (IH, s). Note:methyl signal obscured by water peak at 3.29 mTOR Kinase Assay (Echo): 0.00145μM Example 2u: 1H NMR (400.132 MHz, DMSOd6) δ 1.24-1.25 (3H, d), 1.56-1.59 (2H, q), 1.67-1.70 (2H, q), 2.38 (3H, s), 3.18-3.26 (IH, td), 3.46-3.53 (IH, td), 3.62-3.66 (IH, dd), 3.76-3.79 (IH, d), 3.96-4.00 (IH, dd), 4.21-4.24 (IH, d), 4.58 (IH, bs), 6.57 (IH, s), 6.80 (s, IH), 7.56-7.58 (2H, d), 8.27-8.29 (2H, d), 9.06 (IH, s), 9.47 (IH, s). Note:methyl signal obscured by water peak at 3.29 mTOR Kinase Assay (Echo): 0.00118μM
Example 2v: 1R NMR (400.132 MHz, DMSO-dg) δ 1.24-1.26 (3H, d), 1.56-1.59 (2H, q), 1.67- 1.70 (2H, q), 3.19-3.26 (IH, td), 3.31 (3H, s), 3.46-3.53 (IH, td), 3.63-3.66 (IH, dd), 3.76-3.79 (IH, d), 3.97-4.00 (IH, dd), 4.22-4.25 (IH, d), 4.58 (IH, bs), 6.80 (IH, s), 7.60-7.63 (2H, d), 7.72-7.77 (IH, td), 7.79-7.82 (IH, dd), 8.28-8.30 (3H, m), 9.40 (IH, s), 9.89 (IH, s). mTOR Kinase Assay (Echo): 0.00866μM
Example 2w: 1H NMR (400.132 MHz, DMSO-d6) δ 0.82 (6H, s), 1.23 (3H, d), 1.54 - 1.57 (2H, m), 3.00 (2H, d), 3.15 (2H, d), 3.18 - 3.24 (IH, m), 3.29 (3H, s), 3.48 (IH, dt), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 (IH, d), 4.21 (IH, d), 4.55 - 4.62 (2H, m), 6.24 (IH, t), 6.76 (IH, s), 7.49 (2H, d), 8.20 (2H, d), 8.77 (IH, s). mTOR Kinase Assay (Echo): 0.0685μM
Example 2x: 1U NMR (400.132 MHz, DMSO-de) δ 1.23 (3H, d), 1.54 - 1.57 (2H, m), 1.66 - 1.68 (2H, m), 2.70 (2H, t), 3.21 (IH, dt), 3.27 (3H, s), 3.35 - 3.40 (2H, m), 3.48 (IH, dt), 3.64 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.22 (IH, d), 4.57 (IH, s), 6.53 (IH, t), 6.77 (IH, s), 7.52 (2H, d), 8.21 (2H, d), 8.93 (IH, s). mTOR Kinase Assay (Echo): 0.00164μM
Example 2y: 1R NMR (400.132 MHz, DMSO-de) δ 1.23 (3H, d), 1.54 - 1.57 (2H, m), 1.65 - 1.67 (2H, m), 1.70 - 1.73 (4H, m), 2.46 - 2.50 (4H, m), 3.20 - 3.24 (4H, m), 3.27 (3H, s), 3.48 (IH, dt), 3.63 (IH, dd), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 3.97 (IH, dd), 4.21 (IH, d), 4.56
(IH, s), 6.19 (IH, t), 6.76 (IH, s), 7.50 (2H, d), 8.19 (2H, d), 8.88 (IH, s). mTOR Kinase Assay (Echo): 0.23μM
Example 2z: 1R NMR (400.132 MHz, DMSOd6) δ 1.23 (3H, d), 1.54 - 1.57 (2H, m), 1.66 - 1.68 (2H, m), 3.14 - 3.27 (IH, m), 3.29 (3H, s), 3.45 - 3.56 (2H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.05 - 4.11 (IH, m), 4.21 (IH, d), 4.57 (IH, s), 6.39 (IH, t), 6.49 (IH, d),
6.77 (IH, s), 7.51 (2H, d), 8.21 (2H, d), 8.94 (IH, s). mTOR Kinase Assay (Echo): 0.0181μM
Example 2aa: 1R NMR (400.132 MHz, DMSOd6) δ 1.11 (6H, s), 1.23 (3H, d), 1.54 - 1.57 (2H, m), 1.66 - 1.68 (2H, m), 3.06 (2H, d), 3.18 (IH, d), 3.22 (Η, dd), 3.29 (3H, s), 3.48 (IH, dt), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.21 (IH, d), 4.52 (IH, s), 4.57 (IH, s), 6.25
(IH, t), 6.76 (IH, s), 7.49 (2H, d), 8.20 (2H, d), 8.90 (IH, s). mTOR Kinase Assay (Echo): 0.0274μM
Example 2ab: 1H NMR (400.132 MHz, DMSO-d6) δ 0.63 - 0.67 (2H, m), 0.69 - 0.73 (2H, m), 1.23 (3H, d), 1.54 - 1.57 (2H, m), 1.66 - 1.68 (2H, m), 3.18 - 3.24 (IH, m), 3.29 (3H, s), 3.43 -
3.52 (3H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.21 (IH, d), 4.56 (IH, s), 4.83 (IH, s), 6.57 (IH, s), 6.77 (IH, s), 7.48 (2H, d), 8.20 (2H, d), 8.69 (IH, s). mTOR Kinase Assay (Echo): 0.0553μM
Example 2ac: 1R NMR (400.132 MHz, DMSO-de) δ 1.23 (3H, d), 1.54 - 1.57 (2H, m), 1.66 - 1.68 (2H, m), 3.17 - 3.24 (IH, m), 3.29 (3H, s), 3.48 (IH, dt), 3.63 (IH, dd), 3.76 (IH, d), 3.97
(IH, dd), 4.21 (IH, d), 4.44 (2H, t), 4.56 (IH, s), 4.72 - 4.82 (3H, m), 6.77 (IH, s), 6.95 (IH, d), 7.50 (2H, d), 8.20 (2H, d), 8.78 (IH, s). mTOR Kinase Assay (Echo): 0.00641μM
Example 2ad: 1H NMR (400.132 MHz, DMSO-d6) δ 1.24 (3H, d), 1.55 - 1.58 (2H, m), 1.66 - 1.69 (2H, m), 3.17 - 3.25 (IH, m), 3.27 (3H, s), 3.49 (IH, dt), 3.64 (IH, dd), 3.74 (3H, s), 3.77
(IH, d), 3.98 (IH, dd), 4.22 (IH, d), 4.57 (IH, s), 6.25 (IH, d), 6.79 (IH, s), 7.54 (IH, t), 7.57
(2H, d), 8.25 (2H, d), 8.92 (IH, s), 9.18 (IH, s). mTOR Kinase Assay (Echo): 0.000705μM
Example 2ae: 1R NMR (400.132 MHz, DMSO-de) δ 1.25 (3H, d), 1.56 - 1.59 (2H, m), 1.67 - 1.70 (2H, m), 3.17 - 3.23 (IH, m), 3.27 (3H, s), 3.49 (IH, dt), 3.64 (IH, dd), 3.77 (IH, d), 3.98
(IH, dd), 4.24 (IH, d), 4.58 (IH, s), 6.81 (IH, s), 7.64 (2H, d), 8.30 (2H, d), 8.35 (IH, s), 9.46
(IH, s). mTOR Kinase Assay (Echo): 0.00072μM
Example 2af: 1H NMR (400.132 MHz, DMSO-d6) δ 1.25 (3H, d), 1.57 - 1.60 (2H, m), 1.68 - 1.71 (2H, m), 3.18 - 3.24 (IH, m), 3.27 (3H, s), 3.50 (IH, d), 3.65 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.08 (2H, s), 4.25 (IH, d), 4.61 (IH, s), 6.86 (IH, s), 7.55 (2H, d), 8.14 (IH, s), 8.35 (2H, d), 8.44 (IH, d). mTOR Kinase Assay (Echo): 0.0462μM
Example 2ag: 1R NMR (400.132 MHz, DMSOd6) δ 1.23 (3H, d), 1.54 - 1.57 (2H, m), 1.66 - 1.68 (2H, m), 3.18 (IH, d), 3.22 (IH, dd), 3.49 (IH, dt), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.21 (IH, d), 4.38 (2H, s), 4.44 (IH, s), 4.57 (IH, s), 6.66 (IH, d), 6.77 (IH, s), 7.52 (2H, d), 8.19 (IH, d), 8.21 (2H, d), 8.95 (IH, s), 13.83 (IH, s), 13.83 (IH, s). mTOR Kinase Assay (Echo): 0.0149μM
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]carbamate is described below:
Phenyl N- [4- [4- [(36^-3 -methylmorpholin-4-yll -6-( 1 -methylsulfonylcvclopropyDpyrimidin-2- vHphenyli carbamate
Figure imgf000276_0001
To a solution of 4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]aniline (1.35 g, 3.48 mmol) in 1,4-Dioxane (17.4 mL) was added sodium bicarbonate (0.438 g, 5.21 mmol) and phenyl chloro formate (0.437 mL, 3.48 mmol) and the reaction stirred at RT for 2 hours. The reaction mixture was diluted with DCM (20 mL), and washed with water (20 mL), the organic layer dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a white solid (1.058 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO) δ 1.24 (3H, d), 1.57 (2H, m), 1.68 (2H, m), 3.23 (IH, m), 3.49 (IH, m), 3.58 (3H, s), 3.64 (IH, m), 3.77 (IH, d), 3.97 (IH, m), 4.23 (IH, d), 4.58 (IH, s), 6.81 (IH, s), 7.25 (2H, d), 7.30 (IH, d), 7.45 (2H, m), 7.64 (2H, d), 8.30 (2H, d), 10.44 (IH, s)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 509; HPLC tR = 2.48 min.
4-[4-[(35)-3-Methylmorpholin-4-yll-6-(l-methylsulfonylcvclopropyπpyrimidin-2-yllaniline
Figure imgf000277_0001
To a solution of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidine (1.52 g, 4.58 mmol) in DMF (0.24 mL), DME (9.33 mL), water (4.0 mL) and ethanol (2.67 mL) was added 4-(tert- butoxycarbonylamino)phenylboronic acid (1.629 g, 6.87 mmol), sodium carbonate (5.73 mL, 11.45 mmol), and dichlorobis(triphenylphosphine)palladium(II) (0.161 g, 0.23 mmol) and the suspension heated at 800C for 2 hours. The reaction mixture was cooled to RT, diluted with ethyl acetate (10 mL) and washed with water (10 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was dissolved in DCM (6.67 mL) and trifluoroacetic acid (0.353 mL, 4.58 mmol) added and the reaction was stirred at RT for 16 hours. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% (7.5N ammonia in methanol) in DCM, to give the desired material as a beige solid (1.283 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO) δ 1.24 (3H, d), 1.55 (2H, m), 1.67 (2H, m), 3.23 (IH, m), 3.27 (3H, s), 3.47 (IH, m), 3.63 (IH, m), 3.77 (IH, d), 3.97 (IH, m), 4.24 (IH, s), 4.58 (IH, s), 5.75 (IH, s), 6.68 (2H, d), 8.04 (2H, d) LCMS Spectrum: m/z (ESI+) (M+H)+ = 389; HPLC tR = 1.82 min. Example 3 : 3-Cvclopropyl- 1- [4- rø-d-cyclopropylsulfonylcyclopropyD-θ- K3SV3- methylmorpholin-4-yll pyrimidin-2-yll phenyll urea
Figure imgf000278_0001
[4-(3-Cyclopropylureido)phenyl]boronic acid, pinacol ester (199 mg, 0.66 mmol), 2-chloro-4- (l-cyclopropylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (189mg, 0.53 mmol), dichlorobis(triphenylphosphine)palladium(II) (37.1 mg, 0.05 mmol) and sodium carbonate (1.32 mL, 2.64 mmol) were dissolved in a solution of 18% DMF in DME:Water:Ethanol 7:3:2 (4 mL) and sealed into a microwave tube. The reaction was heated to 1000C for 20 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol and pure fractions were evaporated to dryness to afford a crude product. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a colourless gum (69.0 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO) δ 0.40 - 0.44 (2H, m), 0.62 - 0.67 (2H, m), 0.91 - 0.97 (IH, m), 0.94 (IH, s), 1.02 - 1.04 (2H, m), 1.23 (3H, t), 1.55 - 1.58 (2H, m), 1.64 - 1.66 (2H, m), 2.56 (IH, s), 2.98 - 3.02 (IH, m), 3.18 (IH, d), 3.46 - 3.52 (IH, m), 3.62 - 3.66 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.17 - 4.21 (IH, m), 4.53 (IH, s), 6.42 (IH, d), 6.85 (IH, s), 7.49 - 7.51 (2H, m), 8.20 - 8.22 (2H, m), 8.53 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 498; HPLC tR = 1.95 min. mTOR Kinase Assay (Echo): 0.00195μM
Example 3 , 3 -cyclopropyl- 1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropyl)-6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, may also be prepared as described below.
To a solution of phenyl Λ/-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (150 mg, 0.28 mmol) in DMF (2 mL) was added triethylamine (0.177 mL, 0.84 mmol) followed by cyclopropylamine (0.097 mL, 1.40mmol) and the reaction heated at 500C for 2 hours. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and acetonitrile as eluents, to give the desired material as a white solid (103 mg). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.40 - 0.44 (2H, m), 0.62 - 0.67 (2H, m), 0.90 - 0.97 (2H, m), 1.02 - 1.04 (2H, m), 1.24 (3H, d), 1.56 - 1.60 (2H, m), 1.65 (2H, d), 2.60 (IH, t), 2.96 - 3.02 (IH, m), 3.20 - 3.24 (IH, m), 3.46 - 3.52 (IH, m), 3.62 - 3.66 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.19 (IH, d), 4.53 (IH, s), 6.42 (IH, d), 6.85 (IH, s), 7.50 (2H, d), 8.21 (2H, d), 8.53 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 498; HPLC tR = 2.13 min.
The following compounds were prepared in an analogous fashion from phenyl N-[4-[4-(l- cyclopropylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate using the appropriate amine.
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Example 3a: 1H NMR (400.13 MHz, DMSOd6) δ 0.90 - 0.97 (2H, m), 1.02 - 1.04 (2H, m), 1.23 (3H, d), 1.56 - 1.59 (2H, m), 1.63 (2H, d), 1.65 (2H, d), 1.83 (IH, d), 1.86 (IH, t), 2.17 - 2.25 (2H, m), 2.97 - 3.01 (IH, m), 3.17 - 3.24 (IH, m), 3.46 - 3.52 (IH, m), 3.62 - 3.66 (IH, m), 3.77 (IH, d), 3.96 - 3.99 (IH, m), 4.11 - 4.17 (IH, m), 4.20 (IH, s), 4.53 (IH, d), 6.45 (IH, d), 6.84 (IH, s), 7.46 - 7.48 (2H, m), 8.20 (2H, d), 8.55 (IH, s). mTOR Kinase Assay (Echo): 0.00445μM
Example 3b: 1H NMR (400.13 MHz, DMSOd6) δ 0.88 - 0.98 (2H, m), 0.99 - 1.06 (2H, m), 1.25 (3H, d), 1.57 - 1.62 (2H, m), 1.65 - 1.68 (2H, m), 2.99 - 3.05 (IH, m), 3.19 - 3.23 (IH, m), 3.47 - 3.54 (IH, m), 3.63 - 3.67 (IH, m), 3.78 (IH, d), 3.97 - 4.01 (IH, m), 4.21 (IH, d), 4.54 (IH, d), 6.88 (IH, s), 7.02 - 7.05 (IH, m), 7.56 (IH, d), 7.63 (2H, d), 7.75 - 7.77 (IH, m), 8.29 - 8.31 (3H, m), 9.44 (IH, d), 10.58 (IH, s). mTOR Kinase Assay (Echo): 0.00385μM
Example 3c: 1R NMR (400.13 MHz, DMSOd6) δ 0.88 - 0.90 (6H, m), 0.94 (2H, t), 1.00 - 1.06 (2H, m), 1.24 (3H, d), 1.55 - 1.58 (2H, m), 1.64 - 1.66 (2H, m), 1.67 - 1.74 (IH, m), 2.94 (2H, t), 2.98 - 3.02 (IH, m), 3.20 - 3.24 (IH, m), 3.46 - 3.52 (IH, m), 3.62 - 3.66 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.19 (IH, d), 4.53 (IH, s), 6.23 (IH, t), 6.84 (IH, s), 7.47 - 7.50 (2H, m), 8.20 - 8.22 (2H, m), 8.63 (IH, s). mTOR Kinase Assay (Echo): 0.0124μM Example 3d: 1H NMR (400.13 MHz, DMSOd6) δ 0.91 - 0.97 (2H, m), 1.00 - 1.05 (2H, m), 1.11 (6H, d), 1.23 (3H, d), 1.55 - 1.58 (2H, m), 1.64 - 1.66 (2H, m), 2.97 - 3.03 (IH, m), 3.17 - 3.24 (IH, m), 3.46 - 3.52 (IH, m), 3.62 - 3.66 (IH, m), 3.76 (2H, d), 3.96 - 4.00 (IH, m), 4.19 (IH, d), 4.53 (IH, s), 6.05 (IH, d), 6.84 (IH, s), 7.46 - 7.49 (2H, m), 8.19 - 8.22 (2H, m), 8.52 (IH, s). mTOR Kinase Assay (Echo): 0.0135μM
Example 3e: 1R NMR (400.13 MHz, DMSO-d6) δ 0.92 - 0.94 (2H, t), 1.02 - 1.04 (2H, m), 1.07 (3H, t), 1.23 (3H, d), 1.58 (2H, d), 1.64 - 1.66 (2H, m), 2.98 - 3.02 (IH, m), 3.17 - 3.18 (IH, m), 3.14 - 3.24 (2H, m), 3.47 - 3.52 (IH, m), 3.62 - 3.66 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.19 (IH, d), 4.53 (IH, s), 6.15 (IH, t), 6.84 (IH, s), 7.47 - 7.51 (2H, m), 8.19 - 8.22 (2H, m), 8.65 (IH, s). mTOR Kinase Assay (Echo): 0.00166μM
Example 3f: 1U NMR (400.13 MHz, DMSO-d6) δ 0.91 - 0.97 (2H, m), 0.98 - 1.05 (2H, m), 1.23 (3H, d), 1.55 - 1.58 (2H, m), 1.64 - 1.66 (2H, m), 2.18 (6H, s), 2.34 (2H, t), 2.97 - 3.03 (IH, m), 3.19 (3H, q), 3.46 - 3.52 (IH, m), 3.62 - 3.66 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.19 (IH, d), 4.53 (IH, s), 6.15 (IH, t), 6.84 (IH, s), 7.47 - 7.50 (2H, m), 8.19 - 8.22 (2H, m), 8.88 (IH, s). mTOR Kinase Assay (Echo): 0.0214μM
Example 3g: 1R NMR (400.13 MHz, DMSO-d6) δ 0.91 - 0.97 (2H, m), 1.00 - 1.05 (2H, m), 1.23 (3H, d), 1.55 - 1.58 (2H, m), 1.64 - 1.66 (2H, m), 2.97 - 3.03 (IH, m), 3.16 - 3.21 (3H, m), 3.44 - 3.52 (3H, m), 3.62 - 3.66 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.17 - 4.21 (IH, m), 4.53 (IH, s), 4.72 (IH, t), 6.25 (IH, t), 6.84 (IH, s), 7.47 - 7.50 (2H, m), 8.20 - 8.22 (2H, m), 8.79 (IH, s). mTOR Kinase Assay (Echo): 0.00134μM
Example 3h: 1H NMR (400.13 MHz, DMSO-d6) δ 0.89 (3H, t), 0.91 - 0.95 (2H, m), 1.02 -
1.04 (2H, m), 1.23 (3H, d), 1.41 - 1.50 (2H, m), 1.56 - 1.60 (2H, m), 1.64 - 1.66 (2H, m), 2.98
- 3.02 (IH, m), 3.04 - 3.09 (2H, m), 3.20 - 3.24 (IH, m), 3.47 - 3.52 (IH, m), 3.62 - 3.66 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.19 (IH, d), 4.53 (IH, s), 6.20 (IH, t), 6.84 (IH, s),
7.47 - 7.50 (2H, m), 8.20 - 8.22 (2H, m), 8.64 (IH, s). mTOR Kinase Assay (Echo): 0.0165μM
Example 3i: 1H NMR (400.13 MHz, DMSOd6) δ 0.92 - 0.95 (2H, m), 1.02 - 1.05 (2H, m),
1.23 (3H, d), 1.56 - 1.60 (2H, m), 1.63 - 1.66 (2H, m), 2.66 (3H, d), 2.98 - 3.02 (IH, m), 3.17 - 3.24 (IH, m), 3.46 - 3.52 (IH, m), 3.62 - 3.66 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m),
4.19 (IH, d), 4.53 (IH, s), 6.05 (IH, t), 6.84 (IH, s), 7.48 - 7.51 (2H, m), 8.19 - 8.22 (2H, m), 8.73 (IH, s). mTOR Kinase Assay (Echo): 0.000932μM
Example 3j: 1U NMR (400.13 MHz, DMSOd6) δ 0.92 - 0.98 (2H, m), 1.01 - 1.05 (2H, m), 1.25 (3H, d), 1.57 - 1.62 (IH, m), 1.61 (IH, d), 1.65 - 1.68 (2H, m), 2.97 - 3.04 (IH, m), 3.22
- 3.26 (IH, m), 3.47 - 3.53 (IH, m), 3.63 - 3.67 (IH, m), 3.78 (IH, d), 3.97 - 4.00 (IH, m), 4.21 (IH, d), 4.55 (IH, s), 6.87 (IH, s), 7.57 - 7.59 (2H, m), 7.63 - 7.70 (4H, m), 8.29 (2H, d), 9.04 (1H, s), 9.13 (IH, s). mTOR Kinase Assay (Echo): 0.00422μM Example 3k: 1H NMR (400.13 MHz, DMSO-d6) δ 0.94 (2H, t), 1.04 (2H, d), 1.23 (6H, d),
1.24 (3H, d), 1.56 - 1.59 (2H, m), 1.64 - 1.66 (2H, m), 2.98 - 3.02 (IH, m), 3.18 (IH, d), 3.39 (2H, d), 3.46 - 3.52 (IH, m), 3.62 - 3.66 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.19 (IH, d), 4.52 (IH, s), 4.95 (IH, t), 6.00 (IH, s), 6.84 (IH, s), 7.43 - 7.47 (2H, m), 8.19 - 8.21 (2H, m), 8.73 (IH, s). mTOR Kinase Assay (Echo): 0.00227μM
Example 31: 1H NMR (400.13 MHz, DMSO-d6) δ 0.91 - 0.94 (2H, m), 1.01 - 1.05 (2H, m), 1.23 (3H, d), 1.55 - 1.58 (2H, m), 1.60 -1.61 (2H, m), 1.65 (IH, m), 2.98 - 3.02 (IH, m), 3.17 (IH, d), 3.18 - 3.23 (2H, m), 3.45 - 3.49 (3H, m), 3.50 (IH, d), 3.62 - 3.66 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.17 (IH, s), 4.47 (IH, t), 4.53 (IH, s), 6.20 (IH, t), 6.84 (IH, s), 7.48 - 7.50 (2H, m), 8.21 (2H, d), 8.70 (IH, s). mTOR Kinase Assay (Echo): 0.00257μM Example 3m: 1H NMR (400.13 MHz, DMSO-d6) δ 0.93 - 0.95 (2H, m), 1.02 - 1.05 (2H, m), 1.24 (3H, d), 1.57 - 1.60 (2H, m), 1.65 - 1.67 (2H, m), 2.98 - 3.02 (IH, m), 3.18 (IH, t), 3.46 - 3.50 (IH, m), 3.63 - 3.66 (IH, m), 3.76 (IH, s), 3.79 (3H, s), 3.96 - 4.00 (IH, m), 4.18 (IH, s), 4.53 (IH, s), 6.86 (IH, s), 7.38 - 7.38 (IH, m), 7.55 (2H, t), 7.76 (IH, s), 8.25 (2H, d), 8.38 (IH, s), 8.83 (IH, s). mTOR Kinase Assay (Echo): 0.000497μM
Example 3n: 1H NMR (400.13 MHz, DMSOd6) δ 0.81 (6H, s), 0.91 - 0.95 (2H, m), 1.01 - 1.05 (2H, m), 1.23 (3H, d), 1.56 - 1.60 (3H, m), 1.63 - 1.66 (2H, m), 2.98 - 3.02 (2H, m), 3.15 (2H, d), 3.21 (IH, dt), 3.49 (IH, dt), 3.64 (IH, dd), 3.77 (IH, d), 4.19 (IH, d), 4.53 (IH, s), 4.61 (IH, t), 6.26 (IH, t), 6.84 (IH, s), 7.48 (2H, d), 8.21 (2H, d), 8.78 (IH, s). mTOR Kinase Assay (Echo): 0.0396μM Example 3o: 1U NMR (400.13 MHz, DMSOd6) δ 0.90 - 0.95 (2H, m), 1.00 - 1.06 (2H, m),
1.24 (3H, d), 1.56 - 1.60 (2H, m), 1.63 - 1.66 (2H, m), 2.70 (2H, t), 2.96 - 3.03 (IH, m), 3.17 -
3.25 (IH, m), 3.35 - 3.39 (2H, m), 3.49 (IH, dt), 3.64 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.19 (IH, d), 4.53 (IH, s), 6.52 (IH, t), 6.85 (IH, s), 7.51 (2H, d), 8.22 (2H, d), 8.91 (IH, s). mTOR Kinase Assay (Echo): 0.00596μM
Example 3p: 1H NMR (400.13 MHz, DMSO-d6) δ 0.93 - 0.94 (2H, m), 1.02 - 1.04 (2H, m), 1.23 (3H, d), 1.56 - 1.58 (2H, m), 1.64 - 1.67 (2H, m), 1.72 (8H, m), 2.94 - 3.02 (IH, m), 3.18 - 3.24 (5H, m), 3.49 (IH, t), 3.64 (IH, d), 3.77 (IH, d), 3.97 (IH, d), 4.19 (IH, d), 4.53 (IH, s), 6.22 (IH, s), 6.84 (IH, s), 7.49 (2H, d), 8.21 (2H, d), 8.88 (IH, s). mTOR Kinase Assay (Echo): 0.193μM
Example 3q: 1H NMR (400.13 MHz, DMSO-d6) δ 0.91 - 0.95 (2H, m), 1.00 - 1.06 (2H, m), 1.23 (3H, d), 1.56 - 1.60 (2H, m), 1.63 - 1.66 (2H, m), 2.96 - 3.03 (IH, m), 3.14 - 3.25 (2H, m), 3.46 - 3.55 (2H, m), 3.64 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.07 - 4.08 (IH, m), 4.19 (IH, d), 4.52 (IH, s), 6.42 (IH, t), 6.49 (IH, s), 6.85 (IH, s), 7.50 (2H, d), 8.22 (2H, d), 8.95 (IH, s). mTOR Kinase Assay (Echo): 0.00839μM
Example 3r: 1R NMR (400.13 MHz, DMSO-d6) δ 0.91 - 0.95 (2H, m), 1.00 - 1.06 (2H, m), 1.10 (6H, s), 1.23 (3H, d), 1.56 - 1.60 (2H, m), 1.61 - 1.66 (2H, m), 2.97 - 3.02 (IH, m), 3.06 (2H, d), 3.22 (IH, dd), 3.49 (IH, dt), 3.64 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.19 (IH, d), 4.52 (IH, s), 4.54 (IH, s), 6.24 (IH, t), 6.84 (IH, s), 7.48 (2H, d), 8.21 (2H, d), 8.88 (IH, s). mTOR Kinase Assay (Echo): 0.0488μM Example 3s: 1U NMR (400.13 MHz, DMSO-d6) δ 0.63 - 0.67 (2H, m), 0.69 - 0.73 (2H, m), 0.91 - 0.95 (2H, m), 1.02 - 1.04 (2H, m), 1.23 (3H, d), 1.56 - 1.60 (2H, m), 1.63 - 1.66 (2H, m), 2.97 - 3.03 (IH, m), 3.17 - 3.25 (2H, m), 3.44 (IH, d), 3.46 - 3.52 (IH, m), 3.64 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.19 (IH, d), 4.52 (IH, s), 4.83 (IH, s), 6.56 (IH, s), 6.85 (IH, s), 7.47 (2H, d), 8.21 (2H, d), 8.67 (IH, s). mTOR Kinase Assay (Echo): 0.0263μM
Example 3t: 1R NMR (400.13 MHz, DMSOd6) δ 0.91 - 0.95 (2H, m), 1.00 - 1.07 (2H, m), 1.23 (3H, d), 1.56 - 1.61 (2H, m), 1.63 - 1.66 (2H, m), 2.96 - 3.02 (IH, m), 3.21 (IH, dt), 3.49 (IH, dt), 3.64 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.19 (IH, d), 4.45 (2H, t), 4.52 (IH, s), 4.72 - 4.83 (3H, m), 6.85 (IH, s), 6.95 (IH, d), 7.49 (2H, d), 8.22 (2H, d), 8.78 (IH, s). mTOR Kinase Assay (Echo): 0.00479μM Example 3u: 1H NMR (400.13 MHz, DMSOd6) δ 0.91 - 0.95 (2H, m), 1.00 - 1.07 (2H, m),
1.23 (3H, d), 1.56 - 1.61 (2H, m), 1.63 - 1.66 (2H, m), 2.96 - 3.02 (IH, m), 3.21 (IH, dt), 3.49 (IH, dt), 3.64 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.19 (IH, d), 4.45 (2H, t), 4.52 (IH, s), 4.72 - 4.83 (3H, m), 6.85 (IH, s), 6.95 (IH, d), 7.49 (2H, d), 8.22 (2H, d), 8.78 (IH, s). mTOR Kinase Assay (Echo): 0.000604μM Example 3v: 1R NMR (400.13 MHz, DMSO-d6) δ 0.94 - 0.96 (2H, m), 1.03 - 1.05 (2H, m),
1.24 (3H, d), 1.57 - 1.59 (2H, m), 1.64 - 1.66 (2H, m), 2.98 - 3.03 (IH, m), 3.19 - 3.25 (IH, m), 3.50 (IH, t), 3.65 (IH, d), 3.74 (3H, s), 3.77 (IH, d), 3.98 (IH, d), 4.21 (IH, d), 4.54 (IH, s), 6.24 (IH, d), 6.86 (IH, s), 7.54 - 7.55 (IH, m), 7.56 (2H, d), 8.26 (2H, d), 8.92 (IH, s), 9.17 (IH, s). Example 3w: 1H NMR (400.13 MHz, DMSO-d6) δ 0.92 - 0.96 (2H, m), 1.02 - 1.06 (2H, m),
1.25 (3H, d), 1.58 - 1.60 (2H, m), 1.66 - 1.67 (2H, m), 2.98 - 3.05 (IH, m), 3.20 - 3.23 (IH, m), 3.50 (IH, t), 3.65 (IH, d), 3.78 (IH, d), 3.99 (IH, d), 4.21 (IH, d), 4.55 (IH, s), 6.89 (IH, s), 7.63 (2H, d), 8.31 - 8.36 (3H, m), 9.43 (IH, s). mTOR Kinase Assay (Echo): 0.00089μM
The preparation of phenyl Λ/-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below: Phenyl N- [4- [4-(1-CVCIOPrOPVISUIfOnVIcVcIoPrOPvI)-O- [(36^-3 -methylmorpholin-4- vHpyrimidin-2-vHphenvHcarbamate
Figure imgf000288_0001
Phenyl chloroformate (0.729 mL, 5.79 mmol) was added dropwise to 4-[4-(l- cyclopropylsulfonylcyclopropyl)-6- [(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-yl] aniline (2.40 g, 5.79 mmol) and sodium bicarbonate (0.730 g, 8.68 mmol) in dioxane (45 mL) under nitrogen. The resulting suspension was stirred at 200C for 2 hours. The reaction mixture was evaporated to dryness and redissolved in ethyl acetate (200 mL) and washed with water (200 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the desired material as a white solid (3.03 g).
NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 0.92 - 0.95 (2H, m), 1.03 - 1.05 (2H, m), 1.25 (3H, d), 1.57 - 1.61 (IH, m), 1.61 (IH, d), 1.65 - 1.68 (2H, m), 2.99 - 3.03 (IH, m), 3.46 - 3.47 (IH, m), 3.49 - 3.53 (IH, m), 3.63 - 3.66 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.22 (IH, d), 4.56 (IH, s), 6.89 (IH, s), 7.26 (IH, t), 7.24 - 7.30 (2H, m), 7.43 - 7.47 (2H, m), 7.60 - 7.65 (2H, m), 8.29 - 8.32 (2H, m), 10.43 (IH, s)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 535; HPLC tR = 2.84 min.
4-r4-(l-Cvclopropylsulfonylcvclopropyl)-6-r(36^-3-methylmorpholin-4-yllpyrimidin-2- yll aniline
Figure imgf000288_0002
Dichlorobis(triphenylphosphine)palladium(II) (0.524 g, 0.75 mmol) was added to a degassed solution of 2-chloro-4-(l -cyclopropylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4- yljpyrimidine (2.67 g, 7.46 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (2.043 g, 9.33 mmol) and sodium carbonate (18.65 mL, 37.31 mmol) in 18% DMF in 7:3:2 DME:Water:Ethanol (20 mL). The resulting solution was stirred at 85°C for 1 hour. The reaction mixture was concentrated and diluted with DCM (150 mL), and washed with water (100 mL) and brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 2.5% methanol in DCM, to give the desired material as a brown solid (2.4O g).
NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 0.90 - 0.98 (2H, m), 0.98 - 1.05 (2H, m), 1.22 (3H, d), 1.52 - 1.59 (2H, m), 1.62 - 1.64 (2H, m), 2.95 - 3.02 (IH, m), 3.14 - 3.22 (IH, m), 3.45 - 3.51 (IH, m), 3.61 - 3.65 (IH, m), 3.76 (IH, d), 3.95 - 3.98 (IH, m), 4.14 - 4.17 (IH, m), 4.48 - 4.51 (IH, m), 5.53 (2H, d), 6.60 (2H, d), 6.75 (IH, s), 8.03 - 8.06 (2H, m).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 415; HPLC tR = 2.13 min.
2-Chloro-4-(l-cvclopropylsulfonylcvclopropyl)-6- [(36^-3 -methylmorpholin-4-vHpyrimidine
Figure imgf000289_0001
5N Sodium hydroxide solution (1.74 mL, 8.68 mmol) was added to tetrabutylammonium bromide (0.140 g, 0.43 mmol), 1 ,2-dibromoethane (0.374 mL, 4.34 mmol) and 2-chloro-4- (cyclopropylsulfonylmethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (1.44 g, 4.34 mmol) in DCM (20 mL). The resulting mixture was stirred at 400C for 2 hours. Additional solid sodium hydroxide (4 g, 0.1 mol) was added directly to the reaction and stirred at 400C for a further 1 hour. The reaction mixture was diluted with DCM (20 mL) and washed with water (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the desired material (1.68 g). LCMS Spectrum: m/z (ESI+) (M+H)+ = 358; HPLC tR = 1.87 min.
2-Chloro-4-(cvclopropylsulfonylmethyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000289_0002
Cyclopropanesulfinic acid, sodium salt (381 mg, 2.97 mmol) was added in one portion to 2- chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (700 mg, 1.98 mmol) in acetonitrile (20 mL) at RT. The resulting suspension was stirred at 900C for 3 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and washed with water (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to gve the desired material as a white solid (458 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSO) δ 0.95 - 0.98 (2H, m), 1.02 - 1.06 (2H, m), 1.18 - 1.23 (3H, m), 2.77 - 2.83 (IH, m), 3.19 - 3.25 (IH, m), 3.42 - 3.49 (IH, m), 3.58 - 3.62 (IH, m), 3.73 (IH, d), 3.92 - 3.96 (2H, m), 4.30 (IH, s), 4.48 (2H, s), 6.92 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 332; HPLC tR = 1.68 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Example 4: 3-Methyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yll-6-Q- methylsulfonylcvclopentyl)pyrimidin-2-yll phenyll urea
Figure imgf000290_0001
Triethylamine (0.15 mL, 1.1 mmol) was added to a solution of phenyl N-[4-[4-[(3S)-3- methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl] carbamate (200 mg, 0.37 mmol) and methylamine (2M in THF, 1.48 mmol) in NMP (2 mL). The reaction was heated at 8O0C for 2 hours the purified by prep HPLC, using a mixture of water (containing 1% NH3) and acetonitrile as eluents, to give the desired material as a solid (126 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 1.52-1.62 (2H, m), 1.75- 1.90 (2H, m), 2.38-2.50 (2H, m), 2.65 (3H, d), 2.65-2.78 (2H, m), 2.89 (3H, s), 3.20 (IH, dd), 3.50 (IH, dd), 3.64 (IH, d), 3.75 (IH, d), 3.95 (IH, dd), 4.25 (IH, d), 4.55 (IH, s), 6.05 (IH, q), 6.79 (IH, s), 7.50 (2H, d), 8.22 (2H, d), 8.72 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 474; HPLC tR = 1.96 min mTOR Kinase Assay (Echo): 0.000699μM
The following compounds were prepeared in an analogous fashion from phenyl N- [4- [4- [(3S)- 3 -methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl] carbamate and the appropriate amine.
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Example 4a: 1H NMR (400.132 MHz, DMSO) δ 1.05 (3H, t), 1.21 (3H, d), 1.50-1.62 (2H, m), 1.78-1.85 (2H, m), 2.35-2.45 (2H, m), 2.65-2.75 (2H, m), 2.89 (3H, s), 3.12 (2H, q), 3.18 (IH, dd), 3.50 (IH, dd), 3.65 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.24 (IH, d), 4.55 (IH, s), 6.15 (IH, t), 6.78 (IH, s), 7.48 (2H, d), 8.22 (2H, d), 8.65 (IH, s). mTOR Kinase Assay (Echo): 0.00216μM
Example 4b: 1R NMR (400.132 MHz, DMSO) δ 0.41 (2H, q), 0.62 (2H, q), 1.21 (3H, d), 1.51-1.61 (2H, m), 1.75-1.86 (2H, m), 2.35-2.45 (2H, m), 2.55 (IH, m), 2.65-2.85 (2H, m), 2.89 (3H, s), 3.20 (IH, dd), 3.50 (IH, dd), 3.65 (IH, dd), 3.75 (IH, d), 3.97 (IH, dd), 4.25 (IH, d), 4.55 (IH, s), 6.41 (IH, d), 6.78 (IH, s), 7.50 (2H, d), 8.25 (2H, d), 8.55 (IH, s). mTOR Kinase Assay (Echo): 0.00203μM
Example 4c: 1U NMR (400.132 MHz, DMSO) δ 1.11 (6H, d), 1.21 (3H, d), 1.50-1.62 (2H, m), 1.75-1.85 (2H, m), 2.38-2.50 (3H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3.20 (IH, dd), 3.50 (IH, dd), 3.65 (IH, dd), 3.75 (IH, dd), 3.99 (IH, dd), 4.23 (IH, d), 4.55 (IH, s), 6.05 (IH, d), 6.79 (IH, s), 7.48 (2H, d), 8.22 (2H, d), 8.54 (IH, s). mTOR Kinase Assay (Echo): 0.0169μM
Example 4d: 1R NMR (400.132 MHz, DMSO) δ 1.21 (3H, d), 1.50-1.65 (4H, m), 1.75-1.90 (4H, m), 2.15-2.20 (2H, m), 2.35-2.50 (2H, m), 2.65-2.80 (2H, m), 2.88 (3H, s), 3.20 (IH, dd), 3.50 (IH, dd), 3.65 (IH, dd), 3.75 (IH, dd), 3.95 (IH, dd), 4.15 (IH, q), 4.22 (IH, d), 4.55 (IH, s), 6.42 (IH, d), 6.79 (IH, s), 7.45 (2H, d), 8.22 (2H, d), 8.55 (IH, s). mTOR Kinase Assay (Echo): 0.01 μM
Example 4e: 1U NMR (400.132 MHz, DMSO) δ 1.21 (3H, d), 1.50-1.62 (2H, m), 1.78-1.85 (2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3.15-3.22 (3H, m), 3.40-3.50 (3H, m), 3.65 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.22 (IH, d), 4.55 (IH, s), 4.71 (IH, t), 6.22 (IH, t), 6.78 (IH, s), 7.45 (2H, d), 8.22 (2H, d), 8.80 (IH, s). mTOR Kinase Assay (Echo): 0.00119μM
Example 4f: 1H NMR (400.132 MHz, DMSO) δ 1.21 (3H, d), 1.50-1.62 (2H, m), 1.75-1.85 (2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3.20 (IH, dd), 3.35-3.40 (2H, m), 3.50 (IH, dd), 3.65 (IH, dd), 3.75 (IH, d), 3.95 (IH, dd), 4.22 (IH, d), 4.55 (IH, s), 4.95 (IH, t), 6.0 (IH, s), 6.78 (IH, s), 7.45 (2H, d), 8.22 (2H, d), 8.72 (IH, s). mTOR Kinase Assay (Echo): 0.01 μM
Example 4g: 1U NMR (400.132 MHz, DMSO) δ 1.21 (3H, d), 1.50-1.60 (2H, m), 1.75-1.85 (2H, m), 2.18 (6H, s), 2.31 (2H, t), 2.38-2.50 (2H, m), 2.65-2.75 (2H, m), 2.89 (3H, s), 3.15- 3.22 (3H, m), 3.50 (IH, dd), 3.65 (IH, dd), 3.75 (IH, dd), 3.96 (IH, dd), 4.22 (IH, dd), 4.55 (IH, s), 6.15 (IH, t), 6.79 (IH, s), 7.48 (2H, d), 8.22 (2H, d), 8.87 (IH, s). mTOR Kinase Assay (Echo): 0.0626μM
Example 4h: 1U NMR (400.132 MHz, DMSO) δ 0.88 (3H, t), 1.21 (3H, d), 1.45 (2H, q), 1.50-1.62 (2H, m), 1.75-1.85 (2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3.05 (2H, m), 3.20 (IH, dd), 3.50 (IH, dd), 3.65 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.22 (IH, d), 4.55 (IH, s), 6.20 (IH, t), 6.78 (IH, s), 7.48 (2H, d), 8.21 (2H, d), 8.62 (IH, s). mTOR Kinase Assay (Echo): 0.00157μM Example 4i: 1U NMR (400.132 MHz, DMSO) δ 0.88 (6H, d), 1.21 (3H, d), 1.50-1.62 (2H, m), 1.70 (IH, m), 1.75-1.85 (2H, m), 2.35-2.50 (2H, m), 2.65-2.80 (2H, m), 2.90 (3H, s), 2.94 (2H, t), 3.20 (IH, dd), 3.50 (IH, dd), 3.65 (IH, dd), 3.75 (IH, dd), 3.97 (IH, dd), 4.24 (IH, d), 4.54 (IH, s), 6.22 (IH, t), 6.78 (IH, s), 7.50 (2H, d), 8.22 (2H, d), 8.63 (IH, s). mTOR Kinase Assay (Echo): 0.0115μM
Example 4j: 1H NMR (400.132 MHz, DMSO) δ 1.21 (3H, d), 1.50-1.62 (4H, m), 1.75-1.85 (2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3.10-3.22 (3H, m), 3.45-3.52 (3H, m), 3.65 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.22 (IH, d), 4.45 (IH, t), 4.55 (IH, s), 6.1991H, t), 6.79 (IH, s), 7.49 (2H, d), 8.22 (2H, d), 8.70 (IH, s). mTOR Kinase Assay (Echo): 0.00461μM
Example 4k: 1U NMR (400.132 MHz, DMSO) δ 1.21 (3H, d), 1.50-1.62 (2H, m), 1.75-1.85 (2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3, 22 (IH, dd), 3.50 (IH, dd), 3.65 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.25 (IH, d), 4.55 (IH, s), 6.80 (IH, s), 7.58 (2H, d), 7.62-7.70 (4H, m), 8.30 (2H, d), 9.04 (IH, s), 9.10 (IH, s). mTOR Kinase Assay (Echo): 0.00905μM
Example 41: 1R NMR (400.132 MHz, DMSO) δ 1.21 (3H, d), 1.55-1.62 (2H, m), 1.78-1.90 (2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3.20 (IH, dd), 3.50 (IH, dd), 3.65 (IH, dd), 3.75 (IH, d), 3.9791H, dd), 4.2591H, d), 4.55 (IH, s), 6.80 (IH, s), 7.02 (IH, dd), 7.58 (IH, d), 7.61 (2H, d), 7.74 (IH, dd), 8.25-8.35 (4H, m), 9.41 (IH, s). mTOR Kinase Assay (Echo): 0.00369μM
Example 4m: 1R NMR (400.132 MHz, DMSO) δ 1.20 (3H, d), 1.50-1.62 (2H, m), 1.78-1.85 (2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3.20 (IH, dd), 3.50 (IH, dd), 3.65 (IH, dd), 3.75-40 (4H, m), 3.97 (IH, dd), 4.25 (IH, d), 4.55 (IH, s), 6.80 (IH, s), 7.38 (IH, s), 7.55 (2H, d), 7.73 (IH, s), 8.25 (2H, d), 8.35 (IH, s), 8.85 (IH, s). mTOR Kinase Assay (Echo): 0.00245μM
Example 4n: 1U NMR (400.132 MHz, DMSO) δ 1.21 (3H, d), 1.50-1.62 (2H, m), 1.75-1.85 (2H, m), 2.35-2.50 (2H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3.20 (IH, dd), 3.50 (IH, dd), 3, 65 (IH, dd), 3.75 (IH, d), 3.97 (IH, dd), 4.24 (IH, d), 4.35 (IH, d), 4.55 (IH, s), 6.65 (IH, t), 6.78 (IH, s), 7.04 (2H, s), 7.52 (2H, d), 8.25 (2H, d), 9.0 (IH, s), 12.6 (IH, s). mTOR Kinase Assay (Echo): 0.0392μM The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl Λ/-[4-[4-[(36f)-3-methylmorpholin-4-yll-6-(l-methylsulfonylcvclopentvπpyrimidin-2- yllphenyl] carbamate
Figure imgf000296_0001
Sodium hydrogen carbonate (1.150 g, 13.68 mmol) was added to 4-[4-[(35)-3- methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopentyl)pyrimidin-2-yl] aniline (3.8 g, 9.12 mmol), in dioxane (100 mL) at 210C under nitrogen. The resulting mixture was cooled to 1O0C and phenyl chloro formate (1.72 mL, 13.68 mmol) added slowly then the reaction stirred for 3 hours and allowed to warm to RT and left for 16 hours. The reaction mixture was diluted with ethyl acetate (250 mL), and washed with water (150 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude solid was triturated with a mixture of diethyl ether, iso-hexane and acetone to give the desired material as a white solid (4.5O g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.50-1.62 (2h, m), 1.75- 1.85 (2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m), 3.21 (IH, dd), 3.30 (3H, s), 3.50 (IH, dd), 3.63 (IH, dd), 3.75 (IH, d), 3.97 (IH, dd), 4.28 (IH, d), 4.57 (IH, s), 6.81 (IH, s), 7.22- 7.30 (3Hh, m), 7.43 (2H, dd), 7.61 (IH, d), 8.32 (2H, d), 10.45 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 537 ; HPLC tR = 2.98 min
4-r4-r(35)-3-Methylmorpholin-4-yll-6-(l-methylsulfonylcvclopentyl)pyrimidin-2-yllaniline
Figure imgf000296_0002
Bis (triphenylphosphine)palladium (II) chloride (0.390 g, 0.56 mmol) was added to 2-chloro- 4-[(35)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopentyl)pyrimidine (4.Og, 11.12 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (3.17 g, 14.45 mmol) and sodium carbonate (20 mL, 40.0 mmol) in a mixture of DMF (20 mL), DME (50 mL), ethanol (20 mL) and water (20 mL) at RT under nitrogen. The resulting mixture was stirred at 950C for 12 hours. The reaction mixture was diluted with ethyl acetate (400 mL), washed twice with water (200 mL followed by 250 mL), the organic layer dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was chromatographed on silica, eluting with 5 - 50% ethyl acetate in iso-hexane, to give a yellow solid which was subsequently triturated with a mixture of diethyl ether and iso-hexane to give the desired material as a white solid (4.25 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.50-1.60 (2H, m), 1.75- 1.90 (2H, m), 2.34-2.43 (2H, m), 2.62-2.78 (2H, m), 2.88 (3H, s), 3.18 (IH, dd), 3.48 (IH, dd), 3.65 (IH, dd), 3.75 (IH, dd), 3.95 (IH, dd), 4.20 (IH, d), 4.51 (IH, s), 5.55 (2H, s), 6.62 (2H, d), 6.68 (IH, s), 8.09 (IH, d).
Mass Spectrum: m/z (ESI+)(M+H)+ = 417
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(l-methylsulfonylcvclopentyl)pyrimidine
Figure imgf000297_0001
Tetrabutylammonium bromide (0.495 g, 1.54 mmol) was added toa mixture of 2-chloro-4-[ (35)-3-methylmorpholin-4-yl]-6- (methylsulfonylmethyl)pyrimidine (4.7 g, 15.37 mmol), 1, 4-dibromobutane (1.84 mL, 15.37 mmol) and aqueous sodium hydroxide solution (30 mL, 368.9 mmol) in DCM (150 mL) at RT under nitrogen. The resulting mixture was stirred at 4O0C for 6 hours. The reaction mixture was diluted with DCM (200 mL), and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was chromatographed on silica, eluting with 5 - 50% ethyl acetate in iso-hexane, to give the desired material as a yellow solid (3.90 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20 (3H, d), 1.50-1.60 (2H, m), 1.72- 1.82 (2H, m), 2.30-2.41 (2H, m, ), 2.50-2.60 (2H, m), 2.88 (3H, s), 3.20 (IH, dd), 3.45 (IH, dd), 3.60 (IH, dd), 3.71 (IH, d), 3.94 (IH, dd), 4.0-4.10 (IH, m), 4.42 (IH, s), 6.89 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 360 ; HPLC tR = 2.22 min
The preparation of 2-chloro-4-[ (35)-3-methylmorpholin-4-yl]-6- (methylsulfonylmethyl)pyrimidine was described earlier.
Example 5: 3-Methyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yll-6-q- methylsulfonylcvclobutyl)pyrimidin-2-yll phenyll urea
Figure imgf000298_0001
Triethylamine (0.07 mL, 0.48mmol) was added to a solution of phenyl N-[4-[4-[(3S)-3- methylmorpholin-4-yl]-6-(l-methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]carbamate (86 mg, 0.16 mmol) and methylamine (2M in THF, 0.65 mmol) in NMP (2 mL). The reaction was heated at 8O0C for 2 hours the purified by prep HPLC, using a mixture of water (containing 1% NH3) and acetonitrile as eluents, to give the desired material as a solid (48 mg). NMR Spectrum: 1R NMR (400.13 MHz, DMSOd6) δ 1.24 (3H, d), 1.91 (2H, m), 2.08 (2H, m), 2.62(3H,d), 2.80 (2H, m), 2.87 (3H, s), 3.21 (IH, td), 3.50 (IH, td), 3.65 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.24 (IH, d), 4.60 (IH, s), 6.07 (IH, d), 6.71 (IH, s), 7.50 (2H, d), 8.22 (2H, d), 8.75 (IH, s).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 460; HPLC tR = 1.5 min mTOR Kinase Assay (Echo): 0.000802μM
The following compounds were prepared in an analogous fashion from phenyl N- [4- [4- [(3S)- 3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]carbamate and the appropriate amine.
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Example 5a: 1H NMR (400.132 MHz, DMSO) δ 1.07 (3H, t), 1.24 (3H, d), 1.91 (2H, m), 2.07 (2H, m), 2.81 (2H, m), 2.87 (3H, s), 3.12 (2H, m), 3.22 (IH, m), 3.50 (IH, td), 3.65 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.24 (IH, d), 4.59 (IH, s), 6.16 (IH, t), 6.71 (IH, s), 7.49 (2H, d), 8.22 (2H, d), 8.68 (IH, s). mTOR Kinase Assay (Echo): 0.000289μM
Example 5b: 1U NMR (400.132 MHz, DMSO) δ 0.42 (2H, m), 0.65 (2H, m), 1.24 (3H, d), 1.92 (2H, m), 2.08 (2H, m), 2.56 (2H, m), 2.80 (2H, m), 2.88 (3H, s), 3.21 (IH, td), 3.54 (IH, s), 3.65 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.24 (IH, d), 4.59 (IH, s), 6.45 (IH, s), 6.72 (IH, s), 7.51 (2H, d), 8.22 (2H, d), 8.55 (IH, s). mTOR Kinase Assay (Echo): 0.000383μM
Example 5c: 1R NMR (400.132 MHz, DMSO) δ 1.11 (6H, d), 1.24 (3H, d), 1.86 - 1.96 (2H, m), 2.03 - 2.13 (2H, m), 2.76 - 2.84 (2H, m), 2.86 (3H, s), 3.21 (IH, td), 3.50 (IH, td), 3.65 (IH, dd), 3.73 - 3.80 (2H, m), 3.98 (IH, dd), 4.25 (IH, d), 4.61 (IH, s), 6.05 (IH, d), 6.72 (IH, s), 7.48 (2H, d), 8.21 (2H, d), 8.54 (IH, s). mTOR Kinase Assay (Echo): 0.00681 μM
Example 5d: 1U NMR (400.132 MHz, DMSO) δ 1.23 (3H, d), 1.58 - 1.67 (3H, m), 1.81 - 1.94 (4H, m), 2.02 - 2.11 (2H, m), 2.20 (2H, m), 2.76 - 2.84 (2H, m), 2.87 (3H, s), 3.21 (IH, td), 3.50 (IH, td), 3.65 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.13 (IH, quintet), 4.25 (IH, d), 4.61 (IH, s), 6.45 (IH, d), 6.71 (IH, s), 7.47 (2H, d), 8.21 (3H, d), 8.58 (2H, s). mTOR Kinase Assay (Echo): 0.00385μM
Example 5e: 1R NMR (400.132 MHz, DMSO) δ 1.24 (3H, d), 1.87 - 1.97 (2H, m), 2.01 - 2.12 (2H, m), 2.77 - 2.85 (2H, m), 2.88 (3H, s), 3.15 - 3.25 (3H, m), 3.43 - 3.54 (3H, m), 3.65 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.24 (IH, d), 4.60 (IH, s), 4.72 (IH, t), 6.26 (IH, t),
6.71 (IH, s), 7.49 (2H, d), 8.23 (2H, d), 8.82 (IH, s). mTOR Kinase Assay (Echo): 0.000864μM
Example 5f: 1H NMR (400.132 MHz, DMSO) δ 1.25 (14H, s), 1.87 - 1.95 (2H, m), 2.03 - 2.11 (2H, m), 2.76 - 2.83 (7H, m), 2.88 (7H, s), 3.17 - 3.25 (15H, m), 3.39 (2H, d), 3.65 (IH, dd), 3.77 (IH, d), 3.98 (IH, d), 4.24 (IH, d), 4.59 (IH, s), 4.95 (IH, t), 6.02 (IH, s), 6.72 (IH, s), 7.44 (2H, d), 8.21 (2H, d), 8.75 (IH, s). mTOR Kinase Assay (Echo): 0.00736μM
Example 5g: 1R NMR (400.132 MHz, DMSO) δ 1.24 (3H, d), 1.87 - 1.96 (2H, m), 2.02 - 2.12 (2H, m), 2.21 (6H, s), 2.34 (2H, t), 2.74 - 2.85 (2H, m), 2.88 (3H, s), 3.15 - 3.26 (3H, m),
3.50 (IH, td), 3.65 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.24 (IH, d), 4.60 (IH, s), 6.15 (IH, t), 6.72 (IH, s), 7.48 (2H, d), 8.21 (2H, d), 8.91 (IH, s). mTOR Kinase Assay (Echo): 0.0668μM
Example 5h: 1U NMR (400.132 MHz, DMSO) δ 0.89 (3H, t), 1.24 (3H, d), 1.40 - 1.51 (2H, m), 1.87 - 1.97 (2H, m), 2.01 - 2.12 (2H, m), 2.76 - 2.84 (2H, m), 2.89 (3H, s), 3.06 (2H, q),
3.17 - 3.27 (IH, m), 3.50 (IH, td), 3.65 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.24 (IH, d),
4.57 (IH, s), 6.20 (IH, t), 6.72 (IH, s), 7.49 (2H, d), 8.21 (2H, d), 8.66 (IH, s). mTOR Kinase Assay (Echo): 0.00234μM
Example 5i: 1R NMR (400.132 MHz, DMSO) δ 0.89 (6H, d), 1.24 (3H, d), 1.65 - 1.75 (2H, m), 1.85 - 1.96 (2H, m), 2.01 - 2.12 (2H, m), 2.75 - 2.84 (2H, m), 2.88 (3H, s), 2.89 - 2.99
(3H, m), 3.16 - 3.26 (IH, m), 3.50 (IH, td), 3.65 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.24
(IH, d), 4.56 (IH, s), 6.24 (IH, t), 6.72 (IH, s), 7.49 (2H, d), 8.22 (2H, d), 8.65 (IH, s). mTOR Kinase Assay (Echo): 0.00988μM
Example 5j: 1H NMR (400.132 MHz, DMSO) δ 1.24 (3H, d), 1.59 (2H, q), 1.86 - 1.96 (2H, m), 2.02 - 2.14 (2H, m), 2.76 - 2.85 (2H, m), 2.88 (3H, s), 3.13 - 3.26 (3H, m), 3.45 - 3.54
(3H, m), 3.65 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.24 (IH, d), 4.48 (IH, t), 4.56 (IH, s),
6.20 (IH, t), 6.72 (IH, s), 7.49 (2H, d), 8.21 (2H, d), 8.73 (IH, s). mTOR Kinase Assay (Echo): 0.000239μM
Example 5k: mTOR Kinase Assay (Echo): 0.00333μM Example 51: mTOR Kinase Assay (Echo): 0.000248μM
Example 5m: 1R NMR (400.132 MHz, DMSO) δ 1.24 (3H, d), 1.87 - 1.98 (2H, m), 2.03 -
2.12 (2H, m), 2.76 - 2.84 (2H, m), 2.88 (3H, s), 3.17 - 3.30 (4H, m), 3.51 (IH, td), 3.65 (IH, dd), 3.73 - 3.80 (IH, m), 3.98 (IH, dd), 4.25 (IH, d), 4.62 (IH, s), 6.73 (IH, s), 7.39 (IH, s), 7.54 (2H, d), 7.77 (IH, s), 8.27 (2H, d), 8.40 (IH, s), 8.86 (IH, s). mTOR Kinase Assay (Echo): 0.00069μM
Example 5n: 1R NMR (400.132 MHz, DMSO) δ 1.24 (3H, d), 1.87 - 1.97 (2H, m), 2.03 - 2.12 (2H, m), 2.75 - 2.85 (2H, m), 2.88 (3H, s), 3.21 (IH, td), 3.50 (IH, td), 3.65 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.25 (IH, d), 4.32 (2H, d), 4.60 (IH, s), 6.62 (IH, t), 6.98 (2H, s), 7.52 (2H, d), 8.24 (2H, d), 11.88 (IH, s). mTOR Kinase Assay (Echo): 0.00828μM
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl Λ/-r4-r4-r(36f)-3-methylmorpholin-4-yll-6-(l-methylsulfonylcvclobutyl)pyrimidin-2- yllphenyll carbamate
Figure imgf000304_0001
Sodium hydrogen carbonate (0.313 g, 3.73 mmol) was added to 4-[4-[(35)-3- methylmorpholin-4-yl]-6-(l-methylsulfonylcyclobutyl)pyrimidin-2-yl]aniline (1 g, 2.48 mmol), in dioxane (20 mL) at RT under nitrogen. The resulting mixture was cooled to 1O0C and phenyl chloro formate (0.468 mL, 3.73 mmol) added slowly. The reaction was stirred for 3 hours then diluted with ethyl acetate (150 mL), and washed with water (100 mL). The organic layer was dried (Na2SO4), filtered and evaporated. The crude solid was triturated with a mixture of diethyl ether, iso-hexane and acetone to give the desired material as a white solid (1.35 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.21(3H,d), 1.88-1.96(2H,m), 2.02- 2.11(2H,m), 2.75-2.85(2H,m), 2.85(3H,s), 3.21(lH,dd), 3.50(lH,dd), 3.64(lH,d), 3.75(lH,d), 3.98(lH,dd), 4.25(lH,d), 4.57(lH,s), 6.72(lH,s), 7.20-7.30(3H,m), 7.42(2H,dd), 7.61(2H,d), 8.32(2H,m), 10.44(lH,s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 523; HPLC tR = 2.88 min 4-r4-r(36^-3-Methylmorpholin-4-yll-6-(l-methylsulfonylcvclobutyl)pyrimidin-2-yllaniline
Figure imgf000305_0001
Bis(triphenylphosphine)palladium(II) chloride (0.101 g, 0.14 mmol) was added to 2-chloro-4- [(35)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclobutyl)pyrimidine (1 g, 2.89 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.824 g, 3.76 mmol) and sodium carbonate (5 mL, 10.00 mmol) in a mixture of DMF (5 mL), DME (50 mL), ethanol (20 mL) and water (20 mL) at RT under nitrogen. The resulting mixture was stirred at 950C for 12 hours. The reaction mixture was diluted with ethyl acetate (400 mL), and washed twice with water (200 mL followed by 250 mL), the organic layer dried (Na2SO4), filtered and evaporated. The crude product was chromatographed on silica, eluting with 5 - 60% ethyl acetate in iso-hexane, to give the desired material as a cream solid (0.98 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.21(3H,d), 1.85-1.95(2H,m), 2.0- 2.10(2FLm), 2.71-2.82(2FLm), 2.82(3FLs), 3.18(lH,dd), 3.50(lH,dd), 3.62(lH,dd), 3.75(1FLd), 3.95(lH,dd), 4.20(lH,d), 4.53(lH,s), 5.55(2H,s), 6.60(3H,d), 8.05(2H,d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 403; HPLC tR = 2.17 min
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(l-methylsulfonylcvclobutyl)pyrimidine
Figure imgf000305_0002
Tetrabutylammonium bromide (0.45 g, 1.40 mmol) was added to 2-chloro-4-[(35)-3- methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (4.27 g, 13.96 mmol), 1,3- dibromopropane (1.42 mL, 13.96 mmol) and aqueous sodium hydroxide solution (30 mL, 368.9 mmol) in DCM (100 mL) at RT under nitrogen. The resulting mixture was stirred at 350C for 5 hours then diluted with DCM (50 mL), and washed with water (25 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was chromatographed on silica, eluting with 5 - 50% ethyl acetate in iso-hexane, to give the desired material (1.0 g).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 346; HPLC tR = 1.92 min
The preparation of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6- (methylsulfonylmethyl)pyrimidine was described earlier.
Example 6: 3-Cvclobutyl-l-[4-[4-[f3S)-3-methylmorpholin-4-yll-6-Q-pyridin-4- ylsulfonylcyclopr()pyl)pyrimidin-2-yll phenyll urea
Figure imgf000306_0001
To a solution of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]carbamate (122 mg, 0.21 mmol) in DMF (2 mL) was added triethylamine (0.088 mL, 0.63 mmol) followed by cyclobutylamine (0.090 mL, 1.05 mmol) and the reaction heated at 500C overnight. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and acetonitrile as eluents, to give the desired material as a white solid (90 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.18-1.20 (3H, d), 1.57-1.70 (4H, m), 1.82-1.91 (2H, m), 1.95-1.98 (2H, q), 2.18-2.25 (2H, m), 3.12-3.20 (IH, td), 3.43-3.50 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.11-4.17 (2H, m), 4.46 (IH, bs), 6.42-6.44 (IH, d), 6.67 (IH, s), 7.33-7.35 (2H, q), 7.65-7.67 (2H, d), 7.76-7.78 (2H, q), 8.53 (IH, s), 8.85-8.87 (2H, q).
LCMS Spectrum: m/z (ESI+) (M+H)+549 = HPLC tR =2.25 min. mTOR Kinase Assay (Echo): O.OOlμM
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[(35)-3- methylmorpholin-4-yl]-6-(l-pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl] carbamate using the appropriate amine.
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Example 6a: 1H NMR (400.132 MHz, DMSOd6) δ 1.19-1.21 (3H, d), 1.69-1.72 (2H, q),
1.97-2.00 (2H, q), 3.15-3.22 (IH, td), 3.44-3.51 (IH, td), 3.61-3.64 (IH, dd), 3.74-3.77 (IH, d), 3.95-3.99 (IH, dd), 4.17-4.20 (IH, d), 4.48 (IH, bs), 6.71 (IH, s), 7.02-7.06 (IH, m), 7.49- 7.51 (2H, d), 7.56-7.58 (IH, d), 7.74-7.79 (5H, m), 8.30-8.32 (IH, d), 8.88-8.89 (2H, q), 9.43
(IH, s), 10.55 (IH, s). mTOR Kinase Assay (Echo): 0.00293μM
Example 6b: 1H NMR (400.132 MHz, DMSOd6) δ 0.88-0.90 (6H, d), 1.18-1.20 (3H, d),
1.68-1.74 (3H, m), 1.96-1.98 (2H, q), 2.93-2.96 (2H, t), 3.13-3.20 (IH, td), 3.43-3.50 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.99 (IH, dd), 4.15-4.18 (IH, d), 4.45 (IH, bs),
6.20-6.23 (IH, t), 6.67 (IH, s), 7.34-7.36 (2H, d), 7.65-7.67 (2H, d), 7.77-7.78 (2H, q), 8.62
(IH, s), 8.86-8.87 (2H, q). mTOR Kinase Assay (Echo): 0.00612μM Example 6c: 1H NMR (400.132 MHz, DMSO-Cl6) δ 1.11-1.12 (6H, d), 1.18-1.20 (3H, d), 1.67-1.71 (2H, q), 1.96-1.98 (2H, q), 3.13-3.20 (IH, td), 3.43-3.50 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.82 (2H, m), 3.94-3.98 (IH, dd), 4.14-4.18 (IH, d), 4.46 (IH, bs), 6.02-6.04 (IH, d), 6.67 (IH, s), 7.32-7.36 (2H, q), 7.64-7.67 (2H, q), 7.76-7.78 (2H, q), 8.50 (IH, s), 8.86- 8.87 (2H, q). mTOR Kinase Assay (Echo): 0.00321μM
Example 6d: 1H NMR (400.132 MHz, DMSOd6) δ 1.05-1.09 (2H, t), 1.18-1.20 (3H, d), 1.67-1.71 (2H, q), 1.96-1.98 (2H, q), 3.09-3.20 (4H, m), 3.43-3.50 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.15-4.17 (IH, d), 4.46 (IH, bs), 6.12-6.15 (IH, t), 6.67 (IH, s), 7.35-7.37 (2H, q), 7.65-7.67 (2H, d), 7.77-7.78 (2H, q), 8.63 (IH, s), 8.86-8.87 (2H, q). mTOR Kinase Assay (Echo): 0.000874μM
Example 6e: 1U NMR (400.132 MHz, DMSO-de) δ 1.18-1.20 (3H, d), 1.67-1.71 (2H, q), 1.96-1.98 (2H, q), 2.18 (6H, s), 2.32-2.35 (2H, t), 3.13-3.21 (3H, m), 3.43-3.50 (IH, td), 3.59- 3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.15-4.18 (IH, d), 4.47 (IH, bs), 6.12- 6.15 (IH, t), 6.67 (IH, s), 7.34-7.37 (2H, q), 7.65-7.67 (2H, d), 7.76-7.78 (2H, q), 8.86-8.87 (3H, m). mTOR Kinase Assay (Echo): 0.0673μM Example 6f: 1U NMR (400.132 MHz, DMSO-d6) δ 1.18-1.20 (3H, d), 1.67-1.71 (2H, q), 1.96-1.98 (2H, q), 3.13-3.20 (3H, m), 3.43-3.50 (3H, m), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.15-4.18 (IH, d), 4.46 (IH, bs), 4.71-4.74 (IH, t), 6.21-6.24 (IH, t), 6.67 (IH, s), 7.34-7.36 (2H, q), 7.65-7.67 (2H, d), 7.76-7.78 (2H, q), 8.77 (IH, s), 8.86-8.87 (2H, q). mTOR Kinase Assay (Echo): 0.000794μM Example 6g: 1R NMR (400.132 MHz, DMSO-de) δ 0.87-0.91 (3H, t), 1.18-1.20 (3H, d), 1.41-1.50 (2H, m), 1.67-1.71 (2H, q), 1.96-1.98 (2H, q), 3.04-3.09 (2H, q), 3.13-3.19 (IH, td), 3.43-3.50 (IH, td), 3.59-3.63 (IH, td), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.14-4.18 (IH, d), 4.47 (IH, bs), 6.16-6.19 (IH, t), 6.67 (IH, s), 7.34-7.36 (2H, d), 7.65-7.67 (2H, dθ, 7.77- 7.78 (2H, q), 8.62 (IH, s), 8.86-8.87 (2H, q). mTOR Kinase Assay (Echo): 0.00225μM
Example 6h: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18-1.20 (3H, d), 1.67-1.71 (2H, q), 1.96-1.98 (2H, q), 2.65-2.67 (3H, d), 3.13-3.20 (IH, td), 3.43-3.50 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.15-4.17 (IH, d), 4.46 (IH, bs), 6.02-6.06 (IH, q), 6.67 (IH, s), 7.35-7.38 (2H, q), 7.65-7.67 (2H, d), 7.77-7.78 (2H, q), 8.71 (IH, s), 8.86-8.87 (2H, q). mTOR Kinase Assay (Echo): 0.000799μM Example 6i: 1H NMR (400.132 MHz, DMSOd6) δ 1.19-1.21 (3H, d), 1.69-1.72 (2H, q), 1.97-2.00 (2H, q), 3.14-3.21 (IH, td), 3.44-3.50 (IH, td), 3.61-3.64 (IH, dd), 3.74-3.77 (IH, d), 3.95-3.98 (IH, dd), 4.16-1.20 (IH, d), 4.48 (IH, bs), 6.70 (IH, s), 7.44-7.46 (2H, d), 7.64- 7.70 (4H, q), 7.72-7.75 (2H, q), 7.78-7.79 (2H, q), 8.87-8.89 (2H, q), 9.03 (IH, s), 9.11 (IH, s). mTOR Kinase Assay (Echo): 0.00462μM
Example 6j: 1H NMR (400.132 MHz, DMSOd6) δ 1.18-1.20 (3H, d), 1.24 (6H, s), 1.67-1.70 (2H, q), 1.96-1.99 (2H, q), 3.13-3.20 (IH, td), 3.38-3.40 (2H, d), 3.43-3.50 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.15-4.18 (IH, d), 4.46 (IH, bs), 4.94-4.96 (IH, t), 5.97 (IH, s), 6.67 (IH, s), 7.30-7.32 (2H, d), 7.63-7.65 (2H, q), 7.76-7.78 (2H, q), 8.71 (IH, s), 8.86-8.87 (2H, q). mTOR Kinase Assay (Echo): 0.00593μM
Example 6k: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18-1.20 (3H, d), 1.57-1.63 (2H, m), 1.67-1.71 (2H, q), 1.96-1.98 (2H, q), 3.13-3.20 (3H, m), 3.43-3.50 (3H, m), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.14-4.18 (IH, d), 4.46 (IH, bs), 4.46-4.49 (IH, t), 6.16-6.19 (IH, t), 6.67 (IH, s), 7.34-7.36 (2H, q), 7.65-7.67 (2H, d), 7.76-7.78 (2H, q), 8.68 (IH, s), 8.86-8.87 (2H, q). mTOR Kinase Assay (Echo): 0.00186μM
Example 61: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19-1.20 (3H, d), 1.68-1.71 (2H, q), 1.96-1.99 (2H, q), 3.13-3.21 (IH, td), 3.44-3.50 (IH, td), 3.60-3.63 (IH, dd), 3.74-3.77 (IH, d), 3.79 (3H, s), 3.95-3.98 (IH, dd), 4.16-4.19 (IH, d), 4.47 (IH, bs), 6.68 (IH, s), 7.39-7.42 (3H, m), 7.68-7.70 (2H, d), 7.77-7.79 (3H, m), 8.37 (IH, s), 8.82 (IH, s), 8.86-8.88 (2H, q). mTOR Kinase Assay (Echo): 0.00119μM
Example 6m: 1H NMR (400.132 MHz, DMSO-d6) δ 0.40-0.44(2H, m), 0.63-0.67(2H, m), 1.18-1.20(3H, d), 1.68-1.71(2H, q), 1.96-1.99(2H, q), 2.53-2.59(1H, m), 3.13-3.2O(1H, td), 3.43-3.63(1H, td), 3.59-3.63(1H, dd), 3.73-3.76(1H, d), 3.94-3.98(1H, dd), 4.15-4.18(1H, d), 4.46(1H, bs), 6.4O-6.41(1H, d), 6.67(1H, s), 7.36-7.38(2H, q), 7.65-7.68(2H, q), 7.77- 7.78(2H, q), 8.51(1H, s), 8.86-8.87(2H, q). mTOR Kinase Assay (Echo): 0.000936μM
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl N- [4- [4- [(36^-3 -methylmorpholin-4-yl1-6-(l-pyridin-4- ylsulfonylcvclopropyl)pyrimidin-2-yllphenyllcarbamate
Figure imgf000312_0001
Phenyl chloro formate (0.341 mL, 2.71 mmol) was added to 4-[4-[(35)-3-methylmorpholin-4- yl]-6-(l-pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2-yl]aniline (1.224 g, 2.71 mmol) and sodium bicarbonate (0.342 g, 4.07 mmol) in dioxane (175 mL) at RT under air. The resulting slurry was stirred at RT for 2 hours. Additional portions of phenyl chloro formate (2 x 0.005 mL) were added to the reaction. Water was added to the reaction mixture and the material extracted with DCM. The combined organics were dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 4% methanol in DCM, to give the desired material as a beige solid (1.72 g).
NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.28-1.29 (3H, d), 1.60-1.69 (2H, m), 1.97-2.05 (2H, m), 3.22-3.30 (IH, td), 3.52-3.59 (IH, td), 3.71-3.72 (IH, dd), 3.78-3.81 (IH, d), 3.99-4.03 (IH, dd), 4.09-4.13 (IH, d), 4.38-4.39 (IH, bs), 6.72 (IH, s), 7.13-7.15 (2H, d), 7.19-7.21 (IH, t), 7.32-7.36 (2H, t), 7.46-7.48 (2H, d), 7.61-7.63 (2H, q), 7.97-7.99 (2H, d), 8.74-8.75 (2H, q). LCMS Spectrum: m/z (ES+) (M+H)+=450; HPLC tR=2.66 min. 4-r4-r(35)-3-Methylmorpholin-4-yll-6-(l-pyridin-4-ylsulfonylcvclopropyl)pyrimidin-2- yll aniline
Figure imgf000313_0001
trans-Dichlorobis(triphenylphosphine)palladium (II) (0.095 g, 0.14 mmol) was added to 2- chloro-4- [(35)-3 -methylmorpholin-4-yl] -6-( 1 -pyridin-4-ylsulfonylcyclopropyl)pyrimidine (1.07 g, 2.71 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.89 g, 4.06 mmol) and sodium carbonate (6.77 mL, 13.55 mmol) in 18% DMF in a 7:3:2 mixture of DME:water:ethanol (50 mL) at RT under nitrogen. The resulting solution was stirred at 800C for 5 hours. The reaction was cooled and diluted with ethyl acetate and water. The reaction mixture was extracted with ethyl acetate, the combined organics dried (MgSO4), filtered and evaporated to afford the desired material (1.224 g). LCMS Spectrum: m/z (ES+) (M+H)+=452; HPLC tR=2.03 min.
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(l-pyridin-4-ylsulfonylcvclopropyl)pyrimidine
Figure imgf000313_0002
50% v/v Aqueous sodium hydroxide (23 mL, 9.52 mmol) was added to 2-chloro-4-[(35)-3- methylmorpholin-4-yl]-6-(pyridin-4-ylsulfonylmethyl)pyrimidine (3.51 g, 9.52 mmol), 1,2- dibromoethane (0.820 mL, 9.52 mmol) and tetrabutylammonium bromide (0.307 g, 0.95 mmol) in DCM (100 mL) and the reaction warmed to 3O0C under air. The resulting slurry was stirred at 300C for 4 hours then allowed to cool, DCM added and the layers separated. The organic layer was washed with water, dried (MgSO4) and filtered. The resulting solution was evaporated on to silica and purified by flash silica chromatography, eluting with 0 to 60% ethyl acetate in DCM, to give the desired material as a yellow solid (1.07 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-Cl6) δ 1.15-1.16 (3H, d), 1.61-1.65 (2H, m), 1.90-1.93 (2H, m), 3.11-3.19 (IH, td), 3.37-3.44 (IH, td), 3.53-3.57 (IH, dd), 3.68-3.71 (IH, d), 3.89-3.96 (IH, dd), 3.96 (IH, bs), 4.28 (IH, bs), 6.75 (IH, s), 7.74-7.75 (2H, dd), 8.88- 8.90 (2H, dd). LCMS Spectrum: m/z (ES+) (M+H)+=395; HPLC tR=1.65 min.
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(pyridin-4-ylsulfonylmethyl)pyrimidine
Figure imgf000314_0001
A solution of hydrogen peroxide (1.799 mL, 58.19 mmol) was added dropwise to a stirred solution of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(pyridin-4- ylsulfanylmethyl)pyrimidine (0.980 g, 2.91 mmol), sodium tungstate dihydrate (0.005 mL, 0.06 mmol) and 2N sulfuric acid (0.075 mL) in dioxane (200 mL) at 550C, over a period of 5 minutes under air. The resulting solution was stirred at 55 0C for 3 hours. Water (20OmL) was added and the reaction was cooled, the solids filtered, washed with water and dried in the vacuum oven at 5O0C overnight to give the desired material as a white solid (0.580 g). Additional material was obtained by extracting the aqueous layer with DCM. The extracts were dried (MgSO4), filtered, evaporated and chromatographed on silica, eluting with 0 - 3% methanol in DCM, to give a further portion of the desired material (0.144 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.17-1.19(3H, d), 3.14-3.22(1H, td), 3.4O-3.47(1H, td), 3.56-3.60(1H, dd), 3.71-3.74(1H, d), 3.9O(1H, bs), 3.91-3.95(1H, dd), 4.2O(1H, bs), 4.79(2H, s), 6.79(1H, s), 7.77-7.79(2H, q), 8.92-8.93(2H, q). LCMS Spectrum: m/z (ES+) (M+H)+=369; HPLC tR=1.40 min.
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(pyridin-4-ylsulfanylmethyl)pyrimidine
Figure imgf000314_0002
4-Mercaptopyridine (0.752 g, 6.77 mmol) was added to 2-chloro-4-(iodomethyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidine (1.596 g, 4.51 mmol) in acetonitrile (100 mL) at RT under air. DBU (0.3 mL, 2.01 mmol) was then added and the resulting solution was stirred at RT for 2 minutes. The solvent was removed and DCM was added. The reaction mixture was washed sequentially with water, the organic layer dried (MgSO4), filtered and evaporated. The crude product was chromatographed on silica, eluting with 0 - 2% methanol in DCM. Impure fractions were further chromatographed on silica, eluting with 0 - 4.5% methanol in DCM and combined with the initial pure fractions to give the desired material as a yellow gum (0.980 g). NMR Spectrum: 1U NMR (400.13 MHz, DMSOd6) δ 1.14-1.16(3H, d), 3.11-3.18(1H, td), 3.37-3.44(1H, td), 3.53-3.57(1H, dd), 3.64-3.67(1H, d), 3.86-3.90(2H, dd), 4.01(2H, s), 4.14(1H, bs), 6.43(1H, s), 7.04-7.06(2H, d), 8.29-8.30(2H, d). LCMS Spectrum: m/z (ES+) (M+H)+=337; HPLC tR=1.62 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier
Example 7: 3-Methyl-l- [4- [4- [(3S)-3-methylmorpholin-4-vH -6-(l-propan-2- ylsulfonylcvclopropyl)pyrimidin-2-yll phenyll urea
Figure imgf000315_0001
To a solution of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l-propan-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]carbamate (120 mg, 0.22 mmol) in DMF (2 mL) was added triethylamine (0.094 mL, 0.67 mmol) followed by methylamine (0.5 mL, 1.1 mmol) and the reaction heated at 500C for 2 hours. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and acetonitrile as eluents, to give the desired material as a white solid (71 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.23 (3H, d), 1.34 (6H, dd), 1.55 - 1.62 (4H, m), 2.66 (3H, d), 3.17 - 3.24 (IH, m), 3.48 (IH, dt), 3.60 - 3.67 (2H, m), 3.76 (IH, d), 3.98 (IH, dd), 4.19 (IH, d), 4.53 (IH, s), 6.07 (IH, d), 6.79 (IH, s), 7.50 (2H, d), 8.18 (2H, d), 8.74 (IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 474; HPLC tR = 1.92 min. mTOR Kinase Assay (Echo): 0.00315μM
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[(35)-3- methylmorpholin-4-yl]-6-(l-propan-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]carbamate using the appropriate amine.
Figure imgf000316_0001
Figure imgf000317_0001
Figure imgf000318_0001
Example 7a: 1U NMR (400.132 MHz, DMSO-d6) δ 1.07 (3H, t), 1.23 (3H, d), 1.34 (6H, dd), 1.52 - 1.61 (4H, m), 3.09 - 3.16 (2H, m), 3.16 - 3.23 (IH, m), 3.49 (IH, dt), 3.62 - 3.67 (2H, m), 3.76 (IH, d), 3.97 (IH, d), 4.19 (IH, d), 4.53 (IH, s), 6.17 (IH, t), 6.79 (IH, s), 7.50 (2H, d), 8.18 (2H, d), 8.66 (IH, s). mTOR Kinase Assay (Echo): 0.0023 lμM
Example 7b: 1R NMR (400.132 MHz, DMSO-de) δ 1.11 (6H, d), 1.23 (3H, d), 1.34 (6H, dd), 1.52 - 1.61 (4H, m), 3.15 - 3.24 (IH, m), 3.49 (IH, dt), 3.60 - 3.67 (2H, m), 3.73 - 3.82 (2H, m), 3.97 (IH, dd), 4.19 (IH, d), 4.53 (IH, s), 6.07 (IH, d), 6.79 (IH, s), 7.48 (2H, d), 8.18 (2H, d), 8.53 (IH, s). mTOR Kinase Assay (Echo): 0.0181μM
Example 7c: 1U NMR (400.132 MHz, DMSOd6) δ 1.23 (3H, d), 1.33 (3H, d), 1.35 (3H, d), 1.52 - 1.66 (6H, m), 1.81 - 1.91 (2H, m), 2.18 - 2.25 (2H, m), 3.20 (IH, dt), 3.48 (IH, dt), 3.60 - 3.67 (2H, m), 3.76 (IH, d), 3.97 (IH, dd), 4.09 - 4.21 (2H, m), 4.53 (IH, s), 6.47 (IH, d), 6.79 (IH, s), 7.48 (2H, d), 8.18 (2H, d), 8.56 (IH, s). mTOR Kinase Assay (Echo): 0.00646μM
Example 7d: 1R NMR (400.132 MHz, DMSO-de) δ 0.40 - 0.44 (2H, m), 0.63 - 0.67 (2H, m), 1.23 (3H, d), 1.33 (3H, d), 1.35 (3H, d), 1.53 - 1.62 (4H, m), 2.54 - 2.58 (IH, m), 3.17 - 3.24 (IH, m), 3.49 (IH, dt), 3.60 - 3.67 (2H, m), 3.76 (IH, d), 3.97 (IH, dd), 4.20 (IH, d), 4.53 (IH, s), 6.44 (IH, d), 6.80 (IH, s), 7.51 (2H, d), 8.19 (2H, d), 8.53 (IH, s). mTOR Kinase Assay (Echo): 0.0038μM
Example 7e: 1R NMR (400.132 MHz, DMSO-d6) δ 1.23 (3H, d), 1.33 (3H, d), 1.35 (3H, d), 1.54 - 1.61 (4H, m), 3.16 - 3.24 (3H, m), 3.44 - 3.52 (3H, m), 3.60 - 3.67 (2H, m), 3.76 (IH, d), 3.97 (IH, dd), 4.19 (IH, d), 4.52 (IH, s), 4.73 (IH, t), 6.26 (IH, t), 6.79 (IH, s), 7.50 (2H, d), 8.19 (2H, d), 8.80 (IH, s). mTOR Kinase Assay (Echo): 0.00212μM
Example 7f: 1U NMR (400.132 MHz, DMSO-de) δ 1.23 (3H, d), 1.24 (6H, s), 1.34 (3H, d), 1.35 (3H, d), 1.55 - 1.62 (4H, m), 3.15 - 3.23 (IH, m), 3.39 (2H, d), 3.49 (IH, dt), 3.62 - 3.68 (2H, m), 3.76 (IH, d), 3.97 (IH, d), 4.20 (IH, d), 4.52 (IH, s), 4.95 (IH, t), 6.01 (IH, s), 6.79 (IH, s), 7.46 (2H, d), 8.18 (2H, d), 8.73 (IH, s). mTOR Kinase Assay (Echo): 0.00915μM
Example 7g: 1R NMR (400.132 MHz, DMSO-d6) δ 1.23 (3H, d), 1.33 (3H, d), 1.35 (3H, d), 1.52 - 1.61 (4H, m), 2.18 (6H, s), 2.34 (2H, t), 3.17 - 3.24 (3H, m), 3.49 (IH, dt), 3.60 - 3.67 (2H, m), 3.76 (IH, d), 3.97 (IH, dd), 4.19 (IH, d), 4.52 (IH, s), 6.16 (IH, t), 6.79 (IH, s),
7.49 (2H, d), 8.18 (2H, d), 8.89 (IH, s). mTOR Kinase Assay (Echo): 0.211 μM
Example 7h: 1R NMR (400.132 MHz, DMSO-de) δ 0.89 (3H, t), 1.23 (3H, d), 1.33 (3H, d), 1.35 (3H, d), 1.43 - 1.49 (2H, m), 1.53 - 1.62 (4H, m), 3.07 (2H, q), 3.16 - 3.23 (IH, m), 3.49
(IH, dt), 3.60 - 3.67 (2H, m), 3.76 (IH, d), 3.97 (IH, d), 4.20 (IH, d), 4.54 (IH, s), 6.21 (IH, t), 6.79 (IH, s), 7.50 (2H, d), 8.19 (2H, d), 8.64 (IH, s). mTOR Kinase Assay (Echo): 0.0116μM
Example 7i: 1R NMR (400.132 MHz, DMSO-(I6) δ 0.89 (6H, d), 1.23 (3H, d), 1.33 (3H, d), 1.35 (3H, d), 1.55 - 1.62 (4H, m), 1.67 - 1.74 (IH, m), 2.94 (2H, t), 3.18 - 3.23 (IH, m), 3.46 -
3.51 (IH, m), 3.60 - 3.67 (2H, m), 3.76 (IH, d), 3.97 (IH, dd), 4.20 (IH, d), 4.51 (IH, s), 6.25
(IH, t), 6.79 (IH, s), 7.49 (2H, d), 8.19 (2H, d), 8.64 (IH, s). mTOR Kinase Assay (Echo): 0.0182μM
Example 7j: 1U NMR (400.132 MHz, DMSO-de) δ 1.23 (3H, d), 1.33 (3H, d), 1.35 (3H, d), 1.53 - 1.63 (4H, m), 3.15 - 3.23 (4H, m), 3.45 - 3.51 (4H, m), 3.60 - 3.67 (2H, m), 3.76 (IH, d), 3.97 (IH, d), 4.19 (IH, d), 4.47 (IH, t), 4.53 (IH, s), 6.21 (IH, t), 6.79 (IH, s), 7.50 (2H, d), 8.18 (2H, d), 8.71 (IH, s). mTOR Kinase Assay (Echo): 0.0105μM
Example 7k: 1R NMR (400.132 MHz, DMSO-de) δ 1.24 (3H, d), 1.34 (3H, d), 1.36 (3H, d), 1.54 - 1.64 (4H, m), 3.19 - 3.25 (IH, m), 3.50 (IH, t), 3.61 - 3.66 (2H, m), 3.77 (IH, d), 3.98
(IH, d), 4.22 (IH, d), 4.55 (IH, s), 6.82 (IH, s), 7.59 (2H, d), 7.64 - 7.70 (4H, m), 8.27 (2H, d), 9.04 (IH, s), 9.14 (IH, s). mTOR Kinase Assay (Echo): 0.00482μM
Example 71: 1H NMR (400.132 MHz, DMSO-de) δ 1.24 (3H, d), 1.35 (3H, d), 1.37 (3H, d), 1.57 - 1.61 (4H, m), 3.18 - 3.27 (IH, m), 3.50 (IH, dt), 3.63 - 3.70 (2H, m), 3.77 (IH, d), 3.98
(IH, dd), 4.21 (IH, d), 4.55 (IH, s), 6.82 (IH, s), 7.02 - 7.05 (IH, m), 7.55 - 7.58 (IH, m),
7.65 (2H, d), 7.77 (IH, t), 8.27 - 8.31 (3H, m), 9.47 (IH, s), 10.62 (IH, s). mTOR Kinase Assay (Echo): 0.00913μM
Example 7m: 1R NMR (400.132 MHz, DMSO-de) δ 1.24 (3H, d), 1.34 (3H, d), 1.36 (3H, d), 1.53 - 1.63 (4H, m), 3.17 - 3.25 (IH, m), 3.49 (IH, t), 3.61 - 3.68 (2H, m), 3.77 (IH, d), 3.79
(3H, s), 3.97 (IH, d), 4.20 (IH, d), 4.53 (IH, s), 6.81 (IH, s), 7.38 (IH, s), 7.55 (2H, d), 7.76
(IH, s), 8.22 (2H, d), 8.39 (IH, s), 8.83 (IH, s). mTOR Kinase Assay (Echo): 0.00504μM
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l-propan-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl N-r4-r4-r(3y)-3-methylmorpholin-4-yl1-6-(l-propan-2- ylsulfonylcvclopropyl)pyrimidin-2-yllphenyllcarbamate
Figure imgf000321_0001
To a solution of 4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l-propan-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]aniline (1.47 g, 3.53 mmol) in 1,4-dioxane (17.65 mL) was added sodium bicarbonate (0.445 g, 5.29 mmol) and phenyl chloro formate (0.474 mL, 3.77 mmol) and the reaction stirred at RT for 2 hours. The reaction mixture was diluted with DCM (20 mL), and washed with water (20 mL), the organic layer dried (MgSO4), filtered and evaporated. The crude solid was triturated with diethyl ether to give a solid which was collected by filtration and dried under vacuum to give the desired product as a white solid (1.56 g).
NMR Spectrum: 1H NMR (400.132 MHz. DMSO-cU) δ 1.17 (3H, d), 1.27 (3H, d), 1.28 (3H, d), 1.49 - 1.55 (4H, m), 3.14 (IH, dt), 3.39 - 3.44 (IH, m), 3.53 - 3.60 (2H, m), 3.70 (IH, d), 3.90 (IH, dd), 4.14 (IH, d), 4.47 (IH, s), 6.77 (IH, s), 7.17 - 7.23 (3H, m), 7.38 (2H, t), 7.57 (2H, d), 8.22 (2H, d), 10.37 (IH, s)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 537; HPLC tR = 2.39 min.
4-r4-r(35)-3-Methylmorpholin-4-yll-6-(l-propan-2-ylsulfonylcvclopropyl)pyrimidin-2- yll aniline
Figure imgf000322_0001
To a solution of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(l-propan-2- ylsulfonylcyclopropyl)pyrimidine (1.6 g, 4.45 mmol) in DMF (0.24 mL), DME (9.33 mL), water (4.0 mL) and ethanol (2.67 mL) was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-
5 2-yl)aniline (1.266 g, 5.78 mmol), sodium carbonate (5 mL, 10.00 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.156 g, 0.22 mmol) and the suspension heated at 95°C for 2 hours. The reaction mixture was cooled to RT, diluted with ethyl acetate (10 mL) and washed with water (2 x 10 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 5 io to 60% ethyl acetate in isohexane, to give the desired material as a cream solid (1.47 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.32 (3H, d), 1.34 (3H, d), 1.50 - 1.59 (4H, m), 3.17 (IH, dt), 3.44 - 3.51 (IH, m), 3.59 - 3.66 (2H, m), 3.75 (IH, d), 3.96 (IH, dd), 4.16 (IH, d), 4.49 (IH, d), 5.56 (2H, s), 6.61 (2H, d), 6.69 (IH, s), 8.02 (2H, d) LCMS Spectrum: m/z (ESI+) (M+H)+ = 417; HPLC tR = 2.09 min.
15
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(l-propan-2-ylsulfonylcvclopropyl)pyrimidine
Figure imgf000322_0002
2-Chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(propan-2-ylsulfonylmethyl)pyrimidine (2.4 g, 7.19 mmol) was dissolved in DCM (40 mL) and sodium hydroxide concentrate (7.2 mL, 20 71.89 mmol) was added to the reaction, followed by dibromoethane (0.325 mL, 14.38 mmol). The reaction was stirred at 400C for 10 hours. The reaction mixture was washed with water (50 mL) and the organic layer dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in DCM, to give the desired material as a white solid (1.49 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 1.27 (6H, d), 1.52 - 1.54 (2H, m), 1.56 - 1.59 (2H, m), 3.21 - 3.24 (IH, m), 3.41 - 3.47 (IH, m), 3.55 - 3.61 (2H, m), 3.72 (IH, d), 3.93 (IH, dd), 4.02 (IH, d), 4.37 (IH, s), 6.94 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ 360, HPLC tR = 1.89 min
2-Chloro-4-r(3S)-3-methylmorpholin-4-yll-6-(propan-2-ylsulfonylmethyl)pyrimidine
Figure imgf000323_0001
2,4-Dichloro-6-[(isopropylsulfonyl)methyl]pyrimidine (2.65 g, 9.85 mmol) was dissolved in DCM (50 mL) and stirred (under nitrogen) at -5°C. Triethylamine (1.5 mL, 10.84 mmol) was added to give a clear brown solution. (35)-3 -Methyl morpholine (997 mg, 9.85 mmol) was dissolved in DCM and added dropwise keeping the reaction below -5°C. The cooling bath was then removed and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was then washed with water (50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The crude material was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM to give the desired material as a white solid (2 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (d, 3H), 1.31 (d, 6H), 3.22 (m, IH), 3.43 (m, 2H), 3.60 (m, IH), 3.74 (d, IH), 3.98 (m, IH), 4.30 (s, IH), 4.43 (s, 2H), 6.91 (s, IH) LCMS Spectrum: m/z (ESI+)(M+H)+ 332, HPLC tR = 1.70 min
2,4-Dichloro-6-r(isopropylsulfonyl)methvHpyrimidine
Figure imgf000323_0002
2,4-Dichloro-6-[(isopropylthio)methyl]pyrimidine (6.2 g, 26.16 mmol) was dissolved in DCM (100 mL) and 3,5-dichlorobenzenecarboperoxoic acid (13.5 g, 78.4 mmol) was added portionwise over 10 minutes. The reaction was stirred at room temperature for 4 hours. The reaction mixture was then washed with saturated aqueous sodium bicarbonate (50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo to give a cream solid. Purification by normal phase chromatography, eluting with 0-50% ethyl acetate in iso-hexane gave the desired material as a cream solid (5.3 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.25 (d, 6H), 3.43 (m, IH), 4.77 (s, 2H), 7.87 (s, IH) LCMS Spectrum: m/z (M-H)" 267, HPLC tR = 1.64 min
2,4-Dichloro-6-r(isopropylthio)methvHpyrimidine
Figure imgf000324_0001
6-[(Isopropylthio)methyl]pyrimidine-2,4(lH,3H)-dione (8 g, 40 mmol) was added to phosphorus oxychloride (100 mL) and the mixture heated to reflux for 16 hours. The reaction was then cooled to room temperature and the excess phosphorus oxychloride was removed in vacuo,. The residue was azeotroped with toluene (2 x 100 mL) and dissolved in DCM. This mixture was then poured slowly onto ice (1 L) and stirred for 20 minutes, then extracted with DCM (3 x 500 mL) The extracts were combined, dried over magnesium sulphate, then concentrated in vacuo to give the desired material as a brown oil (6.5 g). The material was used without further purification.
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (d, 6H), 2.96 (m, IH), 3.85 (s, 2H), 7.82 (s, IH) LCMS Spectrum: No mass ion observed, HPLC tR = 2.51 min
6-r(Isopropylthio)methyllpyrimidine-2,4(lH,3H)-dione
Figure imgf000324_0002
6-(Chloromethyl)-lH-pyrimidine-2,4-dione (8 g, 50 mmol) was dissolved in acetonitrile (200 mL) and l,8-Diazabicyclo[5.4.0]undec-7-ene (13 mL, 87.19 mmol) was added and the reaction stirred at room temperature for 15 minutes. Isopropyl mercaptan (8.1 mL, 87.19 mmol) was then added and the reaction stirred at room temperature for a further 2 hours. Solvent removed in vacuo and the resulting brown oil was dissolved in DCM and washed with water. Organic phase dried over magnesium sulphate, filtered and concentrated in vacuo. The resulting oil was chromatographed on silica, eluting with 0-10% methanol in DCM to give the desired material as a white solid (8 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (d, 6H), 2.90 (m, IH), 3.42 (s, 2H), 5.49 (s, IH), 10.82 (s, IH), 10.94 (s, IH)
LCMS Spectrum: m/z (M-H)" 199, HPLC tR = 0.63 min
Example 8: l-[4-[4-[l-f4-Fluorophenyl)sulfonylcvclopropyll-6-[(3S)-3-methylmorpholin- 4-yllpyrimidin-2-yllphenyll-3-methyl-urea
Figure imgf000325_0001
To a solution of phenyl Λ/-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate (100 mg, 0.17 mmol) in DMF (2 mL) was added triethylamine (0.071 mL, 0.51 mmol) followed by methylamine (0.5 mL, 1.1 mmol) and the reaction heated at 500C for 2 hours. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and acetonitrile as eluents, to give the desired material as a white solid (51 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.59 - 1.62 (2H, m), 1.88 - 1.90 (2H, m), 2.66 (3H, d), 3.15 (IH, dt), 3.46 (IH, dt), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.13 (IH, d), 4.42 (IH, s), 6.03 (IH, d), 6.65 (IH, s), 7.38 - 7.44 (4H, m), 7.79 - 7.86 (4H, m), 8.71 (IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 526; HPLC tR = 2.09 min. mTOR Kinase Assay (Echo): 0.000576μM
The following compounds were prepared in an analogous fashion from phenyl 7V-[4-[4-[l-(4- fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate using the appropriate amine.
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0001
Example 8 can also be prepared in an analogous fashion to that described above but using NMP as the solvent and stirring at 750C for 30 minutes. The material can then be partitioned between ethyl acetate and water and the organic materials purified by chromatography on silica, eluting with 0-3% methanol in ethyl acetate. The material can then be dissolved in DCM and either evapourated rapidly to give the desired material as a foam or left to stand for approximately 6 weeks upon which time the deired material precipitated from solution.
Example 8a: 1U NMR (400.132 MHz, DMSOd6) δ 1.06 (3H, t), 1.18 (3H, d), 1.59 - 1.62
(2H, m), 1.88 - 1.90 (2H, m), 3.09 - 3.18 (3H, m), 3.46 (IH, dt), 3.61 (IH, dd), 3.75 (IH, d), 3.95 (IH, dd), 4.13 (IH, d), 4.42 (IH, s), 6.12 (IH, t), 6.65 (IH, s), 7.37 - 7.46 (4H, m), 7.79 -
7.86 (4H, m), 8.63 (IH, s). mTOR Kinase Assay (Echo): 0.00096μM
Example 8b: 1H NMR (400.132 MHz, DMSOd6) δ 0.40 - 0.43 (2H, m), 0.62 - 0.67 (2H, m),
1.19 (3H, d), 1.58 - 1.63 (2H, m), 1.89 - 1.91 (2H, m), 2.55 - 2.58 (IH, m), 3.15 (IH, t), 3.46 (IH, t), 3.61 (IH, d), 3.75 (IH, d), 3.96 (IH, d), 4.14 (IH, d), 4.42 (IH, s), 6.39 (IH, s), 6.65
(IH, s), 7.39 - 7.44 (4H, m), 7.80 - 7.86 (4H, m), 8.51 (IH, s). mTOR Kinase Assay (Echo): 0.00123μM
Example 8c: 1R NMR (400.132 MHz, DMSOd6) δ 1.11 (6H, d), 1.18 (3H, d), 1.58 - 1.62
(2H, m), 1.88 - 1.90 (2H, m), 3.15 (IH, t), 3.46 (IH, t), 3.61 (IH, d), 3.73 - 3.81 (2H, m), 3.96 (IH, d), 4.13 (IH, d), 4.42 (IH, s), 6.02 (IH, d), 6.65 (IH, s), 7.37 (2H, d), 7.42 (2H, t), 7.79 -
7.86 (4H, m), 8.51 (IH, s). mTOR Kinase Assay (Echo): 0.00185μM
Example 8d: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.59 - 1.66 (4H, m), 1.83 - 1.91 (4H, m), 2.18 - 2.26 (2H, m), 3.12 - 3.19 (IH, m), 3.46 (IH, t), 3.61 (IH, d), 3.74 (IH, d), 3.95 (IH, d), 4.11 - 4.17 (2H, m), 4.42 (IH, s), 6.42 (IH, d), 6.65 (IH, s), 7.37 (2H, d),
7.42 (2H, t), 7.79 - 7.86 (4H, m), 8.54 (IH, s). mTOR Kinase Assay (Echo): 0.00134μM
Example 8e: 1R NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.59 - 1.62 (2H, m), 1.88 - 1.90 (2H, m), 3.15 - 3.18 (2H, m), 3.40 - 3.48 (2H, m), 3.61 (2H, dd), 3.74 (IH, d), 3.95 (IH, d), 4.05 - 4.16 (2H, m), 4.13 (IH, d), 4.73 (IH, t), 6.22 (IH, t), 6.64 (IH, s), 7.37 - 7.44 (4H, m), 7.79 - 7.86 (4H, m), 8.78 (IH, s). mTOR Kinase Assay (Echo): 0.000342μM
Example 8f: 1U NMR (400.132 MHz, DMSO-d6) δ 1.18 (3H, d), 1.24 (6H, s), 1.57 - 1.63 (2H, m), 1.86 - 1.91 (2H, m), 3.10 - 3.18 (IH, m), 3.38 (2H, d), 3.46 (IH, t), 3.61 (IH, d),
3.75 (IH, d), 3.96 (IH, d), 4.14 (IH, d), 4.41 (IH, s), 4.95 (IH, t), 5.97 (IH, s), 6.64 (IH, s),
7.34 (2H, d), 7.42 (2H, t), 7.78 - 7.86 (4H, m), 8.71 (IH, s). mTOR Kinase Assay (Echo): 0.00882μM
Example 8g: 1R NMR (400.132 MHz, DMSO-de) δ 1.18 (3H, d), 1.59 - 1.62 (2H, m), 1.88 - 1.90 (2H, m), 2.18 (6H, s), 2.33 (2H, t), 3.15 - 3.21 (3H, m), 3.46 (IH, dt), 3.61 (IH, dd), 3.75
(IH, d), 3.96 (IH, dd), 4.13 (IH, d), 4.42 (IH, s), 6.13 (IH, t), 6.65 (IH, s), 7.37 - 7.43 (4H, m), 7.79 - 7.86 (4H, m), 8.86 (IH, s). mTOR Kinase Assay (Echo): 0.0613μM
Example 8h: 1H NMR (400.132 MHz, DMSO-d6) δ 0.89 (3H, t), 1.18 (3H, d), 1.45 (2H, sextet), 1.59 - 1.62 (2H, m), 1.88 - 1.90 (2H, m), 3.06 (2H, q), 3.12 - 3.16 (IH, m), 3.40 - 3.49
(IH, m), 3.61 (IH, dd), 3.74 (IH, d), 3.96 (IH, dd), 4.13 (IH, d), 4.42 (IH, s), 6.17 (IH, t),
6.64 (IH, s), 7.37 - 7.44 (4H, m), 7.79 - 7.86 (4H, m), 8.63 (IH, s). mTOR Kinase Assay (Echo): 0.00176μM
Example 8i: 1H NMR (400.132 MHz, DMSO-d6) δ 0.88 (6H, d), 1.19 (3H, d), 1.59 - 1.62 (2H, m), 1.67 - 1.74 (IH, m), 1.88 - 1.90 (2H, m), 2.94 (2H, t), 3.12 - 3.19 (IH, m), 3.46 (IH, dt), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.14 (IH, d), 4.42 (IH, s), 6.21 (IH, t), 6.65
(IH, s), 7.37 - 7.43 (4H, m), 7.79 - 7.85 (4H, m), 8.62 (IH, s). mTOR Kinase Assay (Echo): 0.0198μM
Example 8j: 1U NMR (400.132 MHz, DMSO-d6) δ 1.18 (3H, d), 1.56 - 1.63 (4H, m), 1.88 -
1.90 (2H, m), 3.12 - 3.19 (3H, m), 3.47 (2H, q), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.13 (IH, d), 4.43 (IH, s), 4.47 (2H, t), 6.17 (IH, t), 6.65 (IH, s), 7.37 - 7.45 (4H, m), 7.79 - 7.86 (4H, m), 8.68 (IH, s). mTOR Kinase Assay (Echo): 0.000751 μM
Example 8k: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.60 - 1.63 (2H, m), 1.89 - 1.92 (2H, m), 3.13 - 3.21 (IH, m), 3.47 (IH, dt), 3.62 (IH, dd), 3.75 (IH, d), 3.97 (IH, dd), 4.15 (IH, d), 4.43 (IH, s), 6.68 (IH, s), 7.41 - 7.49 (4H, m), 7.63 - 7.69 (4H, m), 7.84 - 7.89 (4H, m), 9.02 (1H, s), 9.10 (IH, s). mTOR Kinase Assay (Echo): 0.0173μM
Example 81: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.61 - 1.63 (2H, m), 1.89 - 1.92 (2H, m), 3.14 - 3.21 (IH, m), 3.47 (IH, t), 3.62 (IH, d), 3.76 (IH, d), 3.96 (IH, d), 4.16 (IH, d), 4.44 (IH, s), 6.68 (IH, s), 7.02 - 7.05 (IH, m), 7.43 (2H, t), 7.53 (2H, d), 7.57 - 7.62 (IH, m), 7.75 - 7.79 (IH, m), 7.83 - 7.91 (4H, m), 8.30 (IH, d), 9.40 (IH, s), 10.50 (IH, s). mTOR Kinase Assay (Echo): 0.00813μM Example 8m: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 1.60 - 1.62 (2H, m), 1.89 -
1.91 (2H, m), 3.12 - 3.20 (IH, m), 3.47 (IH, dt), 3.62 (IH, dd), 3.75 (IH, d), 3.79 (3H, s), 3.96 (IH, dd), 4.14 (IH, d), 4.43 (IH, s), 6.66 (IH, s), 7.38 - 7.45 (5H, m), 7.77 (IH, s), 7.83 ■ 7.87 (4H, m), 8.35 (IH, s), 8.82 (IH, s). mTOR Kinase Assay (Echo): 0.00136μM
The preparation of phenyl Λ/-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below:
Phenyl N- [4- [4- [ 1 -(4-fluorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000330_0001
To a solution of 4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl] aniline (1.33 g, 2.84 mmol) in 1,4-dioxane (15 mL) was added sodium bicarbonate (0.358 g, 4.26 mmol) and phenyl chloroformate (0.357 mL, 2.84 mmol) and the reaction stirred at RT for 2 hours. The reaction mixture was diluted with DCM (20 mL), and washed with water (20 mL), the organic layer dried (MgSO4), filtered and evaporated. The crude solid was triturated with diethyl ether to give a solid which was collected by filtration and dried under vacuum to give the desired product as a white solid (1.46 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.60 - 1.65 (2H, m), 1.89 - 1.92 (2H, m), 3.18 (IH, dt), 3.47 (IH, dt), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.17 (IH, d), 4.45 (IH, s), 6.69 (IH, s), 7.25 (3H, d), 7.40 - 7.47 (4H, m), 7.55 (2H, d), 7.83 - 7.87 (2H, m), 7.92 (2H, d), 10.42 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 589; HPLC tR = 2.92 min.
4- [4- r 1 -(4-Fluorophenyl)sulfonylcvclopropyll -6- [(3 S)-3 -methylmorpholin-4-yllpyrimidin-2- yll aniline
Figure imgf000331_0001
To a solution of 2-chloro-4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidine (1.5 g, 3.64 mmol) in DMF (0.48 mL), DME (9.33 mL), water (4.0 mL) and ethanol (2.67 mL) was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)aniline (1.037 g, 4.73 mmol), sodium carbonate (5 mL, 10.00 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.128 g, 0.18 mmol) and the suspension heated at 95°C for 2 hours. The reaction mixture was cooled to RT, diluted with ethyl acetate (10 mL) and washed with water (2 x 10 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 5 to 60% ethyl acetate in isohexane, to give the desired as a cream solid (1.33 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.17 (3H, d), 1.57 - 1.59 (2H, m), 1.86 - 1.88 (2H, m), 3.12 (IH, dt), 3.45 (IH, dt), 3.60 (IH, dd), 3.73 (IH, d), 3.95 (IH, dd), 4.10 (IH, d), 4.38 (IH, s), 5.52 (2H, s), 6.49 (2H, d), 6.55 (IH, s), 7.41 (2H, t), 7.64 (2H, d),
7.82 - 7.85 (2H, m)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 469; HPLC tR = 2.47 min.
2-Chloro-4-[l-(4-fluorophenyl)sulfonylcvclopropyll-6-[(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000332_0001
2-Chloro-4-[(4-fluorophenyl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine
(3.0 g, 7.78 mmol) was dissolved in DCM (40 mL) and sodium hydroxide concentrate (7.8 mL, 77.75 mmol) was added to the reaction, followed by dibromoethane (0.352 mL, 15.55 mmol). The reaction was stirred at 400C for 16 hours. The reaction mixture was washed with water (50 mL) and the organic layer dried (MgSO4), filtered and evaporated to afford crude product.
The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in DCM, to give the desired material as a white solid (1.50 g,).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.15 (3H, d), 1.53 - 1.56 (2H, m),
1.82 - 1.85 (2H, m), 3.14 (IH, dt), 3.40 (IH, dt), 3.55 (IH, dd), 3.70 (IH, d), 3.91 (2H, dd),
4.25 (IH, s), 6.70 (IH, s), 7.45 (2H, t), 7.79 - 7.84 (2H, m)
LCMS Spectrum: m/z (ESI+)(M+H)+ 412, HPLC tR = 2.14 min
2-Chloro-4-r(4-fluorophenyl)sulfonylmethyll-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000332_0002
Triethylamine (1.117 ml, 8.01 mmol) was added to 2,4-dichloro-6-[(4- fluorophenyl)sulfonylmethyl]pyrimidine (2.34 g, 7.29 mmol) in DCM (36.4 mL) at 00C followed by (35)-3-methylmorpholine (0.737 g, 7.29 mmol) in DCM (20 mL) over 15 minutes. The reaction was then stirred at RT for 16 hours. The reaction mixture was washed with water (50 mL), the organic layer dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in DCM, to give the desired material as a beige solid (1.530 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 3.13 - 3.20 (IH, m), 3.27 - 3.28 (IH, m), 3.39 - 3.46 (IH, m), 3.57 (IH, dd), 3.72 (IH, d), 3.93 (IH, dd), 4.17 (IH, s), 4.65 (2H, s), 6.71 (IH, s), 7.48 (2H, t), 7.83 - 7.87 (2H, m) LCMS Spectrum: MH+ 386, retention time 1.94 min.
2.4-Dichloro-6-[(4-fluorophenvπsulfonylmethyllpyrimidine
Figure imgf000333_0001
3-Chloroperoxybenzoic acid (3.78 g, 21.89 mmol) was added portionwise to 2,4-dichloro-6- [(4-fluorophenyl)sulfanylmethyl]pyrimidine (2.11 g, 7.30 mmol), in DCM (36.5 mL) and the reaction stirred at RT for 2 hours. The reaction mixture was washed with a saturated aqueous solution ofsodium hydrogen carbonate (50 mL) and the organic layer dried (MgSO4), filtered and evaporated to afford desired product (2.35 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 4.99 (2H, s), 7.48 - 7.52 (2H, m), 7.76 (IH, s), 7.85 - 7.88 (2H, m) LCMS Spectrum: MH+ 319, retention time 2.01 min.
2,4-Dichloro-6-r(4-fluorophenyl)sulfanylmethvHpyrimidine
Figure imgf000333_0002
Phosphorus oxy chloride (15.2 g, 99.1 mmol) was added to 6-[(4- fluorophenyl)sulfanylmethyl]-lH-pyrimidine-2,4-dione (2.5 g, 9.91 mmol), and the resulting solution was stirred at reflux for 7 hours. The reaction was allowed to cool and the phosphorus oxychloride removed under reduced pressure to give a brown oil. This was dissolved in DCM and ice water (50 mL) added followed by solid sodium bicarbonate (until effervescence stops). The aqueous layer was extracted with DCM (2 x 50 mL) and the organics dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in isohexane, to give the desired material as a yellow gum (2.11 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 4.21 (2H, s), 7.09 - 7.14 (2H, m), 7.34 - 7.38 (2H, m), 7.58 (IH, s) LCMS Spectrum: M-H+ 287, retention time 2.51 min.
6-r(4-Fluorophenyl)sulfanylmethyll-lH-pyrimidine-2,4-dione
Figure imgf000334_0001
DBU (4.02 mL, 26.91 mmol) was added to 4-fluorobenzenethiol (3.45 g, 26.91 mmol), in DMF (90 mL) at RT. The resulting solution was stirred at 200C for 15 minutes. 6- (Chloromethyl)-lH-pyrimidine-2,4-dione (2.88 g, 17.94 mmol) was then added and the reaction stirred for 4 hours. The reaction mixture was concentrated and diluted with DCM (100 mL), and washed with water (100 mL). The aqueous layer was acidified with 2M hydrochloric acid to give a white solid which was filtered and washed with water then dried under vacuum to give desired product (2.5 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 3.80 (2H, s), 5.20 (IH, s), 7.18 - 7.23 (2H, m), 7.45 - 7.49 (2H, m), 10.90 (IH, s), 10.93 (IH, s) LCMS Spectrum: M-H- 251 , retention time 0.80 min.
Example 9: l-[4-[4-Q-Cyclopentylsulfonylcyclopropyr)-6-[(3S)-3-methylmorpholin-4- yll pyrimidin-2-yll phenyll -3-cyclopr opyl-urea
Figure imgf000334_0002
To a solution of phenyl Λ/-[4-[4-(l-cyclopentylsulfonylcyclopropyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (200 mg, 0.36 mmol) and amine (1.44 mmol) in NMP (2 mL) was added triethylamine (0.198 mL, 1.44 mmol) and mixture heated at 750C for 6 hours. The reaction was allowed to cool and purified by prep HPLC using decreasingly polar mixtures of water (containing 1% NH3) and acetonitrile as eluents, to give the desired material as a solid (130 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.40 - 0.43 (2H, m), 0.62 - 0.67 (2H, m), 1.23 (3H, d), 1.50 - 1.70 (8H, m), 1.85 - 1.94 (2H, m), 1.99 - 2.07 (2H, m), 3.16 - 3.25 (IH, m), 3.49 (IH, dd), 3.63 (IH, dd), 3.76 (IH, d), 3.89 - 4.00 (2H, m), 4.20 (IH, d), 4.55 (IH, s), 6.46 (IH, s), 6.82 (IH, s), 7.51 (2H, d), 8.20 (2H, d), 8.54 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 526; HPLC tR = 2.42 min mTOR Kinase Assay (Echo): 0.0018μM
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-(l- cyclopentylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate using the appropriate amine.
Figure imgf000335_0001
Figure imgf000336_0001
Figure imgf000337_0001
Example 9a: 1H NMR (400.132 MHz, DMSOd6) δ 1.23 (3H, d), 1.51 - 1.70 (1OH, m), 1.82 1.94 (4H, m), 1.98 - 2.08 (2H, m), 2.17 - 2.25 (2H, m), 3.17 - 3.25 (IH, m), 3.49 (IH, td), 3.63 (IH, dd), 3.76 (IH, d), 3.88 - 4.00 (2H, m), 4.10 - 4.22 (2H, m), 4.55 (IH, s), 6.47 (IH, d), 6.81 (IH, s), 7.48 (2H, d), 8.19 (2H, d), 8.56 (IH, s). mTOR Kinase Assay (Echo): 0.0129μM
Example 9b: 1H NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.53 - 1.70 (8H, m), 1.86 - 1.96 (2H, m), 2.00 - 2.09 (2H, m), 3.18 - 3.25 (IH, m), 3.46 - 3.54 (IH, m), 3.65 (IH, dd),
3.77 (IH, d), 3.90 - 4.01 (2H, m), 4.22 (IH, d), 4.57 (IH, s), 6.85 (IH, s), 7.04 (IH, t), 7.56
(IH, d), 7.65 (2H, d), 7.77 (IH, t), 8.26 - 8.32 (5H, m), 9.48 (IH, s), 10.63 (3H, s). mTOR Kinase Assay (Echo): 0.0215μM
Example 9c: 1R NMR (400.132 MHz, DMSO-(I6) δ 0.89 (6H, d), 1.23 (3H, d), 1.51 - 1.75 (8H, m), 1.85 - 1.96 (2H, m), 1.99 - 2.08 (2H, m), 2.94 (2H, t), 3.16 - 3.25 (IH, m), 3.49 (IH, td), 3.63 (IH, dd), 3.76 (IH, d), 3.89 - 4.00 (2H, m), 4.20 (IH, d), 4.55 (IH, s), 6.24 (IH, t),
6.82 (IH, s), 7.49 (2H, d), 8.19 (2H, d), 8.65 (IH, s). mTOR Kinase Assay (Echo): 0.0483μM
Example 9d: 1H NMR (400.132 MHz, DMSO-d6) δ 1.11 (6H, d), 1.23 (3H, d), 1.51 - 1.69 (8H, m), 1.85 - 1.94 (2H, m), 1.98 - 2.08 (2H, m), 3.20 (IH, td), 3.49 (IH, td), 3.63 (IH, dd),
3.73 - 3.81 (2H, m), 3.89 - 4.00 (2H, m), 4.19 (IH, d), 4.55 (IH, s), 6.07 (IH, d), 6.83 (IH, s),
7.48 (2H, d), 8.19 (2H, d), 8.54 (IH, s). mTOR Kinase Assay (Echo): 0.0151μM
Example 9e: 1R NMR (400.132 MHz, DMSO-de) δ 1.07 (3H, t), 1.23 (3H, d), 1.49 - 1.71 (8H, m), 1.86 - 1.96 (2H, m), 1.99 - 2.07 (2H, m), 3.12 (2H, q), 3.17 - 3.25 (IH, m), 3.45 -
3.53 (IH, m), 3.61 - 3.66 (IH, m), 3.89 - 3.99 (2H, m), 4.19 (IH, d), 4.56 (IH, s), 6.17 (IH, t),
6.82 (IH, s), 7.50 (2H, d), 8.18 (2H, d), 8.67 (IH, s). mTOR Kinase Assay (Echo): 0.00187μM
Example 9f: 1U NMR (400.132 MHz, DMSO-d6) δ 1.23 (3H, d), 1.50 - 1.70 (8H, m), 1.84 - 1.95 (2H, m), 1.98 - 2.08 (2H, m), 2.20 (6H, s), 2.33 (2H, t), 3.17 - 3.23 (2H, m), 3.49 (IH, td), 3.63 (IH, dd), 3.76 (IH, d), 3.90 - 4.00 (2H, m), 4.20 (IH, d), 4.56 (IH, s), 6.16 (IH, t),
6.82 (IH, s), 7.49 (2H, d), 8.19 (2H, d), 8.90 (IH, s). mTOR Kinase Assay (Echo): 0.144μM
Example 9g: 1R NMR (400.132 MHz, DMSO-de) δ 1.23 (3H, d), 1.50 - 1.71 (8H, m), 1.85 - 1.95 (2H, m), 1.98 - 2.07 (2H, m), 3.14 - 3.24 (3H, m), 3.43 - 3.52 (3H, m), 3.63 (IH, d), 3.76
(IH, d), 3.89 - 4.00 (2H, m), 4.19 (IH, d), 4.55 (IH, s), 4.73 (IH, t), 6.26 (IH, t), 6.82 (IH, s),
7.49 (2H, d), 8.19 (2H, d), 8.81 (IH, s). mTOR Kinase Assay (Echo): 0.00127μM
Example 9h: 1H NMR (400.132 MHz, DMSO-d6) δ 0.89 (3H, t), 1.23 (3H, d), 1.42 - 1.70 (1OH, m), 1.84 - 1.94 (2H, m), 1.98 - 2.08 (2H, m), 3.03 - 3.09 (2H, m), 3.16 - 3.25 (IH, m), 3.50 (IH, d), 3.63 (IH, d), 3.76 (IH, d), 3.90 - 4.00 (2H, m), 4.20 (IH, d), 4.55 (IH, s), 6.21 (IH, t), 6.82 (IH, s), 7.49 (2H, d), 8.19 (2H, d), 8.66 (IH, s). mTOR Kinase Assay (Echo): 0.0057μM Example 9i: 1H NMR (400.132 MHz, DMSOd6) δ 1.23 (3H, d), 1.49 - 1.71 (8H, m), 1.85 -
1.95 (2H, m), 1.99 - 2.08 (2H, m), 3.16 - 3.24 (IH, m), 3.49 (IH, td), 3.63 (IH, dd), 3.76 (IH, d), 3.87 - 4.01 (2H, m), 4.20 (IH, d), 4.56 (IH, s), 6.09 (IH, q), 6.82 (IH, s), 7.50 (2H, d), 8.19 (2H, d), 8.75 (IH, s). mTOR Kinase Assay (Echo): 0.0024μM
Example 9j: 1U NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.52 - 1.70 (8H, m), 1.87 -
1.96 (2H, m), 1.99 - 2.07 (2H, m), 3.17 - 3.27 (IH, m), 3.46 - 3.54 (IH, m), 3.64 (IH, d), 3.77 (IH, d), 3.89 - 4.01 (2H, m), 4.21 (IH, d), 4.57 (IH, s), 6.85 (IH, s), 7.59 (2H, d), 7.67 (4H, q), 8.27 (2H, d), 9.05 (IH, s), 9.15 (IH, s). mTOR Kinase Assay (Echo): 0.046μM
Example 9k: 1H NMR (400.132 MHz, DMSO-d6) δ 1.21 - 1.26 (9H, m), 1.51 - 1.71 (8H, m), 1.86 - 1.93 (2H, m), 1.98 - 2.09 (2H, m), 3.16 - 3.24 (IH, m), 3.39 (2H, d), 3.49 (IH, dd), 3.63 (IH, dd), 3.76 (IH, d), 3.90 - 4.01 (2H, m), 4.20 (IH, d), 4.55 (IH, s), 4.95 (IH, t), 6.02 (IH, s), 6.81 (IH, s), 7.45 (2H, d), 8.18 (2H, d), 8.75 (IH, s). mTOR Kinase Assay (Echo): 0.0115μM
Example 91: 1H NMR (400.132 MHz, DMSO-d6) δ 1.23 (3H, d), 1.50 - 1.70 (8H, m), 1.85 - 1.95 (2H, m), 1.98 - 2.07 (2H, m), 3.12 - 3.25 (3H, m), 3.23 - 3.33 (2H, m), 3.43 - 3.53 (3H, m), 3.63 (IH, d), 3.77 (IH, d), 3.89 - 4.01 (2H, m), 4.20 (IH, d), 4.48 (IH, t), 4.56 (IH, s), 6.21 (IH, t), 6.81 (IH, s), 7.49 (2H, d), 8.19 (2H, d), 8.72 (IH, s). mTOR Kinase Assay (Echo): 0.00395μM
Example 9m: 1H NMR (400.132 MHz, DMSO-d6) δ 1.23 (9H, d), 1.51 - 1.70 (2OH, m), 1.86 - 1.95 (6H, m), 1.99 - 2.07 (4H, m), 3.15 - 3.25 (25H, m), 3.50 (IH, d), 3.64 (IH, d), 3.78 (IH, d), 3.90 - 4.01 (2H, m), 4.20 (IH, d), 4.56 (IH, s), 6.86 (IH, s), 7.43 (IH, s), 7.56 (2H, d), 7.81 (IH, s), 8.23 (2H, d), 8.44 (IH, s), 8.87 (IH, s). mTOR Kinase Assay (Echo): 0.00401μM The preparation of phenyl Λ/-[4-[4-(l-cyclopentylsulfonylcyclopropyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N- [4- [4-(l-cvclopentylsulfonylcvclopropyπ-6- |"(35)-3 -methylmorpholin-4- yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000340_0001
Phenyl chloroformate (1.701 mL, 13.56 mmol) was added to 4-[4-(l- cyclopentylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl] aniline (4 g,
9.04 mmol) and sodium hydrogen carbonate (1.139 g, 13.56 mmol) in dioxane (120 mL) cooled to 50C under nitrogen. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with water (125 mL).
The organic layer was dried (MgSO4), filtered and evaporated to afford crude material which was triturated with diethyl ether and isohexane to give the desired material as a white solid
(4-77 g). NMR Spectrum: 1H NMR (400.132 MHz. DMSOdn) δ 1.24 (3H, d), 1.51 - 1.70 (4H, m),
1.85 - 1.95 (2H, m), 1.98 - 2.08 (2H, m), 3.21 (IH, td), 3.49 (IH, td), 3.64 (IH, dd), 3.77 (IH, d), 3.90 - 4.00 (2H, m), 4.21 (IH, d), 4.58 (IH, s), 6.88 (IH, s), 7.22 - 7.32 (3H, m), 7.41 -
7.49 (2H, m), 7.64 (2H, d), 8.30 (2H, d), 10.45 (IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 563; HPLC tR = 3.02 min
4-r4-(l-Cvclopentylsulfonylcvclopropyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-2- yll aniline
Figure imgf000340_0002
Bis(triphenylphosphine)palladium(II) chloride (300 mg, 0.43 mmol) was added to 2-chloro-4- (l-cyclopentylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (4.15 g, 10.75 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (3.53 g, 16.13 mmol) and sodium carbonate (25 mL, 50.0 mmol) in ethanol (20 mL), DMF (40 mL), water (25 mL) and DME (40 mL) at Rt and the resulting mixture degassed then stirred at 950C for 18 hours. The reaction mixture was diluted with ethyl acetate (400 mL), and washed with water (2 x 150 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 80% ethyl acetate in isohexane, to give the desired material as a cream solid (4.00 g). NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.21 (3H, d), 1.46 - 1.72 (7H, m), 1.84 - 1.95 (2H, m), 3.13 - 3.22 (IH, m), 3.47 (IH, td), 3.62 (IH, dd), 3.75 (IH, d), 3.89 - 3.99 (2H, m), 4.15 (IH, d), 4.54 (IH, s), 5.58 (2H, s), 6.61 (2H, d), 6.72 (IH, s), 8.02 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 443; HPLC tR = 2.4 min
2-Chloro-4-(l -cvclopentylsulfonylcvclopropyl)-6- r(3ιSV3 -methylmorpholin-4-vHpyrimidine
Figure imgf000341_0001
Sodium hydroxide (62.5 mL, 125.04 mmol) was added to 2-chloro-4- (cyclopentylsulfonylmethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (4.50 g, 12.50 mmol), 1 ,2-dibromoethane (4.31 mL, 50.02 mmol) and tetrabutylammonium bromide (0.403 g, 1.25 mmol) in toluene (100 mL) at 3O0C under nitrogen. The resulting mixture was stirred at 6O0C for 3 hours. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 45% ethyl acetate in isohexane, to give the desired material as a colourless gum (4.47 g).
NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.21 (3H, d), 1.47 - 1.68 (8H, m), 1.80 - 1.89 (2H, m), 1.91 - 1.98 (2H, m), 3.21 (IH, dt), 3.44 (IH, td), 3.58 (IH, dd), 3.72 (IH, d), 3.82 (IH, q), 3.93 (IH, dd), 3.98 - 4.06 (IH, m), 4.41 (IH, s), 6.97 (IH, s) 2-Chloro-4-(cvclopentylsulfonylmethyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000342_0001
Hydrogen peroxide (19.54 mL, 632 mmol) was added to 2-chloro-4- (cyclopentylsulfanylmethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (10.36 g, 31.60 mmol), sodium tungstate dihydrate (0.208 g, 0.63 mmol) (dissolved in minimum quantity of water) and 2M sulphuric acid solution (0.177 mL) in dioxane (100 mL) at 550C under air. The resulting solution was stirred at 550C for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water then a 10% aqueous solution of sodium metabisulfite. The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 70% ethyl acetate in isohexane, to give the desired material as a colourless gum (9.7 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.64 (4H, m), 1.95 (4H, m), 3.24 (IH, m), 3.45 (IH, td), 3.60 (IH, dd), 3.71 (IH, m), 3.95 (2H, m), 4.35 (IH, s), 4.40 (2H, s), 6.91 (IH, s) Mass Spectrum: m/z (ESI+)(M+H)+ = 360
2-Chloro-4-(cvclopentylsulfanylmethyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000342_0002
DIPEA (9.62 mL, 55.57 mmol) was added to cyclopentanethiol (5.93 mL, 55.57 mmol), in DMF (80 mL) at RT under nitrogen. The resulting solution was stirred at RT for 20 minutes. 2-Chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (13. Ig, 37.05 mmol) was added to the reaction and stirred for 2 hours at RT. The reaction mixture was diluted with ethyl acetate (500 mL), and washed with water (2 x 200 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% ethyl acetate in isohexane, to give the desired material as a colourless gum (11.13 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.43 (2H, m), 1.53 (2H, m), 1.65 (2H, m), 1.94 (2H, m), 3.16 (2H, m), 3.44 (IH, td), 3.71 (IH, d), 3.95 (2H, m), 4.35 (IH, s), 6.79 (IH, s)
Mass Spectrum: m/z (ESI+)(M+H)+ = 328
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier
Example 10 : 3-C vclopropyl- 1- [4- [4- [(3S)-3-methylmorpholin-4-yll -6- [ 1- [2- (trifluoromethvDphenyll sulfonylcyclopropyll pyrimidin-2-yll phenyll urea
Figure imgf000343_0001
To a solution of phenyl N-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-[2- (trifluoromethyl)phenyl] sulfonylcyclopropyl]pyrimidin-2-yl]phenyl] carbamate (200 mg,0.31 mmol) and cyclopropylamine (1.25 mmol) in NMP (2 mL) was added triethylamine (0.175 mL,1.25 mmol). The reaction mixture was heated at 750C for 6 hours. The reaction mixture was purified by prep HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and acetonitrile as eluents, to give the desired material (140 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.39 - 0.44 (2H, m), 0.63 - 0.67 (2H, m), 1.14 (3H, d), 1.70 - 1.75 (2H, m), 1.92 - 1.95 (2H, m), 3.11 (IH, td), 3.39 - 3.48 (IH, m), 3.59 (IH, dd), 3.73 (IH, d), 3.94 (IH, dd), 4.09 (IH, d), 4.43 (IH, s), 6.41 (IH, d), 6.62 (IH, s), 7.37 (2H, d), 7.76 (2H, d), 7.82 - 7.86 (2H, m), 7.91 - 7.95 (IH, m), 8.16 - 8.19 (IH, m), 8.49 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 602; HPLC tR = 2.52 min. mTOR Kinase Assay (Echo): 0.00448μM The following compounds were prepared in an analogous fashion from phenyl N- [4- [4- [(35)- 3-methylmorpholin-4-yl]-6-[l-[2-(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2- yl]phenyl]carbamate using the appropriate amine.
Figure imgf000344_0001
Figure imgf000345_0001
Figure imgf000346_0001
Example 10a: 1R NMR (400.132 MHz, DMSOd6) δ 1.13 (3H, d), 1.56 - 1.75 (4H, m), 1.80 - 1.96 (4H, m), 2.17 - 2.25 (2H, m), 3.11 (IH, td), 3.39 - 3.48 (IH, m), 3.59 (IH, dd), 3.73 (IH, d), 3.94 (IH, dd), 4.04 - 4.18 (2H, m), 4.43 (IH, s), 6.44 (IH, d), 6.61 (IH, s), 7.34 (2H, d), 7.75 (2H, d), 7.82 - 7.86 (2H, m), 7.92 - 7.95 (IH, m), 8.15 - 8.20 (IH, m), 8.52 (IH, s). mTOR Kinase Assay (Echo): 0.0395μM
Example 10b: mTOR Kinase Assay (Echo): 0.0266μM
Example 10c: 1U NMR (400.132 MHz, DMSO-(I6) δ 0.88 (6H, d), 1.14 (3H, d), 1.67 - 1.75
(2H, m), 1.91 - 1.95 (2H, m), 2.94 (2H, t), 3.11 (IH, td), 3.44 (IH, td), 3.59 (IH, dd), 3.73 (IH, d), 3.94 (IH, dd), 4.09 (IH, d), 4.43 (IH, s), 6.22 (IH, t), 6.61 (IH, s), 7.35 (2H, d), 7.76
(2H, d), 7.81 - 7.87 (2H, m), 7.92 - 7.96 (IH, m), 8.16 - 8.21 (IH, m), 8.60 (IH, s). mTOR Kinase Assay (Echo): 0.147μM
Example 1Od: 1H NMR (400.132 MHz, DMSO-d6) δ 1.09 - 1.15 (9H, m), 1.68 - 1.77 (2H, m), 1.92 - 1.95 (2H, m), 3.11 (IH, td), 3.44 (IH, td), 3.59 (IH, dd), 3.71 - 3.82 (2H, m), 3.94 (IH, dd), 4.09 (IH, d), 4.42 (IH, s), 6.04 (IH, d), 6.61 (IH, s), 7.34 (2H, d), 7.75 (2H, d), 7.82
- 7.87 (2H, m), 7.91 - 7.95 (IH, m), 8.16 - 8.20 (IH, m), 8.49 (IH, s). mTOR Kinase Assay (Echo): 0.0432μM
Example 1Oe: 1U NMR (400.132 MHz, DMSO-de) δ 1.06 (3H, t), 1.13 (3H, d), 1.69 - 1.75
(2H, m), 1.91 - 1.95 (2H, m), 3.07 - 3.19 (3H, m), 3.44 (IH, td), 3.59 (IH, dd), 3.73 (IH, d), 3.94 (IH, dd), 4.04 - 4.12 (IH, m), 4.44 (IH, s), 6.14 (IH, t), 6.62 (IH, s), 7.36 (2H, d), 7.75
(2H, d), 7.81 - 7.85 (2H, m), 7.91 - 7.95 (IH, m), 8.16 - 8.20 (IH, m), 8.62 (IH, s). mTOR Kinase Assay (Echo): 0.00691μM
Example 1Of: 1H NMR (400.132 MHz, DMSO-d6) δ 1.14 (3H, d), 1.69 - 1.74 (2H, m), 1.91 -
1.95 (2H, m), 2.19 (6H, s), 2.33 (2H, t), 3.11 (IH, td), 3.16 - 3.22 (2H, m), 3.44 (IH, td), 3.59 (IH, dd), 3.73 (IH, d), 3.94 (IH, dd), 4.09 (IH, d), 4.43 (IH, s), 6.15 (IH, t), 6.62 (IH, s),
7.35 (2H, d), 7.75 (2H, d), 7.82 - 7.87 (2H, m), 7.91 - 7.96 (IH, m), 8.16 - 8.20 (IH, m), 8.86
(IH, s). mTOR Kinase Assay (Echo): 0.174μM
Example 1Og: 1U NMR (400.132 MHz, DMSO-de) δ 1.13 (3H, d), 1.68 - 1.76 (2H, m), 1.92 - 1.95 (2H, m), 3.08 - 3.20 (3H, m), 3.39 - 3.48 (3H, m), 3.59 (IH, dd), 3.74 (IH, d), 3.94 (IH, dd), 4.09 (IH, d), 4.43 (IH, s), 4.72 (IH, t), 6.23 (IH, t), 6.62 (IH, s), 7.35 (2H, d), 7.75 (2H, d), 7.82 - 7.85 (2H, m), 7.92 - 7.95 (IH, m), 8.16 - 8.19 (IH, m), 8.76 (IH, s). mTOR Kinase Assay (Echo): 0.00156μM
Example 1Oh: 1H NMR (400.132 MHz, DMSO-d6) δ 0.88 (3H, t), 1.14 (3H, d), 1.45 (2H, q), 1.70 - 1.74 (2H, m), 1.90 - 1.95 (2H, m), 3.03 - 3.15 (3H, m), 3.40 - 3.48 (IH, m), 3.59 (IH, dd), 3.73 (IH, d), 3.94 (IH, dd), 4.09 (IH, d), 4.41 (IH, s), 6.18 (IH, t), 6.62 (IH, s), 7.36 (2H, d), 7.75 (2H, d), 7.82 - 7.87 (2H, m), 7.92 - 7.95 (IH, m), 8.17 - 8.20 (IH, m), 8.61 (IH, s). mTOR Kinase Assay (Echo): 0.0268μM
Example 1Oi: 1R NMR (400.132 MHz, DMSOd6) δ 1.13 (3H, d), 1.69 - 1.75 (2H, m), 1.92 - 1.95 (2H, m), 2.66 (3H, d), 3.11 (IH, td), 3.44 (IH, td), 3.59 (IH, dd), 3.73 (IH, d), 3.94 (IH, dd), 4.09 (IH, d), 4.43 (IH, s), 6.04 (IH, q), 6.61 (IH, s), 7.37 (2H, d), 7.76 (2H, d), 7.82 - 7.85 (2H, m), 7.92 - 7.95 (IH, m), 8.16 - 8.19 (IH, m), 8.70 (IH, s). mTOR Kinase Assay (Echo): 0.00591μM
Example 1Oj: 1H NMR (400.132 MHz, DMSOd6) δ 1.14 (3H, d), 1.71 - 1.76 (2H, m), 1.91 - 1.96 (2H, m), 3.09 - 3.17 (IH, m), 3.45 (IH, dd), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, d), 4.11 (IH, d), 4.44 (IH, s), 6.64 (IH, s), 7.45 (2H, d), 7.63 - 7.70 (4H, m), 7.81 - 7.87 (4H, m),
7.93 - 7.96 (IH, m), 8.17 - 8.21 (IH, m), 9.01 (IH, s), 9.12 (IH, s). mTOR Kinase Assay (Echo): 0.11 μM
Example 10k: 1H NMR (400.132 MHz, DMSO-d6) δ 1.14 (3H, d), 1.25 (6H, s), 1.69 - 1.75 (2H, m), 1.91 - 1.95 (2H, m), 3.11 (IH, td), 3.37 - 3.48 (3H, m), 3.59 (IH, dd), 3.74 (IH, d),
3.94 (IH, dd), 4.09 (IH, d), 4.42 (IH, s), 4.95 (IH, t), 5.99 (IH, s), 6.62 (IH, s), 7.32 (2H, d), 7.74 (2H, d), 7.82 - 7.87 (2H, m), 7.92 - 7.95 (IH, m), 8.17 - 8.20 (IH, m), 8.69 (IH, s). mTOR Kinase Assay (Echo): 0.0502μM
Example 101: 1R NMR (400.132 MHz, DMSO-d6) δ 1.14 (3H, d), 1.56 - 1.63 (2H, m), 1.69 - 1.74 (2H, m), 1.91 - 1.95 (2H, m), 3.07 - 3.19 (3H, m), 3.40 - 3.50 (3H, m), 3.59 (IH, dd), 3.73 (IH, d), 3.94 (IH, dd), 4.09 (IH, d), 4.43 (IH, s), 4.47 (IH, t), 6.18 (IH, t), 6.62 (IH, s), 7.36 (2H, d), 7.76 (2H, d), 7.82 - 7.86 (2H, m), 7.91 - 7.96 (IH, m), 8.15 - 8.20 (IH, m), 8.67 (IH, s). mTOR Kinase Assay (Echo): 0.0183μM Example 10m: 1H NMR (400.132 MHz, DMSO-d6) δ 1.14 (3H, d), 1.70 - 1.75 (2H, m), 1.90 - 1.96 (2H, m), 3.12 (IH, td), 3.44 (IH, td), 3.59 (IH, dd), 3.73 (IH, d), 3.95 (IH, dd), 4.10 (IH, d), 4.43 (IH, s), 6.62 (IH, s), 7.37 - 7.44 (3H, m), 7.76 - 7.81 (3H, m), 7.83 - 7.87 (2H, m), 7.92 - 7.95 (IH, m), 8.17 - 8.20 (IH, m), 8.38 (IH, s), 8.80 (IH, s). mTOR Kinase Assay (Echo): 0.00497μM The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-[2- (trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N-r4-r4-r(3^-3-methylmorpholin-4-yll-6-π -[2-
(trifluoromethyl)phenyllsulfonylcvclopropyllpyrimidin-2-yllphenyllcarbamate
Phenyl chloroformate (1.669 mL, 13.31 mmol) was added to 4-[4-[(3S)-3-methylmorpholin- 4-yl]-6-[l-[2-(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]aniline (4.6 g, 8.87 mmol) and sodium hydrogen carbonate (1.118 g, 13.31 mmol) in dioxane (20 mL) at 50C under nitrogen. The resulting mixture was stirred at RT for 2 hours then the reaction mixture diluted with ethyl acetate (200 mL), and washed with water (125 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material (4.55 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.14 (3H, d), 1.71 - 1.76 (2H, m), 1.92 - 1.96 (2H, m), 3.12 (IH, td), 3.41 - 3.47 (IH, m), 3.59 (IH, d), 3.73 (IH, d), 3.95 (IH, dd), 4.11 (IH, d), 4.45 (IH, s), 6.65 (IH, s), 7.22 - 7.31 (2H, m), 7.43 - 7.52 (3H,
4-r4-r(35)-3-Methylmorpholin-4-yll-6-ri-r2- (trifluoromethyl)phenyllsulfonylcvclopropyllpyrimidin-2-vHaniline
Figure imgf000349_0002
Bis(triphenylphosphine)palladium(II) chloride (300 mg, 0.43 mmol) was added to 2-chloro-4- [(35)-3-methylmorpholin-4-yl]-6-[l-[2- (trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidine (5 g, 10.83 mmol), 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (3.56 g, 16.24 mmol) and sodium carbonate (20 mL, 40.0 mmol) in a mixture of ethanol (10 mL), DMF (20 mL), water (15 mL) and DME (40 mL) at RT. The resulting mixture was degassed then stirred at 950C for 18 hours. The reaction was allowed to cool, diluted with ethyl acetate (400 mL), and washed with water (2 x 200 mL). The combined organics were dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 10 to 70% ethyl acetate in isohexane, to give the desired material as a cream solid (5.40 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.11 (3H, d), 1.68 - 1.73 (2H, m), 1.90 - 1.93 (2H, m), 3.07 (IH, td), 3.38 - 3.47 (IH, m), 3.58 (IH, dd), 3.72 (IH, d), 3.93 (2H, dd), 4.02 - 4.07 (IH, m), 4.39 (IH, s), 5.50 (2H, s), 6.45 - 6.50 (3H, m), 7.61 (2H, d), 7.81 - 7.85 (2H, m), 7.93 (IH, dd), 8.17 (IH, dd) LCMS Spectrum: m/z (ESI+)(M+H)+ = 519; HPLC tR = 2.51 min.
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll -641 - \2- (trifluoromethvDphenvHsulfonylcvclopropyHpyrimidine
Figure imgf000350_0001
An aqueous solution of sodium hydroxide (30 mL, 247.8 mmol) was added to 2-chloro-4- [(35)-3-methylmorpholin-4-yl]-6-[[2-(trifluoromethyl)phenyl]sulfonylmethyl]pyrimidine (4.5 g, 10.32 mmol), 1 ,2-dibromoethane (4.45 mL, 51.62 mmol) and tetrabutylammonium bromide (0.333 g, 1.03 mmol) in toluene (100 mL) at 3O0C under nitrogen. The resulting mixture was stirred at 3O0C for 3 hours. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 60% ethyl acetate in isohexane, to give the desired material (4.70 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.10 (3H, d), 1.61 - 1.66 (2H, m), 1.86 - 1.91 (2H, m), 3.09 (IH, td), 3.37 (IH, td), 3.52 (IH, dd), 3.68 (IH, d), 3.84 - 3.93 (2H, m), 4.27 (IH, s), 6.69 (IH, s), 7.85 - 7.93 (2H, m), 8.00 (IH, d), 8.07 (IH, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 462; HPLC tR = 2.43 min. 2-Chloro-4- IY35V3 -methylmorpholin-4-yll -6- IT2-
(trifluoromethyOphenylisulfonylmethylipyrimidine
Figure imgf000351_0001
Sodium 2-(trifluoromethyl)benzenesulfinate (10.24 g, 44 mmol) was added to 2-chloro-4- (iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (13 g, 36.77 mmol), in acetonitrile (500 mL) at RT under nitrogen. The resulting mixture was stirred at 8O0C for 3 hours. Additional sodium 2-(trifiuoromethyl)benzenesulfmate (10.2 g, 44 mmol) was added and reaction heated at 8O0C for 1 hour. The reaction mixture allowed to cool and concentrated in vacuo. The material was dissolved in ethyl acetate (500 mL), and washed with water (200 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in isohexane, to give the desired material as an orange/cream solid (9.48 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 3.17 (IH, td), 3.43 (IH, td), 3.58 (IH, dd), 3.72 (IH, d), 3.93 (2H, m), 4.27 (IH, s), 4.68 (2H, s), 6.79 (IH, s), 7.94 (3H, m), 8.08 (IH, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 436; HPLC tR = 2.35 min.
Sodium 2-(trifluoromethvDbenzenesulfinate
Figure imgf000351_0002
Sodium sulfite (3.92 mL, 81.88 mmol) was dissolved in water and stirred at RT 10 minutes. Sodium bicarbonate (13.74 g, 163.52 mmol) was added and the mixture stirred at 5O0C for 1 hour. 2-(Trifluoromethyl)benzene-l-sulfonyl chloride (12.62 mL, 81.76 mmol) was added drop wise to the reaction mixture which was then stirred at 5O0C for 18 hours. The reaction mixture was evaporated to dryness and the residue suspended in methanol (250 mL) and stirred at RT for 20 minutes. The solid was removed by filtration and the filtrate evaporated to give the desired material (20.00 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 7.40 (IH, d), 7.51 (IH, d), 7.64 (IH, d), 8.05 (IH, d)
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Example 11: 3-Cvclopropyl-l-[4-[4-Q-ethylsulfonylcvclopropyl)-6-[(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll urea
Figure imgf000352_0001
To a solution of phenyl Λ/-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate (150 mg, 0.29 mmol) in DMF (2 mL) was added triethylamine (0.120 mL, 0.86 mmol) followed by cyclopropylamine (0.100 mL, 1.44 mmol) and the reaction heated at 500C for 2 hours. The crude product was purified by preparative
HPLC using decreasingly polar mixtures of water (containing 1% NH3) and acetonitrile as eluents, to give the desired material as a white solid (90 mg).
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.40 - 0.44 (2H, m), 0.63 - 0.67 (2H, m), 1.23 (3H, d), 1.32 (3H, t), 1.55 (2H, t), 1.62 - 1.65 (2H, m), 2.52 - 2.58 (IH, m), 3.17 - 3.24 (IH, m), 3.43 (2H, q), 3.45 - 3.52 (IH, m), 3.61 - 3.65 (IH, m), 3.76 (IH, d), 3.95 - 3.99
(IH, m), 4.19 - 4.22 (IH, m), 4.56 (IH, s), 6.44 (IH, d), 6.78 (IH, s), 7.50 - 7.52 (2H, m),
8.18 - 8.20 (2H, m), 8.54 (IH, s).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 486; HPLC tR = 1.96 min. mTOR Kinase Assay (Echo): 0.00165μM
The following compounds were prepared in an analogous fashion from phenyl N-[4-[4-(l- ethylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate using the appropriate amine.
Figure imgf000353_0001
Figure imgf000354_0001
Figure imgf000355_0001
Example 11m can also be prepared in an analogous fashion but using DMA as the solvent and stirring at 5O0C for 18 hours.
Example 11a: 1H NMR (400.13 MHz, DMSOd6) δ 1.23 (3H, d), 1.32 (3H, t), 1.55 (2H, t), 1.62 - 1.64 (2H, m), 2.67 (3H, t), 3.20 - 3.24 (IH, m), 3.43 (2H, q), 3.45 - 3.52 (IH, m), 3.61 3.65 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.19 - 4.22 (IH, m), 4.55 (IH, s), 6.07 (IH, d), 6.77 (IH, s), 7.49 - 7.52 (2H, m), 8.17 - 8.19 (2H, m), 8.74 (IH, s). mTOR Kinase Assay (Echo): 0.00418μM Example lib: 1H NMR (400.13 MHz, DMSOd6) δ 1.07 (3H, t), 1.23 (3H, d), 1.32 (3H, t), 1.55 (2H, t), 1.62 - 1.65 (2H, m), 3.09 - 3.16 (2H, m), 3.20 - 3.24 (IH, m), 3.43 (2H, q), 3.45 3.52 (IH, m), 3.61 - 3.65 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.20 (IH, d), 4.56 (IH, s), 6.16 (IH, t), 6.77 (IH, s), 7.48 - 7.52 (2H, m), 8.17 - 8.19 (2H, m), 8.66 (IH, s). mTOR Kinase Assay (Echo): 0.00333μM Example lie: 1U NMR (400.13 MHz, DMSO-d6) δ 1.11 (6H, d), 1.23 (3H, d), 1.32 (3H, t), 1.55 (2H, t), 1.60 - 1.65 (2H, m), 3.20 - 3.24 (IH, m), 3.43 (2H, q), 3.45 - 3.52 (IH, m), 3.61 - 3.65 (IH, m), 3.77 (IH, d), 3.80 (IH, m), 3.95 - 3.99 (IH, m), 4.19 - 4.22 (IH, m), 4.55 (IH, s), 6.07 (IH, d), 6.77 (IH, s), 7.47 - 7.50 (2H, m), 8.17 - 8.19 (2H, m), 8.53 (IH, s). mTOR Kinase Assay (Echo): 0.0247μM
Example Hd: 1H NMR (400.13 MHz, DMSOd6) δ 1.23 (3H, d), 1.32 (3H, t), 1.53 - 1.58 (2H, m), 1.62 - 1.64 (2H, m), 1.81 - 1.89 (3H, m), 2.18 - 2.24 (3H, m), 3.20 - 3.24 (IH, m), 3.43 (2H, q), 3.48 - 3.51 (IH, m), 3.61 - 3.65 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.16 (2H, m), 4.55 (IH, s), 6.46 - 6.48 (IH, m), 6.78 (IH, s), 7.46 - 7.50 (2H, m), 8.18 (2H, d), 8.56 (IH, s). mTOR Kinase Assay (Echo): 0.00642μM
Example He: 1U NMR (400.13 MHz, DMSOd6) δ 1.23 (3H, d), 1.32 (3H, t), 1.55 (2H, t), 1.62 - 1.64 (2H, m), 3.18 (IH, q), 3.20 (2H, d), 3.40 - 3.51 (2H, m), 3.46 (IH, d), 3.42 - 3.52 (2H, m), 3.61 - 3.65 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.20 (IH, d), 4.56 (IH, s), 4.73 (IH, t), 6.26 (IH, t), 6.78 (IH, s), 7.48 - 7.50 (2H, m), 8.19 (2H, d), 8.80 (IH, s). mTOR Kinase Assay (Echo): 0.00135μM
Example Hf: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.24 (6H, s), 1.32 (3H, d), 1.53 - 1.58 (2H, m), 1.62 - 1.64 (2H, m), 3.17 - 3.24 (IH, m), 3.39 (2H, d), 3.45 (2H, q), 3.45 - 3.52 (IH, m), 3.61 - 3.65 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.19 - 4.22 (IH, m), 4.54 (IH, s), 4.95 (IH, t), 6.01 (IH, s), 6.77 (IH, s), 7.44 - 7.48 (2H, m), 8.18 (2H, d), 8.74 (IH, s). mTOR Kinase Assay (Echo): 0.00337μM
Example Hg: 1U NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.32 (3H, t), 1.53 - 1.58 (2H, m), 1.62 - 1.64 (2H, m), 2.18 (6H, s), 2.34 (2H, t), 3.17 - 3.23 (3H, m), 3.43 (2H, q), 3.45 - 3.52 (IH, m), 3.61 - 3.65 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.19 (IH, s), 4.56 (IH, s), 6.16 (IH, t), 6.77 (IH, s), 7.48 - 7.51 (2H, m), 8.17 - 8.19 (2H, m), 8.89 (IH, s). mTOR Kinase Assay (Echo): 0.313μM
Example Hh: 1H NMR (400.13 MHz, DMSO-d6) δ 0.89 (3H, t), 1.23 (3H, d), 1.32 (3H, t), 1.41 - 1.50 (2H, m), 1.55 (2H, t), 1.62 - 1.65 (2H, m), 3.04 - 3.09 (2H, m), 3.17 - 3.24 (IH, m), 3.43 (2H, q), 3.45 - 3.52 (IH, m), 3.61 - 3.65 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.20 (IH, d), 4.55 (IH, s), 6.21 (IH, t), 6.77 (IH, s), 7.48 - 7.51 (2H, m), 8.17 - 8.20 (2H, m), 8.65 (IH, s). mTOR Kinase Assay (Echo): 0.00913μM
Example Hi: 1U NMR (400.13 MHz, DMSO-d6) δ 0.89 (6H, d), 1.23 (3H, d), 1.32 - 1.38
(3H, m), 1.55 (2H, t), 1.62 - 1.65 (2H, m), 1.69 - 1.76 (IH, m), 2.94 (2H, t), 3.17 - 3.24 (IH, m), 3.43 (2H, q), 3.45 - 3.52 (IH, m), 3.61 - 3.65 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.20 (IH, d), 4.56 (IH, s), 6.25 (IH, t), 6.78 (IH, s), 7.48 - 7.51 (2H, m), 8.18 (IH, t), 8.20
(IH, s), 8.64 (IH, s). mTOR Kinase Assay (Echo): 0.0294μM
Example Hj: 1H NMR (400.13 MHz, DMSOd6) δ 1.23 (3H, d), 1.32 (3H, t), 1.55 (2H, q),
1.58 (2H, m), 1.62 - 1.64 (2H, m), 3.15 - 3.19 (3H, m), 3.43 (2H, q), 3.46 - 3.47 (2H, m), 3.50 (IH, d), 3.61 - 3.65 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.20 (IH, d), 4.47 (IH, t), 4.55
(IH, s), 6.21 (IH, t), 6.77 (IH, s), 7.48 - 7.51 (2H, m), 8.17 - 8.20 (2H, m), 8.71 (IH, s). mTOR Kinase Assay (Echo): 0.0122μM
Example Hk: 1H NMR (400.13 MHz, DMSOd6) δ 1.24 (3H, d), 1.33 (3H, t), 1.56 (2H, t),
1.63 - 1.66 (2H, m), 3.18 - 3.26 (IH, m), 3.44 (2H, q), 3.46 - 3.53 (IH, m), 3.62 - 3.66 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.22 (IH, d), 4.57 (IH, s), 6.81 (IH, s), 7.58 - 7.60 (2H, m), 7.64 - 7.70 (4H, m), 8.27 (2H, d), 9.05 (IH, s), 9.14 (IH, s). mTOR Kinase Assay (Echo): 0.00332μM
Example 111: 1R NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 1.34 (3H, t), 1.55 - 1.59
(2H, m), 1.63 - 1.66 (2H, m), 3.18 - 3.23 (IH, m), 3.45 (2H, q), 3.47 - 3.53 (IH, m), 3.62 - 3.66 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.20 - 4.24 (IH, m), 4.57 (IH, s), 6.81 (IH, s), 7.02 - 7.05 (IH, m), 7.56 (IH, d), 7.65 (2H, d), 7.75 - 7.77 (IH, m), 8.26 - 8.31 (IH, m),
8.27 - 8.31 (2H, m), 9.45 (IH, d), 10.61 (IH, s). mTOR Kinase Assay (Echo): 0.00356μM
Example Hm: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 1.33 (3H, t), 1.56 (2H, t), 1.63 - 1.65 (2H, m), 3.17 - 3.25 (IH, m), 3.44 (2H, q), 3.46 - 3.52 (IH, m), 3.62 - 3.66 (IH, m), 3.75 (IH, s), 3.79 (3H, s), 3.96 - 4.00 (IH, m), 4.21 (IH, d), 4.56 (IH, s), 6.79 (IH, s),
7.38 - 7.39 (IH, m), 7.53 - 7.57 (2H, m), 7.76 (IH, s), 8.22 (2H, d), 8.39 (IH, s), 8.84 (IH, s). mTOR Kinase Assay (Echo): 0.00437μM
The preparation of phenyl Λ/-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin- 4-yl]pyrimidin-2-yl]phenyl] carbamate is described below. Phenyl Λ/-r4-r4-(l-ethylsulfonylcvclopropyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-2- yllphenyll carbamate
Figure imgf000358_0001
Phenyl chloroformate (0.566 mL, 4.50 mmol) was added dropwise to 4-[4-(l- ethylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl] aniline (1.81 g, 4.50 mmol) and sodium bicarbonate (0.567 g, 6.75 mmol) in dioxane (30 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in ethyl acetate (200 mL) and washed with water (200 mL). The organic layer was dried (MgSO4), filtered and evaporated to give the desired material as a white solid (2.36 g).
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.24 (3H, d), 1.33 (3H, t), 1.55 - 1.59 (2H, m), 1.63 - 1.65 (2H, m), 3.21 - 3.25 (IH, m), 3.43 - 3.48 (2H, m), 3.41 - 3.52 (IH, m), 3.62 - 3.65 (IH, m), 3.77 (IH, d), 3.96 - 3.99 (IH, m), 4.21 (IH, s), 4.57 (IH, s), 6.82 (IH, s), 7.24 - 7.30 (3H, m), 7.43 - 7.47 (2H, m), 7.64 (2H, d), 8.27 - 8.30 (2H, m), 10.44 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 523; HPLC tR = 2.83 min.
4- r4-(l-Ethylsulfonylcvclopropyl)-6- [(36^-3 -methylmorpholin-4-vHpyrimidin-2-vH aniline
Figure imgf000358_0002
Dichlorobis(triphenylphosphine)palladium(II) (0.317 g, 0.45 mmol) was added to a degassed solution of 2-chloro-4-(l -ethylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4- yljpyrimidine (1.56 g, 4.51 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.235 g, 5.64 mmol) and sodium carbonate (11.28 ml, 22.55 mmol) in a mixture of 18% DMF in DME:water:ethanol (7:3:2) (20 mL). The resulting solution was stirred at 85°C for 30 minutes. The reaction mixture was concentrated and partitioned between DCM (100 mL) and water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 2.5% methanol in DCM, to give the desired material as a brown oil (2.15 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.22 (3H, d), 1.31 (3H, t), 1.53 (2H, m), 1.60 - 1.62 (2H, m), 3.17 - 3.21 (IH, m), 3.37 - 3.47 (2H, m), 3.50 (IH, m), 3.60 - 3.64 (IH, m), 3.75 (IH, d), 3.94 - 3.98 (IH, m), 4.15 - 4.19 (IH, m), 4.51 - 4.53 (IH, m), 5.55 (2H, d), 6.60 - 6.62 (2H, m), 6.67 (IH, s), 8.00 - 8.04 (2H, m) LCMS Spectrum: m/z (ESI+) (M+H)+ = 403; HPLC tR = 2.14 min.
2-Chloro-4-(l-ethylsulfonylcvclopropyπ-6-[(35)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000359_0001
An aqueous sodium hydroxide solution (25.4 mL, 254.1 mmol) was added to tetrabutylammonium bromide (0.328 g, 1.02 mmol), 1 ,2-dibromoethane (0.876 mL, 10.16 mmol) and 2-chloro-4-(ethylsulfonylmethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (3.25 g, 10.16 mmol) in DCM (75 mL). The resulting mixture was stirred at 400C for 4 hours. The reaction mixture was diluted with DCM (50 mL) and washed with water (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a white solid (1.56 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.17 (3H, d), 1.23 (3H, s), 1.49 - 1.52 (2H, m), 1.55 - 1.62 (2H, m), 3.18 - 3.23 (IH, m), 3.35 (2H, t), 3.41 - 3.46 (IH, m), 3.56 - 3.60 (IH, m), 3.72 (IH, d), 3.91 - 3.95 (IH, m), 4.15 - 4.19 (IH, m), 4.40 (IH, s), 6.93 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 346; HPLC 1.97 tR = min.
2-Chloro-4-(ethylsulfonylmethyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000359_0002
Ethane sulfuric acid sodium salt (3.94 g, 33.94 mmol) was added in one portion to 2-chloro-4- (iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (12.0 g, 33.94 mmol) in acetonitrile (250 mL) at RT. The resulting suspension was stirred at 800C for 16 hours. The reaction mixture was evaporated to dryness and the residue partitioned between DCM (25OmL), and water (20OmL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a yellow solid (5.94 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.23 (3H, m), 1.28 (3H, t), 3.22 (2H, d), 3.32 (IH, s), 3.42 - 3.49 (IH, m), 3.58 - 3.62 (IH, m), 3.73 (IH, d), 3.92 - 3.96 (2H, m), 4.25 - 4.31 (IH, m), 4.43 (2H, s), 6.92 (IH, s)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 320; HPLC tR = 1.46 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Example 12: 3-Cvclopropyl-l-[4-[4-Q-methylsulfonylcvclopropyl)-6-morpholin-4- ylpyrimidin-2-yll phenyll urea
Figure imgf000360_0001
To a solution of phenyl Λ/-[4-[4-(l-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]carbamate (150 mg, 0.29 mmol) in DMF (2 mL) was added triethylamine (0.127 mL, 0.91 mmol) followed by cyclopropylamine (0.106 mL, 1.52 mmol) and the reaction heated at 500C for 20 hours. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (80 mg). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.40 - 0.44 (2H, m), 0.64 - 0.66 (2H, m), 1.54 - 1.57 (IH, m), 1.55 (IH, d), 1.67 (IH, d), 1.65 - 1.68 (IH, m), 2.60 (IH, m), 3.30 (3H, s), 3.72 (8H, s), 6.43 (IH, d), 6.81 (IH, s), 7.50 - 7.52 (2H, m), 8.19 - 8.22 (2H, m), 8.55 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 458; HPLC tR = 1.44 min. mTOR Kinase Assay (Echo): 0.00421μM
The following compounds were made in an analogous fashion from either phenyl 7V-[4-[4-(l- methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]carbamate, phenyl N-[4- [4-( 1 -methylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]carbamate or phenyl N- [4- [4-( 1 -methylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]carbamate and the appropriate amines.
Figure imgf000361_0001
Figure imgf000362_0001
Figure imgf000363_0001
Figure imgf000364_0001
* Reaction stirred at 550C for 6 hours ** Reaction stirred at 4O0C for 6 hours
The crude material for Example 12 can also be purified either by chromatography on silica, eluting with 50-80% ethyl acetate in isohexane, or by dissolving the material in ethyl acetate and allowing the desired material to precipitate from solution on stirring.
Example 12a: 1R NMR (400.13 MHz, DMSOd6) δ 1.53 - 1.57 (IH, m), 1.55 - 1.56 (IH, m), 1.67 (IH, d), 1.65 - 1.68 (IH, m), 2.66 (3H, d), 3.30 (3H, s), 3.72 (8H, s), 6.06 (IH, d), 6.81 (IH, s), 7.49 - 7.52 (2H, m), 8.19 - 8.21 (2H, m), 8.75 (IH, s). mTOR Kinase Assay (Echo): 0.00167μM
Example 12b: 1H NMR (400.13 MHz, DMSOd6) δ 1.07 (3H, t), 1.54 - 1.57 (IH, m), 1.55 (IH, d), 1.67 (IH, d), 1.65 - 1.68 (IH, m), 3.11 - 3.14 (2H, m), 3.30 (3H, s), 3.72 (8H, s), 6.16 (IH, s), 6.81 (IH, s), 7.49 - 7.51 (2H, m), 8.19 - 8.21 (2H, m), 8.67 (IH, s). mTOR Kinase Assay (Echo): 0.00271μM
Example 12c: 1U NMR (400.13 MHz, DMSO-d6) δ 1.53 - 1.57 (2H, m), 1.55 (2H, d), 1.59 - 1.67 (2H, m), 1.82 - 1.85 (IH, m), 1.89 (IH, t), 2.18 - 2.25 (2H, m), 3.30 (3H, s), 3.72 (8H, s), 4.14 (IH, d), 6.46 (IH, d), 6.81 (IH, s), 7.47 - 7.49 (2H, m), 8.20 (2H, d), 8.57 (IH, s). mTOR Kinase Assay (Echo): 0.00152μM
Example 12d: 1H NMR (400.13 MHz, DMSOd6) δ 1.54 - 1.57 (IH, m), 1.55 - 1.56 (IH, m),
1.67 (IH, d), 1.65 - 1.68 (IH, m), 3.18 (2H, q), 3.30 (3H, s), 3.46 (2H, q), 3.72 (8H, s), 4.73 (IH, t), 6.25 (IH, t), 6.81 (IH, s), 7.48 - 7.50 (2H, m), 8.19 - 8.22 (2H, m), 8.81 (IH, s). mTOR Kinase Assay (Echo): 0.00155μM Example 12e: 1U NMR (400.13 MHz, DMSOd6) δ 1.24 (6H, s), 1.54 - 1.57 (IH, m), 1.55
(IH, d), 1.67 (IH, d), 1.65 - 1.68 (IH, m), 3.30 (3H, s), 3.39 (2H, d), 3.72 (8H, s), 4.95 (IH, t), 6.00 (IH, s), 6.80 (IH, s), 7.44 - 7.47 (2H, m), 8.18 - 8.20 (2H, m), 8.74 (IH, s). mTOR Kinase Assay (Echo): 0.00459μM
Example 12f: 1H NMR (400.13 MHz, DMSO-d6) δ 1.54 - 1.57 (IH, m), 1.55 - 1.56 (IH, m), 1.67 (IH, d), 1.65 - 1.68 (IH, m), 2.18 (6H, s), 2.34 (2H, t), 3.20 (2H, t), 3.30 (3H, s), 3.72
(8H, s), 6.16 (IH, t), 6.80 (IH, s), 7.47 - 7.51 (2H, m), 8.20 (2H, d), 8.90 (IH, s). mTOR Kinase Assay (Echo): 0.0605μM
Example 12g: 1R NMR (400.13 MHz, DMSO-d6) δ 0.89 (3H, t), 1.41 - 1.50 (2H, m), 1.54 -
1.57 (IH, m), 1.55 (IH, d), 1.67 (IH, d), 1.65 - 1.68 (IH, m), 3.04 - 3.09 (2H, m), 3.30 (3H, s), 3.72 (8H, s), 6.20 (IH, t), 6.81 (IH, s), 7.48 - 7.51 (2H, m), 8.18 - 8.22 (2H, m), 8.66 (IH, s). mTOR Kinase Assay (Echo): 0.00273μM
Example 12h: 1H NMR (400.13 MHz, DMSO-d6) δ 1.53 - 1.58 (2H, m), 1.61 (2H, d), 1.65 -
1.68 (2H, m), 3.17 (2H, d), 3.30 (3H, s), 3.45 - 3.48 (2H, m), 3.72 (8H, s), 4.47 (IH, t), 6.20 (IH, s), 6.81 (IH, s), 7.48 - 7.51 (2H, m), 8.19 - 8.21 (2H, m), 8.72 (IH, s). mTOR Kinase Assay (Echo): 0.00392μM
Example 12i: 1U NMR (400.13 MHz, DMSO-d6) δ 1.54 - 1.58 (IH, m), 1.56 - 1.56 (IH, m), 1.67 (2H, t), 3.30 (3H, s), 3.72 (8H, s), 3.79 (3H, s), 6.82 (IH, s), 7.38 - 7.38 (IH, m), 7.54 - 7.56 (2H, m), 7.76 (IH, s), 8.23 - 8.25 (2H, m), 8.38 (IH, s), 8.84 (IH, s). mTOR Kinase Assay (Echo): 0.000771μM Example 12j: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40 - 0.44 (2H, m), 0.63 - 0.67 (2H, m), 1.58 (2H, t), 1.81 (2H, d), 2.39 - 2.47 (2H, m), 2.57 (IH, t), 2.74 (2H, t), 2.91 (3H, s), 3.73 (8H, s), 6.42 (IH, d), 6.84 (IH, s), 7.49 - 7.53 (2H, m), 8.22 - 8.26 (2H, m), 8.54 (IH, s). mTOR Kinase Assay (Echo): 0.00167μM Example 12k: 1H NMR (400.13 MHz, DMSOd6) δ 1.56 - 1.57 (2H, m), 1.80 - 1.82 (2H, m), 2.42 (2H, d), 2.46 (2H, d), 2.67 (3H, t), 2.91 (3H, s), 3.73 (8H, s), 6.06 (IH, d), 6.84 (IH, s),
7.49 - 7.52 (2H, m), 8.22 - 8.25 (2H, m), 8.74 (IH, s). mTOR Kinase Assay (Echo): 0.0043μM
Example 121: 1R NMR (400.13 MHz, DMSOd6) δ 1.58 (2H, t), 1.81 (2H, d), 2.41 - 2.44 (2H, m), 2.73 (2H, d), 2.91 (3H, s), 3.18 (2H, q), 3.46 (2H, q), 3.73 (8H, s), 4.72 (IH, t), 6.25 (IH, s), 6.84 (IH, s), 7.48 - 7.50 (2H, m), 8.23 - 8.25 (2H, m), 8.81 (IH, s). mTOR Kinase Assay (Echo): 0.00138μM
Example 12m: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (6H, s), 1.58 (2H, t), 1.81 (2H, d), 2.41 - 2.44 (2H, m), 2.71 - 2.75 (2H, m), 2.91 (3H, s), 3.39 (2H, d), 3.73 (8H, s), 4.95 (IH, t), 6.00 (IH, s), 6.84 (IH, s), 7.44 - 7.47 (2H, m), 8.22 - 8.24 (2H, m), 8.74 (IH, s). mTOR Kinase Assay (Echo): O.OlOlμM
Example 12n: 1H NMR (400.13 MHz, DMSO-d6) δ 1.56 - 1.57 (2H, m), 1.81 (2H, d), 2.18 (6H, s), 2.34 (2H, t), 2.39 - 2.46 (2H, m), 2.73 (2H, q), 2.91 (3H, s), 3.19 (2H, q), 3.73 (8H, s), 6.15 (IH, t), 6.84 (IH, s), 7.48 - 7.50 (2H, m), 8.23 - 8.25 (2H, m), 8.90 (IH, s). mTOR Kinase Assay (Echo): 0.238μM
Example 12o: 1R NMR (400.13 MHz, DMSO-d6) δ 1.56 - 1.59 (2H, m), 1.57 - 1.63 (2H, m), 1.81 (2H, d), 2.39 - 2.46 (2H, m), 2.72 - 2.74 (2H, t), 2.91 (3H, s), 3.15 - 3.19 (2H, m), 3.45 -
3.50 (2H, m), 3.73 (8H, s), 4.47 (IH, t), 6.20 (IH, t), 6.84 (IH, s), 7.48 - 7.51 (2H, m), 8.22 - 8.25 (2H, m), 8.71 (IH, s). mTOR Kinase Assay (Echo): 0.00509μM
Example 12p: 1H NMR (400.13 MHz, DMSO-d6) δ 0.41 - 0.43 (2H, m), 0.63 - 0.66 (2H, m), 1.90 (IH, m), 2.08 (IH, m), 2.33 (IH, t), 2.68 (IH, t), 2.80 - 2.82 (lH,m), 2.87 (3H, s), 2.90 (2H, m), 3.73 (8H, s), 6.43 - 6.44 (IH, m), 6.77 (IH, s), 7.49 - 7.51 (2H, m), 8.21 - 8.24 (2H, m), 8.56 (IH, s). mTOR Kinase Assay (Echo): 0.0014μM Example 12q: 1H NMR (400.13 MHz, DMSO-d6) δ 1.99 - 2.06 (IH, m), 2.09 (IH, m), 2.32 -
2.34 (3H, m), 2.87 (3H, s), 2.90 (2H, s), 2.93 (2H, s), 3.73 (8H, s), 6.06 (IH, d), 6.76 (IH, s),
7.50 (2H, d), 8.22 (2H, d), 8.74 (IH, s). mTOR Kinase Assay (Echo): 0.00162μM Example 12r: 1R NMR (400.13 MHz, DMSOd6) δ 1.89 (IH, t), 2.07 (IH, d), 2.76 - 2.83
(2H, m), 2.87 (3H, s), 2.90 - 2.93 (2H, m), 3.18 (2H, m), 3.46 (2H, m), 3.73 (8H, s), 4.72 (IH, t), 6.25 (IH, t), 6.76 (IH, s), 7.48 - 7.50 (2H, m), 8.21 - 8.23 (2H, m), 8.81 (IH, s). mTOR Kinase Assay (Echo): 0.00099 lμM
Example 12s: 1H NMR (400.13 MHz, DMSOd6) δ 1.89 (IH, t), 2.07 (IH, t), 2.18 (6H, s), 2.34 (2H, t), 2.80 (2H, d), 2.87 (3H, s), 2.90 (2H, m), 3.19 (2H, t), 3.73 (8H, s), 6.16 (IH, s),
6.76 (IH, s), 7.47 - 7.50 (2H, m), 8.21 - 8.23 (2H, m), 8.90 (IH, s). mTOR Kinase Assay (Echo): 0.134μM
Example 12t: 1H NMR (400.13 MHz, DMSO-d6) δ 1.58 (2H, t), 1.87 - 1.92 (IH, m), 2.06 -
2.10 (IH, m), 2.76 - 2.82 (2H, m), 2.87 (3H, s), 2.90 - 2.93 (2H, m), 3.14 - 3.19 (2H, m), 3.45 - 3.49 (2H, m), 3.73 (8H, s), 4.47 (IH, t), 6.20 (IH, t), 6.76 (IH, s), 7.48 - 7.50 (2H, m), 8.21 -
8.23 (2H, m), 8.71 (IH, s). mTOR Kinase Assay (Echo): 0.0366μM
The preparation of phenyl 7V-[4-[4-(l-methylsulfonylcyclopropyl)-6-morpholin-4- ylpyrimidin-2-yl]phenyl] carbamate is described below:
Phenyl Λ/-[4-[4-(l-methylsulfonylcvclopropyπ-6-morpholin-4-ylpyrimidin-2- yllphenyl] carbamate
Figure imgf000367_0001
Phenyl chloroformate (0.4 mL, 3.18 mmol) was added dropwise to 4-(4-(l-
(methylsulfonyl)cyclopropyl)-6-morpholinopyrimidin-2-yl)aniline (1.19 g, 3.18 mmol) and sodium bicarbonate (0.40 g, 4.77 mmol) in dioxane (30 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in ethyl acetate (10OmL) and washed with water (10OmL). The organic layer was dried (MgSO4), filtered and evaporated to afford the desired material as a yellow solid (1.68 g)-
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.57 (IH, d), 1.55 - 1.62 (IH, m), 1.68 (IH, d), 1.66 - 1.69 (IH, m), 3.40 (3H, s), 3.73 (8H, s), 6.86 (IH, s), 7.24 - 7.30 (3H, m), 7.43 - 7.47 (2H, m), 7.63 - 7.65 (2H, m), 8.29 - 8.31 (2H, m), 10.44 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 495; HPLC tR = 2.58 min.
4- r4-(l-Methylsulfonylcvclopropyl)-6-morpholin-4-ylpyrimidin-2-yll aniline
Figure imgf000368_0001
Dichlorobis(triphenylphosphine)palladium(II) (0.636 g, 0.91 mmol) was added to 2-chloro-4- (l-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidine (2.88 g, 9.06 mmol), 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (2.482 g, 11.33 mmol) and sodium carbonate (22.66 mL, 45.31 mmol) in 18% DMF in 7:3:2 DME:Water:Ethanol (4OmL). The resulting solution was stirred at 85°C for 1 hour. The reaction mixture was concentrated, diluted with DCM (200 mL), and washed with water (200 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with 0 to 2.5% methanol in DCM, to give the desired material as a yellow solid (1.19 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.51 - 1.53 (2H, m), 1.65 - 1.66 (2H, m), 3.40 (3H, s), 3.70 (8H, s), 5.56 (2H, d), 6.61 (2H, d), 6.70 (IH, s), 8.04 (2H, d) LCMS Spectrum: m/z (ESI+) (M+H)+ = 375; HPLC tR = 1.65 min.
2-Chloro-4-(l-methylsulfonylcvclopropyl)-6-morpholin-4-ylpyrimidine
Figure imgf000368_0002
Sodium hydroxide (9.60 mL, 95.97 mmol) was added to 2-chloro-4-(methylsulfonylmethyl)- 6-morpholin-4-yl-pyrimidine (2.80 g, 9.60 mmol), 1 ,2-dibromoethane (1.654 mL, 19.19 mmol) and tetrabutylammonium bromide (0.619 g, 1.92 mmol) in toluene (120 mL) at RT. The resulting solution was stirred at 600C for 3 hours. The reaction mixture was evaporated to dryness, redissolved in ethyl acetate (200 mL), and washed sequentially with water (200 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with 0 to 2.5% methanol in DCM, to give the desired material as a yellow solid (2.88 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.49 -1.51 (2H, m), 1.62 - 1.65 (2H, m), 3.19 (3H, s), 3.67 (8H, d), 6.96 (IH, s)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 318; HPLC 1.37 tR = min.
2-Chloro-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidine
Figure imgf000369_0001
A suspension of 2,4-dichloro-6-(methylsulfonylmethyl)pyrimidine (10.56 g) in DCM (230 mL) was stirred magnetically (under nitrogen) and cooled to -5°C. Triethylamine (6.78 mL) was added followed by the dropwise addition of a solution of morpholine (3.85 mL) in DCM (30 mL) maintaining the reaction temperature below -5°C. The reaction was stirred at room temperature for 1 hour and then the organic mixture washed with water (300 mL). The organic phase was dried ( MgSO4), filtered and evaporated to a brown solid which was chromatographed on silica, eluting with 50% ethyl acetate in DCM, to give the desired material (6.8Ig) as a white solid. NMR Spectrum: 1R NMR (400.13 MHz, DMSOd6) δ 3.12 (3H, s), 3.63 (4H, s), 3.68 - 3.70 (4H, m), 4.45 (2H, s), 6.96 (IH, s) Mass Spectrum: MH+ 292.
2,4-Dichloro-6-(methylsulfonylmethyl)pyrimidine
Figure imgf000370_0001
6-(Methylsulfonylmethyl)-lH-pyrimidine-2,4-dione (132 g, 0.65 mol) was added to phosphorus oxychloride (1.2 L) and the mixture heated to reflux for 16 hours, then cooled to room temperature. The excess phosphorus oxychloride was removed in vacuo, the residue azeotroped with toluene (2 x 500 mL) and dissolved in dichloromethane. This mixture was then poured slowly onto ice (4 L) and stirred for 20 minutes, then extracted with dichloromethane (3 x 1 L) (the insoluble black material was filtered off and discarded) and ethyl acetate (2 x 1 L). The extracts were combined, dried, then evaporated to leave the desired material as a dark brown solid (51 g). The material was used without further purification.
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 3.13 (s, 3H), 4.79 (s, 2H), 7.87 (s, IH) LCMS Spectrum: m/z (ESI+) (M+H)+ = 239; HPLC 1.21 tR = min.
6-(Methylsulfonylmethyl)-lH-pyrimidine-2,4-dione
Figure imgf000370_0002
6-(Chloromethyl)-lH-pyrimidine-2,4-dione (175 g, 1.09 mol) was dissolved in DMF (2 L) and methanesulphinic acid sodium salt (133.5 g, 1.31 mol) was added. The reaction was heated to 125°C for 2 hours then allowed to cool and the suspension filtered and concentrated in vacuo to give a yellow solid. The crude material was washed with water, filtered, then triturated with toluene. The solid was filtered then triturated with isohexane to leave the desired compound as a yellow solid (250 g). The material was used without further purification.
6-(Chloromethyl)-lH-pyrimidine-2,4-dione is a commercially available material.
The preparation of phenyl 7V-[4-[4-(l-methylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin- 2-yl]phenyl]carbamate is described below. Phenyl Λ/-r4-r4-(l-methylsulfonylcvclopentyl)-6-morpholin-4-ylpyrimidin-2- yllphenyll carbamate
Figure imgf000371_0001
Phenyl chloroformate (0.541 mL, 4.30 mmol) was added dropwise to 4-[4-(l- methylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2-yl]aniline (1.73 g, 4.30 mmol) and sodium bicarbonate (0.542 g, 6.45 mmol) in dioxane (50 mL) under nitrogen. The resulting suspension was stirred at RT for 1 hour. The reaction mixture was evaporated to dryness and partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the desired material as a yellow solid (1.7 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.58 (2H, t), 1.82 (2H, d), 2.40 - 2.47 (2H, m), 2.73 - 2.75 (2H, m), 2.91 (3H, s), 3.74 (8H, s), 6.88 (IH, s), 7.24 - 7.30 (3H, m), 7.43 - 7.47 (2H, m), 7.64 (2H, d), 8.33 - 8.35 (2H, m), 10.43 (IH, s), LCMS Spectrum: m/z (ESI+) (M+H)+ = 523; HPLC tR = 2.90 min.
4-r4-(l-Methylsulfonylcvclopentyl)-6-morpholin-4-ylpyrimidin-2-yllaniline
Figure imgf000371_0002
Dichlorobis(triphenylphosphine)palladium (II) (0.224 g, 0.32 mmol) was added to a solution of 2-chloro-4-(l-methylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidine (2.21 g, 6.39 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.75 g, 7.99 mmol) and aqueous sodium carbonate solution (15.98 mL, 31.95 mmol) in a solvent mixture of 18% DMF in 7:3:2 DME:Water:Ethanol (40 mL). The resulting solution was stirred at 85°C for 1 hour. The reaction mixture was concentrated and diluted with DCM (200 mL) and washed with water (200 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 2.5% methanol in DCM, to give the desired material as a yellow solid (1.73 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.57 (2H, t), 1.80 (2H, d), 2.37 - 2.44 (2H, m), 2.69 - 2.74 (2H, m), 2.90 (3H, s), 3.71 (8H, s), 5.55 (2H, d), 6.59 - 6.63 (2H, m), 6.74 (IH, s), 8.05 - 8.09 (2H, m)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 403; HPLC tR = 2.22 min.
2-Chloro-4-(l-methylsulfonylcvclopentyl)-6-morpholin-4-ylpyrimidine
Figure imgf000372_0001
ION Sodium hydroxide solution (8.57 mL, 85.69 mmol) was added to 2-chloro-4- (methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidine (2.50 g, 8.57 mmol), 1,4- dibromobutane (1.014 mL, 8.57 mmol) and tetrabutylammonium bromide (0.552 g, 1.71 mmol) in toluene (120 mL) at RT. The resulting solution was stirred at 600C for 4 hours. The reaction mixture was evaporated to dryness and the residue partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% ethyl acetate in isohexane, to give the desired material as a yellow solid (2.215 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.51 - 1.58 (2H, m), 1.76 - 1.80 (2H, m), 2.33 - 2.40 (2H, m), 2.52 - 2.59 (2H, m), 2.89 (3H, s), 3.67 (8H, s), 6.96 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 346; HPLC 2.12 tR = min.
The preparation of 2-chloro-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidine was described earlier.
The preparation of phenyl 7V-[4-[4-(l-methylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin- 2-yl]phenyl]carbamate is described below. Phenyl Λ/-r4-r4-(l-methylsulfonylcvclobutyl)-6-morpholin-4-ylpyrimidin-2- yllphenyll carbamate
Figure imgf000373_0001
Phenyl chloroformate (0.084 mL, 0.67 mmol) was added dropwise to 4-[4-(l- methylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2-yl] aniline (260 mg, 0.67 mmol) and sodium bicarbonate (84 mg, 1.00 mmol) in dioxane (20 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness, redissolved in ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the desired material as a cream solid (380 mg).
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.91 (IH, d), 2.06 (IH, t), 2.80 - 2.84 (2H, m), 2.88 (3H, s), 2.93 (2H, d), 3.74 (8H, d), 6.80 (IH, s), 7.24 - 7.26 (2H, m), 7.25 - 7.30 (IH, m), 7.43 - 7.47 (2H, m), 7.63 (2H, d), 8.32 (2H, d), 10.43 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 509; HPLC tR = 2.77 min.
4-r4-(l-Methylsulfonylcvclobutyl)-6-morpholin-4-ylpyrimidin-2-yllaniline
Figure imgf000373_0002
Dichlorobis(triphenylphosphine)palladium(II) (0.167 g, 0.24 mmol) was added to a degassed solution of 2-chloro-4-(l-methylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidine (0.790 g, 2.38 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.652 g, 2.98 mmol) and an aqueous solution of sodium carbonate (5.95 mL, 11.90 mmol) in a solvent mixture of 18% DMF in 7:3:2 DME:Water:Ethanol (40 mL). The resulting solution was stirred at 85°C for 1 hour. The reaction mixture was concentrated, diluted with DCM (200 mL), and washed with water (200 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in isohexane, to give the desired material as a white solid (0.22 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.89 (IH, d), 2.03 - 2.07 (IH, m), 2.74 - 2.81 (2H, m), 2.86 (3H, s), 2.88 - 2.93 (2H, m), 3.71 (8H, s), 5.54 (2H, d), 6.59 - 6.62 (2H, m), 6.66 (IH, s), 8.04 - 8.07 (2H, m)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 389; HPLC tR = 2.05 min.
2-Chloro-4-(l-methylsulfonylcvclobutyl)-6-morpholin-4-ylpyrimidine
Figure imgf000374_0001
ION Sodium hydroxide solution (9.60 mL, 95.97 mmol) was added to 1,3-dibromopropane (0.979 mL, 9.60 mmol), 2-chloro-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidine (2.80 g, 9.60 mmol) and tetrabutylammonium bromide (0.619 g, 1.92 mmol) in toluene (120 mL) at RT. The resulting solution was stirred at 600C for 18 hours. The reaction mixture was evaporated to dryness, redissolved in ethyl acetate (200 mL), and washed sequentially with water (200 mL) and saturated brine solution (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in isohexane, to give the NMR Spectrum: 1U NMR (400.13 MHz, DMSOd6) δ 1.87 - 1.89 (IH, m), 2.01 (IH, d), 2.66 - 2.73 (2H, m), 2.81 - 2.84 (2H, m), 2.86 (3H, s), 3.67 (8H, s), 6.88 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 332; HPLC 1.44 tR = min.
The preparation of 2-chloro-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidine was described earlier. Example 13: 3-Cvclopropyl-l-[4-[4-(l-cvclopropylsulfonylcvclopropyl)-6-morpholin-4- ylpyrimidin-2-yll phenyll urea
Figure imgf000375_0001
To a solution of phenyl 7V-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-morpholin-4- ylpyrimidin-2-yl]phenyl] carbamate (100 mg, 0.19 mmol) in DMF (2 mL) was added triethylamine (0.08 mL, 0.58 mmol) followed by cyclopropylamine (55 mg, 0.96 mmol) and the reaction heated at 500C for 8 hours. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (60 mg). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.41 - 0.43 (2H, m), 0.64 - 0.66 (2H, m), 0.93 - 0.95 (2H, m), 1.02 - 1.05 (2H, m), 1.57 (2H, d), 1.65 (2H, d), 2.56 (IH, m), 3.02 (IH, s), 3.71 (8H, s), 6.42 (IH, s), 6.88 (IH, s), 7.50 (2H, d), 8.22 (2H, d), 8.53 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 484; HPLC tR = 1.80 min. mTOR Kinase Assay (Echo): 0.00357μM
The following compounds were made in an analogous fashion from either phenyl 7V-[4-[4-(l- cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]carbamate, phenyl N-[4-[4-(l-cyclopropylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]carbamate or phenyl 7V-[4-[4-(l-cyclopropylsulfonylcyclobutyl)-6-morpholin-4- ylpyrimidin-2-yl]phenyl]carbamate and the appropriate amine.
Figure imgf000375_0002
Figure imgf000376_0001
Figure imgf000377_0001
Figure imgf000378_0001
Figure imgf000379_0001
* Reaction stirred at 4O0C for 6 hours
Example 13a: 1H NMR (400.13 MHz, DMSOd6) δ 0.93 - 0.95 (2H, m), 1.02 - 1.05 (2H, m),
1.55 - 1.58 (2H, m), 1.63 - 1.66 (2H, m), 2.66 (3H, d), 3.02 (IH, s), 3.71 (8H, s), 6.06 (IH, d), 6.88 (IH, s), 7.48 - 7.51 (2H, m), 8.20 - 8.22 (2H, m), 8.73 (IH, s). mTOR Kinase Assay (Echo): 0.00341μM
Example 13b: 1H NMR (400.13 MHz, DMSOd6) δ 0.93 - 0.96 (2H, m), 1.02 (2H, m), 1.06 (3H, q), 1.56 - 1.58 (2H, m), 1.62 - 1.66 (2H, m), 3.00 - 3.04 (IH, m), 3.10 - 3.16 (2H, m), 3.71 (8H, s), 6.15 (IH, t), 6.88 (IH, s), 7.47 - 7.51 (2H, m), 8.20 - 8.23 (2H, m), 8.65 (IH, s). mTOR Kinase Assay (Echo): 0.0037μM
Example 13c: 1R NMR (400.13 MHz, DMSOd6) δ 0.93 - 1.00 (2H, m), 1.02 - 1.05 (2H, m),
1.56 (2H, d), 1.56 - 1.60 (2H, m), 1.61 - 1.68 (2H, m), 1.82 - 1.88 (2H, m), 2.17 - 2.24 (2H, m), 3.00 - 3.04 (IH, m), 3.71 (8H, s), 4.14 (IH, d), 6.45 (IH, d), 6.88 (IH, s), 7.46 - 7.48 (2H, m), 8.20 - 8.22 (2H, m), 8.55 (IH, s). mTOR Kinase Assay (Echo): 0.0024μM
Example 13d: 1H NMR (400.13 MHz, DMSO-d6) δ 0.93 - 0.95 (2H, m), 1.03 - 1.04 (2H, d), 1.55 - 1.58 (2H, m), 1.63 - 1.66 (2H, m), 3.02 (IH, s), 3.18 (2H, d), 3.45 (2H, t), 3.71 (8H, s), 4.73 (IH, s), 6.25 (IH, s), 6.88 (IH, s), 7.47 - 7.49 (2H, m), 8.22 (2H, d), 8.80 (IH, s). mTOR Kinase Assay (Echo): 0.00351 μM Example 13e: 1U NMR (400.13 MHz, DMSO-d6) δ 0.93 - 0.95 (2H, m), 1.03 - 1.05 (2H, m), 1.24 (6H, s), 1.56 (2H, d), 1.63 -1.65 (2H, d), 3.02 (IH, m), 3.38 - 3.40 (2H, m), 3.71 (8H, s), 4.95 (IH, s), 5.99 (IH, s), 6.88 (IH, s), 7.45 (2H, d), 8.20 (2H, d), 8.73 (IH, s). mTOR Kinase Assay (Echo): 0.0301μM Example 13f: 1H NMR (400.13 MHz, DMSOd6) δ 0.93 - 0.96 (2H, m), 1.03 - 1.05 (2H, m), 1.55 - 1.58 (2H, m), 1.63 - 1.66 (2H, m), 2.18 (6H, s), 2.34 (2H, t), 3.02 (IH, t), 3.19 (2H, q), 3.71 (8H, s), 6.15 (IH, s), 6.88 (IH, s), 7.47 - 7.49 (2H, m), 8.20 - 8.22 (2H, m), 8.88 (IH, s). mTOR Kinase Assay (Echo): 0.386μM Example 13g: 1R NMR (400.13 MHz, DMSOd6) δ 0.89 (3H, t), 0.93 - 0.96 (2H, m), 1.03 (2H, d), 1.41 - 1.50 (2H, m), 1.56 - 1.58 (2H, t), 1.62 - 1.66 (2H, m), 3.00 - 3.02 (IH, m), 3.06 (2H, s), 3.71 (8H, s), 6.19 (IH, t), 6.88 (IH, s), 7.49 (2H, d), 8.21 (2H, d), 8.64 (IH, s). mTOR Kinase Assay (Echo): 0.00479μM
Example 13h: 1H NMR (400.13 MHz, DMSO-d6) δ 0.92 - 0.98 (2H, m), 0.98 - 1.07 (2H, m), 1.55 - 1.56 (2H, m), 1.58 (2H, d), 1.61 - 1.66 (2H, m), 2.99 - 3.05 (IH, m), 3.15 - 3.19 (2H, m), 3.45 - 3.50 (2H, m), 3.71 (8H, s), 4.47 (IH, t), 6.19 (IH, t), 6.88 (IH, s), 7.47 - 7.51 (2H, m), 8.20 - 8.23 (2H, m), 8.70 (IH, s). mTOR Kinase Assay (Echo): 0.0106μM
Example 13i: 1R NMR (400.13 MHz, DMSO-d6) δ 0.94 (2H, t), 1.03 - 1.06 (2H, m), 1.55 - 1.59 (2H, m), 1.64 - 1.67 (2H, m), 3.02 (IH, s), 3.72 (8H, s), 3.79 (3H, s), 6.89 (IH, s), 7.38 (IH, s), 7.54 (2H, d), 7.76 (IH, s), 8.25 (2H, d), 8.38 (IH, s), 8.84 (IH, s). mTOR Kinase Assay (Echo): 0.00275μM
Example 13j: 1H NMR (400.13 MHz, DMSO-d6) δ 0.39 - 0.43 (2H, m), 0.62 - 0.67 (2H, m), 0.71 - 0.73 (2H, m), 0.84 - 0.87 (2H, m), 1.55 (2H, t), 1.81 (2H, d), 2.33 (IH, t), 2.43 - 2.45 (2H, m), 2.57 - 2.61 (IH, m), 2.82 (2H, t), 3.72 (8H, s), 6.45 (IH, d), 6.87 (IH, s), 7.50 (2H, d), 8.25 (2H, d), 8.56 (IH, s). mTOR Kinase Assay (Echo): 0.0178μM
Example 13k: 1H NMR (400.13 MHz, DMSO-d6) δ 0.71 - 0.73 (2H, m), 0.84 - 0.87 (2H, m), 1.55 (2H, t), 1.79 (IH, d), 1.82 (IH, s), 2.43 (2H, t), 2.57 - 2.61 (IH, m), 2.65 (3H, d), 2.82 (2H, d), 3.72 (8H, s), 6.08 (IH, d), 6.86 (IH, s), 7.49 - 7.51 (2H, m), 8.23 - 8.25 (2H, m), 8.77 (IH, s). mTOR Kinase Assay (Echo): 0.0179μM Example 131: 1U NMR (400.13 MHz, DMSO-d6) δ 0.71 - 0.73 (2H, m), 0.83 - 0.88 (2H, m), 1.55 (2H, t), 1.77 - 1.82 (2H, m), 2.43 - 2.48 (2H, m), 2.55 - 2.62 (IH, m), 2.81 (IH, t), 2.84 (IH, s), 3.15 - 3.18 (2H, m), 3.45 (2H, q), 3.72 (8H, s), 4.77 (IH, t), 6.26 (IH, t), 6.86 (IH, s), 7.47 - 7.50 (2H, m), 8.23 - 8.26 (2H, m), 8.83 (IH, s). mTOR Kinase Assay (Echo): 0.0108μM
Example 13m: 1H NMR (400.13 MHz, DMSO-d6) δ 0.72 - 0.74 (2H, m), 0.85 - 0.88 (2H, m), 1.24 (6H, s), 1.55 (2H, t), 1.79 (2H, d), 2.42 (IH, s), 2.45 (IH, d), 2.59 (IH, s), 2.80 (2H, s), 3.38 (2H, d), 3.72 (8H, s), 4.99 (IH, t), 6.01 (IH, s), 6.86 (IH, s), 7.44 - 7.46 (2H, m), 8.22 -
8.24 (2H, m), 8.75 (IH, s). mTOR Kinase Assay (Echo): 0.0532μM
Example 13n: 1H NMR (400.13 MHz, DMSOd6) δ 0.71 - 0.73 (2H, m), 0.85 - 0.87 (2H, m), 1.55 (2H, t), 1.79 (2H, d), 2.17 (6H, s), 2.33 (2H, t), 2.42 (IH, s), 2.45 (IH, d), 2.59 (IH, s), 2.81 (2H, s), 3.19 (2H, q), 3.72 (8H, s), 6.17 (IH, s), 6.86 (IH, s), 7.47 - 7.49 (2H, m), 8.23 -
8.25 (2H, m), 8.92 (IH, s). mTOR Kinase Assay (Echo): 0.997μM
Example 13o: 1R NMR (400.13 MHz, DMSO-d6) δ 0.71 - 0.73 (2H, m), 0.83 - 0.88 (2H, m), 1.53 - 1.62 (4H, m), 1.79 - 1.82 (IH, m), 1.81 (IH, d), 2.44 (2H, d), 2.57 - 2.61 (IH, m), 2.81 (IH, t), 2.84 (IH, s), 3.14 - 3.18 (2H, m), 3.44 - 3.49 (2H, m), 3.72 (8H, s), 4.52 (IH, t), 6.21 (IH, t), 6.86 (IH, s), 7.48 - 7.50 (2H, m), 8.23 - 8.25 (2H, m), 8.73 (IH, s). mTOR Kinase Assay (Echo): 0.0287μM
Example 13p: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40 - 0.44 (2H, m), 0.62 - 0.67 (2H, m), 0.74 - 0.78 (2H, m), 0.85 - 0.87 (2H, m), 1.88 - 1.91 (IH, m), 2.07 (IH, t), 2.50 (IH, s), 2.53 - 2.58 (IH, m), 2.85 - 2.89 (2H, m), 2.94 - 2.99 (2H, m), 3.73 (8H, s), 6.42 (IH, d), 6.77 (IH, s), 7.48 - 7.52 (2H, m), 8.23 - 8.26 (2H, m), 8.53 (IH, s). mTOR Kinase Assay (Echo): 0.00202μM
Example 13q: 1H NMR (400.13 MHz, DMSO-d6) δ 0.74 - 0.78 (2H, m), 0.84 - 0.89 (2H, m), 1.88 - 1.91 (IH, m), 2.07 (IH, t), 2.50 (IH, m), 2.66 (3H, d), 2.85 - 2.89 (2H, m), 2.94 - 2.99 (2H, m), 3.72 (8H, s), 6.06 (IH, q), 6.76 (IH, s), 7.48 - 7.51 (2H, m), 8.22 - 8.26 (2H, m), 8.73 (IH, s). mTOR Kinase Assay (Echo): 0.00192μM
Example 13r: 1R NMR (400.13 MHz, DMSO-d6) δ 0.76 - 0.78 (2H, m), 0.85 - 0.88 (2H, m), 1.91 (IH, s), 2.07 (IH, t), 2.50 (IH, s), 2.85 - 2.89 (2H, m), 2.94 - 2.97 (2H, m), 3.17 (2H, q), 3.46 (2H, q), 3.72 (8H, s), 4.72 (IH, t), 6.24 (IH, t), 6.76 (IH, s), 7.47 - 7.49 (2H, m), 8.23 -
8.25 (2H, m), 8.79 (IH, s). mTOR Kinase Assay (Echo): 0.00198μM
Example 13s: 1R NMR (400.13 MHz, DMSO-d6) δ 0.76 - 0.79 (2H, m), 0.85 - 0.88 (2H, m), 1.24 (6H, s), 1.91 (IH, s), 2.07 (IH, t), 2.50 (IH, s), 2.85 - 2.89 (2H, m), 2.94 (IH, d), 2.96 -
2.97 (IH, m), 3.39 (2H, d), 3.72 (8H, s), 4.95 (IH, t), 6.00 (IH, s), 6.76 (IH, s), 7.44 - 7.46
(2H, m), 8.22 - 8.24 (2H, m), 8.73 (IH, s). mTOR Kinase Assay (Echo): 0.00846μM
Example 13t: 1H NMR (400.13 MHz, DMSOd6) δ 0.75 - 0.77 (2H, m), 0.85 - 0.88 (2H, m), 1.88 - 1.91 (IH, m), 2.07 (IH, t), 2.18 (6H, s), 2.32 (IH, s), 2.34 (2H, t), 2.86 (IH, d), 2.88
(IH, s), 2.94 (IH, d), 2.96 (IH, s), 3.20 (2H, t), 3.72 (8H, s), 6.15 (IH, s), 6.76 (IH, s), 7.47 -
7.49 (2H, m), 8.23 - 8.25 (2H, m), 8.88 (IH, s). mTOR Kinase Assay (Echo): 0.172μM
Example 13u: 1H NMR (400.13 MHz, DMSO-d6) δ 0.74 - 0.78 (2H, m), 0.84 - 0.89 (2H, m), 1.57 (IH, d), 1.61 (IH, t), 1.88 - 1.91 (IH, m), 2.06 (IH, d), 2.50 (IH, m), 2.85 - 2.89 (2H, m), 2.94 - 2.99 (2H, m), 3.14 - 3.19 (2H, m), 3.45 - 3.49 (2H, m), 3.72 (8H, s), 4.47 (IH, t),
6.19 (IH, t), 6.76 (IH, s), 7.47 - 7.50 (2H, m), 8.23 - 8.25 (2H, m), 8.70 (IH, s). mTOR Kinase Assay (Echo): 0.00477μM
The preparation of phenyl Λ/-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-morpholin-4- ylpyrimidin-2-yl]phenyl] carbamate is described below:
Phenyl N- [4- [4-d -cvclopropylsulfonylcvclopropyl)-6-morpholin-4-ylpyrimidin-2- yllphenyll carbamate
Figure imgf000382_0001
Phenyl chloroformate (0.440 mL, 3.50 mmol) was added dropwise to 4-[4-(l- cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]aniline (1.4Og, 3.50 mmol) and sodium bicarbonate (0.440 g, 5.24 mmol) in dioxane (50 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness, redissolved in ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the desired material as a yellow solid (1.82 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.93 - 0.95 (2H, m), 1.05 (2H, d), 1.59 (IH, s), 1.60 (IH, t), 1.65 (IH, t), 1.67 (IH, d), 3.01 - 3.05 (IH, m), 3.58 (IH, s), 3.73 (8H, s), 6.94 (IH, s), 7.24 - 7.30 (3H, m), 7.43 - 7.47 (2H, m), 7.64 (2H, d), 8.31 (2H, d), 10.44 (IH, s)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 521; HPLC tR = 2.68 min.
4-r4-(l-Cvclopropylsulfonylcvclopropyπ-6-morpholin-4-ylpyrimidin-2-yl1aniline
Figure imgf000383_0001
Dichlorobis(triphenylphosphine)palladium(II) (0.376 g, 0.54 mmol) was added to 2-chloro-4- (l-cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidine (1.84 g, 5.35 mmol), 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.466 g, 6.69 mmol) and sodium carbonate (13.38 mL, 26.76 mmol) in 18% DMF in 7:3:2 DME:Water:Ethanol (40 mL). The resulting solution was stirred at 85°C for 1 hour. The reaction mixture was concentrated and diluted with DCM (200 mL), and washed with water (200 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with 0 to 50% ethyl acetate in isohexane, to give the desired material as a yellow solid (1.40 g).
NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 0.91 - 0.97 (2H, m), 0.98 - 1.06 (2H, m), 1.52 - 1.58 (2H, m), 1.59 - 1.64 (2H, m), 2.97 - 3.04 (IH, m), 3.68 (4H, d), 3.71 - 3.71 (4H, m), 5.54 (2H, d), 6.58 - 6.62 (2H, m), 6.79 (IH, s), 8.03 (2H, d) LCMS Spectrum: m/z (ESI+) (M+H)+ = 401; HPLC tR = 1.62 min.
2-Chloro-4-(l-cvclopropylsulfonylcvclopropyl)-6-morpholin-4-ylpyrimidine
Figure imgf000384_0001
Sodium hydroxide (8.81 mL, 88.11 mmol) was added to 2-chloro-4- (cyclopropylsulfonylmethyl)-6-morpholin-4-ylpyrimidine (2.80 g, 8.81 mmol), 1,2- dibromoethane (1.519 mL, 17.62 mmol) and tetrabutylammonium bromide (0.568 g, 1.76 mmol) in toluene (120 mL) at RT. The resulting solution was stirred at 600C for 3 hours. The reaction mixture was evaporated to dryness, redissolved in ethyl acetate (200 mL), and washed sequentially with water (200 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with 0 to 50% ethyl acetate in isohexane, to give the desired material as a yellow solid (1.84 g).
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.89 - 0.93 (2H, m), 1.00 - 1.05 (2H, m),), 1.50 (2H, d), 1.62 (2H, d), 2.89 - 2.96 (IH, m), 3.65 (4H, m), 3.66 - 3.67 (4H, m), 7.01 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 344; HPLC 1.48 tR = min.
2-Chloro-4-(cvclopropylsulfonylmethyl)-6-morpholin-4-ylpyrimidine
Figure imgf000384_0002
Cyclopropanesulfinic acid sodium salt (5.66 g, 44.17 mmol) was added in one portion to 2- chloro-4-(iodomethyl)-6-morpholin-4-ylpyrimidine (12.5 g, 36.81 mmol) in acetonitrile (300 mL) at RT. The resulting suspension was stirred at 80 0C for 24 hours. The resulting mixture was evaporated to dryness and the residue was azeotroped with MeCN to afford the desired material (7.12 g).
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.94 - 0.99 (2H, m), 1.01 - 1.07 (2H, m), 2.77 - 2.84 (IH, m), 3.62 (4H, s), 3.67 - 3.69 (4H, s), 4.47 (2H, s), 6.95 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 318; HPLC tR = 1.46 min. 2-Chloro-4-(iodomethyl)-6-morpholin-4-ylpyrimidine
Figure imgf000385_0001
Sodium iodide (27.2 g, 181.31 mmol) was added to (2-chloro-6-morpholin-4-ylpyrimidin-4- yl)methyl methanesulfonate (27.9 g, 90.66 mmol) in acetone (400 mL) at RT under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness, redissolved in DCM (400 mL) and was washed with water (200 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the desired material as a brown solid (33.9 g).
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 3.59 (4H, s), 3.63 - 3.68 (4H, m), 4.29 (2H, s), 6.97 (IH, s)
LCMS Spectrum: m/z (ESI+) (M+H)+339 = ; HPLC tR = 1.87 min.
(2-Chloro-6-morpholin-4-ylpyrimidin-4-yl)methyl methanesulfonate
Figure imgf000385_0002
Methanesulfonyl chloride (10.57 mL, 136 mmol) was added dropwise to (2-chloro-6- morpholin-4-ylpyrimidin-4-yl)methanol (20.83 g, 90.70 mmol) and DIPEA (23.70 mL, 136 mmol) in DCM (375 mL) at O0C over a period of 15 minutes, under a nitrogen atmosphere. The resulting solution was stirred at RT for 1 hour. The reaction mixture was diluted with water (100 mL) and the organic layer dried (MgSO4), filtered and evaporated to afford the desired material as a brown oil (27.9 g).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 308; HPLC tR = 1.58 min. (2-Chloro-6-morpholin-4-ylpyrimidin-4-v0methanol
Figure imgf000386_0001
To a suspension of methyl 2-chloro-6-morpholin-4-ylpyrimidine-4-carboxylate (60 g, 232.85 mmol) in THF (1200 mL) at -5°C was added lithium borohydride (2M in THF, 0.122 L,
5 244.50 mmol) dropwise over 30 minutes. The reaction mixture was warmed to RT and stirred for 1 hour. To this was added water (600 mL), the mixture stirred for 2 hours and then filtered. Further water (600 mL) was added and the solution was extracted three times with ethyl acetate (600 mL). The combined organics were washed with 50% aqueous brine (900 mL), dried (MgSO4) and the solvent was then removed under reduced pressure to give theo desired product as a white solid (49.8 g).
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 3.59 - 3.68 (8H, m), 4.35 (2H, dd),
5.50 (IH, t), 6.77 (IH, s).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 230; HPLC tR = 1.08 min s Methyl 2-chloro-6-morpholin-4-ylpyrimidine-4-carboxylate
Figure imgf000386_0002
To a solution of 2,6-dichloropyrimidine-4-carboxylate (60 g, 289.84 mmol) in DCM (400 mL) at -5°C was added triethylamine (44.4 mL, 318.82 mmol), washing in with DCM (80 mL). To the resulting solution was added morpholine (26.6 mL, 304.33 mmol) in DCM (1200 mL) dropwise over 2 hours, maintaining the temperature below 5°C. The reaction mixture was stirred at 00C for 2 hours and then warmed to RT. Water (600 mL) was added and the layers were separated. The organic layer was washed twice with water (180 mL) and the combined aqueous fractions extracted twice with DCM (180 mL). The combined organics were washed twice with 75% aqueous brine (180 mL), dried (MgSO4) and the solvent5 removed under reduced pressure to give the crude product. This was purified by crystallisation from ethyl acetate/isohexane to give the desired product as a white solid (65.4g).
NMR Spectrum: 1H NMR (400.13 MHz, CDCl3) δ 3.72 - 3.82 (8H, m), 3.99 (3H, s), 7.20 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 258; HPLC tR = 1.38 min
The preparation of phenyl Λ/-[4-[4-(l-cyclopropylsulfonylcyclopentyl)-6-morpholin-4- ylpyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl N- [4- [4-d -cvclopropylsulfonylcvclopentviyό-morpholin^-ylpyrimidin^- yllphenyl] carbamate
Figure imgf000387_0001
Phenyl chloroformate (0.455 mL, 3.62 mmol) was added dropwise to 4-[4-(l- cyclopropylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2-yl]aniline (1.55 g, 3.62 mmol) and sodium bicarbonate (0.456 g, 5.43 mmol) in dioxane (50 mL) under nitrogen. The resulting suspension was stirred at RT for 3 hours. The reaction mixture was evaporated to dryness, redissolved in ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to give the desired material as a yellow solid (2.3 I g). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.71 - 0.75 (2H, m), 0.84 - 0.89 (2H, m), 1.56 (2H, t), 1.78 - 1.83 (2H, m), 2.45 (IH, t), 2.57 - 2.63 (2H, m), 2.81 - 2.84 (2H, m), 3.73 (8H, s), 6.90 (IH, s), 7.23 - 7.30 (3H, m), 7.43 - 7.47 (2H, m), 7.63 (2H, d), 8.33 - 8.36 (2H, m), 10.42 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 549; HPLC tR = 3.02 min. 4-r4-(l-Cvclopropylsulfonylcvclopentyl)-6-morpholin-4-ylpyrimidin-2-yllaniline
Figure imgf000388_0001
Dichlorobis(triphenylphosphine)palladium(II) (0.170 g, 0.24 mmol) was added to a degassed solution of 2-chloro-4-(l-cyclopropylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidine (1.80 g, 4.84 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.326 g, 6.05 mmol) and an aqueous solution of sodium carbonate (12.10 mL, 24.20 mmol) in a solvent mixture of 18% DMF in 7:3:2 DME:Water:Ethanol (40 mL). The resulting solution was stirred at 85°C for 1 hour. The reaction mixture was concentrated, diluted with DCM (100 mL), and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 70% ethyl acetate in isohexane, to give the desired material as a yellow solid (1.55 g).
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.73 - 0.75 (2H, m), 0.83 - 0.88 (2H, m), 1.55 (2H, t), 1.78 (IH, s), 1.81 (IH, t), 2.41 (IH, d), 2.45 - 2.47 (IH, m), 2.54 - 2.58 (IH, m), 2.79 (IH, t), 2.82 (IH, s), 3.70 (8H, d), 5.53 (2H, s), 6.59 - 6.62 (2H, m), 6.77 (IH, s), 8.07 - 8.09 (2H, m) LCMS Spectrum: m/z (ESI+) (M+H)+ = 429; HPLC tR = 2.36 min.
2-Chloro-4-(l-cvclopropylsulfonylcvclopentyl)-6-morpholin-4-ylpyrimidine
Figure imgf000388_0002
ION Sodium hydroxide solution (5.70 mL, 56.96 mmol) was added to 2-chloro-4- (cyclopropylsulfonylmethyl)-6-morpholin-4-ylpyrimidine (1.81 g, 5.70 mmol), 1,4- dibromobutane (0.674 mL, 5.70 mmol) and tetrabutylammonium bromide (0.367 g, 1.14 mmol) in toluene (100 mL) at RT. The resulting solution was stirred at 600C for 3 hours. The reaction mixture was evaporated to dryness, redissolved in ethyl acetate (75 mL) and washed with water (75 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a white solid (1.8 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.71 - 0.75 (2H, m), 0.90 - 0.94 (2H, m), 1.50 - 1.59 (2H, m), 1.77 - 1.80 (2H, m), 2.36 - 2.44 (2H, m), 2.57 - 2.68 (3H, m), 3.67 (8H, s), 6.97 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 372; HPLC tR = 2.26 min.
The preparation of 2-chloro-4-(cyclopropylsulfonylmethyl)-6-morpholin-4-ylpyrimidine was described earlier.
The preparation of phenyl Λ/-[4-[4-(l-cyclopropylsulfonylcyclobutyl)-6-morpholin-4- ylpyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl N- [4- [4-(l -cvclopropylsulfonylcvclobutyl)-6-morpholin-4-ylpyrimidin-2- yllphenyl] carbamate
Figure imgf000389_0001
Phenyl chloroformate (0.106 mL, 0.84 mmol) was added dropwise to 4-[4-(l- cyclopropylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2-yl]aniline (350 mg, 0.84 mmol) and sodium bicarbonate (106 mg, 1.27 mmol) in dioxane (20 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness, redissolved in ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to give the desired material as a cream solid (453 mg). NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 0.75 - 0.77 (2H, m), 0.85 - 0.88 (2H, m), 1.90 (IH, d), 2.07 (IH, d), 2.54(1H, m), 2.86 - 2.90 (2H, m), 2.93 - 2.98 (2H, s), 3.73 (8H, s), 6.80 (IH, s), 7.24 - 7.30 (3H, m), 7.43 - 7.47 (2H, m), 7.63 (2H, d), 8.33 - 8.35 (2H, m), 10.42 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 535; HPLC tR = 2.91 min.
4-r4-(l-Cvclopropylsulfonylcvclobutyl)-6-morpholin-4-ylpyrimidin-2-yllaniline
Figure imgf000390_0001
2-Chloro-4-(l-cyclopropylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidine (430 mg, 1.20 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (329 mg, 1.50 mmol), dichlorobis(triphenylphosphine)palladium(II) (42.2 mg, 0.06 mmol) and an aqueous solution of sodium carbonate (3.00 mL, 6.01 mmol) were suspended in a solvent mixture of 18% DMF in 7:3:2 DME:Water:Ethanol (8 mL) and sealed into a microwave tube. The reaction was heated to 1000C for 30 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography using an SCX column, the desired product was eluted from the column using 7M ammonia in methanol. The isolated material was further purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in DCM, to give the desired material as a white solid (350 mg). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.74 - 0.78 (2H, m), 0.83 - 0.88 (2H, m), 1.85 - 1.91 (IH, m), 2.03 - 2.07 (IH, m), 2.44 - 2.48 (IH, m), 2.83 - 2.87 (2H, m), 2.90- 2.97 (2H, m), 3.70 - 3.71 (8H, m), 5.52 (2H, d), 6.58 - 6.62 (2H, m), 6.67 (IH, s), 8.06 - 8.09 (2H, m) LCMS Spectrum: m/z (ESI+) (M+H)+ = 415; HPLC tR = 2.19 min.
2-Chloro-4-(l-cvclopropylsulfonylcvclobutyl)-6-morpholin-4-ylpyrimidine
Figure imgf000390_0002
ION Sodium hydroxide solution (9.60 mL, 95.97 mmol) was added to 1,3-dibromopropane (0.979 mL, 9.60 mmol), 2-chloro-4-(cyclopropylsulfonylmethyl)-6-morpholin-4-ylpyrimidine (2.80 g, 9.60 mmol) and tetrabutylammonium bromide (0.619 g, 1.92 mmol) in toluene (120 mL) at RT. The resulting solution was stirred at 600C for 18 hours. The reaction mixture was evaporated to dryness, redissolved in ethyl acetate (200 mL), and washed sequentially with water (200 mL) and saturated brine solution (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in isohexane, to give the desired material as a yellow solid (0.795 g).
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.73 - 0.77 (2H, m), 0.89 - 0.94 (2H, m), 1.85 - 1.92 (IH, m), 2.04 - 2.08 (IH, m), 2.53 - 2.57 (IH, m), 2.70 - 2.78 (2H, m), 2.85 - 2.93 (2H, m), 3.66 (8H, d), 6.88 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 358; HPLC 1.95 tR = min.
The preparation of 2-chloro-4-(cyclopropylsulfonylmethyl)-6-morpholin-4-ylpyrimidine was described earlier.
Example 14: 3-Cvclopropyl-l-[5-[4-Q-cvclopropylsulfonylcvclopropyl)-6-[(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll pyridin-2-yll urea
Figure imgf000391_0001
Triethylamine (0.208 mL, 1.5 mmol) was added to a solution of phenyl Λ/-[5-[4-(l- cyclopropylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2- yljcarbamate (200 mg, 0.37 mmol) and cyclopropylamine (1.48 mmol) in NMP (2 mL). The reaction was heated at 750C for 4 hours then purified by prep HPLC, using a mixture of water (containing 1% NH3) and acetonitrile as eluents, to give the desired material as a solid (40 mg). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.44 - 0.50 (2H, m), 0.64 - 0.72 (2H, m), 0.89 - 0.96 (2H, m), 1.00 - 1.06 (2H, m), 1.23 (3H, d), 1.54 - 1.60 (2H, m), 1.59 - 1.68 (2H, m), 2.59 - 2.66 (IH, m), 2.96 - 3.01 (IH, m), 3.16 - 3.25 (IH, m), 3.44 - 3.52 (IH, m), 3.63 (IH, dd), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.20 (IH, s), 4.54 (IH, s), 6.90 (IH, s), 7.50 (IH, d), 8.18 (IH, s), 8.50 (IH, d), 9.09 (IH, s), 9.37 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 499; HPLC tR = 2.15 min. mTOR Kinase Assay (Echo): 0.0465μM
The following compounds were prepared in an analogous fashion from either phenyl N- [5- [4- 5 (l-cyclopropylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyridin- 2-yl]carbamate, phenyl 7V-[5-[4-[ 1 -(4-fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]pyrimidin-2-yl]carbamate, phenyl 7V-[5-[4-[ 1 -(4- fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2- yljcarbamate, phenyl Λ/-[5-[4-[(35)-3-methylmorpholin-4-yl]-6-(l- i o methylsulfonylcyclopentyl)pyrimidin-2-yl]pyridin-2-yl] carbamate, phenyl N- [5 - [4- [(35)-3 - methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopentyl)pyrimidin-2-yl]pyrimidin-2- yl] carbamate or phenyl Λ/-[5-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]pyrimidin-2 -yljcarbamate using the appropriate amine.
Figure imgf000392_0001
Figure imgf000393_0001
Figure imgf000394_0001
Figure imgf000395_0001
Figure imgf000396_0001
Figure imgf000397_0001
* Isolated as a by product from the reaction to generate 14g
Example 14a: 1R NMR (400.13 MHz, DMSOd6) δ 0.90 - 0.96 (2H, m), 1.01 - 1.06 (2H, m),
1.24 (3H, d), 1.55 - 1.60 (2H, m), 1.62 - 1.68 (2H, m), 2.78 (3H, s), 3.18 - 3.27 (IH, m), 3.44 - 3.54 (IH, m), 3.64 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.20 (IH, d), 4.56 (IH, s), 6.91 (IH, s),
7.43 (IH, d), 8.15 (IH, s), 8.49 (IH, d), 9.12 (IH, s), 9.48 (IH, s), 9.49 (IH, s). mTOR Kinase Assay (Echo): 0.0136μM
Example 14b: 1H NMR (400.13 MHz, DMSOd6) δ 0.91 - 0.95 (2H, m), 1.00 - 1.05 (2H, m),
1.23 (3H, d), 1.56 - 1.60 (2H, m), 1.63 - 1.66 (2H, m), 2.18 (6H, s), 2.36 (2H, t), 2.98 - 3.04 (IH, m), 3.17 - 3.29 (3H, m), 3.48 (IH, td), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.20
(IH, s), 4.54 (IH, s), 6.90 (IH, s), 7.53 (IH, d), 8.05 (IH, s), 8.49 (IH, d), 9.09 (IH, d), 9.48
(IH, s). mTOR Kinase Assay (Echo): 1.39μM
Example 14c: 1R NMR (400.13 MHz, DMSOd6) δ 0.90 - 0.94 (2H, m), 1.01 - 1.05 (2H, m), 1.23 (3H, d), 1.55 - 1.60 (2H, m), 1.63 - 1.67 (2H, m), 2.96 - 3.03 (IH, m), 3.16 - 3.28 (3H, m), 3.43 - 3.52 (2H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.20 (IH, s), 4.54 (IH, s),
4.80 (IH, t), 6.90 (IH, s), 7.47 (IH, d), 8.29 (IH, s), 8.50 (IH, d), 9.10 (IH, s), 9.51 (IH, s). mTOR Kinase Assay (Echo): 0.0401μM
Example 14d: 1H NMR (400.13 MHz, DMSO-d6) δ 0.89 - 0.96 (2H, m), 1.00 - 1.05 (2H, m),
1.24 (3H, d), 1.58 - 1.61 (2H, m), 1.64 - 1.70 (2H, m), 2.97 - 3.04 (IH, m), 3.22 (IH, td), 3.43
- 3.55 (IH, m), 3.64 (IH, dd), 3.75 - 3.82 (4H, m), 3.98 (IH, dd), 4.23 (IH, s), 4.55 (IH, s), 6.92 (IH, s), 7.49 (IH, d), 7.87 (IH, s), 8.55 (IH, d), 9.18 (IH, s), 9.73 (IH, s), 10.36 (IH, s). mTOR Kinase Assay (Echo): 0.0143μM
Example 14e: 1R NMR (400.13 MHz, DMSOd6) δ 0.53 - 0.55 (2H, m), 0.69 - 0.74 (2H, m), 1.19 (3H, d), 1.60 - 1.63 (2H, m), 1.88 - 1.92 (2H, m), 3.12 - 3.21 (IH, m), 3.44 (IH, d), 3.60 (IH, d), 3.74 (IH, d), 3.95 (IH, d), 4.14 - 4.24 (IH, m), 4.40 - 4.54 (IH, m), 6.77 (IH, s), 7.44 (2H, t), 7.85 (2H, dd), 8.88 (2, s), 9.11 (IH, d), 10.11 (IH, s). mTOR Kinase Assay (Echo): 0.11 μM
Example 14f: 1H NMR (400.13 MHz, DMSOd6) δ 1.19 (3H, d), 1.59 - 1.65 (2H, m), 1.89 - 1.92 (2H, m), 2.79(3H,d), 3.17 (IH, t), 3.46 - 3.63 (2H, m), 3.74 (IH, d), 3.95 (IH, d), 4.18 (IH, s), 4.46 (IH, s), 6.77 (IH, s), 7.43 (2H, t), 7.85 (2H, dd), 8.94 (2H, s), 10.08 (IH, s). mTOR Kinase Assay (Echo): 0.189μM
Example 14g: 1H NMR (400.13 MHz, DMSO-d6) δ 1.19 (3H, d), 1.59 - 1.66 (2H, m), 1.88 - 1.92 (2H, m), 3.18 (IH, d), 3.30 (2H, q), 3.44 (IH, d), 3.49 - 3.54 (2H, m), 3.60 (IH, d), 3.72
- 3.98 (4H, m), 4.18(lH,s), 4.45(lH,s), 6.77 (IH, s), 7.43 (2H, t), 7.79 - 7.89 (2H, m), 8.91(2H,s), 9.13 - 9.20 (IH, m), 10.08 (IH, s). mTOR Kinase Assay (Echo): 0.0857μM
Example 14h: 1H NMR (400.13 MHz, DMSO-d6) δ 1.20 (3H, d), 1.61 - 1.65 (2H, m), 1.89 - 1.94 (2H, m), 3.19 (IH, d), 3.41 - 3.50 (IH, m), 3.61 (IH, d), 3.75 (IH, d), 3.82 (3H, s), 3.96 (IH, d), 4.22 (IH, s), 4.48 (IH, s), 6.78 (IH, s), 7.46 (2H, t), 7.54 (IH, s), 7.86 (2H, dd), 7.90 (IH, s), 8.97 (2H, s), 10.47 (IH, s). mTOR Kinase Assay (Echo): 0.14μM
Example 14i: 1U NMR (400.13 MHz, DMSO-d6) δ 0.46 - 0.51 (2H, m), 0.65 - 0.70 (2H, m), 1.18 (3H, d), 1.57 - 1.64 (2H, m), 1.86 - 1.92 (2H, m), 2.60 - 2.65 (IH, m), 3.14 - 3.19 (IH, m), 3.45 (IH, dd), 3.60 (IH, dd), 3.74 (IH, d), 3.92 - 3.99 (IH, m), 4.45 (IH, s), 6.73 (IH, s), 7.38 - 7.48 (2H, m), 7.84 (2H, dd), 8.05 - 8.16 (3H, m), 8.62 (IH, s), 9.37 (IH, s). mTOR Kinase Assay (Echo): 0.0339μM
Example 14j: 1H NMR (400.13 MHz, DMSO-d6) δ 1.18 (3H, d), 1.57 - 1.64 (2H, m), 1.88 - 1.91 (2H, m), 2.74 (3H, d), 3.11 - 3.21 (IH, m), 3.42 - 3.50 (IH, m), 3.60 (IH, d), 3.74 (IH, d), 3.93 - 3.98 (IH, m), 4.13 - 4.19 (IH, m), 4.40 - 4.47 (IH, m), 6.71 (IH, s), 7.35 (IH, d), 7.43 (2H, t), 7.84 (2H, dd), 7.98 - 8.07 (2H, m), 8.67 (IH, s), 9.50 (IH, s). mTOR Kinase Assay (Echo): 0.0129μM
Example 14k: 1H NMR (400.13 MHz, DMSOd6) δ 1.19 (3H, d), 1.58 - 1.62 (2H, m), 1.88 - 1.91 (2H, m), 2.19 (6H, s), 2.32 - 2.35 (2H, m), 3.17 (IH, d), 3.24 - 3.29 (2H, m), 3.44 (IH, d), 3.60 (IH, d), 3.74 (IH, d), 3.95 (IH, d), 4.13 - 4.21 (IH, m), 4.41 - 4.49 (IH, m), 6.71 (IH, s), 7.39 - 7.46 (3H, m), 7.84 (2H, dd), 7.98 (IH, s), 8.06 (IH, d), 8.65 (IH, s), 9.48 (IH, s). mTOR Kinase Assay (Echo): 0.275μM Example 141: 1U NMR (400.13 MHz, DMSOd6) δ 1.18 (3H, d), 1.59 - 1.65 (2H, m), 1.85 - 1.92 (2H, m), 3.12 - 3.21 (IH, m), 3.22 - 3.27 (2H, m), 3.43 - 3.50 (3H, m), 3.60 (IH, d), 3.74 (IH, d), 3.95 (IH, d), 4.17 (IH, s), 4.44 (IH, s), 4.79 (IH, t), 6.71 (IH, s), 7.37 - 7.46 (3H, m), 7.80 - 7.89 (2H, m), 7.84 (3H, dd), 8.04 (IH, d), 8.16 (IH, s), 8.70 (IH, s), 9.49 (IH, s). mTOR Kinase Assay (Echo): 0.0137μM Example 14m: 1H NMR (400.13 MHz, DMSO-d6) δ 1.19 (3H, d), 1.58 - 1.65 (2H, m), 1.88 - 1.92 (2H, m), 3.13 - 3.22 (IH, m), 3.42 - 3.49 (IH, m), 3.61 (IH, d), 3.75 (IH, d), 3.81 (3H, s), 3.96 (IH, d), 4.14 - 4.24 (IH, m), 4.43 - 4.51 (IH, m), 6.73 (IH, s), 7.42 - 7.50 (3H, m), 7.82 - 7.90 (2H, m), 8.07 - 8.20 (IH, m), 8.71 (IH, s), 9.72 (IH, s), 10.28 (IH, s). mTOR Kinase Assay (Echo): 0.0143μM Example 14n: 1H NMR (400.13 MHz, DMSO-d6) δ 0.44 - 0.51 (2H, m), 0.66 - 0.71 (2H, m), 1.22 (3H, d), 1.50 - 1.61 (2H, m), 1.78 - 1.85 (2H, m), 2.40 - 2.47 (2H, m), 2.60 - 2.66 (IH, m), 2.69 - 2.78 (2H, m), 2.90 (3H,s), 3.15 - 3.27 (IH, m), 3.44 - 3.54 (IH, m), 3.64 (IH, d), 3.76 (IH, d), 3.98 (IH, d), 4.29 (IH, s), 4.58 (IH, s), 6.84 (IH, s), 7.51 (IH, d), 8.20 (IH, s), 8.53 (IH, d), 9.12 (IH, s), 9.37 (IH, s). mTOR Kinase Assay (Echo): 0.0363μM
Example 14o: 1U NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.51 - 1.60 (2H, m), 1.75 - 1.86 (2H, m), 2.40 - 2.47 (2H, m), 2.71 - 2.79 (5H, m), 2.90(3H,s), 3.22 (IH, d), 3.48 (IH, d), 3.64 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.21 - 4.32 (IH, m), 4.58 (IH, s), 6.84 (IH, s), 7.42 (IH, d), 8.18 (IH, s), 8.52 (IH, d), 9.14 (IH, s), 9.52 (IH, s). mTOR Kinase Assay (Echo): 0.0217μM
Example 14p: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.54 - 1.61 (2H, m), 1.78 - 1.84 (2H, m), 2.18 (6H, s), 2.32 - 2.38 (2H, m), 2.38 - 2.47 (2H, m), 2.69 - 2.79 (2H, m), 2.90 (3H,s), 3.14 - 3.29 (3H, m), 3.43 - 3.55 (IH, m), 3.64 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.26 (IH, s), 4.58 (IH, s), 6.84 (IH, s), 7.54 (IH, d), 8.03 (IH, s), 8.52 (IH, d), 9.12 (IH, s), 9.48 (IH, s). mTOR Kinase Assay (Echo): 0.537μM Example 14q: 1H NMR (400.13 MHz, DMSOd6) δ 1.23 (3H, d), 1.51 - 1.61 (2H, m), 1.76 - 1.86 (2H, m), 2.37 - 2.46 (2H, m), 2.69 - 2.78 (2H, m), 2.90 (3H, s), 3.17 - 3.29 (3H, m), 3.42
- 3.54 (3H, m), 3.64 (IH, dd), 3.76 (IH, d), 3.92 - 4.01 (IH, m), 4.26 (IH, s), 4.57 (IH, s), 4.80 (IH, t), 6.84 (IH, s), 7.47 (IH, d), 8.31 (IH, s), 8.53 (IH, d), 9.12 (IH, s), 9.50 (IH, s). mTOR Kinase Assay (Echo): 0.0265μM Example Ur: 1U NMR (400.13 MHz, DMSOd6) δ 1.24 (3H, d), 1.55 - 1.60 (2H, m), 1.79 - 1.85 (2H, m), 2.39 - 2.47 (2H, m), 2.71 - 2.81 (2H, m), 2.90 (3H, s), 3.17 - 3.26 (IH, m), 3.46
- 3.55 (IH, m), 3.65 (2H, d), 3.78 (4H, d), 3.98 (IH, d), 4.28 (IH, s), 4.59 (IH, s), 6.86 (IH, s), 7.50 (2H, d), 7.87 (IH, s), 8.58 (IH, d), 9.20 (IH, s), 9.73 (IH, s), 10.34 (IH, s). mTOR Kinase Assay (Echo): 0.0103μM Example 14s: 1U NMR (400.13 MHz, DMSO-d6) δ 0.51 - 0.58 (2H, m), 0.67 - 0.76 (2H, m), 1.23 (3H, d), 1.50 - 1.62 (2H, m), 1.76 - 1.88 (2H, m), 2.31 - 2.49 (2H, m), 2.64 - 2.79 (2H, m), 2.90 (3H, s), 3.15 - 3.26 (IH, m), 3.49 (IH, t), 3.64 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.29 (IH, s), 4.59 (IH, s), 6.88 (IH, s), 9.15 (IH, s), 9.36 (2H, s), 10.13 (IH, s). mTOR Kinase Assay (Echo): 0.122μM Example 14t: 1H NMR (400.13 MHz, DMSO-d6) δ 1.21 (3H, d), 1.56 (2H,m), 1.77 - 1.87 (2H, m), 2.34 (3H, d), 2.38 - 2.46 (2H, m), 2.68 - 2.76 (2H, m), 2.80 (3H, d), 3.16 - 3.23 (IH, m), 3.46 - 3.51 (IH, m), 3.64 (IH, d), 3.76 (IH, d), 3.96 (IH, d), 4.22 - 4.35 (IH, m), 4.54 - 4.68 (IH, m), 6.89 (IH, s), 8.97 - 9.07 (IH, m), 9.36 (2H, s), 10.11 (IH, s). mTOR Kinase Assay (Echo): 0.197μM Example 14u: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.52 - 1.59 (2H, m), 1.78 -
1.85 (2H, m), 2.38 - 2.52 (4H, m), 2.69 - 2.79 (2H, m), 3.20 (IH, d), 3.32 (3H, s), 3.42 - 3.47 (IH, m), 3.49 - 3.55 (2H, m), 3.61 - 3.67 (IH, m), 3.76 (IH, d), 3.97 (IH, d), 4.30 (IH, s), 4.61 (IH, s), 4.83 (IH, t), 6.89 (IH, s), 9.15 - 9.26 (IH, m), 9.36 (2H, s), 10.11 (IH, s). mTOR Kinase Assay (Echo): 0.123μM Example 14v: 1R NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 1.54 - 1.60 (2H, m), 1.79 -
1.86 (2H, m), 2.38 - 2.47 (2H, m), 2.65 - 2.81 (5H, m), 3.11 - 3.27 (IH, m), 3.46 - 3.53 (IH, m), 3.65 (IH, d), 3.76 (IH, d), 3.81 (3H, s), 3.98 (IH, d), 4.27 - 4.35 (IH, m), 4.57 - 4.65 (IH, m), 6.91 (IH, s), 7.55 (IH, s), 7.92 (IH, s), 9.08 (IH, s), 9.44 (2H, s), 10.49 (IH, s). mTOR Kinase Assay (Echo): 0.0823μM
Example 14w: 1H NMR (400.13 MHz, DMSOd6) δ 0.52 - 0.57 (2H, m), 0.68 - 0.74 (2H, m), 0.91 - 0.95 (2H, m), 0.99 - 1.04 (2H, m), 1.23 (3H, d), 1.56 - 1.61 (2H, m), 1.63 - 1.68 (2H, m), 2.65 - 2.73 (IH, m), 2.95 - 3.03 (IH, m), 3.22 (IH, dd), 3.43 - 3.53 (IH, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.23 (IH, s), 4.56 (IH, s), 6.95 (IH, s), 9.15 (IH, s), 9.33 (2H, s), 10.13 (IH, s). mTOR Kinase Assay (Echo): 0.208μM Example 14x: 1U NMR (400.13 MHz, DMSOd6) δ 0.89 - 0.96 (2H, m), 1.00 - 1.06 (2H, m), 1.24 (3H, d), 1.56 - 1.61 (2H, m), 1.63 - 1.67 (2H, m), 2.80 (3H, d), 2.98 - 3.05 (IH, m), 3.19 - 3.25 (IH, m), 3.48 (IH, dd), 3.57 - 3.66 (IH, m), 3.70 - 3.80 (IH, m), 3.90 - 4.00 (IH, m), 4.21 (IH, s), 4.56 (IH, s), 6.94 (IH, s), 8.98 (IH, d), 9.33 (2H, s), 10.10 (IH, s). mTOR Kinase Assay (Echo): 0.63μM Example 14y: 1U NMR (400.13 MHz, DMSO-d6) δ 0.89 - 0.95 (2H, m), 1.00 - 1.05 (2H, m), 1.24 (3H, d), 1.57 - 1.61 (2H, m), 1.64 - 1.69 (2H, m), 2.98 - 3.04 (IH, m), 3.18 - 3.27 (IH, m), 3.29 - 3.34 (2H, m), 3.44 - 3.55 (3H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.23 (IH, s), 4.56 (IH, s), 4.83 (IH, t), 6.95 (IH, s), 9.20 (IH, t), 9.35 (2H, s), 10.11 (IH, s). mTOR Kinase Assay (Echo): 0.152μM Example 14z: 1H NMR (400.13 MHz, DMSO-d6) δ 0.92 - 0.95 (2H, m), 0.98 - 1.07 (2H, m), 1.23 (3H, d), 1.58 - 1.61 (2H, m), 1.62 - 1.68 (2H, m), 2.97 - 3.03 (IH, m), 3.23 (IH, td), 3.49 (IH, td), 3.64 (IH, d), 3.76 - 3.85 (4H, m), 3.98 (IH, dd), 4.24 (IH, s), 4.57 (IH, s), 6.96 (IH, s), 7.56 (IH, s), 7.91 (IH, s), 9.41 (2H, s), 10.49 (IH, s), 11.15 (IH, s). mTOR Kinase Assay (Echo): 0.171 μM Example 14aa: 1U NMR (400.13 MHz, DMSO-d6) δ 1.18 (3H, d), 1.53 - 1.61 (2H, m), 1.74 - 1.79 (2H, m), 3.10 - 3.19 (2H, m), 3.28 - 3.36 (4H, m), 3.45 (IH, t), 3.48 - 3.56 (2H, m), 3.60 (IH, d), 3.74 (IH, d), 3.95 (IH, d), 4.10 (IH, s), 4.34 (IH, s), 4.75 (IH, t), 4.85 (IH, t), 6.62 (2H, d), 6.65 - 6.70 (2H, m), 7.41 (2H, d), 9.11 (2H, s), 9.20 (IH, t), 10.04 (IH, s). mTOR Kinase Assay (Echo): 0.0186μM
The preparation of phenyl Λ/-[5-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2-yl]carbamate is described below. Phenyl N- [5 -[4-(1-CVCIOPrOPVISUIfOnVIcVcIoPrOPvI)-O- [(36^-3 -methylmorpholin-4- yl1pyrimidin-2-vHpyridin-2-vHcarbamate
Figure imgf000402_0001
Phenyl chloroformate (0.543 mL, 4.33 mmol) was added to a mixture of 5-[4-(l- cyclopropylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2- amine (1.2 g, 2.89 mmol) and sodium hydrogen carbonate (0.364 g, 4.33 mmol) in dioxane (30 mL) at 50C under nitrogen. The resulting mixture was stirred at RT for 1 hour, then at 4O0C for 3 hours and again at RT overnight. Additional phenyl chloroformate (1 mL) was added and the mixture heated at 4O0C until complete. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (2 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product which was then purified chromatography on silica, eluting with 10 to 80% ethyl acetate in isohexane, to give a mixture of the desired material and material where an additional carbamate group was present (phenyl N- [5 - [4-( 1 -cyclopropylsulfonylcyclopropyl)-6- [(35)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]pyridin-2-yl]-N-phenoxycarbonylcarbamate). This material (1 g) was used in the subsequent step without further attempts to purify. LCMS Spectrum: m/z (ESI+)(M+H)+ = 536; HPLC tR = 2.65 min.
5 - \4-( 1 -C yclopropylsulfonylcvclopropyD-ό- [(36^-3 -methylmorpholin^-yllpyrimidin^- yllpyridin-2-amine
Figure imgf000402_0002
Bis(triphenylphosphine)palladium(II) chloride (118 mg, 0.17 mmol) was added to 2-chloro-4- (l-cyclopropylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (900 mg, 2.51 mmol), 2-amino-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (830 mg, 3.77 mmol) and sodium carbonate (5.03 mL, 10.06 mmol) in a mixture of DMF (6 mL), DME (8 mL), water (2 mL) and ethanol (1.5 mL) at RT . The resulting mixture was stirred at 9O0C for 18 hours then the reaction mixture diluted with ethyl acetate (200 mL) and washed with water (2 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by chromatography on silica, eluting with 0 to 5% methanol in ethyl acetate. The material was further purified by ion exchange chromatography using an SCX column with the desired material eluted using 7M ammonia in methanol, to give the pure desired material as a white solid (1.2 g).
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.92 - 0.95 (2H, m), 1.00 - 1.04 (2H, m), 1.22 (3H, d), 1.53 - 1.59 (2H, m), 1.62 - 1.65 (2H, m), 2.94 - 3.02 (IH, m), 3.19 (IH, td), 3.48 (IH, td), 3.63 (IH, d), 3.75 (IH, d), 3.96 (IH, d), 4.17 (IH, d), 4.53 (IH, s), 6.39 (2H, s), 6.50 (IH, d), 6.81 (IH, s), 8.23 (IH, d), 8.89 (IH, d)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 416; HPLC tR = 1.81 min.
The preparation of 2-chloro-4-(l-cyclopropylsulfonylcyclopropyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidine was described earlier.
The preparation of phenyl Λ/-[5-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]pyrimidin-2-yl] carbamate is described below.
Phenyl N- \5- [4- [ 1 -(4-fluorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- yl1pyrimidin-2-yl1pyrimidin-2-yl"| carbamate
Figure imgf000403_0001
Phenyl chloro formate (0.306 mL, 2.44 mmol) was added to a mixture of 5-[4-[l-(4- fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]pyrimidin-2-amine (765 mg, 1.63 mmol) and sodium hydrogen carbonate (205 mg, 2.44 mmol) in dioxane (10 mL) at 50C under nitrogen. The resulting mixture was stirred at RT overnight. Additional phenyl chloro formate (0.2 mL) was added and reaction left to stir overnight. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (2 x 100 mL), and a saturated brine solution (50 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford a gum. The crude gum was triturated with diethyl ether to give a solid which was collected by filtration and dried under vacuum to give the desired material as a yellow solid (1.0 g). No further purification was performed at this stage. LCMS Spectrum: m/z (ESI+)(M+H)+ = 591; HPLC tR = 2.61 min.
Figure imgf000404_0001
yllpyrimidin-2-amine
Figure imgf000404_0002
Bis(triphenylphosphine)palladium(II) chloride (0.143 g, 0.20 mmol) was added to 2-chloro-4- [l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (1.25 g, 3.03 mmol), 2-amino-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.868 g, 3.95 mmol) and sodium carbonate (3 mL, 6.00 mmol) in a mixture of DMF (3 mL), DME (8 mL), water (2 mL) and ethanol (1.5 mL) at RT and the atmosphere replaced with nitrogen. The mixture was stirred at 9O0C for 5 hours the left to stir at RT overnight. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (2 x 100 mL), and the organic layer dried (Na2SO4), filtered and evaporated to afford crude product. The crude solid was triturated with DCM to give a solid which was collected by filtration and dried under vacuum to give the desired material as a beige solid (1.1 g).
NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.18 (3H, d), 1.56 - 1.61 (2H, m), 1.86 - 1.90 (2H, m), 3.15 (IH, td), 3.45 (IH, td), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.14 (IH, d), 4.46 (IH, s), 6.69 (IH, s), 7.13 (2H, s), 7.41 (2H, t), 7.80 - 7.85 (2H, m), 8.65 (2H, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 471; HPLC tR = 1.94 min. The preparation of 2-chloro-4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidine was described earlier.
The preparation of phenyl 7V-[5-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3<S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2-yl]carbamate is described below.
Phenyl N- [5- [4- [ 1 -(4-fluorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidin-2-yllpyridin-2-vHcarbamate
Figure imgf000405_0001
Phenyl chloro formate (0.962 mL, 7.67 mmol) was added to a mixture of 5-[4-[l-(4- fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2- amine (900 mg, 1.92 mmol) and sodium hydrogen carbonate (242 mg, 2.88 mmol) in dioxane (50 mL) at 50C under nitrogen. The resulting mixture was stirred at RT for 3 days, additional phenyl chloro formate (2 mL) added and the reaction stirred at RT for an additional 16 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (100 mL), and the organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude solid was triturated with diethyl ether to give a solid which was collected by filtration and dried under vacuum to give the desired material as a cream solid (900 mg). LCMS Spectrum: m/z (ESI+)(M+H)+ = 591; HPLC tR = 2.63 min.
Figure imgf000405_0002
yllpyridin-2-amine
Figure imgf000405_0003
Bis(triphenylphosphine)palladium(II) chloride (0.143 g, 0.20 mmol) was added to (2-chloro- 4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (1.25 g, 3.03 mmol), 2-amino-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.868 g, 3.95 mmol) and sodium carbonate (3 mL, 6.00 mmol) in a mixture of DMF (3 mL), DME (8 mL), water (2 mL) and ethanol (1.5 mL) at RT under at nitrogen atmosphere. The resulting mixture was stirred at 9O0C for 5 hours then at RT for 16 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (2 x 100 mL), and the organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with 20 to 80% ethyl acetate in isohexane. The isolated material was further purified by ion exchange chromatography using an SCX column with the desired material eluted from the column using 7M ammonia in methanol. The desired material was isolated as as a white solid (0.94 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.17 (3H, d), 1.57 - 1.61 (2H, m), 1.86
- 1.89 (2H, m), 3.09 - 3.17 (IH, m), 3.41 - 3.49 (IH, m), 3.60 (IH, dd), 3.74 (IH, d), 3.96 (IH, d), 4.11 (IH, d), 4.43 (IH, s), 6.35 - 6.41 (3H, m), 6.63 (IH, s), 7.38 - 7.45 (2H, m), 7.78
- 7.85 (3H, m), 8.51 (IH, d)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 470; HPLC tR = 2.06 min.
The preparation of 2-chloro-4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidine was described earlier.
The preparation of phenyl Λ/-[5-[4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopentyl)pyrimidin-2-yl]pyridin-2-yl]carbamate is described below.
Phenyl N- \5 -\4- [(36^-3 -methylmorpholin-4-yll-6-(l-methylsulfonylcvclopentyl)pyrimidin-2- yllpyridin-2-vH carbamate
Figure imgf000406_0001
Phenyl chloroformate (1.23 mL, 9.82 mmol) was added to 5-[4-[(35)-3-methylmorpholin-4- yl]-6-(l-methylsulfonylcyclopentyl)pyrimidin-2-yl]pyridin-2-amine (1.025 g, 2.45 mmol) and sodium hydrogen carbonate (0.309 g, 3.68 mmol) in dioxane (50 mL) at 50C under nitrogen. The resulting mixture was stirred at RT for 3 days then additional phenyl chloroformate (2 mL) added and the reaction left to stir at 350C for 3 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (2 x 100 mL), and the organic layer dried (Na2SO4), filtered and evaporated to afford crude product. The crude liquid was triturated with diethyl ether to give a solid which was collected by filtration and dried under vacuum to give the desired material as a cream solid (1.2 g). LCMS Spectrum: m/z (ESI+)(M+H)+ = 538; HPLC tR = 2.89 min.
5-r4-r(35)-3-Methylmorpholin-4-yll-6-(l-methylsulfonylcvclopentyl)pyrimidin-2-yllpyridin- 2-amine
Figure imgf000407_0001
Bis(triphenylphosphine)palladium(II) chloride (0.261 g, 0.37 mmol) was added to 2-chloro-4- [(35)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopentyl)pyrimidine (2 g, 5.56 mmol), 2-amino-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.835 g, 8.34 mmol) and aqueous sodium carbonate solution (11.12 mL, 22.23 mmol) in a mixture of DMF (6 mL), DME (8 mL), water (2 mL) and ethanol (1.5 mL) at RT under an atmosphere of nitrogen. The resulting mixture was stirred at 9O0C for 18 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (2 x 100 mL) and the organic layer dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with 10 to 100% ethyl acetate in isohexane. The isolated material was dissolved in methanol, the solid removed and the filtrate purified by ion exchange chromatography using an SCX column with the desired product eluted from the column using 7M ammonia in methanol. The desired material was isolated as a white solid (2-2 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22 (3H, d), 1.54 - 1.60 (2H, m), 1.78 - 1.85 (2H, m), 2.37 - 2.46 (2H, m), 2.65 - 2.78 (2H, m), 2.90 (3H, s), 3.18 (IH, dd), 3.49 (IH, td), 3.64 (IH, dd), 3.75 (IH, d), 3.97 (IH, dd), 4.22 (IH, d), 4.56 (IH, s), 6.39 (2H, s), 6.50 (IH, d), 6.75 (IH, s), 8.25 (IH, d), 8.92 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 418; HPLC tR = 2.05 min.
The preparation of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopentyl)pyrimidine was described earlier.
The preparation of phenyl Λ/-[5-[4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopentyl)pyrimidin-2-yl]pyrimidin-2-yl]carbamate is described below.
Phenyl N- \5 -\4- [(36^-3 -methylmorpholin-4-yll-6-(l-methylsulfonylcvclopentyl)pyrimidin-2- yllpyrimidin-2-vHcarbamate
Figure imgf000408_0001
Phenyl chloro formate (0.315 mL, 2.51 mmol) was added to 5-[4-[(35)-3-methylmorpholin-4- yl]-6-(l-methylsulfonylcyclopentyl)pyrimidin-2-yl]pyrimidin-2-amine (700 mg, 1.67 mmol), sodium hydrogen carbonate (211 mg, 2.51 mmol) in dioxane (20 mL) at 50C under nitrogen. The resulting mixture was stirred at RT for 48 hours. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (2 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product which was triturated with diethyl ether to give the desired material as a yellow solid (790 mg). LCMS Spectrum: m/z (ESI+)(M+H)+ = 539; HPLC tR = 2.52 min.
S-^-ffS^-S-Methylmorpholin^-yll-ό-d-methylsulfonylcvclopentvπpyrimidin^- yllpyrimidin-2-amine
Figure imgf000409_0001
Bis(triphenylphosphine)palladium(II) chloride (0.261 g, 0.37 mmol) was added to 2-chloro-4- [(35)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopentyl)pyrimidine (2 g, 5.56 mmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-pyrimidin-2-ylamine (1.843 g, 8.34 mmol) and aqueous sodium carbonate solution (11.12 mL, 22.23 mmol) in a mixture of DMF (6 mL), DME (8 mL), water (2 mL) and ethanol (1.5 mL) at RT. The resulting mixture was stirred at 9O0C for 18 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with water (2 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% methanol in ethyl acetate. The isolated material was triturated with a mixture of diethyl ether and isohexane and filtered to give the desired material as a cream solid (2.0 g).
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.22 (3H, d), 1.53 - 1.60 (2H, m), 1.76 - 1.83 (2H, m), 2.37 - 2.47 (2H, m), 2.64 - 2.76 (2H, m), 2.91 (3H, s), 3.15 - 3.23 (IH, m), 3.49 (IH, td), 3.63 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.24 (IH, d), 4.59 (IH, s), 6.82 (IH, s), 7.14 (2H, s), 9.09 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 419; HPLC tR = 1.83 min.
The preparation of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopentyl)pyrimidine was described earlier.
The preparation of phenyl Λ/-[5-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]pyrimidin-2-yl] carbamate is described below. Phenyl N- [5 -[4-(1-CVCIOPrOPVISUIfOnVIcVcIoPrOPvI)-O- [(36^-3 -methylmorpholin-4- yl1pyrimidin-2-vHpyrimidin-2-vHcarbamate
Figure imgf000410_0001
Phenyl chloroformate (0.976 mL, 7.78 mmol) was added dropwise to 5-[4-(l- cyclopropylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyrimidin-
2-amine (2.16 g, 5.19 mmol), sodium hydrogen carbonate (0.654 g, 7.78 mmol) in dioxane
(30 mL) cooled to 1O0C under nitrogen. The resulting mixture was stirred at RT for 48 hours.
The reaction mixture was diluted with ethyl acetate (150 mL), and washed with water (150 mL followed by 125 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product which was purified by trituration with diethyl ether to give the desired material as a yellow solid (2.5 g).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 537; HPLC tR = 2.33 min.
5 - \4-( 1 -C vclopropylsulfonylcyclopropyD-ό- r(3iSV3 -methylmorpholin-4-yllpyrimidin-2- vHpyrimidin-2-amine
Figure imgf000410_0002
Bis(triphenylphosphine)palladium(II) chloride (0.381 g, 0.54 mmol) was added to 2-chloro-4- (l-cyclopropylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (2.9 g, 8.10 mmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-pyrimidin-2-ylamine (2.69 g, 12.16 mmol) and aqueous sodium carbonate solution (4 mL, 8.00 mmol) in a mixture of DMF (18 mL), DME (8 mL), water (2 mL) and ethanol (1.5 mL) at RT .The resulting mixture was stirred at 9O0C for 18 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with water (2 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 7% methanol in ethyl acetate. The isolated material was further purified by ion exchange chromatography using an SCX column, eluting with methanol followed by 7M ammonia in methanol, to give the desired material as a white solid (2.16 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.90 - 0.94 (2H, m), 0.99 - 1.04 (2H, m), 1.22 (3H, d), 1.54 - 1.58 (2H, m), 1.60 - 1.65 (2H, m), 2.95 - 3.02 (IH, m), 3.16 - 3.23 (IH, m), 3.47 (IH, td), 3.62 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.18 (IH, s), 4.50 (IH, s), 6.85 (IH, s), 7.16 (2H, s), 9.05 (2H, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 417; HPLC tR = 1.70 min.
The preparation of 2-chloro-4-(l-cyclopropylsulfonylcyclopropyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidine was described earlier.
Example 15 : 3-C yclopr opyl- 1- [4- [4- [ l-f2-hvdroxyethylsulfonyl)cvclopropyll -6- [(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll urea
Figure imgf000411_0001
Bis (triphenylphosphine)palladium (II) chloride (6.84 mg, 0.00975 mmol) was added to 2-[l- [2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonylethoxy- tri(propan-2-yl)silane (0.101 g, 0.19 mmol), l-cyclopropyl-3-(4- (4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)urea (0.088 g, 0.29 mmol) and sodium carbonate (0.487 mL, 0.97 mmol) in a solvent mixture (18% DMF, 82% of a 7:3:2 mixture of DME:water:Ethanol) at RT under nitrogen. The resulting suspension was stirred at 800C for 17 hours. The solvent was removed and the residue partitioned between DCM and water. The organic layer was dried (MgSO4), filtered and tetrabutylammonium fluoride (0.975 mL, 0.97 mmol) added to the filtrate and stirred for 2 hours. The mixture was washed with water, the organic layer concentrated in vacuo and purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (0.057 g). NMR Spectrum: 1H NMR (400MHz, DMSO-d6) δ 0.41-0.44 (2H, m), 0.63-0.68 (2H, m), 1.23-1.25 (3H, d), 1.53-1.56 (2H, m), 1.65-1.66 (2H, m), 2.55-2.59 (IH, m), 3.17-3.25 (IH, td), 3.56-3.52 (IH, td), 3.62-3.66 (3H, m), 3.75-3.78 (IH, d), 3.88-3.89 (2H, m), 3.96-4.00 (IH, dd), 4.20-4.23 (IH, d), 4.56 (IH, bs), 5.03 (IH, bs), 6.45-6.46 (IH, d), 6.78 (IH, s), 7.50- 7.52 (2H, d), 8.20-8.22 (2H, d), 8.56 (IH, s).
LCMS Spectrum: m/z (ES+) (M+H)+ = 502; HPLC tR = 1.86min. mTOR Kinase Assay (Echo): 0.00154μM
The compound below was prepared in an analogous fashion using the appropriate boronate.
Figure imgf000412_0001
Example 15a: 1H NMR (400MHz, DMSOd6) δ 1.05-1.09 (3H, t), 1.23-1.24 (3H, d), 1.53- 1.56 (2H, m), 1.64-1.67 (2H, m), 3.10-3.17 (2H, m), 3.17-3.25 (IH, td), 3.45-3.52 (IH, td), 3.62-3.66 (3H, m), 3.75-3.78 (IH, d), 3.87-3.91 (2H, t), 3.96-3.99 (IH, dd), 4.19-4.22 (IH, d), 4.55 (IH, bs), 5.03 (IH, bs), 6.17-6.20 (IH, t), 6.77 (IH, s), 7.49-7.51 (2H, q), 8.19-8.21 (2H, q), 8.68 (IH, s). mTOR Kinase Assay (Echo): 0.00059 lμM
The preparation of 2-[ 1 -[2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4- yl]cyclopropyl]sulfonylethoxy-tri(propan-2-yl)silane is described below.
2-[l-[2-Chloro-6-[(36f)-3-methylmorpholin-4-yllpyrimidin-4-yllcvclopropyllsulfonylethoxy- tri(propan-2-yl)silane
Figure imgf000413_0001
A 50% v/v aqueous sodium hydroxide solution (35 mL, 5.20 mmol) was added to 2-[[2- chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]ethoxy-tri(propan-2- yl)silane (2.56 g, 5.20 mmol), 1 ,2-bibromoethane (1.345 mL, 15.61 mmol) and tetrabutylammonium bromide (0.168 g, 0.52 mmol) in toluene (100 mL) at RT. The resulting slurry was stirred at 600C for 3 hours then the reaction mixture diluted with water and extracted sequentially with toluene and DCM. The organic layers were combined, dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with 0 to 10% ethyl acetate in DCM, to give the desired material as a colourless oil which solidified on standing (0.304 g).
NMR Spectrum: 1H NMR (400MHz, CDCl3) δ 1.01-1.11 (2 IH, m), 1.30-1.32 (3H, d), 1.47- 1.50 (2H, q), 1.77-1.80 (2H, q), 3.24-3.31 (IH, td), 3.40-3.44 (2H, t), 3.48-3.55 (IH, td), 3.64- 3.68 (IH, td), 3.75-3.78 (IH, d), 3.97-4.01 (2H, m), 4.10-4.14 (2H, t), 4.32 (IH, bs), 6.86 (IH, s). LCMS Spectrum: m/z (ES+) (M+H)+=518; HPLC tR=3.86min.
2-rr2-Chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-yllmethylsulfonyllethoxy- tri(propan-2-vDsilane
Figure imgf000413_0002
2-[[2-Chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]ethanol (4.21 g, 12.53 mmol) was added to triisopropylsilyl chloride (3.22 mL, 15.03 mmol) and imidazole (2.046 g, 30.06 mmol) in DMF at RT. The resulting solution was stirred at RT overnight under a nitrogen atmosphere. The DMF was removed in vacuo and ethyl acetate added. The solids were removed by filtration and the filtrate concentrated in vacuo and purified by flash silica chromatography, eluting with 0 to 4% methanol in DCM. The isolated material was again purified by chromatography on silica, eluting with 0 - 10% ethyl acetate in DCM, to give the desired material to as a clear gum (4.15 g).
NMR Spectrum: 1H NMR
Figure imgf000414_0001
CDCl3) δ 1.03-1.15 (21H, m), 1.27-1.29 (3H, d), 3.20- 3.28 (IH, td), 3.37-3.40 (2H, m), 3.45-3.52 (IH, td), 3.61-3.65 (IH, dd), 3.71-3.74 (IH, d), 3.93-4.04 (2H, m), 4.15-4.18 (2H, t), 4.28 (3H, s), 6.50 (IH, s). LCMS Spectrum: m/z (ES+) (M+H)+ = 492; HPLC tR = 3.72min.
2-rr2-Chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-yllmethylsulfonyllethanol
Figure imgf000414_0002
A solution of hydrogen peroxide (30%aqueous solution, 0.225 mL, 7.29 mmol) was added to a stirred solution of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-[2-(oxan-2- yloxy)ethylsulfonylmethyl]pyrimidine (0.141 g, 0.36 mmol), sodium tungstate dihydrate (2.4 mg, 0.0073 mmol) in water (0.2 mL) and 2N sulfuric acid (0.011 mL) in 1,4-dioxane (1.4 mL) and methanol (1.4 mL) and the reaction stirred at 55°C for 4 hours. Water (50 mL) was added and the reaction cooled. 10% Sodium metabisulfite aqueous solution was added and the mixture extracted with DCM. The organics were dried (MgSO4), filtered and concentrated in vacuo to give the desired material as a opaque oil (0.198 g). LCMS Spectrum: m/z (ES+) (M+H)+=336; HPLC tR=1.18 min.
2-Chloro-4-r(3y)-3-methylmorpholin-4-yl1-6-r2-(oxan-2- yloxy)ethylsulfonylmethvHpyrimidine
Figure imgf000414_0003
DIPEA (0.211 g, 1.63 mmol) was added dropwise to 2-chloro-4-(iodomethyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidine (0.231 g, 0.65 mmol) and 2-(tetrahydro-2H-pyran-2- yloxy)ethanethiol (0.133 g, 0.82 mmol) in acetonitrile at RT. The resulting solution was stirred at RT for 1 hour. The solvent was removed and the residue partitioned between DCM and water. The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with 0 to 2% methanol in DCM, to give the desired material as a colourless oil (0.141 g). NMR Spectrum: 1H NMR (400MHz, CDCB) δ 1.24-1.26 (3H, d), 1.40-1.55 (4H, m), 1.60- 1.67 (IH, m), 1.69-1.77 (IH, m), 2.68-2.71 (2H, t), 3.17-3.24 (IH, td), 3.41-3.47 (2H, m), 3.50-3.58 (IH, m), 3.59 (2H, s), 3.62-3.63 (IH, d), 3.69-3.72 (IH, d), 3.76-3.86 (2H, m), 3.91-3.95 (IH, dd), 3.97 (IH, bs), 4.25 (IH, bs), 4.52-4.54 (IH, t), 6.44 (IH, s). LCMS Spectrum: m/z (ES+) (M+H)+=386; HPLC tR=2.11 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier
Example 16 : 1- [4- [4- [ l-(2-Hydroxyethylsulfonylkyclopropyll -6- \(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-methylurea
Figure imgf000415_0001
Methylamine (0.542 mL, 1.08 mmol) was added to (S)-phenyl 4- (4- (1- (2- hydroxyethylsulfonyl)cyclopropyl)-6- (3-methylmorpholino)pyrimidin-2-yl)phenylcarbamate (0.117 g, 0.22 mmol) and triethylamine (0.091 mL, 0.65 mmol) in DMF (3 mL) and the solution stirred at RT for 5 minutes. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (0.08 g).
NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 1.22-1.24 (3H, d), 1.53-1.56 (2H, m), 1.64- 1.66 (2H, m), 2.66-2.67 (3H, d), 3.16-3.24 (IH, td), 3.45-3.51 (IH, td), 3.61-3.67 (3H, m), 3.75-3.78 (IH, d), 3.86-3.91 (2H, q), 3.96-3.99 (IH, dd), 4.20-4.23 (IH, d), 4.56 (IH, bs), 5.06-5.09 (IH, t), 6.08-6.11 (IH, q), 6.77 (IH, s), 7.50-7.52 (2H, d), 8.18-8.21 (2H, d), 8.79 (IH, s).
LCMS Spectrum: m/z (ES+) (M+H)+=476; HPLC tR=1.69 min. mTOR Kinase Assay (Echo): 0.00142μM The following compounds were prepared in an analogous fashion from phenyl N-[4-[4-[l-(2- hydroxyethylsulfonyl)cyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate using the appropriate amine.
Figure imgf000416_0001
Figure imgf000417_0001
Example 16a: 1R NMR (400 MHz, DMSOd6) δ 1.23-1.24(3H, d), 1.53-1.69(7H, m), 1.82- 1.92(2H, m), 2.18-2.25(2H, m), 3.17-3.24(1H, td), 3.45-3.52(1H, td), 3.63-3.66(3H, m), 3.75- 3.78(1H, d), 3.86-3.91(2H, m), 3.96-3.99(1H, dd), 4.2O-4.22(1H, d), 4.56(1H, bs), 5.01- 5.04(1H, t), 6.46-6.48(1H, d), 6.78(1H, s), 7.47-7.49(2H, d), 8.19-8.21(2H, d), 8.57(1H, s). mTOR Kinase Assay (Echo): O.OlOlμM
Example 16b: 1H NMR (400 MHz, DMSOd6) δ 1.23-1.24(3H, d), 1.53-1.56(2H, m), 1.64- 1.67(2H, m), 3.16-3.24(3H, m), 3.45-3.52(3H, m), 3.62-3.66(3H, m), 3.75-3.78(1H, d), 3.87- 3.91(2H, q), 3.96-3.99(1H, dd), 4.19-4.23(1H, d), 4.56(1H, bs), 4.72-4.75(1H, t), 5.01- 5.04(1H, t), 6.25-6.27(1H, t), 6.77(1H, s), 7.48-7.51(2H, d), 8.20-8.22(2H, d), 8.81(1H, s). mTOR Kinase Assay (Echo): 0.00577μM
Example 16c: 1U NMR (400 MHz, DMSO-d6) δ 1.24-1.26(3H, d), 1.55-1.58(2H, m), 1.66-
1.68(2H, m), 3.19-3.26(1H, td), 3.47-3.53(1H, td), 3.63-3.67(3H, m), 3.77-3.79(1H, d), 3.88-
3.93(2H, m), 3.97-4.01(1H, dd), 4.22-4.24(1H, d), 4.58(1H, bs), 5.02-5.05(1H, t), 6.83(1H, s), 7.62-7.65(2H, d), 8.31-8.33(2H, d), 8.38(1H, s), 9.43(1H, s), 11.37(1H, bs). mTOR Kinase Assay (Echo): 0.0016μM
Example 16d: 1H NMR (400 MHz, DMSOd6) δ 1.23-1.25(3H, d), 1.54-1.57(2H, m), 1.65-
1.67(2H, m), 3.17-3.25(1H, td), 3.46-3.53(1H, td), 3.62-3.67(3H, m), 3.76-3.79(1H, d),
3.79(3H, s), 3.87-3.92(2H, m), 3.97-4.00(1H, dd), 4.2O-4.23(1H, d), 4.56(1H, bs), 5.02- 5.05(1H, t), 6.79(1H, s), 7.39-7.40(1H, s), 7.54-7.56(2H, d), 7.76(1H, s), 8.23-8.25(2H, d),
8.39(1H, s), 8.84(1H, s). mTOR Kinase Assay (Echo): 0.00364μM
Example 16e: 1U NMR (400 MHz, DMSOd6) δ 0.87-0.91 (3H, t), 1.23-1.25 (3H, d), 1.42-
1.51 (2H, m), 1.53-1.56 (2H, m), 1.64-1.67 (2H, m), 3.05-3.09 (2H, q), 3.17-3.25 (IH, td), 3.46-3.52 (IH, td), 3.62-3.66 (3H, m), 3.75-3.78 (IH, d), 3.87-3.91 (2H, q), 3.96-3.99 (IH, dd), 4.20-4.23 (IH, d), 4.56 (IH, bs), 5.01-5.04 (IH, t), 6.19-6.22 (IH, t), 6.78 (IH, s), 7.49-
7.51 (2H, d), 8.19-8.21 (2H, d), 8.65 (IH, s)
Example 16f: 1H NMR (400 MHz, DMSOd6) δ 1.23-1.25 (3H, d), 1.53-1.57 (2H, m), 1.59-
1.62 (2H, t), 1.64-1.67 (2H, m), 3.15-3.24 (3H, m), 3.46-3.50 (3H, m), 3.63-3.66 (3H, m), 3.75-3.78 (IH, d), 3.87-3.91 (2H, q), 3.96-3.99 (IH, dd), 4.19-4.23 (IH, d), 4.47-4.49 (IH, t),
4.55 (IH, bs), 5.01-5.04 (IH, t), 6.20-6.23 (IH, t), 6.77 (IH, s), 7.49-7.51 (2H, d), 8.19-8.21
(2H, d), 8.72 (IH, s).
Example 16g: 1R NMR (400 MHz, DMSOd6) δ 1.23-1.25 (3H, d), 1.54-1.56 (2H, m), 1.65-
1.67 (2H, m), 2.69-2.72 (2H, t), 3.17-3.25 (IH, td), 3.35-3.40 (2H, q), 3.46-3.52 (IH, td), 3.62-3.66 (3H, m), 3.75-3.78 (IH, d), 3.87-3.91 (2H, q), 3.96-4.00 (IH, dd), 4.20-4.23 (IH, d), 4.56 (IH, bs), 5.01-5.04 (IH, t), 6.52-6.55 (IH, t), 6.78 (IH, s), 7.51-7.53 (2H, d), 8.21-
8.23 (2H, d), 8.93 (IH, s).
Example 16h: 1H NMR (400 MHz, DMSOd6) δ 1.23-1.25 (3H, d), 1.54-1.56 (2H, m), 1.64-
1.67 (2H, m), 3.17-3.25 (IH, td), 3.46-3.52 (IH, td), 3.62-3.66 (3H, m), 3.75-3.78 (IH, d), 3.87-3.91 (2H, q), 3.96-3.99 (IH, dd), 4.20-4.23 (IH, d), 4.32-4.34 (2H, d), 4.56 (IH, bs),
5.01-5.04 (IH, t), 6.62-6.64 (IH, t), 6.78 (IH, s), 6.93-6.96 (2H, bs), 7.51-7.53 (2H, d), 8.21-
8.23 (2H, d), 8.94 (IH, s), 11.84 (IH, s). Example 16i: 1U NMR (400 MHz, DMSO-d6) δ 0.64-0.67 (2H, m), 0.70-0.73 (2H, m), 1.23- 1.24 (3H, d), 1.53-1.56 (2H, m), 1.64-1.67 (2H, m), 3.17-3.25 (IH, td), 3.44-3.52 (3H, m), 3.62-3.66 (3H, m), 3.75-3.78 (IH, d), 3.87-3.91 (2H, q), 3.96-4.00 (IH, dd), 4.19-4.23 (IH, d), 4.55 (IH, bs), 4.84 (IH, bs), 5.01-5.04 (IH, t), 6.58 (IH, s), 6.78 (IH, s), 7.47-7.49 (2H, d), 8.20-8.22 (2H, d), 8.68 (IH, s).
The preparation of phenyl Λ/-[4-[4-[l-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl N- [4- [4- [ 1 -(2-hvdroxyethylsulfonvπcvclopropyll-6-[(36f)-3-methylmorpholin-4- yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000419_0001
Phenyl chloroformate (0.043 mL, 0.34 mmol) was added to 2-[l-[2-(4-aminophenyl)-6-[(35)- 3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonylethanol (0.144 g, 0.34 mmol) and sodium bicarbonate (0.043 g, 0.52 mmol) in dioxane (20 mL) and the resulting slurry stirred at RT overnight. The reaction mixture was partitioned between DCM and water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, eluting with 0 to 40% ethyl acetate in DCM, to give the desired material as a beige solid (0.117 g). LCMS Spectrum: m/z (ES+) (M+H)+=539; HPLC tR=2.50 min.
2-ri-r2-(4-Aminophenyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4- yll cyclopropyll sulfonylethanol
Figure imgf000419_0002
Bis(triphenylphosphine)palladium (II) chloride (0.012 g, 0.02 mmol) was added to 2-[[2- chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]ethoxy-tri(propan-2- yl)silane (0.178 g, 0.34 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.113 g, 0.52 mmol) and an aqueous solution of sodium carbonate (0.859 mL, 1.72 mmol) in a mixture of solvents (18% DMF, 82% of a 7:3:2 mixture of DME:water:Ethanol). The resulting solution was stirred at 800C for 4 hours, the solvent removed and the residue partitioned between DCM and water. The organic layer was separated and tetrabutylammonium fluoride (1.718 mL, 1.72 mmol) added. The reaction was allowed to stir for several hours and then additional tetrabutylammonium fluoride (2 mL) was added and the reaction allowed to stir for 2 days. The mixture was washed with a saturated aqueous solution of ammonium chloride, dried (MgSO4) filtered and concentrated in vacuo to give the desired material which was used without further purification.
LCMS Spectrum: m/z (ES+) (M+H)+ = 419; HPLC tR = 1.83 min.
Example 17: l-[4-[4-H-(5-Fluoropyridin-3-yl)sulfonylcvclopropyll-6-K3SV3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-(2-hydroxyethyl)urea
Figure imgf000420_0001
To a solution of phenyl Λ/-[4-[4-[l-(5-fluoropyridin-3-yl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate (140 mg, 0.24 mmol) in DMF (2 mL) was added triethylamine (0.099 mL, 0.71 mmol) followed by ethanolamine (72mg, 1.19 mmol) and the reaction heated at 500C for 2 hours. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (55 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.64 - 1.67 (2H, m), 1.99 - 2.02 (2H, m), 3.15 - 3.20 (3H, m), 3.44 - 3.49 (2H, m), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.18 (IH, d), 4.50 (IH, s), 4.73 (IH, t), 6.29 (IH, t), 6.70 (IH, s), 7.38 (2H, d), 7.74 (2H, d), 8.18 - 8.21 (IH, m), 8.81 (2H, d), 8.95 (IH, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 557; HPLC tR = 1.82 min. mTOR Kinase Assay (Echo): 0.00116μM
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[l-(5- fluoropyridin-3-yl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yljphenyl] carbamate using the appropriate amine.
Figure imgf000421_0001
Example 17a: 1H NMR (400.132 MHz, DMSOd6) δ 1.07 (3H, t), 1.20 (3H, d), 1.64 - 1.67
(2H, m), 1.99 - 2.02 (2H, m), 3.09 - 3.21 (3H, m), 3.47 (IH, dt), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.18 (IH, d), 4.50 (IH, s), 6.19 (IH, t), 6.70 (IH, s), 7.38 (2H, d), 7.74 (2H, d),
8.18 - 8.19 (IH, m), 8.20 - 8.21 (IH, m), 8.68 (IH, s), 8.81 (IH, s), 8.95 (IH, d). mTOR Kinase Assay (Echo): 0.000942μM
Example 17b: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.64 - 1.67 (2H, m), 1.99 -
2.02 (2H, m), 2.66 (3H, d), 3.14 - 3.21 (IH, m), 3.47 (IH, dt), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.18 (IH, d), 4.50 (IH, s), 6.09 - 6.12 (IH, m), 6.70 (IH, s), 7.39 (2H, d), 7.74
(2H, d), 8.18 - 8.22 (IH, m), 8.79 (2H, d), 8.94 (IH, d). mTOR Kinase Assay (Echo): 0.000584μM
Example 17c: 1U NMR (400.132 MHz, DMSO-Cl6) δ 0.41 - 0.44 (2H, m), 0.60 - 0.67 (2H, m), 1.20 (3H, d), 1.65 - 1.66 (2H, m), 1.99 - 2.02 (2H, m), 3.15 - 3.21 (2H, m), 3.42 - 3.49 (IH, m), 3.61 (IH, d), 3.75 (IH, d), 3.96 (IH, d), 4.18 (IH, d), 4.50 (IH, s), 6.60 (IH, s), 6.70 (IH, s), 7.40 (2H, d), 7.74 (2H, d), 8.18 - 8.22 (IH, m), 8.69 (IH, s), 8.81 (IH, s), 8.95 (IH, d). mTOR Kinase Assay (Echo): 0.00179μM
The preparation of phenyl 7V-[4-[4-[l-(5-fluoropyridin-3-yl)sulfonylcyclopropyl]-6-[(3<S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl Λ/-[4-[4-[ 1 -(S-fluoropyridin-S-yDsulfonylcvclopropyll-ό-rfS^-S-methylmorpholin^- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000422_0001
To a solution of 4-[4-[l-(5-fiuoropyridin-3-yl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]aniline (220 mg, 0.47 mmol) in 1,4-dioxane (5 mL) was added sodium bicarbonate (59 mg, 0.70 mmol) and phenyl chloroformate (0.059 mL, 0.47 mmol) and the reaction stirred at RT for 2 hours. The reaction mixture was diluted with DCM (10 mL), and washed with water (10 mL), the organic layer dried (MgSO4), filtered and evaporated. The crude solid was triturated with diethyl ether to give a solid which was collected by filtration and dried under vacuum to give the desired product as a white solid (280 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO-dg) δ 1.21 (3H, d), 1.65 - 1.69 (2H, m), 2.00 - 2.03 (2H, m), 3.15 - 3.22 (IH, m), 3.44 - 3.52 (IH, m), 3.62 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.21 (IH, d), 4.51 (IH, s), 6.75 (IH, s), 7.24 - 7.27 (3H, m), 7.45 (2H, t), 7.53 (2H, d), 7.85 (2H, d), 8.20 - 8.23 (IH, m), 8.81 (IH, s), 8.94 (IH, d), 10.40 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 590; HPLC tR = 2.96 min. 4- [4- r 1 -(5 -Fluoropyridin-3 -vOsulfonylcvclopropyli -6- [(36^-3 -methylmorpholin-4- yllpyrimidin-2-vH aniline
Figure imgf000423_0001
To a solution of 2-chloro-4-[l-(5-fluoropyridin-3-yl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidine (700 mg, 1.70 mmol) in DMF (0.48 mL), DME (9.33 mL), water (4.0 mL) and ethanol (2.67 mL) was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)aniline (483mg, 2.2 mmol), sodium carbonate (2.5 mL, 5.09 mmol) and dichlorobis(triphenylphosphine)palladium(II) (59.5 mg, 0.08 mmol) and the suspension heated at 95°C for 2 hours. The reaction mixture was cooled to RT, diluted with ethyl acetate (10 mL) and washed with water (2 x 10 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 5 to 60% ethyl acetate in isohexane, to give the desired material as a cream solid (160 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.61 - 1.65 (2H, m), 1.96 - 2.00 (2H, m), 3.11 - 3.18 (IH, m), 3.42 - 3.49 (IH, m), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.14 (IH, d), 4.46 (IH, s), 5.53 (2H, s), 6.49 (2H, d), 6.60 (IH, s), 7.57 (2H, d), 8.16 - 8.20 (IH, m), 8.80 - 8.80 (IH, m), 8.93 (IH, d) LCMS Spectrum: m/z (ESI+) (M+H)+ = 470; HPLC tR = 2.30 min.
2-Chloro-4- r 1 -(5 -fluoropyridin-3 -vOsulfonylcvclopropyli -6- [(36^-3 -methylmorpholin-4- yllpyrimidine
Figure imgf000423_0002
2-Chloro-4- [(5 -fluoropyridin-3 -yl)sulfonylmethyl] -6- [(35)-3-methylmorpholin-4- yljpyrimidine (950 mg, 2.40 mmol) was dissolved in toluene (15 mL) and ION sodium hydroxide solution (2.45 mL, 24.5 mmol) added, followed by 1 ,2-dibromoethane (0.42 mL, 4.91 mmol). The reaction was stirred at 600C for 3 hours. The reaction mixture was evaporated to dryness, redissolved in ethyl acetate (200 mL), and washed sequentially with water (200 mL) and saturated brine solution (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in DCM, to give the desired product as a white solid (700 mg,).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 1.61 - 1.63 (2H, m), 1.94 - 1.97 (2H, m), 3.16 (IH, dt), 3.40 (IH, dt), 3.55 (IH, dd), 3.70 (IH, d), 3.91 (IH, dd), 4.00 (IH, s), 4.33 (IH, s), 6.78 (IH, s), 8.21 (IH, dt), 8.79 (IH, t), 8.96 (IH, d) LCMS Spectrum: m/z (ESI+)(M+H)+ 413, HPLC tR = 2.14 min
2-Chloro-4-r(5-fluoropyridin-3-yl)sulfonylmethyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000424_0001
3-Chloroperoxybenzoic acid (2.107 g, 9.16 mmol) was added portion- wise to 2-chloro-4-[(5- fluoropyridin-3-yl)sulfanylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (1.3 g, 3.66 mmol), in DCM (18.32 mL) and the reaction stirred at RT for 2 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (50 mL) and the organic layer dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% ethyl acetate in DCM, to give the desired material as a white solid (0.940 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 3.16 - 3.23 (IH, m), 3.44 (IH, dt), 3.59 (IH, dd), 3.72 (IH, d), 3.93 (IH, dd), 3.97 (IH, s), 4.22 (IH, s), 4.84 (2H, s), 6.84 (IH, s), 8.21 (IH, dt), 8.80 (IH, t), 8.99 (IH, d) LCMS Spectrum: m/z (ESI+)(M+H)+ 387, HPLC tR = 1.86 min 2-Chloro-4-r(5-fluoropyridin-3-yl)sulfanylmethyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000425_0001
Potassium hydroxide (1.235 g, 22.01 mmol) was added to (5-fluoropyridin-3-yl) dimethylaminomethanedithioate (1.19 g, 5.50 mmol) in ethanol (27.5 mL) at RT. The resulting solution was heated at 650C for 4 hours The reaction was cooled and 2-chloro-4- (iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (2.72 g, 7.70 mmol) added. The reaction mixture was then stirred at RT for 4 hours. Water (50 mL) was added and the reaction mixture extracted with DCM (2 x 100 mL). The combined organics were dried (MgSO4), filtered and concentrated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in DCM, to give the desired material as a white waxy solid (1.5 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.14 (3H, d), 3.11 - 3.18 (IH, m), 3.37 - 3.44 (IH, m), 3.56 (IH, dd), 3.70 (IH, d), 3.91 (IH, dd), 3.95 (IH, s), 4.21 (3H, $mult$), 6.81 (IH, s), 7.89 (IH, dt), 8.40 - 8.42 (2H, m)
LCMS Spectrum: m/z (ESI+)(M+H)+ 355, HPLC tR = 2.12 min
(5 -Fluoropyridin-3 -yl) dimethylaminomethanedithioate
I
FvfTYsγN>
N 3-Bromo-5-fluoropyridine (2.26g, 12.84 mmol) was added portion- wise to isopropylmagnesium chloride - lithium chloride complex (14% in THF, 13.32 mL, 12.84 mmol) at O0C over a period of 2 minutes under a nitrogen atmosphere. The resulting solution was warmed to RT over a period of 2 hours then cooled to 00C and tetramethylthiuram disulfide (3.09 g, 12.84 mmol) in DCM (12.84 mL) added. The reaction was warmed to RT and stirred for 3 hours. The reaction was poured into a saturated aqueous solution of ammonium chloroid (50 mL) and the aqueous layer extracted with DCM (2 x 10OmL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% ethyl acetate in DCM, to give the desired material as a cream waxy solid (1.69 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 3.48 (3H, s), 3.52 (3H, s), 7.89 (IH, ddd), 8.41 (IH, t), 8.71 (IH, d) LCMS Spectrum: m/z (ESI+)(M+H)+ 217, HPLC tR = 1.80 min
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Example 18: l-[4-[4-Q-tert-Butylsulfonylcvclopropyl)-6-[(3S)-3-methylmorpholin-4- yll pyrimidin-2-yll phenyll -3-cvclopropylurea
Figure imgf000426_0001
Cyclopropylamine (57 mg, 1.0 mmol) was added to phenyl Λ/-[4-[4-(l-tert- butylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (120 mg, 0.22 mmol) and triethylamine (0.20 mL, 1.4 mmol) in DMF (1 mL). The reaction mixture was allowed to stand at RT for 4 days. The crude product was purified by preparative
HPLC, using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents, to afford the desired material as a colourless solid (63 mg).
NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 0.40 - 0.44 (2H, m), 0.63 - 0.68 (2H, m), 1.21 -1.27 (12H, m), 1.47 - 1.53 (IH, m), 1.62 - 1.69 (3H, m), 2.54 - 2.60 (IH, m), 3.15 -
3.24 (IH, m), 3.46 - 4.54 (IH, m), 3.63 - 3.67 (IH, m), 3.77 (IH, d), 3.95 - 4.02 (IH, d), 4.18
(IH, d), 4.43 (IH, br, s), 6.44 (IH, d), 6.97 (IH, s), 7.51 (2H, d), 8.23 (2H, d), 8.56 (IH, s).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 514; HPLC tR = 2.39 min. mTOR Kinase Assay (Echo): 0.00135μM
The following compounds were made in an analogous fashion from phenyl 7V-[4-[4-(l-tert- butylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamateand the appropriate amine.
Figure imgf000427_0001
Figure imgf000428_0001
Figure imgf000429_0001
Example 18a: 1H NMR (399.9 MHz, DMSOd6) δ 1.21 - 1.27 (12H, m), 1.47 - 1.53 (IH, m), 1.59 - 1.68 (3H, m), 1.81 - 1.91 (2H, m), 2.17 - 2.26 (2H, m), 3.15 - 3.23 (IH, m), 3.45 - 3.54 (IH, m), 3.62 - 3.68 (IH, m), 3.77 (IH, d), 3.95 - 4.02 (IH, m), 4.10 - 4.24 (2H, m), 4.42 (IH, br, s), 6.47 (IH, d), 6.97 (IH, s), 7.48 (2H, d), 8.22 (2H, d), 8.57 (IH, s). mTOR Kinase Assay (Echo): 0.00967μM
Example 18b: 1U NMR (399.9 MHz, DMSOd6) δ 1.25 (12H, m), 1.49 - 1.54 (IH, m), 1.63 - 1.73 (3H, m), 3.16 - 3.25 (IH, m), 3.48 - 3.54 (IH, m), 3.64 - 3.68 (IH, m), 3.78 (IH, d), 3.98 - 4.01 (IH, m), 4.20 (IH, d), 4.43 (IH, br, s), 7.00 (IH, s), 7.03 - 7.06 (IH, m), 7.58 (IH, d), 7.65 (2H, d), 7.78 (IH, t), 8.29 - 8.34 (3H, m), 9.45 (IH, s), 10.57 (IH, s). mTOR Kinase Assay (Echo): 0.0147μM
Example 18c: 1R NMR (399.9 MHz, DMSOd6) δ 0.90 (6H, d), 1.22 - 1.25 (12H, m), 1.47 - 1.53 (IH, m), 1.62 - 1.75 (4H, m), 2.95 (2H, t), 3.16 - 3.23 (IH, m), 3.47 - 3.53 (IH, m), 3.63 - 3.67 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.18 (IH, d), 4.42 (IH, br, s), 6.25 (IH, t), 6.97 (IH, s), 7.50 (2H, d), 8.23 (2H, d), 8.66 (IH, s). mTOR Kinase Assay (Echo): 0.032μM
Example 18d: 1R NMR (399.9 MHz, DMSOd6) δ 1.12 (6H, d), 1.21 - 1.26 (12H, m), 1.45 - 1.53 (IH, m), 1.62 - 1.71 (3H, m), 3.13 - 3.25 (IH, m), 3.44 - 3.53 (IH, m), 3.62 - 3.67 (IH, m), 3.73 - 3.82 (2H, m), 3.95 - 4.02 (IH, m), 4.18 (IH, d), 4.42 (IH, br, s), 6.07 (IH, d), 6.97
(IH, s), 7.48 (2H, d), 8.23 (2H, d), 8.55 (IH, s). mTOR Kinase Assay (Echo): 0.0151μM
Example 18e: 1R NMR (399.9 MHz, DMSOd6) δ 1.07 (3H, t), 1.23 (3H, d), 1.25 (9H, s), 1.44 - 1.53 (IH, m), 1.60 - 1.71 (3H, m), 3.08 - 3.25 (3H, m), 3.49 (IH, t), 3.65 (IH, d), 3.77
(IH, d), 3.96 - 3.99 (IH, m), 4.18 (IH, d), 4.43 (IH, br, s), 6.17 (IH, t), 6.97 (IH, s), 7.50
(2H, d), 8.23 (2H, d), 8.68 (IH, s). mTOR Kinase Assay (Echo): 0.000654μM
Example 18f: 1U NMR (399.9 MHz, DMSO-d6) δ 1.20 - 1.28 (12H, m), 1.47 - 1.54 (IH, m), 1.62 - 1.69 (3H, m), 2.19 (6H, s), 2.34 (2H, t), 3.14 - 3.24 (3H, m), 3.45 - 3.53 (IH, m), 3.62 -
3.67 (IH, m), 3.77 (IH, d), 3.95 - 4.00 (IH, m), 4.18 (IH, d), 4.42 (IH, br, s), 6.17 (IH, t),
6.97 (IH, s), 7.49 (2H, d), 8.23 (2H, d), 8.91 (IH, s). mTOR Kinase Assay (Echo): 0.12μM
Example 18g: 1R NMR (399.9 MHz, DMSO-d6) δ 1.22 - 1.25 (12H, m), 1.48 - 1.52 (IH, m), 1.62 - 1.69 (3H, m), 3.16 - 3.23 (3H, m), 3.45 - 3.53 (3H, m), 3.63 - 3.67 (IH, m), 3.77 (IH, d), 3.97 - 4.00 (IH, m), 4.18 (IH, d), 4.43 (IH, br, s), 4.74 (IH, t), 6.26 (IH, t), 6.97 (IH, s),
7.49 (2H, d), 8.23 (2H, d), 8.82 (IH, s). mTOR Kinase Assay (Echo): 0.00123μM
Example 18h: 1U NMR (399.9 MHz, DMSO-de) δ 0.90 (3H, t), 1.19 - 1.28 (12H, m), 1.42 - 1.54 (3H, m), 1.61 - 1.69 (3H, m), 3.07 (2H, q), 3.13 - 3.23 (IH, m), 3.45 - 3.53 (IH, m), 3.61
- 3.68 (IH, m), 3.77 (IH, d), 3.94 - 4.01 (IH, m), 4.18 (IH, d), 4.42 (IH, br, s), 6.21 (IH, t), 6.97 (IH, s), 7.50 (2H, d), 8.23 (2H, d), 8.67 (IH, s). mTOR Kinase Assay (Echo): 0.00664μM
Example 18i: 1R NMR (399.9 MHz, DMSO-d6) δ 1.22 (3H, d), 1.25 (9H, s), 1.45 - 1.55 (IH, m), 1.60 - 1.69 (3H, m), 2.67 (3H, d), 3.14 - 3.23 (IH, m), 3.50 (IH, t), 3.65 (IH, d), 3.77 (IH, d), 3.94 - 3.99 (IH, m), 4.18 (IH, d), 4.43 (IH, br, s), 6.08 (IH, d), 6.97 (IH, s), 7.51 (2H, d), 8.23 (2H, d), 8.76 (IH, s). mTOR Kinase Assay (Echo): 0.00555μM
Example 18j: 1U NMR (399.9 MHz, CDCl3) δ 1.31 (3H, d), 1.35 (9H, s), 1.50 - 1.71 (2H, m), 1.81 - 1.91 (2H, m), 3.23 - 3.33 (IH, m), 3.53 - 3.62 (IH, m), 3.68 - 3.74 (IH, m), 3.81 (IH, d), 3.98 - 4.05 (IH, m), 4.17 (IH, d), 4.42 (IH, br, s), 7.03 (IH, s), 7.23 (IH, s), 7.28 (IH, s), 7.48 (2H, d), 7.52 - 7.55 (4H, m), 8.38 (2H, d). mTOR Kinase Assay (Echo): 0.0303μM
Example 18k: 1R NMR (399.9 MHz, DMSOd6) δ 1.20 - 1.27 (18H, m), 1.48 - 1.52 (IH, m), 1.62 - 1.69 (3H, m), 3.14 - 3.23 (IH, m), 3.40 (2H, d), 3.45 - 3.53 (IH, m), 3.63 - 3.67 (IH, m), 3.77 (IH, d), 3.95 - 4.01 (IH, m), 4.18 (IH, d), 4.41 (IH, br, s), 4.96 (IH, t), 6.01 (IH, s), 6.97 (IH, s), 7.46 (2H, d), 8.22 (2H, d), 8.75 (IH, s). mTOR Kinase Assay (Echo): 0.0113μM
Example 181: 1U NMR (399.9 MHz, DMSOd6) δ 1.22 - 1.25 (12H, m), 1.48 - 1.52 (IH, m), 1.57 - 1.68 (5H, m), 3.15 - 3.23 (3H, m), 3.43 - 3.54 (3H, m), 3.63 - 3.67 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.18 (IH, d), 4.43 (IH, br, s), 4.49 (IH, t), 6.21 (IH, t), 6.97 (IH, s), 7.50 (2H, d), 8.23 (2H, d), 8.73 (IH, s). mTOR Kinase Assay (Echo): 0.0102μM
Example 18m: 1H NMR (399.9 MHz, DMSO-de) δ 1.21 - 1.29 (12H, m), 1.48 - 1.55 (IH, m), 1.61 - 1.71 (3H, m), 3.16 - 3.25 (IH, m), 3.49 (IH, t), 3.66 (IH, d), 3.74 - 3.83 (4H, m), 3.99 (IH, d), 4.19 (IH, d), 4.43 (IH, br, s), 6.99 (IH, s), 7.39 (IH, s), 7.55 (2H, d), 7.77 (IH, s), 8.27 (2H, d), 8.39 (IH, s), 8.85 (IH, s). mTOR Kinase Assay (Echo): 0.00315μM
The preparation of phenyl Λ/-[4-[4-(l-tert-butylsulfonylcyclopropyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N- [4- r4-(l-tert-butylsulfonylcvclopropyl)-6- [(36^-3 -methylmorpholin-4-vHpyrimidin- 2-vHphenyll carbamate
Figure imgf000431_0001
Phenyl chloroformate (0.809 mL, 6.44 mmol) was added to 4-[4-(l-tert- butylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (2.52g, 5.85 mmol) and sodium hydrogen carbonate (0.738 g, 8.78 mmol) in dioxane (45 mL) at RT. The mixture was stirred at RT for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 10% - 100% ethyl acetate in isohexane, to give the desired material as a near colourless solid (2.99 g).
NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.31 - 1.34 (12H, m), 1.48 - 4.58 (IH, m), 1.62 - 1.70 (IH, m), 1.80 - 1.89 (2H, m), 3.31 (IH, dt), 3.60 (IH, dt), 3.75 (IH, dd), 3.82 (IH, d), 4.04 (IH, dd), 4.20 (IH, d), 4.45 (IH, br), 7.06 - 7.11 (2H, m), 7.19 - 7.28 (3H, m), 7.41 (2H, t), 7.54 (2H, d), 8.40 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 551; HPLC tR = 3.06 min.
4-r4-(l-tert-Butylsulfonylcvclopropyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-2- yl] aniline
Figure imgf000432_0001
Dichlorobis(triphenylphosphine)-palladium(II) (0.185 g, 0.26 mmol) was added to 4-(l-tert- butylsulfonylcyclopropyl)-2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (1.97 g, 5.27 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.501 g, 6.85 mmol) and 2M aqueous sodium carbonate (9.48 mL, 18.97 mmol) in DMF (11 mL), DME (11 mL), ethanol (11 mL) and water (27.5 mL) at RT under nitrogen. The reaction was purged with nitrogen for 15 minutes and the resulting mixture was stirred at 800C for 16 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 25% - 100% ethyl acetate in isohexane, to give the desired material as a yellow solid (2.24 g). NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.31 (3H, d), 1.32 (9H, s), 1.44 - 1.55 (IH, m), 1.60 - 1.68 (IH, m), 1.77 - 1.86 (2H, m), 3.28 (IH, dt), 3.59 (IH, dt), 3.74 (IH, dd), 3.81 (IH, d), 3.90 (2H, s), 4.03 (IH, dd), 4.18 (IH, d), 4.44 (IH, br), 6.71 (2H, d), 6.99 (IH, s), 8.24 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 431 ; HPLC tR = 2.43 min.
4-(l-tert-Butylsulfonylcvclopropyl)-2-chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000433_0001
1 ,2-Dibromoethane (0.349 mL, 15.40 mmol) was added to 4-(tert-butylsulfonylmethyl)-2- chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (2.68 g, 7.7 mmol) in toluene (40 mL) followed by tetrabutylammonium bromide (0.248 g, 0.77 mmol) and sodium hydroxide concentrate (7.70 mL, 77 mmol). The reaction mixture was vigorously stirred and heated at 600C for 1 hour. The reaction mixture was cooled and diluted with ethyl acetate and washed with water. The organic solution was concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 0 to 50% ethyl acetate in DCM, to give the desired material as a colourless solid (1.97 g).
NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.20 - 1.35 (12H, m), 1.46 - 1.50 (IH, m), 1.52 - 1.61 (IH, m), 1.77 - 1.86 (2H, m), 3.26 (IH, dt), 3.54 (IH, dt), 3.68 (IH, dd), 3.78 (IH, d), 3.98 - 4.08 (2H, m), 4.29 (IH, br, s), 7.14 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 374; HPLC tR = 2.34 min.
4-(tert-Butylsulfonylmethyl)-2-chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000433_0002
A solution of hydrogen peroxide (35% aqueous solution, 9.48 mL, 107.30 mmol) was added dropwise to a stirred solution of 4-(tert-butylsulfanylmethyl)-2-chloro-6-[(35)-3- methylmorpholin-4-yl]pyrimidine (9.82 g, 31.1 mmol), sodium tungstate dihydrate (0.205 g, 0.62 mmol) and sulfuric acid (0.6 mL, IM, 0.6 mmol) in dioxane (80 mL). The mixture was heated at 550C for 1 hour then diluted with water and cooled. A solution of sodium metabisulfite (10% w/v) was added to destroy remaining peroxide. The solution was extracted with DCM, dried (MgSO4), filtered and concentrated in vacuo to give the desired material as a near colourless gum (9.34 g).
NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.33 (3H, d), 1.44 (9H, s), 3.29 (IH, dt), 3.54 (IH, dt), 3.69 (IH, dd), 3.78 (IH, d), 3.97 - 4.13 (2H, m), 4.21 (2H, s), 4.30 (IH, br, s), 6.71 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 348; HPLC tR = 1.82 min.
4-(tert-Butylsulfanylmethyl)-2-chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000434_0001
DIPEA (8.61 mL, 49.78 mmol) was added to 2-methyl-2-propanethiol (4.21 mL, 37.33 mmol), in DMF (55 mL) at RT under nitrogen. The resulting solution was stirred at RT for 20 minutes. 2-Chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (11.00 g, 31.11 mmol) was added to the reaction mixture in one portion. The mixture was stirred for 4 hours at RT then at 6O0C for 1.5 hours before being partitioned between ethyl acetate and water. The organic layer was washed with additional water and then dried (MgSO4), filtered and evaporated to give the desired material as a yellow gum (10.02 g). The material was used without further purification.
NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.31 (3H, d), 1.34 (9H, s), 3.27 (IH, dt), 3.54 (IH, dt), 3.66 - 3.71 (3H, m), 3.78 (IH, d), 3.97 - 4.07 (2H, m), 4.31 (IH, br, s), 6.56 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 316, 318; HPLC tR = 2.61 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier. Example 19 : 3-C vclopropyl- 1- [4- [4- [ l-(3,5-difluor ophenyDsulfonylcyclopropyll -6- [(3S)- 3-methylmorpholin-4-yll pyrimidin-2-yll phenyll urea
Figure imgf000435_0001
Phenyl Λ/-[4-[4-[l-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] carbamate (120 mg, 0.22 mmol) was added to a mixture of cyclopropylamine (59 mg, 1.03 mmol) and triethylamine (0.2 mL, 1.49 mmol) in DMF (1 mL) at RT. The reaction mixture was allowed to stand at RT for 65 hours. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents, to give the desired material as a colourless solid (55 mg).
NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 0.41 - 0.44 (2H, m), 0.63 - 0.68 (2H, m), 1.20 (3H, d), 1.62 -1.69 (2H, m), 1.96 - 2.00 (2H, m), 2.53 - 2.59 (IH, m), 3.13 - 3.23 (IH, m), 3.42 - 3.50 (IH, m), 3.59 - 3.63 (IH, m), 3.75 (IH, d), 3.94 - 4.00 (IH, m), 4.18 (IH, d), 4.48 (IH, br, s), 6.42 (IH, d), 6.67 (IH, s), 7.42 (2H, d), 7.54 - 7.59 (2H, m), 7.70 - 7.76 (IH, m), 7.82 (2H, d), 8.53 (IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 572; HPLC tR = 2.72 min. mTOR Kinase Assay (Echo): 0.00131μM
The following compounds were made in an analogous fashion from phenyl 7V-[4-[4-[l-(3,5- difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000436_0001
Figure imgf000437_0001
Figure imgf000438_0001
Example 19a: 1H NMR (399.9 MHz, DMSOd6) δ 1.20 (3H, d), 1.58 - 1.70 (4H, m), 1.80 -
1.90 (2H, m), 1.95 - 2.02 (2H, m), 2.16 - 2.25 (2H, m), 3.10 - 3.20 (IH, m), 3.40 - 3.48 (IH, m), 3.58 - 3.62 (IH, m), 3.75 (IH, d), 3.92 - 3.98 (IH, m), 4.10 - 4.20 (2H, m), 4.48 (IH, br, s), 6.45 (IH, d), 6.67 (IH, s), 7.39 (2H, d), 7.55 - 7.57 (2H, m), 7.71 - 7.75 (IH, m), 7.82 (2H, d), 8.55 (IH, s). mTOR Kinase Assay (Echo): 0.00425μM
Example 19b: 1R NMR (399.9 MHz, DMSOd6) δ 1.21 (3H, d), 1.62 - 1.71 (2H, m), 1.96 -
2.03 (2H, m), 3.13 - 3.23 (IH, m), 3.42 - 3.51 (IH, m), 3.60 - 3.65 (IH, m), 3.76 (IH, d), 3.93 - 3.99 (IH, m), 4.19 (IH, d), 4.50 (IH, br, s), 6.71 (IH, s), 7.03 - 7.06 (IH, m), 7.51 - 7.59
(5H, m), 7.70 - 7.80 (2H, m), 7.92 (2H, d), 8.31 (IH, d), 9.44 (IH, s), 10.55 (IH, s). mTOR Kinase Assay (Echo): 0.00119μM
Example 19c: 1U NMR (399.9 MHz, DMSOd6) δ 0.89 (3H, s), 0.90 (3H, s), 1.20 (3H, d),
1.63 - 1.75 (3H, m), 1.94 - 2.00 (2H, m), 2.95 (2H, t), 3.11 - 3.21 (IH, m), 3.41 - 3.50 (IH, m), 3.57 - 3.63 (IH, m), 3.75 (IH, d), 3.92 - 3.98 (IH, m), 4.17 (IH, d), 4.48 (IH, br, s), 6.23
(IH, t), 6.67 (IH, s), 7.40 (2H, d), 7.52 - 7.59 (2H, m), 7.68 - 7.76 (IH, m), 7.83 (2H, d), 8.64
(IH, s). mTOR Kinase Assay (Echo): 0.0214μM
Example 19d: 1R NMR (399.9 MHz, DMSO-dg) δ 1.11 (3H, s), 1.13 (3H, s), 1.20 (3H, d), 1.62 - 1.69 (2H, m), 1.95 - 2.00 (2H, m), 3.11 - 3.20 (IH, m), 3.42 - 3.50 (IH, m), 3.57 - 3.63 (IH, m), 3.72 - 3.82 (2H, m), 3.92 - 3.98 (IH, m), 4.17 (IH, d), 4.48 (IH, br, s), 6.05 (IH, d),
6.67 (IH, s), 7.39 (2H, d), 7.52 - 7.59 (2H, m), 7.69 - 7.76 (IH, m), 7.82 (2H, d), 8.53 (IH, s). mTOR Kinase Assay (Echo): 0.00318μM
Example 19e: 1R NMR (399.9 MHz, DMSOd6) δ 1.07 (3H, t), 1.20 (3H, d), 1.63 - 1.68 (2H, m), 1.95 - 2.00 (2H, m), 3.09 - 3.22 (3H, m), 3.37 (IH, d), 3.42 - 3.49 (IH, m), 3.58 - 3.63
(IH, m), 3.75 (IH, d), 3.93 - 3.98 (IH, m), 4.17 (IH, d), 4.49 (IH, br, s), 6.15 (IH, t), 6.67
(IH, s), 7.40 (2H, d), 7.54 - 7.57 (2H, m), 7.69 - 7.76 (IH, m), 7.82 (2H, d), 8.65 (IH, s). mTOR Kinase Assay (Echo): 0.00135μM
Example 19f: 1R NMR (399.9 MHz, DMSOd6) δ 1.20 (3H, d), 1.63 - 1.70 (2H, m), 1.95 - 2.00 (2H, m), 2.19 (6H, s), 2.34 (2H, t), 3.11 - 3.23 (3H, m), 3.41 - 3.50 (IH, m), 3.58 - 3.63
(IH, m), 3.75 (IH, d), 3.92 - 3.98 (IH, m), 4.17 (IH, d), 4.49 (IH, br, s), 6.16 (IH, t), 6.67
(IH, s), 7.40 (2H, d), 7.51 - 7.58 (2H, m), 7.68 - 7.76 (IH, m), 7.83 (2H, d), 8.88 (IH, s). mTOR Kinase Assay (Echo): 0.0804μM
Example 19g: 1U NMR (399.9 MHz, DMSO-d6) δ 1.20 (3H, d), 1.66 (2H, s), 1.92 - 2.01 (2H, m), 3.11 - 3.20 (3H, m), 3.40 - 3.51 (3H, m), 3.57 - 3.64 (IH, m), 3.75 (IH, d), 3.92 - 3.99
(IH, m), 4.17 (IH, d), 4.48 (IH, br, s), 4.74 (IH, t), 6.24 (IH, t), 6.67 (IH, s), 7.40 (2H, d),
7.50 - 7.59 (2H, m), 7.68 - 7.74 (IH, t), 7.83 (2H, d), 8.79 (IH, s). mTOR Kinase Assay (Echo): 0.000274μM
Example 19h: 1R NMR (399.9 MHz, DMSO-d6) δ 0.89 (3H, t), 1.20 (3H, d), 1.41 - 1.51 (2H, m), 1.66 (2H, s), 1.94 - 2.00 (2H, m), 3.07 (2H, q), 3.12 - 3.17 (IH, m), 3.42 - 3.49 (IH, m),
3.58 - 3.64 (IH, m), 3.75 (IH, d), 3.92 - 3.98 (IH, m), 4.17 (IH, d), 4.48 (IH, br, s), 6.20 (IH, t), 6.67 (IH, s), 7.40 (2H, d), 7.52 - 7.61 (2H, m), 7.68 - 7.76 (IH, m), 7.82 (2H, d), 8.64 (IH, s). mTOR Kinase Assay (Echo): 0.00246μM Example 19i: 1U NMR (399.9 MHz, DMSO-de) δ 1.20 (3H, d), 1.61 - 1.70 (2H, m), 1.94 -
2.01 (2H, m), 2.67 (3H, d), 3.10 - 3.20 (IH, m), 3.40 - 3.49 (IH, m), 3.58 - 3.63 (IH, m), 3.75
(IH, d), 3.92 - 3.98 (IH, m), 4.17 (IH, d), 4.48 (IH, br, s), 6.02 - 6.08 (IH, m), 6.67 (IH, s),
7.41 (2H, d), 7.53 - 7.58 (2H, m), 7.68 - 7.75 (IH, m), 7.82 (2H, d), 8.73 (IH, s). mTOR Kinase Assay (Echo): 0.00152μM Example 91j: 1R NMR (399.9 MHz, DMSO-d6) δ 1.21 (3H, d), 1.67 (2H, s), 1.94 - 2.03 (2H, m), 3.13 - 3.22 (IH, m), 3.42 - 3.50 (IH, m), 3.59 - 3.64 (IH, m), 3.76 (IH, d), 3.93 - 3.98 (IH, m), 4.19 (IH, d), 4.49 (IH, br, s), 6.70 (IH, s), 7.50 (2H, d), 7.54 - 7.61 (2H, m), 7.62 - 7.78 (5H, m), 7.91 (2H, d), 9.04 (IH, s), 9.12 (IH, s). mTOR Kinase Assay (Echo): 0.0199μM
Example 19k: 1R NMR (399.9 MHz, DMSOd6) δ 1.19 (3H, d), 1.23 (6H, s), 1.62 - 1.68 (2H, m), 1.94 - 1.98 (2H, m), 3.13 - 3.20 (IH, m), 3.38 (2H, d), 3.42 - 3.50 (IH, m), 3.58 - 3.64 (IH, m), 3.75 (IH, d), 3.93 - 3.98 (IH, m), 4.17 (IH, d), 4.48 (IH, br, s), 4.94 (IH, t), 5.97 (IH, s), 7.35 (2H, d), 7.52 - 7.58 (2H, m), 7.69 - 7.77 (IH, m), 7.81 (2H, d), 8.71 (IH, s). mTOR Kinase Assay (Echo): 0.00415μM
Example 191: 1H NMR (399.9 MHz, DMSO-(I6) δ 1.20 (3H, d), 1.55 - 1.70 (4H, m), 1.95 - 2.01 (2H, m), 3.13 - 3.21 (3H, m), 3.42 - 3.50 (3H, m), 3.58 - 3.65 (IH, m), 3.75 (IH, d), 3.93
- 3.99 (IH, m), 4.18 (IH, d), 4.43 - 4.52 (2H, m), 6.19 (IH, t), 6.67 (IH, s), 7.39 (2H, d), 7.52
- 7.61 (2H, m), 7.69 - 7.78 (IH, m), 7.83 (2H, d), 8.69 (IH, s). mTOR Kinase Assay (Echo): 0.00152μM
Example 19m: 1U NMR (399.9 MHz, DMSO-d6) δ 1.20 (3H, d), 1.60 - 1.69 (2H, m), 1.94 - 2.01 (2H, m), 3.13 - 3.21 (IH, m), 3.42 - 3.50 (3H, m), 3.58 - 3.64 (IH, m), 3.73 - 3.81 (4H, m), 3.93 - 3.98 (IH, m), 4.18 (IH, d), 4.49 (IH, br, s), 6.67 (IH, s), 7.37 (IH, s), 7.43 (2H, d), 7.51 - 7.60 (2H, m), 7.68 - 7.78 (2H, m), 7.76 (2H, d), 8.35 (IH, s), 8.81 (IH, s). mTOR Kinase Assay (Echo): 0.000944μM
The preparation of phenyl N-[4-[4-[l-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamateis described below.
Phenyl Λ/-[4-[4-[l-(3.5-difluorophenvπsulfonylcvclopropyll-6-[(36f)-3-methylmorpholin-4- vHpγrimidin-2-vHphenvH carbamate
Figure imgf000440_0001
Phenyl chloroformate (0.764 mL, 6.08 mmol) was added to 4-[4-[l-(3,5- difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (2.69 g, 5.53 mmol) and sodium hydrogen carbonate (0.697 g, 8.29 mmol) in dioxane (40 mL) at RT. The resulting slurry was stirred at RT for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 25% - 80% ethyl acetate in isohexane, to give the desired material as a yellow dry film (3.07 g). NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.32 (3H, d), 1.61 - 1.66 (IH, m), 1.68 - 1.73 (IH, m), 1.94 - 2.05 (2H, m), 3.30 (IH, dt), 3.61 (IH, dt), 3.75 (IH, dd), 3.84 (IH, d), 4.05 (IH, dd), 4.16 (IH, d), 4.43 (IH, br, s), 6.79 (IH, s), 6.94 - 7.03 (2H, m), 7.18 - 7.28 (3H, m), 7.30 - 7.35 (2H, m), 7.37 - 7.47 (4H, m), 8.10 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 607; HPLC tR = 3.12 min.
4- [4- [ 1 -(3.5 -DifluorophenvDsulfonylcvclopropyll -6- [(36^-3 -methylmorpholin-4-yllpyrimidin- 2-vHaniline
Figure imgf000441_0001
A stream of nitrogen was passed through a mixture of 2-chloro-4-[l-(3,5- difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (2.5 g, 5.82 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.656 g, 7.56 mmol) and 2M aqueous sodium carbonate (10.47 mL, 20.94 mmol) in DMF (11 mL), DME (11 mL), ethanol (11 mL) and water (27.5 mL) at RT for 15 minutes. Dichlorobis(triphenylphosphine)- palladium(II) (0.204 g, 0.29 mmol) was added in one portion and the reaction mixture stirred at 800C under nitrogen for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 25% - 60% ethyl acetate in isohexane, to give the desired material as a near colourless solid (2.76 g). NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.31 (3H, d), 1.62 - 1.66 (IH, m), 1.70 - 1.74 (IH, m), 1.93 - 2.03 (2H, m), 3.28 (IH, dt), 3.59 (IH, dt), 3.72 - 3.74 (IH, dd), 3.79 - 3.89 (3H, m), 4.03 (IH, dd), 4.10 - 4.18 (IH, m), 4.37 - 4.45 (IH, m), 6.61 - 6.65 (2H, m), 6.73 (IH, s), 6.98 (IH, tt), 7.31 - 7.36 (2H, m), 7.93 - 7.96 (2H, m) LCMS Spectrum: m/z (ESI+)(M+H)+ = 487; HPLC tR = 2.86 min. 2-Chloro-4- r 1 -(3 ,5 -difluorophenyDsulfonylcvclopropyli -6- [(36^-3 -methylmorpholin-4- yllpyrimidine
Figure imgf000442_0001
1 ,2-Dibromoethane (1.0 mL, 11.6 mmol) was added to 2-chloro-4-[(3,5- difluorophenyl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (3.68 g, 9.11 mmol) in toluene (55 mL) followed by tetrabutylammonium bromide (0.294 g, 0.91 mmol) and sodium hydroxide concentrate (9.00 mL, 90 mmol). The reaction mixture was stirred at RT overnight. The mixture was then heated to 8O0C and vigorous stirring continued for 3 hours. A further quantity of 1 ,2-dibromoethane (1 mL, 11.6 mmol) was added and heating was continued for a further 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic solution was concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 10 to 40% ethyl acetate in isohexane, to give the desired material as a colourless solid (3.0 g). NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.32 (3H, d), 1.56 - 1.60 (IH, m), 1.63 - 1.68 (IH, m), 1.92 - 2.01 (2H, m), 3.28 (IH, dt), 3.55 (IH, dt), 3.70 (IH, dd), 3.80 (IH, d), 4.00 - 4.09 (2H, m), 4.28 (IH, br, s), 6.87 (IH, s), 7.07 (IH, tt), 7.24 - 7.29 (2H, m) LCMS Spectrum: m/z (ESI+)(M+H)+ = 430, 432; HPLC tR = 2.55 min.
2-Chloro-4-[(3.5-difluorophenyl)sulfonylmethyll-6-[(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000442_0002
A solution of sodium tungstate dihydrate (199 mg, 0.60 mmol) in water (2 mL) was added to a stirred solution of 2-chloro-4-[(3,5-difluorophenyl)sulfanylmethyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidine (11.23 g, 30.2 mmol) and sulfuric acid (0.302 mL, 2M, 0.60 mmol) in dioxane (40 mL). Hydrogen peroxide (3.22 mL, 104.19 mmol) was added and the mixture was stirred at RT overnight. A precipitate was collected by filtration and dried in vacuo, to give the desired material as a near colourless solid (3.61 g). The filtrate was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 5% - 20% ethyl acetate in DCM, to give the desired material as a near colourless solid (7.66 g).
NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.34 (3H, s), 3.31 (IH, dt), 3.56 (IH, dt), 3.71 (IH, dd), 3.80 (IH, d), 3.98 - 4.10 (2H, m), 4.31 (2H, s), 6.55 (IH, s), 7.12 (IH, tt), 7.30 - 7.36 (2H, m).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 404, 406; HPLC tR = 2.32 min.
2-Chloro-4-r(3,5-difluorophenyl)sulfanylmethyll-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000443_0001
DIPEA (8.07 mL, 46.67 mmol) was added to 3,5-difluorobenzenethiol (5.00 g, 34.22 mmol), in DMF (55 mL) at RT under nitrogen. The resulting solution was stirred at RT for 20 minutes. 2-Chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (11.00 g, 31.11 mmol) was added to the reaction mixture in one portion. The mixture was stirred for 4 hours at RT. The reaction mixture was heated in a water bath at 6O0C for 1.5 hours before being partitioned between ethyl acetate and water. The organic solution was washed with further water then was dried (MgSO4), filtered and evaporated to give the desired material as a gum (12.24 g).
NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.27 (3H, d), 3.24 (IH, dt), 3.52 (IH, dt), 3.66 (IH, dd), 3.76 (IH, d), 3.96 - 4.04 (4H, m), 4.21 (IH, br, s), 6.41 (IH, s), 6.59 - 6.66 (IH, m), 6.80 - 6.86 (2H, m).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 372, 374; HPLC tR = 2.66 min. The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Example 20 : 3-C vclopropyl- 1- [4- [4- [(3S)-3-methylmorpholin-4-yll -6-(4- methylsulfonylpiperidin-4-yl)pyrimidin-2-yll phenyll urea
Figure imgf000444_0001
Cyclopropylamine (0.055 mL, 0.76 mmol) was added to tert-butyl 4-[6-[(35)-3- methylmorpholin-4-yl]-2-[4-(phenoxycarbonylamino)phenyl]pyrimidin-4-yl]-4- methylsulfonylpiperidine-1-carboxylate (115 mg, 0.17 mmol) and triethylamine (0.153 mL, 1.10 mmol) in DMF (1 mL) at RT and the reaction was allowed to stand overnight at RT. The mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water then concentrated under reduced pressure. The residue was dissolved in DCM (1 mL) and treated with TFA (2 mL). The resulting solution was stirred for 30 minutes at RT before being concentrated under reduced pressure. The sample was dissolved in DMF (1.5 mL) and purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents, to give the desired material as a colourless solid (26.7 mg).
NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 0.38 - 0.44 (2H, m), 0.61 - 0.68 (2H, m), 1.24 (3H, d), 1.97 - 2.10 (2H, m), 2.30 - 2.45 (2H, m), 2.57 (IH, obscured by DMSO signal), 2.73 - 2.86 (5H, m), 2.90 - 3.00 (2H, m), 3.15 - 3.25 (IH, m), 3.47 - 3.55 (IH, m), 3.63 - 3.69 (IH, m), 3.77 (IH, d), 3.95 - 4.01 (IH, m), 4.29 (IH, d), 4.56 (IH, br, s), 6.45 (IH, s), 6.79 (IH, s), 7.51 (2H, d), 8.23 (2H, d), 8.57 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 515; HPLC tR = 1.50 min. mTOR Kinase Assay (Echo): 0.0128μM
The following compounds were made in an analogous fashion from tert-butyl 4-[6-[(35)-3- methylmorpholin-4-yl]-2-[4-(phenoxycarbonylamino)phenyl]pyrimidin-4-yl]-4- methylsulfonylpiperidine-1-carboxylate and the appropriate amine.
Figure imgf000445_0001
Example 20a: 1H NMR (399.9 MHz, DMSOd6) δ 1.23 (3H, d), 1.97 - 2.09 (2H, m), 2.30 -
2.45 (2H, m), 2.67 (3H, d), 2.70 - 2.85 (5H, m), 2.90 - 3.02 (2H, m), 3.15 - 3.25 (IH, m), 3.45 - 3.55 (IH, m), 3.67 (IH, d), 3.77 (IH, d), 3.99 (IH, d), 4.28 (IH, d), 4.56 (IH, br, s), 6.05 -
6.12 (IH, m), 6.79 (IH, s), 7.51 (2H, d), 8.22 (2H, d), 8.76 (IH, s). mTOR Kinase Assay (Echo): 0.0163μM
Example 20b: 1U NMR (399.9 MHz, DMSOd6) δ 1.23 (3H, d), 1.98 - 2.09 (2H, m), 2.19
(6H, s), 2.30 - 2.47 (4H, m), 2.72 - 2.83 (5H, m), 2.92 - 3.02 (2H, m), 3.16 - 3.27 (3H, m, obscured by water signal), 3.45 - 3.57 (IH, m), 3.63 - 3.69 (IH, m), 3.77 (IH, d), 3.95 - 4.00
(IH, m), 4.28 (IH, d), 4.57 (IH, br, s), 6.17 (IH, t), 6.79 (IH, s), 7.49 (2H, d), 8.22 (2H, d),
8.91 (IH, s). mTOR Kinase Assay (Echo): 0.874μM Example 20c: 1U NMR (399.9 MHz, DMSO-d6) δ 1.23 (3H, d), 1.97 - 2.10 (2H, m), 2.32 -
2.46 (2H, m), 2.74 - 2.83 (5H, m), 2.92 - 3.02 (2H, m), 3.14 - 3.26 (3H, m), 3.41 - 3.55 (4H, m), 3.63 - 3.69 (IH, m), 3.77 (IH, d), 3.95 - 4.01 (IH, m), 4.28 (IH, d), 4.57 (IH, br, s), 4.74 (IH, t), 6.25 (IH, t), 6.79 (IH, s), 7.49 (2H, d), 8.23 (2H, d), 8.82 (IH, s). mTOR Kinase Assay (Echo): 0.00559μM
Example 2Od: 1R NMR (399.9 MHz, DMSO-de) δ 1.24 (3H, d), 2.00 - 2.09 (2H, m), 2.32 -
2.47 (2H, m), 2.75 - 2.84 (5H, m), 2.92 - 3.02 (IH, m), 3.17 - 3.26 (IH, m), 3.47 - 3.55 (IH, m), 3.64 - 3.70 (IH, m), 3.75 - 3.82 (4H, m), 3.95 - 4.03 (IH, m), 4.29 (IH, d), 4.57 (IH, br, s), 6.80 (IH, s), 7.38 (IH, d), 7.55 (2H, d), 7.77 (IH, s), 8.26 (2H, d), 8.44 (IH, s), 8.89 (IH, S). mTOR Kinase Assay (Echo): 0.0133μM
The preparation of tert-butyl 4-[6-[(35)-3-methylmorpholin-4-yl]-2-[4- (phenoxycarbonylamino)phenyl]pyrimidin-4-yl]-4-methylsulfonylpiperidine- 1 -carboxylate is described below.
tert-Butyl 4-\6-\(3S)-3 -methylmorpholin-4-yll -244- (phenoxycarbonylamino)phenyl1pyrimidin-4-vH -4-methylsulfonylpiperidine- 1 -carboxylate
Figure imgf000446_0001
Phenyl chloro formate (0.150 mL, 1.20 mmol) was added to tert-butyl 4-[2-(4-aminophenyl)- 6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]-4-methylsulfonylpiperidine-l -carboxylate (530 mg, 1.00 mmol) and sodium hydrogen carbonate (126 mg, 1.50 mmol) in dioxane (7 mL) at RT. The resulting slurry was stirred at RT for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 10% - 60% ethyl acetate in DCM, to give a colourless gum which was subsequently triturated with diethyl ether to give the desired material as a colourless solid (576 mg). NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.36 (3H, d), 1.44 (9H, s), 2.29 - 2.41 (2H, m), 2.72 (3H, s), 2.73 - 2.85 (4H, m), 3.33 (IH, dt), 3.61 (IH, dt), 3.76 (IH, dd), 3.84 (IH, d), 4.06 (IH, dd), 4.10 - 4.32 (3H, m), 4.46 (IH, br, s), 6.65 (IH, s), 7.12 (IH, br, s), 7.17 - 7.28 (3H, m), 7.36 - 7.44 (2H, m), 7.54 (2H, d), 8.35 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 652; HPLC tR = 3.11 min.
tert-Butyl 4-r2-(4-aminophenyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-yll-4- methylsulfonylpiperidine- 1 -carboxylate
Figure imgf000447_0001
A stream of nitrogen was passed through tert-butyl 4-[2-chloro-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-4-yl]-4-methylsulfonylpiperidine-l -carboxylate (500 mg, 1.05 mmol), 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (300 mg, 1.37 mmol) and 2M aqueous sodium carbonate (1.895 mL, 3.79 mmol) in DMF (2 mL), DME (2 mL), ethanol (2 mL) and water (5 mL) at RT for 15 minutes. The reaction mixture was treated with dichlorobis(triphenylphosphine)-palladium(II) (36.9 mg, 0.05 mmol) and the mixture was stirred at 800C for 30 minutes. The mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 10% - 50% ethyl acetate in DCM. The isolated material was triturated with diethyl ether to give the desired material as a pale orange solid (544 mg).
NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.34 (3H, d), 1.44 (9H, s), 2.30 - 2.36 (2H, m), 2.71 (3H, s), 2.69 - 2.85 (4H, m), 3.30 (IH, dt), 3.60 (IH, dt), 3.74 (IH, dd), 3.83 (IH, d), 3.93 (2H, s), 4.04 (IH, dd), 4.09 - 4.29 (3H, m), 4.45 (IH, br, s), 6.58 (IH, s), 6.71 (2H, d), 8.18 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 532; HPLC tR = 2.52 min. tert-Butyl 4-r2-chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-yll-4- methylsulfonylpiperidine- 1 -carboxylate
Figure imgf000448_0001
1-Chloroethyl chloro formate (0.315 mL, 2.92 mmol) was added to a solution of 4-(l-benzyl- 4-methylsulfonylpiperidin-4-yl)-2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (679 mg, 1.46 mmol) in DCM (10 mL). The solution was heated at reflux for 3 hours. The mixture was cooled, diluted with methanol (10 mL) and allowed to stand overnight. The mixture was treated with di-tert-butyl dicarbonate (0.738 mL, 3.21 mmol) and DIPEA (0.505 mL, 2.92 mmol) and this solution was stirred at RT for 1.5 hours. The solution was partitioned between DCM and water and the organic phase concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 10% - 30% ethyl acetate in DCM , to give the desired material as a colourless dry film (519 mg). NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.33 (3H, d), 1.45 (9H, s), 2.23 - 2.34 (2H, m), 2.59 - 2.78 (7H, m), 3.30 (IH, dt), 3.55 (IH, dt), 3.70 (IH, dd), 3.80 (IH, d), 3.98 - 4.40 (5H, m), 6.61 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 475, 477; HPLC tR = 2.53 min.
4-(l-Benzyl-4-methylsulfonylpiperidin-4-yl)-2-chloro-6- [(36^-3 -methylmorpholin-4- yllpyrimidine
Figure imgf000448_0002
A solution of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (750 mg, 2.45 mmol) in NMP (8 mL) was treated with sodium hydride (324 mg, 8.10 mmol). The mixture was stirred at RT for 10 minutes before being treated with tetrabutylammonium bromide (979 mg, 3.04 mmol) and N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (692 mg, 2.58 mmol). The reaction mixture was stirred for 5 minutes, warmed to 5O0C for 1 hour then warmed to 8O0C for 2.5 hours. The mixture was allowed to cool and stirred for 65 hours at RT. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The organic solution was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 10% - 50% ethyl acetate in DCM, to give the desired material as a colourless solid (710 mg).
NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.33 (3H, d), 1.89 - 1.99 (2H, m), 2.40 - 2.50 (2H, m), 2.57 - 2.64 (2H, m), 2.75 (3H, s), 2.87 - 2.95 (2H, m), 3.29 (IH, dt), 3.41 (2H, s), 3.55 (IH, dt), 3.69 (IH, dd), 3.79 (IH, d), 3.95 - 4.08 (2H, m), 4.29 (IH, br, s), 6.59 (IH, s), 7.21 - 7.32 (5H, m)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 465, 467; HPLC tR = 2.59 min.
The preparation of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6- (methylsulfonylmethyl)pyrimidine was described earlier.
Example 21 : 3-C yclopr opyl- 1- [4- ^-(^-cyclopropylsulfonylpiperidin^-yD-o- \(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll urea
Figure imgf000449_0001
Cyclopropylamine (0.055 mL, 0.76 mmol) was added to tert-butyl 4-cyclopropylsulfonyl-4- [6-[(35)-3-methylmorpholin-4-yl]-2-[4-(phenoxycarbonylamino)phenyl]pyrimidin-4- yl]piperidine-l-carboxylate (120 mg, 0.18 mmol) and triethylamine (0.16 mL, 1.15 mmol) in DMF (1 mL) at RT and the reaction was allowed to stand for overnight at RT. The mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water then concentrated under reduced pressure. The residue was dissolved in DCM (1 mL) and treated with TFA (2 mL). The resulting solution was stirred for 30 minutes at RT before being concentrated under reduced pressure. The sample was dissolved in DMF (1.5 mL). The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% cone, ammonia) and acetonitrile as eluents, to give the desired material as a colourless solid (53 mg).
NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 0.38 - 0.44 (2H, m), 0.63 - 0.68 (2H, m), 0.70 - 0.74 (2H, m), 0.83 - 0.87 (2H, m), 1.23 (3H, d), 1.98 - 2.12 (2H, m), 2.32 - 2.60 (4H, m), 2.82 - 2.98 (4H, m), 3.15 - 3.24 (IH, m), 3.47 - 3.56 (IH, m), 3.64 - 3.69 (IH, m), 3.77 (IH, d), 3.95 - 4.01 (IH, m), 4.26 (IH, d), 4.50 - 4.60 (IH, m), 6.44 (IH, s), 6.81 (IH, s), 7.51 (2H, d), 8.23 (2H, d), 8.54 (IH, s).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 541; HPLC tR = 1.85 min. mTOR Kinase Assay (Echo): 0.0253μM
The following compounds were made in an analogous fashion from tert-butyl 4- cyclopropylsulfonyl-4- [6- [(35)-3 -methylmorpholin-4-yl]-2- [4-
(phenoxycarbonylamino)phenyl]pyrimidin-4-yl]piperidine-l-carboxylate and the appropriate amine.
Figure imgf000450_0001
Figure imgf000451_0001
Example 21a: 1H NMR (399.9 MHz, DMSO-d6) δ 0.68 - 0.74 (2H, m), 0.83 - 0.87 (2H, m),
1.23 (3H, d), 1.98 - 2.10 (2H, m), 2.32 - 2.49 (3H, m), 2.67 (3H, d), 2.82 - 2.97 (4H, m), 3.15
- 3.24 (IH, m), 3.47 - 3.57 (IH, m), 3.64 - 3.69 (IH, m), 3.77 (IH, d), 3.95 - 4.01 (IH, m), 4.26 (IH, d), 4.50 - 4.59 (IH, m), 6.07 (IH, q), 6.81 (IH, s), 7.50 (2H, d), 8.22 (2H, d), 8.74
(IH, s). mTOR Kinase Assay (Echo): 0.0378μM
Example 21b: 1R NMR (399.9 MHz, DMSOd6) δ 0.69 - 0.76 (2H, m), 0.82 - 0.89 (2H, m),
1.23 (3H, d), 1.95 - 2.10 (2H, m), 2.31 - 2.49 (3H, m), 2.83 - 2.97 (4H, m), 3.15 - 3.26 (3H, m), 3.43 - 3.58 (3H, m), 3.64 - 3.69 (IH, m), 3.77 (IH, d), 3.95 - 4.01 (IH, m), 4.26 (IH, d),
4.50 - 4.59 (IH, m), 4.74 (IH, t), 6.26 (IH, t), 6.81 (IH, s), 7.49 (2H, d), 8.23 (2H, d), 8.81
(IH, s). mTOR Kinase Assay (Echo): 0.0133μM
Example 21c: 1U NMR (399.9 MHz, DMSOd6) δ 0.73 (2H, br, s), 0.87 (2H, d), 1.23 (3H, d), 1.99 - 2.11 (2H, m), 2.33 - 2.48 (3H, m), 2.83 - 2.98 (4H, m), 3.15 - 3.20 (IH, m), 3.45 -
3.56 (IH, m), 3.68 (IH, d), 3.74 - 3.83 (4H, m), 3.99 (IH, d), 4.27 (IH, d), 4.55 (IH, br, s),
6.82 (IH, s), 7.38 (IH, s), 7.55 (2H, d), 7.76 (IH, s), 8.26 (2H, d), 8.42 (IH, s), 8.86 (IH, s). mTOR Kinase Assay (Echo): 0.0234μM
The preparation of tert-butyl 4-cyclopropylsulfonyl-4-[6-[(35)-3-methylmorpholin-4-yl]-2-[4- (phenoxycarbonylamino)phenyl]pyrimidin-4-yl]piperidine- 1 -carboxylateis described below. tert-Butyl 4-cvclopropylsulfonyl-4-r6-r(36f)-3-methylmorpholin-4-yll-2-r4- (phenoxycarbonylamino)phenyllpyrimidin-4-yllpiperidine-l-carboxylate
Figure imgf000452_0001
Phenyl chloroformate (0.235 mL, 1.87 mmol) was added to tert-butyl 4-[2-(4-aminophenyl)- 6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]-4-cyclopropylsulfonylpiperidine-l- carboxylate (950 mg, 1.70 mmol) and sodium hydrogen carbonate (215 mg, 2.56 mmol) in dioxane (15 mL) at RT. The resulting slurry was stirred at RT for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 25% - 80% ethyl acetate in isohexane. The isolated material was triturated with diethyl ether to give the desired material as a near colourless dry film (1.06 g). NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 0.80 - 0.85 (2H, m), 0.94 - 1.06 (2H, m), 1.35 (3H, d), 1.44 (9H, s), 2.14 - 2.22 (IH, m), 2.25 - 2.39 (2H, m), 2.69 - 2.95 (4H, m), 3.33 (IH, dt), 3.62 (IH, dt), 3.76 (IH, dd), 3.84 (IH, d), 4.03 - 4.31 (4H, m), 4.39 - 4.49 (IH, m), 6.68 (IH, s), 7.11 (IH, br, s), 7.19 - 7.28 (3H, m), 7.41 (2H, t), 7.54 (2H, d), 8.37 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 678; HPLC tR = 3.18 min.
tert-Butyl 4-r2-(4-aminophenyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-vH-4- cvclopropylsulfonylpiperidine- 1 -carboxylate
Figure imgf000452_0002
A stream of nitrogen was passed through tert-butyl 4-[2-chloro-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-4-yl]-4-cyclopropylsulfonylpiperidine-l -carboxylate (0.94 g, 1.88 mmol), 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.534 g, 2.44 mmol) and 2M aqueous sodium carbonate (3.38 mL, 6.75 mmol) in DMF (3.75 mL), DME (5 mL), ethanol (5 mL) and water (12.5 mL) at RT for 15 minutes. The reaction mixture was treated with dichlorobis(triphenylphosphine)-palladium(II) (0.066 g, 0.09 mmol) and the mixture was stirred at 800C for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 10% - 50% ethyl acetate in DCM. The isolated material was triturated with diethyl ether to give the desired material as a pale brown solid (0.990 g). NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 0.77 - 0.85 (2H, m), 0.95 - 1.04 (2H, m), 1.32 (3H, d), 1.42 (9H, s), 2.14 - 2.21 (IH, m), 2.24 - 2.37 (2H, m), 2.69 - 2.93 (4H, m), 3.29 (IH, dt), 3.60 (IH, dt), 3.75 (IH, dd), 3.81 (IH, d), 3.90 (2H, s), 4.04 (IH, dd), 4.07 - 4.30 (3H, m), 4.39 - 4.48 (IH, m), 6.61 (IH, s), 6.61 (2H, d), 8.20 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 558; HPLC tR = 2.64 min.
tert-Butyl 4-[2-chloro-6-[(3y)-3-methylmorpholin-4-yllpyrimidin-4-yll-4- cvclopropylsulfonylpiperidine- 1 -carboxylate
Figure imgf000453_0001
1-Chloroethyl chloro formate (0.971 mL, 9.00 mmol) was added to a solution of 4-(l-benzyl- 4-cyclopropylsulfonylpiperidin-4-yl)-2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (2.21 g, 4.50 mmol) in DCM (15 mL). The solution was heated at reflux for 1.5 hours. The mixture was diluted with methanol (15 mL) and heating was continued for 2 hours. The mixture was treated with di-tert-butyl dicarbonate (2.16 g, 9.90 mmol) and DIPEA (1.6 mL, 9.0 mmol) and this solution was stirred at RT for 1 hour. The solution was partitioned between DCM and water. The organic phase was concentrated under reduced pressure and the residue was purified by chromatography on silica, eluting with 10% - 30% ethyl acetate in DCM, to give the desired material as a colourless solid (1.9 g). NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 0.93 - 1.00 (4H, m), 1.32 (3H, d), 1.44 (9H, s), 2.19 - 2.30 (3H, m), 2.62 - 2.80 (4H, m), 3.29 (IH, dt), 3.55 (IH, dt), 3.69 (IH, dd), 3.79 (IH, d), 3.95 - 4.37 (5H, m), 6.65 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 501, 503; HPLC tR = 2.70 min.
4-(l -BenzyM-cvclopropylsulfonylpiperidin^-vD^-chloro-ό- [(36^-3 -methylmorpholin-4- yllpyrimidine
Figure imgf000454_0001
A solution of 2-chloro-4-(cyclopropylsulfonylmethyl)-6-[(35)-3-methylmorpholin-4- yljpyrimidine (2 g, 6.03 mmol) in NMP (18 mL) was treated with sodium hydride (0.796 g, 19.89 mmol). The mixture was stirred at RT for 10 minutes before being treated with tetrabutylammonium bromide (2.91 g, 9.04 mmol) and 7V-benzyl-2-chloro-7V-(2- chloroethyl)ethanamine hydrochloride (1.781 g, 6.63 mmol). The reaction mixture was stirred for 5 minutes, warmed to 5O0C for 1 hour then warmed to 8O0C for 1.5 hours. The mixture was then allowed to cool to RT. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The organic solution was washed three times with water then dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 10% - 70% ethyl acetate in DCM, to give the desired material as a colourless foam (2.23 g).
NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 0.92 - 0.96 (2H, m), 0.97 - 1.02 (2H, m), 1.32 (3H, d), 1.92 - 2.00 (2H, m), 2.24 - 2.31 (IH, m), 2.40 - 2.49 (2H, m), 2.68 - 2.74 (2H, m), 2.88 - 2.92 (2H, m), 3.29 (IH, dt), 3.40 (2H, s), 3.55 (IH, dt), 3.70 (IH, dd), 3.79 (IH, d), 3.98 - 4.09 (2H, m), 4.28 (lH,br, s), 6.63 (IH, s), 7.21 - 7.33 (5H, m) LCMS Spectrum: m/z (ESI+)(M+H)+ = 491, 493; HPLC tR = 2.71 min. The preparation of 2-chloro-4-(cyclopropylsulfonylmethyl)-6-[(35)-3-methylmorpholin-4- yljpyrimidine was described earlier.
Example 22: l-[4-[4-[l-Benzyl-4-(3,5-difluorophenyl)sulfonylpiperidin-4-yll-6-[(35V3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-cyclopropylurea
Figure imgf000455_0001
A stream of nitrogen was passed through [4-(3-cyclopropylureido)phenylboronic acid, pinacol ester (121 mg, 0.40 mmol), 4-[l-benzyl-4-(3,5-difluorophenyl)sulfonylpiperidin-4-yl]-2- chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (225 mg, 0.40 mmol) and 2M aqueous sodium carbonate (0.719 mL, 1.44 mmol) in DMF (0.8 mL), DME (5 mL), ethanol (5 mL) and water (12.5 mL) at 250C for 15 minutes. The reaction mixture was treated with dichlorobis(triphenylphosphine)-palladium(II) (14.02 mg, 0.02 mmol) and the mixture was stirred at 800C for 2 hours. The mixture was partitioned between DCM and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by ion exchange chromatography using an SCX column, eluting with 2M ammonia in methanol. The isolated material was further purified by chromatography on silica, eluting with 10% - 60% ethyl acetate in DCM, to give the desired material as a colourless dry film (125 mg). NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 0.67 - 0.71 (2H, m), 0.85 - 0.90 (2H, m), 1.36 (3H, d), 1.77 - 1.98 (2H, m), 2.47 - 2.67 (3H, m), 2.74 (2H, t), 2.85 - 2.96 (2H, m), 3.30 -
3.38 (3H, m), 3.64 (IH, dt), 3.76 - 3.87 (2H, m), 4.08 (IH, dd), 4.16 (IH, d), 4.40 - 4.51 (IH, m), 4.92 (IH, s), 6.63 (IH, s), 6.80 - 6.86 (IH, m), 6.95 - 7.03 (3H, m), 7.20 - 7.31 (5H, m),
7.39 (2H, d), 7.93 (2H, d).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 703.6; HPLC tR = 2.97 min. mTOR Kinase Assay (Echo): 0.503μM The preparation of 4-[l-benzyl-4-(3,5-difluorophenyl)sulfonylpiperidin-4-yl]-2-chloro-6- [(35)-3-methylmorpholin-4-yl]pyrimidine is described below.
4-ri-Benzyl-4-(3.5-difluorophenvnsulfonylpiperidin-4-yll-2-chloro-6-r(3^-3- methylmorpholin-4-yllpyrimidine
Figure imgf000456_0001
A mixture of 2-chloro-4-[(3,5-difluorophenyl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4- yljpyrimidine (874 mg, 2.16 mmol) in NMP (10 mL) was treated with sodium hydride (299 mg, 7.47 mmol) and stirred for 5 minutes at RT. Tetrabutylammonium bromide (698 mg, 2.16 mmol) and Λ/-benzyl-2-chloro-Λ/-(2-chloroethyl)ethanamine hydrochloride (669 mg, 2.49 mmol) were added and the mixture heated at 8O0C for 2 hours. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The organic solution was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 10% -50% ethyl acetate in isohexane, to give the desired material as a colourless solid (582 mg).
NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.35 (3H, d), 1.85 - 1.93 (2H, m), 2.41 - 2.49 (2H, m), 2.55 (2H, d), 2.88 - 2.93 (2H, m), 3.32 (IH, dt), 3.38 (2H, s), 3.59 (IH, dt), 3.74 (IH, dd), 3.81 (IH, d), 3.98 - 4.08 (2H, m), 4.31 (IH, br, s), 6.64 (IH, s), 6.97 - 7.11 (3H, m), 7.22 - 7.33 (5H, m).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 563, 565; HPLC tR = 3.18 min.
The preparation of 2-chloro-4- [(3,5 -difluorophenyl)sulfonylmethyl] -6- [(3 S)-3- methylmorpholin-4-yl]pyrimidine was described earlier. Example 23 : 3-C vclopropyl- 1- [4- [4- [(3SV3-methylmorpholin-4-yll -6-(4- methylsulfonyloxan-4-yl)pyrimidin-2-yll phenyll urea
Figure imgf000457_0001
Cyclopropylamine (0.100 mL, 1.45 mmol) was added to phenyl N-[4-[4-[(3S)-3- methylmorpholin-4-yl]-6-(4-methylsulfonyloxan-4-yl)pyrimidin-2-yl]phenyl] carbamate (100 mg, 0.18 mmol) in DMF (2 mL). The resulting solution was stirred at 600C for 4 hours. The mixture was evaporated to dryness and the residue was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents, to give the desired material as a white solid (67 mg). NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 0.71 (2H, ddd), 0.89 (2H, ddd), 1.35 (3H, d), 2.54 (3H, ddd), 2.64 (IH, m), 2.71 (3H, s), 2.72 (2H, br.d), 3.34 (IH, ddd), 3.42 (IH, ddd), 3.62 (IH, ddd), 3.77 (IH, dd), 3.84 (IH, d), 4.05 (3H, m), 4.20 (IH, d), 4.46 (IH, br.d), 4.89 (IH, s), 6.64 (IH, s), 7.00 (IH, s), 7.51 (2H, d), 8.31 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 516; HPLC tR = 1.92 min. mTOR Kinase Assay (Echo): 0.00492μM
The following compounds were made in an analogous fashion from either phenyl N-[4-[4- [(3S)-3-methylmorpholin-4-yl]-6-(4-methylsulfonyloxan-4-yl)pyrimidin-2- yl]phenyl]carbamate, phenyl N-[4-[4-(4-cyclopropylsulfonyloxan-4-yl)-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate or phenyl N-[4-[4-[4-(4- chlorophenyl)sulfonyloxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000458_0001
Figure imgf000459_0001
Figure imgf000460_0001
Example 23a: 1H NMR (399.902 MHz, CDCl3) δ 1.35 (3H, d), 2.54 (2H, ddd), 2.71 (3H, s), 2.72 (2H, d), 2.89 (3H, d), 3.35 (IH, ddd), 3.41 (2H, dd), 3.62 (IH, ddd), 3.76 (IH, dd), 3.84 (IH, d), 4.0-4.1 (3H, m), 4.19 (IH, d), 4.46 (IH, br.d), 4.62 (IH, br.q), 6.32 (IH, s), 6.64 (IH, s), 7.40 (2H, d), 8.31 (2H, d). mTOR Kinase Assay (Echo): 0.00459μM
Example 23b: 1R NMR (399.902 MHz, CDCl3) δ 1.35 (3H, d), 2.32 (6H, s), 2.5-2.6 (4H, m),
2.71 (3H, s), 2.72 (2H, d), 3.3-3.4 (3H, m), 3.41 (2H, ddd), 3.62 (IH, ddd), 3.76 (IH, dd), 3.84 (IH, d), 4.0-4.1 (3H, m), 4.19 (IH, d), 4.46 (IH, br.d), 5.22 (IH, br.t), 6.62 (IH, s), 7.44 (2H, d), 8.28 (2H, d). mTOR Kinase Assay (Echo): 0.197μM
Example 23c: 1U NMR (399.902 MHz, CDCl3) δ 1.35 (3H, d), 2.5-2.6 (3H, m), 2.71 (3H, s),
2.72 (2H, d), 3.34 (IH, ddd), 3.41 (2H, dd), 3.45 (4H, dt), 3.62 (IH, ddd), 3.76 (IH, dd), 3.78 (2H, m), 3.84 (IH, d), 4.0-4.1 (3H, m), 4.19 (IH, d), 4.45 (IH, br.d), 5.25 (IH, t), 6.64 (IH, s), 6.86 (IH, s), 7.41 (2H, d), 8.30 (2H, d). mTOR Kinase Assay (Echo): 0.000831 μM
Example 23d: 1R NMR (399.902 MHz, CDCl3) δ 1.35 (3H, d), 2.54 (2H, ddd), 2.72 (3H, s), 2.72 (2H, m), 3.33 (IH, ddd), 3.41 (2H, dd), 3.61 (IH, ddd), 3.75 (IH, dd), 3.83 (IH, d), 3.90 (3H, s), 4.0-4.1 (3H, m), 4.18 (IH, d), 4.45 (IH, br.d), 6.25 (IH, br.s), 6.64 (IH, s), 6.78 (IH, s), 7.41 (IH, s), 7.44 (2H, d), 7.61 (IH, s), 8.29 (2H, d). mTOR Kinase Assay (Echo): 0.00534μM
Example 23e: 1U NMR (399.902 MHz, CDCl3) δ 0.71 (2H, ddd), 0.83 (2H, m), 0.89 (2H, ddd), 1.02 (2H, m), 1.34 (3H, d), 2.18 (IH, tt), 2.53 (2H, ddd), 2.64 (IH, tt), 2.82 (2H, br.d),
3.34 (2H, ddd), 3.43 (3H, ddd), 3.63 (IH, ddd), 3.77 (IH, dd), 3.84 (IH, d), 4.02 (2H, m), 4.06 (IH, dd), 4.19 (IH, d), 4.46 (IH, br.d), 4.86 (IH, s), 6.67 (IH, s), 6.97 (IH, s), 7.51 (2H, d), 8.33 (2H, d). mTOR Kinase Assay (Echo): 0.00876μM
Example 23f: 1R NMR (399.902 MHz, CDCl3) δ 0.83 (2H, m), 1.02 (2H, m), 1.34 (3H, d),
2.18 (IH, tt), 2.52 (2H, m), 2.82 (2H, br.d), 2.86 (3H, d), 3.33 (IH, ddd), 3.42 (2H, ddd), 3.62 (IH, ddd), 3.76 (IH, dd), 3.83 (IH, d), 4.01 (2H, m), 4.05 (IH, dd), 4.18 (IH, d), 4.45 (IH, br.d), 4.83 (IH, q), 6.63 (IH, s), 6.67 (IH, s), 7.40 (2H, d), 8.31 (2H, d). mTOR Kinase Assay (Echo): 0.0199μM
Example 23g: 1U NMR (399.902 MHz, CDCl3) δ 0.82 (2H, m), 1.01 (2H, m), 1.34 (3H, d),
2.18 (IH, tt), 2.32 (6H, s), 2.52 (4H, m), 2.82 (2H, d), 3.32 (3H, m), 3.43 (2H, ddd), 3.62 (IH, ddd), 3.76 (IH, dd), 3.83 (IH, d), 4.01 (2H, m), 4.05 (2H, dd), 4.18 (IH, d), 4.46 (IH, br.d),
5.30 (IH, br.t), 6.66 (IH, s), 7.44 (2H, d), 8.30 (2H, d). mTOR Kinase Assay (Echo): 1.21 μM
Example 23h: 1R NMR (399.902 MHz, CDCl3) δ 0.83 (2H, m), 1.02 (2H, m), 1.34 (3H, d),
2.18 (IH, tt), 2.53 (3H, m), 2.82 (2H, br.d), 3.33 (IH, ddd), 3.43 (2H, dd), 3.46 (2H, t), 3.62 (IH, ddd), 3.76 (IH, dd), 3.78 (2H, t), 3.83 (IH, d), 4.01 (2H, m), 4.05 (IH, dd), 4.18 (IH, d),
4.45 (IH, br.d), 5.26 (IH, t), 6.67 (IH, s), 6.85 (IH, s), 7.40 (2H, d), 8.32 (2H, d). mTOR Kinase Assay (Echo): 0.00808μM
Example 23i: 1U NMR (399.902 MHz, CDCl3) δ 0.84 (2H, m), 1.03 (2H, m), 1.34 (3H, d),
2.19 (IH, tt), 2.53 (2H, m), 2.82 (2H, br.d), 3.33 (IH, ddd), 3.42 (2H, ddd), 3.61 (IH, ddd), 3.76 (IH, dd), 3.83 (IH, d), 3.92 (3H, s), 4.02 (2H, m), 4.05 (IH, dd), 4.17 (IH, d), 4.45 (IH, br.d), 6.03 (IH, s), 6.60 (IH, s), 6.67 (IH, s), 7.42 (2H, d), 7.43 (IH, s), 7.60 (IH, s), 8.31 (2H, d). mTOR Kinase Assay (Echo): 0.0254μM
Example 23j: 1R NMR (399.902 MHz, CDCl3) δ 1.36 (3H, d), 2.55 (2H, td), 2.64 (2H, br.d), 2.87 (3H, d), 3.30 (IH, ddd), 3.34 (IH, ddd), 3.65 (IH, ddd), 3.79 (IH, dd), 3.86 (IH, d), 3.99 (2H, m), 4.08 (IH, dd), 4.16 (IH, d), 4.45 (IH, br.d), 4.64 (IH, br.q), 6.29 (IH, s), 6.62 (IH, s), 7.27 (4H, m), 7.39 (2H, d), 7.83 (2H, d). mTOR Kinase Assay (Echo): 0.0314μM
Example 23k: 1U NMR (399.902 MHz, CDCl3) δ 1.36 (3H, d), 2.32 (6H, s), 2.52 (2H, t), 2.55 (2H, ddd), 2.63 (2H, d), 3.26 - 3.37 (5H, m), 3.64 (IH, ddd), 3.79 (IH, dd), 3.85 (IH, d), 3.98 (2H, m), 4.07 (IH, dd), 4.17 (IH, d), 4.45 (IH, br.d), 5.18 (IH, br.t), 6.61 (IH, s), 7.27 (2H, d), 7.32 (2H, d), 7.39 (2H, d), 7.80 (2H, d). mTOR Kinase Assay (Echo): 1.14μM
Example 231: 1R NMR (399.902 MHz, CDCl3) δ 1.36 (3H, d), 2.37 (IH, t), 2.55 (4H, ddd), 2.64 (2H, br.d), 3.26 - 3.37 (3H, m), 3.46 (2H, dt), 3.64 (IH, ddd), 3.77 - 3.81 (3H, m), 3.86 (IH, d), 3.99 (2H, m), 4.08 (IH, dd), 4.16 (IH, d), 4.45 (IH, br.d), 5.07 (IH, t), 6.49 (IH, s), 6.63 (IH, s), 7.26 (2H, d), 7.28 (2H, d), 7.39 (2H, d), 7.84 (2H, d). mTOR Kinase Assay (Echo): 0.00888μM
Example 23m: 1U NMR (399.902 MHz, CDCl3) δ 1.35 (3H, d), 2.53 (3H, ddd), 2.64 (2H, br.d), 3.26 - 3.37 (3H, m), 3.64 (IH, ddd), 3.78 (21H, dd), 3.85 (IH, d), 3.91 (3H, s), 3.99 (2H, m), 4.07 (IH, dd), 4.15 (IH, d), 4.44 (IH, br.d), 6.11 (IH, s), 6.61 (IH, s), 6.63 (IH, s), 7.28 (2H, d), 7.32 (2H, d), 7.41 (2H, d), 7.42 (IH, s), 7.61 (IH, s), 7.84 (2H, d). mTOR Kinase Assay (Echo): 0.0577μM
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-(4-methylsulfonyloxan- 4-yl)pyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl N- [4- [4- [(36^-3 -methylmorpholin-4-yll-6-(4-methylsulfonyloxan-4-yl)pyrimidin-2- vHphenyli carbamate
Figure imgf000462_0001
Phenyl chloroformate (0.196 mL, 1.56 mmol) was added dropwise to 4-[4-[(35)-3- methylmorpholin-4-yl]-6-(4-methylsulfonyloxan-4-yl)pyrimidin-2-yl]aniline (615 mg, 1.42 mmol) and sodium hydrogen carbonate (179 mg, 2.13 mmol) in dioxane (50 mL) at RT. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was concentrated, diluted with ethyl acetate (100 mL) and washed sequentially with water (2 x 100 mL) and saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 40 to 80% ethyl acetate in z'sø-hexane, to afford the desired material as a white solid (714 mg). NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.36 (3H, d), 2.55 (2H, m), 2.71 (3H, s), 2.73 (2H, d), 3.35 (IH, ddd), 3.42 (2H, ddd), 3.62 (IH, ddd), 3.77 (IH, dd), 3.84 (IH, d), 4.02 - 4.08 (3H, m), 4.20 (IH, d), 4.47 (IH, br.d), 6.66 (IH, s), 7.11 (IH, s), 7.21 (2H, d), 7.26 (IH, dd), 7.41 (2H, dd), 7.54 (2H, d), 8.35 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 553; HPLC tR = 2.57 min.
4-[4-[(35)-3-Methylmorpholin-4-yll-6-(4-methylsulfonyloxan-4-vπpyrimidin-2-yllaniline
Figure imgf000463_0001
Sodium carbonate (2M in water, 5.75 mL, 11.49 mmol) was added to 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)aniline (0.839 g, 3.83 mmol) and 2-chloro-4-[(3S>3- methylmorpholin-4-yl]-6-(4-methylsulfonyloxan-4-yl)pyrimidine (1.200 g, 3.19 mmol) in a mixture of ethylene glycol diethyl ether (10 mL), ethanol (10 mL), DMF (10 mL) and water (20 mL) at RT under nitrogen. The mixture was degassed and purged with nitrogen. Bis(triphenylphosphine)palladium(II) chloride (0.112 g, 0.16 mmol) was added and the mixture was degassed and purged with nitrogen. The resulting suspension was stirred under nitrogen at 800C for 90 minutes. The reaction mixture was concentrated and diluted with ethyl acetate (150 mL) and washed sequentially with water (2 x 150 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 40 to 100% ethyl acetate in iso- hexane, to afford the desired material as a white solid (690 mg). NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.34 (3H, d), 2.53 (2H, ddd), 2.70 (3H, s), 2.72 (2H, br.d), 3.33 (IH, ddd), 3.41 (2H, ddd), 3.61 (IH, ddd), 3.76 (IH, dd), 3.83 (IH, d), 3.93 (2H, s), 4.03 (3H, m), 4.18 (IH, d), 4.45 (IH, br.d), 6.58 (IH, s), 6.71 (2H, d), 8.18 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 433; HPLC tR = 1.98 min. 2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(4-methylsulfonyloxan-4-yl)pyrimidine
Figure imgf000464_0001
Sodium tert-butoxide (1.38 g, 14.39 mmol) was added portionwise to a mixture of 2-chloro-4- [(35)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (2.00 g, 6.54 mmol) and bis(2-bromoethyl) ether (2.055 mL, 16.35 mmol) in DMF (75 mL) at O0C over a period of 10 minutes under nitrogen. The resulting solution was allowed to warm to RT and stirred for 7 hours. Further sodium tert-butoxide (629 mg, 6.54 mmol) was added portionwise and the solution was stirred at RT for a further 45 hours. The reaction mixture was concentrated, diluted with ethyl acetate (200 mL) and washed sequentially with water (2 x 200 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 40 to 100% ethyl acetate in z'sø-hexane. Pure fractions were evaporated to dryness and the residue crystallised from ethyl acetate / z'sø-hexane to afford the desired material as a white crystalline solid (1.42 g).
NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.34 (3H, d), 2.50 (2H, m), 2.55 (2H, m), 2.73 (3H, s), 3.33 (3H, m), 3.56 (IH, ddd), 3.71 (IH, dd), 3.80 (IH, d), 4.01 (4H, m), 4.31 (IH, br.s), 6.62 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 376, 378; HPLC tR = 1.85 min.
The preparation of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6- (methylsulfonylmethyl)pyrimidine was described earlier.
The preparation of phenyl 7V-[4-[4-(4-cyclopropylsulfonyloxan-4-yl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N- [4- r4-(4-cvclopropylsulfonyloxan-4-yl)-6- [(36^-3 -methylmorpholin-4-vHpyrimidin- 2-vHphenyll carbamate
Figure imgf000465_0001
Phenyl chloro formate (0.211 mL, 1.68 mmol) was added to 4-[4-(4-cyclopropylsulfonyloxan- 4-yl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl] aniline (700 mg, 1.53 mmol) and sodium hydrogen carbonate (192 mg, 2.29 mmol) in 1,4-dioxane (50 mL) at RT. The resulting suspension was stirred at RT for 16 hours. The reaction mixture was concentrated and diluted with ethyl acetate (75 mL) and washed sequentially with water (75 mL) and saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 70% ethyl acetate in iso- hexane, to afford the desired material as a white solid (850 mg). NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 0.83 (2H, m), 1.02 (2H, m), 1.35 (3H, d), 2.18 (IH, tt), 2.54 (2H, m), 2.83 (2H, d), 3.34 (2H, ddd), 3.43 (2H, dd), 3.63 (IH, ddd), 3.77 (IH, dd), 3.84 (IH, d), 4.02 (2H, m), 4.06 (IH, dd), 4.20 (IH, d), 4.47 (IH, br.d), 6.69 (IH, s), 7.08 (IH, s), 7.21 (2H, d), 7.26 (IH, dd), 7.41 (2H, dd), 7.54 (2H, d), 8.37 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 579.5; HPLC tR = 2.72 min.
4-r4-(4-Cvclopropylsulfonyloxan-4-yl)-6-r(3S)-3-methylmorpholin-4-yllpyrimidin-2- yll aniline
Figure imgf000465_0002
Sodium carbonate (2M in water, 7.48 mL, 14.96 mmol) was added to 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)aniline (1.092 g, 4.99 mmol) and 2-chloro-4-(4- cyclopropylsulfonyloxan-4-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (1.67 g, 4.16 mmol) in a mixture of ethylene glycol diethyl ether (10 mL), ethanol (10 mL), DMF (10 mL) and water (20 mL) at RT under nitrogen. The mixture was degassed and purged with nitrogen. Bis(triphenylphosphine)palladium(II) chloride (0.146 g, 0.21 mmol) was added and the mixture was degassed and purged with nitrogen. The resulting suspension was stirred under nitrogen at 800C for 90 minutes. The reaction mixture was concentrated and diluted with ethyl acetate (150 mL) and washed sequentially with water (2 x 150 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 40 to 70% ethyl acetate in iso- hexane, to afford the desired material as a white solid (740 mg).
NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 0.82 (2H, m), 1.01 (2H, m), 1.33 (3H, d), 2.17 (IH, tt), 2.51 (2H, m), 2.82 (2H, br.d), 3.32 (IH, ddd), 3.43 (2H, ddd), 3.62 (IH, ddd), 3.76 (IH, dd), 3.83 (IH, d), 3.91 (2H, s), 3.98 (2H, m), 4.05 (IH, dd), 4.17 (IH, d), 4.45 (IH, br.d), 6.62 (IH, s), 6.71 (2H, d), 8.21 (2H, d).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 459; HPLC tR = 2.05 min.
2-Chloro-4-(4-cvclopropylsulfonyloxan-4-yl)-6-r(3S)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000466_0001
Sodium tert-butoxide (1.738 g, 18.08 mmol) was added portionwise to 2-choro-4-
(cyclopropylsulfonylmethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (2.00 g, 6.03 mmol) and bis(2-bromoethyl) ether (2.273 mL, 18.08 mmol) in DMF (75 mL) at RT over a period of 5 minutes under nitrogen. The resulting solution was stirred at RT for 5 hours. Further bis(2- bromoethyl) ether (0.758 mL, 6.03 mmol), and sodium tert-butoxide (0.579 g, 6.03 mmol) were added and the solution was stirred at RT for a further 20 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (0.5 mL), concentrated, diluted with ethyl acetate (200 mL) and washed sequentially with water (2 x 200 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 40 to 60% ethyl acetate in z'sø-hexane, to afford the desired material as a colourless oil which crystallised on standing (1.734 g). NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.01 (2H, m), 1.01 (2H, m), 1.33 (3H, d), 2.22 (IH, tt), 2.47 (2H, ddd), 2.64 (2H, br.d), 3.30 (IH, ddd), 3.36 (2H, dd), 3.56 (IH, ddd), 3.71 (IH, dd), 3.80 (IH, d), 3.97 - 4.04 (4H, m), 4.30 (IH, br.d), 6.66 (IH, s). LCMS Spectrum: m/z (ESI-)(M-H)- = 400.4; HPLC tR = 2.04 min.
The preparation of 2-choro-4-(cyclopropylsulfonylmethyl)-6-[(35)-3-methylmorpholin-4- yljpyrimidine was described earlier.
The preparation of phenyl Λ/-[4-[4-[4-(4-chlorophenyl)sulfonyloxan-4-yl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl Λ/-r4-r4-r4-(4-chlorophenyl)sulfonyloxan-4-yll-6-r(36^-3-methylmorpholin-4- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000467_0001
Phenyl chloroformate (0.198 mL, 1.58 mmol) was added to 4-[4-[4-(4- chlorophenyl)sulfonyloxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (759 mg, 1.43 mmol) and sodium hydrogen carbonate (181 mg, 2.15 mmol) in 1,4-dioxane (50 mL) at RT. The resulting suspension was stirred at RT for 16 hours. The reaction mixture was concentrated and diluted with ethyl acetate (75 mL) and washed sequentially with water (75 mL) and saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 70% ethyl acetate in z'sø-hexane, to afford the desired material as a white dry film (780 mg). NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.36 (3H, d), 2.56 (2H, ddd), 2.64 (2H, br.d), 3.31 (2H, ddd), 3.35 (IH, ddd), 3.65 (IH, ddd), 3.80 (IH, dd), 3.86 (IH, d), 4.00 (2H, m), 4.08 (IH, dd), 4.18 (IH, d), 4.45 (IH, br.d), 6.64 (IH, s), 7.04 (IH, s), 7.21 (2H, d), 7.22 (IH, dd), 7.27 (2H, d), 7.39 (2H, d), 7.40 (2H, dd), 7.43 (2H, d), 7.87 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 649, 651; HPLC tR = 3.02 min. 4-r4-r4-(4-Chlorophenyl)sulfonyloxan-4-yll-6-r(3S)-3-methylmorpholin-4-yllpyrimidin-2- yll aniline
Figure imgf000468_0001
Sodium carbonate (2M in water, 4.02 mL, 8.05 mmol) was added to 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)aniline (490 mg, 2.24 mmol) and 2-chloro-4-[4-(4- chlorophenyl)sulfonyloxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (1056 mg, 2.24 mmol) in a mixture of ethanol (10 mL), water (20 mL), DMF (10 mL) and ethylene glycol diethyl ether (10 mL) at RT under nitrogen. The mixture was degassed and purged with nitrogen. Bis(triphenylphosphine)palladium(II) chloride (78 mg, 0.11 mmol) was added and the mixture degassed and purged with nitrogen. The resulting suspension was stirred at 800C for 2 hours. The reaction mixture was concentrated and diluted with ethyl acetate (100 mL) and water (100 mL). The resulting precipitate was removed by filtration. The organic layer was washed sequentially with water (100 mL) and saturated brine (100 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% ethyl acetate in z'sø-hexane, to afford the desired material as a white dry film (790 mg).
NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.35 (3H, d), 2.54 (2H, ddd), 2.63 (2H, d), 3.27 - 3.35 (3H, m), 3.64 (IH, ddd), 3.79 (IH, dd), 3.85 (IH, d), 3.87 (2H, s), 3.98 (2H, m), 4.06 (IH, dd), 4.16 (IH, d), 4.44 (IH, br.d), 6.56 (IH, s), 6.60 (2H, d), 7.27 (2H, d), 7.39 (2H, d), 7.69 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 529.5, 531.5; HPLC tR = 2.49 min.
2-Chloro-4-r4-(4-chlorophenyl)sulfonyloxan-4-yll-6-r(3S)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000469_0001
Sodium tert-butoxide (1.566 g, 16.30 mmol) was added portionwise to 2-chloro-4-[(4- chlorophenyl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (1.873 g, 4.66 mmol) and bis(2-bromoethyl) ether (1.463 mL, 11.64 mmol) in DMF (75 mL) at RT over a period of 5 minutes under nitrogen. The resulting solution was stirred at RT for 6 hours. Further sodium tert-butoxide (0.895 g, 9.31 mmol) was added and the solution was stirred at RT for a further 4 days. The reaction mixture was concentrated and diluted with ethyl acetate (200 mL), and washed sequentially with water (2 x 200 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 40 to 50% ethyl acetate in iso- hexane, to afford the desired material as a white dry film (1.0 g).
NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.35 (3H, d), 2.45 - 2.49 (4H, m), 3.22 - 3.35 (3H, m), 3.59 (IH, ddd), 3.73 (IH, dd), 3.82 (IH, d), 3.95 - 4.00 (3H, m), 4.04 (IH, dd), 4.31 (IH, br.s), 6.67 (IH, s), 7.39 (2H, d), 7.45 (2H, d). LCMS Spectrum: m/z (ESI-)(M-H)- = 470, 472; HPLC tR = 2.62 min.
2-Chloro-4-r(4-chlorophenyl)sulfonylmethyll-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000469_0002
4-Chlorobenzenesulphinic acid sodium salt (5.39 g, 27.15 mmol) was added in one portion to 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (8.00 g, 22.63 mmol) in acetonitrile (400 mL) at RT. The resulting suspension was stirred at 850C under reflux for 5 hours. The reaction mixture was concentrated and diluted with DCM (400 mL) and washed with water (400 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 25 to 40% ethyl acetate in isohexane, to give the desired material as a white solid (6.90 g). NMR Spectrum: 1H NMR (399.902 MHz, CDCB) δ 1.33 (3H, d), 3.30 (IH, ddd), 3.55 (IH, ddd), 3.70 (IH, dd), 3.80 (IH, d), 4.02 (2H, m), 4.28 (IH, br.s), 4.29 (2H, s), 6.55 (IH, s), 7.51 (2H, d), 7.70 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 402, 404; HPLC tR = 2.26 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Example 24 : 1- [4- [4- [4-(4-Chlorophenyl)sulfonyloxan-4-yll -6- [(3S)-3-methylmorpholin- 4-yll pyrimidin-2-yll phenyll -3-cvclopropylurea
Figure imgf000470_0001
Sodium carbonate (0.381 mL, 0.76 mmol) was added to 2-chloro-4-[4-(4- chlorophenyl)sulfonyloxan-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (100 mg, 0.21 mmol) and 4-(3-cyclopropylureido)phenylboronic acid (47 mg, 0.21 mmol) in DME (2 mL), ethanol (2 mL), DMF (2 mL) and water (4 mL) at RT under nitrogen. The mixture was degassed and purged with nitrogen then bis(triphenylphosphine)palladium(II) chloride (7.4 mg, 0.011 mmol) added and the mixture stirred at 85°C for 2 hours. The reaction mixture was concentrated, diluted with ethyl acetate (25 mL) and washed sequentially with water (2 x 25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% ethyl acetate in isohexane. The isolated material was further purified trituration with diethyl ether to afford the desired material as a white solid (26 mg). NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 0.70 (2H, m), 0.88 (2H, m), 1.36 (3H, d), 2.58 (5H, m), 3.31 (2H, m), 3.34 (IH, ddd), 3.65 (IH, ddd), 3.79 (IH, dd), 3.86 (IH, d), 3.99 (2H, m), 4.08 (IH, dd), 4.17 (IH, d), 4.45 (IH, d), 4.88 (IH, s), 6.63 (IH, s), 6.94 (IH, s), 7.27 (2H, d), 7.39 (2H, d), 7.39 (2H, d), 7.84 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 612, 6144; HPLC tR = 2.48 min. mTOR Kinase Assay (Echo): 0.00517μM The preparation of 2-chloro-4-[4-(4-chlorophenyl)sulfonyloxan-4-yl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidine was described earlier.
Example 25 : 3-C yclopropyl- 1- [4- [4- [(3S)-3-methylmorpholin-4-yll -6- [1- [(4-methyl- 1 ,3- thiazol-2-yl)sulfonyllcyclopropyllpyrimidin-2-yllphenyllurea
Figure imgf000471_0001
To cyclopropylamine (57 mg, 1 mmol) was added a solution of phenyl N-[4-[4-[(3S)-3- methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2- yl]phenyl]carbamate (100 mg, 0.17 mmol) in DMF (1.5 mL). Triethylamine (0.082 mL, 0.59 mmol) was then added and the resultant mixture was heated to 5O0C and stirred overnight (-18 hours). The reaction mixture was cooled then purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% ammonia) in acetonitrile as eluents, to give the desired material as a white solid (50 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.40 - 0.43 (2H, m), 0.62 - 0.67 (2H, m), 1.21 (3H, d), 1.75 - 1.80 (2H, m), 1.93 - 1.97 (2H, m), 2.47 - 2.49 (3H, m), 2.51 - 2.58 (IH, m), 3.17 (IH, td), 3.47 (IH, td), 3.62 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.10 - 4.20 (IH, m), 4.41 - 4.48 (IH, m), 6.41 (IH, d), 6.77 (IH, s), 7.41 - 7.44 (2H, m), 7.83 (IH, d), 7.87 - 7.90 (2H, m), 8.52 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 555; HPLC tR = 2.13 min. mTOR Kinase Assay (Echo): 0.00155μM
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[(35)-3- methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2- yljphenyl] carbamate using the appropriate amine.
Figure imgf000472_0001
Figure imgf000473_0001
Figure imgf000474_0001
Example 25a: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.56 - 1.67 (2H, m), 1.75 - 1.79 (2H, m), 1.82 - 1.88 (2H, m), 1.93 - 1.95 (2H, m), 2.16 - 2.24 (2H, m), 2.48 (3H, s), 3.17 (IH, td), 3.46 (IH, td), 3.61 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.08 - 4.20 (2H, m), 4.41 - 4.49 (IH, m), 6.45 (IH, d), 6.77 (IH, s), 7.39 (2H, d), 7.83 - 7.88 (3H, m), 8.57 (IH, s). mTOR Kinase Assay (Echo): 0.00224μM
Example 25b: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.78 - 1.82 (2H, m), 1.95 - 1.99 (2H, m), 2.49 - 2.50 (3H, m), 3.20 (IH, td), 3.48 (IH, td), 3.63 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.13 - 4.21 (IH, m), 4.43 - 4.50 (IH, m), 6.81 (IH, s), 7.02 - 7.05 (IH, m), 7.53 - 7.62 (3H, m), 7.75 - 7.79 (IH, m), 7.85 - 7.87 (IH, m), 7.96 - 7.99 (2H, m), 8.29 - 8.31 (IH, m), 9.42 (IH, s), 10.53 (IH, s). mTOR Kinase Assay (Echo): 0.000817μM Example 25c: 1U NMR (400.132 MHz, DMSO-Cl6) δ 0.89 (6H, d), 1.21 (3H, d), 1.65 - 1.75 (IH, m), 1.75 - 1.80 (2H, m), 1.93 - 1.98 (2H, m), 2.48 - 2.49 (3H, m), 2.94 (2H, t), 3.18 (IH, td), 3.47 (IH, td), 3.62 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.12 - 4.20 (IH, m), 4.41 - 4.49 (IH, m), 6.22 (IH, t), 6.77 (IH, s), 7.39 - 7.42 (2H, m), 7.83 - 7.84 (IH, m), 7.87 - 7.90 (2H, m), 8.62 (IH, s). mTOR Kinase Assay (Echo): 0.00385μM
Example 25d: 1H NMR (400.132 MHz, DMSOd6) δ 1.11 (6H, d), 1.21 (3H, d), 1.76 - 1.80 (2H, m), 1.93 - 1.97 (2H, m), 2.48 - 2.49 (3H, m), 3.18 (IH, td), 3.47 (IH, td), 3.62 (IH, dd), 3.73 - 3.81 (2H, m), 3.97 (IH, dd), 4.12 - 4.19 (IH, m), 4.41 - 4.48 (IH, m), 6.03 (IH, d), 6.77 (IH, s), 7.38 - 7.41 (2H, m), 7.84 - 7.84 (IH, m), 7.87 - 7.90 (2H, m), 8.51 (IH, s). mTOR Kinase Assay (Echo): 0.00157μM
Example 25e: 1U NMR (400.132 MHz, DMSO-de) δ 1.07 (3H, t), 1.21 (3H, d), 1.76 - 1.80 (2H, m), 1.94 - 1.97 (2H, m), 2.48 - 2.49 (3H, m), 3.09 - 3.21 (3H, m), 3.47 (IH, td), 3.62 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.12 - 4.19 (IH, m), 4.41 - 4.49 (IH, m), 6.15 (IH, t), 6.77 (IH, s), 7.39 - 7.43 (2H, m), 7.83 - 7.84 (IH, m), 7.86 - 7.90 (2H, m), 8.65 (IH, s). mTOR Kinase Assay (Echo): 0.000277μM
Example 25f: 1H NMR (400.132 MHz, DMSO-d6) δ 1.26 (3H, d), 1.81 - 1.85 (2H, m), 1.99 - 2.02 (2H, m), 2.23 (6H, s), 2.39 (2H, t), 2.53 - 2.54 (3H, m), 3.19 - 3.27 (3H, m), 3.52 (IH, td), 3.67 (IH, dd), 3.81 (IH, d), 4.02 (IH, dd), 4.17 - 4.24 (IH, m), 4.47 - 4.53 (IH, m), 6.20 (IH, t), 6.82 (IH, s), 7.44 - 7.47 (2H, m), 7.88 - 7.90 (IH, m), 7.92 - 7.95 (2H, m), 8.92 (IH, s). mTOR Kinase Assay (Echo): 0.0547μM
Example 25g: 1U NMR (400.132 MHz, DMSO-de) δ 1.21 (3H, d), 1.76 - 1.80 (2H, m), 1.93 - 1.97 (2H, m), 2.47 - 2.48 (3H, m), 3.13 - 3.21 (3H, m), 3.43 - 3.50 (3H, m), 3.62 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.12 - 4.19 (IH, m), 4.41 - 4.49 (IH, m), 4.73 (IH, t), 6.23 (IH, t), 6.77 (IH, s), 7.39 - 7.42 (2H, m), 7.83 - 7.84 (IH, m), 7.87 - 7.90 (2H, m), 8.78 (IH, s). mTOR Kinase Assay (Echo): 0.00119μM
Example 25h: 1H NMR (400.132 MHz, DMSO-d6) δ 0.89 (3H, t), 1.21 (3H, d), 1.46 (2H, sextet), 1.76 - 1.80 (2H, m), 1.94 - 1.97 (2H, m), 2.48 - 2.49 (3H, m), 3.06 (2H, q), 3.14 - 3.21 (IH, m), 3.47 (IH, td), 3.62 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.12 - 4.19 (IH, m), 4.41 - 4.49 (IH, m), 6.19 (IH, t), 6.77 (IH, s), 7.39 - 7.43 (2H, m), 7.83 - 7.84 (IH, m), 7.86 - 7.90 (2H, m), 8.63 (IH, s). mTOR Kinase Assay (Echo): 0.000993μM
Example 25i: 1U NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 1.76 - 1.80 (2H, m), 1.94 -
1.97 (2H, m), 2.48 - 2.49(3H, m), 2.66 (3H, d), 3.18 (IH, td), 3.47 (IH, td), 3.62 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.11 - 4.20 (IH, m), 4.40 - 4.50 (IH, m), 6.05 (IH, q), 6.77 (IH, s), 7.40 - 7.44 (2H, m), 7.83 - 7.84 (IH, m), 7.86 - 7.90 (2H, m), 8.72 (IH, s). mTOR Kinase Assay (Echo): O.OOlμM
Example 25j: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.77 - 1.81 (2H, m), 1.95 - 1.99 (2H, m), 2.48 - 2.49 (3H, m), 3.19 (IH, td), 3.48 (IH, td), 3.63 (IH, dd), 3.77 (IH, d),
3.98 (IH, dd), 4.13 - 4.21 (IH, m), 4.42 - 4.51 (IH, m), 6.80 (IH, s), 7.49 - 7.52 (2H, m), 7.63 - 7.70 (4H, m), 7.85 - 7.86 (IH, m), 7.95 - 7.98 (2H, m), 9.03 (IH, s), 9.12 (IH, s). mTOR Kinase Assay (Echo): 0.00576μM
Example 25k: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.24 (6H, s), 1.76 - 1.79 (2H, m), 1.94 - 1.97 (2H, m), 2.48 - 2.49 (3H, m), 3.18 (IH, td), 3.39 (2H, d), 3.47 (IH, td), 3.62 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.12 - 4.19 (IH, m), 4.41 - 4.48 (IH, m), 4.95 (IH, t), 5.98 (IH, s), 6.76 (IH, s), 7.34 - 7.39 (2H, m), 7.84 - 7.89 (3H, m), 8.72 (IH, s). mTOR Kinase Assay (Echo): 0.00292μM
Example 251: 1R NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 1.60 (2H, quintet), 1.76 - 1.80 (2H, m), 1.94 - 1.97 (2H, m), 2.48 - 2.49 (3H, m), 3.14 - 3.21 (3H, m), 3.44 - 3.50 (3H, m), 3.62 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.12 - 4.19 (IH, m), 4.42 - 4.49 (2H, m), 6.18 (IH, t), 6.77 (IH, s), 7.39 - 7.43 (2H, m), 7.83 - 7.84 (IH, m), 7.86 - 7.90 (2H, m), 8.69 (IH, s). mTOR Kinase Assay (Echo): 0.000956μM
Example 25m: 1H NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 1.77 - 1.80 (2H, m), 1.94 - 1.98 (2H, m), 2.48 - 2.49 (3H, m), 3.15 - 3.22 (IH, m), 3.48 (IH, td), 3.62 (IH, dd), 3.75 - 3.79 (4H, m), 3.97 (IH, dd), 4.13 - 4.20 (IH, m), 4.42 - 4.49 (IH, m), 6.79 (IH, s), 7.38 - 7.39 (IH, m), 7.44 - 7.49 (2H, m), 7.77 (IH, s), 7.84 - 7.85 (IH, m), 7.90 - 7.94 (2H, m), 8.38 (IH, s), 8.83 (IH, s). mTOR Kinase Assay (Echo): 0.00025μM
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3- thiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]carbamate is described below: Phenyl JV-r4-r4-r(35^-3-methylmorpholin-4-yl1-6-ri-r(4-methyl-1.3-thiazol-2- vDsulfonyli cvclopropyllpyrimidin-2-yllphenyll carbamate
Figure imgf000477_0001
A solution of 4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]aniline (1.56 g, 3.31 mmol) in 1,4-dioxane (18 mL) was treated with sodium bicarbonate (0.445 g, 5.29 mmol). Phenyl chloro formate (0.5 mL, 3.99 mmol) was then added dropwise and the resulting suspension was stirred at RT, under nitrogen for 150 minutes. The reaction mixture was evaporated to dryness and the residue partitioned between DCM (100 mL) and water (50 mL). The organic layer washed with brine, dried (MgSO4), filtered and evaporated to an amber gum/foam which was triturated under isohexane / diethyl ether (-1:1 v/v,~100 mL) with sonication and resultant solid collected by suction filtration and dried, under vacuum, at 5O0C, to give the desired material as a beige solid (1.72 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.15 (3H, d), 1.71 - 1.75 (2H, m), 1.87 - 1.91 (2H, m), 2.40 - 2.41 (3H, m), 3.12 (IH, td), 3.40 (IH, td), 3.55 (IH, dd), 3.69 (IH, d), 3.90 (IH, dd), 4.07 - 4.14 (IH, m), 4.35 - 4.44 (IH, m), 6.75 (IH, s), 7.16 - 7.23 (3H, m), 7.35 - 7.40 (2H, m), 7.47 - 7.50 (2H, m), 7.76 - 7.77 (IH, m), 7.90 - 7.93 (2H, m), 10.32 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 592.1; HPLC tR = 2.87 min.
4-r4-r(35)-3-Methylmorpholin-4-yll-6-ri-r(4-methyl-1.3-thiazol-2- yl)sulfonyllcvclopropyllpyrimidin-2-vHaniline
Figure imgf000477_0002
A mixture of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidine (1.9 g, 4.58 mmol), 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (1.36 g, 6.21 mmol) and 2M aqueous sodium carbonate solution (5.72 mL, 11.45 mmol) in a mixture of ethanol (5.50 mL), DME (11 mL), water (5.50 mL) and DMF (0.7 mL) was purged with nitrogen for 10 minutes before addition of bis(triphenylphosphine)palladium(II) chloride (0.161 g, 0.23 mmol). The reaction mixture was then heated to 85°C and stirred for 3 hours. The reaction mixture was cooled and partitioned between ethyl acetate (150 mL) and water (250 mL), the organic layer separated and aqueous re-extracted with ethyl acetate (100 mL). The combined organics were washed with brine, dried (MgSO4), filtered and evaporated to dryness to afford the crude product, which was purified by flash silica chromatography, elution gradient 25 to 75% ethyl acetate in isohexane. The isolated material was further purified by trituration with hot isohexane and diethyl ether to give the desired material as a beige solid (1.6 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.73 - 1.77 (2H, m), 1.92 - 1.95 (2H, m), 2.48 - 2.49 (3H, m), 3.15 (IH, td), 3.46 (IH, td), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.08 - 4.16 (IH, m), 4.37 - 4.45 (IH, m), 5.52 (2H, s), 6.50 - 6.54 (2H, m), 6.67 (IH, s), 7.70 - 7.74 (2H, m), 7.82 - 7.84 (IH, m). LCMS Spectrum: m/z (ESI+) (M+H)+ = 472.1; HPLC tR = 2.24 min.
2-Chloro-4-r(3y)-3-methylmorpholin-4-yl1-6-ri-r(4-methyl-1.3-thiazol-2- yDsulfonyllcvclopropyllpyrimidine
Figure imgf000478_0001
A solution of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-[(4-methyl-l,3-thiazol-2- yl)sulfonylmethyl]pyrimidine (3.29 g, 8.46 mmol) in toluene (45 mL) was treated with 1,2- dibromoethane (1.4 mL, 16.25 mmol). Tetrabutylammonium bromide (0.273 g, 0.85 mmol) was then added followed by a solution of sodium hydroxide (3.4 g, 85.01 mmol) in water (3.4 mL). The resulting mixture was heated to 65°C, under an atmosphere of nitrogen, for 1 hour then at 750C for 2.5 hours. The mixture was allowed to cool and partitioned between ethyl acetate (60 mL) and water (30 mL). The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated to a brown gum. The crude product was purified by flash silica chromatography, elution gradient 25 to 75% ethyl acetate in isohexane, to give the desired material as a yellow gum (2.76 g).
NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.12 (3H, d), 1.63 - 1.66 (2H, m), 1.81 - 1.85 (2H, m), 2.39 - 2.41 (3H, m), 3.11 (IH, td), 3.32 - 3.38 (IH, m), 3.49 (IH, dd), 3.65 (IH, d), 3.82 - 3.92 (2H, m), 4.16 - 4.27 (IH, m), 6.83 (IH, s), 7.81 - 7.84 (IH, m). LCMS Spectrum: m/z (ESI+) (M+H)+ = 415.10; HPLC tR = 2.12 min.
2-Chloro-4- r(3^)-3 -methylmorpholin-4-yli -6- IY4-methyl- 1.3 -thiazol-2- vDsulfonylmethyllpyrimidine
Figure imgf000479_0001
A solution of 2,4-dichloro-6-[(4-methyl-l,3-thiazol-2-yl)sulfonylmethyl]pyrimidine (8.35 g, 25.76 mmol) in DCM (100 mL) was cooled to 40C. Triethylamine (4.3 mL, 30.85 mmol) was then added and mixture stirred for 5 minutes before dropwise addition, over 10 minutes, of a solution of (S)-3-methylmorpholine (2.9 g, 28.67 mmol) in DCM (25 mL). The reaction mixture was then stirred in cooling bath for 45 minutes then at RT overnight. Water (200 mL) was added to reaction mixture and stirred for 10 minutes before the organic layer was separated and aqueous layer extracted with DCM (50 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the crude product, which was purified by flash silica chromatography, eluting with 50% ethyl acetate in isohexane, to give the desired material as a yellow gum (5.80 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18 (3H, d), 2.49 - 2.50 (3H, m), 3.18 (IH, td), 3.43 (IH, td), 3.58 (IH, dd), 3.72 (IH, d), 3.88 - 3.96 (2H, m), 4.15 - 4.29 (IH, m), 4.82 (2H, s), 6.80 (IH, s), 7.89 - 7.90 (IH, m). LCMS Spectrum: m/z (ESI+) (M+H)+ =389.2; HPLC tR = 1.87min. 2,4-Dichloro-6-r(4-methyl-l,3-thiazol-2-yl)sulfonylmethyllpyrimidine
Figure imgf000480_0001
A solution of 2,4-dichloro-6-[(4-methyl-l,3-thiazol-2-yl)sulfanylmethyl]pyrimidine (7.39 g, 25.29 mmol) in DCM (130 ml) was cooled to 40C and treated portionwise, over 15 minutes with 3-chloroperoxybenzoic acid (13.60 g, 60.70 mmol). The resulting suspension was stirred in cooling bath for 15 minutes then at RT for 24 hours. A saturated aqueous solution of sodium bicarbonate (200 mL) was added to the reaction mixture and stirred for 30 minutes. The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated to give the desired material as an oil which solidified on standing (8.40 g). The material was used without further purification.
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 2.47 - 2.49 (3H, m), 5.19 (2H, s), 7.84
(IH, s), 7.93 - 7.95 (IH, m).
LCMS Spectrum: m/z (ESI-) (M-H)- = 322.0; HPLC tR = 1.53 min.
2.4-Dichloro-6-[(4-methyl-1.3-thiazol-2-vπsulfanylmethyllpyrimidine
Figure imgf000480_0002
A suspension of 6-[(4-methyl-l,3-thiazol-2-yl)sulfanylmethyl]-lH-pyrimidine-2,4-dione (14.4 g, 56.40 mmol) in phosphorus oxychloride (60 mL, 643.70 mmol) was warmed to 1000C and stirred for 6 hours. The reaction mixture cooled before evaporating to a brown oil and partitioning between DCM (100 mL) and water (100 mL). With stirring solid sodium hydrogen carbonate was then added carefully to adjust the mixture to pH8, additional aliquots of water (100 mL) and DCM (100 mL) were added during this time. Additional DCM (100 mL) and water (100 mL) were added and the organic layer separated and the aqueous layer re- extracted with DCM (2 x 100 mL). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to dryness to give the desired material as a tan solid (15.76 g). the material was used without further purification. NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 2.30 - 2.32 (3H, m), 4.55 (2H, s), 7.22
- 7.24 (IH, m), 7.84 (IH, s)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 292.1; HPLC tR = 2.36min.
6-[(4-Methyl-1.3-thiazol-2-yl)sulfanylmethyll-lH-pyrimidine-2.4-dione
Figure imgf000481_0001
To a solution of 4-methylthiazole-2 -thiol (10 g, 76.21 mmol) in DMF (150 mL) at RT was added DBU (14 mL, 93.80 mmol) dropwise over 5 minutes. The resulting solution was stirred at RT for 30 minutes. 6-(Chloromethyl)-lH-pyrimidine-2,4-dione (10 g, 62.28 mmol) was then added portionwise over a period of 20 minutes under nitrogen. The resulting solution was stirred at RT for 19 hours then the reaction mixture evaporated to dryness and the residue partitioned between DCM (150 mL) and water (150 mL). The solid precipitate was collected by filtration to give the desired material as a cream solid (11.1 g). Additional desired material (4.3 g) was obtained after the filtrate was acidified with 2M hydrochloric acid and the resultant precipitate collected by filtration.
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 2.34 (3H, s), 4.08 (2H, s), 5.43 (IH, s), 7.27 (IH, s), 10.98 (2H, s)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 256.2; HPLC tR = 0.58 min.
Example 26: l-[4-[4-Q-Cyclohexylsulfonylcyclopropyl)-6-[(35V3-methylmorpholin-4- yll pyrimidin-2-yll phenyll -3-cvclopropylurea
Figure imgf000481_0002
To cyclopropylamine (56 mg, 0.98 mmol) was added a solution of phenyl 7V-[4-[4-(l- cyclohexylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl] carbamate (79.5 mg, 0.14 mmol) in DMF (2 mL). Triethylamine (0.067 mL, 0.48 mmol) was then added and the resultant mixture was heated to 5O0C and stirred for 2 hours. The reaction mixture was cooled and purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% TFA) and acetonitrile as eluants, followed by purification by preparative HPLC, using decreasingly polar mixtures of water (containing 1% ammonia) in acetonitrile as eluants, to give the desired material as a white solid (28 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.40 - 0.44 (2H, m), 0.63 - 0.67 (2H, m), 1.13 - 1.29 (6H, m), 1.37 - 1.66 (7H, m), 1.82 - 1.88 (2H, m), 2.26 - 2.34 (2H, m), 2.53 - 2.59 (IH, m), 3.16 - 3.25 (IH, m), 3.44 - 3.53 (2H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 - 4.26 (IH, m), 4.49 - 4.59 (IH, m), 6.47 (IH, d), 6.76 (IH, s), 7.50 - 7.54 (2H, m), 8.19 - 8.23 (2H, m), 8.58 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 540; HPLC tR = 2.57 min. mTOR Kinase Assay (Echo): 0.00605μM
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-(l- cyclohexylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate using the appropriate amine.
Figure imgf000482_0001
Figure imgf000483_0001
Figure imgf000484_0001
Example 26a: 1H NMR (400.132 MHz, DMSO-Cl6) δ 1.13 - 1.28 (6H, m), 1.37 - 1.69 (9H, m), 1.81 - 1.92 (4H, m), 2.17 - 2.25 (2H, m), 2.26 - 2.34 (2H, m), 3.20 (IH, td), 3.44 - 3.52 (2H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.09 - 4.25 (2H, m), 4.50 - 4.58 (IH, m), 6.49 (IH, d), 6.76 (IH, s), 7.47 - 7.50 (2H, m), 8.19 - 8.22 (2H, m), 8.60 (IH, s). mTOR Kinase Assay (Echo): 0.00672μM
Example 26b: 1H NMR (400.132 MHz, DMSOd6) δ 1.07 (3H, t), 1.13 - 1.29 (6H, m), 1.36 - 1.66 (7H, m), 1.81 - 1.89 (2H, m), 2.26 - 2.35 (2H, m), 3.09 - 3.16 (2H, m), 3.20 (IH, td), 3.45 - 3.53 (2H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 - 4.25 (IH, m), 4.50 - 4.58 (IH, m), 6.20 (IH, t), 6.76 (IH, s), 7.48 - 7.52 (2H, m), 8.18 - 8.23 (2H, m), 8.70 (IH, s). mTOR Kinase Assay (Echo): 0.0039μM
Example 26c: 1R NMR (400.132 MHz, DMSO-de) δ 1.12 - 1.29 (6H, m), 1.36 - 1.66 (7H, m), 1.82 - 1.88 (2H, m), 2.18 (6H, s), 2.27 - 2.35 (4H, m), 3.16 - 3.24 (3H, m), 3.44 - 3.52 (2H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 - 4.25 (IH, m), 4.50 - 4.58 (IH, m), 6.17 (IH, t), 6.76 (IH, s), 7.47 - 7.51 (2H, m), 8.19 - 8.23 (2H, m), 8.90 (IH, s). mTOR Kinase Assay (Echo): 0.119μM
Example 26d: 1H NMR (400.132 MHz, DMSO-d6) δ 1.11 - 1.28 (6H, m), 1.38 - 1.65 (7H, m), 1.81 - 1.88 (2H, m), 2.27 - 2.34 (2H, m), 3.16 - 3.24 (3H, m), 3.44 - 3.52 (4H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 - 4.25 (IH, m), 4.50 - 4.58 (IH, m), 4.73 (IH, t), 6.27 (IH, t), 6.76 (IH, s), 7.48 - 7.51 (2H, m), 8.19 - 8.23 (2H, m), 8.83 (IH, s). mTOR Kinase Assay (Echo): 0.0012μM
Example 26e: 1R NMR (400.132 MHz, DMSO-de) δ 1.13 - 1.29 (6H, m), 1.37 - 1.66 (7H, m), 1.82 - 1.88 (2H, m), 2.27 - 2.34 (2H, m), 2.66 (3H, d), 3.20 (IH, td), 3.45 - 3.53 (2H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 - 4.25 (IH, m), 4.50 - 4.59 (IH, m), 6.09 (IH, q), 6.76 (IH, s), 7.49 - 7.53 (2H, m), 8.19 - 8.22 (2H, m), 8.77 (IH, s). mTOR Kinase Assay (Echo): 0.00395μM
Example 26f: 1H NMR (400.132 MHz, DMSO-d6) δ 1.12 - 1.29 (12H, m), 1.37 - 1.67 (7H, m), 1.82 - 1.88 (2H, m), 2.27 - 2.34 (2H, m), 3.20 (IH, td), 3.39 (2H, d), 3.45 - 3.53 (2H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 - 4.25 (IH, m), 4.49 - 4.59 (IH, m), 4.95 (IH, t), 6.01 (IH, s), 6.75 (IH, s), 7.44 - 7.47 (2H, m), 8.18 - 8.22 (2H, m), 8.77 (IH, s). mTOR Kinase Assay (Echo): 0.00457μM
Example 26g: 1R NMR (400.132 MHz, DMSOd6) δ 1.14 - 1.29 (6H, m), 1.37 - 1.66 (9H, m), 1.81 - 1.88 (2H, m), 2.27 - 2.34 (2H, m), 3.14 - 3.24 (3H, m), 3.44 - 3.52 (4H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.18 - 4.24 (IH, m), 4.47 (IH, t), 4.50 - 4.58 (IH, m), 6.23 (IH, t), 6.76 (IH, s), 7.48 - 7.52 (2H, m), 8.19 - 8.22 (2H, m), 8.74 (IH, s). mTOR Kinase Assay (Echo): 0.00746μM
Example 26h: 1H NMR (400.132 MHz, DMSOd6) δ 1.13 - 1.30 (6H, m), 1.37 - 1.67 (7H, m), 1.82 - 1.89 (2H, m), 2.28 - 2.34 (2H, m), 3.21 (IH, td), 3.45 - 3.53 (2H, m), 3.64 (IH, dd), 3.74 - 3.79 (4H, m), 3.98 (IH, dd), 4.18 - 4.26 (IH, m), 4.51 - 4.59 (IH, m), 6.77 (IH, s), 7.39 (IH, d), 7.54 - 7.57 (2H, m), 7.77 (IH, s), 8.23 - 8.26 (2H, m), 8.42 (IH, s), 8.87 (IH, s). mTOR Kinase Assay (Echo): 0.004μM
The preparation of phenyl Λ/-[4-[4-(l-cyclohexylsulfonylcyclopropyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below:
Phenyl N- [4- r4-(l-cvclohexylsulfonylcvclopropyl)-6- [(36^-3 -methylmorpholin-4- yl1pyrimidin-2-yl1phenvHcarbamate
Figure imgf000485_0001
A suspension of 4-[4-(l-cyclohexylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]aniline (615 mg, 1.35 mmol) in 1,4-dioxane (7 mL) was treated with sodium bicarbonate (182 mg, 2.17 mmol). Phenyl chloroformate (0.20 mL, 1.59 mmol) was then added dropwise and resultant mixture left to stir under nitrogen at RT overnight (-16 hours). The reaction mixture was evaporated to dryness and the residue partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated and evaporated to an amber gum which was azeotroped with diethyl ether to give the desired material as a beige solid (726 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.13 - 1.29 (6H, m), 1.37 - 1.48 (2H, m), 1.50 - 1.65 (5H, m), 1.81 - 1.87 (2H, m), 2.26 - 2.34 (2H, m), 3.22 (IH, td), 3.44 - 3.52 (2H, m), 3.64 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.20 - 4.29 (IH, m), 4.52 - 4.60 (IH, m), 6.83 (IH, s), 7.23 - 7.30 (3H, m), 7.42 - 7.47 (2H, m), 7.63 - 7.67 (2H, m), 8.28 - 8.32 (2H, m), 10.45 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 577.1; HPLC tR = 3.12min.
4-[4-(l-Cvclohexylsulfonylcvclopropyπ-6-[(36f)-3-methylmorpholin-4-yllpyrimidin-2- yll aniline
Figure imgf000486_0001
A mixture of 2-chloro-4-(l -cyclohexylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4- yljpyrimidine (1.78 g, 4.45 mmol) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.474 g, 6.73 mmol) in a mixture of DMF (8 mL), ethanol (8 mL), DME (8 mL) and water (20 mL) was treated with 2M aqueous sodium carbonate solution (11 mL, 22.00 mmol). The resulting mixture was purged with nitrogen for 10 minutes before addition of bis(triphenylphosphine)palladium(II) chloride (0.156 g, 0.22 mmol). The mixture was heated to 85°C and stirred, under nitrogen for 4 hours before being cooled and partitioned between ethyl acetate (100 mL) and water (100 mL). The biphasic mixture was filtered and the organic layer was separated. The aqueous layer was re-extracted with ethyl acetate (2 x 50 mL) and the combined organics were washed with brine, dried (MgSO4) and evaporated to afford the crude product, which was purified by flash silica chromatography, elution gradient 25 to 75% ethyl acetate in isohexane, to give the desired material as a beige solid (0.627 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.07 - 1.21 (6H, m), 1.31 - 1.49 (6H, m), 1.53 - 1.58 (IH, m), 1.74 - 1.82 (2H, m), 2.19 - 2.26 (2H, m), 3.07 - 3.14 (IH, m), 3.37 - 3.47 (2H, m), 3.55 (IH, dd), 3.68 (IH, d), 3.89 (IH, dd), 4.07 - 4.14 (IH, m), 4.40 - 4.48 (IH, m), 5.50 (2H, s), 6.54 (2H, d), 6.58 (IH, s), 7.98 (2H, d).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 457.3; HPLC tR = 2.55 min.
2-Chloro-4-d -cvclohexylsulfonylcvclopropyD-6- [(36^-3 -methylmorpholin-4-yllpyrimidine
Figure imgf000487_0001
A solution of 2-chloro-4-(cyclohexylsulfonylmethyl)-6-[(35)-3-methylmorpholin-4- yljpyrimidine (2.8 g, 7.49 mmol) in toluene (40 mL) was treated with 1 ,2-dibromoethane (1.3 mL, 15.09 mmol). Tetrabutylammonium bromide (0.241 g, 0.75 mmol) was then added followed by a solution of sodium hydroxide (3.00 g, 74.89 mmol) in water (3 mL). The resulting mixture was heated to 64°C and stirred for 90 minutes. The reaction mixture was cooled before addition of ethyl acetate (50 mL) and water (20 mL). The mixture was stirred for 5 minutes then the organic layer separated, washed with brine (30 mL) and evaporated to afford the crude product, which was purified by flash silica chromatography, elution gradient 25 to 75% ethyl acetate in isohexane, to give the desired compound as a pale yellow oil which crystallised on standing (1.785 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.10 - 1.41 (8H, m), 1.48 - 1.55 (4H, m), 1.60 - 1.66 (IH, m), 1.77 - 1.84 (2H, m), 2.14 - 2.20 (2H, m), 3.16 - 3.24 (IH, m), 3.32 - 3.47 (2H, m), 3.58 (IH, dd), 3.72 (IH, d), 3.93 (IH, dd), 3.99 - 4.07 (IH, m), 4.32 - 4.43 (IH, m), 6.93 (IH, s).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 400.3; HPLC tR = 2.56 min.
2-Chloro-4-(cvclohexylsulfonylmethyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000487_0002
To a solution of 2,4-dichloro-6-(cyclohexylsulfonylmethyl)pyrimidine (1.7g, 5.50 mmol) in DCM (25 ml), cooled with a water / ice bath, was added triethylamine (0.85 mL, 6.10 mmol). The resulting solution was treated, dropwise over 5 minutes, with a solution of (S)-3- methylmorpholine (0.658 g, 6.51 mmol) in DCM (5 mL). The mixture was stirred in cooling bath for 30 minutes then at RT for 3 hours. Water (25 mL) was added to the reaction mixture and stirred for 15 minutes. The organic layer was separated, dried (MgSO4), filtered and evaporated to give the crude product, which was purified by flash silica chromatography, elution gradient 25 to 75% ethyl acetate in isohexane, to give the desired material as a yellow oil which crystallised on standing (1.3 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.16 - 1.45 (8H, m), 1.63 - 1.69 (IH, m), 1.81 - 1.87 (2H, m), 2.11 - 2.17 (2H, m), 3.16 - 3.25 (2H, m), 3.45 (IH, td), 3.60 (IH, dd), 3.73 (IH, d), 3.92 - 4.05 (2H, m), 4.26 - 4.34 (IH, m), 4.40 (2H, s), 6.90 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ =374.3; HPLC tR = 2.22 min.
2,4-Dichloro-6-(cvclohexylsulfonylmethyl)pyrimidine
Figure imgf000488_0001
To a solution of 2,4-dichloro-6-(cyclohexylsulfanylmethyl)pyrimidine (4.23 g, 15.26 mmol) in DCM (90 mL), cooled in a water / ice bath, was added 3-chloroperoxybenzoic acid (8.55 g, 38.15 mmol) over a period of 30 minutes under nitrogen, so as to control temperature below 1O0C. The resulting suspension was stirred at RT for 3 hours. Saturated aqueous sodium hydrogen carbonate solution (120 mL) was then carefully added portionwise and reaction mixture stirred for 30 minutes before separating the organic layer, drying (MgSO4) and evaporating to give the desired material as an off white solid (4.90 g). The material was used without further purification. NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.13 - 1.46 (5H, m), 1.62 - 1.68 (IH, m), 1.81 - 1.87 (2H, m), 2.10 - 2.16 (2H, m), 3.22 (IH, tt), 4.74 (2H, s), 7.85 (IH, s). LCMS Spectrum: m/z (ESI-) (M-H)- = 307.2; HPLC tR = 2.22 min. 2,4-Dichloro-6-(cvclohexylsulfanylmethyl)pyrimidine
Figure imgf000489_0001
A suspension of 6-(cyclohexylsulfanylmethyl)-lH-pyrimidine-2,4-dione (6.4 g, 26.63 mmol) in phosphorus oxychloride (25 mL, 268.2 mmol) was warmed to 1000C, over a period of 15 minutes. The resulting dark orange solution was stirred at 1000C for 7 hours before being cooled and evaporated to a brown oil. The oil was partitioned between DCM (150 mL) and water (150 mL). With stirring solid sodium hydrogen carbonate was then added carefully to adjust the mixture to pH8, aliquots of water (100 mL) and DCM (50 mL) were added during addition. The organic layer was separated, the aqueous layer was re-extracted with more DCM (2 x 75 mL) and the combined organic layers washed with brine (200 mL), dried (MgSO4) and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with 15% ethyl acetate in isohexane, to give the desired material as an orange liquid (4.24 g). NMR Spectrum: 1H NMR (400.132 MHz. DMSOdn) δ 1.20 - 1.31 (5H, m), 1.51 - 1.57 (IH, m), 1.64 - 1.72 (2H, m), 1.86 - 1.92 (2H, m), 2.71 - 2.77 (IH, m), 3.85 (2H, s), 7.82 (IH, s). LCMS Spectrum: m/z (ESI-) (M-H)- = 275.2 & 277.2 HPLC tR = 3.01 min.
6-(CvclohexylsulfanylmethyiyiH-pyrimidine-2,,4-dione
Figure imgf000489_0002
A solution of cyclohexanethiol (10 mL, 81.74 mmol) in DMF (150 mL) at RT was treated with DBU (14 mL, 93.80 mmol). The resulting solution was stirred at RT for 20 minutes then 6-(chloromethyl)-lH-pyrimidine-2,4-dione (10 g, 62.28 mmol) added portionwise over a period of 30 minutes, under nitrogen, so as to maintain the internal temperature below 350C. The resulting solution was stirred at RT overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between DCM (100 mL) and water (150 mL). On mixing a precipitate formed, this was removed by filtration to give the desired material as a white solid (6.45 g). Additional desired material (3.62 g) was obtained by separating the filtrate, adjusting the aqueous layer to pH2 and collecting the resultant precipitate by filtration.
NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.16 - 1.34 (5H, m), 1.51 - 1.58 (IH, m), 1.63 - 1.72 (2H, m), 1.87 - 1.96 (2H, m), 2.65 - 2.72 (IH, m), 3.41 (2H, s), 5.49 (IH, s), 10.75 - 10.96 (2H, m). LCMS Spectrum: m/z (ESI+) (M+H)+ = 241.3; HPLC tR = 0.99min.
Example 27: l-[4-[4-[l-(4-Chlorophenyl)sulfonylcvclopropyll-6-[(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-cvclopropylurea
Figure imgf000490_0001
Cyclopropylamine (0.137 mL, 1.98 mmol) was added to phenyl Λ/-[4-[4-[l-(4- chlorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate (150 mg, 0.25 mmol) in DMF (2 mL). The resulting solution was stirred at 600C for 4 hours. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate (15 mL) and water (15 mL). The organic layer was washed with IM aqueous citric acid (15 mL) and water (15 mL) and evaporated to dryness. The residue was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents, to afford the desired material as a white solid (62 mg). NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 0.69 (2H, m), 0.87 (2H, m), 1.32 (3H, d), 1.57 (IH, ddd), 1.64 (IH, ddd), 1.98 (2H, m), 2.63 (IH, m), 3.29 (IH, ddd), 3.59 (IH, ddd), 3.74 (IH, dd), 3.83 (IH, d), 4.04 (IH, dd), 4.14 (IH, d), 4.41 (IH, br.d), 4.87 (IH, s), 6.77 (IH, s), 6.93 (IH, s), 7.40 (2H, d), 7.42 (2H, d), 7.68 (2H, d), 7.99 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 568, 570; HPLC tR = 2.33 min. mTOR Kinase Assay (Echo): 0.00144μM The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[l-(4- chlorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate using the appropriate amine.
Figure imgf000491_0001
Figure imgf000492_0001
Figure imgf000493_0001
Example 27a: 1H NMR (399.902 MHz, CDCl3) δ 1.31 (3H, d), 1.59 (2H, m), 1.71 (2H, m), 1.84 (2H, m), 1.98 (2H, m), 2.38 (2H, m), 3.29 (IH, ddd), 3.59 (IH, ddd), 3.74 (IH, dd), 3.83 (IH, d), 4.04 (IH, dd), 4.13 (IH, d), 4.30 (IH, tt), 4.41 (IH, br.d), 4.82 (IH, d), 6.26 (IH, s), 6.76 (IH, s), 7.30 (2H, d), 7.40 (2H, d), 7.67 (2H, d), 7.98 (2H, d). mTOR Kinase Assay (Echo): 0.00388μM
Example 27b: 1H NMR (399.902 MHz, CDCl3) δ 1.32 (3H, d), 1.59 (IH, ddd), 1.66 (IH, ddd), 1.99 (2H, m), 3.30 (IH, ddd), 3.61 (IH, ddd), 3.75 (IH, dd), 3.83 (IH, d), 4.05 (IH, dd), 4.15 (IH, d), 4.42 (IH, m), 6.71 (IH, d), 6.78 (IH, s), 6.98 (IH, dd), 7.25 (IH, s), 7.41 (2H, d), 7.60 (2H, d), 7.66 (IH, ddd), 7.69 (2H, d), 8.03 (2H, d), 8.30 (IH, d), 11.92 (IH, s). mTOR Kinase Assay (Echo): 0.00425μM
Example 27c: 1R NMR (399.902 MHz, CDCl3) δ 0.94 (6H, d), 1.31 (3H, d), 1.56 (IH, ddd), 1.63 (IH, ddd), 1.80 (IH, m), 1.98 (2H, m), 3.10 (2H, dd), 3.29 (IH, ddd), 3.59 (IH, ddd), 3.74 (IH, dd), 3.82 (IH, d), 4.04 (IH, dd), 4.13 (IH, d), 4.41 (IH, br.d), 4.81 (IH, t), 6.41 (IH, s), 6.75 (IH, s), 7.30 (2H, d), 7.40 (2H, d), 7.67 (2H, d), 7.98 (2H, d). mTOR Kinase Assay (Echo): 0.014μM
Example 27d: 1H NMR (399.902 MHz, CDCl3) δ 1.19 (6H, d), 1.31 (3H, d), 1.56 (IH, ddd), 1.63 (IH, ddd), 1.98 (2H, m), 3.29 (IH, ddd), 3.59 (IH, ddd), 3.74 (IH, dd), 3.82 (IH, d),
4.03 (2H, m), 4.13 (IH, d), 4.41 (IH, d), 4.54 (IH, br.d), 6.31 (IH, s), 6.75 (IH, s), 7.29 (2H, d), 7.40 (2H, d), 7.67 (2H, d), 7.97 (2H, d). mTOR Kinase Assay (Echo): 0.00307μM
Example 27e: 1R NMR (399.902 MHz, CDCl3) δ 1.32 (3H, d), 1.56 (IH, ddd), 1.62 (IH, ddd), 1.98 (2H, m), 2.87 (3H, d), 3.29 (IH, ddd), 3.59 (IH, ddd), 3.74 (IH, dd), 3.83 (IH, d),
4.04 (IH, dd), 4.13 (IH, d), 4.41 (IH, br.d), 4.65 (IH, q), 6.31 (IH, s), 6.76 (IH, s), 7.30 (2H, d), 7.40 (2H, d), 7.67 (2H, d), 7.98 (2H, d). mTOR Kinase Assay (Echo): 0.000719μM
Example 27f: 1H NMR (399.902 MHz, CDCl3) δ 1.17 (3H, t), 1.31 (3H, d), 1.56 (IH, ddd), 1.62 (IH, ddd), 1.98 (2H, m), 3.28 (3H, ddd), 3.32 (3H, dq), 3.59 (IH, ddd), 3.74 (IH, dd),
3.82 (IH, d), 4.04 (IH, dd), 4.13 (IH, d), 4.41 (IH, br.d), 4.71 (IH, t), 6.38 (IH, s), 6.75 (IH, s), 7.30 (2H, d), 7.40 (2H, d), 7.67 (2H, d), 7.98 (2H, d). mTOR Kinase Assay (Echo): 0.000959μM
Example 27g: 1R NMR (399.902 MHz, CDCl3) δ 1.31 (3H, d), 1.56 (IH, ddd), 1.63 (IH, ddd), 1.97 (2H, m), 2.31 (6H, s), 2.51 (2H, t), 3.28 (3H, ddd), 3.32 (3H, dt), 3.59 (IH, ddd),
3.74 (IH, dd), 3.82 (IH, d), 4.04 (IH, dd), 4.14 (IH, d), 4.41 (IH, br.d), 5.25 (IH, br.t), 6.74
(IH, s), 7.26 (IH, s), 7.35 (2H, d), 7.40 (2H, d), 7.67 (2H, d), 7.95 (2H, d). mTOR Kinase Assay (Echo): 0.0189μM
Example 27h: 1H NMR (399.902 MHz, CDCl3) δ 1.31 (3H, d), 1.56 (IH, ddd), 1.62 (IH, ddd), 1.98 (2H, m), 2.64 (IH, br.s), 3.28 (IH, ddd), 3.43 (2H, dt), 3.59 (IH, ddd), 3.73 (IH, dd), 3.75 (2H, m), 3.82 (IH, d), 4.04 (IH, dd), 4.12 (IH, d), 4.40 (IH, br.d), 5.27 (IH, t), 6.73
(IH, s), 6.81 (IH, s), 7.31 (2H, d), 7.40 (2H, d), 7.67 (2H, d), 7.98 (2H, d). mTOR Kinase Assay (Echo): 0.0000856μM
Example 27i: 1R NMR (399.902 MHz, CDCl3) δ 0.94 (3H, t), 1.31 (3H, d), 1.56 (2H, m), 1.56 (IH, ddd), 1.63 (IH, ddd), 1.98 (2H, m), 3.24 (2H, dt), 3.30 (IH, dd), 3.59 (IH, ddd),
3.74 (IH, dd), 3.82 (IH, d), 4.04 (IH, dd), 4.13 (IH, d), 4.41 (IH, br.d), 4.74 (IH, t), 6.36
(IH, s), 6.75 (IH, s), 7.30 (2H, d), 7.40 (2H, d), 7.67 (2H, d), 7.98 (2H, d). mTOR Kinase Assay (Echo): 0.00302μM
Example 27j: 1H NMR (399.902 MHz, CDCl3) δ 1.31 (3H, d), 1.57 (IH, ddd), 1.63 (IH, ddd), 1.99 (2H, m), 3.29 (IH, ddd), 3.59 (IH, ddd), 3.74 (IH, dd), 3.83 (IH, d), 4.04 (IH, dd), 4.12 (IH, d), 4.40 (IH, br.d), 6.72 (IH, s), 6.77 (IH, s), 6.88 (IH, s), 7.37 (2H, d), 7.41 (2H, d), 7.50 (2H, d), 7.55 (2H, d), 7.69 (2H, d), 8.03 (2H, d). mTOR Kinase Assay (Echo): 0.00761μM
Example 27k: 1H NMR (399.902 MHz, CDCl3) δ 1.31 (3H, d), 1.57 (IH, ddd), 1.63 (IH, ddd), 1.98 (2H, m), 3.29 (IH, ddd), 3.59 (IH, ddd), 3.64 (2H, d), 3.73 (IH, dd), 3.82 (IH, d), 4.04 (IH, dd), 4.13 (IH, d), 4.40 (IH, br.d), 4.45 (IH, t), 4.88 (IH, s), 6.54 (IH, s), 6.75 (IH, s), 7.27 (2H, d), 7.40 (2H, d), 7.67 (2H, d), 7.99 (2H, d). mTOR Kinase Assay (Echo): 0.00462μM
Example 271: 1U NMR (399.902 MHz, CDCl3) δ 1.31 (3H, d), 1.56 (IH, ddd), 1.62 (IH, ddd), 1.71 (2H, tt), 1.98 (2H, m), 2.94 (IH, br.s), 3.28 (IH, ddd), 3.44 (2H, dt), 3.59 (IH, ddd), 3.72 (IH, br.s), 3.73 (IH, dd), 3.82 (IH, d), 4.04 (IH, dd), 4.12 (IH, d), 4.40 (IH, br.d), 5.13 (IH, t), 6.62 (IH, s), 6.74 (IH, s), 7.30 (2H, d), 7.40 (2H, d), 7.67 (2H, d), 7.98 (2H, d). mTOR Kinase Assay (Echo): 0.00112μM
Example 27m: 1H NMR (399.902 MHz, CDCl3) δ 1.31 (3H, d), 1.57 (IH, ddd), 1.63 (IH, ddd), 1.98 (2H, m), 3.29 (IH, ddd), 3.59 (IH, ddd), 3.74 (IH, dd), 3.83 (IH, d), 3.90 (3H, s), 4.04 (IH, dd), 4.13 (IH, d), 4.40 (IH, br.d), 6.12 (IH, s), 6.63 (IH, s), 6.76 (IH, s), 7.35 (2H, d), 7.40 (2H, d), 7.41 (IH, s), 7.60 (IH, s), 7.67 (2H, d), 7.99 (2H, d). mTOR Kinase Assay (Echo): 0.00144μM
The preparation of phenyl Λ/-[4-[4-[l-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl Λ/-[4-[4-[ 1 -^-chlorophenvOsulfonylcvclopropyli-ό-rOiSyS-methylmorpholin^- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000495_0001
Phenyl chloroformate (0.829 mL, 6.60 mmol) was added dropwise to 4-[4-[l-(4- chlorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (3.20 g, 6.60 mmol) and sodium hydrogen carbonate (0.554 g, 6.60 mmol) in 1,4-dioxane (150 mL) at RT. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (400 mL) and washed with water (2 x 400 mL) and saturated brine (200 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% ethyl acetate in isohexane, to afford the desired material as a white dry film (3.78 g). NMR Spectrum: 1R NMR (399.902 MHz, CDCl3) δ 1.32 (3H, d), 1.57 (IH, ddd), 1.64 (IH, ddd), 1.99 (2H, m), 3.30 (IH, ddd), 3.60 (IH, ddd), 3.74 (IH, dd), 3.83 (IH, d), 4.05 (IH, dd), 4.15 (2H, br.d), 4.42 (IH, br.d), 6.78 (IH, s), 7.04 (IH, s), 7.20 (2H, d), 7.25 (2H, dd), 7.40 (2H, d), 7.40 (2H, dd), 7.45 (2H, d), 7.68 (2H, d), 8.02 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 605, 607; HPLC tR = 3.15 min.
4-r4-ri-(4-Chlorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-2- yl] aniline
Figure imgf000496_0001
Sodium carbonate (13.45 mL, 26.89 mmol) was added to 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (1.637 g, 7.47 mmol), 2-chloro-4-[l-(4- chlorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (3.20 g, 7.47 mmol) in a mixture of DME (20 mL), DMF (20 mL), ethanol (20 mL) and water (40 mL) at RT under nitrogen. The mixture was degassed and purged with nitrogen before bis(triphenylphosphine)palladium(II) chloride (0.262 g, 0.37 mmol) was added and the mixture stirred at 800C under nitrogen for 90 minutes. The reaction mixture was concentrated and diluted with ethyl acetate (250 mL), and washed sequentially with water (2 x 200 mL) and saturated brine (150 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 45% ethyl acetate in isohexane, to afford the desired material as a beige dry film (3.32 g). NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.30 (3H, d), 1.56 (IH, ddd), 1.62 (IH, ddd), 1.96 (2H, m), 3.27 (IH, ddd), 3.59 (IH, ddd), 3.73 (IH, dd), 3.81 (IH, d), 3.86 (2H, s), 4.03 (IH, dd), 4.13 (IH, br.d), 4.41 (IH, br.d), 6.63 (2H, d), 6.70 (IH, s), 7.40 (2H, d), 7.67 (2H, d), 7.85 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 485, 487; HPLC tR = 2.70 min.
2-Chloro-4-ri-(4-chlorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000497_0001
ION Sodium hydroxide solution (7.46 mL, 74.57 mmol) was added to 2-chloro-4-[(4- chlorophenyl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (3.00 g, 7.46 mmol), 1 ,2-dibromoethane (1.285 mL, 14.91 mmol) and tetrabutylammonium bromide (0.240 g, 0.75 mmol) in toluene (50 mL). The resulting solution was stirred at 600C for 1 hour. The reaction mixture was concentrated, diluted with ethyl acetate (300 mL), washed with water (2 x 300 mL) and saturated brine (200 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% ethyl acetate in isohexane, to afford the desired material as a white dry film (2.85 g)-
NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.31 (3H, d), 1.54 (IH, ddd), 1.60 (IH, ddd), 1.95 (2H, m), 3.27 (IH, ddd), 3.54 (IH, ddd), 3.69 (IH, dd), 3.79 (IH, d), 4.01 (2H, m), 4.27 (IH, br.s), 6.87 (IH, s), 7.46 (2H, d), 7.64 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 428, 430; HPLC tR = 2.51 min.
The preparation of 2-chloro-4-[(4-chlorophenyl)sulfonylmethyl]-6-[(35)-3-methylmorpholin- 4-yl]pyrimidine was described earlier. Example 28: 3-Cvclopropyl-l-[4-[4-[(35V3-methylmorpholin-4-yll-6-a-pyridin-2- ylsulfonylcvclopropyl)pyrimidin-2-yll phenyll urea
Figure imgf000498_0001
Cyclopropylamine (0.76 mmol) was added in one portion to phenyl N-[4-[4-[(3S)-3- methylmorpholin-4-yl]-6-(l-pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl] carbamate (104 mg, 0.19 mmol), in DMF (2 mL) at RT under nitrogen. The resulting solution was stirred at RT for 60 minutes. The reaction mixture was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents, to afford the desired material as a white solid (49 mg). NMR Spectrum: 1H NMR (399.902 DMSOdn) δ 0.33 (2H. s). 0.54 - 0.60 (2H. m). 1.06 - 1.10 (3H, m), 1.62 - 1.70 (2H, m), 1.92 (2H, s), 3.01 - 3.11 (IH, m), 3.37 (IH, t), 3.52 (IH, d), 3.66 (IH, d), 3.87 (IH, d), 4.00 - 4.11 (IH, m), 4.32 (IH, s), 6.33 (IH, s), 6.59 (IH, s), 7.29 (2H, d), 7.61 - 7.69 (3H, m), 7.89 - 7.93 (IH, m), 7.98 - 8.03 (IH, m), 8.41 (IH, s), 8.75 (IH, s); LCMS Spectrum: m/z (ESI+)(M+H)+ = 535.4; HPLC tR = 1.91 min. mTOR Kinase Assay (Echo): 0.000816μM
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[(35)-3- methylmorpholin-4-yl]-6-(l-pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl] carbamate using the appropriate amine.
Figure imgf000498_0002
Figure imgf000499_0001
Figure imgf000500_0001
Figure imgf000501_0001
Example 28a: 1H NMR (399.902 DMSO-d6) δ 1.16 (d, 3H), 1.57 - 1.68 (m, 2H), 1.70 - 1.78 (m, 2H), 1.80 - 1.92 (m, 2H), 1.96 - 2.04 (m, 2H), 2.17 - 2.26 (m, 2H), 3.10 - 3.18 (m, IH), 3.41 - 3.49 (m, IH), 3.57 - 3.63 (m, IH), 3.75 (d, IH), 3.93 - 3.98 (m, IH), 4.09 - 4.19 (m, 2H), 4.40 (s, IH), 6.44 (d, IH), 6.67 (s, IH), 7.34 (d, 2H), 7.72 (d, 2H), 7.73 - 7.77 (m, IH), 7.99 (d, IH), 8.06 - 8.11 (m, IH), 8.52 (s, IH), 8.81 - 8.84 (m, IH). mTOR Kinase Assay (Echo): 0.00253μM
Example 28b: 1H NMR (399.902 DMSOd6) δ 1.18 (d, 3H), 1.71 - 1.82 (m, 2H), 1.98 - 2.05 (m, 2H), 3.11 - 3.21 (m, IH), 3.42 - 3.51 (m, IH), 3.59 - 3.64 (m, IH), 3.76 (d, IH), 3.94 - 4.00 (m, IH), 4.15 (d, IH), 4.42 (s, IH), 6.71 (s, IH), 7.02 - 7.07 (m, IH), 7.50 (d, 2H), 7.56 - 7.60 (m, IH), 7.75 - 7.80 (m, 2H), 7.81 (d, 2H), 7.99 - 8.02 (m, IH), 8.08 - 8.13 (m, IH), 8.29 - 8.32 (m, IH), 8.83 - 8.85 (m, IH), 9.42 - 9.44 (m, IH), 10.53 (s, IH). mTOR Kinase Assay (Echo): 0.00149μM Example 28c: 1U NMR (399.902 DMSOd6) δ 0.79 (d, 6H), 1.07 (d, 3H), 1.57 - 1.68 (m, 3H), 1.88 - 1.92 (m, 2H), 2.84 (t, 2H), 3.00 - 3.09 (m, IH), 3.31 - 3.40 (m, IH), 3.48 - 3.53 (m, IH), 3.65 (d, IH), 3.84 - 3.89 (m, IH), 4.00 - 4.07 (m, IH), 4.30 (s, IH), 6.13 (t, IH), 6.57 (s, IH), 7.24 - 7.28 (m, 2H), 7.62 (d, 2H), 7.64 - 7.67 (m, IH), 7.88 - 7.91 (m, IH), 7.97 - 8.02 (m, IH), 8.51 (s, IH), 8.72 - 8.74 (m, IH). mTOR Kinase Assay (Echo): 0.00847μM Example 28d: 1H NMR (399.902 DMSO-d6) δ 1.11 (d, 6H), 1.16 (d, 3H), 1.70 - 1.79 (m, 2H), 1.96 - 2.04 (m, 2H), 3.10 - 3.18 (m, IH), 3.41 - 3.49 (m, IH), 3.57 - 3.63 (m, IH), 3.72 - 3.83 (m, 2H), 3.93 - 3.99 (m, IH), 4.13 (d, IH), 4.40 (s, IH), 6.04 (d, IH), 6.67 (s, IH), 7.34 (d, 2H), 7.72 (d, 2H), 7.74 - 7.77 (m, IH), 7.98 - 8.01 (m, IH), 8.06 - 8.12 (m, IH), 8.49 (s, IH), 8.82 - 8.84 (m, IH). mTOR Kinase Assay (Echo): 0.00237μM
Example 28e: 1U NMR (399.902 DMSO-d6) δ 1.16 (d, 3H), 1.70 - 1.80 (m, 2H), 1.96 - 2.03 (m, 2H), 2.66 (d, 3H), 3.10 - 3.18 (m, IH), 3.41 - 3.49 (m, IH), 3.58 - 3.63 (m, IH), 3.75 (d, IH), 3.93 - 3.98 (m, IH), 4.13 (d, IH), 4.41 (s, IH), 6.05 (q, IH), 6.67 (s, IH), 7.37 (d, 2H), 7.72 (d, 2H), 7.73 - 7.77 (m, IH), 7.99 (d, IH), 8.07 - 8.12 (m, IH), 8.70 (s, IH), 8.82 - 8.84 (m, IH). mTOR Kinase Assay (Echo): 0.000434μM
Example 28f: 1H NMR (399.902 DMSOd6) δ 1.17 (d, 3H), 1.69 - 1.80 (m, 2H), 1.97 - 2.03 (m, 2H), 2.19 (s, 6H), 2.34 (t, 3H), 3.10 - 3.22 (m, 3H), 3.41 - 3.49 (m, IH), 3.58 - 3.63 (m, IH), 3.75 (d, IH), 3.94 - 3.98 (m, IH), 4.12 (d, IH), 4.40 (s, IH), 6.15 (t, IH), 6.67 (s, IH), 7.35 (d, 2H), 7.72 (d, 2H), 7.74 - 7.78 (m, IH), 8.00 (d, IH), 8.09 (t, IH), 8.81 - 8.87 (m, 2H). mTOR Kinase Assay (Echo): 0.0674μM Example 28g: 1U NMR (399.902 DMSOd6) δ 1.14 - 1.21 (m, 3H), 1.70 - 1.79 (m, 2H), 1.97
- 2.04 (m, 2H), 3.10 - 3.24 (m, 3H), 3.41 - 3.51 (m, 3H), 3.57 - 3.65 (m, IH), 3.75 (d, IH), 3.93 - 3.99 (m, IH), 4.13 (d, IH), 4.41 (s, IH), 4.73 (t, IH), 6.23 (t, IH), 6.67 (s, IH), 7.35 (d, 2H), 7.70 - 7.77 (m, 3H), 7.99 (d, IH), 8.09 (t, IH), 8.76 (s, IH), 8.83 (d, IH). mTOR Kinase Assay (Echo): 0.0118μM Example 28h: 1H NMR (399.902 DMSO-d6) δ 0.87 - 0.94 (m, 3H), 1.15 - 1.21 (m, 3H), 1.42
- 1.52 (m, 2H), 2.01 (s, 2H), 3.03 - 3.20 (m, 3H), 3.47 (t, IH), 3.62 (d, IH), 3.76 (d, IH), 3.97 (d, IH), 4.15 (d, IH), 4.42 (s, IH), 6.20 (s, IH), 6.69 (s, IH), 7.37 (d, 2H), 7.70 - 7.79 (m,
3H), 7.98 - 8.03 (m, IH), 8.07 - 8.14 (m, IH), 8.63 (s, IH), 8.84 (s, IH). mTOR Kinase Assay (Echo): 0.00093μM
Example 28i: 1U NMR (399.902 DMSO-de) δ 1.18 (d, 4H), 1.72 - 1.79 (m, 2H), 2.00 - 2.02
(m, 2H), 3 (d, IH), 3.11 - 3.20 (m, IH), 3.43 - 3.50 (m, 2H), 3.59 - 3.64 (m, IH), 3.75 (d, IH), 3.94 - 3.99 (m, 2H), 4.14 (d, IH), 4.42 (s, IH), 6.70 (s, IH), 7.45 (d, 2H), 7.67 (q, 4H), 7.74 -
7.82 (m, 3H), 8.08 - 8.13 (m, IH), 8.82 - 8.85 (m, IH), 9.01 (s, IH), 9.11 (s, IH). mTOR Kinase Assay (Echo): 0.00153μM
Example 28j: 1H NMR (399.902 DMSO-d6) δ 1.16 (d, 3H), 1.24 (s, 6H), 1.68 - 1.80 (m, 2H),
1.96 - 2.04 (m, 2H), 3.09 - 3.18 (m, IH), 3.39 (d, 2H), 3.41 - 3.49 (m, IH), 3.58 - 3.63 (m, IH), 3.75 (d, IH), 3.93 - 3.98 (m, IH), 4.13 (d, IH), 4.40 (s, IH), 4.96 (t, IH), 5.98 (s, IH),
6.67 (s, IH), 7.32 (d, 2H), 7.71 (d, 2H), 7.74 - 7.78 (m, IH), 7.99 (d, IH), 8.09 (t, IH), 8.70
(s, IH), 8.82 - 8.85 (m, IH). mTOR Kinase Assay (Echo): 0.00557μM
Example 28k: 1H NMR (399.902 DMSO-d6) δ 1.17 (d, 3H), 1.56 - 1.64 (m, 2H), 1.69 - 1.80
(m, 2H), 1.96 - 2.04 (m, 2H), 3.10 - 3.20 (m, 3H), 3.41 - 3.51 (m, 3H), 3.58 - 3.63 (m, IH),
3.74 (d, IH), 3.93 - 3.98 (m, IH), 4.13 (d, IH), 4.40 (s, IH), 4.48 (t, IH), 6.19 (t, IH), 6.67 (s, IH), 7.36 (d, 2H), 7.72 (d, 2H), 7.73 - 7.77 (m, IH), 7.99 (d, IH), 8.09 (t, IH), 8.67 (s, IH),
8.82 - 8.84 (m, IH). mTOR Kinase Assay (Echo): 0.000954μM
Example 281: 1R NMR (399.902 DMSO-de) δ 1.17 (d, 3H), 1.69 - 1.81 (m, 2H), 1.96 - 2.05
(m, 2H), 3.10 - 3.19 (m, IH), 3.42 - 3.50 (m, IH), 3.58 - 3.64 (m, IH), 3.75 (d, IH), 3.79 (s, 3H), 3.93 - 3.99 (m, IH), 4.14 (d, IH), 4.41 (s, IH), 6.68 (s, IH), 7.38 - 7.44 (m, 3H), 7.73 -
7.78 (m, 4H), 8.00 (d, IH), 8.07 - 8.12 (m, IH), 8.37 (s, IH), 8.80 (s, IH), 8.82 - 8.85 (m,
IH). mTOR Kinase Assay (Echo): 0.000442μM
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl N- [4- [4- [(36^-3 -methylmorpholin-4-yl1-6-(l-pyridin-2- ylsulfonylcvclopropyl)pyrimidin-2-yllphenyllcarbamate
Figure imgf000503_0001
Phenyl chloroformate (0.693 g, 4.43 mmol) was added dropwise to 4-[4-[(35)-3- methylmorpholin-4-yl]-6-(l-pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2-yl]aniline (2.0 g, 4.43 mmol) and sodium hydrogen carbonate (0.744 g, 8.86 mmol) in dioxane (40 mL) at RT. The resulting slurry was stirred at RT for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 0% - 20% ethyl acetate in DCM, to afford the desired material as a yellow gum (2.07 g). NMR spectrum: 1H NMR (399.902 CDCIi) δ 1.23 (5H, d), 1.61 - 1.71 (2H, m), 2.06 - 2.15 (2H, m), 3.17 - 3.24 (IH, m), 3.47 - 3.54 (IH, m), 3.75 (IH, d), 4.05 - 4.11 (2H, m), 4.35 (IH, s), 6.82 (IH, s), 6.95 (IH, s), 7.13 (2H, m), 7.16 - 7.21 (IH, m), 7.31 - 7.37 (4H, m), 7.38 - 7.43 (IH, m), 7.73 - 7.77 (IH, m), 7.86 (IH, d), 7.93 - 7.97 (2H, m) LCMS Spectrum: m/z (ESI+)(M+H)+ = 572.6; HPLC tR = 2.81 min.
4-r4-r(35)-3-Methylmorpholin-4-yll-6-(l-pyridin-2-ylsulfonylcvclopropyl)pyrimidin-2- yll aniline
Figure imgf000504_0001
Sodium carbonate (20.51 mL, 41.03 mmol) was added to 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (2.498 g, 11.4 mmol) and 2-chloro-4-[(35)-3-methylmorpholin-4- yl]-6-(l-pyridin-2-ylsulfonylcyclopropyl)pyrimidine (4.5 g, 11.40 mmol) in a mixture of DME (20 mL), ethanol (20 mL), DMF (20 mL) and water (40 mL). The mixture was purged with nitrogen then bis(triphenylphosphine)palladium(II) chloride (0.4 g, 0.57 mmol) was added and the resulting suspension was stirred at 800C for 90 minutes. The reaction mixture was concentrated, diluted with ethyl acetate (150 mL), and washed sequentially with water (2 x 150 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 45% ethyl acetate in DCM, to afford the desired material as a beige solid (3.64 g).
NMR spectrum: 1H NMR (399.902 CDCIi) δ 1.20 (3H, d), 1.60 - 1.72 (2H, m), 2.04 - 2.12 (2H, m), 3.14 - 3.22 (IH, m), 3.46 - 3.53 (IH, m), 3.71 - 3.78 (3H, m), 3.92 - 3.96 (IH, m), 4.02 - 4.08 (IH, m), 4.33 (IH, s), 6.53 (2H, d), 6.76 (IH, s), 7.37 - 7.41 (IH, m), 7.72 - 7.77 (IH, m), 7.78 - 7.86 (3H, m), 8.64 - 8.66 (IH, m) LCMS Spectrum: m/z (ESI+)(M+H)+ = 452.6; HPLC tR = 1.40 min. 2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(l-pyridin-2-ylsulfonylcvclopropyl)pyrimidine
Figure imgf000505_0001
1 ,2-Dibromoethane (5.61 mL, 65.08 mmol) was added to 2-chloro-4-[(35)-3- methylmorpholin-4-yl]-6-(pyridin-2-ylsulfonylmethyl)pyrimidine (6 g, 16.27 mmol), ION sodium hydroxide solution (32.5 mL, 325.35 mmol) and tetrabutylammonium bromide (0.524 g, 1.63 mmol) in toluene (400 mL). The resulting solution was stirred at 600C for 3 hours. The reaction mixture was concentrated and diluted with ethyl acetate (150 mL), then washed with water (2 x 100 mL) and saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 20% ethyl acetate in DCM, to afford the desired material as a white dry film (3.02 g).
NMR spectrum: 1R NMR (399.902 CDCl3) δ 1.22 (3H, d), 1.56 - 1.67 (2H, m), 1.97 - 2.07 (2H, m), 3.14 - 3.22 (IH, m), 3.41 - 3.49 (IH, m), 3.58 - 3.62 (IH, m), 3.70 (IH, d), 3.89 - 3.99 (2H, m), 4.21 (IH, s), 7.02 (IH, s), 7.44 - 7.48 (IH, m), 7.81 - 7.89 (2H, m), 8.62 - 8.64 (IH, m)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 395.4; HPLC tR = 1.98 min.
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(pyridin-2-ylsulfonylmethyl)pyrimidine
Figure imgf000505_0002
A 35% aqueous solution of hydrogen peroxide (8.26 mL, 93.53 mmol) was added dropwise to a stirred solution of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(pyridin-2- ylsulfanylmethyl)pyrimidine (10.5g, 31.17 mmol), sodium tungstate dihydrate (0.206 g, 0.62 mmol) and 2N Sulfuric acid (0.6 mL) in dioxane (300 mL) and then the solution warmed to 550C. The solution was stirred at 55°C for 4 hours. Further hydrogen peroxide (8.26 mL) was added and the mixture stirred at 5O0C for 18 hours. 3-Chloroperoxybenzoic acid (5.38 g, 31.17 mmol) was added and the mixture stirred at RT for 2 hours. The solution was diluted with water (500 mL) and cooled to 2O0C. A 10% solution of sodium metabisulfite was added to destroy any remaining peroxide and the solution was extracted with ethyl acetate. The organic layer was dried (MgSO4) and filtered. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in DCM, to give the desired material as a yellow gum (10.5 g,).
NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.24 (d, 3H), 3.20 (m, IH), 3.46 (m, IH), 3.61 (d, IH), 3.71 (d, IH), 3.90 - 3.98 (m, 2H), 4.21 (s, IH), 4.51 (s, 2H), 6.50 (s, IH), 7.51 - 7.53 (m, IH), 7.86 - 7.95 (m, 2H), 8.72 - 8.74 (m, IH) LCMS Spectrum: m/z (ESI+)(M+H)+ = 369.4; HPLC tR = 1.73 min.
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(pyridin-2-ylsulfanylmethyl)pyrimidine
Figure imgf000506_0001
DIPEA (8.77 ml, 50.71 mmol) was added to 2-mercaptopyridine (3.80 g, 34.22 mmol), in DMF (300 mL) at RT in an atmosphere of nitrogen. The resulting solution was stirred at RT for 15 minutes. 2-Chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (11 g, 31.11 mmol) was added portionwise over 5 minutes and the mixture stirred at RT for 3 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (200 mL) and washed sequentially with saturated sodium hydrogen carbonate solution (100 mL) and saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in DCM, to give the desired material as a tan oil (10.50 g). NMR shows the presence of 0.6 eq. of 3-chlorobenzoic acid. This material was used in the subsequent step without further purification. NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.23 (d, 3H), 3.17 - 3.25 (m, IH), 3.46 - 3.54 (m, IH), 3.62 - 3.67 (m, IH), 3.74 (d, IH), 3.93 - 4.01 (m, 2H), 4.20 (s, IH), 4.29 - 4.38 (m, 2H), 6.60 (s, IH), 6.99 - 7.02 (m, IH), 7.20 (d, IH), 7.47 - 7.51 (m, IH), 8.40 - 8.42 (m, IH). LCMS Spectrum: m/z (ESI+)(M+H)+ = 337.5; HPLC tR = 2.19 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Example 29: [4-[4-[(3S)-3-Methylmorpholin-4-yll-6-q- methylsulfonylcvclopropyl)pyrimidin-2-yll phenyll urea
Figure imgf000507_0001
6-Aminopyridin-2(l//)-one hydrochloride salt (0.218 g, 1.49 mmol) was added to phenyl N- [4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]carbamate (0.151 g, 0.30 mmol) and triethylamine (0.249 mL, 1.78 mmol) in DMF (2 mL) at RT. The resulting solution was stirred at 500C for 1 day. The solution was cooled and purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents, to give the desired material as a white solid (0.094 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.22-1.25(3H, d), 1.55-1.58(2H, q), 1.66-1.69(2H, q), 3.17-3.26(1H, td), 3.30(3H, s), 3.45-3.52(1H, td), 3.62-3.65(1H, dd), 3.75- 3.78(1H, d), 3.96-3.99(1H, dd), 4.2O-4.23(1H, d), 4.57(1H, bs), 5.91(2H, s), 6.77(1H, s), 7.50- 7.52(2H, q), 8.19-8.21(2H, q), 8.76(1H, s). LCMS Spectrum: m/z (ES+)(M+H)+=432; HPLC tR=1.66 min. mTOR Kinase Assay (Echo): 0.0042μM
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]carbamate was described earlier. Example 30: 3-Cvclopropyl-l-[4-[4-[4-(3,5-difluorophenyl)sulfonylpiperidin-4-yll-6- [(3S)-3-methylmorpholin-4-yll pyrimidin-2-yll phenyll urea
Figure imgf000508_0001
1-Chloroethyl chloroformate (0.015 mL, 0.14 mmol) and l-[4-[4-[l-benzyl-4-(3,5- difluorophenyl)sulfonylpiperidin-4-yl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea (50 mg, 0.07 mmol) were dissolved in DCM (1 mL) and sealed into a microwave tube. The reaction was heated to 1100C for 5 minutes in a microwave reactor and then cooled to RT. Methanol (1 mL) was added and the mixture was heated to 1100C for 5 minutes in a microwave reactor and then cooled to RT. The mixture was purified by ion exchange chromatography using an SCX column, eluting with methanol followed by 2M ammonia in methanol. The isolated material was further purified by chromatography on silica, eluting with 2% methanol in DCM to 20% methanol in DCM containing 1% ammonia. The isolated material was triturated with diethyl ether to give the desired material as a colourless solid (26 mg). NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 0.68 - 0.72 (2H, m), 0.86 - 0.90 (2H, m), 1.36 (3H, d), 2.27 - 2.36 (2H, m), 2.52 - 2.65 (3H, m), 2.70 - 2.79(2H, m), 3.10 - 3.15 (2H, m), 3.34 (IH, dt), 3.64 (IH, dt), 3.77 - 3.87 (2H, m), 4.05 - 4.18 (2H, m), 4.43 - 4.52 (IH, m), 4.91 (IH, s), 6.65 (IH, s), 6.81 - 6.87 (IH, m), 6.95 - 7.02 (3H, m), 7.39 (2H, d), 7.93 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 613.5; HPLC tR = 2.16 min. mTOR Kinase Assay (Echo): 0.025μM
The preparation of l-[4-[4-[l-benzyl-4-(3,5-difiuorophenyl)sulfonylpiperidin-4-yl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-cyclopropylurea was described earlier. Example 31: 1- [4- [4- [ l-O-Hydroxypropylsulfonylkyclopropyll -6- \(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-propan-2-ylurea
Figure imgf000509_0001
Triethylamine (0.126 mL, 0.90 mmol) was added to phenyl 7V-[4-[4-[l-(3- hydroxypropylsulfonyl)cyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl] carbamate (100 mg, 0.18 mmol) and propan-2-amine (0.078 mL, 0.90 mmol) in NMP (2 mL) at RT under air. The resulting solution was stirred at RT for 1 hour. The crude product was purified by preparative, using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents, to give the desired material as a white solid (65 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.11 (6H, d), 1.22 (3H, d), 1.54 - 1.58 (2H, m), 1.60 - 1.64 (2H, m), 1.90 - 1.97 (2H, m), 3.16 - 3.23 (IH, m), 3.31 - 3.34 (IH, m), 3.44 . 3.55 (4H, m), 3.61 - 3.64 (IH, m), 3.73 - 3.81 (2H, m), 3.95 - 3.99 (IH, m), 4.16 - 4.26 (IH, m), 4.52 - 4.59 (IH, m), 4.73 (IH, t), 6.08 (IH, d), 6.77 (IH, s), 7.47 (2H, d), 8.20 (2H, d), 8.57 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 518; HPLC tR = 2.04min. mTOR Kinase Assay (Echo): 0.00452μM
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[l-(3- hydroxypropylsulfonyl)cyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000510_0001
Figure imgf000511_0001
Figure imgf000512_0001
Example 31a: 1R NMR (400.132 MHz, DMSOd6) δ 0.40 - 0.43 (2H, m), 0.62 - 0.67 (2H, m), 1.22 (3H, d), 1.54 - 1.58 (2H, m), 1.60 - 1.64 (2H, m), 1.90 - 1.97 (2H, m), 2.53 - 2.58 (IH, m), 3.16 - 3.22 (IH, m), 3.44 - 3.55 (5H, m), 3.61 - 3.64 (IH, m), 3.76 (IH, d), 3.95 - 3.98 (IH, m), 4.17 - 4.25 (IH, m), 4.53 - 4.59 (IH, m), 4.73 (IH, t), 6.46 (IH, s), 6.77 (IH, s),
7.50 (2H, d), 8.21 (2H, d), 8.58 (IH, s). mTOR Kinase Assay (Echo): 0.00265μM
Example 31b: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.54 - 1.63 (6H, m), 1.81 - 1.97 (4H, m), 2.17 - 2.23 (2H, m), 3.17 - 3.22 (IH, m), 3.45 - 3.54 (5H, m), 3.61 - 3.63 (IH, m), 3.76 (IH, d), 3.96 - 3.98 (IH, m), 4.10 - 4.24 (2H, m), 4.51 - 4.58 (IH, m), 4.73 (IH, t),
6.48 (IH, d), 6.77 (IH, s), 7.47 (2H, d), 8.20 (2H, d), 8.60 (IH, s). mTOR Kinase Assay (Echo): 0.00497μM
Example 31c: 1R NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.55 - 1.58 (2H, m), 1.62 - 1.66 (2H, m), 1.91 - 1.98 (2H, m), 3.18 - 3.25 (IH, m), 3.46 - 3.57 (5H, m), 3.62 - 3.65 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.20 - 4.27 (IH, m), 4.52 - 4.61 (IH, m), 4.75 (IH, t),
6.80 (IH, s), 7.02 - 7.05 (IH, m), 7.55 - 7.58 (IH, m), 7.64 (2H, d), 7.75 - 7.79 (IH, m), 8.29 -
8.31 (IH, m), 8.30 (2H, d), 9.49 (IH, s), 10.63 (IH, s). mTOR Kinase Assay (Echo): 0.00131μM Example 31d: 1H NMR (400.132 MHz, DMSO-d6) δ 0.88 (6H, d), 1.22 (3H, d), 1.54 - 1.56
(2H, m), 1.60 - 1.64 (2H, m), 1.90 - 1.97 (2H, m), 2.94 (2H, t), 3.16 - 3.23 (IH, m), 3.45 -
3.55 (6H, m), 3.61 - 3.64 (IH, m), 3.76 (IH, d), 3.96 - 3.98 (IH, m), 4.16 - 4.26 (IH, m), 4.52
- 4.59 (IH, m), 4.73 (IH, t), 6.26 (IH, t), 6.77 (IH, s), 7.48 (2H, d), 8.21 (2H, d), 8.68 (IH, s). mTOR Kinase Assay (Echo): 0.00955μM Example 31e: 1R NMR (400.132 MHz, DMSO-de) δ 1.06 (3H, t), 1.22 (3H, d), 1.54 - 1.58 (2H, m), 1.60 - 1.64 (2H, m), 1.90 - 1.97 (2H, m), 3.09 - 3.23 (3H, m), 3.44 - 3.55 (5H, m), 3.61 - 3.64 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.18 - 4.24 (IH, m), 4.53 - 4.59 (IH, m), 4.73 (IH, t), 6.18 (IH, t), 6.77 (IH, s), 7.49 (2H, d), 8.20 (2H, d), 8.70 (IH, s). mTOR Kinase Assay (Echo): 0.00107μM Example 31f: 1H NMR (400.132 MHz, DMSO-d6) δ 1.22 (3H, d), 1.54 - 1.64 (4H, m), 1.90 - 1.97 (2H, m), 3.15 - 3.19 (2H, m), 3.43 - 3.54 (8H, m), 3.61 - 3.63 (IH, m), 3.76 (IH, d), 3.95
- 3.98 (IH, m), 4.17 - 4.24 (IH, m), 4.51 - 4.59 (IH, m), 4.73 - 4.79 (2H, m), 6.28 (IH, t), 6.76 (IH, s), 7.48 (2H, d), 8.21 (2H, d), 8.84 (IH, s). mTOR Kinase Assay (Echo): 0.0016μM Example 31g: 1R NMR (400.132 MHz, DMSO-de) δ 1.22 (3H, d), 1.54 - 1.58 (2H, m), 1.60 - 1.64 (2H, m), 1.90 - 1.97 (2H, m), 2.66 (3H, d), 3.16 - 3.23 (IH, m), 3.44 - 3.55 (5H, m), 3.61 - 3.64 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.17 - 4.23 (IH, m), 4.52 - 4.59 (IH, m), 4.73 (IH, t), 6.07 - 6.10 (IH, m), 6.77 (IH, s), 7.50 (2H, d), 8.20 (2H, d), 8.78 (IH, s). mTOR Kinase Assay (Echo): 0.00323μM
Example 31h: 1H NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.55 - 1.59 (2H, m), 1.62 - 1.65 (2H, m), 1.91 - 1.98 (2H, m), 3.17 - 3.25 (IH, m), 3.45 - 3.56 (5H, m), 3.62 - 3.65 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.18 - 4.26 (IH, m), 4.53 - 4.61 (IH, m), 4.75 (IH, t), 6.80 (IH, s), 7.58 (2H, d), 7.64 - 7.70 (4H, m), 8.29 (2H, d), 9.09 (IH, s), 9.17 (IH, s). mTOR Kinase Assay (Echo): 0.000209μM
Example 31i: 1R NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.54 - 1.64 (6H, m), 1.90 - 1.97 (2H, m), 3.14 - 3.23 (3H, m), 3.44 - 3.55 (7H, m), 3.61 - 3.64 (IH, m), 3.76 (IH, d), 3.95
- 3.99 (IH, m), 4.17 - 4.25 (IH, m), 4.52 (IH, t), 4.53 - 4.59 (IH, m), 4.73 (IH, t), 6.22 (IH, t), 6.77 (IH, s), 7.49 (2H, d), 8.20 (2H, d), 8.75 (IH, s). mTOR Kinase Assay (Echo): 0.00326μM
Example 31j: 1H NMR (400.132 MHz, DMSO-d6) δ 1.23 (3H, d), 1.54 - 1.58 (2H, m), 1.61 - 1.64 (2H, m), 1.90 - 1.98 (2H, m), 3.16 - 3.24 (IH, m), 3.46 - 3.56 (4H, m), 3.61 - 3.65 (IH, m), 3.79 (3H, s), 3.96 - 3.99 (IH, m), 4.18 - 4.25 (IH, m), 4.53 - 4.58 (IH, m), 4.74 (IH, t),
6.78 (IH, s), 7.39 (IH, s), 7.54 (2H, d), 7.77 (IH, s), 8.24 (2H, d), 8.43 (IH, s), 8.89 (IH, s). mTOR Kinase Assay (Echo): 0.00103μM
Example 31k: 1H NMR (400.132 MHz, DMSO-d6) δ 0.88 (3H, t), 1.22 (3H, d), 1.41 - 1.50 (2H, m), 1.54 - 1.58 (2H, m), 1.60 - 1.64 (2H, m), 1.88 - 1.97 (2H, m), 3.03 - 3.08 (2H, m),
3.16 - 3.23 (IH, m), 3.44 - 3.55 (5H, m), 3.61 - 3.64 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.17 - 4.24 (IH, m), 4.51 - 4.59 (IH, m), 4.73 (IH, t), 6.22 (IH, t), 6.77 (IH, s), 7.49 (2H, d), 8.20 (2H, d), 8.69 (IH, s). mTOR Kinase Assay (Echo): 0.00191μM Example 311: 1U NMR (400.132 MHz, DMSO-d6) δ 1.22 (3H, d), 1.54 - 1.58 (2H, m), 1.60 -
1.64 (2H, m), 1.90 - 1.97 (2H, m), 2.18 (6H, s), 2.33 (2H, t), 3.17 - 3.23 (3H, m), 3.44 - 3.55
(5H, m), 3.61 - 3.64 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.17 - 4.25 (IH, m), 4.50 -
4.60 (IH, m), 4.73 (IH, t), 6.17 (IH, t), 6.77 (IH, s), 7.48 (2H, d), 8.20 (2H, d), 8.92 (IH, s). mTOR Kinase Assay (Echo): 0.214μM Example 31m: 1H NMR (400.132 MHz, DMSO-d6) δ 1.24 (6H, s), 1.54 - 1.58 (2H, m), 1.60
- 1.64 (2H, m), 1.90 - 1.97 (2H, m), 3.16 - 3.23 (IH, m), 3.38 (2H, d), 3.44 - 3.55 (5H, m),
3.61 - 3.64 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.17 - 4.25 (IH, m), 4.51 - 4.59 (IH, m), 4.74 (IH, t), 4.99 (IH, t), 6.01 (IH, s), 6.76 (IH, s), 7.45 (2H, d), 8.19 (2H, d), 8.77 (IH, s). mTOR Kinase Assay (Echo): 0.00591μM
The preparation of phenyl Λ/-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below:
Phenyl N-\4-\4-\ 1 -(3-hvdroxypropylsulfonyl)cvclopropyll-6-r(36^-3-methylmorpholin-4- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000515_0001
Phenyl chloroformate (0.581 mL, 4.63 mmol) was added to 3-[l-[2-(4-aminophenyl)-6-[(35)- 3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonylpropan-l-ol (1.82 g, 4.21 mmol) and sodium bicarbonate (0.530 g, 6.31 mmol) in dioxane (100 mL) at 50C under a nitrogen atmosphere. The resulting suspension was stirred overnight and allowed to come to RT. The reaction mixture was diluted with ethyl acetate (200 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford desired product as a gum. The gum was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (2.32 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 1.48 - 1.52 (2H, m), 1.55 - 1.61 (2H, m), 1.83 - 1.90 (2H, m), 3.11 - 3.18 (IH, m), 3.38 - 3.46 (4H, m), 3.54 - 3.58 (IH, m), 3.69 (IH, d), 3.75 - 3.94 (2H, m), 3.88 - 3.92 (IH, m), 4.14 - 4.18 (IH, m), 4.47 - 4.53 (IH, m), 6.75 (IH, s), 7.17 - 7.23 (3H, m), 7.36 - 7.39 (2H, m), 7.56 (2H, d), 8.23 (2H, d), 10.37 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 553; HPLC tR = 2.51min.
3-ri-r2-(4-Aminophenyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4- yllcvclopropyllsulfonylpropan-l-ol
Figure imgf000516_0001
Dichlorobis(triphenylphosphine)palladium (II) (0.218 g, 0.31 mmol) was added to 3-[l-[2- chloro-6- [(35)-3 -methylmorpholin-4-yl]pyrimidin-4-yl] cyclopropyl]sulfonylpropan- 1 -ol (2.33 g, 6.20 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.766 g, 8.06 mmol) and 2M aqueous sodium carbonate solution (11.16 mL, 22.32 mmol) in DMF (15 mL), water (37.5 mL), ethanol (15 mL) and DME (15 mL) at RT under a nitrogen atmosphere. The resulting solution was stirred at 800C for 17 hours. The reaction mixture was diluted with ethyl acetate (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product as a brown solid. The crude product was purified by flash silica chromatography, eluting with 0 to 75% ethyl acetate in DCM, to give the desired material as a cream solid (1.82 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.52 - 1.54 (2H, m), 1.60 - 1.62 (2H, m), 1.90 - 1.97 (2H, m), 3.14 - 3.21 (IH, m), 3.44 - 3.52 (5H, m), 3.60 - 3.64 (IH, m), 3.75 (IH, d), 3.94 - 3.98 (IH, m), 4.16 - 4.19 (IH, m), 4.48 - 4.55 (IH, m), 4.67 (IH, t), 5.56 (2H, s), 6.60 (2H, d), 6.67 (IH, s), 8.04 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 433; HPLC tR = 1.81min.
3 - r 1 - [2-ChIQrQ-O- r(3ιSV3 -methylmorpholin-4-yllpyrimidin-4-vH cvclopropyllsulfonylpropan- l -θl
Figure imgf000516_0002
Tetrabutylammonium fluoride (IM in THF, 31 mL, 31 mmol) was added to 3-[l-[2-chloro-6- [(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonylpropoxy-tri(propan-2- yl)silane (3.28 g, 6.16 mmol) in THF (30 mL) at RT. The resulting solution was stirred at RT for 1 hour then concentrated in vacuo and diluted with saturated ammonium chloride (10 mL) and water. The mixture was extracted twice with ethyl acetate, the combined organic extracts washed with brine,dried (MgSO4), filtered and evaporated to give the desired material as a gum (2.33 g).
NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.33 (3H, d), 1.42 - 1.51 (4H, m), 2.07 - 2.14 (2H, m), 2.40 (IH, s), 3.28 - 3.32 (2H, m), 3.37 - 3.42 (3H, m), 3.51 - 3.57 (IH, m), 3.66 - 3.70 (IH, m), 3.77 - 3.80 (2H, m), 3.99 - 4.02 (IH, m), 4.28 - 4.38 (IH, m), 6.84 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 376; HPLC tR = 1.58min.
3 - r 1 - [2-Chloro-6- [(36^-3 -methylmorpholin-4-yllpyrimidin-4-yll cyclopropyll sulfonylpropoxy- tri(propan-2-vDsilane
Figure imgf000517_0001
1 ,2-dibromoethane (1.723 mL, 20 mmol) was added to 3-[[2-chloro-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]propoxy-tri(propan-2-yl)silane (5.O g, 9.88 mmol), 40% sodium hydroxide solution (10 mL, 98.78 mmol) and tetrabutylammonium bromide (0.645 g, 2 mmol) in toluene (50 mL) at RT under air. The resulting mixture was stirred at 600C for 4 hours. The reaction mixture was evaporated to dryness and redissolved in ethyl acetate (100 mL) and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with 0 to 20% ethyl acetate in DCM, to give the desired material as a colourless gum (2.86 g).
NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.00 - 1.05 (21H, m), 1.32 (3H, d), 1.49 - 1.52 (2H, m), 1.78 - 1.81 (2H, m), 2.02 - 2.09 (2H, m), 3.21 - 3.32 (3H, m), 3.50 - 3.56 (IH, m), 3.65 - 3.69 (IH, m), 3.77 - 3.80 (3H, m), 3.98 - 4.02 (2H, m), 4.28 - 4.36 (IH, m), 6.90 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 532; HPLC tR = 3.37min.
3-rr2-Chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-yllmethylsulfonyllpropoxy- tri(propan-2-yl)silane
Figure imgf000518_0001
3-[[2-Chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]propan-l-ol (5.04 g, 14.41 mmol) in DMF (25 mL) was added to chlorotrisopropylsilane (3.70 mL, 17.29 mmol) and imidazole (2.354 g, 34.58 mmol) in DMF (25 mL) at RT over a period of 5 minutes under a nitrogen atmosphere. The resulting solution was stirred at RT for 18 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (200 mL) then washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to give the desired material as an oil (7.29 g). NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 0.99 - 1.07 (21H, m), 1.33 (3H, d), 2.06 - 2.13 (2H, m), 3.20 - 3.24 (2H, m), 3.26 - 3.34 (IH, m), 3.50 - 3.57 (IH, m), 3.66 - 3.70 (IH, m), 3.77 - 3.83 (3H, m), 3.99 - 4.03 (2H, m), 4.16 (2H, s), 4.25 - 4.37 (IH, m), 6.54 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 506; HPLC tR = 3.42min.
3-rr2-Chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-yllmethylsulfonvHpropan-l-ol
Figure imgf000518_0002
3-Chlorobenzoperoxoic acid (4.00 g, 23.16 mmol) was added to 3-[[2-chloro-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfanyl]propan-l-ol (3.68 g, 11.58 mmol) in DCM (100 mL) at RT over a period of 5 minutes. The resulting solution was stirred at RT for 3 hours. A further portion of 3-chlorobenzoperoxoic acid (2.00 g, 11.58 mmol) was added and the resulting solution was stirred at RT for an additional 1 hour. The reaction mixture was washed sequentially with 10% aqueous sodium metabisulphite solution (2 x 100 mL), a saturated aqueous solution of sodium hydrogen carbonate (100 mL), and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to give the desired material as a gum (4.05 g). NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.34 (3H, d), 2.12 - 2.18 (2H, m), 3.27 (2H, t), 3.31 - 3.35 (IH, m), 3.51 - 3.57 (IH, m), 3.67 - 3.70 (IH, m), 3.77 - 3.82 (3H, m), 3.99 - 4.03 (IH, m), 4.18 (2H, s), 4.26 - 4.37 (IH, m), 6.51 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 350; HPLC tR = 1.30min.
3-rr2-Chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-yllmethylsulfanyllpropan-l-ol
Figure imgf000519_0001
A solution of 2-chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (12.4 g, 35.07 mmol) in DCM (50 mL) was added to a stirred solution of 3-mercapto-l-propanol (3.64 mL, 42.08 mmol) and DIPEA (9.77 mL, 56.11 mmol) in DCM (100 mL) at RT, over a period of 40 minutes under a nitrogen atmosphere. The resulting solution was stirred at RT for 18 hours. The reaction mixture was washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate (2 x 50 mL) and saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product as a dark brown oil. The crude product was purified by flash silica chromatography, eluting with 0 to 75% ethyl acetate in DCM, to give the desired material as a yellow gum (5.86 g).
NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.32 (3H, d), 1.84 - 1.90 (2H, m), 1.94 (IH, s), 2.69 (2H, t), 3.24 - 3.32 (IH, m), 3.51 - 3.58 (IH, m), 3.61 (2H, s), 3.67 - 3.71 (IH, m), 3.73 - 3.80 (3H, m), 3.98 - 4.04 (2H, m), 4.28 - 4.34 (IH, m), 6.45 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 318; HPLC tR = 1.55min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine was described earlier. Example 32: NJV-Dimethyl-l-[2-[4-(methylcarbamoylamino)phenyll-6-morpholin-4- ylpyrimidin^-yllcvclopropane-l-carboxamide
Figure imgf000520_0001
DIPEA (0.127 mL, 0.72 mmol) was added to a suspension of l-[2-[4- (methylcarbamoylamino)phenyl] -6-morpholin-4-ylpyrimidin-4-yl] cyclopropane- 1 -carboxylic acid (96 mg, 0.24 mmol), dimethylamine (2.0M in THF, 0.36 mL, 0.72 mmol) and HBTU (138 mg, 0.36 mmol) in DMF (3 mL). The reactions were stirred at RT for 3 hours. The reaction mixture was passed down a SCX-2 ion exchange column, eluting with methanol followed by 7N ammonia in methanol. The isolated material was further purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents, to give the desired material as a white solid (54 mg). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.28 - 1.31 (2H, m), 1.51 - 1.54 (2H, m), 2.65 (3H, d), 2.87 - 2.89 (3H, s), 2.94 (3H, s), 3.64 (4H, m), 3.69 - 3.71 (4H, m), 6.08 (IH, d), 6.22 (IH, s), 7.46 - 7.49 (2H, m), 8.16 - 8.18 (2H, m), 8.76 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 425; HPLC tR = 1.45 min. mTOR Kinase Assay (Echo): 0.00315μM
The following compounds were made in an analogous fashion from l-[2-[4- (methylcarbamoylamino)phenyl] -6-morpholin-4-ylpyrimidin-4-yl] cyclopropane- 1 -carboxylic acid and the appropriate amine.
Figure imgf000520_0002
Figure imgf000521_0001
Example 32a: 1R NMR (400.13 MHz, DMSOd6) δ 1.23 (3H, d), 1.31 (2H, d), 1.62 (2H, d), 2.65 - 2.66 (3H, m), 3.17 (IH, d), 3.48 (IH, d), 3.50 (IH, m), 3.66 (4H, s), 3.70 (4H, s), 3.70 (IH, s), 3.85 (IH, m), 4.23 (IH, d), 4.47 - 4.49 (IH, m), 6.07 (IH, q), 6.23 (IH, d), 7.48 (2H, d), 8.19 (2H, d), 8.76 (IH, s). mTOR Kinase Assay (Echo): 0.0425μM
Example 32b: 1H NMR (400.13 MHz, DMSOd6) δ 0.42 - 0.46 (2H, m), 0.60 - 0.65 (2H, m),
1.30 - 1.37 (4H, m), 2.66 (3H, d), 2.67 - 2.68 (IH, m), 3.67 (8H, s), 6.08 (IH, d), 6.46 (IH, s),
7.48 - 7.50 (2H, m), 8.14 - 8.17 (2H, m), 8.37 (IH, d), 8.77 (IH, s). mTOR Kinase Assay (Echo): 0.00829μM
Example 32c: 1R NMR (400.13 MHz, DMSOd6) δ 0.64 (2H, s), 0.69 (2H, s), 1.32 (2H, s),
1.49 (2H, t), 2.33 (IH, t), 2.65 - 2.66 (3H, m), 2.73 - 2.76 (3H, m), 3.64 (4H, s), 3.69 - 3.71 (4H, m), 6.07 (IH, q), 6.30 (IH, s), 7.46 - 7.49 (2H, m), 8.16 - 8.18 (2H, m), 8.75 (IH, s). mTOR Kinase Assay (Echo): 0.00288μM Example 32d: 1H NMR (400.13 MHz, DMSO-d6) δ 1.29 - 1.32 (2H, m), 1.50 - 1.53 (2H, m), 2.11 - 2.11 (3H, m), 2.14 (2H, s), 2.33 (2H, t), 2.65 - 2.66 (3H, m), 3.30 (2H, s), 3.57 (2H, s), 3.67 - 3.70 (8H, m) 6.08 (IH, q), 6.26 (IH, s), 7.46 - 7.50 (2H, m), 8.17 - 8.20 (2H, m), 8.76
(IH, s). mTOR Kinase Assay (Echo): 0.0131μM
The preparation of l-[2-[4-(methylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4- yl]cyclopropane-l-carboxylic acid is described below:
l-r2-r4-(Methylcarbamoylamino)phenyll-6-morpholin-4-ylpyrimidin-4-yllcvclopropane-l- carboxylic acid
Figure imgf000522_0001
Lithium hydroxide- 1 -hydrate (59.5 mg, 1.42 mmol) was added in one portion to methyl l-[2- [4-(methylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4-yl]cyclopropane-l- carboxylate (583 mg, 1.42 mmol) in methanol (8 mL) and water (8 mL). The resulting suspension was stirred at 600C for 5 hours. The reaction mixture was evaporated to dryness, redissolved in water (25 mL), and washed with diethyl ether (25 mL). The aqueous layer was acidified with 2M hydrochloric acid and the precipitate was collected by filtration, washed with diethyl ether and dried under vacuum to give the desired material as a brown solid (486 mg). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.51 - 1.58 (4H, m), 2.65 - 2.66 (3H, m), 3.70 (8H, s), 6.09 (IH, q), 6.73 (IH, s), 7.49 - 7.52 (2H, m), 8.13 - 8.15 (2H, m), 8.80 (IH, s), 14.09 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 398; HPLC tR = 1.21 min.
Methyl l-r2-r4-(methylcarbamoylamino)phenyll-6-morpholin-4-ylpyrimidin-4- yll cyclopropane- 1-carboxylate
Figure imgf000523_0001
Methylamine (1.97 mL, 3.94 mmol) was added in one portion to methyl l-[6-morpholin-4-yl- 2-[4-(phenoxycarbonylamino)phenyl]pyrimidin-4-yl]cyclopropane-l-carboxylate (934 mg, 1.97 mmol) in DMF (20 mL) The resulting solution was stirred at RT for 4 hours. The reaction mixture was evaporated to dryness and the residue purified by ion exchange chromatography using an SCX column, eluting with methanol followed by 7M ammonia in methanol, to give the desired material as a yellow solid (713 mg).
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.49 - 1.55 (4H, m), 2.66 (3H, d), 3.65 (3H, s), 3.69 (8H, s), 6.05 (IH, t), 6.83 (IH, s), 7.46 - 7.49 (2H, m), 8.16 - 8.19 (2H, m), 8.71 (IH, s)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 412; HPLC tR = 1.93 min.
Methyl l-[6-morpholin-4-yl-2-[4-(phenoxycarbonylamino)phenyllpyrimidin-4- yll cyclopropane- 1-carboxylate
Figure imgf000523_0002
Phenyl chloro formate (0.53 mL, 4.20 mmol) was added dropwise to methyl l-[2-(4- aminophenyl)-6-morpholin-4-ylpyrimidin-4-yl]cyclopropane-l-carboxylate (1.49 g, 4.20 mmol) and sodium bicarbonate (0.53 g, 6.31 mmol) in dioxane (50 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness, redissolved in ethyl acetate (60 mL) and washed with water (60 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the desired material as a yellow solid (2.1 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.52 - 1.54 (4H, m), 3.57 (3H, s), 3.71 (8H, s), 6.89 (IH, s), 7.24 - 7.30 (3H, m), 7.43 - 7.47 (2H, m), 7.62 (2H, d), 8.27 (2H, d), 10.46 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 475; HPLC tR = 2.83 min.
Methyl 1 -r2-(4-aminophenyl)-6-morpholin-4-ylpyrimidin-4-vH cyclopropane- 1 -carboxylate
Figure imgf000524_0001
Sodium hydride (434 mg, 10.84 mmol) was added in one portion to methyl 2-[2-(4- aminophenyl)-6-morpholin-4-ylpyrimidin-4-yl] acetate (3.56 g, 10.84 mmol) in DMF (75 mL) cooled to O0C under nitrogen. The resulting solution was stirred at 00C for 10 minutes then 1 ,2-dibromoethane (0.981 mL, 11.38 mmol) added and the reaction stirred at 00C for 5 minutes. Further sodium hydride (434 mg, 10.84 mmol) was added in one portion and the reaction stirred at 00C for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (10 mL). The reaction mixture was evaporated to dryness, redissolved in ethyl acetate (100 mL), and washed sequentially with water (100 mL) and saturated brine solution (100 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was triturated with diethyl ether to give the desired material as a yellow solid (2.23 g). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.47 - 1.53 (4H, m), 3.64 (8H, t), 3.69 - 3.71 (3H, m), 5.50-5.60 (2H, s), 6.57 - 6.60 (2H, m), 6.73 (IH, s), 7.99 - 8.03 (2H, m) LCMS Spectrum: m/z (ESI+) (M+H)+ = 355; HPLC tR = 2.06 min.
Methyl 2-r2-(4-aminophenyl)-6-morpholin-4-ylpyrimidin-4-yllacetate
Figure imgf000524_0002
DBU (2.2 mL, 14.68 mmol) was added to methyl 2-[2-(4-aminophenyl)-6-hydroxypyrimidin- 4-yl]acetate (3.46 g, 13.35 mmol) and N-phenyltrifluoromethanesulfonimide (5.24 g, 14.68 mmol) in DCM (120 mL). The resulting solution was stirred at RT for 2 hours. Morpholine (2.91 mL, 33.36 mmol) was added and the reaction stirred at RT for 2 hours. The reaction mixture was diluted with DCM (20 mL) and washed with a saturated aqueous solution of sodium hydrogen carbonate (100 mL). The organic layer was dried (MgSO4) filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a yellow solid (3.65 g). NMR Spectrum: 1H NMR (400.13 MHz, CDCl3) δ 3.62 (2H, d), 3.66 (8H,m), 3.72 - 3.73 (3H, m), 6.27 (IH, s), 6.61 - 6.64 (2H, m), 7.17 - 7.23 (2H, m), 8.12 - 8.16 (2H, m) LCMS Spectrum: m/z (ESI+) (M+H)+ = 329; HPLC tR = 1.74 min.
Methyl 2- r2-(4-aminophenyl)-6-hvdroxypyrimidin-4-vH acetate
Figure imgf000525_0001
To a stirred solution of dimethyl 3-oxopentanedioate (15.06g, 86.50 mmol) in methanol (125 mL) was added 4-aminobenzimidamide dihydrochloride (12 g, 57.67 mmol) and potassium carbonate (19.93 g, 144.17 mmol) and the reaction mixture heated at 9O0C for 5 hours then allowed to cool to RT. The mixture was concentrated in vacuo, redissoved in water (150 mL) and extracted with DCM (150 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The aqueous layer was adjusted to pH5 using acetic acid and the precipitate formed was filtered and dried in a vacuum oven to give the desired material as a yellow solid (3.49g). LCMS Spectrum: m/z (ES+)(M+H)+=260; HPLC tR=1.06 min. Example 33: l-[2-[4-(Cvclopropylcarbamoylamino)phenyll-6-morpholin-4-ylpyrimidin- 4-yll-N.,N-dimethylcvclopropane-l-carboxamide
Figure imgf000526_0001
DIPEA (0.142 mL, 0.81 mmol) was added to a suspension of l-[2-[4- (cyclopropylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4-yl]cyclopropane- 1 - carboxylic acid (115 mg, 0.27 mmol), dimethylamine (2.0M in THF, 0.405 mL, 0.81 mmol) and HBTU (155 mg, 0.36 mmol) in DMF (3 mL). The reactions were stirred at RT for 3 hours then purified on a ion exchange SCX-2 coulmn, eluting with methanol followed by 7N ammonia in methanol. The residue was further purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents, to give the desired material as a white solid (20 mg).
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.39 - 0.43 (2H, m), 0.62 - 0.67 (2H, m), 1.28 - 1.31 (2H, m), 1.51 - 1.54 (2H, m), 2.54 - 2.56 (IH, m), 2.87 (3H, s), 2.94 (3H, s), 3.64 (4H, d), 3.69 - 3.71 (4H, m), 6.22 (IH, s), 6.44 (IH, d), 7.47 - 7.49 (2H, m), 8.16 - 8.19 (2H, m), 8.55 (IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 451; HPLC tR = 1.83 min. mTOR Kinase Assay (Echo): 0.00929μM
The following compounds were made in an analogous fashion from l-[2-[4- (cyclopropylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4-yl]cyclopropane- 1 - carboxylic acid and the appropriate amine.
Figure imgf000527_0001
Example 33a: 1R NMR (400.13 MHz, DMSOd6) δ 0.39 - 0.43 (2H, m), 0.62 - 0.67 (2H, m), 1.16 (IH, s), 1.23 (2H, d), 1.32 - 1.36 (2H, m), 1.40 (IH, d), 1.61 - 1.64 (2H, m), 2.52 - 2.57 (IH, m), 3.17 (IH, q), 3.15 - 3.21 (IH, m), 3.46 - 3.49 (IH, m), 3.66 - 3.66 (4H, m), 3.69 (4H, d), 3.71 (IH, s), 4.20 (IH, d), 4.48 (IH, d), 6.24 (IH, s), 6.45 (IH, d), 7.48 (2H, d), 8.19 (2H, d), 8.55 (IH, s). mTOR Kinase Assay (Echo): 0.0584μM Example 33b: 1H NMR (400.13 MHz, DMSO-d6) δ 0.41 - 0.45 (4H, m), 0.61 - 0.66 (4H, m), 1.31 - 1.35 (4H, m), 2.54 - 2.56 (IH, m), 2.71 (IH, d), 3.67 - 3.72 (8H, m), 6.45 (2H, d), 7.50 (2H, d), 8.15 - 8.17 (2H, m), 8.36 (IH, d), 8.56 (IH, s). mTOR Kinase Assay (Echo): 0.012μM Example 33c: 1R NMR (400.13 MHz, DMSOd6) δ 0.39 - 0.43 (2H, m), 0.50 (2H, m), 0.63 - 0.65 (2H, m), 0.68 (2H, d), 1.32 -1.40 (2H, m), 1.49 (2H, t), 2.54 - 2.57 (IH, m), 2.75 (3H, d), 2.89 (IH, s), 3.64 (4H, d), 3.69 (4H, d), 6.31 (IH, s), 6.45 (IH, d), 7.48 (2H, d), 8.18 (2H, d), 8.54 (IH, s). mTOR Kinase Assay (Echo): 0.00258μM Example 33d: 1H NMR (400.13 MHz, DMSOd6) δ 0.39 - 0.43 (2H, m), 0.62 - 0.67 (2H, m), 1.30 - 1.32 (2H, m), 1.51 (2H, t), 2.12 (4H, s), 2.33 (3H, s), 2.53 - 2.56 (IH, m), 3.58 (4H, s), 3.67 - 3.71 (8H, d), 6.27 (IH, s), 6.45 (IH, d), 7.47 - 7.50 (2H, m), 8.18 - 8.20 (2H, m), 8.55 (IH, s). mTOR Kinase Assay (Echo): 0.133μM
The preparation of l-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin- 4-yl]cyclopropane-l-carboxylic acid is described below:
l-r2-r4-(Cvclopropylcarbamoylamino)phenyll-6-morpholin-4-ylpyrimidin-4- yll cyclopropane- 1-carboxylic acid
Figure imgf000528_0001
Lithium hydroxide- 1 -hydrate (67 mg, 1.59 mmol) was added in one portion to methyl l-[2-[4- (cyclopropylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4-yl]cyclopropane-l- carboxylate (697 mg, 1.59 mmol) in methanol (8 mL) and water (8 mL) The resulting suspension was stirred at 800C for 1 hour. The reaction mixture was evaporated to dryness, redissolved in water (25 mL), and washed with diethyl ether (25 mL). The aqueous layer was acidified with 2M hydrochloric acid, the precipitate collected by filtration, washed with diethyl ether and dried under vacuum to give the desired material as a brown solid (580 mg). NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40 - 0.43 (2H, m), 0.62 - 0.67 (2H, m), 1.51 - 1.58 (4H, m), 2.53 - 2.57 (IH, m), 3.71 (8H, s), 6.48 (IH, d), 6.75 (IH, s), 7.51 (2H, d), 8.15 (2H, d), 8.63 (IH, s), 14.02 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 424; HPLC tR = 1.09 min.
Methyl l-r2-r4-(cvclopropylcarbamoylamino)phenyll-6-morpholin-4-ylpyrimidin-4- yll cyclopropane- 1-carboxylate
Figure imgf000529_0001
Cyclopropanamine (0.219 mL, 3.15 mmol) was added in one portion to methyl l-[6- morpholin-4-yl-2-[4-(phenoxycarbonylamino)phenyl]pyrimidin-4-yl]cyclopropane-l- carboxylate (998 mg, 2.10 mmol) in DMF (20 mL) The resulting solution was stirred at RT for 4 hours and the reaction mixture evaporated to dryness. The crude product was purified by ion exchange chromatography using an SCX column, eluting with methanol followed by 7M ammonia in methanol, to give the desired material as a yellow solid (757 mg). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.39 - 0.43 (2H, m), 0.62 - 0.67 (2H, m), 1.50 - 1.53 (4H, m), 2.52 - 2.56 (IH, m), 3.64 (3H, s), 3.69 (8H, d), 6.43 (IH, d), 6.84 (IH, s), 7.47 - 7.49 (2H, m), 8.18 (2H, d), 8.55 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 438; HPLC tR = 2.10 min.
The preparation of methyl l-[6-morpholin-4-yl-2-[4-
(phenoxycarbonylamino)phenyl]pyrimidin-4-yl]cyclopropane- 1 -carboxylate was described earlier. Example 34: l-[2-[4-(2-Hydroxyethylcarbamoylamino)phenyll-6-morpholin-4- ylpyrimidin^-yll-NJ'J-dimethylcyclopropane-l-carboxamide
Figure imgf000530_0001
DIPEA (0.106 mL, 0.60 mmol) was added to a suspension of l-[2-[4-(2- hydroxyethylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4-yl]cyclopropane- 1 - carboxylic acid (86 mg, 0.20 mmol), dimethylamine (2.0M in THF, 0.30 mL, 0.60 mmol) and HBTU (115 mg, 0.30 mmol) in DMF (3 mL). The reactions were stirred at RT for 1 hour then purified by ion exchange using a SCX-2 column, eluting with methanol followed by 7N ammonia in methanol. The isolated material was further purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents, to give the desired material as a white solid (56 mg).
NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 1.30 - 1.31 (2H, m), 1.53 (2H, d), 2.89 (3H, s), 2.94 (3H, s), 3.17 - 3.19 (2H, m), 3.47 (2H, d), 3.65 (4H, d), 3.70 -3.71 (4H, d), 4.74 (IH, s), 6.23 (2H, m), 7.47 (2H, d), 8.18 (2H, d), 8.79 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 455; HPLC tR = 1.52 min. mTOR Kinase Assay (Echo): 0.00405μM
The following compounds were made in an analogous fashion from l-[2-[4-(2- hydroxyethylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4-yl]cyclopropane-l- carboxylic acid and the appropriate amine.
Figure imgf000530_0002
Figure imgf000531_0001
Example 34a: 1H NMR (399.9 MHz, DMSOd6) δ 1.22 - 1.25 (3H, m), 1.33 (2H, d), 1.63 (2H, d), 3.16 - 3.20 (IH, m), 3.17 - 3.19 (3H, m), 3.46 (3H, m), 3.67 (4H, s), 3.71 (4H, d), 3.71 (2H, s), 4.20 (IH, d), 4.5O(1H, s), 4.74 (IH, t), 6.25 (2H, m), 7.47 (2H, d), 8.20 (2H, d), 8.79 (IH, s). mTOR Kinase Assay (Echo): 0.0387μM
Example 34b: 1H NMR (399.9 MHz, DMSOd6) δ 0.44 - 0.46 (2H, m), 0.62 - 0.65 (2H, m), 1.32 - 1.37 (4H, m), 2.73 (IH, d), 3.18 (2H, d), 3.46 (2H, t), 3.68 (4H, d), 3.71 - 3.71 (4H, d), 4.74 (IH, t), 6.25 (IH, s), 6.46 (IH, s), 7.47 - 7.50 (2H, m), 8.15 - 8.18 (2H, m), 8.35 (IH, s), 8.80 (IH, s). mTOR Kinase Assay (Echo): 0.0109μM
Example 34c: 1R NMR (399.9 MHz, DMSOd6) δ 0.69 (4H, s), 1.50 (4H, m), 2.40 (IH, s), 2.80 (3H, m), 3.16 - 3.19 (2H, m), 3.47 (2H, q), 3.65 (4H, d), 3.70 - 3.72 (4H, m), 4.74 (IH, t), 6.25 (2H, m), 7.46 - 7.48 (2H, m), 8.17 - 8.19 (2H, m), 8.78 (IH, s). mTOR Kinase Assay (Echo): 0.00345μM
Example 34d: 1H NMR (399.9 MHz, DMSO-d6) δ 1.30 - 1.33 (2H, m), 1.51 - 1.54 (2H, m), 2.10 - 2.15 (5H, m), 2.33 - 2.34 (IH, t), 3.18 - 3.19 (3H, m), 3.36 (IH, d), 3.47 (2H, q), 3.58 (3H, s), 3.66 - 3.71 (4H, m), 3.71 (4H, d), 4.74 (IH, t), 6.25 (IH, t), 6.27 (IH, s), 7.46 - 7.49 (2H, m), 8.18 - 8.21 (2H, m), 8.79 (IH, s). mTOR Kinase Assay (Echo): 0.0863μM
The preparation of l-[2-[4-(2-hydroxyethylcarbamoylamino)phenyl]-6-morpholin-4- ylpyrimidin-4-yl]cyclopropane-l-carboxylic acid is described below:
l-[2-[4-(2-Hvdroxyethylcarbamoylamino)phenyll-6-morpholin-4-ylpyrimidin-4- yll cyclopropane- 1-carboxylic acid
Figure imgf000532_0001
Lithium hydroxide- 1 -hydrate (67.2 mg, 1.60 mmol) was added in one portion to methyl l-[2- [4-(2-hydroxyethylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4-yl]cyclopropane- 1-carboxylate (707 mg, 1.60 mmol) in methanol (8 mL) and water (8 mL). The resulting suspension was stirred at 800C for 1 hour. The reaction mixture was evaporated to dryness, redissolved in water (25 mL), and washed with diethyl ether (25 mL). The aqueous layer was acidified with 2M hydrochloric acid, the precipitate collected by filtration, washed with diethyl ether and dried under vacuum to give the desired material as a beige solid (439 mg). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.51 - 1.58 (4H, m), 3.17 (2H, q), 3.45 (2H, t), 3.70 (8H, s), 4.77 (IH, s), 6.28 (IH, t), 6.74 (IH, s), 7.48 - 7.50 (2H, m), 8.14 - 8.16 (2H, m), 8.86 (IH, s), 14.06 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 428; HPLC tR = 0.92 min. Methyl l-r2-r4-(2-hvdroxyethylcarbamoylamino)phenyll-6-morpholin-4-ylpyrimidin-4- yll cyclopropane- 1-carboxylate
Figure imgf000533_0001
2-Aminoethanol (0.127 mL, 2.10 mmol) was added in one portion to methyl l-[6-morpholin- 4-yl-2-[4-(phenoxycarbonylamino)phenyl]pyrimidin-4-yl]cyclopropane-l-carboxylate (998 mg, 2.10 mmol) in DMF (20 mL) The resulting solution was stirred at RT for 16 hours. The reaction mixture was evaporated to dryness and the crude product purified by ion exchange chromatography using an SCX column, eluting with methanol followed by 7N ammonia in methanol, to give the desired material as a yellow solid (767 mg). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.50 - 1.52 (4H, m), 3.17 (2H, q), 3.45 (2H, q), 3.64 (3H, s), 3.70 (8H, s), 4.77 (IH, t), 6.25 (IH, t), 6.83 (IH, s), 7.45 - 7.47 (2H, m), 8.16 - 8.19 (2H, m), 8.81 (IH, s) LCMS Spectrum, m/z (ESI+) (M+H)+ = 442; HPLC tR = 1.71 min.
The preparation of methyl l-[6-morpholin-4-yl-2-[4-
(phenoxycarbonylamino)phenyl]pyrimidin-4-yl]cyclopropane- 1 -carboxylate was described earlier.
Example 35: 3-Methyl-l-[4-[4-[(35V3-methylmorpholin-4-yll-6-q- methylsulfonylcyclopropyDpyrimidin-l-yll phenyll thiourea
Figure imgf000533_0002
To a solution of 4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl] aniline (60mg, 0.16 mmol) in DCM (2 mL) and THF (1 mL) was added a solution of di(imidazol-l-yl)methanethione (37 mg, 0.21 mmol) in DCM (1 mL) and the resulting solution stirred at RT for 3 hours. Methylamine (2M in THF, 0.4 mL, 0.80 mmol) was added followed by triethylamine (0.022 mL, O.lόmmol) and the solution stirred for 1 hour at RT. The solvent was evaporated and the crude product purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (19 mg).
NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 1.24 (3H, d), 1.55 - 1.58 (2H, m), 1.66 - 1.69 (2H, m), 2.95 (3H, d), 3.16 (3H, s), 3.21 - 3.26 (IH, m), 3.45 - 3.52 (IH, m), 3.61 - 3.65 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.20 - 4.23 (IH, m), 4.55 - 4.63 (IH, m), 6.80 (IH, s), 7.55 (2H, d), 7.84 (IH, s), 8.26 (2H, d), 9.73 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 462; HPLC tR = 1.86min. mTOR Kinase Assay (Echo): 0.00531 μM
The compounds below were prepared in an analogous fashion from 4-[4-[(35)-3- methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2-yl]aniline using the appropriate amine.
Figure imgf000534_0001
Figure imgf000535_0001
Example 35a: 1U NMR (400.13 MHz, DMSOd6) δ 1.14 (3H, t), 1.24 (3H, d), 1.55 - 1.58 (2H, m), 1.66 - 1.69 (2H, m), 3.17 - 3.25 (IH, m), 3.29 (3H, s), 3.45 - 3.51 (3H, m), 3.61 - 3.65 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.20 - 4.23 (IH, m), 4.55 - 4.62 (IH, m), 6.80 (IH, s), 7.57 (2H, d), 7.88 (IH, s), 8.25 (2H, d), 9.63 (IH, s). mTOR Kinase Assay (Echo): 0.00552μM
Example 35b: 1H NMR (400.13 MHz, DMSOd6) δ 1.24 (3H, d), 1.55 - 1.58 (2H, m), 1.66 - 1.69 (2H, m), 3.17 - 3.25 (IH, m), 3.29 (3H, s), 3.45 - 3.52 (IH, m), 3.57 (4H, s), 3.61 - 3.65 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.20 - 4.23 (IH, m), 4.55 - 4.62 (IH, m), 4.77 - 4.85 (IH, m), 6.80 (IH, s), 7.63 (2H, d), 7.86 (IH, s), 8.26 (2H, d), 9.81 (IH, s). mTOR Kinase Assay (Echo): 0.000577μM
Example 35c: 1H NMR (400.13 MHz, DMSOd6) δ 1.24 (3H, d), 1.55 - 1.58 (2H, m), 1.66 - 1.69 (2H, m), 2.20 (6H, s), 2.45 (2H, t), 3.18 - 3.25 (IH, m), 3.26 (3H, s), 3.45 - 3.52 (IH, m), 3.56 (2H, s), 3.61 - 3.65 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.21 (IH, d), 4.56 - 4.61 (IH, m), 6.80 (IH, s), 7.65 (2H, d), 7.77 (IH, s), 8.25 (2H, d), 9.90 (IH, s). mTOR Kinase Assay (Echo): 0.108μM
Example 35d: 1H NMR (400.13 MHz, DMSO-d6) δ 0.58 - 0.62 (2H, m), 0.74 - 0.79 (2H, m), 1.24 (3H, d), 1.55 - 1.59 (2H, m), 1.67 - 1.69 (2H, m), 2.89 - 2.97 (IH, m), 3.17 - 3.27 (IH, m), 3.30 (3H, s), 3.46 - 3.52 (IH, m), 3.62 - 3.66 (IH, m), 3.77 (IH, d), 3.96 - 3.99 (IH, m), 4.21 - 4.24 (IH, m), 4.60 (IH, s), 6.81 (IH, s), 7.62 (2H, d), 8.14 (IH, s), 8.25 (2H, d), 9.51 (IH, s). mTOR Kinase Assay (Echo): 0.0041 lμM
The preparation of 4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl] aniline was described earlier.
Example 36
The following compounds were prepared according to the following general procedure:
The appropriate phenyl carbamate and an excess of both triethylamine and the appropriate amine were dissolved in either DMF, NMP or DMA and stirred at 5O0C - 7O0C for between 2 - 18 hours (unless otherwise specified). The materials were purifed by preparative HPLC except where specified.
Figure imgf000536_0001
Figure imgf000537_0001
Figure imgf000538_0001
Figure imgf000539_0001
Figure imgf000540_0001
Figure imgf000541_0001
Figure imgf000542_0001
Figure imgf000543_0001
Figure imgf000544_0001
Figure imgf000545_0001
Figure imgf000546_0001
Example Structure NAME LCMS Retention
MH+ time
(min)
36bd l-[4-[4-[l- 548 2.61 (benzenesulfonyl)cyclopropyl]-
6-[(3S)-3-methylmorpholin-4-
Figure imgf000547_0001
yl]pyrimidin-2-yl]phenyl]-3- cyclobutylurea
36be l-[4-[4-[l- 606 2.45
(benzenesulfonyl)cyclopropyl]-
6-[(3S)-3-methylmorpholin-4-
Figure imgf000547_0002
yl]pyrimidin-2-yl]phenyl]-3-
(3,3,3-trifluoro-2- hydroxypropyl)urea
36bf l-[4-[4-[l- 536 2.51 (benzenesulfonyl)cyclopropyl]-
6-[(3S)-3-methylmorpholin-4-
Figure imgf000547_0003
yl]pyrimidin-2-yl]phenyl]-3- propan-2-ylurea
36bg 3-[4-[4-[l- 522 2.32 (benzenesulfonyl)cyclopropyl]-
6-[(3S)-3-methylmorpholin-4-
Figure imgf000547_0004
yl]pyrimidin-2-yl]phenyl]- 1 - ethylurea
36bh l-[4-[4-[l- 538 1.98
(benzenesulfonyl)cyclopropyl]-
6-[(3S)-3-methylmorpholin-4-
Figure imgf000547_0005
yl]pyrimidin-2-yl]phenyl]-3-(2- hydroxyethyl)urea
Figure imgf000548_0001
Figure imgf000549_0001
Figure imgf000550_0001
Figure imgf000551_0001
Figure imgf000552_0001
Figure imgf000553_0001
Figure imgf000554_0001
Figure imgf000555_0001
Example Structure NAME LCMS Retention
MH+ time
(min)
36cz 3-[4-[4.[4. 567 2.29
(benzenesulfonyl)oxan-4-yl]-6-
[(3S)-3-methylmorpholin-4-
Figure imgf000556_0001
yl]pyrimidin-2-yl]phenyl]- 1 - ethylurea
36da l-[4-[4-[4- 579 2.29
(benzenesulfonyl)oxan-4-yl]-6-
[(3S)-3-methylmorpholin-4-
Figure imgf000556_0002
yl]pyrimidin-2-yl]phenyl]-3- cyclopropylurea
36db l-[4-[4.[4. 583 1.93
(benzenesulfonyl)oxan-4-yl]-6-
[(3S)-3-methylmorpholin-4-
Figure imgf000556_0003
yl]pyrimidin-2-yl]phenyl]-3-(2- hydroxyethyl)urea
36dc l-[4-[4-[l- 520 2.24
(benzenesulfonyl)cyclopropyl]-
6-morpholin-4-ylpyrimidin-2- yl]phenyl]-3-cyclopropylurea
36dd 3-[4-[4-[l- 508 2.24
(benzenesulfonyl)cyclopropyl]-
6-morpholin-4-ylpyrimidin-2-
Figure imgf000556_0004
yl]phenyl]- 1 -ethylurea
36de l-[4-[4-[l- 524 1.89
O O if* N (benzenesulfonyl)cyclopropyl]- if 6-morpholin-4-ylpyrimidin-2- yl]phenyl]-3-(2- hydroxyethyl)urea
Figure imgf000557_0001
Figure imgf000558_0001
Figure imgf000559_0001
Figure imgf000560_0001
Figure imgf000561_0001
Figure imgf000562_0001
Following the initial reaction conditions the mixture was placed in a sealed tube and heated at 1000C in a microwave reactor for 10 minutes.
The material was purified by trituration with diethyl ether Following the initial reaction conditions the mixture was allowed to cool, tetrabutylammonium fluoride (1 equivalent) added and the reaction stirred at RT for 1 hour. The reaction was purified by prep HPLC.
The mixture was stirred at RT for 16 hours
Example 36a: 1H NMR (400.132 MHz, DMSOd6) δ 0.63 - 0.68 (2H, m), 0.68 - 0.73 (2H, m), 1.23 (3H, d), 1.53 - 1.58 (2H, m), 1.60 - 1.66 (2H, m), 1.88 - 1.98 (2H, m), 3.16 - 3.25 (IH, m), 3.28 - 3.35 (4H, m), 3.47 - 3.54 (3H, m), 3.63 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.23 (IH, d), 4.56 (IH, s), 4.69 (IH, t), 6.57 (IH, s), 6.77 (IH, s), 7.47 (2H, d), 8.21 (2H, d), 8.68 (IH, s). mTOR Kinase Assay (Echo): 0.142μM
Example 36b: 1H NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.54 - 1.60 (2H, m), 1.62 - 1.68 (2H, m), 1.92 - 1.99 (2H, m), 3.23 - 3.31 (3H, m), 3.47 - 3.58 (3H, m), 3.64 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.21 (IH, d), 4.57 (IH, s), 4.71 (IH, t), 6.80 (IH, s), 7.64 (2H, d), 8.30 (2H, d), 9.46 (IH, s). mTOR Kinase Assay (Echo): 0.00179μM Example 36c: 1H NMR (400.132 MHz, DMSO-Cl6) δ 1.23 (3H, d), 1.52 - 1.58 (2H, m), 1.62 - 1.65 (2H, m), 1.89 - 1.97 (2H, m), 3.22 - 3.34 (3H, m), 3.44 - 3.56 (3H, m), 3.63 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.16 - 4.24 (IH, m), 4.35 (2H, d), 4.55 (IH, s), 4.69 (IH, s), 6.67 (IH, t), 6.77 (IH, s), 6.99 (2H, s), 7.52 (2H, d), 8.21 (2H, d), 8.99 (IH, s). mTOR Kinase Assay (Echo): 0.114μM
Example 36d: 1H NMR (400.132 MHz, DMSOd6) δ 0.70 - 0.78 (2H, m), 0.81 - 0.88 (2H, m), 1.23 (3H, d), 1.88 - 1.96 (IH, m), 2.01 - 2.14 (IH, m), 2.67 (3H, d), 2.81 - 2.99 (4H, m), 3.15 - 3.26 (2H, m), 3.50 (IH, dd), 3.65 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.21 (IH, d), 4.55 (IH, s), 6.06 (IH, t), 6.70 (IH, s), 7.50 (2H, d), 8.23 (2H, d), 8.73 (IH, s). mTOR Kinase Assay (Echo): 0.00317μM
Example 36e: 1U NMR (400.132 MHz, DMSO-de) δ 0.39 - 0.44 (2H, m), 0.61 - 0.68 (2H, m), 0.72 - 0.78 (2H, m), 0.82 - 0.88 (2H, m), 1.23 (3H, d), 1.84 - 1.96 (IH, m), 2.02 - 2.12 (IH, m), 2.50 - 2.59 (2H, m), 2.81 - 3.01 (4H, m), 3.17 - 3.24 (IH, m), 3.50 (IH, dd), 3.65 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.22 (IH, d), 4.55 (IH, s), 6.42 (IH, t), 6.71 (IH, s), 7.48 (2H, d), 8.24 (2H, d), 8.53 (IH, s). mTOR Kinase Assay (Echo): 0.00667μM
Example 36f: 1H NMR (400.132 MHz, DMSO-d6) δ 0.68 - 0.80 (2H, m), 0.81 - 0.89 (2H, m), 1.23 (3H, d), 1.84 - 1.95 (IH, m), 2.02 - 2.13 (IH, m), 2.76 - 3.00 (4H, m), 3.11 - 3.27 (3H, m), 3.43 - 3.56 (3H, m), 3.65 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.21 (IH, d), 4.54 (IH, s), 4.72 (IH, t), 6.24 (IH, t), 6.70 (IH, s), 7.48 (2H, d), 8.24 (2H, d), 8.79 (IH, s). mTOR Kinase Assay (Echo): 0.00278μM
Example 36g: 1U NMR (400.132 MHz, DMSO-de) δ 0.69 - 0.79 (2H, m), 0.81 - 0.89 (2H, m), 1.23 (3H, d), 1.84 - 1.96 (IH, m), 2.02 - 2.12 (IH, m), 2.63 - 2.73 (2H, m), 2.83 - 3.03 (4H, m), 3.14 - 3.23 (IH, m), 3.33 - 3.43 (2H, m), 3.51 (IH, dd), 3.65 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.22 (IH, d), 4.55 (IH, s), 6.51 (IH, t), 6.71 (IH, s), 7.51 (2H, d), 8.25 (2H, d), 8.90 (IH, s). mTOR Kinase Assay (Echo): 0.00841μM
Example 36h: 1H NMR (400.132 MHz, DMSO-d6) δ 0.70 - 0.80 (2H, m), 0.82 - 0.91 (2H, m), 1.23 (3H, d), 1.86 - 1.97 (IH, m), 2.02 - 2.12 (IH, m), 2.77 - 3.03 (4H, m), 3.15 - 3.29 (5H, m), 3.51 (IH, d), 3.66 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.22 (IH, d), 4.55 (IH, s), 6.72 (IH, s), 7.38 (IH, s), 7.54 (2H, d), 7.76 (IH, s), 8.27 (2H, d), 8.37 (IH, s), 8.83 (IH, s). mTOR Kinase Assay (Echo): 0.00314μM Example 36i: 1H NMR (400.132 MHz, DMSO-d6) δ 0.74 - 0.84 (2H, m), 0.87 - 0.94 (2H, m), 1.28 (3H, d), 1.91 - 2.01 (IH, m), 2.08 - 2.19 (IH, m), 2.84 - 3.09 (4H, m), 3.25 - 3.32 (2H, m), 3.56 (IH, d), 3.71 (IH, d), 3.82 (IH, d), 4.03 (IH, d), 4.27 (IH, d), 4.38 (2H, d), 4.61 (IH, s), 6.68 (IH, t), 6.76 (IH, s), 7.00 (IH, s), 7.56 (2H, d), 8.31 (2H, d), 8.98 (IH, s). mTOR Kinase Assay (Echo): 0.0518μM
Example 36j: 1H NMR (400.132 MHz, DMSOd6) δ 0.39 - 0.43 (2H, m), 0.62 - 0.67 (2H, m), 0.68 - 0.75 (2H, m), 0.80 - 0.87 (2H, m), 1.22 (3H, d), 1.52 - 1.61 (2H, m), 1.76 - 1.86 (2H, m), 2.50 - 2.61 (4H, m), 2.74 - 2.90 (2H, m), 3.14 - 3.24 (IH, m), 3.50 (2H, dd), 3.65 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.22 (IH, d), 4.54 (IH, s), 6.42 (IH, s), 6.81 (IH, s), 7.50 (2H, d), 8.24 (2H, d), 8.53 (IH, s). mTOR Kinase Assay (Echo): 0.018μM
Example 36k: 1H NMR (400.132 MHz, DMSOd6) δ 0.66 - 0.77 (2H, m), 0.80 - 0.89 (2H, m), 1.22 (3H, d), 1.52 - 1.61 (2H, m), 1.76 - 1.86 (2H, m), 2.43 - 2.61 (3H, m), 2.75 - 2.89 (2H, m), 3.16 - 3.22 (3H, m), 3.43 - 3.55 (3H, m), 3.65 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.22 (IH, d), 4.54 (IH, s), 4.73 (IH, t), 6.25 (IH, t), 6.81 (IH, s), 7.49 (2H, d), 8.24 (2H, d), 8.79 (IH, s). mTOR Kinase Assay (Echo): 0.0131μM
Example 361: 1R NMR (400.132 MHz, DMSO-d6) δ 0.66 - 0.76 (2H, m), 0.82 - 0.87 (2H, m), 1.22 (3H, d), 1.53 - 1.60 (2H, m), 1.74 - 1.85 (2H, m), 2.49 - 2.61 (3H, m), 2.65 - 2.72 (2H, m), 2.74 - 2.88 (2H, m), 3.16 - 3.25 (IH, m), 3.33 - 3.40 (2H, m), 3.50 (IH, d), 3.65 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.23 (IH, d), 4.55 (IH, s), 6.52 (IH, t), 6.81 (IH, s), 7.51 (2H, d), 8.26 (2H, d), 8.91 (IH, s). mTOR Kinase Assay (Echo): 0.0428μM Example 36m: 1H NMR (400.132 MHz, DMSO-d6) δ 0.67 - 0.77 (2H, m), 0.81 - 0.89 (2H, m), 1.22 (3H, d), 1.52 - 1.64 (4H, m), 1.78 - 1.85 (2H, m), 2.41 - 2.56 (3H, m), 2.74 - 2.93 (2H, m), 3.13 - 3.25 (3H, m), 3.42 - 3.56 (3H, m), 3.65 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.16 - 4.26 (IH, m), 4.47 (IH, t), 4.54 (IH, s), 6.19 (IH, t), 6.81 (IH, s), 7.49 (2H, d), 8.24 (2H, d), 8.70 (IH, s). mTOR Kinase Assay (Echo): 0.0347μM Example 36n: 1H NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 1.76 - 1.80 (2H, m), 1.93 - 1.97 (2H, m), 2.48 (3H, s), 3.14 - 3.21 (IH, m), 3.47 (IH, t), 3.62 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.14 - 4.17 (IH, m), 4.32 (2H, d), 4.42 - 4.49 (IH, m), 6.61 (IH, t), 6.78 (IH, s), 6.93
(2H, bs), 7.43 (2H, d), 7.84 (IH, s), 7.90 (2H, d), 8.90 (IH, s), 11.85 (IH, s). mTOR Kinase Assay (Echo): 0.0248μM
Example 36o: 1R NMR (400.132 MHz, DMSO-de) δ 1.21 (3H, d), 1.77 - 1.79 (2H, m), 1.94 - 1.97 (2H, m), 2.48 (3H, s), 2.70 (2H, t), 3.14 - 3.22 (IH, m), 3.35 - 3.39 (2H, m), 3.44 - 3.50
(IH, m), 3.60 - 3.64 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.15 - 4.18 (IH, m), 4.42 -
4.48 (IH, m), 6.51 (IH, t), 6.78 (IH, s), 7.43 (2H, d), 7.84 (IH, s), 7.90 (2H, d), 8.90 (IH, s). mTOR Kinase Assay (Echo): 0.00358μM
Example 36p: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.77 - 1.81 (2H, m), 1.95 - 1.99 (2H, m), 2.51 (3H, s), 3.16 - 3.24 (IH, m), 3.45 - 3.51 (IH, m), 3.61 - 3.65 (IH, m), 3.77
(IH, d), 3.96 - 4.00 (IH, m), 4.16 - 4.20 (IH, m), 4.43 - 4.49 (IH, m), 6.82 (IH, s), 7.55 (2H, d), 7.87 (IH, s), 8.00 (2H, d), 8.37 (IH, s), 9.45 (IH, s), 11.32 (IH, s). mTOR Kinase Assay (Echo): 0.00161μM
Example 36q: 1H NMR (400.132 MHz, DMSO-d6) δ 0.63 - 0.66 (2H, m), 0.69 - 0.73 (2H, m), 1.21 (3H, d), 1.77 - 1.80 (2H, m), 1.94 - 1.97 (2H, m), 2.48 (3H, s), 3.14 - 3.21 (IH, m),
3.44 (2H, d), 3.47 - 3.50 (IH, m), 3.60 - 3.64 (IH, m), 3.76 (IH, d), 3.95 - 3.98 (IH, m), 4.14
- 4.17 (IH, m), 4.42 - 4.48 (IH, m), 4.83 (IH, s), 6.54 (IH, s), 6.77 (IH, s), 7.40 (2H, d), 7.84 (IH, s), 7.89 (2H, d), 8.65 (IH, s). mTOR Kinase Assay (Echo): 0.0889μM Example 36r: 1R NMR (400.132 MHz, DMSO-de) δ 1.54 - 1.57 (2H, m), 1.65 - 1.68 (2H, m), 2.70 (2H, t), 3.27 (3H, s), 3.35 - 3.40 (2H, m), 3.72 (8H, s), 6.53 (IH, t), 6.81 (IH, s), 7.50
- 7.54 (2H, m), 8.20 - 8.24 (2H, m), 8.93 (IH, s). mTOR Kinase Assay (Echo): 0.00733μM
Example 36s: 1U NMR (400.132 MHz, DMSO-d6) δ 1.55 - 1.59 (2H, m), 1.67 - 1.70 (2H, m), 3.27 (3H, s), 3.73 (8H, s), 6.86 (IH, s), 7.61 - 7.65 (2H, m), 8.30 - 8.33 (2H, m), 8.37 (IH, s), 9.44 (IH, s), 11.40 (IH, s). mTOR Kinase Assay (Echo): 0.00475μM
Example 36t: 1H NMR (400.132 MHz, DMSO-d6) δ 1.54 - 1.57 (2H, m), 1.65 - 1.68 (2H, m),
3.27 (3H, s), 3.72 (8H, s), 4.32 (2H, d), 6.62 (IH, t), 6.81 - 6.83 (2H, m), 7.03 (IH, s), 7.50 - 7.54 (2H, m), 8.20 - 8.23 (2H, m), 8.94 (IH, s), 11.83 (IH, s). mTOR Kinase Assay (Echo): 0.194μM Example 36u: 1H NMR (400.132 MHz, DMSO-d6) δ 1.23 (3H, d), 1.32 (3H, t), 1.53 - 1.56 (2H, m), 1.62 - 1.65 (2H, m), 2.70 (2H, t), 3.17 - 3.24 (IH, m), 3.35 - 3.52 (5H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 - 4.24 (IH, m), 4.52 - 4.58 (IH, m), 6.53 (IH, t), 6.78 (IH, s), 7.50 - 7.54 (2H, m), 8.18 - 8.22 (2H, m), 8.92 (IH, s). mTOR Kinase Assay (Echo): 0.00922μM
Example 36v: 1R NMR (400.132 MHz, DMSOd6) δ 0.63 - 0.67 (2H, m), 0.69 - 0.73 (2H, m), 1.23 (3H, d), 1.32 (3H, t), 1.53 - 1.58 (2H, m), 1.60 - 1.65 (2H, m), 3.17 - 3.24 (IH, m), 3.40 - 3.52 (5H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 - 4.24 (IH, m), 4.52 - 4.58 (IH, m), 4.81 - 4.86 (IH, m), 6.57 (IH, s), 6.78 (IH, s), 7.46 - 7.50 (2H, m), 8.17 - 8.21 (2H, m), 8.68 (IH, s). mTOR Kinase Assay (Echo): 0.467μM
Example 36w: 1H NMR (400.132 MHz, DMSOd6) δ 1.23 (3H, d), 1.32 (3H, t), 1.53 - 1.56 (2H, m), 1.62 - 1.65 (2H, m), 3.17 - 3.24 (IH, m), 3.40 - 3.52 (3H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.18 - 4.24 (IH, m), 4.32 (2H, d), 4.53 - 4.58 (IH, m), 6.63 (IH, t), 6.78 (IH, s), 6.84 (IH, s), 7.03 (IH, s), 7.50 - 7.54 (2H, m), 8.18 - 8.22 (2H, m), 8.93 (IH, s), 11.84 (IH, s). mTOR Kinase Assay (Echo): 0.11 μM
Example 36x: 1R NMR (400.132 MHz, DMSO-de) δ 0.63 - 0.66 (2H, m), 1.18 (2H, d), 1.59 - 1.62 (3H, m), 1.88 - 1.90 (2H, m), 2.09 (2H, s), 3.15 (IH, dt), 3.30 (2H, s), 3.44 - 3.49 (IH, m), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.14 (IH, d), 4.41 (IH, s), 4.83 (IH, s), 6.53 (IH, s), 6.65 (IH, s), 7.36 - 7.44 (4H, m), 7.80 - 7.86 (4H, m), 8.64 (IH, s). mTOR Kinase Assay (Echo): 0.182μM
Example 36y: 1U NMR (400.132 MHz, DMSO-de) δ 1.19 (3H, d), 1.59 - 1.62 (2H, m), 1.88 - 1.91 (2H, m), 2.70 (2H, t), 3.13 - 3.18 (IH, m), 3.33 - 3.39 (2H, m), 3.46 (IH, t), 3.61 (IH, d), 3.75 (IH, d), 3.96 (IH, d), 4.14 (IH, d), 4.43 (IH, s), 6.49 (IH, t), 6.65 (IH, s), 7.40 - 7.44 (4H, m), 7.81 - 7.86 (4H, m), 8.89 (IH, s). mTOR Kinase Assay (Echo): 0.00131μM
Example 36z: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20 (3H, d), 1.62 - 1.64 (2H, m), 1.90 - 1.94 (2H, m), 3.17 - 3.18 (IH, m), 3.42 - 3.51 (IH, m), 3.62 (IH, d), 3.76 (IH, d), 3.94 - 3.98 (IH, m), 4.16 (IH, d), 4.44 (IH, s), 6.69 (IH, s), 7.43 (2H, t), 7.52 (2H, d), 7.83 - 7.87 (2H, m), 7.92 (2H, d), 8.37 (IH, s), 9.39 (IH, s), 11.34 (IH, s). mTOR Kinase Assay (Echo): 0.00208μM Example 36aa: 1H NMR (400.132 MHz, DMSO-Cl6) δ 1.19 (3H, d), 1.59 - 1.62 (2H, m), 1.88
- 1.91 (2H, m), 3.12 - 3.19 (IH, m), 3.43 - 3.49 (IH, m), 3.59 - 3.63 (IH, m), 3.75 (IH, d), 3.96 (IH, dd), 4.14 (IH, d), 4.32 (2H, d), 4.42 (IH, s), 6.60 (IH, t), 6.65 (IH, s), 6.94 (2H, s), 7.42 (4H, t), 7.81 - 7.86 (4H, m), 8.91 (IH, s), 11.89 (IH, s). mTOR Kinase Assay (Echo): 0.0749μM
Example 36ab: 1H NMR (400.132 MHz, DMSOd6) δ 0.40 - 0.43 (2H, m), 0.62 - 0.67 (2H, m), 1.19 (3H, d), 1.51 - 1.60 (2H, m), 1.80 - 1.89 (2H, m), 2.53 - 2.58 (IH, m), 2.70 - 2.80 (4H, m), 3.12 (IH, dt), 3.47 (IH, dt), 3.63 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.10 (IH, d), 4.46 (IH, d), 6.41 (IH, d), 6.59 (IH, s), 7.37 (2H, d), 7.54 - 7.56 (IH, m), 7.57 - 7.59 (IH, m), 7.76 (2H, d), 7.85 (IH, dt), 8.48 (IH, s), 8.73 - 8.75 (IH, m). mTOR Kinase Assay (Echo): 0.01 lμM Example 36ac: 1U NMR (400.132 MHz, DMSO-de) δ 1.19 (3H, d), 1.52 - 1.58 (2H, m), 1.81
- 1.89 (2H, m), 2.68 - 2.80 (4H, m), 3.08 - 3.15 (2H, m), 3.27 (IH, s), 3.44 - 3.50 (3H, m), 3.62 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.10 (IH, d), 4.47 (IH, s), 4.72 (IH, t), 6.23 (IH, t), 6.59 (IH, s), 7.36 (2H, d), 7.54 - 7.59 (2H, m), 7.76 (2H, d), 7.85 (IH, dt), 8.73 - 8.75 (2H, m). mTOR Kinase Assay (Echo): 0.00441μM
Example 36ad: 1H NMR (400.132 MHz, DMSO-d6) δ 8.87 (IH, s), 8.74 (IH, d), 7.85 (IH, td), 7.77 (2H, d), 7.54 - 7.59 (2H, m), 7.38 (2H, d), 6.60 (IH, s), 6.51 (IH, t), 4.48 (IH, s), 4.10 (IH, d), 3.96 (IH, dd), 3.75 (IH, d), 3.63 (IH, dd), 3.47 (IH, td), 3.37 (2H, q), 3.12 (IH, td), 2.72 - 2.81 (4H, m), 2.70 (2H, t), 1.80 - 1.89 (2H, m), 1.55 - 1.58 (2H, m), 1.19 (3H, d). mTOR Kinase Assay (Echo): 0.0323μM
Example 36ae: 1U NMR (400.132 MHz, DMSO-de) δ 1.19 (3H, d), 1.55 - 1.63 (4H, m), 1.81
- 1.89 (2H, m), 2.68 - 2.80 (4H, m), 3.08 - 3.19 (3H, m), 3.45 - 3.49 (3H, m), 3.62 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.10 (IH, d), 4.48 (2H, t), 6.18 (IH, t), 6.59 (IH, s), 7.36 (2H, d),
7.53 - 7.59 (2H, m), 7.75 (2H, d), 7.85 (IH, dt), 8.65 (IH, s), 8.74 (IH, d). mTOR Kinase Assay (Echo): 0.0151μM
Example 36af: 1H NMR (400.132 MHz, DMSO-d6) δ 0.40 - 0.43 (2H, m), 0.62 - 0.67 (2H, m), 1.18 (3H, d), 1.88 - 1.95 (IH, m), 2.11 - 2.17 (IH, m), 2.53 - 2.57 (2H, m), 2.79 - 2.87 (2H, m), 3.12 (IH, dt), 3.23 - 3.28 (3H, m), 3.46 (IH, dt), 3.62 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.09 (IH, d), 4.44 (IH, s), 6.40 (IH, d), 6.48 (IH, s), 7.37 (2H, d), 7.58 - 7.61 (2H, m), 7.87 (IH, ddt), 8.48 (IH, s), 8.74 - 8.75 (IH, m). mTOR Kinase Assay (Echo): 0.00275μM
Example 36ag: 1U NMR (400.132 MHz, DMSO-Cl6) δ 1.18 (3H, d), 1.86 - 1.97 (IH, m), 2.09
- 2.18 (IH, m), 2.65 (3H, s), 2.79 - 2.87 (2H, m), 3.12 (IH, dt), 3.22 - 3.28 (2H, m), 3.46 (IH, dt), 3.61 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.08 (IH, d), 4.44 (IH, s), 6.04 - 6.07 (IH, m), 6.48 (IH, s), 7.37 (2H, d), 7.58 - 7.61 (2H, m), 7.74 (2H, d), 7.87 (IH, dt), 8.68 (IH, s), 8.75 (IH, d). mTOR Kinase Assay (Echo): 0.0013μM Example 36ah: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.88 - 1.95 (IH, m), 2.10
- 2.17 (IH, m), 2.81 - 2.87 (2H, m), 3.08 - 3.19 (2H, m), 3.22 - 3.27 (3H, m), 3.44 - 3.50 (3H, m), 3.62 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.08 (IH, d), 4.45 (IH, s), 4.72 (IH, t), 6.23
(IH, t), 6.48 (IH, s), 7.35 (2H, d), 7.60 (2H, t), 7.74 (2H, d), 7.87 (IH, t), 8.75 (2H, s). mTOR Kinase Assay (Echo): 0.00247μM
Example 36ai: 1U NMR (400.132 MHz, DMSO-de) δ 1.18 (3H, d), 1.88 - 1.95 (IH, m), 2.09
- 2.16 (IH, m), 2.69 (2H, t), 2.78 - 2.87 (2H, m), 3.10 - 3.16 (IH, m), 3.23 - 3.25 (3H, m), 3.35 - 3.39 (2H, m), 3.47 (IH, t), 3.62 (IH, dd), 3.74 (IH, d), 3.95 (IH, d), 4.09 (IH, d), 4.45
(IH, s), 6.49 (IH, s), 7.38 (2H, d), 7.58 - 7.61 (2H, m), 7.76 (2H, d), 7.87 (IH, dt), 8.74 - 8.75
(IH, m), 8.86 (IH, s). mTOR Kinase Assay (Echo): 0.00561μM
Example 36aj: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18 (3H, d), 1.89 - 1.97 (IH, m), 2.11 - 2.18 (IH, m), 2.79 - 2.87 (2H, m), 3.13 (IH, dt), 3.23 - 3.29 (2H, m), 3.47 (IH, dt), 3.62
(IH, dd), 3.75 (IH, d), 3.79 (3H, s), 3.96 (IH, dd), 4.10 (IH, d), 4.45 (IH, s), 6.50 (IH, s),
7.38 (IH, s), 7.41 (2H, d), 7.59 - 7.62 (IH, m), 7.76 (IH, s), 7.77 (2H, d), 7.86 - 7.90 (IH, m),
7.88 (IH, dt), 8.38 (IH, s), 8.75 - 8.76 (IH, m), 8.80 (IH, s). mTOR Kinase Assay (Echo): 0.00258μM Example 36ak: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 1.89 - 1.98 (IH, m), 2.10
- 2.19 (IH, m), 2.79 - 2.87 (2H, m), 3.13 (IH, dt), 3.23 - 3.28 (2H, m), 3.47 (IH, dt), 3.62 (IH, dd), 3.74 (2H, s), 3.75 (IH, d), 3.96 (IH, dd), 4.10 (IH, d), 4.45 (IH, s), 6.25 (IH, d), 6.51 (IH, s), 7.43 (2H, d), 7.54 (IH, d), 7.59 - 7.63 (IH, m), 7.60 (IH, d), 7.79 (2H, d), 7.88 (IH, dt), 8.75 - 8.76 (IH, m), 8.91 (IH, s), 9.11 (IH, s). mTOR Kinase Assay (Echo): 0.00245μM Example 36al: 1U NMR (400.132 MHz, DMSO-Cl6) δ 0.41 (2H, m), 0.63 - 0.66 (2H, m), 1.59
(2H, m), 1.88 (2H, m), 2.57 - 2.61 (IH, m), 3.66 (4H, s), 3.68 (4H, s), 6.39 (IH, s), 6.71 (IH, s), 7.38 - 7.43 (4H, m), 7.78 (2H, d), 7.85 (2H, t), 8.52 (IH, s). mTOR Kinase Assay (Echo): 0.0187μM Example 36am: 1H NMR (400.132 MHz, DMSO-d6) δ 1.58 - 1.61 (2H, m), 1.87 - 1.90 (2H, m), 2.70 (2H, t), 3.37 (2H, q), 3.67 (4H, s), 3.69 (4H, s), 6.49 (IH, t), 6.72 (IH, s), 7.39 - 7.44
(4H, m), 7.79 - 7.86 (4H, m), 8.90 (IH, s). mTOR Kinase Assay (Echo): 0.0277μM
Example 36an: 1H NMR (400.132 MHz, DMSO-d6) δ 1.59 - 1.62 (2H, m), 1.89 - 1.92 (2H, m), 3.68 (4H, s), 3.70 (4H, s), 6.76 (IH, s), 7.43 (2H, t), 7.51 (2H, d), 7.83 - 7.96 (4H, m),
8.37 (IH, s), 9.39 (IH, s), 11.33 (IH, s). mTOR Kinase Assay (Echo): 0.0104μM
Example 36ao: 1U NMR (400.132 MHz, DMSO-de) δ 1.06 (3H, t), 1.57 - 1.61 (2H, m), 1.87
- 1.90 (2H, m), 3.09 - 3.16 (2H, m), 3.65 - 3.66 (4H, m), 3.69 - 3.70 (4H, m), 6.12 (IH, t), 6.71 (IH, s), 7.37 - 7.44 (4H, m), 7.78 (2H, d), 7.82 - 7.86 (2H, m), 8.64 (IH, s)
Example 36ap: 1H NMR (400.132 MHz, DMSO-d6) δ 1.57 - 1.61 (2H, m), 1.87 - 1.90 (2H, m), 2.66 (3H, d), 3.66 (4H, s), 3.69 - 3.70 (4H, m), 6.01 - 6.05 (IH, m), 6.71 (IH, s), 7.38 -
7.43 (4H, m), 7.78 (2H, d), 7.82 - 7.86 (2H, m), 8.72 (IH, s)
Example 36aq: 1H NMR (400.132 MHz, DMSO-d6) δ 1.58 - 1.61 (2H, m), 1.88 - 1.91 (2H, m), 3.63 - 3.67 (4H, m), 3.69 - 3.73 (4H, m), 3.79 (3H, s), 6.73 (IH, s), 7.38 - 7.45 (5H, m),
7.77 - 7.86 (5H, m), 8.34 (IH, s), 8.82 (IH, s)
Example 36ar: 1U NMR (400.132 MHz, DMSO-de) δ 1.66 - 1.69 (2H, m), 1.95 - 1.98 (2H, m), 3.15 - 3.19 (2H, m), 3.44 - 3.48 (2H, m), 3.69 (8H, s), 4.72 (IH, t), 6.22 (IH, t), 6.73 (IH, s), 7.34 (2H, d), 7.63 (2H, d), 7.77 (2H, d), 8.77 (IH, s), 8.86 (2H, d) Example 36as: 1U NMR (400.132 MHz, DMSO-d6) δ 1.66 - 1.70 (2H, m), 1.96 - 1.99 (2H, m), 3.69 (8H, s), 3.79 (3H, s), 6.74 (IH, s), 7.40 (3H, d), 7.66 (2H, d), 7.77 - 7.78 (3H, m),
8.35 (IH, s), 8.80 (IH, s), 8.87 (2H, d). mTOR Kinase Assay (Echo): 0.0091 lμM
Example 36at: 1H NMR (400.132 MHz, DMSO-d6) δ 1.66 - 1.69 (2H, m), 1.95 - 1.99 (2H, m), 2.66 (3H, d), 3.69 (8H, s), 6.02 - 6.04 (IH, m), 6.73 (IH, s), 7.35 (2H, d), 7.63 (2H, d),
7.77 (2H, d), 8.71 (IH, s), 8.86 (2H, d) Example 36au: 1H NMR (400.132 MHz, DMSO-d6) δ 1.07 (3H, t), 1.66 - 1.69 (2H, m), 1.95
- 1.98 (2H, m), 3.09 - 3.16 (2H, m), 3.69 (8H, s), 6.13 (IH, t), 6.73 (IH, s), 7.35 (2H, d), 7.63
(2H, d), 7.77 (2H, d), 8.63 (IH, s), 8.86 (2H, d)
Example 36av: 1R NMR (400.132 MHz, DMSOd6) δ 0.40 - 0.44 (2H, m), 0.62 - 0.67 (2H, m), 1.66 - 1.69 (2H, m), 1.95 - 1.98 (2H, m), 2.53 - 2.57 (IH, m), 3.69 (8H, s), 6.40 (IH, d),
6.73 (IH, s), 7.36 (2H, d), 7.64 (2H, d), 7.77 (2H, d), 8.50 (IH, s), 8.86 (2H, d). mTOR Kinase Assay (Echo): 0.00995μM
Example 36aw: 1H NMR (400.132 MHz, DMSOd6) δ 1.66 - 1.69 (2H, m), 1.95 - 1.98 (2H, m), 2.70 (2H, t), 3.36 (2H, q), 3.69 (8H, s), 6.49 (IH, t), 6.73 (IH, s), 7.37 (2H, d), 7.64 (2H, d), 7.77 (2H, d), 8.86 (2H, d), 8.89 (IH, s)
Example 36ax: 1U NMR (400.132 MHz, DMSOd6) δ 1.56 - 1.63 (2H, m), 1.66 - 1.69 (3H, m), 1.95 - 1.98 (2H, m), 3.16 (2H, q), 3.47 (2H, q), 3.69 (8H, s), 4.47 (IH, t), 6.17 (IH, t),
6.73 (IH, s), 7.34 (2H, d), 7.63 (2H, d), 7.77 (2H, d), 8.86 (2H, d)
Example 36ay: 1U NMR (400.132 MHz, DMSOd6) δ 1.24-1.26 (3H, d), 1.56-1.59 (2H, q), 1.67-1.70 (2H, q), 3.19-3.26 (IH, td), 3.30 (3H, s), 3.46-3.53 (IH, td), 3.63-3.66 (IH, dd),
3.76-3.79 (IH, d), 3.97-4.00 (IH, dd), 4.22-4.25 (IH, bd), 4.58 (IH, bs), 6.81 (IH, s), 7.14
(IH, s), 7.39-7.40 (IH, d), 7.59-7.62 (2H, d), 8.28-8.30 (2H, d), 9.21 (IH, s), 10.50 (IH, s). mTOR Kinase Assay (Echo): 0.00117μM
Example 36az: 1R NMR (400.132 MHz, DMSOd6) δ 1.24-1.26 (3H, d), 1.56-1.59 (2H, q), 1.67-1.70 (2H, q), 2.44 (3H, s), 3.19-3.26 (IH, td), 3.31 (3H, s), 3.46-3.52 (IH, td), 3.63-3.66
(IH, dd), 3.76-3.79 (IH, d), 3.98-4.00 (IH, dd), 4.22-4.25 (IH, bd), 4.59 (IH, bs), 6.81 (IH, s), 7.61-7.63 (2H, d), 8.21-8.22 (IH, d), 8.28-8.30 (2H, d), 8.99-9.00 (IH, d), 9.41 (IH, s),
9.70 (IH, s). mTOR Kinase Assay (Echo): 0.00149μM Example 36ba: 1H NMR (400.132 MHz, DMSO-d6) δ 1.24-1.26 (3H, d), 1.56-1.59 (2H, q),
1.67-1.70 (2H, q), 3.19-3.25 (IH, td), 3.30 (3H, s), 3.47-3.52 (IH, td), 3.63-3.66 (IH, dd),
3.76-3.79 (IH, d), 3.97-4.00 (IH, dd), 4.22-4.25 (IH, d), 4.59 (IH, bs), 6.81 (IH, s), 7.16 (IH, s), 7.63-7.66 (2H, d), 7.84 (IH, bs), 8.28-8.30 (2H, d), 10.45 (IH, bs), 10.88 (IH, bs). mTOR Kinase Assay (Echo): 0.00312μM Example 36bb: 1U NMR (400.132 MHz, DMSO-d6) δ 1.23-1.24 (3H, d), 1.54-1.58 (2H, q),
1.59-1.63 (2H, m), 1.66-1.69 (2H, q), 3.15-3.25 (3H, m), 3.30 (3H, s), 3.45-3.52 (3H, m),
3.62-3.65 (IH, dd), 3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.20-4.23 (IH, d), 4.46-4.49 (IH, t), 4.58 (IH, bs), 6.19-6.22 (IH, t), 6.77 (IH, s), 7.49-7.51 (2H, d), 8.19-8.21 (2H, d), 8.72
(IH, s). mTOR Kinase Assay (Echo): 0.0205μM
Example 36bc: 1R NMR (400.132 MHz, DMSOd6) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), 1.16-1.18 (3H, d), 1.60-1.68 (2H, m), 1.89-1.92 (2H, m), 3.10-3.18 (IH, td), 3.42-3.49 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.08-4.12 (IH, d), 4.38 (IH, bs), 5.76 (IH, s), 6.40-6.41 (IH, d), 6.63 (IH, s), 7.38-7.40 (2H, d), 7.57-7.61 (2H, t), 7.70- 7.74 (IH, t), 7.78-7.85 (4H, m), 8.49 (IH, s). mTOR Kinase Assay (Echo): 0.00205μM Example 36bd: 1R NMR (400.132 MHz, DMSOd6) δ 1.16-1.18 (3H, d), 1.57-1.67 (4H, m), 1.81-1.92 (4H, m), 2.18-2.25 (2H, m), 3.10-3.18 (IH, td), 3.42-3.49 (IH, td), 3.59-3.62 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.97 (IH, dd), 4.08-4.19 (2H, m), 4.38 (IH, bs), 6.42-6.44 (IH, d), 6.62 (IH, s), 7.35-7.37 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.78-7.85 (4H, m), 8.52 (IH, s). mTOR Kinase Assay (Echo): 0.00258μM
Example 36be: 1U NMR (400.132 MHz, DMSO-de) δ 1.16-1.18 (3H, d), 1.60-1.67 (2H, m), 1.89-1.92 (2H, m), 3.10-3.20 (IH, td), 3.30 (2H, m (under water peak)) 3.42-3.55 (2H, m), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.07-4.11 (IH, d), 4.38 (IH, bs), 6.35-6.38 (IH, t), 6.47-6.49 (IH, d), 6.63 (IH, s), 7.38-7.40 (2H, d), 7.57-7.61 (2H, t), 7.70- 7.74 (IH, tt), 7.78-7.81 (2H, d), 7.84-7.86 (2H, d), 8.89 (IH, s). mTOR Kinase Assay (Echo): 0.00376μM
Example 36bf: 1R NMR (400.132 MHz, DMSO-d6) δ 1.10-1.12 (6H, d), 1.16-1.18 (3H, d), 1.60-1.67 (2H, m), 1.59-1.92 (2H, m), 3.10-3.19 (IH, td), 3.42-3.49 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.81 (2H, m), 3.94-3.97 (IH, dd), 4.09-4.12 (IH, d), 4.38 (IH, bs), 6.02-6.04 (IH, d), 6.62 (IH, s), 7.35-7.38 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.78-7.85 (4H, m), 8.49 (IH, s). mTOR Kinase Assay (Echo): 0.00457μM
Example 36bg: 1H NMR (400.132 MHz, DMSO-d6) δ 1.05-1.08 (3H, t), 1.16-1.18 (3H, d), 1.60-1.67 (2H, m), 1.89-1.90 (2H, m), 3.09-3.16 (3H, m), 3.42-3.49 (IH, m), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.95-3.97 (IH, dd), 4.09-4.12 (IH, d), 4.38 (IH, bs), 6.12-6.15 (IH, t), 6.62 (IH, s), 7.37-7.39 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, t), 7.78-7.85 (4H, m), 8.62 (IH, s). mTOR Kinase Assay (Echo): 0.000922μM
Example 36bh: 1U NMR (400.132 MHz, DMSO-d6) δ 1.16-1.18 (3H, d), 1.60-1.67 (2H, m), 1.89-1.92 (2H, m), 3.10-3.15 (IH, td), 3.17-3.19 (2H, m), 3.42-3.49 (3H, m), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.08-4.11 (IH, d), 4.38 (IH, bs), 4.71-4.74 (IH, t), 6.22-6.24 (IH, t), 6.62 (IH, s), 7.36-7.39 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.78- 7.85 (4H, m), 8.76 (IH, s). mTOR Kinase Assay (Echo): 0.00121μM
Example 36bi: 1H NMR (400.132 MHz, DMSOd6) δ 0.87-0.91 (3H, t), 1.16-1.18 (3H, d), 1.41-1.50 (2H, m), 1.60-1.67 (2H, m), 1.89-1.92 (2H, m), 3.04-3.09 (2H, q), 3.10-3.17 (IH, td), 3.42-3.49 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.97 (IH, dd), 4.08-4.12 (IH, d), 4.39 (IH, bs), 6.16-6.19 (IH, t), 6.62 (IH, s), 7.37-7.39 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.78-7.85 (4H, m), 8.61 (IH, s). mTOR Kinase Assay (Echo): 0.00231 μM
Example 36bj: 1U NMR (400.132 MHz, DMSOd6) δ 1.16-1.18 (3H, d), 1.60-1.68 (2H, m), 1.89-1.92 (2H, m), 2.65-2.66 (3H, d), 3.10-3.17 (IH, td), 3.42-3.49 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.97 (IH, dd), 4.09-4.12 (IH, d), 4.38 (IH, bs), 6.03-6.06 (IH, q), 6.62 (IH, s), 7.38-7.40 (2H, d), 7.57-7.61 (2H, t), 7.70-7.73 (IH, tt), 7.74-7.85 (4H, m), 8.70 (IH, s). mTOR Kinase Assay (Echo): 0.000621μM
Example 36bk: 1H NMR (400.132 MHz, DMSO-d6) δ 1.16-1.18 (3H, d), 1.24 (6H, s), 1.60- 1.67 (2H, m), 1.88-1.91 (2H, m), 3.10-3.17 (IH, td), 3.38-3.40 (2H, d), 3.42-3.49 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.08-4.12 (IH, d), 4.38 (IH, bs), 4.93-4.96 (IH, t), 5.98 (IH, s), 6.62 (IH, s), 7.33-7.35 (2H, d), 7.58-7.61 (2H, t), 7.70-7.74 (IH, m), 7.78-7.84 (4H, m), 8.70 (IH, s). mTOR Kinase Assay (Echo): 0.00433μM
Example 36bl: 1H NMR (400.132 MHz, DMSO-d6) δ 1.16-1.18 (3H, d), 1.56-1.67 (4H, m), 1.89-1.92 (2H, m), 3.10-3.17 (3H, m), 3.42-3.49 (3H, m), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.97 (IH, dd), 4.08-4.12 (IH, d), 4.38 (IH, bs), 4.46-4.49 (IH, t), 6.16-6.19 (IH, t), 6.62 (IH, s), 7.37-7.39 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.78-7.85 (4H, m), 8.67 (IH, s). mTOR Kinase Assay (Echo): 0.00208μM Example 36bm: 1U NMR (400.132 MHz, DMSO-d6) δ 1.17-1.18 (3H, d), 1.60-1.68 (2H, m), 1.89-1.92 (2H, m), 2.68-2.72 (2H, t), 3.11-3.18 (IH, td), 3.34-3.39 (2H, q), 3.43-3.49 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.97 (IH, dd), 4.09-4.12 (IH, d), 4.38 (IH, bs), 6.49-6.52 (IH, t), 6.63 (IH, s), 7.39-7.41 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.78- 7.86 (4H, m), 8.88 (IH, s). mTOR Kinase Assay (Echo): 0.00193μM
Example 36bn: 1R NMR (400.132 MHz, DMSOd6) δ 1.16-1.18 (3H, d), 1.60-1.68 (2H, m), 1.88-1.93 (2H, m), 3.10-3.17 (IH, td), 3.42-3.49 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.97 (IH, dd), 4.08-4.12 (IH, d), 4.31-4.33 (2H, d), 4.38 (IH, bs), 6.59-6.63 (2H, m), 6.94 (2H, bs), 7.39-7.41 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, t), 7.78-7.81 (2H, d), 7.84- 7.87 (2H, d), 8.88 (IH, s), 11.84 (IH, bs). mTOR Kinase Assay (Echo): 0.00637μM
Example 36bo: 1H NMR (400.132 MHz, DMSOd6) δ 0.63-0.66 (2H, q), 0.69-0.73 (2H, q), 1.16-1.18 (3H, d), 1.60-1.67 (2H, m), 1.89-1.92 (2H, m), 3.10-3.17 (IH, td), 3.42-3.49 (3H, m), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.09-4.12 (IH, d), 4.38 (IH, bs), 4.83 (IH, bs), 6.54 (IH, s), 6.63 (IH, s), 7.35-7.37 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.74-7.85 (4H, m), 8.63 (IH, s). mTOR Kinase Assay (Echo): 0.0176μM Example 36bp: 1U NMR (400.132 MHz, DMSO-d6) δ 1.16-1.18 (3H, d), 1.60-1.67 (2H, m), 1.89-1.90 (2H, m), 3.10-3.17 (IH, td), 3.42-3.49 (IH, td), 3.59-3.62 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.97 (IH, dd), 4.08-4.12 (IH, d), 4.38 (IH, bs), 4.43-4.46 (2H, t), 4.72-4.81 (3H, m), 6.63 (IH, s), 6.91-6.93 (IH, d), 7.37-7.39 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.78- 7.86 (4H, m), 8.73 (IH, s). mTOR Kinase Assay (Echo): 0.00198μM Example 36bq: 1R NMR (400.132 MHz, DMSO-d6) δ 1.18-1.19 (3H, d), 1.61-1.66 (2H, m), 1.91-1.92 (2H, m), 3.12-3.18 (IH, td), 3.44-3.50 (IH, td), 3.61-3.64 (IH, dd), 3.74-3.77 (IH, d), 3.95-3.99 (IH, dd), 4.10-4.14 (IH, d), 4.40 (IH, bs), 6.66 (IH, s), 7.52-7.54 (2H, d), 7.59- 7.62 (2H, t), 7.72-7.76 (IH, t), 7.79-7.81 (3H, d), 7.90-7.92 (2H, d), 8.28 (IH, s), 9.39 (IH, s). mTOR Kinase Assay (Echo): 0.00131μM Example 36br: 1U NMR (400.132 MHz, DMSO-de) δ 1.17-1.18 (3H, d), 1.61-1.68 (2H, m), 1.90-1.91 (2H, m), 3.11-3.17 (IH, td), 3.43-3.50 (IH, td), 3.59-3.63 (IH, dd), 3.74-3.76 (IH, d), 3.79 (3H, s), 3.94-3.98 (IH, dd), 4.09-4.13 (IH, d), 4.39 (IH, bs), 6.64 (IH, s), 7.38 (IH, s), 7.42-7.44 (2H, d), 7.58-7.62 (2H, t), 7.71-7.73 (IH, t), 7.77-7.81 (3H, m), 7.86-7.88 (2H, d), 8.36 (IH, s), 8.80 (IH, s). mTOR Kinase Assay (Echo): 0.00188μM
Example 36bs: 1R NMR (400.132 MHz, DMSOd6) δ 0.39-0.43 (2H, m), 0.62-0.67 (2H, m), 1.19-1.20 (3H, d), 1.82-1.93 (IH, m), 2.03-2.14 (IH, m), 2.54 (IH, m), 2.75-2.82 (2H, m), 3.01-3.09 (2H, m), 3.10-3.17 (IH, td), 3.44-3.51 (IH, td), 3.61-3.65 (IH, dd), 3.74-3.77 (IH, d), 3.94-3.98 (IH, dd), 4.06-4.09 (IH, d), 4.44 (IH, bs), 6.40-6.41 (IH, d), 6.46 (IH, s), 7.36- 7.39 (2H, d), 7.43-7.51 (4H, m), 7.58-7.62 (IH, m), 7.78-7.80 (2H, d), 8.48 (IH, s). mTOR Kinase Assay (Echo): 0.00161μM Example 36bt: 1R NMR (400.132 MHz, DMSOd6) δ 1.19-1.21 (3H, d), 1.82-1.93 (IH, m), 2.03-2.14 (IH, m), 2.74-2.82 (2H, m), 3.02-3.10 (2H, m), 3.13-3.19 (3H, m), 3.44-3.51 (3H, m), 3.62-3.65 (IH, dd), 3.74-3.77 (IH, d), 3.94-3.98 (IH, dd), 4.07-4.10 (IH, d), 4.45 (IH, bs), 4.71-4.74 (IH, t), 6.22-6.25 (IH, t), 6.47 (IH, s), 7.35-7.37 (2H, d), 7.44-7.51 (4H, m), 7.58-7.62 (IH, m), 7.78-7.81 (2H, d), 8.74 (IH, s). mTOR Kinase Assay (Echo): 0.00105μM
Example 36bu: 1U NMR (400.132 MHz, DMSO-d6) δ 1.19-1.21 (3H, d), 1.82-1.93 (IH, m), 2.04-2.14 (IH, m), 2.65-2.66 (3H, d), 2.75-2.82 (2H, m), 3.02-3.11 (2H, m), 3.13-3.19 (IH, td), 3.45-3.51 (IH, td), 3.62-3.65 (IH, dd), 3.74-3.77 (IH, d), 3.94-3.98 (IH, dd), 4.06-4.10 (IH, d), 4.45 (IH, bs), 6.03-6.06 (IH, q), 6.46 (IH, s), 7.36-7.38 (2H, d), 7.44-7.51 (4H, m), 7.58-7.62 (IH, m), 7.78-7.80 (2H, d), 8.68 (IH, s). mTOR Kinase Assay (Echo): 0.00118μM
Example 36bv: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20-1.21 (3H, d), 1.83-1.94 (IH, m), 2.04-2.15 (IH, m), 2.76-2.83 (2H, m), 3.02-3.10 (2H, m), 3.11-3.18 (IH, td), 3.45-3.52 (IH, td), 3.62-3.66 (IH, dd), 3.75-3.77 (IH, d), 3.79 (3H, s), 3.95-3.98 (IH, dd), 4.07-4.10 (IH, d), 4.46 (IH, bs), 6.48 (IH, s), 7.38-7.51 (7H, m), 7.59-7.76 (IH, m), 7.76 (IH, s), 7.82-7.84 (2H, d), 8.36 (IH, s), 8.78 (IH, s). mTOR Kinase Assay (Echo): 0.00264μM
Example 36bw: 1H NMR (400.132 MHz, DMSO-d6) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), 1.20-1.22 (3H, d), 1.49-1.58 (2H, m), 1.80-1.87 (2H, m), 2.53 (2H, m), 2.67-2.73 (2H, m), 3.12-3.18 (IH, td), 3.46-3.53 (IH, td), 3.63-3.67 (IH, dd), 3.75-3.78 (IH, d), 3.95-3.99 (IH, dd), 4.09-4.12 (IH, d), 4.48-4.49 (IH, bs), 6.40-6.41 (IH, d), 6.62 (IH, s), 7.37-7.39 (2H, d), 7.42-7.48 (4H, m), 7.57-7.61 (IH, m), 7.80-7.82 (2H, d), 8.48 (IH, s). mTOR Kinase Assay (Echo): 0.00909μM
Example 36bx: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20-1.22 (3H, d), 1.50-1.59 (2H, m), 1.80-1.89 (2H, m), 2.52-2.61 (2H, m), 2.66-2.74 (2H, m), 3.11-3.19 (3H, m), 3.44-3.52 (3H, m), 3.63-3.67 (IH, dd), 3.75-3.78 (IH, d), 3.95-3.99 (IH, dd), 4.08-4.12 (IH, d), 4.48 (IH, bs), 4.71-4.74 (IH, t), 6.22-6.25 (IH, t), 6.62 (IH, s), 7.35-7.38 (2H, d), 7.42-7.48 (4H, m), 7.57-7.61 (IH, m), 7.80-7.82 (2H, d), 8.74 (IH, s). mTOR Kinase Assay (Echo): 0.00269μM
Example 36by: 1H NMR (400.132 MHz, DMSOd6) δ 1.20-1.22 (3H, d), 1.52-1.56 (2H, m), 1.57-1.63 (2H, m), 1.79-1.88 (2H, m), 2.54-2.61 (2H, m), 2.67-2.72 (2H, m), 3.11-3.17 (3H, m), 3.45-3.52 (3H, m), 3.63-3.66 (IH, dd), 3.75-3.78 (IH, d), 3.95-3.99 (IH, dd), 4.09-4.12 (IH, d), 4.46-4.49 (2H, m), 6.17-6.19 (IH, t), 6.62 (IH, s), 7.35-7.38 (2H, d), 7.42-7.48 (4H, m), 7.57-7.61 (IH, m), 7.79-7.82 (2H, d), 8.65 (IH, s). mTOR Kinase Assay (Echo): 0.012μM Example 36bz: 1H NMR (400.132 MHz, DMSOd6) δ 1.21-1.22 (3H, d), 1.50-1.59 (2H, m), 1.81-1.88 (2H, m), 2.53-2.59 (2H, m), 2.67-2.72 (4H, m), 3.11-3.19 (IH, td), 3.34-3.39 (2H, m), 3.46-3.52 (IH, td), 3.63-3.67 (IH, dd), 3.75-3.78 (IH, d), 3.95-3.99 (IH, dd), 4.09-4.13 (IH, d), 4.49 (IH, bs), 6.49-6.52 (IH, t), 6.63 (IH, s), 7.38-7.40 (2H, d), 7.42-7.48 (4H, m), 7.57-7.61 (IH, m), 7.81-7.83 (2H, d), 8.86 (IH, s). mTOR Kinase Assay (Echo): 0.0143μM Example 36ca: 1U NMR (400.132 MHz, DMSO-d6) δ 1.23-1.25 (3H, d), 1.68-1.74 (2H, m), 2.20-2.27 (2H, td), 2.67-2.68 (3H, d), 2.82-2.87 (2H, t), 3.05-3.09 (2H, m), 3.18-3.22 (IH, m), 3.22-3.25 (2H, t), 3.37-3.40 (2H, t), 3.50-3.58 (IH, td), 3.66-3.70 (IH, dd), 3.77-3.80 (IH, d), 3.90-3.96 (2H, m), 3.98-4.01 (IH, dd), 4.39-4.32 (IH, d), 4.57 (IH, s), 6.10-6.13 (IH, q), 6.86 (IH, s), 7.50-7.53 (2H, d), 8.21-8.23 (2H, d), 8.79 (IH, s) Example 36cb: 1R NMR (400.132 MHz, DMSO-(I6) δ 1.23-1.25 (3H, d), 1.68-1.75 (2H, m), 2.20-2.27 (2H, td), 2.54 (3H, d), 2.82-2.87 (2H, t), 3.06-3.11 (2H, m), 3.12-3.16 (IH, m), 3.18-3.24 (2H, m), 3.37-3.40 (2H, t), 3.50-3.57 (IH, td), 3.66-3.70 (IH, dd), 3.77-3.80 (IH, d), 3.91-3.95 (2H, m), 4.00-4.02 (IH, dd), 4.29-4.32 (IH, d), 4.58 (IH, s), 6.27-6.29 (IH, t), 6.86 (IH, s), 7.50-7.52v(2H, d), 8.21-8.23 (2H, d), 8.78 (IH, s) Example 36cc: 1U NMR (400.132 MHz, DMSO-d6) δ 1.23-1.25 (2H, d), 1.68-1.75 (2H, m), 2.20-2.27 (2H, td), 2.538-2.543 (3H, d), 2.82-2.87 (2H, t), 3.06-3.09 (2H, m), 3.16-3.21 (IH, m), 3.22-3.25 (2H, m), 3.37-3.40 (IH, td), 3.66-3.70 (IH, dd), 3.77-3.80 (IH, d), 3.90-3.96 (2H, m), 4.00-4.02 (IH, dd), 4.29-4.33 (IH, d), 4.58 (IH, s), 6.49-6.50 (IH, d), 6.86 (IH, s), 7.51-7.53 (2H, d), 8.22-8.24 (2H, d), 8.61 (IH, s)
Example 36cd: 1U NMR (400.132 MHz, DMSOd6) δ 1.23-1.25 (3H, d), 1.55-1.65 (2H, m), 1.67-1.74 (2H, m), 2.19-2.26 (4H, m), 2.537-2.541 (3H, d), 2.81-2.86 (2H, t), 3.05-3.09 (2H, m), 3.16-3.22 (2H, m), 3.24-3.26 (IH, m), 3.37-3.40 (2H, t), 3.49-3.56 (IH, td), 3.66-3.70 (IH, dd), 3.77-3.79 (IH, d), 3.90-3.96 (2H, m), 3.98-4.01 (IH, dd), 4.11-4.21 (IH, sex), 4.29- 4.32 (IH, d), 4.57 (IH, s), 6.52-6.54 (IH, d), 6.86 (IH, s), 7.48-7.50 (2H, d), 7.54-7.67(1H, m), 8.21-8.23 (2H, d), 8.63 (IH, s) Example 36ce: 1R NMR (400.132 MHz, DMSOd6) δ 1.23-1.35 (3H, d), 1.67-1.74 (2H, m), 2.20-2.27 (2H, td), 2.538-2.541 (3H, d), 2.70-3.73 (2H, t), 2.82-2.87 (2H, t), 3.05-3.09 (2H, m), 3.18-3.23 (2H, m), 3.25-3.26 (IH, m), 3.18-3.23 (2H, m), 2.25-2.26 (IH, m), 3.36-3.40 (4H, m), 3.50-3.56 (IH, td), 3.66-3.70 (IH, dd), 3.77-3.80 (IH, d), 3.90-3.96 (2H, qu), 3.98- 4.02 (IH, dd), 4.30-4.33 (IH, d), 4.56-4.58 (IH, m), 6.54-6.57 (IH, t), 6.86 (IH, s), 7.52-7.54 (2H, d), 8.23-8.25 (2H, d), 8.95 (IH, s) Example 36cf: 1U NMR (400.132 MHz, DMSOd6) δ 1.23-1.25 (3H, d), 1.68-1.75 (2H, m), 2.20-2.27 (2H, td), 2.82-2.87 (2H, t), 3.16-3.22 (2H, m), 3.25 (IH, m), 3.37-3.40 (2H, t), 3.50- 3.56 (IH, td), 3.66-3.70 (IH, dd), 3.77-3.80 (IH, d), 3.90-3.96 (2H, m), 4.00-4.02 (IH, dd), 4.29-4.33 (IH, d), 4.58 (IH, s), 6.23-6.25 (IH, t), 6.86 (IH, t), 7.49-7.52 (2H, d), 8.21-8.23 (2H, d), 8.69 (IH, s) Example 36cg: 1R NMR (400.132 MHz, DMSOd6) δ 1.23-1.25 (3H, d), 1.68-1.75 (2H, m), 2.20-2.27 (2H, td), 2.82-2.87 (2H, t), 3.06-3.09 (2H, m), 3.17-3.23 (4H, m), 3.25-3.26 (IH, m), 3.37-3.40(2H, t), 3.46-3.48 (2H, t), 3.50-3.56 (IH, td), 3.66-3.70 (IH, dd), 3.77-3.80 (IH, d), 3.90-3.96 (2H, qu), 3.98-4.02 (IH, dd) 4.29-4.33 (IH, d), 4.57 (IH, s), 6.30-6.33 (IH, t), 6.86 (IH, s), 7.49-7.51 (2H, d), 8.22-8.24 (2H, d), 8.87 (IH, s) Example 36ch: 1U NMR (400.132 MHz, DMSOd6) δ 1.24-1.26 (3H, d), 1.68-1.75 (2H, m), 2.20-2.28 (2H, td), 2.82-2.87 (2H, t), 3.06-3.10 (2H, m), 3.18-3.22 (2H, m), 3.23-3.25 (IH, m), 3.38-3.41 (2H, t), 3.50-3.57 (IH, td), 3.67-3.70 (IH, dd), 3.77 (IH, s), 3.80 (3H, s), 3.91- 3.96 (2H, qu), 3.98-4.02 (IH, dd), 4.30-4.33 (IH, d), 4.58 (IH, exchange), 6.87 (IH, s), 7.390-7.392 (IH, d), 7.55-7.57 (2H, d), 7.77 (IH, s), 8.25-8.27 (2H, d), 8.49 (IH, exchange), 8.93 (IH, exchange)
Example 36ci: 1R NMR (400.132 MHz, DMSOd6) δ 1.24-1.25 (3H, d), 1.68-1.75 (2H, m), 2.20-2.28 (2H, td), 2.82-2.86 (2H, t), 3.07-3.11 (2H, m), 3.16-3.20 (IH, m), 3.22-3.23 (IH, d), 3.38-3.41 (2H, t), 3.51-3.57 (2H, td), 3.68-3.69 (IH, dd), 3.77-3.80 (IH, d), 3.90-3.96 (2H, t), 3.99-4.01 (IH, d), 4.29-4.33 (IH, d), 4.57-4.58 (IH, exchange), 6.84 (IH, s), 7.23 (IH, s), 7.57-7.59 (IH, m), 7.65-7.67 (2H, d), 8.20-8.22 (2H, d) Example 36cj: 1R NMR (400.132 MHz, DMSOd6) δ 1.24-1.26 (3H, d), 1.63-1.66 (2H, m), 1.93-2.00 (2H, m), 3.15-3.20 (2H, m), 3.217-3.226 (IH, d), 3.47-3.51 (IH, dd), 3.53-3.57 (4H, m), 3.63-3.67 (IH, dd), 3.76-3.79 (IH, d), 3.97-4.01 (IH, dd), 4.22-4.25 (IH, d), 4.57 (IH, exchange), 4.73 (IH, exchange), 6.77 (IH, s), 6.84-6.85 (IH, d), 7.33-7.34 (IH, d), 7.66- 7.68 (2H, d), 8.23-8.25 (2H, d) Example 36ck: 1R NMR (400.132 MHz, DMSO-(I6) δ 0.70-0.74 (2H, m), 0.91-0.93 (2H, dd), 1.24-1.26 (3H, d), 1.56-1.58 (2H, m), 1.64-1.66 (2H, m), 1.92-1.99 (2H, m), 2.72-2.77 (IH, sep), 2.89 (2H, s), 3.16-3.20 (2H, t), 3.22-3.23 (IH, d), 3.4703.50 (IH, dd), 3.51-3.56 (4H, m), 3.63-3.67 (IH, dd), 3.77-3.80 (IH, d), 3.97-4.01 (IH, dd), 4.22-4.25 (IH, d), 4.57 (IH, exchange), 6.79 (IH, s), 7.64-7.67 (2H, dd), 8.22-8.24 (2H, s), 8.41 (IH, exchange) Example 36cl: 1U NMR (400.132 MHz, DMSOd6) δ 0.56-0.59 (2H, t), 0.66-0.68 (2H, t), 1.24-1.26 (3H, d), 1.31-1.36 (3H, m), 1.56-1.60 (2H, m), 1.62-1.66 (2H, m), 1.92-2.00 (2H, m), 3.16-3.21 (2H, t), 3.47-3.50 (IH, dd), 2.52-3.55 (4H, m), 3.63-3.67 (IH, dd), 3.52-3.55 (4H, m), 3.63-3.67 (IH, dd), 3.77-3.79 (IH, d), 4.00-4.01 (IH, dd), 4.21-4.24 (IH, d), 4.56 (IH, exchange), 6.78 (IH, s), 7.49-7.51 (2H, d), 8.21-8.23 (2H, d) Example 36cm: 1R NMR (400.132 MHz, DMSOd6) δ 1.24-1.26 (3H, d), 1.56-1.58 (2H, m), 1.64-1.67 (2H, m), 1.92-1.99 (2H, m), 3.19-3.26 (IH, dd), 3.51-3.55 (6H, m), 3.63-3.67 (IH, dd), 3.77-3.79 (IH, d), 3.97-4.01 (IH, dd), 4.21-4.24 (IH, d), 4.57 (IH, s), 4.71 (IH, s), 5.94- 6.24 (IH, tt), 6.55-6.58 (IH, t), 6.80 (IH, s), 7.51-7.54 (2H, d), 8.23-8.26 (2H, d), 8.96 (IH, s) Example 36cn: 1U NMR (400.132 MHz, DMSOd6) δ 1.24-1.26 (3H, d), 1.32 (9H, s), 1.54- 1.60 (2H, m), 1.61-1.67 (2H, m), 1.92-1.99 (2H, m), 3.18-3.26 (IH, m), 3.47-3.50 (IH, dd), 3.52-3.56 (4H, m), 3.63-3.67 (IH, dd), 3.77-3.80 (IH, d), 3.97-4.01 (IH, dd), 4.21-4.24 (IH, d), 4.57 (IH, s), 4.72 (IH, exchange), 6.09 (IH, s), 6.78 (IH, s), 7.45-7.48 (2H, d), 8.20-8.23 (2H, d), 8.52 (IH, s)
Example 36co: 1R NMR (400.132 MHz, DMSOd6) δ 1.23-1.25 (3H, d), 1.55-1.59 (2H, m), 1.60-1.64 (2H, m), 1.91-1.98 (2H, m), 3.46-3.50 (IH, dd), 3.50-3.54 (4H, m), 3.62-3.66 (IH, dd), 3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.08 (IH, s), 4.19-4.22 (IH, d), 4.55 (exchange), 4.70 (exchange), 6.73 (IH, s), 7.59-7.61 (2H, d), 8.10-8.12 (2H, d), 8.38 (IH, exchange) Example 36cp: 1H NMR (400.132 MHz, DMSO-Cl6) δ 1.24-1.25 (3H, d), 1.55-1.59 (2H, m), 1.62-1.66 (2H, m), 1.77-1.84 (2H, m), 1.91-1.99 (2H, m), 3.16-3.20 (2H, m), 3.21-3.25 (IH, dd), 3.46-3.47 (IH, d), 3.49-3.55 (6H, m), 3.62-3.66 (IH, dd), 3.76-3.79 (IH, d), 3.96-4.00 (IH, dd), 4.21-4.25 (IH, d), 4.31-4.32 (IH, m), 4.56 (exchange), 6.78 (IH, s), 7.64-7.66 (2H, d), 8.20-8.22 (2H, d), 8.34 (exchange)
Example 36cq: 1R NMR (400.132 MHz, DMSO-dg) δ 1.23-1.25 (3H, d), 1.55-1.59 (2H, m), 1.62-1.65 (2H, m), 1.91-1.98 (2H, m), 3.05 (3H, s), 3.16-3.25 (2H, m), 3.33-3.34 (2H, d), 3.46-3.50 (IH, dd), 3.50-3.58 (6H, m), 3.62-3.66 (IH, dd), 3.76-3.79 (IH, d), 3.96-4.00 (IH, dd), 4.20-4.23 (IH, d), 4.56 (exchange), 4.70 (exchange), 6.45-6.48 (IH, t), 6.78 (IH, s), 7.51- 7.53 (2H, d), 8.21-8.24 (2H, d), 9.05 (exchange)
Example 36cr: 1U NMR (400.132 MHz, DMSOd6) δ 1.24-1.26 (3H, d), 1.56-1.60 (2H, m), 1.62-1.66 (2H, m), 1.92-1.99 (2H, m), 3.00-3.05 (IH, dd), 3.16-3.22 (6H, m), 3.42-3.47 (2H, dd), 3.51-3.55 (4H, m), 3.63-3.67 (IH, dd), 3.76-3.79 (IH, d), 3.97-4.00 (IH, dd), 4.21-4.24 (IH, d), 4.45-4.48 (exchange, t), 4.56 (exchange), 6.79 (IH, s), 7.11 (exchange), 7.52-7.54 (2H, d), 8.22-8.24 (2H, d), 9.21 (exchange)
Example 36cs: 1H NMR (400.132 MHz, DMSOd6) δ 1.24-1.25 (3H, d), 1.56-1.58 (2H, m), 1.62-1.66 (2H, m), 1.91-1.98 (2H, m), 2.89 (3H, s), 2.98 (3H, s), 3.16-3.22 (2H, m), 3.46-3.50 (IH, dd), 3.50-2.54 (4H, m), 3.63-3.66 (IH, dd), 3.76-3.79 (IH, d), 3.96-3.97 (IH, d), 3.99- 4.00 (2H, d), 4.20-4.24 (IH, d), 4.57 (IH, exchange), 6.43-6.45 (t, exchange), 6.79 (IH, s), 7.50-7.52 (2H, d), 8.22-8.24 (2H, d), 9.19 (exchange)
Example 36ct: 1R NMR (400.132 MHz, DMSOd6) δ 1.15-1.20 (3H, d), 1.70-1.79 (2H, q), 1.95-2.05 (2H, q), 3.10-3.20 (IH, td), 3.45-3.52 (IH, td), 3.62-3.65 (IH, dd), 3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.10-4.20 (IH, d), 4.45 (IH, bs), 6.70 (IH, s), 7.45-7.52 (2H, d), 7.75- 7.80 (IH, dd), 7.80-7.82 (2H, d), 8.00-8.05 (IH, d), 8.10-8.15 (IH, td), 8.40 (IH, s), 8.85 (IH, d), 9.40 (IH, s), 11.40 (IH, br s). mTOR Kinase Assay (Echo): 0.00157μM
Example 36cu: 1U NMR (400.132 MHz, DMSOd6) δ 1.10-1.15 (3H, d), 1.70-1.79 (2H, q), 1.95-2.00 (2H, q), 3.10-3.20 (IH, td), 3.45-3.50 (IH, td), 3.60-3.62 (IH, dd), 3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.10-4.20 (IH, d), 4.30 (2H, d), 4.45 (IH, bs), 6.60 (IH, t), 6.70 (IH, s), 6.90-7.00 (2H, br d), 7.40 (2H, d), 7.75-7.80 (3H, m), 8.00-8.05 (IH, d), 8.10-8.15 (IH, td), 8.80 (IH, d), 8.90 (IH, s). mTOR Kinase Assay (Echo): 0.0686μM Example 36cv: 1R NMR (400.132 MHz, DMSO-Cl6) δ 0.55-0.65 (2H, q), 0.65-0.75 (2H, q), 1.10-1.15 (3H, d), 1.70-1.79 (2H, q), 1.95-2.00 (2H, q), 3.10-3.20 (IH, td), 3.40-3.50 (2H, m), 3.60-3.62 (IH, dd), 3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.10-4.20 (IH, d), 4.45 (IH, bs), 4.80 (IH, bs), 6.55 (IH, t), 6.65 (IH, s), 7.30 (2H, d), 7.70-7.80 (3H, m), 7.95-8.00 (IH, d), 8.05-8.10 (IH, td), 8.60 (IH, s), 8.80 (IH, d). mTOR Kinase Assay (Echo): 0.259μM
Example 36cw: 1R NMR (400.132 MHz, DMSOd6) δ 1.15-1.20 (3H, d), 1.65-1.70 (2H, q), 1.95-2.00 (2H, q), 3.10-3.20 (IH, td), 3.40-3.50 (IH, td), 3.60-3.64 (IH, dd), 3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.10-4.20 (IH, d), 4.35 (2H, d), 4.45 (IH, bs), 6.60 (IH, t), 6.70 (IH, s), 6.80-7.10 (2H, m), 7.40 (2H, d), 7.70 (2H, d), 7.80 (2H, dd), 8.85 (2H, dd), 8.90 (IH, s), 11.85 (IH, s).
Example 36cx: 1R NMR (400.132 MHz, DMSOd6) δ 0.55-0.65 (2H, q), 0.65-0.75 (2H, q), 1.15-1.20 (3H, d), 1.70-1.75 (2H, q), 1.95-2.00 (2H, q), 3.10-3.20 (IH, td), 3.45 (2H, d), 3.50 (IH, td), 3.60-3.63 (IH, dd), 3.74-3.78 (IH, d), 3.94-3.99 (IH, dd), 4.10-4.20 (IH, d), 4.45 (IH, bs), 4.80-4.90 (IH, t), 6.55 (IH, s), 6.65 (IH, s), 7.30 (2H, d), 7.65 (2H, d), 7.80 (2H, dd), 8.70 (IH, s), 8.85 (2H, dd)
Example 36cy: 1R NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, m), 2.22-2.30 (2H, td), 2.65 (3H, d), 2.75 (2H, t), 3.13 (3H, m), 3.50 (IH, td), 3.65 (IH, dd), 3.75 (IH, d), 3.90-3.95 (2H, d), 3.98 (IH, dd), 4.15 (IH, d), 4.50 (IH, br s), 6.05 (IH, q), 6.68 (IH, s), 7.37 (2H, d), 7.44 (2H, d), 7.46 (2H, d), 7.61 (IH, tt), 7.76 (2H, d), 8.68 (IH, s)
Example 36cz: 1R NMR (400.132 MHz, DMSOd6) δ 1.06 (3H, t), 1.21 (3H, d), 2.26-2.31 (2H, td), 2.74 (2H, t), 3.12 (5H, dt), 3.50 (IH, td), 3.65 (IH, dd), 3.76 (IH, d), 3.90 (2H, d), 3.97 (IH, dd), 4.14 (IH, d), 4.52 (IH, m), 6.14 (IH, t), 6.68 (IH, s), 7.36 (2H, d), 7.44 (4H, q), 7.60 (IH, m), 7.76 (2H, d), 8.60 (IH, s) Example 36da: 1H NMR (400.132 MHz, DMSOd6) δ 0.41 (2H, q), 0.65 (2H, q), 1.21 (3H, d), 2.23-2.32 (2H, td), 2.55 (IH, dd), 2.75 (2H, m), 3.15 (3H, m), 3.50 (IH, td), 3.66 (IH, dd), 3.76 (IH, d), 3.91 (2H, d), 3.97 (IH, dd), 4.14 (IH, d), 4.51 (IH, br s), 6.41 (IH, d), 6.69 (IH, s), 7.37 (2H, d), 7.44 (4H, dd), 7.61 (IH, t), 7.77 (2H, d), 8.48 (IH, s) Example 36db: 1R NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 2.26-2.31 (2H, td), 2.74- 2.78 (2H, t), 3.11-3.17 (5H, m), 3.46 (2H, q), 3.56 (IH, dd), 3.66 (IH, dd), 3.76 (IH, d), 3.90 (2H, d), 3.97 (IH, dd), 4.15 (IH, d), 4.50 (IH, br s), 4.72 (IH, t), 6.24 (IH, t), 6.68 (IH, s), 7.36 (2H, d), 7.44 (4H, q), 7.60 (IH, m), 7.77 (2H, d), 8.75 (IH, s) Example 36dc: 1H NMR (400.132 MHz, DMSO-Cl6) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m),
1.60-1.64 (2H, q), 1.88-1.91 (2H, q), 2.54-2.57 (IH, m), 3.63-3.64 (4H, m), 3.68-3.70 (4H, m), 6.40-6.41 (IH, d), 6.68 (IH, s), 7.37-7.40 (2H, d), 7.57-7.61 (2H, t), 7.71-7.74 (IH, tt),
7.78-7.83 (4H, t), 8.50 (IH, s) Example 36dd: 1R NMR (400.132 MHz, DMSOd6) δ 1.05-1.08 (3H, t), 1.60-1.64 (2H, q),
1.88-1.91 (2H, q), 3.09-3.16 (2H, m), 3.63-3.64 (4H, m), 3.68-3.70 (4H, m), 6.12-6.15 (IH, t),
6.68 (IH, s), 7.36-7.38 (2H, d), 7.57-7.61 (2H, t), 7.71-7.74 (IH, tt), 7.78-7.82 (4H, m), 8.62
(IH, s). mTOR Kinase Assay (Echo): 0.00291μM Example 36de: 1R NMR (400.132 MHz, DMSO-(I6) δ 1.60-1.64 (2H, q), 1.88-1.91 (2H, q),
3.15-3.19 (2H, m), 3.44-3.48 (2H, q), 3.63-3.64 (4H, m), 3.68-3.70 (4H, m), 4.71-4.74 (IH, t),
6.21-6.24 (IH, t), 6.68 (IH, s), 7.36-7.38 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.78-
7.83 (4H, m), 8.76 (IH, s). mTOR Kinase Assay (Echo): 0.00389μM Example 36df: 1U NMR (400.132 MHz, DMSO-d6) δ 1.60-1.64 (2H, q), 1.88-1.91 (2H, q),
2.65-2.66 (3H, d), 3.63-3.64 (4H, m), 3.68-3.69 (4H, m), 6.02-6.06 (IH, m), 6.68 (IH, s),
7.37-7.39 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.78-7.82 (4H, m), 8.70 (IH, s). mTOR Kinase Assay (Echo): 0.00712μM
Example 36dg: 1H NMR (400.132 MHz, DMSO-d6) δ 1.56-1.64 (4H, m), 1.88-1.91 (2H, q), 3.14-3.19 (2H, q), 3.45-3.49 (2H, q), 3.63-3.64 (4H, m), 3.68-3.70 (4H, m), 4.46-4.49 (IH, t),
6.16-6.19 (IH, t), 6.68 (IH, s), 7.36-7.39 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.78-
7.82 (4H, m), 8.67 (IH, s). mTOR Kinase Assay (Echo): 0.0164μM
Example 36dh: 1R NMR (400.132 MHz, DMSO-d6) δ 1.60-1.64 (2H, q), 1.88-1.91 (2H, q), 2.68-2.72 (2H, t), 3.34-3.39 (2H, q), 3.63-3.64 (4H, m), 3.68-3.69 (4H, m), 6.49-6.52 (IH, m),
6.68 (IH, s), 7.38-7.41 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.78-7.84 (4H, m), 8.88
(IH, s). mTOR Kinase Assay (Echo): 0.0034μM
Example 36di: 1H NMR (400.132 MHz, DMSO-d6) δ 1.61-1.65 (2H, q), 1.89-1.92 (2H, q), 3.63-3.66 (4H, m), 3.69-3.71 (4H, m), 6.73 (IH, m), 6.95 (IH, s), 7.08 (IH, s), 7.21 (IH, s),
7.49-7.52 (2H, d), 7.59-7.63 (2H, t), 7.70-7.74 (IH, tt), 7.79-7.91 (2H, d), 7.92-7.94 (2H, d),
8.38 (IH, s), 9.40 (IH, s), 11.39 (IH, s). (ammonium salt) Example 36dj: 1H NMR (400.132 MHz, DMSO-d6) δ 1.61-1.64 (2H, q), 1.89-1.92 (2H, q), 3.63-3.65 (4H, m), 3.69-3.70 (4H, m), 3.79 (3H, s), 6.69 (IH, s), 7.38-7.39 (IH, d), 7.41-7.44 (2H, d), 7.58-7.62 (2H, t), 7.71-7.75 (IH, tt), 7.77 (IH, s), 7.79-7.81 (2H, dd), 7.83-7.86 (2H, d), 8.36 (IH, s), 8.80 (IH, s) Example 36dk: 1H NMR (400.132 MHz, DMSOd6) δ 0.40 - 0.44 (2H, m), 0.63 - 0.67 (2H, m), 1.21 (3H, d), 1.58 - 1.64 (2H, m), 1.86 - 1.88 (2H, m), 2.39 (3H, s), 2.54 - 2.58 (IH, m), 2.75 - 2.78 (4H, m), 3.11 - 3.18 (IH, m), 3.46 - 3.51 (IH, m), 3.62 - 3.66 (IH, m), 3.76 (IH, d), 3.95 - 3.98 (IH, m), 4.13 - 4.16 (IH, m), 4.48 - 4.54 (IH, m), 6.40 (IH, s), 6.66 (IH, s), 7.43 (2H, d), 7.64 (IH, s), 7.89 (2H, d), 8.51 (IH, s). mTOR Kinase Assay (Echo): 0.00905μM
Example 36dl: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.57 - 1.63 (2H, m), 1.84
- 1.89 (2H, m), 2.39 (3H, s), 2.74 - 2.79 (4H, m), 3.12 - 3.20 (3H, m), 3.44 - 3.51 (3H, m), 3.64 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.12 - 4.16 (IH, m), 4.48 - 4.53 (IH, m), 4.72 (IH, t), 6.24 (IH, t), 6.66 (IH, s), 7.41 (2H, d), 7.64 (IH, s), 7.89 (2H, d), 8.78 (IH, s). mTOR Kinase Assay (Echo): 0.00399μM
Example 36dm: 1R NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.57 - 1.64 (2H, m), 1.84 - 1.90 (2H, m), 2.39 (3H, s), 2.70 (2H, t), 2.74 - 2.79 (4H, m), 3.12 - 3.18 (IH, m), 3.35 - 3.39 (2H, m), 3.46 - 3.51 (IH, m), 3.64 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.15 (IH, d), 4.48
- 4.54 (IH, m), 6.51 (IH, t), 6.67 (IH, s), 7.44 (2H, d), 7.64 (IH, s), 7.90 (2H, d), 8.90 (IH, s). mTOR Kinase Assay (Echo): 0.0298μM
Example 36dn: 1R NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 1.57 - 1.61 (4H, m), 1.85
- 1.90 (2H, m), 2.39 (3H, s), 2.74 - 2.79 (4H, m), 3.12 - 3.19 (3H, m), 3.45 - 3.51 (3H, m), 3.64 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.14 (IH, d), 4.47 - 4.54 (IH, m), 4.47 (IH, t), 6.18 (IH, t), 6.66 (IH, s), 7.41 (2H, d), 7.64 (IH, s), 7.89 (2H, d), 8.68 (IH, s). mTOR Kinase Assay (Echo): 0.0138μM
Example 36do: 1H NMR (400.132 MHz, DMSO-d6) δ 1.17-1.19(3H, d), 1.61-1.68(2H, m), 1.78-1.86(1H, m), 1.88-1.98(3H, m), 3.1O-3.18(1H, td), 3.31-3.33(1H, d), 3.43-3.49(4H, m), 3.59-3.63(1H, dd), 3.73-3.76(1H, d), 3.94-3.98(1H, dd), 4.1O-4.13(1H, d), 4.31(1H, bs), 4.38(1H, bs), 4.94-4.95(1H, d), 6.63(1H, s), 7.52-7.55(2H, d), 7.58-7.61(2H, t), 7.70-7.74QH, tt), 7.79-7.84(4H, m), 8.28(1H, s).
Example 36dp: 1R NMR (400.132 MHz, DMSO-d6) δ 1.17-1.18(3H, d), 1.60-1.68(2H, m), 1.87-1.93(2H, m), 3.1O-3.17(1H, td), 3.43-3.49(1H, td), 3.53-3.54(2H, m), 3.59-3.63(1H, dd), 3.73-3.76(1H, d), 3.94-3.97(1H, dd), 4.09-4.12(1H, d), 4.38(1H, bs), 6.47(1H, t), 6.63(1H, s),
7.39-7.41(2H, d), 7.57-7.61(2H, t), 7.7O-7.74(1H, tt), 7.78-7.83(4H, m), 9.27(1H, s). (H from
OH group barried under water peak).
Example 36dq: 1R NMR (400.132 MHz, DMSOd6) δ 1.16-1.18(3H, d), 1.61-1.68(2H, m), 1.87-1.92(2H, m), 2.88(3H, s), 2.97(3H, s), 3.1O-3.18(1H, td), 3.42-3.49(1H, td), 3.59-
3.63(1H, dd), 3.73-3.76(1H, d), 3.94-3.98(3H, m), 4.09-4.12(1H, d), 4.39(1H, bs), 6.37-
6.4O(1H, t), 6.63(1H, s), 7.38-7.40(2H, d), 7.57-7.61(2H, t), 7.69-7.74(1H, tt), 7.78-7.80(2H, dd), 7.84-7.86(2H, d), 9.12(1H, s).
Example 36dr: 1R NMR (400.132 MHz, DMSOd6) δ 0.68-0.72(2H, m), 0.88-0.93(2H, m), 1.17-1.19(3H, d), 1.61-1.68(2H, m), 1.89-1.92(2H, m), 2.69-2.75(1H, m), 2.87(3H, s), 3.11-
3.18(1H, td), 3.43-3.50(1H, td), 3.59-3.63(1H, dd), 3.74-3.76(1H, d), 3.94-3.98(1H, dd), 4.09-
4.14(1H, d), 4.39(1H, bs), 6.64(1H, s), 7.52-7.54(2H, d), 7.58-7.62(2H, t), 7.7O-7.74(1H, tt),
7.79-7.85(4H, m), 8.34(1H, s).
Example 36ds: 1R NMR (400.132 MHz, DMSOd6) δ 1.16-1.18(3H, d), 1.60-1.68(2H, m), 1.87-1.93(2H, m), 3.1O-3.18(1H, td), 3.36-3.40(1H, q), 3.42-3.49(2H, m), 3.59-3.63(1H, dd),
3.73-3.76(1H, d), 3.94-3.98(1H, dd), 4.09-4.12(1H, d), 4.39(1H, bs), 4.4O-4.43(1H, t), 4.52-
4.55(1H, t), 6.4O-6.43(1H, t), 6.63(1H, s), 7.38-7.40(2H, d), 7.57-7.61(2H, t), 7.7O-7.74(1H, tt), 7.78-7.80(2H, dd), 7.84-7.86(2H, d), 8.77(1H, s).
Example 36dt: 1R NMR (400.132 MHz, DMSOd6) δ 1.19-1.21(3H, d), 1.85-1.93(1H, m), 2.04-2.14(1H, m), 2.68-2.72(2H, t), 2.76-2.83(2H, m), 3.02-3.10(2H, m), 3.13-3.19(1H, td),
3.34-3.39(2H, q), 3.45-3.52(1H, td), 3.62-3.65(1H, dd), 3.74-3.77(1H, d), 3.94-3.98(1H, dd),
4.07-4.10(1H, d), 4.45(1H, bs), 6.47(1H, s), 6.49-6.52(1H, t), 7.38-7.40(2H, d), 7.44-7.51(4H, m), 7.58-7.62(1H, tt), 7.80-7.82(2H, d), 8.86(1H, s).
Example 36du: 1R NMR (400.132 MHz, DMSOd6) δ 1.19-1.21(3H, d), 1.82-1.93(1H, m), 2.05-2.13(1H, m), 2.76-2.83(2H, m), 3.02-3.19(4H, m), 3.45-3.51(1H, td), 3.62-3.65(1H, dd),
3.74-3.77(1H, d), 3.94-3.98(1H, dd), 4.06-4.10(1H, d), 4.31-4.33(2H, d), 4.45-4.46(1H, bs),
6.47(1H, s), 6.59-6.62(1H, t), 6.94(2H, bs), 7.38-7.40(2H, d), 7.44-7.51(4H, m), 7.58-
7.62(1H, tt), 7.80-7.82(2H, d), 8.87(1H, s).
Example 36dv: 1H NMR (399.902 MHz, DMSOd6) δ 1.17 (3H, d), 1.64 (2H, m), 1.90 (2H, m), 3.15 (IH, m), 3.47 (IH, m), 3.61 (IH, m), 3.76 (4H, m), 3.95 (IH, m), 4.14 (IH, m), 4.39
(IH, m), 6.26 (IH, m), 6.65 (IH, s), 7.44 (2H, m), 7.59 (3H, m), 7.74 (IH, m), 7.80 (2H, m),
7.88 (2H, m), 8.94 (IH, s), 9.12 (IH, s) Example 36dw: 1H NMR (399.902 MHz, DMSO-d6) δ 1.18 (3H, d), 1.64 (2H, m), 1.91 (2H, m), 3.15 (IH, m), 3.34 (3H, s), 3.46 (IH, m), 3.61 (IH, m), 3.75 (IH, m), 3.96 (IH, m), 4.12 (IH, m), 4.40 (IH, m), 6.58 (IH, m), 6.66 (IH, m), 7.45 (2H, m), 7.60 (2H, m), 7.77 (3H, m), 7.90 (2H, m), 9.03 (IH, s), 9.49 (IH, s) Example 36dx: 1H NMR (399.902 MHz, DMSOd6) δ 1.17 (3H, d), 1.64 (2H, m), 1.90 (2H, m), 3.14 (IH, m), 3.52 (4H, m), 3.75 (IH, m), 3.96 (IH, m), 4.11 (IH, m), 4.38 (IH, m), 6.08 (IH, m), 6.53 (IH, m), 6.63 (IH, s), 7.40 (2H, m), 7.60 (2H, m), 7.72 (IH, m), 7.82 (4H, m), 8.92 (IH, s) Example 36dy: Spectrum not recorded. Example 36dz: 1H NMR (399.902 MHz, DMSOd6) δ 1.18 (3H, d), 1.64 (2H, m), 1.90 (2H, m), 3.15 (IH, m), 3.47 (IH, m), 3.61 (IH, m), 3.75 (IH, m), 3.96 (IH, m), 4.13 (IH, m), 4.40 (IH, m), 6.66 (IH, s), 6.88 (IH, m), 7.46 (2H, m), 7.61 (2H, m), 7.77 (3H, m), 7.90 (2H, m), 8.77 (IH, m), 9.05 (IH, s), 9.64 (IH, s) Example 36ea: 1U NMR (399.902 MHz, DMSOd6) δ 1.17 (3H, d), 1.64 (2H, m), 1.91 (2H, m), 3.14 (IH, m), 3.46 (IH, m), 3.61 (IH, m), 3.75 (IH, m), 3.94 (3H, m), 4.12 (IH, m), 4.39 (IH, m), 6.64 (IH, s), 6.79 (IH, m), 7.40 (2H, m), 7.59 (2H, m), 7.79 (5H, m), 8.99 (IH, s) Example 36eb: 1R NMR (399.902 MHz, DMSOd6) δ 1.18 (3H, d), 1.65 (2H, m), 1.91 (2H, m), 3.15 (IH, m), 3.46 (IH, m), 3.61 (4H, m), 3.75 (IH, m), 3.97 (IH, m), 4.12 (IH, m), 4.40 (IH, m), 6.64 (IH, s), 6.97 (IH, s), 7.41 (3H, m), 7.61 (2H, m), 7.80 (5H, m), 8.70 (IH, s), 9.07 (1H, s)
Example 36ec: 1R NMR (399.902 MHz, DMSOd6) δ 1.08 (3H, d), 1.17 (3H, d), 1.64 (2H, m), 1.90 (2H, m), 3.13 (IH, m), 3.40 (3H, m), 3.67 (3H, m), 3.96 (IH, m), 4.10 (IH, m), 4.37 (IH, m), 4.83 (IH, t), 6.10 (IH, m), 6.63 (IH, s), 7.36 (2H, m), 7.60 (2H, m), 7.78 (5H, m),
8.70 (IH, s) Example 36ed: 1U NMR (399.902 MHz, DMSOd6) δ 1.08 (3H, d), 1.17 (3H, d), 1.64 (2H, m), 1.91 (2H, m), 3.14 (IH, m), 3.42 (3H, m), 3.67 (3H, m), 3.96 (IH, m), 4.11 (IH, m), 4.39 (IH, m), 4.83 (IH, t), 6.10 (IH, m), 6.62 (IH, s), 7.36 (2H, m), 7.59 (2H, m), 7.77 (5H, m),
8.71 (IH, s)
Example 36ee: 1R NMR (399.902 MHz, DMSOd6) δ 1.17 (3H, d), 1.63 (2H, m), 1.90 (2H, m), 3.13 (IH, m), 3.45 (3H, m), 3.67 (4H, m), 3.95 (IH, m), 4.12 (IH, m), 4.39 (IH, m), 6.47 (IH, m), 6.63 (IH, s), 7.39 (2H, m), 7.60 (2H, m), 7.79 (5H, m), 8.91 (IH, s) Example 36ef: 1U NMR (399.902 MHz, DMSO-Cl6) δ 1.23 (d, 3H), 1.33 (t, 3H), 1.52 - 1.58 (m, 2H), 1.60 - 1.66 (m, 2H), 3.20 (td, IH), 3.37 - 3.53 (m, 5H), 3.63 (dd, IH), 3.77 (d, IH), 3.98 (dd, IH), 4.14 - 4.28 (m, IH), 4.42 (t, IH), 4.50 - 4.62 (m, IH), 4.54 (t, IH), 6.47 (t, IH), 6.79 (s, IH), 7.51 (d, 2H), 8.20 (d, 2H), 8.85 (s, IH) Example 36eg: 1R NMR (399.902 MHz, DMSO-de) δ 1.23 (d, 3H), 1.33 (t, 3H), 1.53 - 1.58 (m, 2H), 1.60 - 1.66 (m, 2H), 3.20 (td, IH), 3.44 (q, 2H), 3.48 - 3.65 (m, 4H), 3.77 (d, IH), 3.98 (dd, IH), 4.16 - 4.26 (m, IH), 4.51 - 4.64 (m, IH), 6.07 (tt, IH), 6.56 (t, IH), 6.79 (s, IH), 7.52 (d, 2H), 8.21 (d, 2H), 8.97 (s, IH)
The preparation of the phenyl carbamates required for Examples 36a - 36eg are either described below or have been described previously.
The preparation of phenyl Λ/-[4-[4-(l-cyclopropylsulfonylcyclobutyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N- [4- [4-(l-cvclopropylsulfonylcvclobutvn-6- [(36^-3 -methylmorpholin-4- yl1pyrimidin-2-yl1phenvHcarbamate
Figure imgf000584_0001
Sodium hydrogen carbonate (259 mg, 3.08 mmol) was added to 4-[4-(l- cyclopropylsulfonylcyclobutyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (880 mg, 2.05 mmol) in dioxane (20 mL) at 50C under an atmosphere of nitrogen. Phenyl chloroformate (0.387 mL, 3.08 mmol) was then added and the resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with DCM (50 mL), the organic layer dried (Na2SO4), filtered and evaporated to afford crude product. The crude gum was triturated with a mixture of diethyl ether and isohexane to give the desired material as a cream solid which was collected by filtration and dried under vacuum (1.06 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 0.69 - 0.80 (2H, m), 0.81 - 0.90 (2H, m), 1.23 (3H, d), 1.86 - 1.98 (IH, m), 2.02 - 2.12 (IH, m), 2.80 - 3.04 (5H, m), 3.15 - 3.28 (IH, m), 3.46 - 3.59 (IH, m), 3.66 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.23 (IH, d), 4.57 (IH, s), 6.74 (IH, s), 7.22 - 7.31 (3H, m), 7.41 - 7.49 (2H, m), 7.62 (2H, d), 8.33 (2H, d), 10.42 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 549; HPLC tR = 3.05 min.
4-r4-(l-Cvclopropylsulfonylcvclobutyl)-6-r(36^-3-methylmorpholin-4-yllpyrimidin-2- yll aniline
Figure imgf000585_0001
Bis(triphenylphosphine)palladium(II) chloride (0.164 g, 0.23 mmol) was added to 2-chloro-4- (l-cyclopropylsulfonylcyclobutyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (1.3 g, 3.50 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.149 g, 5.24 mmol) and an aqueous solution of sodium carbonate (1 mL, 2.00 mmol) in a solvent mixture of DMF (5 mL), DME (12 mL), water (1 mL) and ethanol (1 mL) at RT . The resulting mixture was stirred at 9O0C for 5 hours under an atmosphere of nitrogen. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (2 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 70% ethyl acetate in isohexane, and the crude product further purified by ion exchange chromatography using an SCX column, eluting with 7N ammonia in methanol, to give the desired material as a beige solid (0.88 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.70 - 0.89 (4H, m), 1.21 (3H, d), 1.84 - 1.93 (IH, m), 2.02 - 2.10 (IH, m), 2.76 - 2.98 (5H, m), 3.10 - 3.24 (IH, m), 3.45 - 3.55 (IH, m), 3.64 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.18 (IH, d), 4.50 (IH, s), 5.52 (2H, d), 6.60 (2H, d), 8.07 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 429; HPLC tR = 2.41 min. 2-Chloro-4-(l-cvclopropylsulfonylcvclobutyl)-6- [(36^-3 -methylmorpholin-4-yllpyrimidine
Figure imgf000586_0001
1,3-Dibromopropane (2.95 mL, 28.93 mmol) was added to 2-chloro-4- (cyclopropylsulfonylmethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (3.2 g, 9.64 mmol), tetrabutylammonium bromide (0.311 g, 0.96 mmol) and an aqueous solution of sodium hydroxide (2.89 mL, 28.93 mmol) in toluene (24.11 mL). The reaction was stirred at RT for 1 hour then water added and the layers separated. The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% ethyl acetate in isohexane, to give the desired material as a colourless gum (1.3 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.69 - 0.78 (2H, m), 0.88 - 0.93 (2H, m), 1.20 (3H, d), 1.83 - 1.95 (IH, m), 2.02 - 2.12 (IH, m), 2.50 - 2.60 (IH, m), 2.67 - 2.80 (2H, m), 2.83 - 2.96 (2H, m), 3.13 - 3.25 (IH, m), 3.40 - 3.49 (IH, m), 3.61 (IH, d), 3.72 (IH, d), 3.93 (IH, d), 4.06 (IH, s), 4.40 (IH, s), 6.82 (IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 372; HPLC tR = 2.04 min.
The preparation of 2-chloro-4-(cyclopropylsulfonylmethyl)-6-[(35)-3-methylmorpholin-4- yljpyrimidine was described earlier.
The preparation of phenyl Λ/-[4-[4-(l-cyclopropylsulfonylcyclopentyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below. Phenyl Λ/-r4-r4-(l-cvclopropylsulfonylcvclopentyl)-6-r(36f)-3-methylmorpholin-4- ylipγrimidin-2-vHphenvHcarbamate
Figure imgf000587_0001
Sodium hydrogen carbonate (228 mg, 2.71 mmol) was added to 4-[4-(l- cyclopropylsulfonylcyclopentyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (800 mg, 1.81 mmol) in dioxane (20 mL) at 50C under an atmosphere of nitrogen. Phenyl chloro formate (0.341 mL, 2.71 mmol) was then added. The resulting mixture was stirred at RT for 2 hours then diluted with ethyl acetate (100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a cream solid which was collected by filtration and dried under vacuum (700 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.57 - 0.78 (2H, m), 0.79 - 0.90 (2H, m), 1.23 (3H, d), 1.53 - 1.62 (2H, m), 1.77 - 1.87 (2H, m), 2.41 - 2.50 (2H, m), 2.55 - 2.62 (IH, m), 2.76 - 2.91 (2H, m), 3.16 - 3.26 (IH, m), 3.45 - 3.56 (IH, m), 3.66 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.24 (IH, d), 4.55 (IH, s), 6.84 (IH, s), 7.20 - 7.34 (3H, m), 7.41 - 7.51 (2H, m), 7.62 (2H, d), 8.34 (2H, d), 10.42 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 563; HPLC tR = 3.15 min.
4-[4-(l-Cvclopropylsulfonylcvclopentvπ-6-[(3y)-3-methylmorpholin-4-yllpyrimidin-2- yll aniline
Figure imgf000587_0002
Bis(triphenylphosphine)palladium(II) chloride (0.122 g, 0.17 mmol) was added to 2-chloro-4- (l-cyclopropylsulfonylcyclopentyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (1 g, 2.59 mmol), and an aqueous solution of sodium carbonate (1 mL, 2.00 mmol) in a solvent mixture of DMF (5 mL), DME (12 mL), water (1 mL) and ethanol (1 mL). The resulting mixture was stirred at 9O0C for 5 hours under an inert atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (2 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product which was purified by flash silica chromatography, elution gradient 10 to 50% ethyl acetate in isohexane, followed by ion exchange chromatography using an SCX column, eluting with 7N ammonia in methanol, to give the desired material as a beige solid (0.80 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.67 - 0.79 (2H, m), 0.81 - 0.89 (2H, m), 1.22 (3H, d), 1.50 - 1.59 (2H, m), 1.75 - 1.85 (2H, m), 2.41 - 2.51 (2H, m), 2.72 - 2.90 (3H, m), 3.11 - 3.23 (IH, m), 3.45 - 3.56 (IH, m), 3.58 - 3.66 (IH, m), 3.76 (IH, d), 3.97 (IH, d), 4.18 (IH, d), 4.51 (IH, s), 5.52 (IH, d), 6.61 (2H, d), 6.71 (IH, s), 8.07 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 443; HPLC tR = 2.51 min.
2-Chloro-4-(l-cvclopropylsulfonylcvclopentyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000588_0001
1 ,4-Dibromobutane (0.322 mL, 2.71 mmol) was added to 2-chloro-4- (cyclopropylsulfonylmethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (900 mg, 2.71 mmol), tetrabutylammonium bromide (87 mg, 0.27 mmol) and an aqueous solution of sodium hydroxide (0.814 mL, 8.14 mmol) in toluene (20 mL). The reaction was stirred at RT for 1 hour then water added and the organic layer separated, dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% ethyl acetate in isohexane, to give the desired material as a yellow gum (1043 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 0.66 - 0.75 (2H, m), 0.88 - 0.94 (2H, m), 1.20 (3H, d), 1.50 - 1.57 (2H, m), 1.74 - 1.83 (2H, m), 2.36 - 2.46 (2H, m), 2.54 - 2.69 (3H, m), 3.13 - 3.25 (IH, m), 3.40 - 3.50 (IH, m), 3.59 (IH, d), 3.72 (IH, d), 3.93 (IH, d), 4.04 (IH, d), 4.41 (IH, s), 6.92 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 386; HPLC tR = 2.47 min. The preparation of 2-chloro-4-(cyclopropylsulfonylmethyl)-6-[(35)-3-methylmorpholin-4- yljpyrimidine was described earlier.
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]carbamate is described below:
Phenyl N- [4- [4- [(36^-3 -methylmorpholin-4-yl1-6-(l-pyridin-2- ylsulfonylcvclopentyl)pyrimidin-2-yllphenyllcarbamate
Figure imgf000589_0001
Sodium bicarbonate (139 mg, 1.66 mmol) and phenyl chloroformate (0.14 mL, 1.11 mmol) were added to a solution of 4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclopentyl)pyrimidin-2-yl]aniline (530 mg, 1.11 mmol), in 1,4-dioxane (5.6 mL) and the reaction stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (10 mL), washed with water (10 mL), the organic layer dried (MgSO4), filtered and evaporated. The crude product was triturated with diethyl ether to give the desired material as a cream solid (620 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.51 - 1.62 (2H, m), 1.80 - 1.90 (2H, m), 2.68 - 2.82 (4H, m), 3.10 - 3.17 (IH, m), 3.44 - 3.50 (IH, m), 3.61 - 3.64 (IH, m), 3.75 (IH, d), 3.94 - 3.97 (IH, m), 4.12 (IH, d), 4.49 (IH, s), 6.64 (IH, s), 7.24 - 7.30 (3H, m), 7.45 (2H, t), 7.50 (2H, d), 7.55 - 7.59 (2H, m), 7.84 - 7.86 (3H, m), 8.74 (IH, d), 10.37 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 600; HPLC tR = 3.05 min. 4-r4-r(35)-3-Methylmorpholin-4-yll-6-(l-pyridin-2-ylsulfonylcvclopentyl)pyrimidin-2- yll aniline
Figure imgf000590_0001
4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (418 mg, 1.91 mmol), an aqueous solution of sodium carbonate (2.2 mL, 4.40 mmol), and dichlorobis(triphenylphosphine)palladium(II) (51.4 mg, 0.07 mmol) were added to a solution of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclopentyl)pyrimidine (620 mg, 1.47 mmol) in a solvent mixture of DMF (0.24 mL), DME (9.33 mL), water (4.0 mL) and ethanol (2.67 mL). The resultant mixture was heated at 900C for 4 hours. The reaction mixture was cooled to RT, diluted with ethyl acetate
(10 mL) and washed with water (10 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanol in DCM, to give the desired material as a cream solid (530 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 1.51 - 1.58 (2H, m), 1.80 - 1.88 (2H, m), 2.68 - 2.79 (4H, m), 3.09 (IH, dt), 3.46 (IH, dt), 3.61 (IH, dd), 3.74 (IH, d), 3.94 (IH, dd), 4.01 - 4.06 (IH, m), 4.43 (IH, d), 6.46 - 6.49 (3H, m), 7.54 (IH, d), 7.57 -
7.60 (IH, m), 7.60 (2H, d), 7.85 (IH, dt), 8.74 (IH, d)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 480; HPLC tR = 2.37 min.
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(l-pyridin-2-ylsulfonylcvclopentyl)pyrimidine
Figure imgf000590_0002
1 ,4-dibromobutane (0.77 mL, 6.51 mmol) was added to 2-chloro-4-[(3S)-3-methylmorpholin- 4-yl]-6-(pyridin-2-ylsulfonylmethyl)pyrimidine (600 mg, 1.63 mmol) in toluene (4 mL) followed by tetrabutylammonium bromide (52.4 mg, 0.16 mmol) and an aqueous solution of sodium hydroxide (0.976 mL, 9.76 mmol). The reaction was stirred at 600C overnight then the toluene removed under reduced pressure and the reaction redissolved in DCM and washed with water. The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in DCM, to give the desired material as a white solid (620 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 1.50 - 1.58 (2H, m), 1.75 - 1.85 (2H, m), 2.53 - 2.57 (2H, m), 2.63 - 2.71 (3H, m), 3.11 (IH, dt), 3.41 (IH, dt), 3.56 (IH, dd), 3.70 (IH, d), 3.91 (IH, dd), 4.32 (IH, s), 6.67 (IH, s), 7.65 (IH, d), 7.70 - 7.73 (IH, m), 8.03 (IH, dt), 8.74 (IH, d) LCMS Spectrum: m/z (ESI+)(M+H)+ 423, HPLC tR = 2.26 min
The preparation of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(pyridin-2- ylsulfonylmethyl)pyrimidine was described earlier.
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl] carbamate is described below:
Phenyl N- [444- [(36^-3 -methylmorpholin-4-yl1 -6-d-pyridin-2- ylsulfonylcvclobutyl)pyrimidin-2-yllphenyllcarbamate
Figure imgf000591_0001
Sodium bicarbonate (154 mg, 1.84 mmol) and phenyl chloroformate (0.154 mL, 1.22 mmol) were added to a solution of 4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclobutyl)pyrimidin-2-yl]aniline (570 mg, 1.22 mmol), in 1,4-dioxane (6.0 mL) and the reaction stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (10 mL), washed with water (10 mL), the organic layer dried (MgSO4), filtered and evaporated. The crude product was triturated with diethyl ether to give the desired material as a cream solid (600 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 1.86 - 1.98 (IH, m), 2.07 - 2.19 (IH, m), 2.80 - 2.87 (2H, m), 3.10 - 3.17 (IH, m), 3.23 - 3.30 (2H, m), 3.47 (IH, dt), 3.62 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.10 - 4.18 (IH, m), 4.46 (IH, s), 6.52 (IH, s), 6.74 - 6.78 (IH, m), 7.15 (IH, t), 7.23 - 7.30 (3H, m), 7.45 (IH, t), 7.51 (IH, d), 7.60 - 7.62 (2H, m), 7.83 - 7.90 (3H, m), 8.74 (IH, d), 10.39 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 586; HPLC tR = 3.04 min.
4-r4-r(35)-3-Methylmorpholin-4-yll-6-(l-pyridin-2-ylsulfonylcvclobutyl)pyrimidin-2- yll aniline
Figure imgf000592_0001
4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (460 mg, 2.10 mmol), an aqueous solution of sodium carbonate (2.42 mL, 4.84 mmol) and dichlorobis(triphenylphosphine)palladium(II) (56.6 mg, 0.08 mmol) were added to a solution of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(l-pyridin-2-ylsulfonylcyclobutyl)pyrimidine (660 mg, 1.61 mmol) in a solvent mixture of DMF (0.24 mL), DME (9.33 mL), water (4.0 mL) and ethanol (2.67 mL) and the suspension heated at 900C for 4 hours. The reaction mixture was cooled to RT, diluted with ethyl acetate (10 mL) and washed with water (10 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanol in DCM, to give the desired material as a cream solid (570 mg). LCMS Spectrum: m/z (ESI+) (M+H)+ = 466; HPLC tR = 2.27 min.
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(l-pyridin-2-ylsulfonylcvclobutyl)pyrimidine
Figure imgf000592_0002
1,3-Dibromopropane (1.565 mLl, 15.35 mmol) was added to 2-chloro-4-[(3S)-3- methylmorpholin-4-yl]-6-(pyridin-2-ylsulfonylmethyl)pyrimidine (2.83 g, 7.67 mmol), in toluene (20 mL) followed by tetrabutylammonium bromide (0.247 g, 0.77 mmol) and an aqueous solution of sodium hydroxide (2.3 mL, 23.02 mmol). The reaction was stirred at 600C overnight. The toluene was removed under reduced pressure and the reaction redissolved in DCM and the organics washed with water then dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in DCM, to give the desired material as a cream solid (0.66 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.14 (3H, d), 1.86 - 1.95 (IH, m), 2.05 - 2.13 (IH, m), 2.68 - 2.76 (2H, m), 3.07 - 3.18 (3H, m), 3.37 - 3.43 (IH, m), 3.55 (IH, dd), 3.69 (IH, d), 3.90 (2H, dd), 4.28 (IH, s), 6.52 (IH, s), 7.68 - 7.73 (2H, m), 8.03 (IH, dt), 8.74 (IH, d)
LCMS Spectrum: m/z (ESI+)(M+H)+ 409, HPLC tR = 2.03 min
The preparation of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(pyridin-2- ylsulfonylmethyl)pyrimidine was described earlier.
The preparation of phenyl Λ/-[4-[4-[l-(4-fluorophenyl)sulfonylcyclopropyl]-6-morpholin-4- ylpyrimidin-2-yl]phenyl] carbamate is described below:
Phenyl Λ/-[4-[4-[ 1 -(4-fluorophenyl)sulfonylcvclopropyll-6-morpholin-4-ylpyrimidin-2- yllphenyll carbamate
Figure imgf000593_0001
Sodium bicarbonate (0.776 g, 9.24 mmol) was added to 4-[4-[l-(4- fluorophenyl)sulfonylcyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]aniline (2.8 g, 6.16 mmol), in 1,4-dioxane (30.8 mL) at RT, followed by the dropwise addition of phenyl chloro formate (0.775 ml, 6.16 mmol) over 2 minutes and the reaction stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (20 mL), and washed with water (20 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford a solid which was triturated with diethyl ether to give the desired material as a cream solid (3.5 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.59 - 1.62 (2H, m), 1.88 - 1.91 (2H, m), 3.57 (4H, s), 3.69 (4H, s), 6.75 (IH, s), 7.24 - 7.30 (3H, m), 7.40 - 7.47 (4H, m), 7.53 (2H, d), 7.83 - 7.89 (4H, m), 10.40 (IH, s)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 575; HPLC tR = 3.03 min.
4-r4-ri-(4-Fluorophenyl)sulfonylcvclopropyll-6-morpholin-4-ylpyrimidin-2-yllaniline
Figure imgf000594_0001
Bis(triphenylphosphine)palladium(II) chloride (0.285 g, 0.41 mmol) was added to 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (2.312 g, 10.55 mmol) and 2-chloro-4-[l-(4- fluorophenyl)sulfonylcyclopropyl]-6-morpholin-4-ylpyrimidine (3.23 g, 8.12 mmol) and an aqueous solution of sodium carbonate (12.18 mL, 24.36 mmol) in a solvent mixture of DME (20 mL), ethanol (10 mL) and water (10 mL) at RT under an atmosphere of nitrogen. The resulting mixture was stirred at 95°C for 4 hours. The reaction mixture was allowed to cool, diluted with ethyl acetate (20 mL), and washed with water (2 x 2OmL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanol in DCM, to give the desired material as a cream solid (2.8 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.55 - 1.58 (2H, m), 1.85 - 1.88 (2H, m), 3.62 (4H, d), 3.67 - 3.70 (4H, m), 6.49 (2H, d), 6.61 (IH, s), 7.41 (2H, t), 7.62 (2H, d), 7.82 - 7.85 (2H, m) LCMS Spectrum: m/z (ESI+) (M+H)+ = 455; HPLC tR = 2.42 min.
2-Chloro-4-ri-(4-fluorophenyl)sulfonylcvclopropyll-6-morpholin-4-ylpyrimidine
Figure imgf000594_0002
1 ,2-Dibromoethane (0.695 mL, 8.07 mmol) was added to 2-chloro-4-[(4- fluorophenyl)sulfonylmethyl]-6-morpholin-4-ylpyrimidine (3 g, 8.07 mmol), tetrabutylammonium bromide (0.260 g, 0.81 mmol) and an aqueous solution of sodium hydroxide (2.42 mL, 24.21 mmol) in toluene (20.17 mL). The reaction was stirred at RT for 4 hours, the toluene removed under reduced pressure and the residue redissolved in DCM. The organics were washed with water, dried (MgSO4), filtered and evaporated to afford crude product. The crude product was triturated with diethyl ether to give the desired material as a cream solid (3.23 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.52 - 1.55 (2H, m), 1.81 - 1.84 (2H, m), 3.56 (4H, s), 3.63 - 3.65 (4H, m), 6.77 (IH, s), 7.80 - 7.84 (2H, m), 7.82 (2H, t) LCMS Spectrum: m/z (ESI+)(M+H)+ 398, HPLC tR = 2.26 min
2-Chloro-4-r(4-fluorophenyl)sulfonylmethyll-6-morpholin-4-ylpyrimidine
Figure imgf000595_0001
4-Fluorobenzenesulfinic acid sodium salt (3.30 g, 18.11 mmol) was added to 2-chloro-4-
(iodomethyl)-6-morpholin-4-ylpyrimidine (5.00 g, 14.72 mmol) in acetonitrile (150 mL) at
RT under an atmosphere of nitrogen. The resulting solution was stirred at 800C for 20 hours.
The solvent was removed and the residue redissolved in DCM. The organics were washed twice with water, dried (MgSO4) and filtered. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% ethyl acetate in DCM, to give the desired material as a white solid (3.98 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 3.55-3.67 (8H, m), 4.65 (2H, s), 6.78
(IH, s), 7.47-7.52 (2H, m), 7.84-7.87 (2H, m). LCMS Spectrum: m/z (ESI+)(M+H)+ = 372; HPLC tR = 1.99 min.
The preparation of 2-chloro-4-(iodomethyl)-6-morpholin-4-ylpyrimidine was described earlier. The preparation of phenyl Λ/-[4-[4-morpholin-4-yl-6-(l-pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl] carbamate is described below:
Phenyl Λ/-[4-[4-morpholin-4-yl-6-(l-pyridin-4-ylsulfonylcvclopropyπpyrimidin-2- yllphenyll carbamate
Figure imgf000596_0001
Sodium bicarbonate (0.677 g, 8.06 mmol) was added to 4-[4-morpholin-4-yl-6-(l-pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]aniline (2.35 g, 5.37 mmol), in 1,4-dioxane (26.9 mL) at RT, followed by the dropwise addition of phenyl chloro formate (0.676 mL, 5.37 mmol) over 2 minutes and the reaction stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (20 mL), and washed with water (20 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford a solid which was triturated with diethyl ether to give the desired material as a cream solid (3.0 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.67 - 1.70 (2H, m), 1.94 - 1.99 (2H, m), 3.57 (4H, s), 3.69 (4H, s), 6.74 - 6.77 (2H, m), 7.24 - 7.26 (2H, m), 7.43 - 7.50 (3H, m), 7.73 (2H, d), 7.78 (2H, d), 8.86 (2H, d), 9.29 (IH, s), 10.39 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 558; HPLC tR = 2.71 min.
4-r4-Morpholin-4-yl-6-(l-pyridin-4-ylsulfonylcvclopropyl)pyrimidin-2-yllaniline
Figure imgf000596_0002
Bis(triphenylphosphine)palladium(II) chloride (0.309 g, 0.44 mmol) was added to 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (2.505 g, 11.43 mmol) and 2-chloro-4-morpholin- 4-yl-6-(l-pyridin-4-ylsulfonylcyclopropyl)pyrimidine (3.35 g, 8.80 mmol) and an aqueous solution of sodium carbonate (13.19 mL, 26.39 mmol) in a solvent mixture of DME (20 mL), ethanol (10 mL) and water (10 mL) at RT under an atmosphere of nitrogen. The resulting mixture was stirred at 95°C for 4 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with water (2 x 20 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanol in DCM, to give the desired material as a brown solid (2.37 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.63 - 1.67 (2H, m), 1.93 - 1.96 (2H, m), 3.64 (4H, d), 3.67 - 3.69 (4H, m), 5.52 (2H, s), 6.45 (2H, d), 6.62 (IH, s), 7.47 (2H, d), 7.76 (2H, dd), 8.85 (2H, dd)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 438; HPLC tR = 1.94 min.
2-Chloro-4-morpholin-4-yl-6-(l-pyridin-4-ylsulfonylcvclopropyl)pyrimidine
Figure imgf000597_0001
1 ,2-Dibromoethane (0.510 mL, 22.55 mmol) was added to 2-chloro-4-morpholin-4-yl-6- (pyridin-4-ylsulfonylmethyl)pyrimidine (4 g, 11.27 mmol) in toluene (56.4 mL) followed by tetrabutylammonium bromide (0.363 g, 1.13 mmol) and an aqueous solution of sodium hydroxide (5.64 mL, 56.37 mmol). The reaction was stirred at 600C for 7 hours then the toluene removed under reduced pressure and the residue redissolved in DCM. The organics were washed with water, dried (MgSO4), filtered and evaporated to afford crude product. The crude product was triturated with diethyl ether to give the desired material as a brown solid (3.35 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.60 - 1.63 (2H, m), 1.89 - 1.92 (2H, m), 3.58 (4H, d), 3.63 - 3.65 (4H, m), 6.81 (IH, s), 7.74 (2H, d), 8.88 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ 381, HPLC tR = 1.70 min 2-Chloro-4-morpholin-4-yl-6-(pyridin-4-ylsulfonylmethyl)pyrimidine
Figure imgf000598_0001
2-Chloro-4-morpholin-4-yl-6-(pyridin-4-ylsulfanylmethyl)pyrimidine (3.28 g, 10.16 mmol) was dissolved in dioxane (45 mL) and 2N sulfuric acid (0.11 mL) was added. The solution was heated to 55°C. A solution of sodium tungstate dihydrate (0.067 g, 0.20 mmol) in water (1.08 mL) was added to the solution and allowed to stir for 10 minutes. Hydrogen peroxide (6.28 mL, 203.2 mmol) was then added dropwise over several minutes. The solution was heated at 55°C for 3 hours. Water was added and the reaction was allowed to cool. The aqueous solution was extracted with DCM and the organics separated, dried (MgSO4), filtered and evaporated. The crude product was triturated with diethyl ether to give the desired material as a cream solid (3.20 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 3.56 (4H, s), 3.65 - 3.68 (4H, m), 4.77 (2H, s), 6.84 (IH, s), 7.78 (2H, d), 8.92 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ 355, HPLC tR = 1.53 min
2-Chloro-4-morpholin-4-yl-6-(pyridin-4-ylsulfanylmethyl)pyrimidine
Figure imgf000598_0002
2-Chloro-4-(iodomethyl)-6-morpholin-4-ylpyrimidine (5 g, 14.72 mmol) was added portionwise to 4-mercaptopyridine (1.8 g, 16.20 mmol) and DBU (2.344 mL, 16.20 mmol) in acetonitrile (73.6 mL) at RT. The resulting suspension was stirred at RT for 30 minutes. The reaction mixture was evaporated to dryness, redissolved in DCM (50 mL) and the organics washed with water (50 mL), dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in DCM, to give the desired material as a beige solid (3.3 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 3.58 (4H, s), 3.64 - 3.67 (4H, m), 4.24
(2H, s), 6.97 (IH, s), 7.35 (2H, d), 8.38 (2H, d)
LCMS Spectrum: m/z (ESI+)(M+H)+ 323, HPLC tR = 1.75 min
The preparation of 2-chloro-4-(iodomethyl)-6-morpholin-4-ylpyrimidine was described earlier.
The preparation of phenyl Λ/-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl Λ/-[4-[4-[ 1 -(benzenesulfonvπcvclopropyll-6-[(36f)-3-methylmorpholin-4-yllpyrimidin- 2-vHphenyll carbamate
Figure imgf000599_0001
Phenyl chloroformate (0.471 mL, 3.75 mmol) was added dropwise to 4-[4-[l- (benzenesulfonyl)cyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.690 g, 3.75 mmol) and sodium bicarbonate (0.473 g, 5.63 mmol) in dioxane and the resulting mixture stirred at RT for 18 hours. The solvent was removed, DCM added and the organics washed with water dried (MgSO4), filtered and evaporated to give the desired material as a beige solid (2.44 g) which was used without further purification. NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.17-1.19 (3H, d), 1.62-1.69 (2H, m), 1.90-1.93 (2H, m), 3.12-3.19 (IH, td), 3.41-3.49 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.10-4.14 (IH, d), 4.39 (IH, bs), 6.66 (IH, s), 7.24-7.30 (3H, m), 7.43- 7.47 (2H, t), 7.51-7.53 (2H, d), 7.58-7.61 (2H, t), 7.70-7.74 (IH, t), 7.79-7.81 (2H, d), 7.92- 7.94 (2H, d), 10.38 (IH, s). LCMS Spectrum: m/z (ES+) (M+H)+=571; HPLC tR=3.00 min. 4-r4-ri-(Benzenesulfonyl)cvclopropyll-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-2- yll aniline
Figure imgf000600_0001
Bis(triphenylphosphine)palladium (II) chloride (0.246 g, 0.35 mmol) was added in one portion to 4-[l-(benzenesulfonyl)cyclopropyl]-2-chloro-6-[(35)-3-methylmorpholin-4- yljpyrimidine (2.76 g, 7.01 mmol), 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.535 g, 7.01 mmol) and an aqueous solution of sodium carbonate (17.52 mL, 35.04 mmol) in a solvent mixture of 18% DMF, 82% of a 7:3:2 mixture of DME:water:Ethanol) and the resulting mixture stirred at 800C for 3 hours under an atmosphere of nitrogen. The crude product was dissolved in ethyl acetate and washed with water. The organics were dried (MgSO4), filtered and evaporated. The crude product was purified by ion exchange chromatography using an SCX column, eluting with 7M ammonia in methanol, to give the desired material as a yellow solid (3.35 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.15-1.16 (3H, d), 1.58-1.66 (2H, m), 1.85-1.91 (2H, m), 3.07-3.14 (IH, td), 3.41-3.48 (IH, td), 3.58-3.61 (IH, dd), 3.72-3.75 (IH, d), 3.93-3.96 (IH, dd), 4.05-4.08 (IH, d), 4.33 (IH, bs), 5.50 (2H, s), 6.49-6.53 (3H, t), 7.57- 7.61 (2H, t), 7.68-7.71 (3H, m), 7.78-7.81 (2H, d). LCMS Spectrum: m/z (ES+) (M+H)+=451 ; HPLC tR=2.37 min.
4-ri-(Benzenesulfonyl)cvclopropyll-2-chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000600_0002
Sodium hydroxide (50% w/w aqueous solution, 299.03 mmol) was added to 4- (benzenesulfonylmethyl)-2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (2.0 g, 5.44 mmol), 1 ,2-dibromoethane (1.406 mL, 16.31 mmol) and tetrabutylammonium bromide (0.175 g, 0.54 mmol) in toluene (75 mL) and the resulting mixture stirred at 600C for 4 hours. Water was added and the mixture was extracted with toluene. The organics were dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a white solid (2.76 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.13-1.15 (3H, d), 1.55-1.57 (2H, m), 1.83-1.86 (2H, m), 3.09-3.16 (IH, td), 3.36-3.43 (IH, td), 3.52-3.56 (IH, dd), 3.68-3.71 (IH, d), 3.86-3.93 (2H, m), 4.20 (IH, bs), 6.67 (IH, s), 7.60-7.63 (2H, m), 7.72-7.77 (3H, m). LCMS Spectrum: m/z (ES+) (M+H)+=394; HPLC tR=2.28 min.
4-(Benzenesulfonylmethvπ-2-chloro-6-[(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000601_0001
Benzenesulfinic acid, sodium salt (4.22 g, 25.74 mmol) was added to 2-chloro-4- (iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (7.0 g, 19.80 mmol) in acetonitrile (200 mL) and the resulting mixture stirred under a nitrogen atmosphere at 800C for 20 hours. The reaction was cooled and the solvent was removed. DCM was added and the solution was washed with water. The DCM was dried (MgSO4), filtered and the solvent was removed. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% ethyl acetate in DCM, to give the desired material as a cream solid (6.21 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.15-1.16 (3H, d), 3.11-3.18 (IH, td), 3.38-3.45 (IH, td), 3.55-3.58 (IH, dd), 3.70-3.73 (IH, d), 3.85-3.94 (2H, m), 4.15 (IH, bs), 4.64 (2H, s), 6.67 (IH, s), 7.63-7.66 (2H, m), 7.74-7.80 (3H, m). LCMS Spectrum: m/z (ES+) (M+H)+=368; HPLC tR=2.05 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
The preparation of phenyl 7V-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below. Phenyl N- \4- \4- \ 1 -(benzenesulfonyl)cvclobutyll-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-
2-vHphenyll carbamate
Figure imgf000602_0001
Phenyl chloroformate (0.083 mL, 0.66 mmol) was added to 4-[4-[l-
(benzenesulfonyl)cyclobutyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (0.307 g, 0.66 mmol) and sodium hydrogen carbonate (0.083 g, 0.99 mmol) in dioxane and the resulting mixture was stirred at RT for 2 hours. The solvent was removed and the residue partitioned between DCM and water. The organics were washed with water, dried (MgSO4), filtered and evaporated to give the desired material as a gum (0.386 g) which was used without further purification.
NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.31-1.33 (3H, d), 1.87-1.99 (IH, m), 2.20-2.31 (IH, m), 2.75-2.83 (2H, m), 3.17-3.32 (3H, m), 3.57-3.63 (IH, td), 3.73-3.77 (IH, dd), 3.80-3.83 (IH, d), 4.01-4.05 (IH, dd), 4.09-4.12 (IH, d), 4.44 (IH, bs), 6.55 (IH, s), 6.78-6.81 (IH, d), 7.16-7.28 (4H, m), 7.36-7.42 (5H, m), 7.49-7.51 (2H, d), 7.56 (IH, s), 7.89-7.92 (2H, d). LCMS Spectrum: m/z (ES+) (M+H)+=585; HPLC tR=3.30 min.
4-[4-[l-(Benzenesulfonvπcvclobutyll-6-[(36f)-3-methylmorpholin-4-yllpyrimidin-2-yllaniline
Figure imgf000602_0002
Bis(triphenylphosphine)palladium (II) chloride (0.023 g, 0.03 mmol) was added in one portion to 4-[l-(benzenesulfonyl)cyclobutyl]-2-chloro-6-[(35)-3-methylmorpholin-4- yljpyrimidine (0.270 g, 0.66 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.145 g, 0.66 mmol) and an aqueous solution of sodium carbonate (1.653 mL, 3.31 mmol) in a solvent mixture comprising 18% DMF, 82% of a 7:3:2 mixture of DME:water:Ethanol and the resulting mixture was stirred at 800C for 3 hours under an atmosphere of nitrogen. The crude product was purified by ion exchange chromatography using an SCX column, eluting with 7M ammonia in methanol, to give a sample which was further purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired as a colourless gum (0.395 g).
NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.30-1.32 (3H, d), 1.87-1.98 (IH, m), 2.19-2.29 (IH, m), 2.74-2.83 (2H, m), 3.14-3.22 (2H, m), 3.24-3.31 (IH, td), 3.57-3.63 (IH, td), 3.73-3.85 (4H, m), 4.01-4.04 (IH, dd), 4.08-4.12 (IH, d), 4.43-4.45 (IH, m), 6.48 (IH, s), 6.55-6.57 (2H, d), 7.26-7.31 (2H, t), 7.39-7.43 (IH, t), 7.48-7.51 (2H, dd), 7.74-7.76 (2H, d). LCMS Spectrum: m/z (ES+) (M+H)+=465; HPLC tR=2.49 min.
4-ri-(Benzenesulfonyl)cvclobutyll-2-chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000603_0001
Sodium hydroxide (50% w/w aqueous solution, 120.21 mmol) was added to 4-
(benzenesulfonylmethyl)-2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (0.804 g, 2.19 mmol), 1,3-dibromopropane (0.666 mL, 6.56 mmol) and tetrabutylammonium bromide (0.070 g, 0.22 mmol) in toluene (50 mL) and the resulting mixture was stirred at 45°C for 1 hour. Water was added, the organics separated, washed with water, dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a white solid (0.27 g). NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.29-1.31 (3H, d), 1.89-1.96 (IH, m), 2.17-2.28 (IH, m), 2.63-2.67 (2H, m), 3.07-3.16 (2H, m), 3.22-3.29 (IH, td), 3.50-3.57 (IH, td), 3.67-3.70 (IH, dd), 3.76-3.79 (IH, d), 3.95-4.01 (2H, m), 4.28 (IH, bs), 6.52 (IH, s), 7.41-7.44 (2H, t), 7.48-7.50 (2H, m), 7.57-7.61 (IH, m).
LCMS Spectrum: m/z (ES+) (M+H)+=408; HPLC tR=2.35 min. The preparation of 4-(benzenesulfonylmethyl)-2-chloro-6-[(35)-3-methylmorpholin-4- yljpyrimidine was described earlier.
The preparation of phenyl 7V-[4-[4-[l-(benzenesulfonyl)cyclopentyl]-6-[(3<S)-3- 5 methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl Λ/-[4-[4-[ 1 -(benzenesulfonyl)cvclopentyll-6-r(36f)-3-methylmorpholin-4-yllpyrimidin- 2-vHphenyll carbamate
Figure imgf000604_0001
io Phenyl chloroformate (0.244 mL, 1.94 mmol) was added to 4-[4-[l-
(benzenesulfonyl)cyclopentyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (0.930 g, 1.94 mmol) and sodium hydrogen carbonate (0.245 g, 2.91 mmol) in dioxane and the resultant mixture stirred at RT for 2 hours. The solvent was removed and the residue partitioned between DCM and water. The organics were washed with water, dried (MgSO4), is filtered and evaporated to give the desired material as a beige solid (1.19 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.21-1.23 (3H, d), 1.52-1.56 (2H, m), 1.80-1.88 (2H, m), 2.55-2.60 (2H, m), 2.67-2.69 (2H, m), 3.12-3.19 (IH, td), 3.46-3.52 (IH, td), 3.63-3.67 (IH, dd), 3.75-3.78 (IH, d), 3.95-3.99 (IH, dd), 4.12-4.16 (IH, d), 4.50 (IH, bs), 6.66 (IH, s), 7.23-7.30 (3H, m), 7.42-7.51 (8H, m), 7.56-7.60 (IH, m), 7.88-7.90 (2H, d),
20 10.37 (IH, s).
LCMS Spectrum: m/z (ES+) (M+H)+=599; HPLC tR=3.44 min. 4-r4-ri-(Benzenesulfonyl)cvclopentyll-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-2- yll aniline
Figure imgf000605_0001
Bis(triphenylphosphine)palladium (II) chloride (0.072 g, 0.10 mmol) was added in one portion to 4-[l-(benzenesulfonyl)cyclopentyl]-2-chloro-6-[(35)-3-methylmorpholin-4- yljpyrimidine (0.863 g, 2.05 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.448 g, 2.05 mmol) and an aqueous solution of sodium carbonate (5.11 mL, 10.23 mmol) in a solvent mixture comprising 18% DMF, 82% of a 7:3:2 mixture of DME:water:Ethanol and the resultant mixture stirred at 800C for 3 hours. The crude product was purified by ion exchange chromatography using an SCX column, eluting with 7M ammonia in methanol, to give the desired material as a beige solid (0.93 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.19-1.20 (3H, d), 1.52-1.55 (2H, m), 1.81-1.85 (2H, m), 2.50 (2H, m), 2.67-2.70 (2H, m), 3.07-3.15 (IH, td), 3.45-3.51 (IH, td), 3.62-3.65 (IH, dd), 3.74-3.77 (IH, d), 3.94-3.97 (IH, dd), 4.04-4.08 (IH, d), 4.43-4.45 (IH, bs), 5.47 (2H, s), 6.48-6.51 (3H, m), 7.42-7.48 (4H, m), 7.57-7.62 (IH, m), 7.65-7.67 (2H, d). LCMS Spectrum: m/z (ES+) (M+H)+=479; HPLC tR=2.67 min.
4-ri-(Benzenesulfonyl)cvclopentyll-2-chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000605_0002
Sodium hydroxide (50% w/w aqueous solution, 112.53 mmol) was added to 4-
(benzenesulfonylmethyl)-2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (0.753 g, 2.05 mmol), 1 ,4-dibromobutane (0.733 mL, 6.14 mmol) and tetrabutylammonium bromide (0.066 g, 0.20 mmol) in toluene (50 mL) and the resulting suspension stirred at 600C for 4 hours. Water was added, the organic layer separated and washed twice with water. The organics were dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a colourless gum (0.904 g).
NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.28-1.30 (3H, d), 1.52-1.63 (2H, m), 1.83-1.93 (2H, m), 2.41-2.49 (2H, m), 2.56-2.66 (2H, m), 3.20-3.28 (IH, td), 3.49-3.56 (IH, td), 3.65-3.69 (IH, dd), 3.74-3.77 (IH, d), 3.95-3.99 (2H, m), 4.27 (IH, bs), 6.69 (IH, s), 7.38-7.46 (4H, m), 7.54-7.58 (IH, m). LCMS Spectrum: m/z (ES+) (M+H)+=422; HPLC tR=2.61 min.
The preparation of 4-(benzenesulfonylmethyl)-2-chloro-6-[(35)-3-methylmorpholin-4- yljpyrimidine was described earlier.
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-[4-[3-tri(propan-2- yl)silyloxypropylsulfonyl]oxan-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N-r4-r4-r(3y)-3-methylmorpholin-4-yl1-6-r4-r3-tri(propan-2- vπsilyloxypropylsulfonylloxan-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000606_0001
Sodium bicarbonate (0.380 g, 4.53 mmol) was added to 4-[4-[(35)-3-methylmorpholin-4-yl]- 6-[4-[3-tri(propan-2-yl)silyloxypropylsulfonyl]oxan-4-yl]pyrimidin-2-yl]aniline (1.910 g, 3.02 mmol), in 1,4-dioxane (15.09 mL) at RT. Phenyl chloroformate (0.380 mL, 3.02 mmol) was added dropwise over 2 minutes and the reaction stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (40 mL), and washed with water (40 mL), The organic layer was dried (MgSO4), filtered and evaporated to afford a solid which was triturated with diethyl ether to give the desired material as an amber solid (2.25 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.87-0.88 (18H, d), 1.09-1.13 (IH, t), 1.23-1.25 (3H, d), 1.31 (IH, s), 1.74-1.81 (2H, qu), 2.20-2.27 (2H, td), 2.83-2.88 (2H, t), 3.00-3.04 (2H, td), 3.18-3.29 (3H, m), 3.49-3.51 (2H, m), 3.63-3.66 (2H, t), 3.78-3.80 (IH, d), 3.91-3.97 (2H, qu), 3.99-4.03 (IH, dd), 4.30-4.33 (IH, d), 4.58 (IH, exchange), 6.90 (IH, s), 7.25-7.27 (2H, dd), 7.29-7.31 (IH, dd), 7.44-7.47 (2H, d), 7.62-7.64 (2H, d), 8.30-8.32 (2H, d)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 753.4; HPLC tR = 3.97 min.
4- [4- [(35)-3 -Methylmorpholin-4-yll -6- [4- [3 -tri(propan-2-yl)silyloxypropylsulfonylloxan-4- yllpyrimidin-2-vH aniline
Figure imgf000607_0001
Dichlorobis(triphenylphosphine)palladium (II) (0.118 g, 0.17 mmol) was added to 3-[4-[2- chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]oxan-4-yl]sulfonylpropoxy- tri(propan-2-yl)silane (1.94 g, 3.37 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (0.959 g, 4.38 mmol) and 2M aqueous sodium carbonate (6.06 mL, 12.12 mmol) in water (9.35 mL), ethanol (3.74 mL) and DME (3.74 mL) and the resulting solution stirred at 800C for 3 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 75% ethyl acetate in DCM, to give the desired material as an amber solid (1.91 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.90-0.91 (18H, d), 1.21-1.23 (3H, d), 1.73-1.80 (2H, qu), 2.17-2.25 (2H, td), 2.79-2.84 (2H, t), 2.98-3.02 (2H, td), 3.28 (2H, s), 3.31 (2H, s), 3.47-3.53 (IH, td), 3.63-3.67 (3H, m), 3.76-3.79 (IH, d), 3.90-3.96 (2H, qu), 3.97- 4.01 (IH, dd), 4.25-4.29 (IH, d), 4.53-4.54 (IH, m), 5.53-5.55 (IH, d), 6.59-6.61 (2H, d), 6.76 (IH, s), 8.02-8.05 (2H, d)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 633.34; HPLC tR = 3.67 min. 3-r4-r2-Chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-ylloxan-4-yllsulfonylpropoxy- tri(propan-2-yl)silane
Figure imgf000608_0001
Sodium tert-butoxide (1.519 g, 15.80 mmol) was added portionwise to 3-[[2-chloro-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]propoxy-tri(propan-2-yl)silane (2 g, 3.95 mmol) and bis(2-bromoethyl) ether (1.987 mL, 15.80 mmol) in DMF (19.76 mL) at RT over a period of 5 minutes under a nitrogen atmosphere. The resulting solution was stirred at RT for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (0.5 mL), concentrated and diluted with ethyl acetate (200 mL). The organics were separated, washed sequentially with water (2 x 200 mL) and saturated brine (100 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 40 to 60% ethyl acetate in isohexane, to give the desired material as an off white solid (1.94 g). NMR Spectrum: 1R NMR (400.132 MHz, DMSOd6) δ 0.98-1.02 (18H, m), 1.20-1.22 (4H, q), 1.78-1.85 (2H, qu), 2.13-2.20 (2H, t), 2.65-2.69 (2H, m), 2.95-3.03 (2H, m), 3.15-3.24 (3H, q), 3.28-3.31 (3H, d), 3.42-3.49 (IH, td), 3.59-3.63 (IH, dd), 3.72-3.76 (2H, q), 3.87- 3.92 (2H, qu), 3.94-3.98 (IH, dd), 4.11-4.14 (IH, d), 4.45 (IH, exchange), 6.99 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ 576.31; HPLC tR = 4.06 min
The preparation of 3-[[2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4- yl]methylsulfonyl]propoxy-tri(propan-2-yl)silane was described earlier.
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-[3-tri(propan-2- yl)silyloxypropylsulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl] carbamate is described below. Phenyl N-r4-r4-r(3y)-3-methylmorpholin-4-yl1-6-ri-r3-tri(propan-2- yl)silyloxypropylsulfonyllcvclopropyllpyrimidin-2-yllphenyllcarbamate
Figure imgf000609_0001
Sodium bicarbonate (0.749 g, 8.92 mmol) was added to 4-[4-[(35)-3-methylmorpholin-4-yl]- 6-[l-[3-tri(propan-2-yl)silyloxypropylsulfonyl]cyclopropyl]pyrimidin-2-yl]aniline (3.5 g, 5.94 mmol), in 1,4-dioxane (29.7 mL) at RT. Phenyl chloro formate (0.748 mL, 5.94 mmol) was added dropwise over 2 minutes and the reaction stirred at RT for 2 hours. The reaction mixture was evaporated to dryness, redissolved in DCM (100 mL), and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford a solid, which was triturated with diethyl to give the desired material as a light yellow solid (4.13 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.95-0.96 (18H, d), 1.24-1.26 (3H, d), 1.30 (2H, s), 1.58-1.60 (2H, m), 1.54-1.67 (2H, m), 1.95-2.02 (2H, sex), 3.18-3.26 (IH, td), 3.38-3.43 (2H, m), 3.46-3.49 (3H, m), 3.62-3.66 (IH, dd), 3.75-3.78 (2H, t), 3.97-4.01 (IH, dd), 4.21-4.24 (IH, d), 4.57 (IH, exchange), 6.86 (IH, s), 7.25-7.27 (2H, d), 7.29-7.31 (IH, d), 7.44-7.46 (2H, d), 7.63-7.65 (2H, d), 8.27-8.30 (2H, d), 10.45 (IH, exchange) LCMS Spectrum: m/z (ESI+)(M+H)+ 709.41; HPLC tR = 3.82 min
4-r4-r(35)-3-Methylmorpholin-4-yl1-6-ri-r3-tri(propan-2- yl)silyloxypropylsulfonyllcvclopropyllpyrimidin-2-vHaniline
Figure imgf000609_0002
Dichlorobis(triphenylphosphine)palladium (II) (0.214 g, 0.31 mmol) was added to 3-[l-[2- chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonylpropoxy- tri(propan-2-yl)silane (3.25 g, 6.11 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (1.739 g, 7.94 mmol) and 2M aqueous sodium carbonate (10.99 mL, 21.98 mmol) in water (16.96 mL), ethanol (6.79 mL) and DME (6.79 mL) and the resulting solution stirred at 800C for 3 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 75% ethyl acetate in DCM, to give the desired material as an amber gum, which solidified on standing (3.50 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.98-0.99 (18H, d), 1.53-1.58 (2H, m), 1.60-1.64 (2H, m), 1.96-2.03 (4H, m), 3.14-3.22 (IH, td), 3.29-3.31 (IH, d), 3.45-3.49 (3H, m), 3.61-3.64 (IH, dd), 3.75-3.78 (3H, t), 3.96-4.00 (IH, dd), 4.02-4.08 (IH, q), 4.15- 4.19 (IH, d), 4.51 (IH, m), 5.55-5.57 (IH, d), 6.59-6.61 (2H, d), 6.71 (IH, s), 8.02-8.04 (2H, d)
LCMS Spectrum: m/z (ESI+)(M+H)+ 589.88; HPLC tR = 3.80 min
The preparation of 3-[ 1 -[2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4- yl]cyclopropyl]sulfonylpropoxy-tri(propan-2-yl)silane was described earlier.
The preparation of phenyl Λ/-[4-[4-[4-(benzenesulfonyl)oxan-4-yl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl Λ/-r4-r4-r4-(benzenesulfonyl)oxan-4-yll-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-2- yllphenyll carbamate
Figure imgf000610_0001
Phenyl chloroformate (0.098 mL, 0.78 mmol) was added dropwise to 4-[4-[4- (benzenesulfonyl)oxan-4-yl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (0.35 g, 0.71 mmol) and sodium bicarbonate (0.089 g, 1.06 mmol) in dioxane (25 mL) and the resulting suspension stirred at RT for 18 hours. The reaction mixture was diluted with DCM (20 mL), and washed with water (20 mL), the organic layer dried (MgSO4), filtered and evaporated to give the desired material as an orange gum (0.45 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20 (3H, d), 2.20-2.30 (2H, td), 2.75 (2H, m), 3.23 (3H, m), 3.50 (IH, td), 3.65 (IH, dd), 3.75 (IH, d), 3.85 (2H, dd), 3.97 (IH, dd), 4.20 (IH, d), 4.55 (IH, br s), 6.70-6.80 (3H, m), 7.15 (IH, t), 7.25 (2H, dd), 7.40-7.55 (7H, m), 7.85 (2H, d), 10.40 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 615; HPLC tR = 2.93 min.
4-[4-[4-(Benzenesulfonyl)oxan-4-yl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline
Figure imgf000611_0001
Bis(triphenylphosphine)palladium(II) chloride (0.067 g, 0.09 mmol) was added in one portion to 4-[4-(benzenesulfonyl)oxan-4-yl]-2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (0.83 g, 1.90 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.498 g, 2.27 mmol) and an aqueous solution of sodium carbonate (4.74 mL, 9.48 mmol) in a DMF (3.60 mL), DME (9.56 mL), water (4.1 mL) and ethanol (2.72 mL) solution mixture. The resulting solution was stirred at 800C for 3 hours under a nitrogen atmosphere. The reaction mixture was evaporated to dryness, redissolved in ethyl acetate (50 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in DCM, to give the desired material as a beige solid (0.82 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 2.20-2.30 (2H, td), 2.75 (2H, m), 3.10-3.20 (3H, m), 3.50 (IH, td), 3.65 (IH, dd), 3.75 (IH, d), 3.85 (2H, dd), 3.97 (IH, dd), 4.20 (IH, d), 4.50 (IH, d), 5.47 (2H, s), 6.45 (2H, d), 6.60 (IH, s), 7.40 (4H, m), 7.60 (3H, m) LCMS Spectrum: m/z (ESI+) (M+H)+ = 495; HPLC tR = 2.37 min.
4- [4-(Benzenesulfonyl)oxan-4-yl] -2-chloro-6- [(35)-3-methylmorpholin-4-yl]pyrimidine
Figure imgf000612_0001
50% v/v aqueous sodium hydroxide (4.49 g, 112.14 mmol) was added to 4- (benzenesulfonylmethyl)-2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (0.75 g, 2.04 mmol), tetrabutylammonium bromide (0.066 g, 0.20 mmol) and l-bromo-2-(2- bromoethoxy)ethane (1.419 g, 6.12 mmol) in toluene (50 mL). The resulting mixture was stirred at 600C for 6 hours. The reaction mixture was diluted with water (50 mL), and washed twice with more water (25 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in DCM, to give the desired material as a white solid (0.83 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.15 (3H, d), 2.10-2.23 (2H, td), 2.60 (2H, td), 3.10-3.20 (3H, m), 3.25 (IH, d), 3.40 (IH, td), 3.60 (IH, dd), 3.70 (IH, dd), 3.80 (2H, dd), 3.90 (IH, dd), 4.40 (IH, d), 6.70 (IH, s), 7.40 (2H, d), 7.60 (2H, td), 7.75 (IH, td) LCMS Spectrum: m/z (ESI+) (M+H)+ = 438; HPLC tR = 2.45 min.
The preparation of 4-(benzenesulfonylmethyl)-2-chloro-6-[(35)-3-methylmorpholin-4- yljpyrimidine was described earlier.
The preparation of phenyl Λ/-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-morpholin-4- ylpyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl N- [4- [4- [ 1 -(benzenesulfonyl)cvclopropyll-6-morpholin-4-ylpyrimidin-2- yllphenyll carbamate
Figure imgf000612_0002
Phenyl chloroformate (0.307 mL, 2.45 mmol) was added to 4-[4-[l-
(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]aniline (1.069 g, 2.45 mmol) and sodium hydrogen carbonate (0.309 g, 3.67 mmol) in dioxane and the resulting suspension stirred at RT overnight. The solids were filtered and washed with dioxane and water and then dried in the vacuum oven at 5O0C overnight. The filtrate was concentrated and the solids were filtered, rinsed with water and dried in the vacuum oven overnight. The two crops were combined to give the desired material as a beige solid (1.132 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.62-1.65 (2H, q), 1.89-1.92 (2H, q), 3.66-3.70 (8H, m), 6.71 (IH, s), 7.24-7.31 (3H, m), 7.43-7.47 (2H, t), 7.51-7.54 (2H, d), 7.58- 7.62 (2H, t), 7.70-7.74 (IH, tt), 7.79-7.81 (2H, d), 7.90-7.92 (2H, d), 10.40 (IH, bs). LCMS Spectrum: m/z (ES+) (M+H)+=557; HPLC tR=3.03 min.
4-r4-ri-(Benzenesulfonyl)cvclopropyll-6-morpholin-4-ylpyrimidin-2-yllaniline
Figure imgf000613_0001
Bis(triphenylphosphine)palladium (II) chloride (0.088 g, 0.13 mmol) was added in one portion to 4-[l-(benzenesulfonyl)cyclopropyl]-2-chloro-6-morpholin-4-ylpyrimidine (0.956 g, 2.52 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.552 g, 2.52 mmol) and an aqueous solution of sodium carbonate (6.29 mL, 12.59 mmol) in a solvent mixture comprising 18% DMF and 82% of a 7:3:2 mixture of DME:water:Ethanol and the solution stirred at 800C for 3 hours under a nitrogen atmosphere. The crude product was purified by ion exchange chromatography using an SCX column, eluting with 7M ammonia in methanol to give a sample that was further purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a white solid (1.07 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.58-1.62 (2H, q), 1.86-1.89 (2H, q), 3.59-3.60 (4H, m), 3.67-3.69 (4H, m), 5.50 (2H, s), 6.48-6.50 (2H, d), 6.58 (IH, s), 7.57-7.61 (2H, t), 7.66-7.68 (2H, d), 7.69-7.73 (IH, tt), 7.78-7.80 (2H, m). LCMS Spectrum: m/z (ES+) (M+H)+=437; HPLC tR=2.19 min. 4-ri-(Benzenesulfonyl)cvclopropyll-2-chloro-6-morpholin-4-ylpyrimidine
Figure imgf000614_0001
Sodium hydroxide (50% w/w aqueous solution, 248.52 mmol) was added 4- (benzenesulfonylmethyl)-2-chloro-6-morpholin-4-ylpyrimidine (1.599 g, 4.52 mmol), 1,2- dibromoethane (1.168 mL, 13.56 mmol) and tetrabutylammonium bromide (0.146 g, 0.45 mmol) in toluene (75 mL) and the resulting suspension stirred at 600C for 18 hours. Water was added to the mixture, the organics separated, washed twice with water, dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a white solid (0.956 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.53-1.56 (2H, q), 1.82-1.85 (2H, q), 3.53 (4H, bs), 3.63-3.65 (4H, t), 6.72 (IH, s), 7.59-7.63 (2H, m), 7.73-7.77 (3H, m). LCMS Spectrum: m/z (ES+) (M+H)+=380; HPLC tR=2.02 min.
4-(Benzenesulfonylmethyl)-2-chloro-6-morpholin-4-ylpyrimidine
Figure imgf000614_0002
Sodium benzenesulfinate (4.31 g, 26.26 mmol) was added to 2-chloro-4-(iodomethyl)-6- morpholin-4-ylpyrimidine (6.86 g, 20.20 mmol) in acetonitrile (200 mL) at 220C under nitrogen. The resulting slurry was stirred at 80 0C for 3 hours. The reaction had gone to completion. The solvent was removed and DCM and water were added. The DCM was washed with water, dried over MgSOφ filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% ethyl acetate in DCM. Pure fractions were evaporated to dryness to afford 4- (2-chloro-6- (phenylsulfonylmethyl)pyrimidin-4-yl)morpholine (4.96 g, 69.4 %) as a cream solid. NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 3.53 (4H, bs), 3.64-3.67 (4H, t), 4.61 (2H, s), 6.71 (IH, s), 7.63-7.67 (2H, m), 7.75-7.81 (3H, m). LCMS Spectrum: m/z (ES+) (M+H)+=354; HPLC tR=1.79 min.
The preparation of 2-chloro-4-(iodomethyl)-6-morpholin-4-ylpyrimidine was described earlier.
The preparation of phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3- thiazol-2-yl)sulfonyl]cyclopentyl]pyrimidin-2-yl]phenyl]carbamate is described below:
Phenyl N-r4-r4-r(3^-3-methylmorpholin-4-yll-6-ri-r('4-methyl-1.3-thiazol-2- yl)sulfonyllcvclopentyllpyrimidin-2-yllphenyllcarbamate
Figure imgf000615_0001
Phenylchloroformate (0.232 mL, 1.85 mmol) was added to 4-[4-[(35)-3-methylmorpholin-4- yl]-6-[l-[(4-methyl-l,3-thiazol-2-yl)sulfonyl]cyclopentyl]pyrimidin-2-yl]aniline (840 mg, 1.68 mmol) and sodium bicarbonate (212 mg, 2.52 mmol) in dioxane (50 mL) at 1O0C under a nitrogen atmosphere. The resulting mixture was stirred at 100C for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford Phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3- thiazol-2- yl)sulfonyl]cyclopentyl]pyrimidin-2-yl]phenyl] carbamate (1.24g) as a yellow dry film. NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.60 - 1.63 (2H, m), 1.83 - 1.92 (2H, m), 2.38 (3H, s), 2.76 - 2.80 (4H, m), 3.12 - 3.19 (IH, m), 3.49 - 3.55 (IH, m), 3.61 - 3.66 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.15 - 4.18 (IH, m), 4.49 - 4.56 (IH, m), 6.70 (IH, s), 7.24 - 7.26 (3H, m), 7.43 - 7.45 (2H, m), 7.56 (2H, d), 7.64 (IH, s), 7.99 (2H, d), 10.39 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 620; HPLC tR = 3.26min. 4-r4-r(35)-3-Methylmorpholin-4-yll-6-ri-r(4-methyl-1.3-thiazol-2- vDsulfonyli cyclopentyllpyrimidin-2-yll aniline
Figure imgf000616_0001
Bis(triphenylphosphine)palladium (II) chloride (0.162 g, 0.23 mmol) was added to 2-chloro- 4- [(3S)- 3 -methylmorpholin-4-yl] -6- [ 1 - [(4-methyl- 1 ,3 -thiazol-2- yl)sulfonyl]cyclopentyl]pyrimidine (2.05g, 4.63 mmol), 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (1.318 g, 6.02 mmol) and 2M aqueous sodium carbonate (8.33 mL, 16.66 mmol) in DME (10 mL), ethanol (10 mL) and water (25 mL) and the resulting mixture stirred at 800C for 18 hours. The cooled reaction mixture was diluted with ethyl acetate (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 75% ethyl acetate in DCM, to give the desired material as a yellow gum (0.84 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.57 - 1.62 (2H, m), 1.83 - 1.89 (2H, m), 2.40 (3H, s), 2.73 - 2.78 (4H, m), 3.08 - 3.15 (IH, m), 3.44 - 3.50 (IH, m), 3.61 - 3.64 (IH, m), 3.75 (IH, d), 3.94 - 3.97 (IH, m), 4.10 (IH, d), 4.43 - 4.49 (IH, m), 5.50 (2H, s), 6.53 (2H, d), 6.54 (IH, s), 7.64 (IH, s), 7.73 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 500; HPLC tR = 2.66min.
2-Chloro-4-r(3y)-3-methylmorpholin-4-yl1-6-ri-r('4-methyl-1.3-thiazol-2- vDsulfonyllcvclopentyllpyrimidine
Figure imgf000616_0002
1,4-Dibromobutane (0.627 mL, 5.30 mmol) was added to 2-chloro-4-[(35)-3- methylmorpholin-4-yl]-6-[(4-methyl-l,3-thiazol-2-yl)sulfonylmethyl]pyrimidine (2.06 g, 5.30 mmol), 40% aqueous sodium hydroxide solution (5.30 mL, 53 mmol) and tetrabutylammonium bromide (0.342 g, 1.06 mmol) in toluene (100 mL) and the resulting solution stirred at 600C for 3 hours. The reaction mixture was concentrated and diluted with ethyl acetate (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to give the desired material as an orange gum (2.55g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ δ 1.18 (3H, d), 1.57 - 1.62 (2H, m), 1.78 - 1.86 (2H, m), 2.45 (3H, s), 2.55 - 2.68 (4H, m), 3.10 - 3.17 (IH, m), 3.39 - 3.46 (IH, m), 3.55 - 3.59 (IH, m), 3.71 (IH, d), 3.90 - 3.99 (2H, m), 4.32 - 4.38 (IH, m), 6.72 (IH, s), 7.87 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 443; HPLC tR = 2.66min.
The preparation of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-[(4-methyl-l,3-thiazol-2- yl)sulfonylmethyl]pyrimidine was described earlier.
Example 37
The following compounds were prepared according to the following general procedure.
The appropriate aniline was treated with l,l'-thiocarbonyldiimidazole in a solvent mixture of DCM and THF at RT for 2 - 16 hours. Triethylamine and the appropriate amine were added and the reactions stirred at RT for an additional 1 - 16 hours (unless otherwise stated). The mixtures were purified by prep HPLC.
Figure imgf000618_0001
Figure imgf000619_0001
Figure imgf000620_0001
Figure imgf000621_0001
Figure imgf000622_0001
Figure imgf000623_0001
Figure imgf000624_0001
The appropriate aniline was treated with l,l'-thiocarbonyldiimidazole in a solvent mixture of DCM and THF at RT for 16 hours. Triethylamine and the appropriate amine, dissolved in DMF, were added and the reactions stirred at 5O0C for 1 hour. The mixture was purified by prep HPLC.
Example 37a: 1R NMR (400.132 MHz, DMSOd6) δ 0.90 - 0.98 (2H, m), 0.99 - 1.08 (2H, m), 1.24 (3H, d), 1.55 - 1.62 (2H, m), 1.63 - 1.70 (2H, m), 2.91 - 3.05 (4H, m), 3.19 - 3.25 (IH, m), 3.44 - 3.55 (IH, m), 3.64 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.20 (IH, d), 4.56 (IH, s), 6.88 (IH, s), 7.55 (2H, d), 7.83 (IH, s), 8.27 (2H, d), 9.72 (IH, s). mTOR Kinase Assay (Echo): 0.026μM
Example 37b: 1H NMR (400.132 MHz, DMSOd6) δ 0.57 - 0.63 (2H, m), 0.72 - 0.78 (2H, m), 0.90 - 0.96 (2H, m), 0.99 - 1.07 (2H, m), 1.24 (3H, d), 1.55 - 1.62 (2H, m), 1.63 - 1.68 (2H, m), 2.90 - 3.04 (2H, m), 3.17 - 3.27 (IH, m), 3.50 (IH, d), 3.65 (IH, d), 3.77 (IH, d),
3.98 (IH, d), 4.18 (IH, d), 4.56 (IH, s), 6.89 (IH, s), 7.62 (2H, d), 8.27 (2H, d), 9.50 (IH, s). mTOR Kinase Assay (Echo): 0.0124μM
Example 37c: 1R NMR (400.132 MHz, DMSOd6) δ 0.90 - 0.96 (2H, m), 1.00 - 1.07 (2H, m), 1.24 (3H, d), 1.55 - 1.61 (2H, m), 1.64 - 1.69 (2H, m), 2.95 - 3.05 (IH, m), 3.17 - 3.27
(3H, m), 3.44 - 3.56 (3H, m), 3.64 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.20 (IH, d), 4.55 (IH, s), 4.82 (IH, s), 6.88 (IH, s), 7.57 - 7.68 (2H, m), 7.86 (IH, s), 8.27 (2H, d), 9.81 (IH, s). mTOR Kinase Assay (Echo): 0.00344μM
Example 37d: 1H NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.54 - 1.60 (2H, m), 1.62 - 1.71 (3H, m), 1.89 - 1.98 (2H, m), 2.25 - 2.34 (2H, m), 2.42 - 2.52 (2H, m), 3.14 - 3.24 (3H, m), 3.41 - 3.55 (3H, m), 3.64 (IH, d), 3.77 (IH, d), 3.97 (IH, d), 4.20 (IH, d), 4.53 - 4.68
(2H, m), 6.81 (IH, s), 7.60 (2H, d), 8.11 (IH, s), 8.26 (2H, d), 9.58 (IH, s). mTOR Kinase Assay (Echo): 0.00439μM
Example 37e: 1U NMR (400.132 MHz, DMSO-de) δ 1.24 (3H, d), 1.55 - 1.60 (2H, m), 1.62 - 1.68 (2H, m), 1.91 - 1.98 (2H, m), 2.84 - 2.92 (2H, m), 3.13 - 3.24 (IH, m), 3.43 - 3.57 (5H, m), 3.64 (IH, d), 3.72 - 3.80 (3H, m), 3.97 (IH, d), 4.20 (IH, d), 4.57 (IH, s), 4.68 (IH, t),
6.83 (IH, s), 7.56 (2H, d), 8.16 (IH, s), 8.29 (2H, d), 9.98 (IH, s). mTOR Kinase Assay (Echo): 0.0049μM
Example 37f: 1H NMR (400.132 MHz, DMSO-d6) δ 1.24 (3H, d), 1.55 - 1.59 (2H, m), 1.62 - 1.67 (2H, m), 1.93 - 1.98 (4H, m), 2.28 - 2.36 (2H, m), 2.65 - 2.70 (2H, m), 3.13 - 3.23 (IH, m), 3.44 - 3.56 (5H, m), 3.64 (IH, d), 3.77 (IH, d), 3.97 (IH, d), 4.20 (IH, d), 4.58 (IH, s),
4.71 (2H, s), 6.82 (IH, s), 7.00 (2H, s), 7.69 (2H, d), 8.21 (OH, s), 8.29 (2H, s). mTOR Kinase Assay (Echo): 0.12μM
Example 37g: 1U NMR (400.132 MHz, DMSO-de) δ 1.24 (3H, d), 1.54 - 1.59 (2H, m), 1.62 - 1.68 (2H, m), 1.89 - 1.99 (2H, m), 2.96 (3H, s), 3.14 - 3.28 (3H, m), 3.45 - 3.55 (3H, m), 3.64
(IH, d), 3.77 (IH, d), 3.97 (IH, d), 4.21 (IH, d), 4.58 (IH, s), 4.68 (IH, t), 6.82 (IH, s), 7.55
(2H, d), 7.84 (IH, s), 8.27 (2H, d), 9.73 (IH, s). mTOR Kinase Assay (Echo): 0.0179μM
Example 37h: 1H NMR (400.132 MHz, DMSO-d6) δ 0.56 - 0.66 (2H, m), 0.72 - 0.80 (2H, m), 1.24 (3H, d), 1.53 - 1.60 (2H, Im), 1.62 - 1.68 (2H, m), 1.88 - 2.00 (2H, m), 2.92 (IH, s),
3.16 - 3.27 (IH, m), 3.44 - 3.58 (5H, m), 3.64 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.22 (IH, d), 4.57 (IH, s), 4.68 (IH, t), 6.82 (IH, s), 7.62 (2H, d), 8.14 (IH, s), 8.26 (2H, d), 9.50 (IH, s). mTOR Kinase Assay (Echo): 0.0132μM
Example 37i: 1R NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.54 - 1.59 (2H, m), 1.63 - 1.68 (2H, m), 1.89 - 1.97 (2H, m), 3.14 - 3.29 (5H, m), 3.46 - 3.60 (5H, m), 3.64 (IH, d), 3.77
(IH, d), 3.97 (IH, d), 4.21 (IH, d), 4.57 (IH, s), 4.68 (IH, t), 4.81 (IH, s), 6.82 (IH, s), 7.63
(2H, d), 7.96 (IH, s), 8.27 (2H, d), 9.81 (IH, s). mTOR Kinase Assay (Echo): 0.00306μM
Example 37j: 1H NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.54 - 1.60 (2H, m), 1.62 - 1.68 (2H, m), 1.89 - 1.99 (2H, m), 3.15 - 3.25 (IH, m), 3.41 - 3.56 (5H, m), 3.64 (IH, d), 3.82
(IH, d), 3.98 (IH, d), 4.22 (IH, d), 4.58 (IH, s), 4.69 (IH, t), 6.82 (IH, s), 7.51 (IH, s), 7.62
(2H, d), 8.05 (IH, s), 8.28 (2H, d), 9.69 (IH, s). mTOR Kinase Assay (Echo): 0.0309μM
Example 37k: 1H NMR (400.132 MHz, DMSO-d6) δ 1.14 (3H, t), 1.24 (3H, d), 1.53 - 1.60 (2H, m), 1.62 - 1.67 (2H, m), 1.89 - 1.97 (2H, m), 3.14 - 3.28 (3H, m), 3.46 - 3.56 (5H, m),
3.64 (IH, d), 3.77 (IH, d), 3.97 (IH, d), 4.21 (IH, d), 4.58 (IH, s), 4.68 (IH, t), 6.82 (IH, s),
7.56 (2H, d), 7.88 (IH, s), 8.27 (2H, d), 9.62 (IH, s). mTOR Kinase Assay (Echo): 0.0114μM
Example 371: 1R NMR (400.132 MHz, DMSO-d6) δ 0.91 (3H, t), 1.24 (3H, d), 1.53 - 1.60 (4H, m), 1.62 - 1.67 (2H, m), 1.90 - 1.97 (2H, m), 3.16 - 3.27 (3H, m), 3.42 - 3.53 (5H, m),
3.64 (IH, d), 3.77 (IH, d), 3.97 (IH, d), 4.21 (IH, d), 4.57 (IH, s), 4.68 (IH, t), 6.82 (IH, s),
7.58 (2H, d), 7.89 (IH, s), 8.26 (2H, d), 9.63 (IH, s). mTOR Kinase Assay (Echo): 0.032μM
Example 37m: 1H NMR (400.132 MHz, DMSO-d6) δ 1.24 (3H, d), 1.55 - 1.58 (2H, m), 1.67 - 1.75 (4H, m), 3.17 - 3.26 (IH, m), 3.28 (3H, s), 3.45 - 3.58 (5H, m), 3.64 (IH, dd), 3.77 (IH, d), 3.97 (IH, dd), 4.18 - 4.25 (IH, m), 4.52 - 4.63 (2H, m), 6.80 (IH, s), 7.57 - 7.60 (2H, m),
7.91 (IH, s), 8.24 - 8.27 (2H, m), 9.71 (IH, s). mTOR Kinase Assay (Echo): 0.0506μM
Example 37n: 1H NMR (400.132 MHz, DMSO-d6) δ 0.91 (3H, t), 1.24 (3H, d), 1.53 - 1.62 (4H, m), 1.66 - 1.69 (2H, m), 3.22 (IH, td), 3.27 (3H, s), 3.43 - 3.52 (3H, m), 3.64 (IH, dd),
3.77 (IH, d), 3.97 (IH, dd), 4.18 - 4.25 (IH, m), 4.56 - 4.62 (IH, m), 6.80 (IH, s), 7.60 (2H, d), 7.91 (IH, s), 8.24 - 8.28 (2H, m), 9.65 (IH, s). mTOR Kinase Assay (Echo): 0.0393μM
Example 37o: 1U NMR (400.132 MHz, DMSO-Cl6) δ 1.24 (3H, d), 1.56 - 1.59 (2H, m), 1.67 - 1.70 (2H, m), 3.22 (IH, td), 3.27 (3H, s), 3.49 (IH, td), 3.64 (IH, dd), 3.77 (IH, d), 3.81 (3H, s), 3.98 (IH, dd), 4.19 - 4.25 (IH, m), 4.57 - 4.63 (IH, m), 6.81 (IH, s), 7.51 (IH, s), 7.62 - 7.65 (2H, m), 8.05 (IH, s), 8.25 - 8.29 (2H, m), 9.67 - 9.76 (2H, m). mTOR Kinase Assay (Echo): 0.033μM
Example 37p: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.78 - 1.81 (2H, m), 1.95 - 1.98 (2H, m), 2.48 (3H, s), 2.95 (3H, d), 3.16 - 3.23 (IH, m), 3.44 - 3.51 (IH, m), 3.62 (IH, d), 3.76 (IH, d), 3.96 - 3.99 (IH, m), 4.14 - 4.18 (IH, m), 4.44 - 4.50 (IH, m), 6.82 (IH, s), 7.47 (2H, d), 7.80 (IH, s), 7.84 (IH, s), 7.96 (2H, d), 9.70 (IH, s). mTOR Kinase Assay (Echo): 0.00534μM
Example 37q: 1H NMR (400.132 MHz, DMSO-d6) δ 0.58 - 0.62 (2H, m), 0.74 - 0.79 (2H, m), 1.22 (3H, d), 1.78 - 1.81 (2H, m), 1.95 - 1.98 (2H, m), 2.49 (3H, s), 2.87 - 2.97 (IH, m), 3.17 - 3.23 (IH, m), 3.44 - 3.51 (IH, m), 3.61 - 3.64 (IH, m), 3.76 (IH, d), 3.96 - 3.99 (IH, m), 4.15 - 4.18 (IH, m), 4.44 - 4.51 (IH, m), 6.83 (IH, s), 7.54 (2H, d), 7.84 (IH, s), 7.95 (2H, d), 8.15 (1H, s), 9.47 (IH, s). mTOR Kinase Assay (Echo): 0.00294μM
Example 37r: 1R NMR (400.132 MHz, DMSO-de) δ 1.22 (3H, d), 1.78 - 1.81 (2H, m), 1.94 - 1.98 (2H, m), 2.48 (3H, s), 3.16 - 3.23 (IH, m), 3.44 - 3.50 (IH, m), 3.57 (4H, s), 3.61 - 3.64 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.15 - 4.18 (IH, m), 4.43 - 4.52 (IH, m), 4.82 (IH, s), 6.82 (IH, s), 7.54 (2H, d), 7.84 (2H, s), 7.95 (2H, d), 9.78 (IH, s). mTOR Kinase Assay (Echo): 0.00162μM
Example 37s: 1U NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 1.59 - 1.65 (2H, m), 1.89 - 1.91 (2H, m), 2.94 (3H, d), 3.16 (IH, dt), 3.47 (IH, dt), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.14 (IH, d), 4.44 (IH, s), 6.69 (IH, s), 7.44 (4H, t), 7.80 - 7.90 (5H, m), 9.70 (IH, s). mTOR Kinase Assay (Echo): 0.00756μM
Example 37t: 1H NMR (400.132 MHz, DMSO-d6) δ 0.57 - 0.62 (2H, m), 0.74 - 0.79 (2H, m), 1.19 (3H, d), 1.61 - 1.63 (2H, m), 1.89 - 1.91 (2H, m), 2.90 - 2.94 (IH, m), 3.17 (IH, dt), 3.47 (IH, dt), 3.62 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.14 (IH, d), 4.45 (IH, s), 6.69 (IH, s), 7.42 (2H, t), 7.52 (2H, d), 7.83 - 7.89 (4H, m), 8.13 (IH, s), 9.47 (IH, s). mTOR Kinase Assay (Echo): 0.00889μM Example 37u: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (4H, d), 1.59 - 1.63 (3H, m), 1.89 - 1.91 (2H, m), 3.13 - 3.20 (IH, m), 3.43 - 3.50 (IH, m), 3.56 (4H, m), 3.60 - 3.63 (IH, m), 3.75 (IH, d), 3.96 (IH, dd), 4.14 (IH, d), 4.44 (IH, s), 4.81 (IH, s), 6.68 (IH, s), 7.42 (2H, t), 7.53 (2H, d), 7.83 - 7.86 (IH, m), 7.88 (2H, d), 9.78 (IH, s). mTOR Kinase Assay (Echo): 0.000395μM
Example 37v: 1R NMR (400.132 MHz, DMSOd6) δ 0.58-0.62 (2H, m), 0.74-0.79 (2H, m), 1.17-1.19 (3H, d), 1.62-1.69 (2H, m), 1.88-1.93 (2H, m), 2.92 (IH, bs), 3.12-3.19 (IH, td), 3.43-3.50 (IH, td), 3.60-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.10-4.13 (IH, d), 4.41 (IH, bs), 6.67 (IH, s), 7.49-7.52 (2H, d), 7.58-7.62 (2H, t), 7.70-7.74 (IH, tt), 7.79- 7.81 (2H, d), 7.89-7.91 (2H, d), 8.10 (IH, bs), 9.47 (IH, bs). mTOR Kinase Assay (Echo): 0.00549μM
Example 37w: 1H NMR (400.132 MHz, DMSOd6) δ 1.15-1.20 (3H, d), 1.60-1.70 (2H, m), 1.90-1.95 (2H, bs), 3.12-31.7 (IH, m), 3.25-3.30 (IH, m obscured by solvent peak), 3.45-3.50 (IH, m), 3.6 (IH, d), 3.7 (IH, d), 3.8 (3H, s), 4.0 (IH, m), 4.1 (IH, d), 4.40-4.45 (IH, bs), 6.7 (IH, s), 7.49-7.53 (3H, m), 7.68-7.73 (2H, m), 7.7 (IH, t), 7.8 (2H, d), 7.9 (2H, d), 8.0 (IH, bs), 9.7 (IH, bs). mTOR Kinase Assay (Echo): 0.00137μM
Example 37x: 1R NMR (400.132 MHz, DMSO-de) δ 1.17-1.19 (3H, d), 1.61-1.67 (2H, m), 1.68-1.75 (2H, m), 1.88-1.93 (2H, m), 3.11-3.17 (IH, td), 3.43-3.55 (5H, m), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.09-4.12 (IH, d), 4.40 (IH, bs), 4.53-4.54 (IH, t), 6.66 (IH, s), 7.45-7.47 (2H, d), 7.58-7.62 (2H, t), 7.70-7.75 (IH, tt), 7.79-7.81 (2H, dd), 7.86 (IH, bs), 7.89-7.92 (2H, d), 9.64 (IH, bs). mTOR Kinase Assay (Echo): 0.00944μM Example 37y: 1U NMR (400.132 MHz, DMSO-de) δ 1.17-1.19 (3H, d), 1.61-1.68 (2H, m), 1.89-1.92 (2H, m), 2.85-2.88 (2H, t), 3.11-3.19 (IH, td), 3.43-3.49 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.75 (3H, m), 3.94-3.98 (IH, dd), 4.09-4.12 (IH, d), 4.41 (IH, bs), 6.67 (IH, s), 7.42-7.45 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.78-7.81 (2H, dd), 7.90-7.93 (2H, d), 8.08-8.11 (1H, t), 9.91 (IH, s). mTOR Kinase Assay (Echo): 0.00553μM Example 37z: 1H NMR (400.132 MHz, DMSO-d6) δ 1.12-1.19 (6H, m), 1.61-1.69 (2H, m), 1.89-1.92 (2H, m), 3.11-3.19 (IH, td), 3.43-3.52 (3H, m), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.09-4.12 (IH, d), 4.40 (IH, bs), 6.66 (IH, s), 7.44-7.46 (2H, d), 7.58- 7.62 (2H, t), 7.70-7.74 (IH, tt), 7.78-7.81 (2H, d), 7.84 (IH, bs), 7.90-7.92 (2H, d), 9.58 (IH, bs). mTOR Kinase Assay (Echo): 0.00481 μM
Example 37aa: 1R NMR (400.132 MHz, DMSOd6) δ 1.17-1.19 (3H, d), 1.61-1.69 (2H, m), 1.88-1.92 (2H, m), 3.11-3.19 (IH, td), 3.43-3.49 (IH, td), 3.51-3.63 (5H, m), 3.72-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.09-4.12 (IH, d), 4.40 (IH, bs), 4.82 (IH, bs), 6.66 (IH, s), 7.51-7.53 (2H, d), 7.58-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.78-7.81 (2H, d), 7.89-7.91 (3H, m), 9.83 (IH, bs). mTOR Kinase Assay (Echo): 0.00567μM Example 37ab: 1H NMR (400.132 MHz, DMSOd6) δ 1.17-1.19 (3H, d), 1.61-1.68 (2H, m), 1.88-1.92 (2H, m), 2.94-2.95 (3H, d), 3.11-3.17 (IH, td), 3.44-3.49 (IH, td), 3.58-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.08-4.12 (IH, d), 4.41 (IH, bs), 6.67 (IH, s), 7.43-7.45 (2H, d), 7.58-7.62 (2H, t), 7.70-7.74 (IH, tt), 7.79-7.81 (3H, m), 7.90-7.92 (2H, d), 9.70 (IH, bs). mTOR Kinase Assay (Echo): 0.003μM
Example 37ac: 1U NMR (400.132 MHz, DMSO-de) δ 1.17-1.19 (3H, d), 1.62-1.69 (2H, m), 1.90-1.93 (2H, m), 3.12-3.18 (IH, td), 3.43-3.50 (IH, td), 3.59-3.63 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.09-4.13 (IH, d), 4.41 (IH, bs), 4.71-4.72 (2H, d), 6.67 (IH, s), 7.00 (2H, bs), 7.56-7.62 (4H, m), 7.70-7.74 (IH, tt), 7.79-7.81 (2H, dd), 7.91-7.93 (2H, d), 8.17 (IH, bs), 9.98 (IH, bs), 11.98 (IH, bs). mTOR Kinase Assay (Echo): 0.0298μM
Example 37ad: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 1.70 (2H, q), 1.98 (2H, q), 3.10-3.20 (IH, td), 3.40-3.50 (IH, td), 3.50-3.58 (4H, m), 3.58 (IH, dd), 3.75 (IH, d), 3.95 (IH, dd), 4.15 (IH, d), 4.50 (IH, br s), 4.80 (IH, br s), 6.70 (IH, s), 7.50 (2H, d), 7.74-7.77 (4H, m), 7.82 (IH, s), 8.87 (2H, dd), 9.75 (IH, s)
Example 37ae: 1R NMR (400.132 MHz, DMSO-dg) δ δ 0.60 (2H, q), 0.77 (2H, q), 1.20 (3H, d), 1.70 (2H, q), 1.98 (2H, q), 2.85-2.95 (IH, m), 3.19 (IH, td), 3.47 (IH, td), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.17 (IH, d), 4.48 (IH, br s), 6.71 (IH, s), 7.49 (2H, d), 7.72 (2H, d), 7.78 (2H, dd), 8.15 (IH, br s), 8.87 (2H, dd), 9.46 (IH, br s) Example 37af: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 1.70 (2H, q), 1.98 (2H, q), 2.94 (3H, d), 3.17 (IH, td), 3.46 (IH, td), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.10- 4.20 (IH, d), 4.50 (IH, br s), 6.71 (IH, s), 7.43 (2H, d), 7.74-7.76 (2H, d), 7.77-7.79 (2H, dd), 7.82 (IH, m), 8.87 (2H, dd), 9.70 (IH, br s).
Example 37ag: 1U NMR (399.902 MHz, DMSOd6) δ 1.17 (3H, d), 1.45 (6H, s), 1.65 (2H, m), 1.90 (2H, m), 3.14 (IH, m), 3.46 (IH, m), 3.58 (3H, m), 3.75 (IH, m), 3.96 (IH, m), 4.11 (IH, m), 4.41 (IH, m), 6.67 (IH, s), 7.39 (IH, m), 7.50 (2H, m), 7.60 (2H, m), 7.75 (3H, m), 7.88 (2H, m)
The preparations of the anilines required for Examples 37a - 37ag have been described earlier.
Example 38: 3-Cvclopropyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yll-6-[l-[(5-methyl-l,3,4- thiadiazol-2-yl)sulfonyll cyclopropyll pyrimidin-2-yll phenyll urea
Figure imgf000630_0001
Cyclopropylamine (84 mg, 1.48 mmol) was added to phenyl N-[4-[4-[(3S)-3- methylmorpholin-4-yl]-6-[l-[(5-methyl-l,3,4-thiadiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin- 2-yl]phenyl] carbamate (175 mg, 0.30 mmol) and triethylamine (0.205 mL, 1.48 mmol) in NMP (2 mL) at RT and the reaction was allowed to stir for 2 hours. The mixture was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents, to give the desired material as a cream solid (112 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.37 - 0.45 (2H, m), 0.61 - 0.68 (2H, m), 1.21 (3H, d), 1.78 - 1.88 (2H, m), 1.97 - 2.05 (2H, m), 2.83 (3H, s), 3.12 - 3.23 (IH, m), 3.42 - 3.52 (IH, m), 3.61 (IH, d), 3.75 (IH, d), 3.96 (IH, d), 4.20 (IH, s), 4.52 (IH, s), 6.46 (IH, t), 6.77 (IH, s), 7.42 (2H, d), 7.74 (2H, d), 8.57 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 556; HPLC tR = 2.25 min. mTOR Kinase Assay (Echo): 0.00131μM The following compounds were made in an analogous fashion from phenyl N-[4-[4-[(35)-3- methylmorpholin-4-yl]-6-[l-[(5-methyl-l,3,4-thiadiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin- 2-yl]phenyl] carbamate and the appropriate amine.
Figure imgf000631_0002
Example 38a: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.82 - 1.85 (2H, m), 1.98 2.04 (2H, m), 2.66 (3H, s), 2.82 (3H, s), 3.13 - 3.25 (IH, m), 3.40 - 3.47 (IH, m), 3.61 (IH, d), 3.76 (IH, d), 3.96 (IH, d), 4.21 (IH, s), 6.08 (IH, t), 6.77 (IH, s), 7.42 (2H, d), 7.74 (2H, d), 8.78 (IH, s). mTOR Kinase Assay (Echo): 0.000918μM
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-[(5-methyl-l,3,4- thiadiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N- \4- [4- IY3 SV 3 -methylmorpholin-4-yll -6- 1" 1 - IT5 -methyl- 1.3.4-thiadiazol-2- yDsulfonyll cyclopropyllpyrimidin-2-yllphenyll carbamate
Figure imgf000631_0001
Phenyl chloroformate (0.398 mL, 3.17 mmol) was added slowly to 4-[4-[(35)-3- methylmorpholin-4-yl]-6-[l-[(5-methyl-l,3,4-thiadiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin- 2-yl]aniline (1.25 g, 2.65 mmol) and sodium hydrogen carbonate (0.333 g, 3.97 mmol) in dioxane (30 mL) at 50C under an atmosphere of nitrogen. The resulting mixture was stirred at RT for 18 hours then the mixture diluted with ethyl actate (125 mL), and washed sequentially with water (2 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated. The crude material was triturated with diethyl ether and isohexane to give a solid which was collected by filtration and dried under vacuum to give the desired material as a cream solid (1.24 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.82 - 1.88 (2H, m), 2.00 - 2.05 (2H, m), 2.82 (3H, s), 3.20 (IH, dd), 3.42 - 3.50 (IH, m), 3.60 (IH, d), 3.76 (IH, d), 4.00 (IH, d), 4.23 (IH, s), 4.53 (IH, s), 6.81 (IH, s), 7.22 - 7.34 (3H, m), 7.40 - 7.50 (2H, m), 7.55 (2H, d), 7.84 (2H, d), 10.46 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 593; HPLC tR = 2.81 min.
4- [4- \(3S)-3 -Methylmorpholin-4-yll -6- 1" 1 - IY5 -methyl- 1.3.4-thiadiazol-2- yl)sulfonyllcvclopropyllpyrimidin-2-vHaniline
Figure imgf000632_0001
Bis(triphenylphosphine)palladium(II) chloride (0.164 g, 0.23 mmol) was added to 2-chloro-4- [(35)-3-methylmorpholin-4-yl]-6-[l-[(5-methyl-l,3,4-thiadiazol-2- yl)sulfonyl]cyclopropyl]pyrimidine (1.45 g, 3.49 mmol), 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (1.146 g, 5.23 mmol) and aqueous sodium carbonate solution (3 mL, 6.00 mmol) in a solvent mixture of DMF (10 mL), DME (2 mL), water (2 mL) and ethanol (2 mL). The atmosphere was replaced with nitrogen and the reaction stirred at 9O0C for 18 hours. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with saturated brine (2 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 80% ethyl acetate in isohexane, to give the desired material as a beige solid (1.25 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 1.78 - 1.83 (2H, m), 1.98 - 2.01 (2H, m), 2.83 (3H, s), 3.10 - 3.21 (IH, m), 3.38 - 3.51 (IH, m), 3.60 (IH, d), 3.74 (IH, d), 3.95 (IH, d), 4.16 (IH, s), 4.48 (IH, s), 5.59 (2H, s), 6.51 (2H, d), 6.66 (IH, s), 7.57
(2H, d)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 473; HPLC tR = 2.14 min.
2-Chloro-4-r('3y)-3-methylmorpholin-4-yl1-6-ri-r('5-methyl-1.3.4-thiadiazol-2- yDsulfonyllcvclopropyllpyrimidine
Figure imgf000633_0001
An aqueous solution of sodium hydroxide (20 mL, 532.5 mmol) was added to a stirred mixture of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-[(5-methyl-l,3,4-thiadiazol-2- yl)sulfonylmethyl]pyrimidine (1.8 g, 4.62 mmol), 1 ,2-dibromoethane (1.99 ml, 23.08 mmol) and tetraethylammonium bromide (0.097 g, 0.46 mmol) in DCM (40 mL) at RT. The resulting mixture was stirred at RT for 24 hours then the mixture diluted with DCM (50 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product which was chromatographed on silica, elution gradient 10 to 60% ethyl acetate in isohexane, to give the desired material as a yellow gum (1.48 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.79 - 1.84 (2H, m), 1.94 - 2.01 (2H, m), 2.87 (3H, s), 3.17 - 3.23 (IH, m), 3.37 - 3.46 (IH, m), 3.55 (IH, dd), 3.71 (IH, d), 3.92 (IH, dd), 4.06 (IH, s), 4.33 (IH, s), 6.87 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 416; HPLC tR = 1.98 min.
2-Chloro-4-r(3y)-3-methylmorpholin-4-yl1-6-r(5-methyl-1.3.4-thiadiazol-2- vDsulfonylmethyllpyrimidine
Figure imgf000633_0002
3-Chloroperoxybenzoic acid (4.77 g, 27.66 mmol) was added portionwise to 2-chloro-4-[(35)- 3-methylmorpholin-4-yl]-6-[(5-methyl-l,3,4-thiadiazol-2-yl)sulfanylmethyl]pyrimidine (3.3 g, 9.22 mmol), in DCM (70 mL) at RT under a nitrogen atmosphere. The resulting solution was stirred at RT for 2 hours then diluted with ethyl acetate (250 mL), and washed sequentially with a 10% aqueous solution of sodium metabisulphite (100 mL) and 2M sodium carbonate (100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product which was purified by flash silica chromatography, elution gradient 10 to 100% ethyl acetate in isohexane, to give the desired material as a white solid (2.22 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (4H, d), 2.87 (4H, s), 3.15 - 3.26 (IH, m), 3.44 (IH, td), 3.59 (IH, d), 3.73 (IH, d), 3.94 (2H, m), 4.22 (IH, s), 5.03 (2H, s), 6.92 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 390; HPLC tR = 1.83 min.
2-Chloro-4-r(3y)-3-methylmorpholin-4-yl1-6-r(5-methyl-1.3.4-thiadiazol-2- vDsulfanylmethyHpyrimidine
Figure imgf000634_0001
DIPEA (2.94 mL, 16.97 mmol) was added to 5-methyl-l,3,4-thiadiazole-2-thiol (1.645 g, 12.44 mmol), in acetonitrile (40 mL) at RT under an atmosphere of nitrogen. The resulting solution was stirred at RT for 20 minutes then 2-chloro-4-(iodomethyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidine (4 g, 11.31 mmol) was added. The resulting mixture was stirred at RT for 1 hour then then mixture diluted with ethyl acetate (300 mL), and washed with water (150 mL).The organic layer was dried (MgSO4), filtered and evaporated to afford crude product which was purified by flash silica chromatography, elution gradient 0 to 2% methanol in ethyl acetate, to give the desired material as a white solid (3.30 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 6.90 (IH, s), 1.17 (3H, d), 2.68 (3H, s), 3.12 - 3.22 (IH, m), 3.42 (IH, td), 3.57 (IH, dd), 3.71 (IH, d), 3.86 - 4.04 (2H, m), 4.27 (IH, s), 4.42 (2H, s)
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier. Example 39 : 3-C vclopropyl- 1- [4- [4- [(3 S)-3-methylmorpholin-4-yll -6- [ 1-Q ,3-thiazol-2- ylsulfonylkyclopropyll pyrimidin-2-yll phenyll urea
Figure imgf000635_0001
Bis(triphenylphosphine)palladium(II) chloride (17.6 mg, 0.03 mmol) was added to 2-chloro- 4- [(3<S)-3 -methylmorpholin-4-yl] -6- [ 1 -( 1 ,3-thiazol-2-ylsulfonyl)cyclopropyl]pyrimidine (150 mg, 0.37 mmol), l-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)urea (170 mg, 0.56 mmol) and an aqueous solution of sodium carbonate (5 mL, 10.00 mmol) in a solvent mixture of DMF (2 mL), DME (16 mL), water (2 mL) and ethanol (2 mL). The atmosphere was replaced with nitrogen and the mixture stirred at 9O0C for 18 hours. The mixture was allowed to cool and diluted with ethyl acetate (200 mL) and washed with water (2 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product which was purified by flash silica chromatography, elution gradient 0 to 4% methanol in ethyl acetate. The crude material was further purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents, to give the desired material (30 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.37 - 0.45 (2H, m), 0.60 - 0.67 (2H, m), 1.19 (3H, d), 1.76 - 1.82 (2H, m), 1.95 - 2.02 (2H, m), 3.12 - 3.21 (IH, m), 3.45 (IH, d), 3.61 (IH, d), 3.75 (IH, d), 3.96 (IH, d), 4.18 (IH, s), 4.44 (IH, s), 6.45 (IH, s), 6.73 (IH, s), 7.41 (2H, d), 7.83 (2H, d), 8.24 (IH, s), 8.28 (IH, s), 8.54 (IH, s)
The following compound was made in an analogous fashion from 2-chloro-4-[(35)-3- methylmorpholin-4-yl] -6- [ 1 -( 1 ,3 -thiazol-2-ylsulfonyl)cyclopropyl]pyrimidine and the appropriate amine.
Figure imgf000636_0002
Example 39a: 1U NMR (400.132 MHz, DMSO-(I6) δ 1.19 (3H, d), 1.76 - 1.81 (2H, m), 1.96 ■ 2.01 (2H, m), 2.66 (3H, d), 3.11 - 3.22 (IH, m), 3.42 - 3.49 (IH, m), 3.61 (IH, d), 3.75 (IH, d), 3.96 (IH, d), 4.17 (IH, s), 4.44 (IH, s), 6.07 (IH, q), 6.73 (IH, s), 7.40 (2H, d), 7.82 (2H, d), 8.24 (IH, d), 8.28 (IH, d), 8.75 (IH, s)
The preparation of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclopropyl]pyrimidine is described below.
2-Chloro-4- \(3S)-3 -methylmorpholin-4-yll -6-[ 1 -( 1.3 -thiazol-2- ylsulfonvDcvclopropyllpyrimidine
Figure imgf000636_0001
An aqueous solution of sodium hydroxide (0.235 mL, 6.27 mmol) was added to a stirred mixture of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(l ,3-thiazol-2- ylsulfonylmethyl)pyrimidine (2.35 g, 6.27 mmol), 1 ,2-dibromoethane (2.70 mL, 31.34 mmol) and tetraethylammonium bromide (0.132 g, 0.63 mmol) in toluene at RT. The resulting mixture was stirred at 7O0C for 2 hours then was diluted with ethyl acetate (150 mL), and washed with water (100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 60% ethyl acetate in isohexane, to give the desired material as a yellow solid (2.45 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18 (4H, d), 1.69 - 1.75 (2H, m), 1.91 - 1.96 (2H, m), 3.12 - 3.21 (IH, m), 3.40 (IH, d), 3.55 (IH, d), 3.70 (IH, d), 3.92 (IH, d), 4.00 (IH, s), 4.27 (IH, s), 6.84 (IH, s), 8.20 (IH, d), 8.33 (IH, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 401; HPLC tR = 2.04 min.
2-Chloro-4-r(36f)-3-methylmorpholin-4-yll-6-(l,3-thiazol-2-ylsulfonylmethyl)pyrimidine
Figure imgf000637_0001
3-Chloroperoxybenzoic acid (6.04 g, 35.00 mmol) was added portionwise to 2-chloro-4-[(35)- 3-methylmorpholin-4-yl]-6-(l,3-thiazol-2-ylsulfanylmethyl)pyrimidine (4 g, 11.67 mmol), in DCM (10 mL) at RT under an atmosphere of nitrogen. The resulting solution was stirred at RT for 3 hours. The reaction mixture was diluted with ethyl acetate (250 mL), and washed with a 10% aqueous solution sodium metabisulphite (100 mL) and a saturated aqueous solution of sodium carbonate (100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 100% ethyl acetate in isohexane, to give the desired material as a white solid (2.85 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 8.33 (IH, d), 1.18 (4H, d), 3.14 - 3.25 (IH, m), 3.43 (IH, dd), 3.58 (IH, d), 3.72 (IH, d), 3.88 - 4.01 (2H, m), 4.20 (IH, s), 4.87 (2H, s), 6.82 (IH, s), 8.24 (IH, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 375; HPLC tR = 1.86 min.
2-Chloro-4-[(36f)-3-methylmorpholin-4-yll-6-(1.3-thiazol-2-ylsulfanylmethvπpyrimidine
Figure imgf000637_0002
DIPEA (2.94 mL, 16.97 mmol) was added to 2-mercaptothiazole (1.458 g, 12.44 mmol), in acetonitrile (40 mL) at RT under an atmosphere of nitrogen. The resulting solution was stirred at RT for 20 minutes. 2-Chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (4 g, 11.31 mmol) was added and the mixture stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (300 mL), and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 80% ethyl acetate in isohexane, to give the desired material as a colourless gum (3.77 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.15 (5H, d), 3.15 (IH, td), 3.41 (2H, td), 3.56 (IH, dd), 3.70 (IH, d), 3.91 (2H, m), 4.25 (IH, s), 4.36 (2H, s), 6.84 (IH, s), 7.70 (IH, d), 7.76 (IH, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 343; HPLC tR = 2.07 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Example 40: l-[4-[4-[l-αH-Imidazol-2-ylsulfonyl)cvclopropyll-6-[(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-methylurea
Figure imgf000638_0001
Anisole (0.159 mL, 1.46 mmol) was added to l-[4-[4-[l-[l-[(4- methoxyphenyl)methyl]imidazol-2-yl]sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3-methylurea (180 mg, 0.29 mmol) in TFA (8 mL) at RT under an atmosphere of nitrogen. The resulting solution was stirred at 6O0C for 90 minutes then the solvent removed under reduced pressure and the residue chromatographed on an SCX column, eluting with 7M ammonia in methanol. The material was further purified by flash silica chromatography, elution gradient 10 to 90% ethyl acetate in isohexane, to give the desired material as a cream solid (122 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.68 - 1.74 (2H, m), 1.91 - 1.98 (2H, m), 2.66 (3H, s), 3.09 - 3.19 (IH, m), 3.44 - 3.50 (IH, m), 3.61 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.13 (IH, s), 4.40 (IH, s), 6.05 (IH, s), 6.64 (IH, s), 7.35 (2H, s), 7.43
(2H, d), 8.00 (2H, d), 8.71 (IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 493; HPLC tR = 1.33 min. mTOR Kinase Assay (Echo): 0.00436μM
The following compound was made in an analogous fashion from 3-cyclopropyl-l-[4-[4-[l-
[l-[(4-methoxyphenyl)methyl]imidazol-2-yl]sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea.
Figure imgf000639_0001
Example 40a: 1U NMR (400.132 MHz, DMSOd6) δ 0.38 - 0.44 (2H, m), 0.63 - 0.68 (2H, m), 1.19 (3H, d), 1.67 - 1.75 (2H, m), 1.89 - 1.99 (2H, m), 2.51 - 2.57 (IH, m), 3.11 - 3.22 (IH, m), 3.39 - 3.52 (IH, m), 3.61 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.11 (IH, d), 4.39 (IH, s), 6.41 (IH, s), 6.65 (IH, s), 7.36 (2H, s), 7.44 (2H, d), 8.00 (2H, d), 8.50 (IH, s) 13.5(lH,s). mTOR Kinase Assay (Echo): 0.00649μM
The preparation of l-[4-[4-[l-[l-[(4-methoxyphenyl)methyl]imidazol-2- yl] sulfonylcyclopropyl] -6- [(35)-3 -methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] -3 - methylureais described below. 1 -[4-[4-[ 1 -[ 1 -r(4-Methoxyphenyl)methyllimidazol-2-yllsulfonylcvclopropyll-6-r(36f)-3- methylmorpholin-4-yllpyrimidin-2-yllphenyll-3-methylurea
Figure imgf000640_0001
Triethylamine (0.246 mL, 1.76 mmol) was added to phenyl 7V-[4-[4-[l-[l-[(4- methoxyphenyl)methyl]imidazol-2-yl]sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate (240 mg, 0.35 mmol) and methylamine (0.705 mL, 1.41 mmol) in DMF (3 mL) at RT. The resulting solution was stirred at 4O0C for 30 minutes then at RT overnight. The mixture was concentrated in vacuo and chromatographed on silica, elution gradient 100 % ethyl acetate, to give the desired material as a cream solid (190 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.13 (3H, d), 1.68 - 1.72 (2H, m), 1.88 - 1.95 (2H, m), 2.67 (3H, d), 3.07 - 3.20 (IH, m), 3.36 - 3.51 (IH, m), 3.57 (IH, d), 3.68 - 3.79 (4H, m), 3.94 (IH, d), 4.06 (IH, s), 4.35 (IH, s), 5.21 (2H, s), 6.05 (IH, t), 6.55 (IH, s), 6.77 (2H, d), 7.05 (2H, d), 7.23 (IH, s), 7.41 - 7.48 (3H, m), 8.02 (2H, d), 8.72 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 618; HPLC tR = 2.17 min
3-Cyclopropyl- 1 -[4-[4-[ 1 -[ 1 -[(4-methoxyphenyl)methyl]imidazol-2-yl]sulfonylcyclopropyl]- 6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]ureawas made in an analogous fashion from phenyl Λ/-[4-[4-[l-[l-[(4-methoxyphenyl)methyl]imidazol-2- yl]sulfonylcyclopropyl] -6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate and the appropriate amine.
Figure imgf000640_0002
1U NMR (400.132 MHz, DMSO-d6) δ 0.38 - 0.45 (2H, m), 0.60 - 0.69 (2H, m), 1.14 (3H, d), 1.66 - 1.74 (2H, m), 1.88 - 1.94 (2H, m), 2.53 - 2.62 (IH, m), 3.09 - 3.18 (IH, m), 3.39 - 3.48 (IH, m), 3.57 (IH, d), 3.66 - 3.78 (4H, m), 3.95 (IH, d), 4.11 (IH, s), 4.35 (IH, s), 5.21 (2H, s), 6.43 (IH, s), 6.55 (IH, s), 6.77 (2H, d), 7.06 (2H, d), 7.23 (IH, s), 7.42 - 7.49 (3H, m), 8.02 (2H, d), 8.52 (IH, s)
The preparation of phenyl Λ/-[4-[4-[l-[l-[(4-methoxyphenyl)methyl]imidazol-2- yl]sulfonylcyclopropyl] -6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate
Phenyl N-[4-[4-[ 1 -[ 1 -[(4-methoxyphenvπmethyllimidazol-2-yllsulfonylcvclopropyll-6-[(3S)- 3 -methylmorpholin-4-yllpyrimidin-2-yllphenyll carbamate
Figure imgf000641_0001
Phenyl chloroformate (0.202 mL, 1.61 mmol) was added to 4-[4-[l-[l-[(4- methoxyphenyl)methyl]imidazol-2-yl]sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]aniline (600 mg, 1.07 mmol) and sodium hydrogen carbonate (135 mg, 1.61 mmol) in dioxane (10 mL) at 50C under nitrogen. The resulting mixture was stirred at RT for 90 minutes. The reaction mixture was diluted with ethyl acetate (150 mL), and washed with water (2 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude gum was triturated with a mixture of diethyl ether and isohexane to give the desired material as a beige solid which was collected by filtration and dried under vacuum (570 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.13 (3H, d), 1.67 - 1.74 (2H, m), 1.90 - 1.95 (2H, m), 3.03 - 3.21 (IH, m), 3.36 - 3.47 (IH, m), 3.53 - 3.62 (IH, m), 3.64 - 3.76 (4H, m), 3.95 (IH, d), 4.10 (IH, s), 4.37 (IH, s), 5.23 (2H, s), 6.60 (IH, s), 6.77 (2H, d), 7.06 (2H, d), 7.23 - 7.33 (4H, m), 7.42 - 7.50 (3H, m), 7.59 (2H, d), 8.11 (2H, d), 10.41 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 682; HPLC tR = 2.88 min 4- [4- r 1 - r 1 -r(4-Methoxyphenyl)methyl1imidazol-2-vH sulfonylcyclopropyll -6- [(36^-3 - methylmorpholin-4-yllpyrimidin-2-vHaniline
Figure imgf000642_0001
Bis(triphenylphosphine)palladium(II) chloride (42.5 mg, 0.06 mmol) was added to 2-chloro- 4- [ 1 - [ 1 - [(4-methoxyphenyl)methyl] imidazol-2-yl] sulfonylcyclopropyl]-6- [(35)-3 - methylmorpholin-4-yl]pyrimidine (610 mg, 1.21 mmol), 4-(4,4,5,5-Tetramethyl- 1,3,2- dioxaborolan-2-yl)aniline (530 mg, 2.42 mmol) and an aqueous solution of sodium carbonate (2 mL, 4.00 mmol) in a solvent mixture of DMF (2 mL), DME (4 mL), water (0.5 mL) and ethanol (0.5 mL) at RT. The atmosphere was replaced with nitrogen and the mixture stirred at 9O0C for 5 hours. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (2 x 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 100% ethyl acetate in isohexane, to give the desired material as a white solid (600 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.11 (3H, d), 1.65 - 1.69 (2H, m), 1.88 - 1.92 (2H, m), 3.04 - 3.15 (IH, m), 3.41 (IH, td), 3.56 (IH, d), 3.67 - 3.75 (4H, m), 3.93 (IH, d), 4.06 (IH, s), 4.31 (IH, s), 5.16 (2H, s), 5.54 (2H, s), 6.44 (IH, s), 6.57 (2H, d), 6.79 (2H, d), 7.06 (2H, d), 7.22 (IH, s), 7.43 (IH, s), 7.87 (2H, d)
2-Chloro-4-ri-ri-r(4-methoxyphenyl)methyllimidazol-2-yllsulfonylcvclopropyH-6-r(36f)-3- methylmorpholin-4-vHpyrimidine
Figure imgf000642_0002
An aqueous solution of sodium hydroxide (10 mL, 186.4 mmol) was added to 2-chloro-4-[[l- [(4-methoxyphenyl)methyl] imidazol-2-yl] sulfonylmethyl]-6- [(35)-3 -methylmorpholin-4- yljpyrimidine (1.1 g, 2.30 mmol), tetraethylammonium bromide (0.097 g, 0.46 mmol), and 1 ,2-dibromoethane (2.38 mL, 27.62 mmol) in DCM (20 mL) at RT under a nitrogen atmosphere. The reaction was stirred at RT for 4 hours. The reaction mixture was diluted with DCM (50 mL), the phases separated and the organic layer dried (Na2SO4), filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 10 to 75% ethyl acetate in isohexane, to give the desired material as a white solid (0.77 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.10 (4H, d), 1.64 (3H, m), 1.85 - 1.89 (2H, m), 3.03 - 3.15 (IH, m), 3.33 - 3.42 (IH, m), 3.50 (IH, d), 3.68 (IH, d), 3.74 (3H, s), 3.87 - 3.93 (2H, m), 4.06 (IH, s), 5.33 (2H, s), 6.57 (IH, s), 6.87 (2H, d), 7.17 (2H, d), 7.22 (IH, s), 7.59 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 504; HPLC tR = 2.35 min
2-Chloro-4-rri-r(4-methoxyphenyl)methyllimidazol-2-yllsulfonylmethyll-6-r(3I)-3- methylmorpholin-4-vHpyrimidine
Figure imgf000643_0001
4-Methoxybenzyl chloride (0.470 mL, 3.46 mmol) was added to 2-chloro-4-(lH-imidazol-2- ylsulfonylmethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (1.18 g, 3.30 mmol) and potassium carbonate (0.501 g, 3.63 mmol) in DMF (30 mL) at RT under a nitrogen atmosphere. The resulting mixture was stirred at 750C for 1 hour then allowed to cool and diluted with ethyl acetate (100 mL). The mixture was washed with water (2 x 50 mL), the organic layer dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 70% ethyl acetate in isohexane, to give the desired material as a colourless gum (1.27 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.13 (3H, d), 3.10 - 3.19 (IH, m), 3.35 - 3.45 (IH, m), 3.54 (IH, d), 3.70 (IH, d), 3.74 (3H, s), 3.87 - 3.96 (2H, m), 4.14 (IH, s), 4.68 (2H, s), 5.36 (2H, s), 6.55 (IH, s), 6.88 (2H, d), 7.15 - 7.28 (3H, m), 7.57 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 478; HPLC tR = 2.26 min 2-Chloro-4-(l H- imidazol-2-ylsulfonylmethyl)-6- [(36^-3 -methylmorpholin-4-vHpyrimidine
l
Figure imgf000644_0001
3-Chloroperoxybenzoic acid (2.62 g, 15.19 mmol) was added to 2-chloro-4-(lH-imidazol-2- ylsulfanylmethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (2.25 g, 6.91 mmol) in DCM (100 mL) at RT under a nitrogen atmosphere. The resulting solution was stirred at RT for 2 hours. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with an aqueous 10% solution of sodium metabisulphite (200 mL), and a saturated solution of sodium hydrogen carbonate (200 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude solid was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid that was collected by filtration and dried under vacuum (1.8 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 3.06 - 3.21 (IH, m), 3.35 - 3.46 (IH, m), 3.55 (IH, d), 3.71 (IH, d), 3.83 - 3.97 (2H, m), 4.16 (IH, s), 4.66 (2H, s), 6.52 (IH, s), 7.35 (2H, s), 13.65(lH,s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 358; HPLC tR = 0.87 min
2-Chloro-4-d H- imidazol-2-ylsulfanylmethvD-6- [(36^-3 -methylmorpholin-4-yllpyrimidine
Figure imgf000644_0002
DIPEA (2.94 mL, 16.97 mmol) was added to lH-imidazole-2-thiol (1.246 g, 12.44 mmol), in acetonitrile (50 mL) at RT under a nitrogen atmosphere. The resulting solution was stirred at RT for 20 minutes. 2-Chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (4 g, 11.31 mmol) was added and the mixture stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (300 mL), and washed with water (150 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 4% methanol in ethyl acetate, to give the desired material as a white solid (2.80 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.13 (3H, d), 3.11 (IH, dd), 3.34 - 3.45 (IH, m), 3.54 (IH, dd), 3.69 (IH, d), 3.87 - 3.95 (2H, m), 4.06 (2H, s), 4.17 (IH, s), 6.52 (IH, s), 6.96 (IH, s), 7.17 (IH, s), 12.35 (lH,s).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 326; HPLC tR = 1.41 min
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Example 41: 3-α-Cvanoethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yll-6-q- methylsulfonylcvclopropyl)pyrimidin-2-yll phenyll thiourea
Figure imgf000645_0001
A solution of l,l'-thiocarbonyldiimidazole (50 mg, 0.28 mmol) in DCM (1 mL) was added to a suspension of 4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl] aniline (75 mg, 0.19 mmol) in DCM (2 mL) and THF (1 mL). The reaction mixture was stirred at RT for 1 hour before addition of 3- aminopropionitrile (91 mg, 1.30 mmol) and triethylamine (0.026 mL, 0.19 mmol). Stirring was continued at RT overnight. The reaction was incomplete and significant insoluble material was observed so DMF (1 mL) was added and stirring continued for a further 1 hour. The reaction was still incomplete, so the reaction mixture was transferred to a microwave tube, sealed, heated to 1000C in the microwave reactor and held for 10 minutes. The reaction was still incomplete, so further 3-aminopropionitrile (91 mg, 1.30 mmol) was added and the reaction mixture stirred at RT for 2-3 hours. The reaction mixture was evaporated and residue purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents, to give the desired material as a white solid (29 mg). NMR Spectrum: 1H NMR (400.132 MHz. DMSOdn) δ 1.24 (3H, d), 1.55 - 1.58 (2H, m), 1.67 - 1.69 (2H, m), 2.87 (2H, t), 3.19 - 3.26 (IH, m), 3.27 (3H, s), 3.49 (IH, td), 3.64 (IH, dd), 3.74 - 3.78 (3H, m), 3.98 (IH, dd), 4.18 - 4.25 (IH, m), 4.56 - 4.63 (IH, m), 6.82 (IH, s), 7.57 (2H, d), 8.16 (IH, s), 8.26 - 8.30 (2H, m), 9.98 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 501; HPLC tR = 1.99 min mTOR Kinase Assay (Echo): 0.0308μM
The preparation of 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]aniline was described previously.
Example 42: 3-Cvclopropyl-l-[4-[4-[l-[(4-methyl-l,3-thiazol-2-yl)sulfonyllcvclopropyll- 6-morpholin-4-ylpyrimidin-2-yll phenyll urea
Figure imgf000646_0001
Triethylamine (0.119 mL, 0.85mmol) was added to a solution of phenyl 7V-[4-[4-[l-[(4- methyl-l,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-morpholin-4-ylpyrimidin-2- yl]phenyl] carbamate (100 mg, 0.17 mmol) and cyclopropylamine (0.059 mL, 0.85 mmol) in NMP (2 mL) and the resulting solution stirred at ambient temperature for 18 hours. The crude product was purified by preparative HPLC to give the desired material as a white solid (80 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.40 - 0.44 (2H, m), 0.62 - 0.67 (2H, m), 1.75 - 1.78 (2H, m), 1.94 - 1.97 (2H, m), 2.49 (3H, s), 2.54 - 2.58 (IH, m), 3.70 (8H, s), 6.40 (IH, s), 6.82 (IH, s), 7.42 (2H, d), 7.84 (IH, s), 7.87 (2H, d), 8.52 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 541; HPLC tR = 2.15min. mTOR Kinase Assay (Echo): 0.000705μM
The compounds below were prepared in an analogous fashion using the appropriate amine.
Figure imgf000647_0001
Figure imgf000648_0001
Example 42a: 1H NMR (400.132 MHz, DMSOd6) δ 1.75 - 1.78 (2H, m), 1.94 - 1.97 (2H, m), 2.48 (3H, s), 3.15 - 3.20 (2H, m), 3.44 - 3.48 (2H, m), 3.70 (8H, s), 4.72 (IH, t), 6.23 (IH, t), 6.82 (IH, s), 7.40 (2H, d), 7.84 (IH, s), 7.87 (2H, d), 8.78 (IH, s). mTOR Kinase Assay (Echo): 0.00261μM
Example 42b: 1H NMR (400.132 MHz, DMSOd6) δ 1.75 - 1.79 (2H, m), 1.94 - 1.98 (2H, m), 2.50 (3H, s), 3.70 (8H, s), 3.79 (3H, s), 6.83 (IH, s), 7.38 (IH, s), 7.46 (2H, d), 7.77 (IH, s), 7.85 (IH, s), 7.90 (2H, d), 8.36 (IH, s), 8.82 (IH, s).
Example 42c: 1U NMR (400.132 MHz, DMSOd6) δ 1.75 - 1.78 (2H, m), 1.94 - 1.97 (2H, m), 2.49 (3H, s), 2.66 (3H, d), 3.70 (8H, s), 6.04 (IH, q), 6.82 (IH, s), 7.41 (2H, d), 7.84 (IH, s), 7.86 (2H, d), 8.72 (IH, s). mTOR Kinase Assay (Echo): 0.0036μM
Example 42d: 1H NMR (400.132 MHz, DMSOd6) δ 1.07 (3H, t), 1.75 - 1.78 (2H, m), 1.94 -
1.97 (2H, m), 2.49 (3H, s), 3.09 - 3.16 (2H, m), 3.70 (8H, s), 6.14 (IH, t), 6.82 (IH, s), 7.41 (2H, d), 7.84 (IH, s), 7.86 (2H, d), 8.64 (IH, s). mTOR Kinase Assay (Echo): 0.000425μM
Example 42e: 1U NMR (400.132 MHz, DMSO-Cl6) δ 1.57 - 1.66 (2H, m), 1.75 - 1.78 (2H, m), 1.81 - 1.91 (2H, m), 1.94 - 1.97 (2H, m), 2.18 - 2.25 (2H, m), 2.48 (3H, s), 3.70 (8H, s),
4.09 - 4.19 (IH, m), 6.43 (IH, d), 6.82 (IH, s), 7.39 (2H, d), 7.84 (IH, s), 7.86 (2H, d), 8.54 (IH, s). mTOR Kinase Assay (Echo): 0.00257μM
Example 42f: 1H NMR (400.132 MHz, DMSOd6) δ 1.75 - 1.78 (2H, m), 1.94 - 1.97 (2H, m),
2.49 (3H, s), 2.70 (2H, t), 3.34 - 3.39 (2H, m), 3.70 (8H, s), 6.52 (IH, t), 6.83 (IH, s), 7.43
(2H, d), 7.84 (IH, s), 7.88 (2H, d), 8.92 (IH, s). mTOR Kinase Assay (Echo): 0.00264μM
Example 42g: 1U NMR (400.132 MHz, DMSO-de) δ 0.89 (3H, t), 1.41 - 1.50 (2H, m), 1.75 -
1.78 (2H, m), 1.94 - 1.97 (2H, m), 2.49 (3H, s), 3.04 - 3.09 (2H, m), 3.70 (8H, s), 6.18 (IH, t),
6.82 (IH, s), 7.40 (2H, d), 7.84 (IH, s), 7.86 (2H, d), 8.63 (IH, s). mTOR Kinase Assay (Echo): 0.00401μM Example 42h: 1H NMR (400.132 MHz, DMSO-d6) δ 1.11 (6H, d), 1.75 - 1.78 (2H, m), 1.94 -
1.97 (2H, m), 2.48 (3H, s), 3.70 (8H, s), 3.73 - 3.81 (IH, m), 6.03 (IH, d), 6.82 (IH, s), 7.39
(2H, d), 7.84 (IH, s), 7.86 (2H, d), 8.51 (IH, s). mTOR Kinase Assay (Echo): 0.00412μM
The preparation of phenyl Λ/-[4-[4-[l -[(4-methyl- l,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6- morpholin-4-ylpyrimidin-2-yl]phenyl] carbamate is described below:
Phenyl iV-[4-[4-[ 1 -[(4-methyl- 1.3-thiazol-2-vπsulfonyllcvclopropyll-6-morpholin-4- ylpyrimidin-2-vπphenvπ carbamate
Figure imgf000649_0001
Phenyl chloroformate (0.664 mL, 5.29 mmol) was added to 4-[4-[l -[(4-methyl- l,3-thiazol-2- yl)sulfonyl]cyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]aniline (2.2 g, 4.81 mmol) and sodium hydrogen carbonate (0.606 g, 7.21 mmol) in dioxane (100 mL) at 1O0C under a nitrogen atmosphere. The resulting mixture was stirred at 100C for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product as a gum (2.83 g). NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.76 - 1.80 (2H, m), 1.94 - 1.97 (2H, m), 2.48 (3H, s), 3.70 (8H, s), 6.87 (IH, s), 7.24 - 7.30 (3H, m), 7.43 - 7.47 (2H, m), 7.55 (2H, d), 7.85 (IH, s), 7.96 (2H, d), 10.45 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 578; HPLC tR = 2.88 min.
4-[4-[l-[(4-Methyl-1.3-thiazol-2-vπsulfonyllcvclopropyll-6-morpholin-4-ylpyrimidin-2- yl] aniline
Figure imgf000650_0001
Bis(triphenylphosphine)palladium (II) chloride (0.256 g, 0.37 mmol) was added to 2-chloro- 4-[l-[(4-methyl-l,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-morpholin-4-ylpyrimidine (2.93 g, 7.31 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (2.082 g, 9.50 mmol) and 2M aqueous sodium carbonate (13.16 mL, 26.31 mmol) in a solvent mixture of DMF (15 mL), water (37.5 mL), ethanol (15 mL) and DME (15 mL) at RT under an atmosphere of nitrogen. The resulting mixture was stirred at 800C for 16 hours. The cooled reaction mixture was diluted with ethyl acetate (100 mL) and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product which was purified by flash silica chromatography, elution gradient 0 to 75% ethyl acetate in DCM, to give the desired material as a cream solid (2.2 g). NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.72 - 1.75 (2H, m), 1.91 - 1.94 (2H, m), 2.49 (3H, s), 3.62 - 3.71 (8H, m), 5.57 (2H, s), 6.50 (2H, d), 6.71 (IH, s), 7.68 (2H, d), 7.84 (IH, s)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 458; HPLC tR = 2.21min. 2-Chloro-4-[ 1 -[(4-methyl- 1 ,3-thiazol-2-yl)sulfonyllcvclopropyll-6-morpholin-4-ylpyrimidine
Figure imgf000651_0001
1,2-Dibromoethane (0.230 mL, 2.67 mmol) was added to 2-chloro-4-[(4-methyl-l,3-thiazol-2- yl)sulfonylmethyl]-6-morpholin-4-ylpyrimidine (500 mg, 1.33 mmol), 40% sodium hydroxide solution (1.3 mL,13 mmol) and tetrabutylammonium bromide (86 mg, 0.27 mmol) in toluene (10 mL) at RT. The resulting solution was stirred at 600C for 3 hours. The cooled reaction mixture was evaporated to dryness and redissolved in ethyl acetate (50 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4), filtered and evaporated to give the desired material as a pale brown gum (528 mg). NMR Spectrum: 1H NMR (400.13 MHz, CDCl3) δ 1.76 - 1.79 (2H, m), 2.09 - 2.12 (2H, m), 2.52 (3H, s), 3.65 - 3.71 (4H, m), 3.77 - 3.79 (4H, m), 7.29 (IH, s), 7.30 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 401; HPLC tR = 2.04 min.
2-Chloro-4-r(4-methyl-l,3-thiazol-2-yl)sulfonylmethyll-6-morpholin-4-ylpyrimidine
Figure imgf000651_0002
A solution of morpholine (0.994 g, 11.41 mmol) in DCM (25 mL) was added dropwise to a stirred solution of 2,4-dichloro-6-[(4-methyl-l,3-thiazol-2-yl)sulfonylmethyl]pyrimidine (3.7 g, 11.41 mmol) and triethylamine (1.155 g, 11.41 mmol) in DCM (50 mL). The resulting solution was stirred at RT for 18 hours. The reaction mixture was washed three times with water and the organic layer dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in DCM, to give the desired material as a yellow solid (2.84 g). NMR Spectrum: 1H NMR (400.13 MHz, CDCl3) δ 2.57 (3H, s), 3.58 - 3.69 (8H, m), 4.56 (2H, s), 6.58 (IH, s), 7.30 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 375; HPLC tR = 2.14 min.
The preparation of 2,4-dichloro-6-[(4-methyl-l,3-thiazol-2-yl)sulfonylmethyl]pyrimidine was described previously.
Example 43: 3-Cvclopropyl-l-[4-[4-[l-f3-hvdroxypropylsulfonyl)cvclobutyll-6-[(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll urea
Figure imgf000652_0001
Cyclopropylamine (0.122 mL, 1.76 mmol) was added in one portion to a stirred solution of phenyl 7V-[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate (0.2 g, 0.35 mmol) and triethylamine (0.148 mL, 1.06 mmol) in DMA (35.3 mL) at RT. The resulting solution was stirred at 500C for 24 hours. The reaction mixture was then concentrated, and the crude product was purified by flash silica chromatography, elution gradient 0 to 5% methanol in DCM, to give a clear oil which was then triturated with diethyl ether to give the desired material as a white solid (0.126 g). NMR Spectrum: 1R NMR (400.13 MHz, CDCl3) δ 0.60 - 0.67 (2H, m), 0.74 - 0.83 (2H, m), 1.33 (3H, d), 1.94 - 2.01 (3H, m), 2.16 - 2.25 (2H, m), 2.57 - 2.63 (IH, m), 2.80 - 2.88 (2H, m), 2.98 - 3.01 (2H, m), 3.09 - 3.16 (2H, m), 3.28 - 3.35 (IH, m), 3.56 - 3.62 (3H, m), 3.71 - 3.75 (IH, m), 3.81 (IH, d), 4.01 - 4.05 (IH, m), 4.16 (IH, d), 4.46 (IH, d), 5.30 (IH, s), 6.55 (IH, s), 7.31 (IH, s), 7.48 (2H, d), 8.32 (2H, d).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 530; HPLC tR = 2.09 min. mTOR Kinase Assay (Echo): 0.00539μM
The compounds below were prepared in an analogous fashion from either phenyl 7V-[4-[4-[l- (3-hydroxypropylsulfonyl)cyclobutyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate or phenyl Λ/-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopentyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate using the appropriate amine.
Figure imgf000653_0001
Figure imgf000654_0001
Figure imgf000655_0001
Figure imgf000656_0001
* The reactions were stirred in NMP at 7O0C for 2.5 hours
Example 43a: 1H NMR (400.13 MHz, CDCl3) δ 1.30 (3H, d), 1.94 - 1.99 (3H, m), 2.14 - 2.23
(IH, m), 2.73 (3H, d), 2.79 - 2.90 (3H, m), 2.96 - 3.04 (2H, m), 3.06 - 3.13 (2H, m), 3.24 - 3.32 (IH, m), 3.54 - 3.59 (3H, m), 3.68 - 3.72 (IH, m), 3.78 (IH, d), 3.98 - 4.02 (IH, m), 4.10
- 4.15 (IH, m), 4.43 (IH, s), 5.49 (IH, q), 6.52 (IH, s), 7.41 (2H, d), 7.62 (IH, s), 8.29 (2H, d). mTOR Kinase Assay (Echo): 0.00479μM
Example 43b: 1H NMR (400.13 MHz, CDCl3) δ 1.28 (3H, d), 1.90 - 2.00 (3H, m), 2.08 - 2.22 (2H, m), 2.79 - 2.88 (2H, m), 2.94 - 3.09 (4H, m), 3.24 - 3.33 (3H, m), 3.45 - 3.56 (6H, m), 3.68 (IH, d), 3.76 (IH, d), 3.98 (IH, d), 4.11 (IH, d), 4.42 (IH, s), 5.84 (IH, t), 6.50 (IH, s), 7.39 (2H, d), 7.89 (IH, s), 8.27 (2H, d). mTOR Kinase Assay (Echo): 0.00751 μM
Example 43c: 1R NMR (400.13 MHz, CDCl3) δ 1.31 (3H, d), 1.93 - 2.04 (4H, m), 2.16 - 2.25 (IH, m), 2.55 - 2.60 (2H, m), 2.79 - 2.88 (2H, m), 2.97 - 3.06 (2H, m), 3.09 - 3.15 (2H, m),
3.26 - 3.33 (IH, m), 3.43 - 3.49 (2H, m), 3.53 - 3.63 (3H, m), 3.69 - 3.73 (IH, m), 3.79 (IH, d), 3.99 - 4.03 (IH, m), 4.15 (IH, d), 4.44 (IH, s), 5.87 (IH, t), 6.55 (IH, s), 7.42 (2H, d),
7.54 (IH, s), 8.31 (2H, d). mTOR Kinase Assay (Echo): 0.0288μM Example 43d: 1H NMR ^OO- B MHZ5 CDCI3) O 1.30 (3H, d), 1.95 - 2.01 (3H, m), 2.14 - 2.26 (IH, m), 2.78 - 2.91 (2H, m), 3.03 - 3.07 (2H, m), 3.08 - 3.15 (2H, m), 3.25 - 3.32 (IH, m), 3.39 (IH, s), 3.55 - 3.59 (3H, m), 3.67 (3H, s), 3.68 - 3.71 (IH, m), 3.78 (IH, d), 3.98 - 4.02 (IH, m), 4.11 - 4.14 (IH, m), 4.42 (IH, s), 6.53 (IH, s), 7.18 (IH, s), 7.39 (2H, d), 7.44 (IH, s), 7.55 (IH, s), 7.84 (IH, s), 8.29 (2H, d). mTOR Kinase Assay (Echo): 0.01 lμM
Example 43e: 1R NMR (400.13 MHz, CDCl3) δ 1.29 (3H, d), 1.92 - 1.99 (3H, m), 2.13 - 2.20 (IH, m), 2.75 - 2.84 (2H, m), 2.96 - 3.01 (2H, m), 3.05 - 3.12 (2H, m), 3.23 - 3.30 (IH, m), 3.48 - 3.55 (4H, m), 3.69 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.11 (IH, d), 4.36 - 4.41 (3H, m), 6.51 (IH, s), 6.91 (2H, s), 7.00 (IH, t), 7.34 (2H, d), 8.23 - 8.25 (2H, m), 8.63 (IH, s). mTOR Kinase Assay (Echo): 0.188μM
Example 43f: 1H NMR (400.13 MHz, CDCl3) δ 0.53 - 0.56 (2H, m), 0.73 - 0.76 (2H, m), 1.32 (3H, d), 1.63 - 1.66 (2H, m), 1.91 - 1.97 (4H, m), 2.57 - 2.65 (3H, m), 2.73 - 2.80 (3H, m), 3.05 - 3.11 (2H, m), 3.26 - 3.33 (IH, m), 3.55 - 3.62 (3H, m), 3.71 - 3.75 (IH, m), 3.81 (IH, d), 4.00 - 4.04 (IH, m), 4.17 (IH, d), 4.46 (IH, s), 5.81 (IH, s), 6.66 (IH, s), 7.49 (2H, d), 7.82 (IH, s), 8.31 (2H, d). mTOR Kinase Assay (Echo): 0.0392μM
Example 43g: 1R NMR (400.13 MHz, CDCl3) δ 1.28 (3H, d), 1.58 - 1.64 (2H, m), 1.85 - 1.95 (4H, m), 2.53 - 2.63 (3H, m), 2.67 - 2.78 (3H, m), 3.12 - 3.16 (2H, m), 3.26 - 3.30 (3H, m), 3.52 - 3.58 (5H, m), 3.36 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.12 (IH, d), 4.41 (IH, s), 5.05 (IH, s), 5.90 (IH, t), 6.61 (IH, s), 7.41 (2H, d), 7.96 (IH, s), 8.29 (2H, d). mTOR Kinase Assay (Echo): 0.029μM
Example 43h: 1H NMR (400.13 MHz, CDCl3) δ 1.31 (3H, d), 1.64 - 1.67 (3H, m), 1.92 - 1.99 (5H, m), 2.47 - 2.64 (4H, m), 2.74 - 2.79 (2H, m), 3.13 - 3.17 (2H, m), 3.26 - 3.33 (IH, m), 3.43 - 3.48 (2H, m), 3.53 - 3.63 (3H, m), 3.69 - 3.73 (IH, m), 3.79 (IH, d), 3.99 - 4.03 (IH, m), 4.15 (IH, d), 4.44 (IH, s), 5.89 (IH, t), 6.66 (IH, s), 7.42 (2H, d), 7.58 (IH, s), 8.32 (2H, d). mTOR Kinase Assay (Echo): 0.133μM Example 43i: 1R NMR (400.13 MHz, CDCl3) δ 1.29 (3H, d), 1.54 - 1.62 (4H, m), 1.89 - 1.99 (4H, m), 2.55 - 2.64 (2H, m), 2.70 - 2.80 (2H, d), 3.12 - 3.19 (2H, m), 3.24 - 3.29 (4H, m), 3.52 - 3.59 (5H, m), 3.68 - 3.83 (3H, m), 3.98 (IH, d), 4.11 - 4.14 (IH, m), 4.42 (IH, s), 5.75 (IH, t), 6.62 (IH, s), 7.42 (2H, d), 7.79 (IH, s), 8.29 (2H, d). mTOR Kinase Assay (Echo): 0.102μM
Example 43j: 1H NMR (400.13 MHz, DMSO-d6) δ 1.07 (3H, t), 1.23 (3H, d), 1.72 - 1.81 (2H, m), 1.88 - 1.96 (IH, m), 1.99 - 2.10 (IH, m), 2.75 - 2.86 (2H, m), 2.90 - 2.96 (2H, m), 2.98 - 3.04 (2H, m), 3.10 - 3.16 (2H, m), 3.19 - 3.25 (IH, m), 3.35 - 3.42 (2H, m), 3.46 - 3.55 (IH, m), 3.65 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.24 (IH, d), 4.50 - 4.62 (2H, m), 6.17 (IH, s), 6.72 (IH, s), 7.49 (2H, d), 8.21 (2H, d), 8.66 (IH, s)
Example 43k: 1H NMR (400.13 MHz, DMSOd6) δ 0.89 (3H, t), 1.24 (3H, d), 1.39 - 1.50 (2H, m), 1.73 - 1.81 (2H, m), 1.86 - 1.96 (IH, m), 2.00 - 2.09 (IH, m), 2.77 - 2.87 (2H, m), 2.90 - 2.97 (2H, m), 2.97 - 3.08 (4H, m), 3.19 - 3.25 (IH, m), 3.35 - 3.41 (2H, m), 3.46 - 3.55 (IH, m), 3.65 (IH, d), 3.77 (IH, d), 3.97 (IH, d), 4.24 (IH, d), 4.53 - 4.60 (2H, m), 6.20 (IH, t), 6.71 (IH, s), 7.49 (2H, d), 8.22 (2H, d), 8.65 (IH, s)
Example 431: 1U NMR (400.13 MHz, DMSOd6) δ 8.21 (2H, d), 1.23 (3H, d), 1.55 - 1.64 (2H, m), 1.74 - 1.80 (2H, m), 1.88 - 1.98 (IH, m), 2.01 - 2.10 (IH, m), 2.77 - 2.87 (2H, m), 2.90 - 2.97 (2H, m), 2.98 - 3.04 (2H, m), 3.13 - 3.24 (3H, m), 3.34 - 3.42 (2H, m), 3.45 - 3.54 (3H, m), 3.65 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.24 (IH, d), 4.47 (IH, t), 4.53 - 4.59 (2H, m), 6.20 (IH, t), 6.71 (IH, s), 7.49 (2H, d), 8.71 (IH, s)
Example 43m: 1H NMR (400.13 MHz, DMSOd6) δ 1.24 (3H, d), 1.74 - 1.81 (2H, m), 1.88 - 1.97 (IH, m), 2.01 - 2.11 (IH, m), 2.78 - 2.87 (2H, m), 2.90 - 2.99 (2H, m), 3.00 - 3.06 (2H, m), 3.19 - 3.26 (IH, m), 3.36 - 3.42 (2H, m), 3.47 - 3.56 (IH, m), 3.66 (IH, d), 3.77 (IH, d), 3.99 (IH, d), 4.26 (IH, d), 4.53 - 4.61 (2H, m), 6.75 (IH, s), 6.87 (IH, s), 7.57 (2H, d), 8.30 (2H, d), 8.76 (IH, s), 9.08 (IH, s), 9.62 (IH, s)
Example 43n: 1H NMR (400.13 MHz, DMSOd6) δ 1.24 (3H, d), 1.73 - 1.81 (2H, m), 1.86 - 1.96 (IH, m), 2.01 - 2.10 (IH, m), 2.78 - 2.86 (2H, m), 2.90 - 2.98 (2H, m), 2.97 - 3.05 (2H, m), 3.13 - 3.26 (IH, m), 3.34 - 3.41 (2H, m), 3.44 - 3.55 (3H, m), 3.65 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.24 (IH, d), 4.42 (IH, t), 4.51 - 4.59 (2H, m), 6.43 (IH, t), 6.72 (IH, s), 7.50 (2H, d), 8.23 (2H, d), 8.81 (IH, s)
Example 43o: 1U NMR (400.13 MHz, DMSOd6) δ 1.24 (3H, d), 1.72 - 1.81 (2H, m), 1.88 - 1.96 (IH, m), 2.02 - 2.10 (IH, m), 2.78 - 2.87 (2H, m), 2.91 - 2.98 (2H, m), 2.98 - 3.05 (2H, m), 3.17 - 3.26 (IH, m), 3.35 - 3.43 (2H, m), 3.47 - 3.60 (3H, m), 3.65 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.24 (IH, d), 4.53 - 4.60 (2H, m), 5.91 - 6.27 (IH, m), 6.54 (IH, t), 6.73 (IH, s), 7.51 (2H, d), 8.24 (2H, d), 8.93 (IH, s) Example 43p: Η NMR (400.13 MHz, DMSO-d«) δ 1.23 (3H, d), 1.71 - 1.81 (2H, m), 1.86 -
1.96 (IH, m), 2.02 - 2.11 (IH, m), 2.75 - 2.88 (2H, m), 2.91 - 2.98 (2H, m), 2.99 - 3.05 (2H, m), 3.17 - 3.26 (IH, m), 3.27 - 3.31 (2H, m), 3.35 - 3.42 (2H, m), 3.47 - 3.54 (IH, m), 3.65 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.24 (IH, d), 4.51 - 4.60 (2H, m), 4.95 (IH, t), 6.00 (IH, s), 6.71 (IH, s), 7.45 (2H, d), 8.20 (2H, d), 8.73 (IH, s)
Example 43q: 1H NMR (400.13 MHz, DMSOd6) δ 1.08 (3H, d), 1.23 (3H, d), 1.72 - 1.82 (2H, m), 1.89 - 1.95 (IH, m), 2.02 - 2.09 (IH, m), 2.75 - 2.85 (2H, m), 2.90 - 2.97 (2H, m),
2.97 - 3.06 (2H, m), 3.17 - 3.25 (IH, m), 3.33 - 3.41 (2H, m), 3.48 - 3.56 (IH, m), 3.63 - 3.79 (4H, m), 3.98 (IH, d), 4.24 (IH, d), 4.51 - 4.59 (2H, m), 4.78 (IH, t), 6.10 (IH, t), 6.72 (IH, s), 7.47 (2H, d), 8.22 (2H, d), 8.71 (IH, s)
Example 43r: 1U NMR (400.13 MHz, DMSOd6) δ 1.14 (3H, d), 1.29 (3H, d), 1.78 - 1.88 (2H, m), 1.94 - 2.03 (IH, m), 2.07 - 2.16 (IH, m), 2.81 - 2.93 (2H, m), 2.96 - 3.03 (2H, m), 3.03 - 3.10 (2H, m), 3.23 - 3.32 (IH, m), 3.38 - 3.48 (3H, m), 3.53 - 3.61 (IH, m), 3.68 - 3.84 (4H, m), 4.03 (IH, d), 4.30 (IH, d), 4.58 - 4.65 (2H, m), 4.83 (IH, t), 6.15 (IH, t), 6.77 (IH, s), 7.53 (2H, d), 8.27 (2H, d), 8.77 (IH, s)
Example 43s: 1R NMR (400.13 MHz, DMSOd6) δ 1.25 (3H, d), 1.74 - 1.82 (2H, m), 1.89 -
1.98 (IH, m), 2.03 - 2.10 (IH, m), 2.77 - 2.90 (2H, m), 2.92 - 3.00 (2H, m), 3.02 - 3.07 (2H, m), 3.20 - 3.26 (IH, m), 3.36 - 3.44 (2H, m), 3.46 - 3.56 (IH, m), 3.66 (IH, d), 3.78 (IH, d),
3.99 (IH, d), 4.27 (IH, d), 4.51 - 4.63 (2H, m), 6.77 (IH, s), 7.63 (2H, d), 8.28 - 8.39 (3H, m), 9.46 (IH, s)
Example 43t: 1H NMR (400.13 MHz, DMSOd6) δ 1.25 (3H, d), 1.74 - 1.83 (2H, m), 1.88 - 1.96 (IH, m), 2.00 - 2.09 (IH, m), 2.77 - 2.88 (2H, m), 2.91 - 2.98 (2H, m), 3.00 - 3.07 (2H, m), 3.20 - 3.25 (IH, m), 3.37 - 3.43 (2H, m), 3.46 - 3.56 (IH, m), 3.66 (IH, d), 3.78 (IH, d), 3.99 (IH, d), 4.26 (IH, d), 4.53 - 4.62 (2H, m), 6.76 (IH, s), 7.14 (IH, s), 7.40 (IH, s), 7.59 (2H, d), 8.31 (2H, d), 9.20 (IH, s)
The preparation of phenyl Λ/-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below: Phenyl N- \4- \4- \ 1 -(3 -hydroxypropylsulfonyPcyclobutyli -6- r(3ιSy3-methylmorpholin-4- yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000660_0001
Phenyl chloro formate (0.632 niL, 5.04 mmol) was added dropwise to 3-[l-[2-(4- aminoplienyl)-6-[(35)-3-metliylmorpliolin-4-yl]pyrimidin-4-yl]cyclobutyl]sulfonylpropan- 1 -
01 (1.5 g, 3.36 mmol) and sodium hydrogen carbonate (0.423 g, 5.04 mmol) in dioxane (33.6 mL), cooled to 1O0C under a nitrogen atmosphere. The resulting mixture was stirred at RT for
2 hours. The reaction mixture was diluted with ethyl acetate (300 mL), and washed with water (150 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product as a yellow gum. This material was used directly in the next step without further purification. LCMS Spectrum: m/z (ESI+) (M+H)+ = 565; HPLC tR = 2.71 min.
3-ri-r2-(4-Aminophenyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4- yll cyclobutyll sulfonylpropan- 1 -ol
Figure imgf000660_0002
A solution of tetrabutylammonium fluoride (18.25 mL, 18.25 mmol) in THF was added to a stirred solution of 4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-[3-tri(propan-2- yl)silyloxypropylsulfonyl]cyclobutyl]pyrimidin-2-yl] aniline (2.2 g, 3.65 mmol) in THF (24.33 mL) at RT. The resulting solution was stirred at RT for 2 hours. The reaction mixture was concentrated and diluted with ethyl acetate (150 mL), and washed with water (100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane, to give the desired material as a pale yellow oil which solidified on standing (1.50 g).
NMR Spectrum: 1H NMR (400.13 MHz, CDCl3) δ 1.33 (3H, d), 1.57 (IH, t), 1.94 - 2.04 (3H, m), 2.18 - 2.25 (IH, m), 2.82 - 2.88 (2H, m), 2.98 (2H, t), 3.09 - 3.16 (2H, m), 3.28 - 3.35 (IH, m), 3.63 (3H, q), 3.73 - 3.76 (IH, m), 3.82 (IH, d), 3.90 (2H, s), 4.01 - 4.05 (IH, m), 4.16 (IH, d), 4.47 (IH, d), 6.51 (IH, s), 6.70 - 6.72 (2H, m), 8.22 - 8.24 (2H, m). LCMS Spectrum: m/z (ESI+) (M+H)+ = 447; HPLC tR = 2.09 min.
4-r4-r(35)-3-Methylmorpholin-4-yl1-6-ri-r3-tri(propan-2- vπsilyloxypropylsulfonyllcvclobutyllpyrimidin-2-yllaniline
Figure imgf000661_0001
Dichlorobis(triphenylphosphine)palladium(II) (0.132 g, 0.19 mmol) was added in one portion to a carefully degassed solution of 3-[l-[2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin- 4-yl]cyclobutyl]sulfonylpropoxy-tri(propan-2-yl)silane (2.05 g, 3.75 mmol), 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.233 g, 5.63 mmol) and 2M aqueous sodium carbonate solution (6.57 mL, 13.14 mmol) in a solvent mixture of DMF (6.82 mL), water (17.06 mL), ethanol (6.82 mL) and DME (6.82 mL). The resulting mixture was stirred at 800C for 4 hours. The cooled reaction mixture was diluted with ethyl acetate (200 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 75% ethyl acetate in isohexane, to give the desired material as a pale yellow foam which solidified under vacuum (2.2 g). NMR Spectrum: 1H NMR (400.13 MHz, CDCl3) δ 0.89 - 0.98 (21H, m), 1.32 (3H, s), 1.92 - 1.99 (3H, m), 2.15 - 2.25 (IH, m), 2.84 - 2.87 (2H, m), 2.91 - 2.95 (2H, m), 3.07 - 3.13 (2H, m), 3.26 - 3.34 (IH, m), 3.57 - 3.62 (IH, m), 3.65 (2H, t), 3.74 (IH, dd), 3.81 (IH, d), 3.88 (2H, s), 4.03 (IH, dd), 4.15 (IH, d), 4.47 (IH, s), 6.52 (IH, s), 6.68 - 6.70 (2H, m), 8.21 - 8.23 (2H, m). LCMS Spectrum: m/z (ESI+) (M+H)+ = 603; HPLC tR = 3.82 min. 3-ri-r2-Chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-yllcvclobutyllsulfonylpropoxy- tri(propan-2-yl)silane
Figure imgf000662_0001
Aqueous sodium hydroxide solution (50% w/w, 48.7 mL) was added to 3-[[2-chloro-6-[(35)- 3-methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]propoxy-tri(propan-2-yl)silane (5.6 g, 11.06 mmol), 1,3-dibromopropane (3.37 mL, 33.19 mmol) and tetrabutylammonium bromide (0.357 g, 1.11 mmol) in toluene (221 mL) at RT. The resulting suspension was stirred at 45°C for 1 hour. Water was added to the solution. The toluene was washed with water twice, dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a colourless gum (2.05 g).
NMR Spectrum: 1H NMR (400.13 MHz. CDCh) δ 0.97 - 1.08 (21H, m), 1.32 (3H, d), 1.94 - 2.01 (3H, m), 2.21 - 2.23 (IH, m), 2.70 - 2.76 (2H, m), 2.93 (2H, q), 3.03 - 3.08 (2H, m), 3.28 - 3.32 (IH, m), 3.51 - 3.57 (IH, m), 3.66 - 3.70 (IH, m), 3.76 (3H, t), 3.98 - 4.02 (2H, m), 4.32 (IH, s), 6.55 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 546; HPLC tR = 4.05 min.
The preparation of 3-[[2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4- yl]methylsulfonyl]propoxy-tri(propan-2-yl)silane was described earlier.
The preparation of phenyl Λ/-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopentyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below: Phenyl N- \4- \4- \ 1 -(3-hvdroxypropylsulfonyl)cvclopentyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000663_0001
Phenyl chloroformate (1.512 mL, 12.05 mmol) was added dropwise to 3-[l-[2-(4- aminophenyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopentyl]sulfonylpropan- 1 -
01 (3.7 g, 8.03 mmol) and sodium hydrogen carbonate (1.012 g, 12.05 mmol) in dioxane (80 mL) cooled to 1O0C under a nitrogen atmosphere. The resulting mixture was stirred at RT for
2 hours. The reaction mixture was diluted with ethyl acetate (300 mL), and washed with water (150 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude solid was triturated with a mixture of diethyl ether and isohexane to give the desired material as a yellow solid which was used without further purification (3.60 g). LCMS Spectrum: m/z (ESI+) (M+H)+ = 581; HPLC tR = 2.83 min.
3-ri-r2-(4-Aminophenyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4- yllcyclopentyllsulfonylpropan-l-ol
A solution of tetrabutylammonium fluoride (46.2 mL, 46.20 mmol) in THF was added to a stirred solution of 4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-[3-tri(propan-2- yl)silyloxypropylsulfonyl]cyclopentyl]pyrimidin-2-yl] aniline (5.7 g, 9.24 mmol) in THF (61.6 mL) at RT. The resulting solution was stirred at RT for 2 hours. The reaction mixture was concentrated and diluted with ethyl acetate (250 mL), and washed with water (150 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane, to give the desired material as a pale yellow oil which solidified on standing (3.70 g).
NMR Spectrum: 1U NMR (400.13 MHz, CDCl3) δ 1.32 (3H, d), 1.59 (IH, t), 1.61 - 1.70 (2H, m), 1.92 - 1.98 (4H, m), 2.57 - 2.66 (2H, m), 2.74 - 2.83 (2H, m), 3.07 (2H, t), 3.27 - 3.34 (IH, m), 3.57 - 3.65 (3H, m), 3.73 - 3.77 (IH, m), 3.82 (IH, d), 3.90 (2H, s), 4.01 - 4.05 (IH, m), 4.11 - 4.18 (IH, m), 4.46 (IH, d), 6.63 (IH, s), 6.71 (2H, d), 8.23 (2H, d). LCMS Spectrum: m/z (ESI+) (M+H)+ = 461; HPLC tR = 2.18 min.
4-r4-r(35)-3-Methylmorpholin-4-yl1-6-ri-r3-tri(propan-2- vπsilyloxypropylsulfonyllcvclopentyllpyrimidin-2-yllaniline
Figure imgf000664_0001
Dichlorobis(triphenylphosphine)palladium(II) (0.345 g, 0.49 mmol) was added in one portion to a carefully degassed solution of 3-[l-[2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin- 4-yl]cyclopentyl]sulfonylpropoxy-tri(propan-2-yl)silane (5.5 g, 9.82 mmol), 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (3.23 g, 14.73 mmol) and 2M aqueous sodium carbonate solution (17.18 mL, 34.36 mmol) in a solvent mixture of DMF (17.85 mL), water (44.6 mL), ethanol (17.85 mL) and DME (17.85 mL). The resulting mixture was stirred at 800C for 4 hours. The cooled reaction mixture was diluted with ethyl acetate (200 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 75% ethyl acetate in DCM, to give the desired material as a pale yellow foam which solidified under vacuum (5.70 g). NMR Spectrum: 1H NMR (400.13 MHz, CDCl3) δ 0.90 - 0.98 (21H, m), 1.32 (4H, t), 1.63 - 1.66 (2H, m), 1.89 - 1.96 (4H, m), 2.59 - 2.64 (2H, m), 2.77 - 2.81 (2H, m), 2.98 - 3.02 (2H, m), 3.29 - 3.32 (IH, m), 3.57 - 3.63 (IH, m), 3.66 (2H, t), 3.72 - 3.76 (IH, m), 3.81 (IH, d), 3.88 (2H, s), 4.01 - 4.05 (IH, m), 4.15 (IH, d), 4.45 (IH, s), 6.66 (IH, s), 6.69 (2H, d), 8.22 (2H, d). LCMS Spectrum: m/z (ESI+) (M+H)+ = 617; HPLC tR = 3.91 min. 3-ri-r2-Chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-yllcvclopentyllsulfonylpropoxy- tri(propan-2-yl)silane
Figure imgf000665_0001
Aqueous sodium hydroxide solution (50% w/w aq, 48.7 mL) was added to 3-[[2-chloro-6- [(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]propoxy-tri(propan-2-yl)silane (5.6 g, 11.06 mmol), 1 ,4-dibromobutane (3.93 mL, 33.19 mmol) and tetrabutylammonium bromide (0.357 g, 1.11 mmol) in toluene (221 mL) at RT. The resulting suspension was stirred at 45°C for 1 hour and the toluene washed with water twice, dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a white solid (5.57 g). NMR Spectrum: 1H NMR (400.13 MHz. CDCh) δ 0.98 - 1.08 (21H, m), 1.31 (3H, d), 1.60 - 1.65 (2H, m), 1.88 - 1.99 (4H, m), 2.56 - 2.61 (4H, m), 2.97 - 3.00 (2H, m), 3.28 - 3.32 (IH, m), 3.51 - 3.58 (IH, m), 3.67 - 3.71 (IH, m), 3.76 (3H, t), 3.98 - 4.02 (2H, m), 4.31, (IH, s), 6.71 (IH, s).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 560; HPLC tR = 3.86 min.
The preparation of 3-[[2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4- yl]methylsulfonyl]propoxy-tri(propan-2-yl)silane was described earlier.
Example 44 : N- [2- [1- [2- [4-(C vclopropylcarbamoylamino)phenyll -6- [(351-3- methylmorpholin-4-yll pyrimidin-4-yll cyclopropyll sulfonylethyll acetamide
Figure imgf000665_0002
Cyclopropylamine (0.120 mL, 1.73 mmol) was added in one portion to a stirred solution of phenyl 7V-[4-[4-[ 1 -(2-acetamidoethylsulfonyl)cyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate (0.2 g, 0.35 mmol) in THF (34.5 mL) at RT. The resulting solution was stirred at 400C for 24 hours. The reaction mixture was then concentrated, and the crude product was purified by flash silica chromatography, elution gradient 0 to 5% methanol in DCM, to give the desired material as a white solid (0.135 g). NMR Spectrum: 1R NMR (400.13 MHz, CDCl3) δ 0.66 - 0.70 (2H, m), 0.84 - 0.89 (2H, m), 1.34 (3H, d), 1.49 - 1.58 (2H, m), 1.82 - 1.85 (2H, m), 1.93 (3H, s), 2.61 - 2.66 (IH, m), 3.29 3.36 (IH, m), 3.48 - 3.51 (2H, m), 3.56 - 3.63 (IH, m), 3.72 - 3.75 (IH, m), 3.79 - 3.84 (3H, m), 4.03 - 4.06 (IH, m), 4.15 (IH, d), 4.48 (IH, s), 5.05 (IH, s), 6.67 (IH, s), 6.74 (IH, d), 7.13 (IH, s), 7.51 (2H, d), 8.26 (2H, d).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 543; HPLC tR = 1.86 min. mTOR Kinase Assay (Echo): 0.0234μM
The preparation of phenyl Λ/-[4-[4-[l-(2-acetamidoethylsulfonyl)cyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below:
Phenyl Λ/-[4-[4-[ 1 -(2-acetamidoethylsulfonyl)cvclopropyll-6-r(36f)-3-methylmorpholin-4- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000666_0001
Phenyl chloro formate (0.328 mL, 2.61 mmol) was added dropwise to 7V-[2-[l-[2-(4- aminophenyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4- yl]cyclopropyl]sulfonylethyl]acetamide (800 mg, 1.74 mmol) and sodium hydrogen carbonate (219 mg, 2.61 mmol) in dioxane (174 mL) cooled to 1O0C under a nitrogen atmosphere. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (300 mL), and washed with water (150 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude solid was triturated with a mixture of diethyl ether and isohexane to give the desired material as a yellow solid (741 mg). This material was used directly without further purification.
LCMS Spectrum: m/z (ESI+) (M+H)+ = 580; HPLC tR = 2.44 min.
N-[2-[l-[2-(4-Aminophenvπ-6-[(3y)-3-methylmorpholin-4-yllpyrimidin-4- yll c ycloprop yll sulfonylethyll acetamide
Figure imgf000667_0001
Dichlorobis(triphenylphosphine)palladium(II) (0.174 g, 0.25 mmol) was added in one portion to a carefully degassed solution of Λ/-[2-[l-[2-chloro-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-4-yl]cyclopropyl]sulfonylethyl]acetamide (2 g, 4.96 mmol), 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.414 g, 6.45 mmol) and 2M aqueous sodium carbonate solution (8.69 mL, 17.37 mmol) in a solvent mixture of DMF (9.03 mL), water (22.56 mL), ethanol (9.03 mL) and DME (9.03 mL). The resulting mixture was stirred at 800C for 4 hours. The cooled reaction mixture was diluted with ethyl acetate (200 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 75% ethyl acetate in DCM, to give the desired material as a pale yellow foam which solidified under vacuum (1.805 g). NMR Spectrum: 1U NMR (400.13 MHz, CDCl3) δ 1.33 (3H, d), 1.49 - 1.51 (2H, m), 1.80 - 1.84 (2H, m), 1.93 (3H, s), 3.28 - 3.35 (IH, m), 3.47 - 3.50 (2H, m), 3.55 - 3.62 (IH, m), 3.71 - 3.75 (IH, m), 3.79 - 3.83 (3H, m), 3.92 (2H, s), 4.01 - 4.05 (IH, m), 4.10 - 4.17 (IH, m), 4.47 (IH, s), 6.61 (IH, s), 6.69 - 6.72 (2H, m), 6.81 (IH, s), 8.13 - 8.16 (2H, m). LCMS Spectrum: m/z (ESI+) (M+H)+ = 460; HPLC tR = 1.79 min. N- M- r 1 -[2-ChIQrQ-O- IY35V3 -methylmorpholin^-yllpyrimidin^- yll c ycloprop yll sulfonylethyll acetamide
Figure imgf000668_0001
Aqueous sodium hydroxide solution (50% aq, 8.52 mL) was added to 7V-[2-[[2-chloro-6-[(35)- 3-methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]ethyl]acetamide (3.21 g, 8.52 mmol), 1 ,2-dibromoethane (1.468 mL, 17.03 mmol) and tetrabutylammonium bromide (0.549 g, 1.70 mmol) in toluene (122 mL) at RT. The resulting solution was stirred at 600C for 3 hours. The reaction mixture was evaporated to dryness and redissolved in ethyl acetate (200 mL), and washed sequentially with water (200 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in isohexane, to give the desired material as a yellow solid (2.04 g).
NMR Spectrum: 1R NMR (400.13 MHz, CDCl3) δ 1.34 (3H, d), 1.44 - 1.47 (2H, m), 1.80 - 1.84 (2H, m), 2.02 (3H, s), 3.27 - 3.34 (IH, m), 3.35 - 3.38 (2H, m), 3.51 - 3.57 (IH, m), 3.66 - 3.70 (IH, m), 3.75 - 3.80 (3H, m), 3.99 - 4.03 (2H, m), 4.34 (IH, s), 6.73 (IH, s), 6.88 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 403; HPLC tR = 1.51 min.
N-r2-rr2-Chloro-6-r(3y)-3-methylmorpholin-4-yl1pyrimidin-4- yllmethylsulfonyll ethyl! acetamide
Figure imgf000668_0002
N-[2-[[2-Chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4- yljmethylsulfanyl] ethyl] acetamide (3.24 g, 9.40 mmol) was dissolved in dioxane (28.2 mL) and 2N sulfuric acid (0.282 mL) was added. The solution was heated to 55°C. Sodium tungstate dihydrate (0.062 g, 0.19 mmol) dissolved in water (2.82 mL) was added to the solution and allowed to stir for 5 minutes. Hydrogen peroxide (5.42 mL, 56.37 mmol) was then added dropwise over several minutes. The solution was heated at 55°C for 2.5 hours. The heat was removed and water (300 mL) was added. The resulting suspension was stirred for 30 minutes. The solids were filtered, rinsed with water and dried in a vacuum oven at 5O0C overnight, to give the desired material as a white solid (3.30 g). NMR Spectrum: 1R NMR (400.13 MHz, DMSO-de) δ 1.22 (3H, d), 1.82 (3H, s), 3.19 - 3.26 (IH, m), 3.36 - 3.43 (2H, m), 3.45 - 3.51 (3H, m), 3.58 - 3.62 (IH, m), 3.73 (IH, d), 3.92 - 3.96 (2H, m), 4.30 (IH, s), 4.49 (2H, s), 6.92 (IH, s), 8.11 (IH, t). LCMS Spectrum: m/z (ESI+) (M+H)+ = 377; HPLC tR = 1.37 min.
N-r2-rr2-Chloro-6-r(3y)-3-methylmorpholin-4-yl1pyrimidin-4- yllmethylsulfanyl] ethyl] acetamide
Figure imgf000669_0001
7V-Acetylcysteamine (1.804 mL, 16.97 mmol) was added to 2-chloro-4-(iodomethyl)-6-[(35)- 3-methylmorpholin-4-yl]pyrimidine (4 g, 11.31 mmol) and DIPEA (4.93 mL, 28.28 mmol) in acetonitrile (226 mL) at RT. The resulting solution was stirred at RT for 3 hours. The solvent was removed in vacuo, and the crude material was then purified by flash silica chromatography, eluting with ethyl acetate, to give the desired material as a white solid (3.24 g).
NMR Spectrum: 1R NMR (400.13 MHz, CDCl3) δ 1.33 (3H, d), 2.01 (3H, s), 2.71 (2H, t), 3.25 - 3.33 (IH, m), 3.48 - 3.58 (3H, m), 3.59 (2H, s), 3.67 - 3.71 (IH, m), 3.79 (IH, d), 3.99 - 4.03 (2H, m), 4.33 (IH, s), 6.40 (IH, s), 6.55 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 345; HPLC tR = 1.54 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier. Example 45 : N- [2- [ 1- [2- [4-(Ethylcarbamoylamino)phenyll -6- [(3S)-3-methylmorpholin-4- yll pyrimidin-4-yll cyclopr opyll sulfonylethyll acetamide
Figure imgf000670_0001
A solution of ethylamine (2M in THF, 0.863 mL, 1.73 mmol) was added in one portion to a stirred solution of phenyl N-[4-[4-[l-(2-acetamidoethylsulfonyl)cyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (0.2 g, 0.35 mmol) in THF (34.5 mL) at RT. The resulting solution was stirred at 500C for 2 hours. The product was concentrated in vacuo, then purified by flash silica chromatography, elution gradient 0 to 10% methanol in DCM, to give a residue that was triturated with acetonitrile to give the desired material as a white solid (0.147 g).
NMR Spectrum: 1R NMR (400.13 MHz, CDC13) δ 1.16 (3H, t), 1.33 (3H, d), 1.48 - 1.51 (2H, m), 1.81 - 1.84 (2H, m), 1.93 (3H, s), 3.27 - 3.34 (3H, m), 3.49 - 3.52 (2H, m), 3.55 - 3.60 (IH, m), 3.70 - 3.74 (IH, m), 3.78 - 3.83 (3H, m), 4.01 - 4.05 (IH, m), 4.10 - 4.16 (IH, m), 4.46 (IH, s), 5.18 (IH, t), 6.64 (IH, s), 6.89 (IH, t), 7.15 (IH, s), 7.42 (2H, d), 8.23 (2H, d). LCMS Spectrum: m/z (ESI+) (M+H)+ = 531; HPLC tR = 1.87 min. mTOR Kinase Assay (Echo): 0.0219μM
The preparation of phenyl Λ/-[4-[4-[l-(2-acetamidoethylsulfonyl)cyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate was described earlier.
Example 46: 2-[l-[2-[4-(Cyclopropylcarbamoylamino)phenyll-6-morpholin-4- ylpyrimidin-4-yll cyclopropyll sulfonylacetamide
Figure imgf000670_0002
Bis(triphenylphosphine)palladium(II) chloride (19.03 mg, 0.03 mmol) was added to 2-[l-(2- chloro-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]sulfonylacetamide (146 mg, 0.40 mmol), l-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenyl)urea (185 mg, 0.61 mmol) and sodium carbonate (0.809 mL, 1.62 mmol) in a solvent mixture of DMF (3 mL), DME (8 mL), water (2 mL) and ethanol (1.5 mL) at RT. The resulting mixture was stirred at 9O0C for 18 hours under an inert atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (100 mL followed by 75 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude gum was triturated with a mixture of methanol and DCM and the solid removed by filtration. The filtrate was purified by flash silica chromatography, elution gradient 0 to 7% methanol in ethyl acetate, to give a gum which was further purified by ion exchange chromatography on an SCX column, eluting with 7N ammonia in methanol, to give a beige solid which was further purified by prep HPLC to give the desired material (7 mg). LCMS Spectrum: m/z (ESI+)(M+H)+ = 499; HPLC tR = 1.67 min. mTOR Kinase Assay (Echo): 0.00456μM
The following compound was prepared in an analogous fashion from 2-[l-(2-chloro-6- morpholin-4-ylpyrimidin-4-yl)cyclopropyl]sulfonyl-Λ/-methylacetamide.
Example Structure NAME LCMS Retention
MH+ time (min)
46a c 2-[l-[2-[4- 515 1.74
N
(cyclopropylcarbamoylamino)phen yl]-6-morpholin-4-ylpyrimidin-4- yl] cy clopropy 1] sulfony 1-N- methylacetamide
Example 46a: 1U NMR (400.132 MHz, DMSOd6) δ 0.39 - 0.43 (2H, m), 0.61 - 0.67 (2H, m), 1.57 - 1.61 (2H, m), 1.66 - 1.71 (2H, m), 2.63 (3H, d), 3.72 (8H, s), 4.39 (2H, s), 6.46 (IH, s), 6.87 (IH, s), 7.51 (2H, d), 8.20 (2H, d), 8.29 (IH, d), 8.58 (IH, s). mTOR Kinase Assay (Echo): 0.0126μM The preparation of 2-[ 1 -(2-chloro-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]sulfonyl-N- methylacetamide is described below.
2-[l-(2-Chloro-6-morpholin-4-ylpyrimidin-4-vπcvclopropyllsulfonyl-N-methylacetamide
Figure imgf000672_0001
HATU (252 mg, 0.66 mmol) was added to 2-[l-(2-chloro-6-morpholin-4-ylpyrimidin-4- yl)cyclopropyl]sulfonylacetic acid (200 mg, 0.55 mmol) and triethylamine (0.077 mL, 0.55 mmol) in DCM (10 mL) at RT under a nitrogen atmosphere and stirred for 15 minutes. Methylamine (2M in THF, 2 mL) was added and reaction stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with a saturated solution of sodium hydrogen carbonate (100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 90% ethyl acetate in isohexane, to give the desired material as a yellow gum (156 mg) NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.51 - 1.54 (2H, m), 1.62 - 1.67 (2H, m), 2.62 (3H, d), 3.66 (8H, m), 4.27 (2H, s), 7.06 (IH, s), 8.22 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 375; HPLC tR = 1.35 min.
2-[l-(2-Chloro-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]sulfonylacetamide was made by an analogous procedure to that above (chromatographed using 0 - 4% methanol in ethyl acetate).
Figure imgf000672_0002
The preparation of 2-[ 1 -(2-chloro-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]sulfonylacetic acid is described below.
2-[l-(2-Chloro-6-morpholin-4-ylpyrimidin-4-vπcvclopropyllsulfonylacetic acid
Figure imgf000673_0001
Lithium hydroxide (0.812 g, 33.93 mmol) was added to methyl 2-[l-(2-chloro-6-morpholin-4- ylpyrimidin-4-yl)cyclopropyl]sulfonylacetate (2.55 g, 6.79 mmol), in a mixture of THF (40 mL) and water (8 mL). The resulting mixture was stirred at RT for 2 hours then acidified with 2M hydrochloric acid. The reaction mixture was extracted with ethyl acetate (400 mL) and the organic layer dried (Na2SO4), filtered and evaporated to afford crude product. The crude solid was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (1.96 g).
NMR Spectrum: 1R NMR (400.132 MHz, DMSOd6) δ 1.53 - 1.58 (2H, m), 1.69 - 1.72 (2H, m), 3.66 (8H, s), 4.55 (2H, s), 6.98 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 362; HPLC tR = 0.69 min.
Methyl 2-ri-(2-chloro-6-morpholin-4-ylpyrimidin-4-yl)cvclopropyllsulfonylacetate
Figure imgf000673_0002
Lithium diisopropylamide (8.92 mL, 16.05 mmol) was added dropwise to 2-chloro-4-(l- methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidine (4.25 g, 13.37 mmol), in THF (80 mL) at -780C under a nitrogen atmosphere. The resulting mixture was stirred at -78°C for 15 minutes. Dimethyl carbonate (5.63 mL, 66.87 mmol) was added and the resulting mixture stirred at -78 0C for 10 minutes, then left to warm to RT. The mixture was cooled back to - 78C and additional lithium diisopropylamide (8.92 mL, 16.05 mmol) added. The mixture was stirred at -780C for 10 minutes, then dimethyl carbonate (5.63 mL, 66.87 mmol) added and the mixture allowed to come to RT and the pH adjusted to 7 with 2M hydrochloric acid. The reaction mixture was diluted with ethyl acetate (350 mL), and washed with water (150 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 70% ethyl acetate in isohexane, to give a yellow solid which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (3.10 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.56 - 1.60 (2H, m), 1.68 - 1.72 (2H, m), 3.63 - 3.70 (1 IH, m), 4.71 (2H, s), 6.97 (IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 376; HPLC tR = 1.76 min.
The preparation of 2-chloro-4-(l-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidine was described earlier.
Example 47: 3-Cvclopropyl-l-[4-[4-[l-(2-hvdroxyethylsulfonyl)cvclopropyll-6- morpholin-4-ylpyrimidin-2-yll phenyll urea
Figure imgf000674_0001
A solution of phenyl Λ/-[4-[4-[l-(2-hydroxyethylsulfonyl)cyclopropyl]-6-morpholin-4- ylpyrimidin-2-yl]phenyl]carbamate (50 mg, 0.09 mmol), cyclopropylamine (0.48 mmol) and triethylamine (0.066 mL, 0.048 mmol) in NMP (1 mL) was stirred at RT until the reaction had gone to completion. The crude reaction mixture was purifed by prep HPLC to give the desired material as a solid (31 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.40 - 0.45 (2H, m), 0.61 - 0.67 (2H, m), 1.50 - 1.59 (2H, m), 1.59 - 1.69 (2H, m), 2.54 - 2.61 (IH, m), 3.62 - 3.69 (2H, m), 3.69 - 3.76 (8H, m), 3.86 - 3.92 (2H, m), 5.03 (IH, t), 6.44 (IH, s), 6.81 (IH, s), 7.51 (2H, d), 8.21 (2H, d), 8.54 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 488; HPLC tR = 1.61 min. The following compounds were prepared in an analogous fashion from phenyl 7V-[4-[4-[l-(2- hydroxyethylsulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]phenyl]carbamate and the appropriate amine.
Figure imgf000675_0002
Example 47a: 1U NMR (400.132 MHz, DMSOd6) δ 1.48 - 1.58 (2H, m), 1.62 - 1.69 (2H, m), 2.67 (3H, d), 3.61 - 3.68 (2H, m), 3.69 - 3.76 (8H, m), 3.85 - 3.92 (2H, m), 5.03 (IH, s), 6.09 (IH, t), 6.81 (IH, s), 7.50 (2H, d), 8.20 (2H, d), 8.76 (IH, s).
Example 47b: 1R NMR (400.132 MHz, DMSOd6) δ 1.07 (3H, t), 1.51 - 1.57 (2H, m), 1.62 - 1.68 (2H, m), 3.14 (2H, q), 3.60 - 3.69 (2H, m), 3.69 - 3.77 (8H, m), 3.85 - 3.92 (2H, m), 5.03 (IH, t), 6.16 (IH, t), 6.81 (IH, s), 7.47 (2H, d), 8.20 (2H, d), 8.67 (IH, s).
The preparation of phenyl Λ/-[4-[4-[l-(2-hydroxyethylsulfonyl)cyclopropyl]-6-morpholin-4- ylpyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl Λ/-[4-[4-[ 1 -(2-hvdroxyethylsulfonyl)cvclopropyll-6-morpholin-4-ylpyrimidin-2- vHphenyli carbamate
Figure imgf000675_0001
Sodium hydrogen carbonate (65.4 mg, 0.78 mmol) was added to 2-[l-[2-(4-aminophenyl)-6- morpholin-4-ylpyrimidin-4-yl]cyclopropyl]sulfonylethanol (210 mg, 0.52 mmol) in dioxane (8 mL) at 50C under a nitrogen atmosphere. Phenyl chloroformate (0.072 mL, 0.57 mmol) was added and the mixture stirred at RT for 18 hours. The reaction mixture was diluted with ethyl acetate (50 mL), the organic layer dried (Na2SO4), filtered and evaporated to afford crude product. The crude gum was triturated with a mixture of diethyl ether and isohexane to give the desired material as a beige solid (170 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.52 - 1.60 (2H, m), 1.61 - 1.70 (2H, m), 3.61 - 3.79 (1OH, m), 3.82 - 3.96 (2H, m), 6.85 (IH, s), 7.21 - 7.34 (3H, m), 7.45 (2H, d), 7.64 (2H, d), 8.31 (2H, d), 10.45 (IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 525; HPLC tR = 2.40 min.
2-[l-[2-(4-Aminophenyl)-6-morpholin-4-ylpyrimidin-4-yl]cyclopropyl]sulfonylethanol
Figure imgf000676_0001
Bis(triphenylphosphine)palladium(II) chloride (48.5 mg, 0.07 mmol) was added to 2-[l-(2- chloro-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]sulfonylethoxy-tri(propan-2-yl)silane (520 mg, 1.03 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (339 mg, 1.55 mmol) and an aqueous solution of sodium carbonate (1 mL, 2.00 mmol) in a solvent mixture of DMF (5 mL), DME (12 mL), water (1 mL) and ethanol (1 mL) at RT. The atmosphere was replaced with nitrogen and the mixture stirred at 9O0C for 18 hours. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (2 x 100 mL).The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was dissolved in DCM then tetrabutylammonium fluoride (5.16 mL, 5.16 mmol) added and the mixture left to stir for 1 hour. A saturated solution of ammonium chloride was added, the layers separated and the organics dried (Na2SO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 10 to 50% ethyl acetate in isohexane, and the resultant solid further purified by ion exchange chromatography on an SCX column, eluting with 7N ammonia in methanol. The crude solid was triturated with a mixture of diethyl ether and isohexane to give the desired material as a beige solid (210mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.47 - 1.54 (2H, m), 1.59 - 1.67 (2H, m), 3.59 - 3.77 (1OH, m), 3.81 - 3.94 (2H, m), 5.02 (IH, t), 5.57 (2H, s), 6.60 (2H, d), 6.71 (IH, s), 8.04 (2H, d)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 405; HPLC tR = 1.65 min.
2-[l-(2-Chloro-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]sulfonylethoxy-tri(propan-2- yl)silane
Figure imgf000677_0001
2-[l-(2-Chloro-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]sulfonylethanol (550 mg, 1.58 mmol) was added to triisopropylsilyl chloride (0.406 mL, 1.90 mmol) and imidazole (258 mg, 3.80 mmol) in DMF (10 mL) at RT. The resulting solution was stirred under a nitrogen atmosphere overnight. The DMF was removed in vacuo and ethyl acetate added. The solids were removed by filtration and discarded. The filtrate was concentrated in vacuo and purified by flash silica chromatography, elution gradient 0 to 4% methanol in DCM, to give material that was further purified by flash silica chromatography, elution gradient 0-10%ethyl acetate in DCM to give the desired material as a clear gum (700 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.02 (18H, d), 1.49 - 1.53 (2H, m), 1.62 - 1.66 (2H, m), 2.00 (2H, s), 3.33 (2H, s), 3.62 - 3.69 (8H, m), 4.03 - 4.09 (3H, m), 6.95 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 504; HPLC tR = 3.63 min.
2-ri-(2-Chloro-6-morpholin-4-ylpyrimidin-4-yl)cvclopropyllsulfonylethanol
Figure imgf000677_0002
DIPEA (1.052 mL, 6.08 mmol) was added to 2-[l-(2-chloro-6-morpholin-4-ylpyrimidin-4- yl)cyclopropyl]sulfonylacetic acid (1.1 g, 3.04 mmol), in THF (50 mL) at O0C under a nitrogen atmosphere. The resulting solution was stirred at O0C for 5 minutes. Ethyl chloro formate (0.349 mL, 3.65 mmol) was added and the reaction stirred at O0C for 1 hour. The reaction mixture was filtered and filtrate cooled back down to O0C. Lithium borohydride (13.68 mL, 27.36 mmol) was added and the mixture warmed to allowed to come to RT. The mixture was cooled back to O0C and additional lithium borohydride (13.68 mL, 27.36 mmol) added and the reaction was allowed to come to RT. The mixture was cooled back to O0C and additional lithium borohydride (13.68 mL, 27.36 mmol) added and the reaction was allowed to come to RT and stirred for 72 hours. The reaction mixture was adjusted to pH7 with 2M hydrochloric acid and extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL), dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 100% ethyl acetate in isohexane, to give the desired material as a white solid (500 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.47 - 1.52 (2H, m), 1.59 - 1.67 (2H, m), 3.49 - 3.57 (2H, m), 3.60 - 3.70 (8H, m), 3.76 - 3.86 (2H, m), 4.99 (IH, t), 6.98 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 348; HPLC tR = 1.38 min.
The preparation of 2-[ 1 -(2-chloro-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]sulfonylacetic acid was described earlier.
Example 48 : 1- [4- [4- [ l-fS-Fluoropyridin-Z-yDsulfonylcvclopropyll -6- K3SD-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-methylurea
Figure imgf000678_0001
Methylamine (0.509 mL, 1.02 mmol) was added to phenyl Λ/-[4-[4-[l-(5-fluoropyridin-2- yl)sulfonylcyclopropyl] -6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate (200 mg, 0.34 mmol) and triethylamine (0.141 mL, 1.02 mmol) in DMF (1.7 mL) and the reaction stirred at 500C for 2 hours. The crude product was purified by prep HPLC to give the desired material as a white solid (70.0 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.69 - 1.72 (2H, m), 1.96 - 1.99 (2H, m), 2.66 (3H, d), 3.12 - 3.18 (IH, m), 3.43 - 3.48 (IH, m), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, d), 4.15 (IH, d), 4.45 (IH, s), 6.02 - 6.04 (IH, m), 6.68 (IH, s), 7.37 (2H, d), 7.68 (2H, d), 7.95 - 8.00 (IH, m), 8.03 - 8.06 (IH, m), 8.72 (IH, s), 8.87 (IH, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 527; HPLC tR = 1.61 min. mTOR Kinase Assay (Echo): 0.00252μM
The following compound was prepared in an analogous fashion from phenyl Λ/-[4-[4-[l-(5- fluoropyridin-2-yl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000679_0001
Example 48a: 1R NMR (400.132 MHz, DMSOd6) δ 1.66 - 1.70 (2H, m), 1.96 - 1.99 (2H, m), 3.69 (8H, s), 3.79 (3H, s), 6.74 (IH, s), 7.40 (3H, d), 7.66 (2H, d), 7.77 - 7.78 (3H, m), 8.35 (IH, s), 8.80 (IH, s), 8.87 (2H, d). mTOR Kinase Assay (Echo): 0.00103μM
The preparation of phenyl Λ/-[4-[4-[l-(5-fiuoropyridin-2-yl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below: Phenyl Λ/-[4-[4-[ 1 -(5-fluoropyridin-2-yl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000680_0001
Sodium bicarbonate (0.403 g, 4.79 mmol) was added to 4-[4-[l-(5-fluoropyridin-2- yl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.5 g, 3.19 mmol), in 1,4-dioxane (15.97 mL), followed by the dropwise addition of phenyl chloro formate (0.402 mL, 3.19 mmol) over 2 minutes and the reaction stirred at RT for 2 hours. The reaction mixture was evaporated to dryness, redissolved in DCM (20 mL), the organics washed with water (20 mL), dried (MgSO4), filtered and evaporated to give the desired material (2.0 g) which was used without further purification.
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.71 - 1.76 (2H, m), 1.96 - 1.99 (2H, m), 3.14 - 3.22 (IH, m), 3.42 - 3.49 (IH, m), 3.58 - 3.62 (IH, m), 3.75 (IH, d), 3.94 - 3.98 (IH, m), 4.19 (IH, s), 4.48 (IH, s), 6.74 (IH, s), 7.24 - 7.26 (2H, m), 7.45 (2H, t), 7.54 (2H, d), 7.80 (2H, d), 7.99 (IH, dt), 8.07 (IH, dd), 8.89 (IH, d), 10.48 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 590; HPLC tR = 2.95 min.
4- [4- r 1 -(5 -Fluoropyridin-2-yl)sulfonylcvclopropyll -6- [(36^-3 -methylmorpholin-4- vllpyrimidin-2-yll aniline
Figure imgf000680_0002
Bis(triphenylphosphine)palladium(II) chloride (0.136 g, 0.19 mmol) was added to 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.104 g, 5.04 mmol) and 2-chloro-4-[l-(5- fluoropyridin-2-yl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (1.6 g, 3.88 mmol) and an aqueous solution of sodium carbonate (5.81 mL, 11.63 mmol) in a solvent mixture of DMF (0.564 mL), ethanol (4.70 mL) and water (4.70 mL) at RT under an atmosphere of nitrogen. The resulting mixture was stirred at 85°C for 4 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and the organics washed with water (2 x 20 mL), dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% 3.5N methanolic ammonia in DCM, to give the desired material as a cream solid (1.5 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 1.65 - 1.70 (2H, m), 1.94 - 1.97 (2H, m), 3.12 (IH, dt), 3.44 (IH, dt), 3.59 (IH, dd), 3.73 (IH, d), 3.93 (IH, dd), 4.11 - 4.13 (IH, m), 4.41 (IH, s), 6.46 (2H, d), 6.58 (IH, s), 7.49 (2H, d), 7.98 (2H, dt), 8.04 (2H, dd), 8.89 (IH, d) LCMS Spectrum: m/z (ESI+) (M+H)+ = 470; HPLC tR = 2.30 min.
2-Chloro-4-ri-(5-fluoropyridin-2-yl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000681_0001
1 ,2-Dibromoethane (1.025 mL, 11.89 mmol) was added to 2-chloro-4-[(5-fluoropyridin-2- yl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (2.3 g, 5.95 mmol), an aqueous solution of sodium hydroxide (2.97 mL, 29.73 mmol) and tetrabutylammonium bromide (0.383 g, 1.19 mmol) in toluene (29.7 mL) and the resulting solution stirred at 600C for 3 hours. The reaction mixture was evaporated to dryness, redissolved in ethyl acetate (50 mL), and the organics washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 50% ethyl acetate in DCM, to give the desired material as a white solid (1.8 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.14 (3H, d), 1.63 - 1.66 (2H, m), 1.88 - 1.93 (2H, m), 3.11 - 3.17 (IH, m), 3.39 (IH, dt), 3.54 (IH, dd), 3.69 (IH, d), 3.91 (2H, dd), 4.27 (IH, s), 6.81 (IH, s), 8.02 - 8.11 (2H, m), 8.83 (IH, d) LCMS Spectrum: m/z (ESI+)(M+H)+ 413, HPLC tR = 2.10 min 2-Chloro-4-r(5-fluoropyridin-2-yl)sulfonylmethyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000682_0001
3-Chloroperoxybenzoic acid (5.79 g, 25.15 mmol) was added portionwise to 2-chloro-4-[(5- fluoropyridin-2-yl)sulfanylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (3.57 g, 10.06 mmol), in DCM (50.3 mL) and the reaction stirred at RT for 2 hours. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate (50 mL), the organic layer separated, dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% ethyl acetate in DCM, to give the desired material as a white solid (2.3 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 3.17 (IH, t), 3.42 (IH, dt), 3.57 (IH, dd), 3.71 (IH, d), 3.92 (2H, dd), 4.17 (IH, s), 4.74 (2H, d), 6.82 (IH, s), 8.01 - 8.09 (2H, m), 8.89 (IH, d) LCMS Spectrum: m/z (ESI+)(M+H)+ 387, HPLC tR = 1.88 min
2-Chloro-4-r(5-fluoropyridin-2-yl)sulfanylmethyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000682_0002
Potassium hydroxide (3.22 g, 57.33 mmol) was added to (5-fluoropyridin-2-yl) dimethylaminomethanedithioate (3.1 g, 14.33 mmol) in ethanol (71.7 mL) and the resulting solution heated at 65°C for 4 hours. The reaction was cooled, 2-chloro-4-(iodomethyl)-6- [(35)-3-methylmorpholin-4-yl]pyrimidine (7.09 g, 20.06 mmol) added and the reaction stirred at RT for 4 hours. Water (50 mL) was added and the reaction extracted with DCM (2 x 100 mL). The organics were dried (MgSO4), filtered and concentrated to give crude product which was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in DCM, to give the desired material as a beige gum (3.57 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.13 (3H, d), 3.11 - 3.17 (IH, m), 3.41 (IH, dt), 3.54 - 3.57 (IH, m), 3.69 (IH, d), 3.90 (2H, dd), 4.24 - 4.26 (IH, m), 4.29 (2H, d), 6.84 (IH, s), 7.45 (IH, dd), 7.68 (IH, dt), 8.50 (IH, d)
LCMS Spectrum: m/z (ESI+)(M+H)+ 355, HPLC tR = 2.38 min
(5 -Fluoropyridin-2-yl) dimethylaminomethanedithioate
Figure imgf000683_0001
2-Bromo-5-fluoropyridine (4 g, 22.73 mmol) was added portionwise to isopropylmagnesium chloride - lithium chloride complex (14% in THF, 23 mL, 22.73 mmol), at O0C, over a period of 2 minutes under a nitrogen atmosphere. The resulting solution was warmed to RT over a period of 2 hours then cooled back to 00C and tetramethylthiuram disulfide (5.46 g, 22.73 mmol) in DCM (22.73 mL) added. The reaction was warmed to RT and stirred for 6 hours. The reaction was poured into a saturated aqueous solution of ammonium chloride (100 mL) and the aqueous layer extracted with DCM (2 x 100 mL). The organics were dried (MgSO4), concentrated in vacuo and the crude product was purified by flash silica chromatography, elution gradient 0 to 60% ethyl acetate in DCM, to give the desired material as a brown oil which solidified on standing (3.10 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 3.45 (3H, s), 3.46 (3H, s), 7.70 (IH, dd), 7.86 (IH, dt), 8.65 (IH, d) LCMS Spectrum: m/z (ESI+)(M+H)+ 217, HPLC tR = 1.70 min
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier. Example 49 : iVJV-Dimethyl-6- [ 1- [2- [4-(methylcarbamoylamino)phenyll -6- \(3S)-3- methylmorpholin-4-yll pyrimidin-4-yll cyclopropyll sulfonylpyridine-3-carboxamide
Figure imgf000684_0001
Methylamine (0.250 mL, 0.50 mmol) was added to phenyl 7V-[4-[4-[l-[5- (dimethylcarbamoyl)pyridin-2-yl]sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate (0.064 g, 0.10 mmol) and triethylamine (0.042 mL, 0.30 mmol) in DMF (2 mL) and the resulting solution stirred at 500C for 18 hours. The reaction was cooled and the mixture purified by preparative HPLC to give the desired material as a white solid (0.03 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ δ 1.16-1.18 (3H, d), 1.73-1.76 (2H, m), 1.99-2.02 (2H, m), 2.65-2.66 (3H, d), 2.88 (3H, s), 3.05 (3H, s), 3.05-3.17 (IH, td), 3.41- 3.48 (IH, td), 3.58-3.62 (IH, dd), 3.73-3.76 (IH, d), 3.93-3.97 (IH, dd), 4.15 (IH, bs), 4.44 (IH, bs), 6.07-6.10 (IH, q), 6.65 (IH, s), 7.37-7.39 (2H, d), 7.67-7.69 (2H, d), 8.00-8.01 (IH, d), 8.11-8.13 (IH, dd), 8.72 (IH, s), 8.87-8.88 (IH, dd). LCMS Spectrum: m/z (ES+) (M+H)+=580; HPLC tR=1.88min. mTOR Kinase Assay (Echo): 0.00187μM
The compound shown in table below was prepared in an analogous manner from phenyl N- [4- [4-[l-[5-(dimethylcarbamoyl)pyridin-2-yl]sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin- 4-yl]pyrimidin-2-yl]phenyl] carbamate using the appropriate amine.
Figure imgf000685_0002
Example 49a: 1R NMR (400.132 MHz, DMSOd6) δ 0.39-0.43 (2H, m), 0.62-0.67 (2H, m), 1.16-1.18 (3H, d), 1.73-1.76 (2H, m), 2.00-2.02 (2H, m), 2.88 (3H, s), 3.05 (3H, s), 3.11-3.18 (IH, td), 3.42-3.48 (IH, td), 3.58-3.62 (IH, dd), 3.73-3.76 (IH, d), 3.93-3.97 (IH, dd), 4.13 (IH, bs), 4.44 (IH, bs), 6.44-6.45 (IH, d), 6.66 (IH, s), 7.37-7.39 (2H, d), 7.67-7.69 (2H, d), 8.00-8.03 (IH, d), 8.11-8.13 (IH, dd), 8.51 (IH, s), 8.87-8.88 (IH, dd). mTOR Kinase Assay (Echo): 0.00267μM
The preparation of phenyl Λ/-[4-[4-[l-[5-(dimethylcarbamoyl)pyridin-2- yljsulfonylcyclopropyl] -6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl Λ/-[4-[4-[ 1 -[5-(dimethylcarbamovπpyridin-2-yllsulfonylcvclopropyll-6-[(36f)-3- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000685_0001
Phenyl chloroformate (0.015 mL, 0.12 mmol) was added dropwise to 6-[l-[2-(4- aminophenyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonyl-Λ/,Λ/- dimethylpyridine-3 -carboxamide (0.064 g, 0.12 mmol) and sodium hydrogen carbonate (0.015 g, 0.18 mmol) in dioxane (7.5 mL) and the resulting solution stirred at RT for 1 hour. The material was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material.
NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.29-1.31 (3H, d), 1.66-1.74 (2H, m), 2.17-2.19 (2H, m), 2.88 (3H, s), 3.12 (3H, s), 3.24-3.31 (IH, td), 3.54-3.61 (IH, td), 3.70-3.74 (IH, dd), 3.80-3.83 (IH, d), 4.01-4.05 (IH, dd), 4.16-4.17 (IH, bs), 4.42 (IH, bs), 6.79 (IH, s), .16-7.26 (2H, d), 7.22-7.26 (IH, t), 7.37-7.41 (2H, t), 7.47-7.49 (2H, d), 7.64-7.69 (IH, m), 7.84-7.87 (IH, dd), 7.95-7.97 (3H, m), 8.75-8.76 (IH, d). LCMS Spectrum: m/z (ES+) (M+H)+=643; HPLC tR=2.62min.
6-[l-[2-(4-Aminophenvπ-6-[(36f)-3-methylmorpholin-4-yllpyrimidin-4- yl] cvclopropyl] sulfonyl-A/, A/-dimethylpyridine-3 -carboxamide
Figure imgf000686_0001
Bis(triphenylphosphine)palladium (II) chloride (0.015 g, 0.02 mmol) was added to 6-[l-[2- Chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonyl-Λ/,Λ/- dimethylpyridine-3 -carboxamide (0.203 g, 0.44 mmol), 4- (4,4,5, 5-tetramethyl-l, 3,2- dioxaborolan-2-yl)aniline (0.096 g, 0.44 mmol) and an aqueous solution of sodium carbonate (1.09 mL, 2.18 mmol) in a solvent mixture (2 mL) (the solvent mixture comprised 18% DMF, 82% of a 7:3:2 mixture of DME:water:Ethanol) at RT under a nitrogen atmosphere. The resulting solution was stirred at 800C for 3 hours. The reaction was cooled, water added and the solids removed by filtration. The filtrate was extracted twice with ethyl acetate and the combined organics dried (MgSO4), filtered and evaporated. The solids from the filtration were combined with those from the extraction to give the desired material which was used without further purification. LCMS Spectrum: m/z (ES+) (M+H)+=523; HPLC tR=1.98min. 6-ri-r2-Chloro-6-r(36^-3-methylmorpholin-4-yllpyrimidin-4-yllcvclopropyllsulfonyl-Λ/,Λ/- dimethylpyridine-3 -carboxamide
Figure imgf000687_0001
Sodium hydroxide (3.36 g, 83.96 mmol) in water (3.6 mL) was added to 6-[[2-chloro-6-[(35)- 3-methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]-Λ/,Λ/-dimethylpyridine-3- carboxamide (0.666 g, 1.51 mmol), 1 ,2-dibromoethane (0.652 mL, 7.56 mmol) and tetrabutylammonium bromide (0.049 g, 0.15 mmol) in DCM (20 mL) and the resulting solution stirred at RT for 18 hours. The reaction mixture was diluted with water and extracted with DCM. The organics were washed with saturated brine, dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 7% methanol (contaning 0.1% ammonia) in DCM, to give the desired material as a brown gum (0.406 g).
NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.27-1.29 (3H, d), 1.61-1.68 (2H, m), 2.07-2.10 (2H, m), 3.00 (3H, s), 3.14 (3H, s), 3.20-3.28 (IH, td), 3.48-3.54 (IH, td), 3.64-3.67 (IH, dd), 3.75-3.78 (IH, d), 3.96-4.02 (2H, m), 4.26 (IH, bs), 6.95 (IH, s), 7.93-7.99 (2H, m), 8.71-8.72 (IH, d). LCMS Spectrum: m/z (ES+) (M+H)+=466; HPLC tR=1.71min.
6-rr2-Chloro-6-r(36^-3-methylmorpholin-4-yllpyrimidin-4-yllmethylsulfonyll-Λ/,Λ/- dimethylpyridine-3 -carboxamide
Figure imgf000687_0002
6-[[2-Chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfanyl]-Λ/,Λ/- dimethylpyridine-3 -carboxamide (1.47 g, 3.60 mmol) was dissolved in dioxane (45 mL) and 2N sulfuric acid (0.11 mL) added. The solution was heated to 55°C, a solution of sodium tungstate dihydrate (0.024 g, 0.07 mmol) in water (1.08 mL) added and the solution allowed to stir for 10 minutes. Hydrogen peroxide (2.229 mL, 72.07 mmol) was then added dropwise over several minutes and the solution heated at 55°C for 3 hours. Water was added and the reaction was allowed to cool. The aqueous solution was extracted with DCM, the organics dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a cream solid (1.45 g).
NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.31-1.33 (3H, d), 3.04 (3H, s), 3.17 (3H, s), 3.24-3.32 (IH, td), 3.50-3.57 (IH, td), 3.66-3.70 (IH, dd), 3.78-3.80 (IH, d), 3.99-4.03 (2H, m), 4.26 (IH, bs), 4.58 (2H, s), 6.52 (IH, s), 7.97-8.03 (2H, m), 8.82-8.83 (IH, m). LCMS Spectrum: m/z (ES+) (M+H)+=440; HPLC tR=1.59min.
6-rr2-Chloro-6-r(36^-3-methylmorpholin-4-yllpyrimidin-4-yllmethylsulfanyll-Λ/,Λ/- dimethylpyridine-3 -carboxamide
Figure imgf000688_0001
DIPEA (1.043 mL, 5.99 mmol) was added to 6-[[2-chloro-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-4-yl]methylsulfanyl]pyridine-3-carboxylic acid (1.369 g, 3.59 mmol) and HATU (1.366 g, 3.59 mmol) in DMA (10 mL) and the resulting solution stirred at RT for 15 minutes. Dimethylamine (1.497 mL, 2.99 mmol) was added and the reaction allowed to stir for 2.5 hours. Water was added to the solution and the solution extracted with ethyl acetate. The ethyl acetate was washed with a saturated aqueous solution of sodium bicarbonate, dried (MgSO4), filtered and evaporated to give the desired material which was used without further purification. LCMS Spectrum: m/z (ES+) (M+H)+=408; HPLC tR=1.83min. 6-rr2-Chloro-6-r(36^-3-methylmorpholin-4-yllpyrimidin-4-yllmethylsulfanyllpyridine-3- carboxylic acid
Figure imgf000689_0001
2-Chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (2.0 g, 5.66 mmol) was added to 6-mercaptonicotinic acid (1.317 g, 8.48 mmol) and DIPEA (2.463 mL, 14.14 mmol) in acetonitrile (100 mL) and the resulting solution stirred at RT for 2 hours. The solvent was removed under vacuum and the residue dissolved in DCM. The organics were washed sequentially with water and saturated brine, dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanol (containing 0.1% ammonia) in DCM, to give the desired material as a brown solid (1.79 g).
NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.19-1.20 (3H, d), 3.16-3.21 (IH, t), 3.40-3.47 (IH, m), 3.58-3.61 (2H, dd), 3.91-3.94 (2H, d), 4.25 (3H, bs), 6.08 (IH, bs), 6.52 (IH, s), 7.01 (IH, bs), 7.89 (IH, bs), 8.89 (IH, bs). LCMS Spectrum: m/z (ES+) (M+H)+=381; HPLC tR=0.83min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Example 50 : iV,iV-Dimethyl-3- [ 1- [2- [4-(methylcarbamoylamino)phenyll -6- \(3S)-3- methylmorpholin-4-yll pyrimidin-4-yll cyclopropyll sulfonylpyridine-2-carboxamide
Figure imgf000689_0002
Methylamine (0.441 mL, 0.88 mmol) was added to phenyl N-[4-[4-[l-[2- (dimethylcarbamoyl)pyridin-3-yl]sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate (0.113 g, 0.18 mmol) and triethylamine (0.074 mL, 0.53 mmol) in DMF (2 mL) and the resulting solution stirred at 500C for 2 hours. The reaction was cooled and purified by preparative HPLC, to give the desired material as a colourless gum (11 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.16-1.18 (3H, d), 1.62 (2H, bs), 1.98 (2H, bs), 2.55 (3H, s), 2.66 (3H, s), 2.96 (3H, s), 3.13-3.19 (IH, td), 3.41-3.47 (IH, td), 3.58- 3.61 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.98 (IH, dd), 4.16 (IH, bs), 4.47 (IH, bs), 6.12 (IH, bs), 6.73 (IH, s), 7.43-7.46 (2H, d), 7.59-7.62 (IH, q), 7.85-7.87 (2H, d), 8.16-8.18 (IH, d), 8.82 (IH, bs), 8.85-8.86 (IH, dd). LCMS Spectrum: m/z (ES+) (M+H)+=580; HPLC tR=1.76min. mTOR Kinase Assay (Echo): 0.0104μM
The following compound was prepared in an analogous fashion from phenyl Λ/-[4-[4-[l-[2- (dimethylcarbamoyl)pyridin-3-yl]sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] carbamate and the appropriate amine.
Figure imgf000690_0001
Example 50a: 1U NMR (400.132 MHz, DMSOd6) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), 1.16-1.17 (3H, d), 1.60 (2H, bs), 1.96 (2H, bs), 2.55 (3H, s), 2.97 (3H, s), 3.10-3.17 (IH, td), 3.42-3.48 (IH, td), 3.58-3.62 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.97 (IH, dd), 4.15 (IH, bs), 4.45 (IH, bs), 6.45-6.46 (IH, d), 6.72 (IH, s), 7.41-7.43 (2H, d), 7.57-7.60 (IH, q), 7.84-7.86 (2H, d), 8.11-8.14 (IH, dd), 8.55 (IH, s), 8.84-8.85 (IH, dd). mTOR Kinase Assay (Echo): 0.00794μM The preparation of phenyl Λ/-[4-[4-[l-[2-(dimethylcarbamoyl)pyridin-3- yl]sulfonylcyclopropyl] -6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl Λ/-[4-[4-[ 1 -r2-(dimethylcarbamoyl)pyridin-3-yllsulfonylcvclopropyll-6-r(36f)-3- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000691_0001
Phenyl chloro formate (0.071 mL, 0.57 mmol) was added dropwise to 3-[l-[2-(4- aminophenyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonyl-Λ/,Λ/- dimethylpyridine-2-carboxamide (0.296 g, 0.57 mmol) and sodium hydrogen carbonate (0.071 g, 0.85 mmol) in dioxane (18 mL) and the resulting solution stirred at RT for 3 hours. The solids were removed by filtration and the filtrate purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in DCM, to give additional desired material as a yellow gum (0.227 g).
NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.22-1.24 (3H, d), 1.53-1.60 (2H, m), 2.13-2.17 (2H, m), 2.77 (3H, s), 3.14 (3H, s), 3.18-3.25 (IH, td), 3.50-3.57 (IH, td), 3.66-3.70 (IH, dd), 3.77-3.80 (IH, d), 3.98-3.99 (IH, dd), 4.08 (IH, bs), 4.38 (IH, bs), 6.69 (IH, s), 7.16-7.18 (2H, d), 7.21-7.25 (2H, m), 7.36-7.40 (2H, t), 7.48-7.50 (2H, d), 7.67 (IH, bs), 7.94-7.96 (IH, dd), 8.15-8.17 (2H, d), 8.70-8.72 (IH, dd).
LCMS Spectrum: m/z (ES+) (M+H)+=643; HPLC tR=3.09min.
3-ri-r2-(4-Aminophenyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4- yl1cvclopropyl1sulfonyl-Λ/,Λ/-dimethylpyridine-2-carboxamide
Figure imgf000692_0001
Bis(triphenylphosphine)palladium (II) chloride (0.038 g, 0.05 mmol) was added to 3-[l-[2- chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonyl-Λ/,Λ/- dimethylpyridine-2-carboxamide (0.503 g, 1.08 mmol), 4- (4,4,5, 5-tetramethyl-l, 3,2- dioxaborolan-2-yl)aniline (0.237 g, 1.08 mmol) and an aqueous solution of sodium carbonate (2.70 mL, 5.40 mmol) in a solvent mixture (2 mL) (the solvent mixture comprised 18% DMF, 82% of a 7:3:2 mixture of DME:Water:Ethanol) and the resulting solution stirred at 800C for 15 hours. The reaction was cooled to RT and water was added. The solids were filtered to give the desired material. The filtrate was extracted with ethyl acetate and the organics dried (MgSO4), filtered and evaporated to dryness to yield an additional sample of the desired material. Both crops of the desired material were combined and used without further purification. LCMS Spectrum: m/z (ES+) (M+H)+=523; HPLC tR=1.85min.
3-ri-r2-Chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-yllcvclopropyllsulfonyl-Λ/,Λ/- dimethylpyridine-2-carboxamide
Figure imgf000692_0002
Sodium hydroxide (2.373 g, 59.32 mmol) in water (2.373 mL) was added to 3-[[2-chloro-6- [(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]-Λ/,Λ/-dimethylpyridine-2- carboxamide (0.475 g, 1.08 mmol), 1 ,2-dibromoethane (0.465 mL, 5.39 mmol) and tetrabutylammonium bromide (0.035 g, 0.11 mmol) in DCM and the resulting solution stirred at RT for 18 hours. Water was added and the solution was extracted with DCM. The organic layer was dried (MgSO4) and filtered to give the desired material (0.539 g). LCMS Spectrum: m/z (ES+) (M+H)+=466; HPLC tR=1.64min. 3-rr2-chloro-6-r(36^-3-methylmorpholin-4-yllpyrimidin-4-yllmethylsulfonyll-Λ/,Λ/- dimethylpyridine-2-carboxamide
Figure imgf000693_0001
3 - [[2-Chloro-6- [(35)-3 -methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfanyl] -N, N- dimethylpyridine-2-carboxamide (0.533 g, 1.31 mmol) was dissolved in dioxane (15 mL) and 2N sulfuric acid (0.041 mL) was added. The solution was heated to 55°C and a solution of sodium tungstate dihydrate (8.62 mg, 0.03 mmol) in water (0.4 mL) added and the solution allowed to stir for 10 minutes. Hydrogen peroxide (0.808 mL, 26.13 mmol) was then added dropwise over several minutes. The solution was heated at 55°C for 5.5 hours. The heat was removed and the reaction was allowed to stir at RT overnight. Water was added and the reaction was allowed to cool. The aqueous solution was extracted with DCM. The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 7% methanil (containing 0.1% ammonia) in DCM, to give the desired material as a yellow gum (0.475 g). LCMS Spectrum: m/z (ES+) (M+H)+=440; HPLC tR=1.62min.
3-rr2-Chloro-6-r(36^-3-methylmorpholin-4-yllpyrimidin-4-yllmethylsulfanyll-Λ/,Λ/- dimethylpyridine-2-carboxamide
Figure imgf000693_0002
2-Chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (1.009 g, 2.85 mmol) was added to Λ/,Λ/-dimethyl-3-sulfanylpyridine-2-carboxamide (0.520 g, 2.85 mmol) and DIPEA (0.746 mL, 4.28 mmol) in acetonitrile (20 mL) and the resulting solution stirred at RT for 2 hours. Further DIPEA (0.746 mL, 4.28 mmol) was added and the reaction was allowed to stir for several over a weekend. The reaction was heated at 4O0C for 7 days. The solvent was removed and the residue dissolved in DCM and washed with water. The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by ion exchange chromatography using an SCX column, eluting with 7M ammonia in methanol, to give material which was further purified by flash silica chromatography, elution gradient 0 to 7% methanol in DCM, to give the desired material as a brown gum (0.533 g). LCMS Spectrum: m/z (ES+) (M+H)+=408; HPLC tR=1.57min.
Λ/,Λ/-Dimethyl-3-sulfanylpyridine-2-carboxamide
Figure imgf000694_0001
DIPEA (2.164 mL, 12.42 mmol) was added to 3-mercaptopicolinic acid (1.156 g, 7.45 mmol) and HATU (2.83 g, 7.45 mmol) in DMA (30 mL) and the resulting solution stirred at RT for 15 minutes. Dimethylamine (3.11 mL, 6.21 mmol) was added and the reaction was allowed to stir overnight. Water was added to the solution and the solution was extracted with DCM. The organics were washed with a saturated aqueous solution of sodium bicarbonate, dried (MgSO4) and filtered. Most of the solvent was removed and diethyl ether added. The solid was removed by filtration and discarded. Water was added to the filtrate and the product extracted with ethyl acetate. The organics were dried (MgSO4), filtered and evaporated to give the desired material (0.52 g).
LCMS Spectrum: m/z (ES-) (M-H)-=181; HPLC tR=1.17min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Example 51 : 1- [4- [4- [ l-q-Methoxyethylsulfonylkyclopropyll -6- K3SV3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-methylurea
Figure imgf000694_0002
Bis(triphenylphosphine)palladium(II) chloride (5.8 mg, 0.827 mmol) was added to 2-chloro- 4-[l-(2-methoxyethylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (0.062 g, 0.17 mmol), l-methyl-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)urea (0.046 g, 0.17 mmol) and an aqueous solution of sodium carbonate (0.414 mL, 0.83 mmol) in a solvent mixture (2 mL) (the solvent mixture comprised 18% DMF, 82% of a 7:3:2 mixture of DME:water:Ethanol) at RT under an atmosphere of nitrogen. The resulting suspension was stirred at 800C for 6 hours. The crude reaction mixture was put down an SCX column, eluting with 7M ammonia in methanol, to give a sample that was concentrated in vacuo and redissolved in DMF (2 mL). The mixture was purified by preparative HPLC to give the desired material as a white solid (17 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.22-1.23 (3H, d), 1.54-1.57 (2H, m), 1.64-1.66 (2H, m), 2.65-2.66 (3H, d), 3.16-3.23 (IH, td), 3.27 (3H, s), 3.44-3.51 (IH, td), 3.61-3.64 (IH, dd), 3.75-3.78 (IH, d), 3.80-3.81 (4H, t), 3.95-3.99 (IH, dd), 4.21 (IH, bs), 4.57 (IH, bs), 6.07-6.10 (IH, q), 6.76 (IH, s), 7.49-7.51 (2H, d), 8.17-8.19 (2H, d), 8.79 (IH, S).
LCMS Spectrum: m/z (ES+)(M+H)+=490; HPLC tR=1.93min. mTOR Kinase Assay (Echo): 0.00332μM
The preparation of to 2-chloro-4-[l-(2-methoxyethylsulfonyl)cyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidine is described below.
2-Chloro-4-[l-(2-methoxyethylsulfonvπcvclopropyll-6-[(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000695_0001
Sodium hydride (0.026 g, 1.07 mmol) was added to (S)-2-(l-(2-chloro-6-(3- methylmorpholino)pyrimidin-4-yl)cyclopropylsulfonyl)ethanol (0.231 g, 0.64 mmol) in THF (20 mL) cooled to O0C under a nitrogen atmosphere. The resulting solution was stirred at 00C for 10 minutes. To this solution, methyl iodide (0.040 mL, 0.64 mmol) was added and the reaction was slowly allowed to warm to RT. Water was carefully added and the reaction was extracted with DCM. The organics were dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% ethyl acetate in DCM, to give the desired material as a colourless dry film (0.062 g). NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.31-1.32 (3H, d), 1.47-1.50 (2H, q), 1.79-1.82 (2H, q), 3.25-3.32 (IH, td), 3.35 (3H, s), 3.44-3.47 (2H, t), 3.49-3.56 (IH, td), 3.65- 3.69 (IH, dd), 3.76-3.79 (IH, d), 3.79-3.85 (2H, m), 3.98-4.03 (2H, m), 4.33 (IH, bs), 6.84 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=376; HPLC tR=1.87min.
2- [ 1 - [2-Chloro-6- [(36^-3 -methylmorpholin-4-yllpyrimidin-4-yll cvclopropyl] sulfonylethanol
Figure imgf000696_0001
DIPEA (3.70 mL, 21.23 mmol) was added to 2-[l-[2-chloro-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-4-yl]cyclopropyl]sulfonylacetic acid (3.99 g, 10.62 mmol) in THF cooled to O0C under a nitrogen atmosphere. The resulting solution was stirred at 00C for 5 minutes then ethyl chloroformate (1.117 mL, 11.68 mmol) added dropwise. The solution was allowed to stir for 1 hour, the solids removed by filtration and the filtrate cooled back to O0C. Lithium borohydride (17.52 mL, 35.03 mmol) was added and the reaction was slowly allowed to warm to RT. Additional lithium borohydride (10.62 mmol) was added and the mixture stirred for several hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride and then extracted with DCM. The organic layer was separated, washed with saturated brine, dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% ethyl acetate in DCM, to give the desired material as a white solid (1.96 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.21-1.22(3H, d), 1.49-1.52(2H, m), 1.62-1.65(2H, m), 3.17-3.25(1H, td), 3.40-3.47(1H, td), 3.52-3.55(2H, t), 3.56-3.60(1H, dd), 3.71-3.74(1H, d), 3.79-3.84(2H, q), 3.92-3.95(1H, dd), 4.04(1H, bs), 4.4O(1H, bs), 4.98- 5.01(1H, t), 6.95(1H, s). LCMS Spectrum: m/z (ES+)(M+H)+=362; HPLC tR=1.67 min. 2- r 1 - [2-ChIoIO-O- r(3ιSV3 -methylmorpholin-4-yllpyrimidin-4-vH cyclopropyll sulfonylacetic acid
Figure imgf000697_0001
2 M Sodium hydroxide solution (13.85 mL, 27.70 mmol) was added to methyl 2-[l-[2-chloro- 6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonylacetate (3.60 g, 9.23 mmol) in THF (100 mL) and the resulting solution stirred at RT for 6 hours. The solution was adjusted to pH7 with 2M hydrochloric acid and salt was added to concentrate the solution. The aqueous solution was extracted with DCM, the organic layer separated, dried (MgSO4), filtered and evaporated to the desired material as a white solid (3.45 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.20-1.22(3H, d), 1.55-1.58(2H, q), 1.69-1.72(2H, q), 3.18-3.24(1H, m), 3.4O-3.46(1H, td), 3.56-3.59(1H, dd), 3.71-3.74(1H, d), 3.92-3.95(1H, dd), 4.04(1H, bs), 4.41(1H, bs), 4.55(2H, s), 6.95(1H, s), 13.36(1H, s). LCMS Spectrum: m/z (ES+)(M+H)+=376; HPLC tR=0.71 min.
Methyl 2-\ 1 -[2-chloro-6-[(36f)-3-methylmorpholin-4-yllpyrimidin-4- yll cycloprop yll sulfonylacetate
Figure imgf000697_0002
A solution of lithium diisopropylamide (2M solution in THF/n-heptane, 5.46 mL, 9.84 mmol) in THF (60 mL) was added to a stirred solution of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]- 6-(l-methylsulfonylcyclopropyl)pyrimidine (2.720 g, 8.20 mmol), and dimethyl carbonate (6.97 mL, 81.97 mmol) in THF (60 mL), cooled to -780C, over a period of 5 minutes under an atmosphere of nitrogen. The resulting solution was very slowly allowed to come to RT with stirring over 18 hours. The reaction was cooled back to -780C and further lithium diisopropylamide (2.73 mL , 4.92 mmol), and dimethyl carbonate (6.97 mL, 81.97 mmol) added. Again the mixture was allowed to warm slowly to RT with stirring over 24 hours. The reaction mixture was diluted with ethyl acetate (150 mL), washed with IM citric acid (150 mL) and saturated brine (150 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product which was purified by flash silica chromatography, elution gradient 10 to 50% ethyl acetate in isohexane, to give the desired material as a yellow gum. NMR Spectrum: 1R NMR (400.132 MHz, CDCl3) δ 1.33 (3H, d), 1.55 (2H, q), 1.91 (2H, q), 3.30 (IH, m), 3.50 (IH, s), 3.68 (IH, q), 3.79 (4H, t), 4.01 (2H, q), 4.28 (2H, s), 4.41 (IH, s), 6.78 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=390; HPLC tR=2.01 min.
The preparation of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidine was described earlier.
Example 52: 3-Cvclopropyl-l-[2-fluoro-4-[4-[(3S)-3-methylmorpholin-4-yll-6-Q- methylsulfonylcvclopropyl)pyrimidin-2-yll phenyll urea
Figure imgf000698_0001
Cyclopropylamine (0.055 mL, 0.80 mmol) followed by triethylamine (0.067 mL, 0.48 mmol) were added to a solution of phenyl Λ/-[2-fluoro-4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]carbamate (85.4mg, 0.16 mmol) in DMF (2 mL) and the reaction heated at 500C overnight. The crude product was purified by preparative HPLC to give the desired material as a white solid (62 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.40-0.44 (2H, m), 0.64-0.69 (2H, m), 1.23-1.25 (3H, d), 1.55-1.58 (2H, q), 1.66-1.69 (2H, q), 2.55-2.61 (IH, m), 3.18-3.25 (IH, td), 3.28 (3H, s), 3.45-3.52 (IH, td), 3.62-3.65 (IH, dd), 3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.21-4.24 (IH, d), 4.58 (IH, bs), 6.81 (IH, s), 6.88-6.89 (IH, d), 8.01-8.04 (IH, dd), 8.06-8.09 (IH, dd), 8.27-8.31 (IH, t), 8.36-8.37 (IH, d). LCMS Spectrum: m/z (ESI+)(M+H)+490 = HPLC tR =2.28 min. mTOR Kinase Assay (Echo): 0.0184μM The compounds below were prepared in an analogous fashion from phenyl N-[2-fluoro-4-[4- [(35)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000699_0001
Example 52a: 1R NMR (400.132 MHz, DMSO-de) δ 1.23-1.25 (3H, d), 1.55-1.58 (2H, q), 1.66-1.69 (2H, q), 2.68-2.69 (3H, d), 3.18-3.25 (IH, td), 3.28 (3H, s), 3.45-3.52 (IH, td), 3.62- 3.65 (IH, dd), 3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.21-4.24 (IH, d), 4.57 (IH, bs), 6.55- 6.58 (IH, q), 6.81 (IH, s), 8.00-8.04 (IH, dd), 8.05-8.08 (IH, dd), 8.26-8.31 (IH, t), 8.54-8.55 (IH, d). mTOR Kinase Assay (Echo): 0.0103μM Example 52b: 1U NMR (400.132 MHz, DMSO-Cl6) δ 1.06-1.10 (3H, t), 1.23-1.25 (3H, d), 1.55-1.58 (2H, q), 1.66-1.69 (2H, q), 3.11-3.18 (2H, m), 3.18-3.25 (IH, td), 3.28 (3H, s), 3.45- 3.52 (IH, td), 3.62-3.65 (IH, dd), 3.75-3.78 (IH, d), 3.96-3.99 (IH, dd), 4.21-4.24 (IH, d), 4.57 (IH, bs), 6.67-6.69 (IH, t), 6.81 (IH, s), 8.01-8.04 (IH, dd), 8.05-8.08 (IH, dd), 8.27- 8.31 (IH, t), 8.47-8.48 (IH, d). mTOR Kinase Assay (Echo): 0.0307μM
Example 52c: 1H NMR (400.132 MHz, DMSOd6) δ 1.23-1.25 (3H, d), 1.55-1.58 (2H, q), 1.66-1.69 (2H, q), 3.17-3.25 (3H, m), 3.28 (3H, s), 3.45-3.65 (3H, m), 3.62-3.65 (IH, dd), 3.75-3.78 (IH, dd), 3.96-3.99 (IH, dd), 4.21-4.24 (IH, d), 4.58 (IH, bs), 4.73-7.76 (IH, t), 6.81 (IH, s), 6.84-6.87 (IH, t), 8.00-8.04 (IH, dd), 8.05-8.08 (IH, dd), 8.27-8.32 (IH, t), 8.63- 8.64 (IH, d). mTOR Kinase Assay (Echo): 0.0296μM
Example 52d: 1U NMR (400.132 MHz, DMSO-de) δ 1.24-1.25 (3H, d), 1.56-1.59 (2H, q), 1.67-1.70 (2H, q), 3.19-3.26 (IH, td), 3.29 (3H, s), 3.46-3.53 (IH, td), 3.62-3.66 (IH, dd), 3.76-3.79 (IH, d), 3.80 (3H, s), 3.96-3.99 (IH, dd), 4.22-4.25 (IH, d), 4.58 (IH, bs), 6.83 (IH, s), 7.40 (IH, s), 7.79 (IH, s), 8.04-8.08 (IH, dd), 8.09-8.12 (IH, dd), 8.28-8.33 (IH, t), 8.67- 8.68 (IH, d), 8.81 (IH, s). mTOR Kinase Assay (Echo): 0.0107μM
The preparation of phenyl Λ/-[2-fluoro-4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N-r2-fluoro-4-r4-r(3y)-3-methylmorpholin-4-yl1-6-(l- methylsulfonylcvclopropyl)pyrimidin-2-yllphenyllcarbamate
Figure imgf000700_0001
Phenyl chloroformate (0.116 mL, 0.93 mmol) was added to 2-fluoro-4-[4-[(35)-3- methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2-yl] aniline (0.376 g, 0.93 mmol) and sodium hydrogen carbonate (0.117 g, 1.39 mmol) in dioxane (10 mL) and the resulting solution stirred at RT for 2 hours. Water was added and the solution was extracted with DCM. The organics were dried (MgSO4), filtered and evaporated. The residue was triturated with diethyl ether to give the desired material as a white solid (0.427 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.24-1.26 (3H, d), 1.27-1.60 (2H, q), 1.68-1.70 (2H, q), 3.19-3.27 (IH, td), 3.28 (3H, s), 3.46-3.53 (IH, td), 3.62-3.66 (IH, dd), 3.76-3.79 (IH, d), 3.96-4.00 (IH, dd), 4.23-4.26 (IH, d), 4.59 (IH, bs), 6.87 (IH, s), 7.24- 7.30 (3H, m), 7.43-7.47 (2H, t), 7.87-7.91 (IH, t), 8.08-8.18 (2H, dd), 10.15 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=527; HPLC tR=2.93 min.
2-Fluoro-4-[4-[(36f)-3-methylmorpholin-4-yll-6-(l-methylsulfonylcvclopropyπpyrimidin-2- yl] aniline
Figure imgf000701_0001
Bis(triphenylphosphine)palladium(II) chloride (0.031 g, 0.04 mmol) was added in one portion to 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidine (0.297 g, 0.90 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.319 g, 1.34 mmol) and an aqueous solution of sodium carbonate (2.24 mL, 4.48 mmol) in a solvent mixture of 18% DMF, 82% of a 7:3:2 mixture of DME:water:Ethanol. The resulting solution was stirred at 800C under a nitrogen atmosphere for 30 minutes. The solvent was removed and the residue partitioned between water and ethyl acetate. The organic layer was dried (MgSO4), filtered and purified by flash silica chromatography, elution gradient 0 to 30% ethyl acetate in DCM, to give the desired material as a brown gum (0.376 g). NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.31-1.33 (3H, d), 1.52-1.55 (2H, q), 1.81-1.84 (2H, q), 3.08 (3H, s), 3.26-3.33 (IH, td), 3.54-3.60 (IH, td), 3.70-3.73 (IH, dd), 3.79-3.80 (IH, d), 4.00-4.03 (3H, m), 4.13 (IH, bs), 4.46-4.47 (IH, bs), 6.72 (IH, s), 6.76- 6.80 (IH, t), 7.99-8.02 (2H, m).
LCMS Spectrum: m/z (ES+)(M+H)+=407; HPLC tR=2.29 min. The preparation of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidine was described earlier.
Example 53 : 1- [4- [4- [ l-P-FluorophenyDsulfonylcvclopropyll -6- [(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-methylurea
Figure imgf000702_0001
Methylamine (26.4 mg, 0.85 mmol) was added to phenyl N-[4-[4-[l-(3- fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate (100 mg, 0.17 mmol) in NMP (2 mL). The resulting solution was heated at 500C for 2 days. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (41 mg).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.19 (3H, d), 1.65 (2H, m), 1.94 (2H, m), 2.67 (4H, m), 3.46 (IH, m), 3.61 (IH, m), 3.75 (IH, m), 3.96 (IH, m), 4.14 (IH, m), 4.44 (IH, m), 6.05 (IH, m), 6.65 (IH, s), 7.40 (2H, m), 7.63 (4H, m), 7.82 (2H, m), 8.72 (IH, m) LCMS Spectrum: m/z (ESI+)(M+H)+ = 526; HPLC tR = 2.07 min.
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[l-(3- fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000703_0001
Figure imgf000704_0001
Example 53a: 1R NMR (399.902 MHz, DMSO-Cl6) δ 0.43 (2H, m), 0.66 (2H, m), 1.19 (3H, d), 1.65 (2H, m), 1.94 (2H, m), 2.56 (IH, m), 3.16 (IH, m), 3.46 (IH, m), 3.61 (IH, m), 3.75 (IH, m), 3.96 (IH, m), 4.14 (IH, m), 4.44 (IH, m), 6.41 (IH, m), 6.65 (IH, s), 7.40 (2H, m), 7.62 (4H, m), 7.82 (2H, m), 8.52 (IH, s)
Example 53b: 1H NMR (399.902 MHz, DMSOd6) δ 1.19 (3H, d), 1.65 (2H, m), 1.93 (2H, m), 3.18 (3H, m), 3.46 (3H, m), 3.62 (IH, m), 3.75 (IH, m), 3.96 (IH, m), 4.15 (IH, m), 4.43 (IH, m), 4.74 (IH, m), 6.23 (IH, m), 6.65 (IH, s), 7.39 (2H, m), 7.63 (4H, m), 7.83 (2H, m),
8.78 (IH, s) Example 53c: 1U NMR (399.902 MHz, DMSOd6) δ 1.19 (3H, d), 1.65 (2H, m), 1.93 (2H, m), 3.16 (IH, m), 3.43 (3H, m), 3.62 (IH, m), 3.75 (IH, m), 3.96 (IH, m), 4.16 (IH, m), 4.43 (2H, m), 4.54 (IH, m), 6.42 (IH, m), 6.66 (IH, s), 7.40 (2H, m), 7.63 (4H, m), 7.83 (2H, m),
8.79 (IH, s)
Example 53d: 1H NMR (399.902 MHz, DMSOd6) δ 1.19 (3H, d), 1.65 (2H, m), 1.94 (2H, m), 3.16 (IH, m), 3.53 (4H, m), 3.75 (IH, m), 3.96 (IH, m), 4.15 (IH, m), 4.45 (IH, m), 6.07 (IH, m), 6.53 (IH, m), 6.66 (IH, s), 7.41 (2H, m), 7.63 (4H, m), 7.84 (2H, m), 8.91 (IH, s) Example 53e: 1H NMR (399.902 MHz, DMSO-Cl6) δ 1.07 (3H, t), 1.19 (3H, d), 1.65 (2H, m), 1.94 (2H, m), 3.13 (3H, m), 3.47 (IH, m), 3.62 (IH, m), 3.74 (IH, m), 3.96 (IH, m), 4.13 (IH, m), 4.44 (IH, m), 6.14 (IH, m), 6.65 (IH, s), 7.39 (2H, m), 7.63 (4H, m), 7.82 (2H, m), 8.64 (IH, s) Example 53f: 1H NMR (399.902 MHz, DMSO-d6) δ 1.20 (3H, d), 1.65 (2H, m), 1.95 (2H, m), 3.17 (IH, m), 3.47 (IH, m), 3.62 (IH, m), 3.78 (4H, m), 3.97 (IH, m), 4.15 (IH, m), 4.45 (IH, m), 6.66 (IH, s), 7.42 (3H, m), 7.65 (4H, m), 7.77 (IH, s), 7.86 (2H, d), 8.38 (IH, s), 8.81 (IH, s)
The preparation of phenyl Λ/-[4-[4-[l-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamateis described below:
Phenyl N- [4- [4- [ 1 -O-fluorophenyPsulfonylcvclopropyli-o-rOiSyS-methylmorpholin^- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000705_0001
Phenyl chloroformate (0.206 mL, 1.64 mmol) was added dropwise to 4-[4-[l-(3- fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (770 mg, 1.64 mmol) and sodium bicarbonate (138 mg, 1.64 mmol) in dioxane (30 mL). The resulting solution was stirred at RT for 3 hours. The reaction mixture was filtered and the precipitate collected and redissolved in DCM (100 mL). This was washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford the desired material as a yellow gum (722 mg). NMR Spectrum: 1H NMR (399.902 MHz, DMSO-d6) δ 1.19 (3H, d), 1.65 (2H, m), 1.95 (2H, m), 3.17 (IH, m), 3.46 (IH, m), 3.61 (IH, m), 3.75 (IH, m), 3.96 (IH, m), 4.16 (IH, m), 4.46 (IH, m), 6.70 (IH, s), 7.27 (3H, m), 7.55 (8H, m), 7.92 (2H, m), 10.40 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 589; HPLC tR = 3.02 min. 4- [4- r 1 -(3 -FluorophenyDsulfonylcvclopropyll-ό- [(36^-3 -methylmorpholin^-ylipyrimidin^- yll aniline
Figure imgf000706_0001
l,r-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.747 g, 1.03 mmol) was added to 2-chloro-4-[ 1 -(3-fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yljpyrimidine (4.25 g, 10.32 mmol) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (2.487 g, 11.35 mmol) in DME (200 mL) and sodium carbonate (5.47 g, 51.59 mmol) in water (25 mL) under nitrogen. The resulting solution was stirred at 800C for 5 hours. The reaction mixture was diluted with DCM (200 mL), and washed sequentially with water (200 mL) and saturated brine (200 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in DCM, to afford crude product as a yellow gum. The crude product was further purified by flash silica chromatography, elution gradient 0 to 5% ethyl acetate in DCM, to give the desired material as a yellow gum (2.86 g). NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.17 (3H, d), 1.63 (2H, m), 1.92 (2H, m), 3.12 (IH, m), 3.45 (IH, m), 3.60 (IH, m), 3.74 (IH, m), 3.95 (IH, m), 4.11 (IH, m), 4.40 (IH, s), 5.52 (2H, s), 6.50 (2H, m), 6.57 (IH, m), 7.63 (6H, m) LCMS Spectrum: m/z (ESI+)(M+H)+ = 469; HPLC tR = 2.35 min.
2-Chloro-4-ri-(3-fluorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000706_0002
Sodium hydroxide (24.80 g, 620.07 mmol) in water (24.8 mL) was added to 2-chloro-4-[(3- fluorophenyl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (4.35 g, 11.27 mmol), 1 ,2-dibromoethane (2.91 mL, 33.82 mmol) and tetrabutylammonium bromide (0.363 g, 1.13 mmol) in toluene (200 mL). The resulting solution was stirred at 600C for 3 hours. The reaction mixture was diluted with DCM (200 mL), and washed twice with water (200 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in DCM, to give the desired material as a white solid (4.25 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.20 (3H, d), 1.63 (2H, m), 1.94 (2H, m), 3.18 (IH, m), 3.45 (IH, m), 3.60 (IH, m), 3.74 (IH, m), 3.97 (2H, m), 4.32 (IH, m), 6.76 (IH, s), 7.69 (4H, m) LCMS Spectrum: m/z (ESI+)(M+H)+ = 412; HPLC tR = 2.27 min.
2-Chloro-4-[(3-fluorophenvπsulfonylmethyll-6-[(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000707_0001
2-Chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (7 g, 19.80 mmol) was added to sodium 3-fluorobenzenesulfinate (5.41 g, 29.70 mmol) in acetonitrile (100 mL) under nitrogen. The resulting suspension was stirred at 800C for 3 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (200 mL), and washed sequentially with water (200 mL) and saturated brine (200 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% ethyl acetate in DCM, to give the desired material as a white solid (6.38 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.17 (3H, d), 3.16 (IH, m), 3.43 (IH, m), 3.58 (IH, m), 3.73 (IH, m), 3.93 (2H, m), 4.18 (IH, m), 4.71 (2H, s), 6.74 (IH, s), 7.68 (4H, m) LCMS Spectrum: m/z (ESI+)(M+H)+ = 386; HPLC tR = 2.06 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine was described earlier. Sodium 3-fluorobenzenesulfinate
Figure imgf000708_0001
A solution of sodium sulphite (7.77 g, 61.66 mmol) in water (60 mL) was stirred at RT for 10 minutes. Sodium bicarbonate (10.36 g, 123.32 mmol) was added and the resulting solution was stirred at 500C for 1 hour. 3-Fluorobenzene-l-sulfonyl chloride (8.20 mL, 61.66 mmol) was added dropwise and the resulting solution was stirred at 500C for 20 hours. The reaction mixture was evaporated to dryness and redissolved in MeOH. The suspension was allowed to stir at RT for 20 minutes. The suspension was filtered and the filtrate evaporated to afford the desired material (12.60 g) as a white solid, which was air dried overnight under vacuum and used without further purification.
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 7.03 (IH, m), 7.21 (IH, m), 7.29 (IH, m), 7.36 (IH, m)
Example 54 : 3-Methyl- 1- [4- [4- [(3SV3-methylmorpholin-4-yll -6- W-(I- methylphenyDsulfonylcyclopropyll pyrimidin-2-yll phenyll urea
Figure imgf000708_0002
Methylamine (37.27 mg, 1.2 mmol) was added to phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4- yl]-6-[l-(2-methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]carbamate (140 mg, 0.24 mmol) and triethylamine (0.2 mLl, 0.72 mmol) in NMP (2 mL). The resulting solution was heated at 500C for 2 days. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material (87 mg).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.15 (3H, d), 1.66 (2H, m), 1.86 (2H, m), 2.45 (3H, s), 2.66 (3H, m), 3.12 (IH, m), 3.45 (IH, m), 3.60 (IH, m), 3.74 (IH, m), 3.94
(IH, m), 4.06 (IH, m), 4.39 (IH, m), 6.05 (IH, m), 6.60 (IH, s), 7.37 (4H, m), 7.51 (IH, m),
7.85 (3H, m), 8.71 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 522; HPLC tR = 2.29 min.The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[(35)-3-methylmorpholin-4-yl]-6- [ 1 -(2 -me thylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl] carbamate and the appropriate amine.
Figure imgf000709_0001
Figure imgf000710_0001
Example 54a: 1H NMR (399.902 MHz, DMSOd6) δ 0.42 (2H, m), 0.65 (2H, m), 1.15 (3H, d), 1.66 (2H, m), 1.86 (2H, m), 2.46 (3H, s), 2.56 (IH, m), 3.13 (IH, m), 3.44 (IH, m), 3.59 (IH, m), 3.74 (IH, m), 3.95 (IH, m), 4.07 (IH, m), 4.39 (IH, m), 6.42 (IH, m), 6.60 (IH, s), 7.37 (4H, m), 7.51 (IH, m), 7.84 (3H, m), 8.51 (IH, s)
Example 54b: 1H NMR (399.902 MHz, DMSOd6) δ 1.15 (3H, d), 1.66 (2H, m), 1.86 (2H, m), 2.46 (3H, s), 3.14 (3H, m), 3.45 (3H, m), 3.59 (IH, m), 3.74 (IH, m), 3.95 (IH, m), 4.07 (IH, m), 4.38 (IH, m), 4.74 (IH, t), 6.24 (IH, m), 6.60 (IH, s), 7.36 (4H, m), 7.51 (IH, m), 7.84 (3H, m), 8.77 (IH, s) Example 54c: 1H NMR (399.902 MHz, DMSO-Cl6) δ 1.15 (3H, d), 1.66 (2H, m), 1.86 (2H, m), 2.45 (3H, s), 3.12 (IH, m), 3.43 (3H, m), 3.60 (IH, m), 3.74 (IH, m), 3.95 (IH, m), 4.07
(IH, m), 4.40 (2H, m), 4.54 (IH, m), 6.42 (IH, m), 6.61 (IH, s), 7.37 (4H, m), 7.51 (IH, m),
7.85 (3H, m), 8.78 (IH, s) Example 54d: 1H NMR (399.902 MHz, DMSO-d6) δ 1.15 (3H, d), 1.66 (2H, m), 1.86 (2H, m), 2.46 (3H, s), 3.11 (IH, m), 3.51 (4H, m), 3.75 (IH, m), 3.95 (IH, m), 4.07 (IH, m), 4.39
(IH, m), 6.08 (IH, m), 6.52 (IH, m), 6.61 (IH, s), 7.38 (4H, m), 7.51 (IH, m), 7.85 (3H, m),
8.89 (IH, s)
Example 54e: 1R NMR (399.902 MHz, DMSO-(I6) δ 1.07 (3H, t), 1.15 (3H, d), 1.66 (2H, m), 1.85 (2H, m), 2.45 (3H, s), 3.12 (3H, m), 3.44 (IH, m), 3.60 (IH, m), 3.74 (IH, m), 3.95 (IH, m), 4.06 (IH, m), 4.39 (IH, m), 6.15 (IH, m), 6.60 (IH, s), 7.37 (4H, m), 7.51 (IH, m), 7.84
(3H, m), 8.63 (IH, s)
Example 54f: 1H NMR (399.902 MHz, DMSO-d6) δ 1.16 (3H, d), 1.66 (2H, m), 1.86 (2H, m), 2.46 (3H, s), 3.12 (IH, m), 3.45 (IH, m), 3.60 (IH, m), 3.74 (IH, m), 3.80 (3H, s), 3.95 (IH, m), 4.07 (IH, m), 4.39 (IH, m), 6.61 (IH, s), 7.43 (6H, m), 7.80 (2H, m), 7.90 (2H, m),
8.37 (IH, s), 8.80 (IH, s)
The preparation of phenyl N-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-(2- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl] carbamate is described below:
Phenyl N-r4-r4-r(3^-3-methylmorpholin-4-yll-6-π -(2- methylphenvπsulfonylcvclopropyllpyrimidin-2-yllphenyllcarbamate
Phenyl chloroformate (0.205 mL, 1.64 mmol) was added dropwise to 4-[4-[(35)-3- methylmorpholin-4-yl]-6-[ 1 -(2 -methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl] aniline (760 mg, 1.64 mmol) and sodium bicarbonate (151 mg, 1.80 mmol) in dioxane (30 mL). The resulting suspension was stirred at RT for 3 hours. The reaction mixture was filtered and the precipitate was redissolved in DCM (50 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford the desired material as a yellow gum (985 mg).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.16 (3H, d), 1.67 (2H, m), 1.87 (2H, m), 2.47 (3H, s), 3.12 (IH, m), 3.45 (IH, m), 3.61 (IH, m), 3.74 (IH, m), 3.95 (IH, m), 4.08 (IH, m), 4.40 (IH, m), 6.64 (IH, s), 7.30 (5H, m), 7.49 (5H, m), 7.81 (IH, m), 7.95 (2H, m), 10.39 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 585; HPLC tR = 3.08 min.
4-r4-r(35)-3-Methylmorpholin-4-yll-6-ri-(2-methylphenyl)sulfonylcvclopropyllpyrimidin-2- yl] aniline
Figure imgf000712_0001
A solution of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-[l-(2- methylphenyl)sulfonylcyclopropyl]pyrimidine (2.04 g, 5.00 mmol), 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)aniline (1.205 g, 5.50 mmol) and sodium carbonate (2.120 g, 20.00 mmol) in DME (60 mL) and water (15.00 mL) was stirred under nitrogen for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.351 g, 0.50 mmol) was added and the resulting solution was stirred at 800C for 2 hours. The reaction mixture was diluted with DCM (200 mL), and washed with water (200 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% ethyl acetate in isohexane, to give the desired material as a yellow oil which solidified on standing (2.14 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSO-d6) δ 1.18 (3H, d), 1.69 (2H, m), 1.87 (2H, m), 2.51 (3H, s), 3.12 (IH, m), 3.47 (IH, m), 3.63 (IH, m), 3.77 (IH, m), 3.98 (IH, m), 4.08 (IH, m), 4.39 (IH, m), 5.56 (2H, s), 6.54 (3H, m), 7.39 (2H, m), 7.56 (IH, m), 7.77 (2H, m), 7.87 (IH, m)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 465; HPLC tR = 2.41 min. 2-Chloro-4-r(3^-3-methylmorpholin-4-yll-6-ri-(2- methylphenvDsulfonylcvclopropyHpyrimidine
Figure imgf000713_0001
Sodium hydroxide (12.67 g, 317 mmol) in water (12.7 mL) was added to 2-chloro-4-[(35)-3- methylmorpholin-4-yl]-6-[(2-methylphenyl)sulfonylmethyl]pyrimidine (2.2 g, 5.76 mmol), 1 ,2-dibromoethane (1.489 mL, 17.28 mmol) and tetrabutylammonium bromide (0.186 g, 0.58 mmol) in toluene (80 mL). The resulting solution was stirred at 600C for 1 hour. The reaction mixture was diluted with DCM (200 mL), and washed sequentially with water (200 mL) and saturated brine (200 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a colourless gum which solidified on standing (2.04 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.17 (3H, d), 1.63 (2H, m), 1.86 (2H, m), 2.48 (3H, s), 3.14 (IH, m), 3.42 (IH, m), 3.58 (IH, m), 3.74 (IH, m), 3.95 (2H, m), 4.25 (IH, m), 6.70 (IH, s), 7.43 (2H, m), 7.63 (IH, m), 7.79 (IH, m) LCMS Spectrum: m/z (ESI+)(M+H)+ = 408; HPLC tR = 2.44 min.
2-Chloro-4-r(36f)-3-methylmorpholin-4-yll-6-r(2-methylphenyl)sulfonylmethyllpyrimidine
Figure imgf000713_0002
2N sulfuric acid (0.352 mL) was added to 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-[(2- methylphenyl)sulfanylmethyl]pyrimidine (4.37 g, 12.49 mmol) in dioxane (110 mL) and the solution heated to 55°C. Sodium tungstate dihydrate (0.082 g, 0.25 mmol) in water (3.5 mL) was added and the solution was allowed to stir for 5 minutes. Hydrogen peroxide (7.65 mL, 74.94 mmol) was added dropwise to the solution. The resulting solution was stirred at 55°C for 5 hours. The reaction was cooled to RT then water added until precipitation ceased. The precipitate was collected by filtration, washed with water and dried under vacuum to afford the desired material as a white solid (3.70 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.16 (3H, d), 2.63 (3H, s), 3.14 (IH, m), 3.42 (IH, m), 3.56 (IH, m), 3.72 (IH, m), 3.93 (2H, m), 4.18 (IH, s), 4.59 (2H, s), 6.67 (IH, s), 7.44 (2H, m), 7.65 (2H, m)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 382; HPLC tR = 2.23 min. 2-Chloro-4-r(36f)-3-methylmorpholin-4-yll-6-r(2-methylphenyl)sulfanylmethyllpyrimidine
Figure imgf000714_0001
DIPEA (3.70 mL, 21.21 mmol) was added to 2-chloro-4-(iodomethyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidine (5 g, 14.14 mmol) and 2-methylbenzenethiol (2.5 mL, 21.21 mmol) in THF (80 mL). The resulting slurry was stirred at RT for 18 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried over MgSCM, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% ethyl acetate in isohexane, to give the desired material as a yellow gum (4.37 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.13 (3H, d), 2.28 (3H, s), 3.11 (IH, m), 3.40 (IH, m), 3.55 (IH, m), 3.69 (IH, m), 3.90 (2H, m), 4.04 (2H, m), 4.21 (IH, m), 6.65 (IH, s), 7.18 (3H, m), 7.37 (IH, m) LCMS Spectrum: m/z (ESI+)(M+H)+ = 350; HPLC tR = 2.71 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier. Example 55: l-[4-[4-[l-(l,3-Dimethylpyrazol-4-yl)sulfonylcvclopropyll-6-[(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-methylurea
Figure imgf000715_0001
Methylamine (26.4 mg, 0.85 mmol) was added to phenyl 7V-[4-[4-[l-(l,3-dimethylpyrazol-4- yl)sulfonylcyclopropyl] -6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate (100 mg, 0.17 mmol) and triethylamine (0.2 mL, 0.72 mmol) in NMP (2 mL). The resulting solution was heated at 500C for 2 days. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material (77 mg). NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.20 (3H, d), 1.54 (2H, m), 1.74 (2H, m), 2.03 (3H, s), 2.67 (3H, m), 3.20 (IH, m), 3.48 (IH, m), 3.63 (IH, m), 3.77 (4H, m), 3.98 (IH, m), 4.13 (IH, m), 4.46 (IH, m), 6.06 (IH, m), 6.70 (IH, s), 7.45 (2H, d), 7.98 (2H, d), 8.18 (IH, s), 8.72 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 526; HPLC tR = 1.87 min.
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[l-(l,3- dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000715_0002
Figure imgf000716_0001
Figure imgf000717_0001
Example 55a: 1H NMR (399.902 MHz, DMSO-Cl6) δ 0.42 (2H, m), 0.65 (2H, m), 1.20 (3H, d), 1.54 (2H, m), 1.74 (2H, m), 2.03 (3H, s), 2.56 (IH, m), 3.18 (IH, m), 3.48 (IH, m), 3.63 (IH, m), 3.76 (4H, m), 3.98 (IH, m), 4.14 (IH, m), 4.45 (IH, m), 6.42 (IH, m), 6.70 (IH, s), 7.46 (2H, m), 7.99 (2H, m), 8.19 (IH, s), 8.53 (IH, s)
Example 55b: 1H NMR (399.902 MHz, DMSOd6) δ 1.21 (3H, d), 1.54 (2H, m), 1.73 (2H, m), 2.03 (3H, s), 3.18 (3H, m), 3.47 (3H, m), 3.63 (IH, m), 3.76 (4H, m), 3.98 (IH, m), 4.14 (IH, m), 4.46 (IH, m), 4.74 (IH, t), 6.25 (IH, m), 6.70 (IH, s), 7.44 (2H, d), 7.98 (2H, d), 8.19 (1H, s), 8.79 (IH, s)
Example 55c: 1R NMR (399.902 MHz, DMSOd6) δ 1.20 (3H, d), 1.54 (2H, m), 1.74 (2H, m), 2.03 (3H, s), 3.18 (2H, m), 3.39 (IH, m), 3.46 (2H, m), 3.63 (IH, m), 3.76 (4H, m), 3.98 (IH, m), 4.14 (IH, m), 4.49 (2H, m), 6.43 (IH, m), 6.70 (IH, s), 7.46 (2H, d), 7.99 (2H, d), 8.18 (1H, s), 8.80 (IH, s) Example 55d: 1H NMR (399.902 MHz, DMSOd6) δ 1.21 (3H, d), 1.55 (2H, m), 1.74 (2H, m), 2.02 (3H, s), 3.17 (IH, m), 3.54 (4H, m), 3.76 (4H, m), 3.97 (IH, m), 4.14 (IH, m), 4.47 (IH, m), 6.08 (IH, m), 6.52 (IH, m), 6.71 (IH, s), 7.46 (2H, m), 8.01 (2H, m), 8.19 (IH, s), 8.90 (IH, s) Example 55e: 1U NMR (399.902 MHz, DMSOd6) δ 1.07 (3H, t), 1.20 (3H, d), 1.54 (2H, m), 1.74 (2H, m), 2.03 (3H, s), 3.15 (3H, m), 3.48 (IH, m), 3.63 (IH, m), 3.76 (4H, m), 3.98 (IH, m), 4.13 (IH, m), 4.46 (IH, m), 6.16 (IH, m), 6.70 (IH, s), 7.45 (2H, d), 7.98 (2H, d), 8.19 (IH, s), 8.65 (IH, s) Example 55f: 1H NMR (399.902 MHz, DMSO-d6) δ 1.21 (3H, d), 1.54 (2H, m), 1.74 (2H, m), 2.04 (3H, s), 3.18 (IH, m), 3.49 (IH, m), 3.63 (IH, m), 3.77 (7H, m), 3.98 (IH, m), 4.15 (IH, m), 4.47 (IH, m), 6.71 (IH, s), 7.39 (IH, s), 7.50 (2H, d), 7.77 (IH, s), 8.02 (2H, d), 8.19 (IH, s), 8.38 (IH, s), 8.82 (IH, s)
The preparation of phenyl Λ/-[4-[4-[l-(l,3-dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6-[(35)- 3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below:
Phenyl N-r4-r4-ri-(1.3-dimethylpyrazol-4-yl)sulfonylcvclopropyll-6-r(35)-3- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000718_0001
Phenyl chloro formate (0.201 mL, 1.60 mmol) was added dropwise to 4-[4-[l-(l,3- dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yljaniline (750mg, 1.60 mmol) and sodium bicarbonate (148 mg, 1.76 mmol) in dioxane (30 mL). The resulting suspension was stirred at RT for 3 hours. The reaction mixture was filtered and the precipitate was redissolved in DCM (50 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford the desired material as an orange gum which formed a foam solid when heated in desiccator (1.030 g). NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.22 (3H, d), 1.55 (2H, m), 1.75 (2H, m), 2.04 (3H, s), 3.20 (IH, m), 3.49 (IH, m), 3.63 (IH, m), 3.76 (4H, m), 3.98 (IH, m), 4.16 (IH, m), 4.48 (IH, m), 6.75 (IH, s), 7.28 (3H, m), 7.45 (2H, m), 7.59 (2H, m), 8.07 (2H, m), 8.20 (IH, s), 10.43 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 589; HPLC tR = 2.63 min. 4- [4- Fl-(I., 3 -Dimethylpyrazol-4-yl)sulfonylcvclopropyll -6- F(3ιSy3-methylmorphorin-4- yllpyrimidin-2-vHaniline
Figure imgf000719_0001
A solution of 2-chloro-4-[ 1 -(1 ,3-dimethylpyr azol-4-yl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidine (2.44 g, 5.92 mmol), 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (1.428 g, 6.52 mmol) and sodium carbonate (2.51 g, 23.69 mmol) in DME (60 mL) and water (15 mL) was stirred under nitrogen for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.416 g, 0.59 mmol) was added and the resulting solution was stirred at 800C for 5 hours. The reaction mixture was diluted with DCM (200 mL), and washed sequentially with water (200 mL) and saturated brine (200 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 1% MeOH in DCM, to give crude product. The crude product was further purified by ion exchange chromatography using an SCX column, eluting with 2M ammonia in methanol, to give the desired material as a orange solid (1.25 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSO-d6) δ 1.19 (3H, d), 1.52 (2H, m), 1.72 (2H, m), 2.04 (3H, s), 3.15 (IH, m), 3.47 (IH, m), 3.61 (IH, m), 3.75 (4H, m), 3.97 (IH, m), 4.09 (IH, m), 4.42 (IH, m), 5.52 (2H, s), 6.57 (3H, m), 7.82 (2H, m), 8.17 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 469; HPLC tR = 1.87 min.
2-Chloro-4-Fl-(l,3-dimethylpyrazol-4-yl)sulfonylcvclopropyll-6-F(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000719_0002
Sodium hydroxide (14.54 g, 363.47 mmol) in water (14.5 mL) was added to a stirred solution of 2-chloro-4-[(l,3-dimethylpyrazol-4-yl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4- yljpyrimidine (2.55 g, 6.61 mmol), 1 ,2-dibromoethane (1.708 mL, 19.83 mmol) and tetrabutylammonium bromide (0.213 g, 0.66 mmol) in toluene (100 mL).The resulting solution was stirred at 600C for 3 hours. The reaction mixture was diluted with DCM (200 mL), and washed sequentially with water (200 mL) and saturated brine (200 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% ethyl acetate in DCM, to give the desired material as a white solid (2.44 g). NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.18 (3H, d), 1.48 (2H, m), 1.70 (2H, m), 2.05 (3H, s), 3.17 (IH, m), 3.42 (IH, m), 3.57 (IH, m), 3.72 (IH, m), 3.80 (3H, s), 3.93 (2H, m), 4.30 (IH, m), 6.77 (IH, s), 8.20 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 412; HPLC tR = 1.69 min.
2-Chloro-4-r(l,3-dimethylpyrazol-4-yl)sulfonylmethyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000720_0001
2-Chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (5 g, 14.14 mmol) was added to sodium 1,3 -dimethyl- lH-pyrazole-4-sulfinate (4.79 g, 26.29 mmol) in DMF (80 mL). The resulting solution was stirred at RT for 18 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in DCM, to give the desired material as a white solid (4.55 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSO-d6) δ 1.19 (3H, d), 2.13 (3H, s), 3.18 (IH, m), 3.44 (IH, m), 3.58 (IH, m), 3.73 (IH, m), 3.80 (3H, s), 3.94 (2H, m), 4.22 (IH, s), 4.46 (2H, s), 6.72 (IH, s), 8.14 (1H, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 386; HPLC tR = 1.63 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Sodium 1 ,3 -dimethyl- lH-pyrazole-4-sulfmate
Figure imgf000721_0001
A solution of sodium sulfite (2.82 g, 22.35 mmol) in water (30 mL) was stirred for 10 minutes at RT. Sodium bicarbonate (3.75 g, 44.70 mmol) was added and the solution was stirred for 1 hour at 500C. 1,3 -Dimethyl- lH-pyrazole-4-sulfonyl chloride (4.35 g, 22.35 mmol) was added portionwise and the resulting solution was stirred at 500C for 18 hours. The suspension was allowed to stir at RT for 20 minutes. The suspension was filtered and the filtrate evaporated to afford the desired material as a white solid, which was air dried overnight under vacuum and used without further purification (4.79 g).
Example 56: 3-Cvclopropyl-l-[4-[4-morpholin-4-yl-6-(l-pyridin-2- ylsulfonylcvclopr()pyl)pyrimidin-2-yll phenyll urea
Figure imgf000721_0002
A solution of phenyl Λ/-[4-[4-morpholin-4-yl-6-(l-pyridin-2-ylsulfonylcyclopropyl)pyrimidin- 2-yl]phenyl] carbamate (0.100g, 0.18mmol), cycloprpylamine (0.90 mmol) and triethylamine (0.076 mL, 0.54 mmol) in NMP (2 mL) was heated at 5O0C for 16 hours. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a solid (75 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), 1.71-1.74 (2H, q), 1.98-2.01 (2H, q), 2.54-2.58 (IH, m), 3.63-3.65 (4H, m), 3.68-3.70 (4H, m), 6.40-6.41 (IH, d), 6.71 (IH, s), 7.35-7.37 (2H, d), 7.68-7.70 (2H, d), 7.73-7.76 (IH, m), 7.96-7.99 (IH, dt), 8.06-8.10 (IH, td), 8.49 (IH, s), 8.82-8.83 (IH, m). LCMS Spectrum: m/z (ESI+)(M+H)+ = 521; HPLC tR = 1.99min.
The compounds below were prepared in an analogous fashion from phenyl N- [4- [4- morpholin-4-yl-6-(l-pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl] carbamate using the appropriate amine.
Figure imgf000722_0001
Example 56a: 1U NMR (400.132 MHz, DMSO-Cl6) δ 1.70-1.74 (2H, q), 1.98-2.01 (2H, q), 2.65-2.66 (3H, d), 3.63-3.65 (4H, m), 3.68-3.70 (4H, m), 6.02-6.06 (IH, q), 6.71 (IH, s), 7.34- 7.37 (2H, d), 7.67-7.70 (2H, d), 7.73-7.76 (IH, m), 7.96-7.98 (IH, dt), 8.06-8.10 (IH, td), 8.69 (IH, s), 8.82-8.84 (IH, m). Example 56b: 1H NMR (400.132 MHz, DMSOd6) δ 1.05-1.08 (3H, t), 1.70-1.73 (2H, q), 1.98-2.01 (2H, q), 3.09-3.16 (2H, m), 3.63-3.64 (4H, m), 3.68-3.69 (4H, m), 6.12-6.15 (IH, t), 6.71 (IH, s), 7.33-7.36 (2H, d), 7.67-7.70 (2H, d), 7.73-7.76 (IH, m), 7.96-7.99 (IH, dt), 8.06- 8.10 (IH, td), 8.61 (IH, s), 8.82-8.83 (IH, m). Example 56c: 1R NMR (400.132 MHz, DMSO-dg) δ 1.70-1.74 (2H, q), 1.98-2.01 (2H, q), 3.15-3.19 (2H, m), 3.44-3.48 (2H, m), 3.63-3.65 (4H, m), 3.68-3.69 (4H, m), 4.71-4.74 (IH, t), 6.23-6.24 (IH, t), 6.71 (IH, s), 7.33-7.35 (2H, d), 7.68-7.70 (2H, d), 7.73-7.76 (IH, m), 7.96-7.99 (IH, dt), 8.06-8.10 (IH, td), 8.76 (IH, s), 8.82-8.84 (IH, m). Example 56d: 1H NMR (400.132 MHz, DMSOd6) δ 1.71-1.74 (2H, q), 1.99-2.02 (2H, q), 3.64-3.66 (4H, m), 3.68-3.71 (4H, m), 3.79 (3H, s), 6.73 (IH, s), 7.38-7.41(3H m), 7.71-7.76 (4H, m), 7.97-7.99 (IH, dt), 8.07-8.11 (IH, td), 8.36 (IH, s), 8.79 (IH, s), 8.83-8.84 (IH, m).
The preparation of phenyl Λ/-[4-[4-morpholin-4-yl-6-(l-pyridin-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl N- [4- r4-morpholin-4-yl-6-(l-pyridin-2-ylsulfonylcvclopropyl)pyrimidin-2- yllphenyl] carbamate
Figure imgf000723_0001
Phenyl chloro formate (0.363 mL, 2.89 mmol) was added to 4-[4-morpholin-4-yl-6-(l-pyridin- 2-ylsulfonylcyclopropyl)pyrimidin-2-yl]aniline (1.265 g, 2.89 mmol) and sodium hydrogen carbonate (0.364 g, 4.34 mmol) in DCM (50 mL) at RT and the resulting suspension stirred for 2 hours. The mixture was washed with water, dried over MgSO4, filtered and evaporated and the resultant gum dried in the vacuum oven at 5O0C overnight to give the desired material as a colorless gum (1.86 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.73-1.77 (2H, q), 1.99-2.03 (2H, q), 3.68-3.69(8H, m), 6.77 (IH, s), 7.24-7.32 (3H, m), 7.44-7.52 (4H, m), 7.74-7.77 (IH, m), 7.80-7.82 (2H, d), 7.98-8.01 (IH, dt), 8.07-8.11 (IH, td), 8.83-8.85 (IH, dq), 10.4 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=558; HPLC tR=2.75 min.
4-r4-morpholin-4-yl-6-(l-pyridin-2-ylsulfonylcvclopropyl)pyrimidin-2-yllaniline
Figure imgf000724_0001
Bis(triphenylphosphine)palladium(II) chloride (0.131 g, 0.19 mmol) was added in one portion to 2-chloro-4-morpholin-4-yl-6-(l-pyridin-2-ylsulfonylcyclopropyl)pyrimidine (1.42 g, 3.73 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.817 g, 3.73 mmol) and 2M aquoeus sodium carbonate solution (9.32 mL, 18.64 mmol) in a DMF solution (18% DMF, 82% of a 7:3:2 mixture of DME:water:Ethanol) at 220C under nitrogen. The resulting solution was stirred at 800C for 3 hours. The solvent was removed, ethyl acetate added and the organics washed with water. Precipitate was observed in the aqueous layer and was isolated by filtration to give crude product. This material was dissolved in DCM and insoluble material removed by filtration and discarded. The filtrate was purified by ion exchange chromatography using an SCX column, eluting with 7M ammonia in methanol, to give material which was further purified by flash silica chromatography, elution gradient 0 to 60% ethyl acetate in DCM, to give the desired material as a white solid (1.265 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.68-1.71 (2H, q), 1.96-2.00 (2H, q), 3.59-3.61 (4H, m), 3.66-3.69 (4H, m), 5.48-5.50 (IH, d (NH2), 6.45-6.47 (2H, d), 6.61 (IH, s), 7.52-7.54 (2H, d), 7.72-7.75 (IH, m), 7.96-7.98 (IH, dt), 8.05-8.10 (IH, td), 8.81-8.83 (IH, dq). LCMS Spectrum: m/z (ES+)(M+H)+=438; HPLC tR=1.93 min. 2-Chloro-4-morpholin-4-yl-6-(l-pyridin-2-ylsulfonylcvclopropyl)pyrimidine
Figure imgf000725_0001
Sodium hydroxide (50%w/w solution) (12.71 g, 317.77 mmol) was added to 2-chloro-4- morpholin-4-yl-6-(pyridin-2-ylsulfonylmethyl)pyrimidine (2.050 g, 5.78 mmol), 1,2- dibromoethane (1.494 mL, 17.33 mmol) and tetrabutylammonium bromide (0.186 g, 0.58 mmol) in toluene (50 mL) at RT. The resulting suspension was stirred at 600C overnight. Water was added and the layers were separated. The organic layer was washed twice with water, dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a white solid (1.42 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.63-1.66 (2H, q), 1.91-1.95 (2H, q), 3.55 (4H, bs), 3.63-3.65 (4H, t), 6.84 (IH, s), 7.73-7.76 (IH, m), 7.98-8.00 (IH, dt), 8.10-8.14 (IH, td), 8.77-8.79 (IH, dt). LCMS Spectrum: m/z (ES+)(M+H)+=381; HPLC tR=1.71 min.
2-Chloro-4-morpholin-4-yl-6-(pyridin-2-ylsulfonylmethyl)pyrimidine
Figure imgf000725_0002
2-Chloro-4-morpholin-4-yl-6-(pyridin-2-ylsulfanylmethyl)pyrimidine (4.96 g, 15.36 mmol) was dissolved in dioxane (70 mL) and 2N sulfuric acid (0.362 mL) was added. The solution was heated to 55°C. Sodium tungstate dihydrate (0.101 g, 0.31 mmol) dissolved in water (3.54 mL) was added to the solution and allowed to stir for 10 minutes. Hydrogen peroxide (9.50 mL, 307.30 mmol) was then added dropwise over several minutes. The solution was heated at 55°C for 4 hours. Water (30OmL) was added and the reaction was allowed to cool. The reaction mixture was extracted with DCM, the organic layer dried over MgSO4, filtered and evaporated to afford desired product as a pale yellow solid (5.09g). NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 3.64 (3H, bs), 3.75-3.77(5H, t), 4.56 (2H, s), 6.60 (IH, s), 7.57-7.61 (IH, m), 7.97-7.97 (2H, m), 8.78-8.80 (IH, dt). LCMS Spectrum: m/z (ES+)(M+H)+=355; HPLC tR=1.51 min.
2-Chloro-4-morpholin-4-yl-6-(pyridin-2-ylsulfanylmethvπpyrimidine
Figure imgf000726_0001
2-Chloro-4-(iodomethyl)-6-morpholin-4-ylpyrimidine (6.60 g, 19.44 mmol) was added to 2- mercaptopyridine (3.24 g, 29.16 mmol) and DIPEA (5.08 mL, 29.16 mmol) in acetonitrile (140 mL) at RT. The resulting solution was stirred at RT for 2 hours then evaporated to dryness, redissolved in DCM and washed sequentially with water and saturated brine. The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% ethyl acetate in DCM, to give the desired material as a beige oil which solidified on standing (4.96 g)- NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 3.52 (4H, bs), 3.64-3.67 (4H, t), 4.27
(2H, s), 6.58 (IH, s), 6.93-6.96 (IH, q), 7.11-7.13 (IH, dd), 7.41-7.45 (IH, td), 8.34-8.36 (IH, dt).
LCMS Spectrum: m/z (ES+)(M+H)+=323; HPLC tR=1.98 min.
The preparation of 2-chloro-4-(iodomethyl)-6-morpholin-4-ylpyrimidine was described earlier.
Example 57: 1- [4-[4- [l-f2-Fluoro-4-methylaminophenyl)sulfonylcvclopropyll -6- [(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-methylurea
Figure imgf000726_0002
Phenyl 7V-[4-[4-[ 1 -(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate (0.15 g, 0.25 mmol), triethylamine (0.103 mL, 0.74 mmol) and methylamine solution (2M in THF, 1.236 mL, 2.47 mmol) were added to dioxane (10 mL) and heated at 500C over the weekend. The reaction was evaporated to dryness and was purified by preparative HPLC, eluting with decreasingly polar mixtures of water
(containing 1% ammonia) and acetonitrile, to give the desired material as a white solid (0.074 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.51 - 1.48 (2H, m),
1.82 - 1.78 (2H, m), 2.66 (3H, d), 3.14 (IH, ddd), 3.45 (IH, ddd), 3.60 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.06 (IH, d), 4.43 (IH, s), 6.04 (IH, q), 6.33 - 6.32 (IH, m), 6.38 (IH, dd), 6.43 (IH, ddd), 6.54 (IH, s), 7.47 (3H, m), 7.95 (2H, d), 8.72 (IH, s); LCMS Spectrum: m/z (ES+)(M+H)+=555; HPLC tR=2.40 min.
The following compounds were prepared in an analogous fashion from phenyl 7V-[4-[4-[l- (2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000727_0001
Figure imgf000728_0001
Example 57a: 1R NMR (400.132 MHz, DMSOd6) δ 0.43 - 0.40 (2H, m), 0.67 - 0.62 (2H, m), 1.19 (3H, d), 1.67 - 1.64 (2H, m), 1.91 - 1.89 (2H, m), 2.57 - 2.54 (IH, m), 3.16 (IH, ddd), 3.46 (IH, ddd), 3.61 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.16 (IH, d), 4.46 (IH, s), 6.39 (IH, s), 6.69 (IH, s), 7.20 (IH, ddd), 7.38 (2H, d), 7.65 - 7.59 (IH, m), 7.77 - 7.72 (3H, m), 8.51 (IH, s).
Example 57b: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.67 - 1.63 (2H, m), 1.91 1.87 (2H, m), 3.17 (3H, m), 3.48 - 3.42 (3H, m), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, d), 4.15 (IH, d), 4.46 (IH, s), 4.72 (IH, t), 6.22 (IH, t), 6.68 (IH, s), 7.20 (IH, ddd), 7.36 (2H, d), 7.65 - 7.60 (IH, m), 7.77 - 7.72 (3H, m), 8.78 (IH, s). Example 57c: 1R NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.67 - 1.64 (2H, m), 1.91 -
1.89 (2H, m), 3.16 (IH, ddd), 3.38 (IH, q), 3.49 - 3.43 (2H, m), 3.61 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.16 (IH, d), 4.41 (IH, t), 4.47 (IH, s), 4.53 (IH, t), 6.40 (IH, t), 6.69 (IH, s),
7.20 (IH, ddd), 7.38 (2H, d), 7.65 - 7.60 (IH, m), 7.77 - 7.71 (3H, m), 8.79 (IH, s). Example 57d: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.67 - 1.64 (2H, m), 1.92 1.87 (2H, m), 3.16 (IH, ddd), 3.63 - 3.43 (4H, m), 3.74 (IH, d), 3.95 (IH, dd), 4.16 (IH, d), 4.47 (IH, s), 6.07 (IH, ddt), 6.49 (IH, t), 6.69 (IH, s), 7.20 (IH, t), 7.39 (IH, d), 7.65 - 7.60 (IH, m), 7.76 - 7.71 (4H, m), 8.90 (IH, s). Example 57e: Spectrum not recorded. Example 57f: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.67 - 1.64 (2H, m), 1.92 -
1.90 (2H, m), 3.16 (IH, ddd), 3.46 (IH, ddd), 3.61 (IH, dd), 3.75 (IH, d), 3.79 (3H, s), 3.96 (IH, d), 4.16 (IH, d), 4.48 (IH, s), 6.70 (IH, s), 7.20 (IH, ddd), 7.38 (IH, s), 7.42 (2H, d), 7.66 - 7.61 (IH, m), 7.78 - 7.71 (4H, m), 8.34 (IH, s), 8.82 (IH, s).
Example 57g: 1R NMR (400.132 MHz, DMSOd6) δ 0.51 - 0.48 (2H, m), 0.60 - 0.57 (2H, m), 1.19 (3H, d), 1.67 - 1.62 (2H, m), 1.91 - 1.87 (2H, m), 3.22 (2H, d), 3.29 - 3.27 (IH, m), 3.46 (IH, ddd), 3.61 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.17 - 4.14 (IH, m), 4.47 (IH, s), 6.29 (IH, t), 6.68 (IH, s), 7.20 (IH, t), 7.36 (2H, d), 7.63 (IH, t), 7.73 (3H, d), 8.78 (IH, s).
The preparation of phenyl Λ/-[4-[4-[l-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below. Phenyl N-[4-[4-[ 1 -(2,4-difluorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000730_0001
4- [4- [ 1 -(2,4-Difluorophenyl)sulfbnylcyclopropyl] -6-[(3S)-3 -methylmorpholin-4-yl]pyrimidin- 2-yl]aniline (2.1 g, 4.32 mmol) and sodium bicarbonate (0.725 g, 8.63 mmol) were added to dioxane (50 mL) and stirred for 10 minutes. Phenyl chloro formate (0.704 mL, 5.61 mmol) was added slowly and the reaction was stirred for 1 hour. The reaction mixture was quenched with 1.0 N citric acid (50 mL), extracted with ethyl acetate (3 x 75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford an orange solid. This was dissolved in DCM, the solvent was slowly removed until a solid was observed. Diethyl ether was then added to the solution with rapid stirring to afford the desired material as a white solid (1.65 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.69 - 1.66 (2H, m), 1.92 - 1.89 (2H, m), 3.18 (IH, ddd), 3.46 (IH, ddd), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.36 - 4.10 (IH, m), 4.55 - 4.44 (IH, m), 6.75 (IH, s), 7.30 - 7.18 (4H, m), 7.47 - 7.43 (2H, m), 7.54 (2H, d), 7.64 (IH, t), 7.78 - 7.72 (IH, m), 7.85 (2H, d), 10.43 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 607; HPLC tR = 2.97 min
4- [4- [ 1 -(2.4-DifluorophenvDsulfonylcvclopropyll -6- [(36^-3 -methylmorpholin-4-yllpyrimidin- 2-yl]aniline
Figure imgf000730_0002
2-Chloro-4-[l-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yljpyrimidine (3.61 g, 8.40 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (2.208 g, 10.08 mmol), sodium carbonate (4.45 g, 41.99 mmol) and 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.608 g, 0.84 mmol) were added to DME (60.0 mL) and water (15 mL) and heated to 900C over a period of 2 hours under nitrogen. The solvent was evaporated and the residue was quenched water (100 mL), extracted with ethyl acetate (3 x 75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford a black gum. The crude product was purified by flash silica chromatography, elution gradient 40 to 100% ethyl acetate in isohexane, to give the desired material as a yellow gum (2.2 g).
NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.29 (3H, d), 1.58 - 1.55 (IH, m), 1.66 - 1.62 (IH, m), 2.11 - 2.04 (2H, m), 3.26 (IH, ddd), 3.57 (IH, ddd), 3.72 (IH, dd), 3.80 (IH, d), 3.86 (2H, s), 4.02 (IH, dd), 4.11 (IH, m), 4.43 - 4.36 (IH, m), 6.60 (2H, d), 6.65 (IH, s), 6.86 - 6.82 (IH, m), 6.91 (IH, ddd), 7.75 - 7.69 (IH, m), 7.85 (2H, d). LCMS Spectrum: m/z (ESI+) (M+H)+ = 487; HPLC tR = 2.56 min.
2-Chloro-4-ri-(2,4-difluorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000731_0001
Sodium hydroxide (50%w/w solution) (32.7 g, 817.17 mmol) was added to 2-chloro-4-[(2,4- difiuorophenyl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (6.0 g, 14.86 mmol), 1 ,2-dibromoethane (3.84 mL, 44.57 mmol) and tetrabutylammonium bromide (0.479 g, 1.49 mmol) in toluene (75 mL) at RT. The resulting suspension was stirred at 600C overnight. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3 x 100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give a crude material which was dissolved in hot diethyl ether and then stirred for 2 hours to afford the desired material as a white solid (3.61 g). NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.30 (3H, d), 1.56 - 1.52 (IH, m), 1.62 - 1.59 (IH, m), 2.10-2.00 (2H, m), 3.26 (IH, ddd), 3.53 (IH, ddd), 3.68 (IH, dd), 3.78 (IH, d), 4.00 (2H, dd), 4.26 (IH, s), 6.81 (IH, s), 6.99 - 6.90 (2H, m), 7.77 - 7.71 (IH, m). LCMS Spectrum: m/z (ESI+) (M+H)+ = 430; HPLC tR = 2.48 min 2-Chloro-4-r(2Λ-difluorophenyl)sulfonylmethyll-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000732_0001
2,4-Difluorobenzenesulfmic acid, sodium salt (3.98 g, 19.80 mmol) and 2-chloro-4- (iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (7 g, 19.80 mmol) were dissolved in DMF (50 mL) and stirred for 1 hour at RT. The solvent was evaporated to afford a brown gun, this was quenched with saturated aqueous ammonium chloride solution (50 mL), extracted with diethyl ether (3 x 75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford a brown solid. The crude material was passed through a plug of silica, eluting with 80% ethyl acetate in isohexane, to give crude material which was triturated with diethyl ether to give the desired material as a white solid (7.04 g).
NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.32 (3H, d), 3.28 (IH, ddd), 3.54 (IH, ddd), 3.69 (IH, dd), 3.79 (IH, d), 4.03 - 3.99 (2H, m), 4.28 (IH, s), 4.43 (2H, s), 6.55 (IH, s), 7.03 - 6.98 (2H, m), 7.78 - 7.72 (IH, m). LCMS Spectrum: m/z (ESI+) (M+H)+ = 404; HPLC tR = 2.30 min;
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
2.4-Difluorobenzenesulfinic acid, sodium salt
Figure imgf000732_0002
A solution of sodium sulfite (29.6 g, 235.18 mmol) in water (200 mL) was stirred at RT for 10 minutes. Sodium bicarbonate (39.5 g, 470.36 mmol) was added to the stirred solution. The resulting solution was stirred at 500C for 10 minutes. 2,4-Difiuorobenzene-l-sulfonyl chloride (50 g, 235.18 mmol) was added portion wise to the solution and was stirred at 500C for 2 hours. The reaction mixture was evaporated to dryness and re-dissolved in methanol (200 mL). The suspension was allowed to stir at RT for 20 minutes. The suspension was filtered and the filtrate evaporated to afford a white solid, this was stirred with acetonitrile (50 mL) and then filtered to afford the desired material as a white solid (41.6 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 7.10 - 7.04 (2H, m), 7.74 - 7.68 (IH, m);
Example 58 : 1- [4- [4- [ l-a-FluorophenyPsulfonylcyclopropyll -6- \(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-methylurea
Figure imgf000733_0001
Phenyl N- [4- [4- [ 1 -(2-fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate (0.2 g, 0.34 mmol) and methylamine solution (2M in THF, 1.699 mL, 3.40 mmol) were added to dioxane (10 mL) and stirred overnight. The reaction was evaporated to dryness and was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid (0.119 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 1.71 - 1.65 (2H, m),
1.94 - 1.89 (2H, m), 2.66 (3H, d), 3.14 (IH, ddd), 3.45 (IH, ddd), 3.60 (IH, dd), 3.74 (IH, d),
3.95 (IH, dd), 4.12 (IH, d), 4.42 (IH, s), 6.04 (IH, q), 6.66 (IH, s), 7.37 - 7.31 (3H, m), 7.52 - 7.48 (IH, m), 7.78 - 7.70 (4H, m), 8.69 (IH, s); m/z (ESI+) (M+H)+ = 526; HPLC tR = 2.34 min;
The following compounds were prepared in an analogous fashion from phenyl N-[4-[4-[l-(2- fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000734_0001
Figure imgf000735_0001
Example 58a: 1H NMR (400.132 MHz, DMSO-d6) δ 0.43 - 0.40 (2H, m), 0.67 - 0.62 (2H, m), 1.17 (3H, d), 1.71 - 1.65 (2H, m), 1.95 - 1.87 (2H, m), 2.58 - 2.51 (IH, m), 3.14 (IH, ddd), 3.45 (IH, ddd), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.12 (IH, d), 4.43 (IH, s), 6.40 (IH, d), 6.66 (IH, s), 7.37 - 7.31 (3H, m), 7.52 - 7.48 (IH, m), 7.79 - 7.70 (4H, m), 8.48 (IH, s);
Example 58b: 1H NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 1.71 - 1.65 (2H, m), 1.93 - 1.89 (2H, m), 3.19 - 3.10 (3H, m), 3.48 - 3.42 (3H, m), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.12 (IH, d), 4.43 (IH, s), 4.72 (IH, t), 6.23 (IH, t), 6.66 (IH, s), 7.35 - 7.31 (3H, m), 7.52 - 7.48 (IH, m), 7.78 - 7.70 (4H, m), 8.75 (IH, s);
Example 58c: 1R NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 1.71 - 1.65 (2H, m), 1.94 -
1.88 (2H, m), 3.14 (IH, ddd), 3.48 - 3.36 (3H, m), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd),
4.12 (IH, d), 4.46 - 4.40 (2H, m), 4.53 (IH, t), 6.41 (IH, t), 6.66 (IH, s), 7.37 - 7.31 (3H, m), 7.52 - 7.48 (IH, m), 7.78 - 7.69 (4H, m), 8.76 (IH, s); Example 58d: 1H NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 1.71 - 1.67 (2H, m), 1.94 -
1.89 (2H, m), 3.14 (IH, ddd), 3.55 - 3.42 (3H, m), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd),
4.13 (IH, d), 4.42 (IH, s), 6.07 (IH, ddt), 6.51 (IH, t), 6.67 (IH, s), 7.38 - 7.31 (3H, m), 7.52
- 7.48 (IH, m), 7.78 - 7.70 (4H, m), 8.87 (IH, s);
Example 58e: 1R NMR (400.132 MHz, DMSOd6) δ 1.06 (3H, t), 1.17 (3H, d), 1.71 - 1.65 (2H, m), 1.94 - 1.88 (2H, m), 3.17 - 3.09 (3H, m), 3.45 (IH, ddd), 3.60 (IH, dd), 3.74 (IH, d),
3.95 (IH, ddd), 4.12 (IH, d), 4.42 (IH, s), 6.13 (IH, t), 6.66 (IH, s), 7.36 - 7.31 (3H, m), 7.52
- 7.48 (IH, m), 7.78 - 7.71 (4H, m), 8.60 (IH, s);
Example 58f: 1R NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.72 - 1.65 (2H, m), 1.94 - 1.89 (2H, m), 3.15 (IH, ddd), 3.46 (IH, ddd), 3.61 (IH, dd), 3.74 (IH, d), 3.79 (3H, s), 3.95 (IH, dd), 4.13 (IH, d), 4.43 (IH, s), 6.67 (IH, s), 7.34 (IH, t), 7.41 - 7.38 (3H, m), 7.53 - 7.49 (IH, m), 7.79 - 7.70 (5H, m), 8.35 (IH, s), 8.78 (IH, s).
Example 58g: 1U NMR (400.132 MHz, DMSOd6) δ 0.51 - 0.48 (2H, m), 0.59 - 0.57 (2H, m), 1.17 (3H, d), 1.71 - 1.65 (2H, m), 1.94 - 1.90 (2H, m), 3.14 (IH, ddd), 3.22 (2H, d), 3.45 (IH, ddd), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.12 (IH, d), 4.42 (IH, s), 5.36 (IH, s), 6.29 (IH, t), 6.66 (IH, s), 7.35 - 7.31 (3H, m), 7.52 - 7.48 (IH, m), 7.78 - 7.70 (4H, m), 8.76 (IH, s).
The preparation of phenyl Λ/-[4-[4-[l-(2-fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N- \4- \4- \ 1 -(2-fluorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000736_0001
4-[4-[l-(2-Fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yljaniline (used as the hydrochloride salt) (3.2 g, 6.83 mmol) and sodium bicarbonate (11.47 g, 136.59 mmol) were added to DCM (75 mL) and stirred for 10 minutes. Phenyl chloroformate (1.114 mL, 8.88 mmol) was added slowly and the reaction was stirred for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford an orange solid. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% ethyl acetate in isohexane, to give the desired material as a yellow foam (3.5 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.72 - 1.66 (2H, m), 1.97 - 1.88 (2H, m), 3.15 (IH, ddd), 3.45 (IH, ddd), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.14 (IH, d), 4.44 (IH, s), 6.70 (IH, s), 7.35 - 7.23 (4H, m), 7.53 - 7.42 (5H, m), 7.77 -
7.71 (2H, m), 7.83 (2H, d), 10.37 (IH, s).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 589; HPLC tR = 3.04 min;
4- [4- [ 1 -^-FluorophenvOsulfonylcvclopropyl] -6- [(3 S)- 3 -methylmorpholin^-yllpyrimidin^- yll aniline
Figure imgf000737_0001
tert-Butyl N-[4-[4-[ 1 -(2-fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate (3.6 g, 6.33 mmol) was added to 6N hydrogen chloride in propan-2-ol (60 mL) and stirred at RT for 5 hours. The solvent was removed to 80% of the initial volume then diethyl ether rapidly added to afford the desired material (as a hydrochloride salt) as a yellow solid (3.20 g). This was used in the next step without any further purification.
tert-Butγl iV-[4-|"4-[ 1 -(2-fluorophenvπsulfonylcvclopropyll-6-[(36f)-3-methylmorpholin-4- vllpyrimidin-2-yllphenyllcarbamate
Figure imgf000737_0002
tert-Butyl N- [4- [4-[(2-fluorophenyl)sulfonylmethyl] -6- [(35)-3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate (5.75 g, 10.60 mmol) was added to sodium hydride (1.526 g, 31.79 mmol) and 1 ,2-dibromoethane (1.826 mL, 21.19 mmol) in DMF (30 mL) at RT. The resulting suspension was stirred at 45°C for 1 hour. Additional sodium hydride (1.526 g, 31.79 mmol) and 1 ,2-dibromoethane (1.826 mL, 21.19 mmol) were added and the reaction was stirred at 45°C overnight. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford brown gum. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% ethyl acetate in isohexane, to give the desired material as a yellow foam (3.60 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 1.49 (9H, s), 1.71 - 1.65 (2H, m), 1.94 - 1.90 (2H, m), 3.14 (IH, ddd), 3.45 (IH, ddd), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, ddd), 4.13 (IH, d), 4.42 (IH, s), 6.68 (IH, s), 7.33 (IH, t), 7.42 (2H, d), 7.53 - 7.48 (IH, m), 7.78 - 7.70 (4H, m), 9.48 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 569; HPLC tR = 3.13 min;
tert-Butyl Λ/-[4-[4-[(2-fluorophenvπsulfonylmethyll-6-[(3y)-3-methylmorpholin-4- yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000738_0001
[6-[(35)-3-Methylmorpholin-4-yl]-2-[4-[(2-methylpropan-2- yl)oxycarbonylamino]phenyl]pyrimidin-4-yl]methyl methanesulfonate (4.74 g, 9.90 mmol) and lithium iodide (3.98 g, 29.71 mmol) were added to dioxane (70 mL) and heated at 97°C for 30 minutes. To this was added sodium 2-fluorobenzenesulfinate (2.71 g, 14.86 mmol) and DMF (5 mL), the reaction was stirred at 97°C overnight. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford an orange gum. Diethyl ether (100 mL) was added with vigorous stirring to afford the desired material as a white solid (4.0 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.49 (9H, s), 3.17 (IH, ddd), 3.48 (IH, ddd), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.12 (IH, d), 4.39 (IH, s),
4.76 (2H, s), 6.75 (IH, s), 7.34 (IH, t), 7.41 (2H, d), 7.65 - 7.57 (2H, m), 7.71 (2H, d), 7.83 -
7.77 (IH, m), 9.48 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 543; HPLC tR = 2.92 min; Sodium 2-fluorobenzenesulfinate
Figure imgf000739_0001
A solution of sodium sulfite (32.4 g, 256.92 mmol) in water (200 mL) was stirred at RT for 10 minutes. Sodium bicarbonate (43.2 g, 513.85 mmol) was added to the stirred solution. The resulting solution was stirred at 500C for 10 minutes. 2-Fluorobenzene-l-sulfonyl chloride (50 g, 256.92 mmol) was added portionwise to the solution and was stirred at 500C for 2 hours. The reaction mixture was evaporated to dryness and redissolved in methanol (200 mL). The suspension was allowed to stir at RT for 20 minutes. The suspension was filtered and the filtrate evaporated to afford a white solid, this was stirred with acetonitrile (50 mL) and then filtered to afford the desired material as a white solid (41.0 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 6.99 (IH, t), 7.16 (IH, t), 7.28 - 7.22 (IH, m), 7.61 (IH, t).
r6-r(3y)-3-Methylmorpholin-4-yl1-2-r4-r(2-methylpropan-2- vπoxycarbonylaminolphenyllpyrimidin-4-yllmethyl methanesulfonate
Figure imgf000739_0002
tert-Butyl N-[4-[4-(hydroxymethyl)-6-[(35)-3-methylmoipholin-4-yl]pyrimidin-2- yl]phenyl] carbamate (23 g, 57.43 mmol) and DIPEA (12.04 mL, 68.92 mmol) were added to DCM (80 mL), to this was slowly added methanesulphonyl chloride (4.48 mL, 57.43 mmol) and the reaction was stirred for 30 minutes. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (100 mL), extracted with DCM (2 x 100 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford the desired material as a brown gum (27.0 g). This was used without any further purufucation. NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.50 (9H, s), 3.22 (IH, ddd), 3.34 (3H, s), 3.50 (IH, ddd), 3.65 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.19 (IH, d), 4.53 (IH, s), 5.19 (2H, s), 6.71 (IH, s), 7.56 (2H, d), 8.23 (2H, d), 9.55 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 479; HPLC tR = 2.74 min;
tert-Butyl Λ/-r4-r4-(hvdroxymethyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-2- yllphenyl] carbamate
Figure imgf000740_0001
[2-Chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methanol (18.00 g, 73.86 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenylcarbamate (23.58 g, 73.86 mmol), sodium carbonate (39.1 g, 369.32 mmol) and 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium(II) (5.35 g, 7.39 mmol) were added to DME (300 mL) and water (75 mL) and heated to 900C overnight under nitrogen. The solvent was evaporated and the residue was quenched with water (100 mL), extracted with ethyl acetate (3 x 100 mL), the aqueous layer was dried over MgSO4, filtered and evaporated to afford black gum. The residue was filtered through a plug of silica eluting with ethyl acetate to give a pale orange gum. This was triturated with diethyl ether to give the desired material as a white solid (24.4 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.23 (3H, d), 1.49 (9H, s), 3.19 (IH, ddd), 3.49 (IH, ddd), 3.64 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 (IH, d), 4.50 - 4.46 (3H, m), 5.39 (IH, s), 6.67 (IH, s), 7.54 (2H, d), 8.22 (2H, d), 9.50 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 401; HPLC tR = 2.30 min;
The preparation of [2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methanol was described earlier. Example 59: l-[4-[4-H-K3.5-Dimethyl-1.2-oxazol-4-vnsulfonyllcvclopropyll-6-K3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-methylurea
Figure imgf000741_0001
Phenyl N-[4-[4-[l-[(3,5-dimethyl-l,2-oxazol-4-yl)sulfonyl]cyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (0.15 g, 0.25 mmol) and methylamine (2M in THF, 1.272 mL, 2.54 mmol) were added to dioxane (10 mL) and stirred overnight at 500C. The reaction was evaporated to dryness and was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid (0.098 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.59 - 1.52 (2H, m), 1.80 - 1.77 (2H, m), 2.11 (3H, s), 2.33 (3H, s), 2.66 (3H, d), 3.18 (IH, ddd), 3.47 (IH, ddd), 3.62 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 (IH, d), 4.52 (IH, s), 6.07 (IH, q), 6.75 (IH, s), 7.45 (2H, d), 7.96 (2H, d), 8.72 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 527; HPLC tR = 2.18 min
The following samples were prepared in an analogous fashion from phenyl Λ/-[4-[4-[l-[(3,5- dimethyl-l,2-oxazol-4-yl)sulfonyl]cyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000741_0002
Example Structure NAME LCMS Retention
MH+ time (min)
59b l-[4-[4-[l-[(3,5-dimethyl-l,2- 557 2.00 oxazol-4-yl)sulfonyl]cyclopropyl]-
6-[(3S)-3-methylmorpholin-4-
Figure imgf000742_0001
yl]pyrimidin-2-yl]phenyl]-3-(2- hydroxyethyl)urea
59c l-[4-[4-[l-[(3,5-dimethyl-l,2- 559 2.33 oxazol-4-yl)sulfonyl]cyclopropyl]-
6-[(3S)-3-methylmorpholin-4-
Figure imgf000742_0002
yl]pyrimidin-2-yl]phenyl]-3-(2- fluoroethyl)urea
59d 3-(2,2-difluoroethyl)-l-[4-[4-[l- 577 2.44 [(3 ,5 -dimethyl- 1 ,2-oxazol-4- yl)sulfonyl]cyclopropyl]-6-[(3S)-
Figure imgf000742_0003
3 -methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]urea
59e l-[4-[4-[l-[(3,5-dimethyl-l,2- 583 2.16 oxazol-4-yl)sulfonyl]cyclopropyl]-
6-[(3S)-3-methylmorpholin-4-
Figure imgf000742_0004
yl]pyrimidin-2-yl]phenyl]-3-[(l- hydroxycyclopropyl)methyl]urea
59f 3-[4-[4-[l-[(3,5-dimethyl-l,2- 541 2.34 oxazol-4-yl)sulfonyl]cyclopropyl]- 6-[(3S)-3-methylmorpholin-4-
Figure imgf000742_0005
yl]pyrimidin-2-yl]phenyl]- 1 - thylurea Example Structure NAME LCMS Retention
MH+ time
(min)
59g l-[4-[4-[l-[(3,5-dimethyl-l,2- 593 2.21 oxazol-4-yl)sulfonyl]cyclopropyl]-
6-[(3S)-3-methylmorpholin-4-
Figure imgf000743_0001
yl]pyrimidin-2-yl]phenyl]-3-(l- methylpyrazol-4-yl)urea
Example 59a: 1H NMR (400.132 MHz, DMSO-Cl6) δ 0.44 - 0.40 (2H, m), 0.67 - 0.63 (2H, m), 1.21 (3H, d), 1.59 - 1.52 (2H, m), 1.80 - 1.77 (2H, m), 2.11 (3H, s), 2.32 (3H, s), 2.59 - 2.54 (IH, m), 3.18 (IH, ddd), 3.47 (IH, ddd), 3.62 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 (IH, d), 4.52 (IH, s), 6.44 (IH, d), 6.76 (IH, s), 7.45 (2H, d), 7.96 (2H, d), 8.52 (IH, s). Example 59b: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.59 - 1.52 (2H, m), 1.80 - 1.75 (2H, m), 2.11 (3H, s), 2.32 (3H, s), 3.22 - 3.14 (3H, m), 3.51 - 3.45 (3H, m), 3.62 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 (IH, d), 4.52 (IH, s), 4.73 (IH, t), 6.26 (IH, t), 6.75 (IH, s), 7.43 (2H, d), 7.96 (2H, d), 8.79 (IH, s). Example 59c: 1R NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.59 - 1.53 (2H, m), 1.80 - 1.75 (2H, m), 2.11 (3H, s), 2.33 (3H, s), 3.22 - 3.14 (IH, m), 3.39 (IH, q), 3.51 - 3.44 (IH, m), 3.62 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 (IH, d), 4.42 (IH, t), 4.55 - 4.49 (2H, m), 5.75 (IH, s), 6.44 (IH, t), 6.76 (IH, s), 7.45 (2H, d), 7.97 (2H, d), 8.79 (IH, s); Example 59d: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.60 - 1.52 (2H, m), 1.81 - 1.75 (2H, m), 2.11 (3H, s), 2.33 (3H, s), 3.18 (IH, ddd), 3.64 - 3.44 (4H, m), 3.76 (IH, d), 3.97 (IH, dd), 4.18 (IH, d), 4.52 (IH, s), 6.07 (IH, ddt), 6.54 (IH, t), 6.77 (IH, s), 7.46 (2H, d), 7.98 (2H, d), 8.91 (IH, s).
Example 59e: 1U NMR (400.132 MHz, DMSOd6) δ 0.53 - 0.49 (2H, m), 0.60 - 0.56 (2H, m), 1.20 (3H, d), 1.59 - 1.52 (2H, m), 1.80 - 1.77 (2H, m), 2.11 (3H, s), 2.32 (3H, s), 3.18 - 3.14 (IH, m), 3.22 (2H, d), 3.47 (IH, ddd), 3.62 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 (IH, d), 4.52 (IH, s), 5.37 (IH, s), 6.33 (IH, t), 6.76 (IH, s), 7.43 (2H, d), 7.96 (2H, d), 8.80 (IH, s);
Example 59f: 1H NMR (400.132 MHz, DMSOd6) δ 1.07 (3H, t), 1.21 (3H, d), 1.59 - 1.52 (2H, m), 1.80 - 1.77 (2H, m), 2.11 (3H, s), 2.32 (3H, s), 3.22 - 3.09 (3H, m), 3.47 (IH, ddd), 3.62 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.17 (IH, d), 4.53 (IH, s), 6.17 (IH, t), 6.75 (IH, s), 7.44 (2H, d), 7.95 (2H, d), 8.64 (IH, s);
Example 59g: 1U NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.59 - 1.53 (2H, m), 1.81 - 1.78 (2H, m), 2.12 (3H, s), 2.33 (3H, s), 3.23 - 3.15 (IH, m), 3.48 (IH, ddd), 3.63 (IH, dd), 3.76 (IH, d), 3.79 (3H, s), 3.97 (IH, dd), 4.18 (IH, d), 4.53 (IH, s), 6.77 (IH, s), 7.39 (IH, s), 7.49 (2H, d), 7.77 (IH, s), 7.99 (2H, d), 8.40 (IH, s), 8.82 (IH, s).
The preparation of phenyl Λ/-[4-[4-[l-[(3,5-dimethyl-l,2-oxazol-4-yl)sulfonyl]cyclopropyl]-6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N-r4-r4-ri-r(3.5-dimethyl-1.2-oxazol-4-vnsulfonyllcvclopropyll-6-r('3^-3- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000744_0001
4-[4-[l-[(3,5-Dimethyl-l,2-oxazol-4-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]aniline (as the hydrochloride salt) (1.94 g, 3.83 mmol) and sodium bicarbonate (1.61O g, 19.17 mmol) were added to DCM (60 mL) and stirred for 10 minutes.
Phenyl chloroformate (0.625 mL, 4.98 mmol) was added slowly and the reaction was stirred for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford an orange solid. DCM followed by diethyl ether were added and the solvent was slowly removed until a solid was obtained. The solid was collected by filtration and dried under vacuum to give the desired material as as a white solid (1.89 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.60 - 1.52 (2H, m), 1.81 - 1.78 (2H, m), 2.11 (3H, s), 2.33 (3H, s), 3.19 (IH, ddd), 3.48 (IH, ddd), 3.63 (IH, dd),
3.76 (IH, d), 3.97 (IH, dd), 4.19 (IH, d), 4.54 (IH, s), 6.80 (IH, s), 7.30 - 7.24 (3H, m), 7.45
(2H, t), 7.57 (2H, d), 8.04 (2H, d), 10.42 (IH, s).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 590; HPLC tR = 2.86 min 4-r4-ri-r(3,5-Dimethyl-l,2-oxazol-4-yl)sulfonyllcvclopropyll-6-r(36f)-3-methylmorpholin-4- vHpyrimidin-2-yll aniline
Figure imgf000745_0001
tert-Butyl N-[4-[4-[l-[(3,5-dimethyl-l,2-oxazol-4-yl)sulfonyl]cyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (2.6 g, 4.56 mmol) was added to 6N hydrogen chloride in propan-2-ol (40 mL) and stirred for 2 hours at RT. The crude solution was triturated with diethyl ether to give the desired material (as the hydrochloride salt) as a yellow solid (1.96 g). The material was used without further purification. NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.69 - 1.58 (2H, m), 1.84 - 1.82 (2H, m), 2.09 (3H, s), 2.38 (3H, s), 3.30 - 3.24 (IH, m), 3.50 - 3.45 (IH, m), 3.62 (IH, dd), 3.81 - 3.75 (IH, m), 3.99 (IH, dd), 4.28 (IH, s), 4.60 (IH, s), 6.93 (IH, s), 7.23 - 7.13 (2H, m), 8.05 (2H, d). LCMS Spectrum: m/z (ESI+) (M+H)+ = 470; HPLC tR = 1.88 min
tert-Butyl N-r4-r4-ri-r(3.5-dimethyl-1.2-oxazol-4-yl)sulfonyllcvclopropyll-6-r(3^-3- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000745_0002
Sodium hydride (2.177 g, 45.36 mmol) and 1,2-dibromoethane (2.61 mL, 30.24 mmol) in DMF (70 mL) were added rapidly to a solution of tert-butyl Λ/-[4-[4-[(3,5-dimethyl-l,2- oxazol-4-yl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate (4.11 g, 7.56 mmol) in DMF (70 mL) at RT. The resulting suspension was stirred at RT for 1 hour. Additional sodium hydride (1.1 g, 22.68 mmol) and 1,2- dibromoethane (1.305 mL, 15.12 mmol) were added and the reaction was stirred at RT for 30 minutes. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford brown gum. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% ethyl acetate in isohexane, to afford a yellow foam. This was dissolved in 40% ethyl acetate in isohexane and stirred to give the desired material as a white solid which was collected by filtration (2.60 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.50 (9H, s), 1.59 - 1.53 (2H, m), 1.81 - 1.77 (2H, m), 2.11 (3H, s), 2.32 (3H, s), 3.18 (IH, ddd), 3.47 (IH, ddd), 3.62 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.18 (IH, d), 4.53 (IH, s), 6.78 (IH, s), 7.51 (2H, d), 7.97 (2H, d), 9.54 (IH, s).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 570; HPLC tR = 2.99 min
tert-Butyl N-r4-r4-r(3.5-dimethyl-1.2-oxazol-4-vnsulfonylmethyll-6-r(35)-3- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000746_0001
3,5-dimethylisoxazole-4-sulfinic acid, sodium salt (1.443 g, 7.84 mmol) and tert-Butyl Λ/-[4- [4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (4 g, 7.84 mmol) were dissolved in DMF (50 mL) and stirred for 1 hour at RT. The solvent was evaporated to afford a yellow solid, this was quenched with water (50 mL) and extracted with DCM (2 x 75 mL), dried and solvent evaporated to afford an orange gum, this was rapidly stirred with diethyl ether (100 mL) to afford a solid which was collected by filtration and dried under vacuum to give the desired material as an off white solid (4.11 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.50 (9H, s), 2.19 (3H, s), 2.33 (3H, s), 3.20 (IH, ddd), 3.50 (IH, ddd), 3.65 (IH, dd), 3.78 (IH, d), 3.98 (IH, dd), 4.15 (IH, d), 4.44 (IH, s), 4.69 (2H, s), 6.79 (IH, s), 7.51 (2H, d), 7.97 (2H, d), 9.55 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 544; HPLC tR = 2.76 min 3,5-Dimethylisoxazole-4-sulfinic acid, sodium salt
Figure imgf000747_0001
A solution of sodium sulfite (5.03 g, 39.87 mmol) in water (50 mL) was stirred at RT for 10 minutes. Sodium bicarbonate (6.70 g, 79.74 mmol) was added and the resulting solution was stirred at 500C for 10 minutes. 3,5-Dimethylisoxazole-4-sulfonyl chloride (7.8 g, 39.87 mmol) was added portion-wise to the solution and was stirred at 500C for 2 hours. The reaction mixture was evaporated to dryness and re-dissolved in methanol (200 mL). The suspension was allowed to stir at RT for 20 minutes. The suspension was filtered and the filtrate evaporated to afford a white solid, this was stirred with acetonitrile (50 mL) and then filtered to afford the desired material as a white solid (7.16 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 2.24 (3H, s), 2.39 (3H, s).
tert-Butyl Λ/-r4-r4-(iodomethyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-2- yllphenyl] carbamate
Figure imgf000747_0002
[6-[(35)-3-Methylmorpholin-4-yl]-2-[4-[(2-methylpropan-2- yl)oxycarbonylamino]phenyl]pyrimidin-4-yl]methyl methanesulfonate (27 g, 56.42 mmol) and lithium iodide (4.33 mL, 112.84 mmol) were added to dioxane (250 mL) and heated at 600C for 1 hour and then at RT overnight. The solvent was evaporated to dryness, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (100 mL) and extracted with DCM (3 x 75 mL). The organic extracts were then flushed through a two inch silica plug, eluting with ethyl acetate, to give a brown foam. This was rapidly dissolved in diethyl ether and stirred to afford the desired material as a white solid (25.2 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.50 (9H, s), 3.19 (IH, ddd), 3.49 (IH, ddd), 3.64 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.16 (IH, d), 4.39 (2H, s), 4.48 (IH, s), 6.80 (IH, s), 7.55 (2H, d), 8.22 (2H, d), 9.53 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 511; HPLC tR = 2.85 min
The preparation of [6-[(35)-3-methylmorpholin-4-yl]-2-[4-[(2-methylpropan-2- yl)oxycarbonylamino]phenyl]pyrimidin-4-yl]methyl methanesulfonate was described earlier.
Example 60 : 1- [4- [4- [ l-^.S-Difluorophenynsulfonylcyclopropyll -6- \(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-methylurea
Figure imgf000748_0001
Phenyl 7V-[4-[4-[ 1 -(2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate (0.15 g, 0.25 mmol) and methylamine (2M in THF, 1.236 mL, 2.47 mmol) were added to dioxane (10 mL) and stirred overnight. The reaction was evaporated to dryness and was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid (0.113 g) .
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.72 - 1.70 (2H, m), 1.96 - 1.91 (2H, m), 2.66 (3H, d), 3.16 (IH, ddd), 3.46 (IH, ddd), 3.61 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.16 (IH, d), 4.48 (IH, s), 6.05 (IH, q), 6.68 (IH, s), 7.37 (2H, d), 7.54 - 7.50 (IH, m), 7.69 - 7.57 (2H, m), 7.73 (2H, d), 8.70 (IH, s); LCMS Spectrum: m/z (ESI+) (M+H)+ = 544; HPLC tR= 2.30 min
The following compounds were prepared in an analogous fashion from phenyl N-[4-[4-[l- (2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000749_0001
Figure imgf000750_0001
Example 60a: 1U NMR (400.132 MHz, DMSO-Cl6) δ 0.44 - 0.40 (2H, m), 0.67 - 0.62 (2H, m), 1.19 (3H, d), 1.74 - 1.68 (2H, m), 1.96 - 1.90 (2H, m), 2.58 - 2.53 (IH, m), 3.16 (IH, ddd), 3.46 (IH, ddd), 3.61 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.16 (IH, d), 4.48 (IH, s), 6.41 (IH, s), 6.68 (IH, s), 7.38 (2H, d), 7.54 - 7.50 (IH, m), 7.69 - 7.57 (2H, m), 7.73 (2H, d), 8.50 (IH, s); Example 60b: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.74 - 1.68 (2H, m), 1.98 -
1.89 (2H, m), 2.09 (3H, s), 3.20 - 3.12 (3H, m), 3.49 - 3.42 (3H, m), 3.61 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.16 (IH, d), 4.48 (IH, s), 4.73 (IH, t), 6.24 (IH, t), 6.68 (IH, s), 7.36 (2H, d), 7.54 - 7.50 (IH, m), 7.69 - 7.57 (2H, m), 7.73 (2H, d), 8.77 (IH, s);
Example 60c: 1H NMR (400.132 MHz, DMSO-(I6) δ 1.19 (3H, d), 1.74 - 1.68 (2H, m), 1.96 -
1.90 (2H, m), 3.16 (IH, ddd), 3.48 - 3.36 (3H, m), 3.61 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.16 (IH, d), 4.47 (2H, dt), 4.48 (IH, s), 6.41 (IH, t), 6.68 (IH, s), 7.37 (2H, d), 7.54 - 7.50 (IH, m), 7.69 - 7.57 (2H, m), 7.74 (2H, d), 8.77 (IH, s); Example 6Od: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 1.74 - 1.68 (2H, m), 1.96 -
1.91 (2H, m), 3.16 (IH, ddd), 3.63 - 3.43 (4H, m), 3.74 (IH, d), 3.96 (IH, dd), 4.16 (IH, d), 4.48 (IH, s), 6.07 (IH, ddt), 6.51 (IH, t), 6.69 (IH, s), 7.38 (2H, d), 7.54 - 7.50 (IH, m), 7.69 - 7.57 (2H, m), 7.75 (2H, d), 8.89 (IH, s);
Example 6Oe: 1H NMR (400.132 MHz, DMSO-dg) δ 1.07 (3H, t), 1.19 (3H, d), 1.72 - 1.69 (2H, m), 1.95 - 1.91 (2H, m), 3.19 - 3.09 (3H, m), 3.45 (IH, ddd), 3.61 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.16 (IH, d), 4.48 (IH, s), 6.14 (IH, t), 6.68 (IH, s), 7.36 (2H, d), 7.54 - 7.50 (IH, m), 7.69 - 7.57 (2H, m), 7.72 (2H, d), 8.62 (IH, s); Example 6Of: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 1.74 - 1.68 (2H, m), 1.96 -
1.92 (2H, m), 3.17 (IH, ddd), 3.46 (IH, ddd), 3.61 (IH, dd), 3.75 (IH, d), 3.79 (3H, s), 3.96 (IH, dd), 4.17 (IH, d), 4.48 (IH, s), 6.69 (IH, s), 7.38 (IH, s), 7.42 (2H, d), 7.55 - 7.51 (IH, m), 7.70 - 7.58 (2H, m), 7.78 - 7.75 (3H, m), 8.36 (IH, s), 8.80 (IH, s);
The preparation of phenyl 7V-[4-[4-[l-(2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3<S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl Λ/-[4-[4-[ 1 -(2,5-difluorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000751_0001
4-[4-[ 1 -(2,5-Difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin- 2-yl]aniline ( as the hydrochloride salt) (2.54 g, 4.86 mmol) and sodium bicarbonate (2.04 g, 24.28 mmol) were added to DCM (60 mL) and stirred for 10 minutes. Phenyl chloro formate (0.792 mL, 6.31 mmol) was added slowly and the reaction was stirred for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford an orange solid. The solid was passed through a plug of silica, eluting with ethyl acetate, to give a solid that was further purified by trituration with diethyl ether to give the desired material as a white solid (2.20 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.73 - 1.69 (2H, m), 1.98 - 1.91 (2H, m), 3.17 (IH, ddd), 3.51 - 3.44 (IH, m), 3.61 (IH, dd), 3.75 (IH, d), 3.95 (IH, d), 4.18 (IH, d), 4.49 (IH, s), 6.72 (IH, s), 7.30 - 7.24 (3H, m), 7.45 (2H, t), 7.55 - 7.50 (3H, m), 7.69 - 7.57 (2H, m), 7.83 (2H, d), 10.39 (IH, s); LCMS Spectrum: m/z (ESI+) (M+H)+ = 607; HPLC tR = 3.15 min 4- [4- r 1 -(2,5 -DifluorophenyDsulfonylcvclopropyll -6- [(36^-3 -methylmorpholin-4-ylipyrimidin-
2-vHaniline
Figure imgf000752_0001
tert-Butyl N-[4-[4-[ 1 -(2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate (2.85 g, 4.86 mmol) was added to 6N hydrogen chloride in propan-2-ol (30 mL) and stirred for 2 hours at RT. The crude solution was triturated with diethyl ether to give the desired material (as a hydrochloride salt) as a yellow solid (2.4 g, 94
%). The material was used without further purification.
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.78 - 1.71 (2H, m), 1.97 - 1.93 (2H, m), 3.23 (IH, ddd), 3.45 (IH, ddd), 3.59 (IH, dd), 3.82 - 3.73 (IH, m), 3.96
(IH, dd), 4.29 - 4.18 (IH, m), 4.59 - 4.47 (IH, m), 6.81 (IH, s), 7.25 (2H, d), 7.63 - 7.54 (2H, m), 7.72 - 7.66 (IH, m), 7.95 (2H, d);
LCMS Spectrum: m/z (ESI+) (M+H)+ = 487; HPLC tR = 2.52 min
tert-Butyl N-\4-\4-\ 1 -(2,5-difluorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000752_0002
Sodium hydride (1.38 g, 28.56 mmol) was added rapidly to a solution of tert-butyl Λ/-[4-[4- [(2,5-difluorophenyl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate (4.0 g, 7.14 mmol) in DMF (70 mL) and the misture stirred at 400C for 10 minutes before the slow addition 1 ,2-dibromoethane (2.459 mL, 28.54 mmol) in DMF (70 mL) at RT. The resulting suspension was stirred at 400C for 1 hour. Additional sodium hydride (0.69 g, 14.26) and 1 ,2-dibromoethane (1.23 mL, 14.26 mmol) were added and the reaction was stirred at RT for 30 minutes. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford brown gum. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% ethyl acetate in isohexane, to give a yellow foam. This was dissolved in 40% ethyl acetate in isohexane and upon stirring the desired material precipitated out as a white solid (2.85 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.49 (9H, s), 1.74 - 1.68 (2H, m), 1.96 - 1.92 (2H, m), 3.16 (IH, ddd), 3.46 (IH, ddd), 3.61 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.17 (IH, d), 4.48 (IH, s), 6.70 (IH, s), 7.44 (2H, d), 7.54 - 7.50 (IH, m), 7.69 - 7.57 (2H, m), 7.76 (2H, d), 9.50 (IH, s); LCMS Spectrum: m/z (ESI+) (M+H)+ = 587; HPLC tR = 2.94 min
tert-Butyl Λ/-r4-r4-r(2,5-difluorophenyl)sulfonylmethyll-6-r(3^-3-methylmorpholin-4- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000753_0001
Sodium 2,5-difluorobenzenesulfonate (2.117 g, 9.80 mmol) and tert-butyl N-[4-[4-
(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (5 g, 9.80 mmol) were dissolved in DMF (50 mL) and stirred for 1 hour at RT. The solvent was evaporated and the residue partitioned between water (50 mL) and DCM (75 mL). The layers were separated, the aqueous layer further extracted with DCM (75 mL) and the combined organics passed through a plug of silica, eluting with ethyl acetate, to give a yellow solid. This material was triturated with diethyl ether to give the desired material as a white solid (4.90 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.49 (9H, s), 3.19 (IH, ddd), 3.48 (IH, ddd), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.13 (IH, d), 4.41 (IH, s), 4.82 (2H, s), 6.78 (IH, s), 7.44 - 7.42 (3H, m), 7.75 - 7.68 (4H, m), 9.50 (IH, s); LCMS Spectrum: m/z (ESI+) (M+H)+ = 561; HPLC tR = 2.95 min 2,5-Difluorobenzenesulfinic acid, sodium salt
Figure imgf000754_0001
A solution of sodium sulfite (29.6 g, 235.18 mmol) in water (200 mL) was stirred at RT for 10 minutes. Sodium bicarbonate (39.5 g, 470.36 mmol) was added to the stirred solution. The resulting solution was stirred at 500C for 10 minutes. 2,5-difluorobenzene-l-sulfonyl chloride (50 g, 235 mmol) was added portionwise and the solution stirred at 500C for 2 hours. The reaction mixture was evaporated to dryness and redissolved in ethanol (200 mL). The suspension was allowed to stir at RT for 20 minutes. The suspension was filtered and the filtrate evaporated to afford a white solid, this was stirred with acetonitrile (50 mL) and then filtered to afford the desired material as a white solid (43.0 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 7.09 - 7.05 (2H, m), 7.36 - 7.32 (IH, m).
The preparation of tert-\mϊy\ Λ/-[4-[4-(iodomethyl)-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] carbamate was described earlier.
Example 61: 1- [4- [4- [ l-(5-Fluor o-Z-methylphenyDsulfonylcyclopropyll -6- \(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-methylurea
Figure imgf000754_0002
Phenyl 7V-[4-[4-[ 1 -(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (0.15 g, 0.25 mmol) and methylamine (2M in THF, 1.244 mL, 2.49 mmol) were added to dioxane (10 mL) and stirred overnight. The reaction was evaporated to dryness and was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid (0.130 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.16 (3H, d), 1.70 - 1.64 (2H, m), 1.90 - 1.87 (2H, m), 2.41 (3H, s), 2.66 (3H, d), 3.12 (IH, ddd), 3.44 (IH, ddd), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.10 (IH, d), 4.43 (IH, s), 6.05 (IH, q), 6.64 (IH, s), 7.42 - 7.38 (4H, m), 7.62 (IH, d), 7.86 (2H, d), 8.71 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 540; HPLC tR = 2.46 min
The following compounds were prepared in an analogous fashion from phenyl N-[4-[4-[l-(5- fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000755_0001
Figure imgf000756_0001
Example 61a: 1R NMR (400.132 MHz, DMSOd6) δ 0.44 - 0.40 (2H, m), 0.67 - 0.63 (2H, m), 1.16 (3H, d), 1.73 - 1.64 (2H, m), 1.90 - 1.87 (2H, m), 2.41 (3H, s), 2.59 - 2.53 (IH, m), 3.12 (IH, ddd), 3.45 (IH, ddd), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.10 (IH, d), 4.43 (IH, s), 6.42 (IH, s), 6.64 (IH, s), 7.42 - 7.38 (4H, m), 7.63 - 7.61 (IH, m), 7.86 (2H, d), 8.50 (IH, s).
Example 61b: 1H NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 1.70 - 1.64 (2H, m), 1.90 - 1.87 (2H, m), 2.41 (3H, s), 3.20 - 3.09 (3H, m), 3.48 - 3.41 (3H, m), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.10 (IH, d), 4.43 (IH, s), 4.73 (IH, t), 6.24 (IH, t), 6.64 (IH, s), 7.40 - 7.38 (4H, m), 7.63 - 7.60 (IH, m), 7.86 (2H, d), 8.77 (IH, s);
Example 61c: 1R NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 1.70 - 1.64 (2H, m), 1.91 - 1.87 (2H, m), 2.41 (3H, s), 3.13 (IH, ddd), 3.47 - 3.37 (3H, m), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.10 (IH, d), 4.47 - 4.40 (IH, m), 4.47 (2H, dt), 6.42 (IH, t), 6.64 (IH, s), 7.41 - 7.38 (4H, m), 7.61 (IH, d), 7.87 (2H, d), 8.78 (IH, s). Example όld: 1H NMR (400.132 MHz, DMSO-d6) δ 1.16 (3H, d), 1.70 - 1.64 (2H, m), 1.90 -
1.87 (2H, m), 2.41 (3H, s), 3.12 (IH, ddd), 3.62 - 3.41 (4H, m), 3.74 (IH, d), 3.95 (IH, dd),
4.10 (IH, d), 4.44 (IH, s), 6.08 (IH, ddt), 6.52 (IH, t), 6.65 (IH, s), 7.42 - 7.38 (4H, m), 7.62
- 7.60 (IH, m), 7.88 (2H, d), 8.89 (IH, s). Example 61e: 1R NMR (400.132 MHz, DMSOd6) δ 1.07 (3H, t), 1.16 (3H, d), 1.70 - 1.65
(2H, m), 1.90 - 1.85 (2H, m), 2.4 (S, 3H), 3.15 - 3.09 (3H, m), 3.44 (IH, ddd), 3.60 (IH, dd),
3.74 (IH, d), 3.95 (IH, dd), 4.10 (IH, d), 4.43 (IH, s), 6.14 (IH, t), 6.64 (IH, s), 7.39 (4H, d),
7.62 (IH, d), 7.86 (2H, d), 8.63 (IH, s).
Example 61f: 1H NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 1.71 - 1.65 (2H, m), 1.90 - 1.88 (2H, m), 2.41 (3H, s), 3.13 (IH, ddd), 3.45 (IH, ddd), 3.60 (IH, dd), 3.74 (IH, d), 3.77
(3H, s), 3.95 (IH, ddd), 4.43 (IH, s), 6.65 (IH, s), 7.41 - 7.39 (4H, m), 7.45 (2H, d), 7.62 (IH, d), 7.77 (IH, s), 7.89 (2H, d), 8.37 (IH, s), 8.80 (IH, s).
The preparation of phenyl Λ/-[4-[4-[l-(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(35)- 3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl ^-[44441 -(S-fluoro^-methylphenvnsulfonylcvclopropyll-ό-rfS^-S- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000757_0001
4-[4-[l-(5-Fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]aniline (as the hydrochloride salt) (2.4 g, 4.62 mmol) and sodium bicarbonate (1.942 g, 23.12 mmol) were added to DCM (60 mL) and stirred for 10 minutes. Phenyl chloro formate (0.754 mL, 6.01 mmol) was added slowly and the reaction was stirred for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford an orange solid. To this was added DCM and then diethyl ether, the solvent was slowly removed until the desired material precipitated from the mixture as a white solid (2.05 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.17 (3H, d), 1.72 - 1.66 (2H, m), 1.91 - 1.87 (2H, m), 2.41 (3H, s), 3.14 (IH, ddd), 3.47 - 3.38 (IH, m), 3.60 (IH, d), 3.74 (IH, d), 3.95 (IH, dd), 4.12 (IH, d), 4.45 (IH, s), 6.68 (IH, s), 7.30 - 7.24 (3H, m), 7.40 (2H, d), 7.45 (2H, t), 7.54 (2H, d), 7.62 (IH, d), 7.95 (2H, d), 10.39 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 603; HPLC tR = 3.02 min
4-r4-ri-(5-Fluoro-2-methylphenyl)sulfonylcvclopropyll-6-r(3S)-3-methylmorpholin-4- yllpyrimidin-2-vH aniline
Figure imgf000758_0001
tert-Butyl N-[4-[4-[ 1 -(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (2.7 g, 4.63 mmol) was added to 6N hydrogen chloride in propan-2-ol (30 mL) and stirred for 2 hours at RT. The crude solution was triturated with diethyl ether to give the desired material (as the hydrochloride salt) as a yellow solid (2.40 g). The material was used without further purification. NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.73 - 1.69 (2H, m), 1.93 - 1.90 (2H, m), 2.38 (3H, s), 3.20 (IH, ddd), 3.44 (IH, ddd), 3.58 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.26 - 4.12 (IH, m), 4.51 (IH, s), 6.71 (IH, s), 7.17 - 7.13 (2H, m), 7.45 (2H, d), 7.60 (IH, d), 7.97 (2H, d). LCMS Spectrum: m/z (ESI+) (M+H)+ = 483; HPLC tR = 2.57 min
fert-Butyl ^-[44441 -(S-fiuoro^-methylphenvnsulfonylcvclopropyll-ό-rfS^-S- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000758_0002
Sodium hydride (1.987 g, 41.39 mmol) was added rapidly to a solution of tert-butyl 7V-[4-[4- [(5-fluoro-2-methylphenyl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate (3.84 g, 6.90 mmol) in DMF (70 mL) and the mixture stirred at RT for 10 minutes before the slow addition 1 ,2-dibromoethane (2.38 mL, 27.59 mmol) in DMF (70 mL). The resulting suspension was stirred at RT for 30 minutes. Additional sodium hydride (0.95 g, 20.70 mmol) and 1,2 dibromoethane (1.19 g, 20.70 mmol) were added and the reaction was stirred for a further 30 minutes. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford brown gum. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% ethyl acetate in isohexane, to give a material which was further purified by trituration with 40% ethyl acetate in isohexane to give the desired material as a white solid (2.70 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 1.49 (9H, s), 1.70 - 1.64 (2H, m), 1.90 - 1.87 (2H, m), 2.41 (3H, s), 3.13 (IH, ddd), 3.45 (IH, ddd), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.11 (IH, d), 4.43 (IH, s), 6.66 (IH, s), 7.41 - 7.38 (2H, m), 7.46 (2H, d), 7.62 - 7.60 (IH, m), 7.88 (2H, d), 9.50 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 583; HPLC tR = 3.19 min
tert-Butyl N- \4- \4- \(5 -fluoro-2-methylphenvDsulfonylmethvH -6- IY35V3 -methylmorpholin-4- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000759_0001
5-Fluoro-2-methylbenzenesulfinic acid, sodium salt (2.079 g, 9.80 mmol) and tert-butyl 7V-[4- [4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (5 g, 9.80 mmol) were dissolved in DMF (50 mL) and stirred for 1 hour at RT The solvent was evaporated and the residue partitioned between water (50 mL) and DCM (75 mL). The layers were separated, the aqueous layer further extracted with DCM (75 mL) and the combined organics dried and solvent evaporated to afford an orange gum which was further purified by trituration with diethyl ether to give the desired material as an off white solid (4.75 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20 (3H, d), 1.50 (9H, s), 2.61 (3H, s), 3.17 (IH, ddd), 3.48 (IH, ddd), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.11 (IH, d), 4.40 (IH, s), 4.75 (2H, s), 6.69 (IH, s), 7.50 - 7.41 (4H, m), 7.56 - 7.53 (IH, m), 7.82 (2H, d), 9.50 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 557; HPLC tR = 2.91 min
5-fluoro-2-methylbenzenesulfmic acid, sodium salt
Figure imgf000760_0001
A solution of sodium sulfite (30.2 g, 239.65 mmol) in water (200 mL) was stirred at RT for 10 minutes. Sodium bicarbonate (40.3 g, 479.30 mmol) was added to the stirred solution. The resulting solution was stirred at 500C for 10 minutes. 5-Fluoro-2-methyl sulfonyl chloride was added portionwise and the solution stirred at 500C for 2 hours. The reaction mixture was evaporated to dryness and redissolved in ethanol (200 mL). The suspension was allowed to stir at RT for 20 minutes. The suspension was filtered and the filtrate evaporated to afford a white solid, this was stirred with acetonitrile (50 mL) and then filtered to afford the desired material as a white solid (27.0 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 2.41 (3H, s), 6.90 (IH, ddd), 7.05 (IH, dd), 7.36 (IH, dd).
The preparation of tert-butyl Λ/-[4-[4-(iodomethyl)-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] carbamate was described earlier.
Example 62: 3-α-Hydroxyethyl)-l-[4-[4-[(35V3-methylmorpholin-4-yll-6-q- methylsulfonylcvclobutyl)pyrimidin-2-yll phenyll thiourea
Figure imgf000760_0002
1 , l'-Thiocarbonyldiimidazole (57.6 mg, 0.32 mmol) was added to a stirred solution of 4-[4- [(35)-3-methylmorpholin-4-yl]-6-(l-methylsulfonylcyclobutyl)pyrimidin-2-yl]aniline (100 mg, 0.25 mmol) in THF (1.0 mL) and DCM (2.0 mL) at RT. The resulting solution was stirred for 2 hours. Triethylamine (0.035 mL, 0.25 mmol) and ethanolamine (15.18 mg, 0.25 mmol) were added to the reaction mixture and then stirred at RT for a further 1 hour. The reaction mixture was evaporated to dryness and redissolved in acetonitrile (2.0 mL), filtered and purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid (73 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.25 (3H, d), 1.92 (IH, d), 2.07 - 2.09 (IH, m), 2.79 - 2.86 (2H, m), 2.88 (3H, s), 2.87 - 2.95 (2H, m), 3.18 - 3.26 (IH, m), 3.47 - 3.54 (IH, m), 3.57 (3H, s), 3.64 - 3.67 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.30 (IH, d), 4.63 (IH, d), 4.85 (IH, s), 6.75 (IH, s), 7.61 - 7.64 (2H, m), 7.90 (IH, s), 8.27 - 8.30 (2H, m), 9.85 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 506.55; HPLC tR = 2.35 min.
The compounds below were prepared in an analogous fashion from 4-[4-[(35)-3- methylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclobutyl)pyrimidin-2-yl] aniline using the appropriate amine.
Figure imgf000761_0001
Figure imgf000762_0001
Example 62a: 1R NMR (400.132 MHz, DMSOd6) δ 1.25 (3H, d), 1.90 - 1.93 (IH, m), 2.07 - 2.09 (IH, m), 2.79 - 2.86 (2H, m), 2.88 (3H, s), 2.89 - 2.95 (2H, m), 3.20 - 3.26 (IH, m), 3.47
- 3.54 (IH, m), 3.64 - 3.67 (IH, m), 3.77 (IH, d), 3.97 - 4.00 (IH, m), 4.27 (IH, d), 4.60 (IH, s), 4.71 (2H, s), 6.76 (IH, s), 6.88 (IH, s), 7.09 (IH, s), 7.68 (2H, d), 8.24 (IH, s), 8.28 - 8.32
(2H, m), 10.06 (IH, s).
Example 62b: 1H NMR (400.132 MHz, DMSOd6) δ 1.14 - 1.16 (3H, m), 1.24 (3H, s), 1.90 -
1.94 (IH, m), 2.07 - 2.09 (IH, m), 2.79 - 2.84 (2H, m), 2.88 (3H, s), 2.91 - 2.95 (2H, m), 3.20
- 3.26 (IH, m), 3.44 - 3.54 (3H, m), 3.64 - 3.67 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.26 (IH, d), 4.38 (IH, s), 4.60 (IH, s), 4.92 (IH, s), 6.75 (IH, s), 7.63 - 7.66 (2H, m), 7.73 - 7.75 (IH, m), 8.28 (2H, d), 9.75 (IH, s).
Example 62c: 1U NMR (400.132 MHz, DMSOd6) δ 1.14 - 1.16 (3H, m), 1.24 (3H, s), 1.90 - 1.94 (IH, m), 2.07 - 2.09 (IH, m), 2.79 - 2.84 (2H, m), 2.88 (3H, s), 2.91 - 2.95 (2H, m), 3.20
- 3.26 (IH, m), 3.44 - 3.54 (3H, m), 3.64 - 3.67 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.26 (IH, d), 4.38 (IH, s), 4.60 (IH, s), 4.92 (IH, s), 6.75 (IH, s), 7.63 - 7.66 (2H, m), 7.73 - 7.75 (IH, m), 8.28 (2H, d), 9.75 (IH, s).
Example 62d: 1H NMR (400.132 MHz, DMSOd6) δ 1.24 - 1.25 (3H, m), 1.68 - 1.75 (2H, m), 1.90 - 1.93 (IH, m), 2.07 - 2.09 (IH, m), 2.79 - 2.86 (2H, m), 2.88 (3H, s), 2.89 - 2.95 (2H, m), 3.18 - 3.25 (IH, m), 3.47 - 3.54 (5H, m), 3.64 - 3.67 (IH, m), 3.77 (IH, d), 3.96 - 4.00 (IH, m), 4.26 (IH, d), 4.58 (2H, s), 6.75 (IH, s), 7.55 - 7.59 (2H, m), 7.93 (IH, s), 8.27 8.30 (2H, m), 9.74 (IH, s).
The preparation of 4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclobutyl)pyrimidin-2-yl] aniline was described earlier.
Example 63: 3-(lH-Imidazol-2-ylmethylVl-[4-[4-K3S)-3-methylmorpholin-4-yll-6-(l-
Pyridin-4-ylsulfonylcvclobutyl)pyrimidin-2-yll phenyll thiourea
Figure imgf000763_0001
1 , l'-Thiocarbonyldiimidazole (49.8 mg, 0.28 mmol) was added to a stirred solution of 4-[4- [(35)-3-methylmorpholin-4-yl]-6-(l-pyridin-4-ylsulfonylcyclobutyl)pyrimidin-2-yl]aniline (100 mg, 0.21 mmol) in TΗF (1.0 mL) and DCM (2.0 mL) at RT. The resulting solution was stirred for 2 hours. Triethylamine (0.030 mL, 0.21 mmol) and (lΗ-imidazol-2- yl)methanamine (20.86 mg, 0.21 mmol) were then added to the reaction mixture and stirred at RT for 1 hour. The reaction mixture was evaporated to dryness and redissolved in acetonitrile (2.0 mL), filtered and then purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to afford desired material as a white solid (85mg). NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 1.21 - 1.23 (3H, d), 1.94 (IH, m), 2.15 (IH, m), 2.82 (2H, m), 3.14 (2H, m), 3.51 (IH, t), 3.63 (IH, d), 3.68 (IH, d), 3.77 (IH, d), 3.97 (IH, dd), 4.17 (IH, d), 4.55 (IH, s), 4.73 (2H, s), 6.57 (IH, s), 6.89 (IH, s), 7.08 (IH, s), 7.48 (2H, d), 7.56 (2H, d), 7.79 (2H, d), 8.20 (IH, s), 8.73 (2H, d), 10.00 (IH, s), 11.94 (IH, s)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 605.51; HPLC tR = 2.03 min.
The preparation of 4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclobutyl)pyrimidin-2-yl]aniline is described below: 4-r4-r(35)-3-Methylmorpholin-4-yll-6-(l-pyridin-4-ylsulfonylcvclobutyl)pyrimidin-2- yll aniline
Figure imgf000764_0001
Bis(triphenylphosphine)palladium(II) chloride (79 mg, 0.11 mmol) was added to 2-chloro-4- [(35)-3-methylmorpholin-4-yl]-6-(l-pyridin-4-ylsulfonylcyclobutyl)pyrimidine (920 mg, 2.25 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (641 mg, 2.92 mmol) and 2M aqueous sodium carbonate solution (5 mL, 10.0 mmol) in DMF (10 mL), DME (40 mL), ethanol (10 mL) and water (10 mL) at RT under a nitrogen atmosphere. The resulting mixture was stirred at 800C for 2 hours. The reaction mixture was then diluted with ethyl acetate (400 mL) and washed sequentially with water (200 mL) and then brine (250 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, with an elution gradient of 0% to 50% ethyl acetate in DCM, to afford the desired material as a creamy white solid (1.01 g). NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 1.19 - 1.21 (3H, m), 1.88 - 1.95 (IH, m), 2.10 - 2.15 (IH, m), 2.76 - 2.83 (2H, m), 3.05 - 3.18 (3H, m), 3.45 - 3.52 (IH, m), 3.62 - 3.65 (IH, m), 3.75 (IH, d), 3.94 - 3.98 (IH, m), 4.13 (IH, d), 4.47 (IH, d), 5.50 (2H, d), 6.45 - 6.48 (2H, m), 6.52 (IH, s), 7.44 - 7.46 (2H, m), 7.52 - 7.66 (2H, d), 8.70 - 8.72 (2H, m) LCMS Spectrum: m/z (ESI+) (M+H)+ = 466.20; HPLC tR = 2.06 min
2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(l-pyridin-4-ylsulfonylcvclobutyl)pyrimidine
Figure imgf000764_0002
Sodium hydroxide (50%w/w solution) (24.39 g, 609.89 mmol) was added to a mixture of 2- chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(pyridin-4-ylsulfonylmethyl)pyrimidine (4.09 g, 11.09 mmol), 1,3-dibromopropane (3.38 mL, 33.27 mmol) and tetrabutylammonium bromide (0.357 g, 1.11 mmol) in toluene (200 mL) at RT under air. The resulting mixture was warmed to 45°C for 3 hours. Water (100 mL) was added to the solution and the toluene layer was washed with further water, brine and then dried over MgSO4. The mixture was filtered and the filtrate was evaporated to dryness. The crude product was purified by flash silica chromatography, eluting with a gradient of 30 to 50% ethyl acetate in DCM, to afford desired material as a solid (936 mg).
NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 1.17 - 1.19 (3H, m), 1.89 - 1.94 (IH, m), 2.07 - 2.13 (IH, m), 2.68 - 2.75 (2H, m), 2.96 - 3.06 (2H, m), 3.11 - 3.19 (IH, m), 3.39 - 3.46 (IH, m), 3.56 - 3.59 (IH, m), 3.71 (IH, d), 3.91 - 3.94 (2H, m), 4.34 (IH, s), 6.65 (IH, s), 7.47 - 7.49 (2H, m), 8.83 - 8.85 (2H, m) LCMS Spectrum: m/z (ESI+) (M+H)+ = 409; HPLC tR = 2.04 min.
The preparation of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(pyridin-4- ylsulfonylmethyl)pyrimidine was described earlier.
Example 64: 3-Cvclopropyl-l-[4-[4-[l-[4-fdifluoromethoxy)phenyllsulfonylcvclopropyll- 6- [(3 S)-3-methylmorpholin-4-yll pyrimidin-2-yll phenyll urea
Figure imgf000765_0001
Cyclopropylamine (0.136 mL, 0.80 mmol) was added to a solution of phenyl 7V-[4-[4-[l-[4- (difluoromethoxy)phenyl] sulfonylcyclopropyl] -6-[(3S)-3 -methylmorpholin-4-yl]pyrimidin-2- yljphenyl] carbamate (100 mg, 0.16 mmol) and triethylamine (0.066 mL, 0.48 mmol) in DMA (1 mL). The reaction was stirred at RT for 18 hours. The crude product was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile to afford the desired product as a solid (66 mg). NMR Spectrum: 1H NMR (400.13 MHz, DMSOd6) δ 0.41 (2H, m), 0.64 (2H, m), 1.18 (3H, d), 1.61 (2H, m), 1.87 (2H, m), 2.55 (IH, dd), 3.14 (IH, m), 3.46 (IH, td), 3.61 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.14 (IH, s), 4.40 (IH, s), 6.40 (IH, d), 6.63 (IH, s), 7.37 - 7.58 (5H, m), 7.84 (4H, m), 8.50 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 600; HPLC tR = 2.36 min. The compounds below were prepared in an analogous fashion using the appropriate carbamate and the appropriate amine.
Figure imgf000766_0001
Figure imgf000767_0001
Figure imgf000768_0001
Figure imgf000769_0001
Figure imgf000770_0001
Figure imgf000771_0001
Figure imgf000772_0001
Figure imgf000773_0001
* 1.2 Equivalents of amine used
** Reaction heated at 5O0C for 3 hours
*** By product formed and isolated when preparing Example 64j
Example 64a: I 1 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.60 (2H, m), 1.89 (2H, m), 2.66 (3H, d), 3.14 (IH, td), 3.46 (IH, td), 3.62 (IH, dd), 3.74 (IH, d), 3.94 (IH, dd), 4.15 (IH, d), 4.40 (IH, s), 6.04 (IH, q), 6.63 (IH, s), 7.36 - 7.61 (5H, m), 7.84 (4H, m), 8.70 (IH, s) Example 64b: 1H NMR (400.132 MHz, DMSOd6) δ 1.06 (3H, t), 1.18 (3H, d), 1.61 (2H, m), 1.88 (2H, m), 3.13 (3H, m), 3.46 (IH, td), 3.61 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.15 (IH, d), 4.40 (IH, s), 6.13 (IH, t), 6.63 (IH, s), 7.37 - 7.59 (5H, m), 7.84 (4H, m), 8.62 (IH, s)
Example 64c: 1U NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.60 (2H, m), 1.87 (2H, m), 3.16 - 3.18 (3H, m), 3.46 (3H, m), 3.61 (IH, dd), 3.75 (IH, d), 3.95 (IH, dd), 4.15 (IH, d), 4.40 (IH, s), 4.72 (IH, t), 6.24 (IH, t), 6.63 (IH, s), 7.37 - 7.60 (5H, m), 7.84 (4H, m),
8.76 (IH, s)
Example 64d: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.61 (2H, m), 1.89 (2H, m), 3.17 (IH, td), 3.46 (IH, td), 3.61 (IH, dd), 3.75 (IH, d), 3.79 (3H, s), 3.96 (IH, dd), 4.15 (IH, d), 4.40 (IH, s), 6.65 (IH, s), 7.36 - 7.60 (6H, m), 7.76 (IH, s), 7.84 - 7.86 (4H, dd),
8.35 (IH, s), 8.80 (IH, s)
Example 64e: 1R NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.61 (2H, m), 1.89 (2H, m), 3.16 (IH, td), 3.38 (IH, m), 3.45 (2H, m), 3.61 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.15 (IH, d), 4.41 (2H, t), 4.53 (IH, t), 6.41 (IH, t), 6.64 (IH, s), 7.37-7.60 (5H, m), 7.84 (4H, m), 8.77 (IH, s)
Example 64f: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.60 (2H, m), 1.89 (2H, m), 3.16 (IH, td), 3.48 -3.54 (3H, m), 3.61 (IH, dd), 3.74 (IH, d), 3.96 (IH, dd), 4.14 (IH, d), 4.40 (IH, s), 5.90 - 6.40 (IH, m), 6.50 (IH, t), 6.64 (IH, s), 7.38 - 7.60 (5H, m), 7.85 (4H, m), 8.88 (IH, s)
Example 64g: 1R NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, m), 1.61 (2H, dd), 1.93 (2H, dd), 2.67 (3H, t), 3.17 (IH, m), 3.46 (IH, td), 3.62 (IH, dd), 3.75 (IH, m), 3.92 (IH, dd), 4.20 (IH, d), 4.45 (IH br s), 6.04 (IH, q), 6.67 (IH, s), 7.40 (2H, m), 7.67 (2H, m), 7.79 (2H, m), 7.91 (IH, m), 8.73 (IH, s)
Example 64h: 1H NMR (400.132 MHz, DMSOd6) δ 1.07 (3H, t), 1.19 (3H, d), 1.61 (2H, dd), 1.93 (2H, dd), 3.12 (2H, m), 3.16 (IH, m), 3.45 (IH, td), 3.62 (IH, dd), 3.75 (IH, d), 3.95 (IH, dd), 4.15 (IH, d), 4.45 (IH, br s), 6.13 (IH, t), 6.67 (IH, s), 7.39 (2H, m), 7.65 (IH, d), 7.67 (IH, t), 7.79 (2H, m), 7.91 (IH, m), 8.65 (IH, s) Example 64i: 1U NMR (400.132 MHz, DMSOd6) δ 0.42 (2H, dt), 0.65 (2H, td), 1.19 (3H, d), 1.61 (2H, dd), 1.93 (2H, dd), 2.56 (IH, m), 3.18 (IH, td), 3.46 (IH, td), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.15 (IH, d), 4.47 (IH, br s), 6.30 (IH, s), 6.67 (IH, s), 7.40 (2H, m), 7.66 (2H, m), 7.80 (2H, m), 7.90 (IH, td), 8.53 (IH, s) Example 64j: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.61 (2H, dd), 1.93 (2H, m), 3.17 (3H, q), 3.45 (3H, m), 3.61 (IH, dd), 3.73 (IH, d), 3.91 (IH, dd), 4.15 (IH, d), 4.50 (IH, br s), 4.72 (IH, t), 6.22 (IH, s), 6.67 (IH, s), 7.38 (2H, m), 7.66 (IH, t), 7.67 (IH, s), 7.79 (2H, m), 7.90 (IH, m), 8.79 (IH, s)
Example 64k: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.62 (2H, dd), 1.94 (2H, dd), 3.17 (IH, td), 3.47 (IH, td), 3.62 (IH, dd), 3.74 (IH, d), 3.79 (3H, s), 3.96 (IH, dd), 4.17 (IH, d), 4.47 (IH, br s), 6.68 (IH, s), 7.38 (IH, d), 7.45 (2H, m), 7.67 (2H, m), 7.77 (IH, d), 7.83 (2H, d), 7.91 (IH, t), 8.35 (IH, s), 8.84 (IH, s)
Example 641: 1U NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, m), 1.61 (2H, dd), 1.93 (2H, dd), 3.17 (IH, td), 3.39 (IH, t), 3.45 (2H, q), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.15 (IH, d), 4.42 (IH, t), 4.50 (IH, br s), 4.53 (IH, t), 6.40 (IH, t), 6.67 (IH, s), 7.40 (2H, m), 7.66 (IH, d), 7.67 (IH, t), 7.80 (2H, d), 7.90 (IH, m), 8.80 (IH, s)
Example 64m: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.61 (2H, dd), 1.94 (2H, dd), 3.17 (IH, td), 3.45 (IH, td), 3.54 (2H, m), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.17 (IH, d), 4.47 (IH, br s), 5.90-6.20 (IH, tt), 6.50 (IH, t), 6.68 (IH, s), 7.41 (2H, m), 7.67 (2H, m), 7.82 (2H, m), 7.90 (IH, m), 8.92 (IH, s)
Example 64n: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.56 (2H, m), 1.81 (2H, m), 3.15 (IH, m), 3.17 (2H, m), 3.46 (3H, q), 3.57 (2H, q), 3.62 (IH, m), 3.75 (IH, d), 3.96 (IH, dd), 4.06 (IH, m), 4.37 (IH, br s), 4.73 (2H, q), 6.25 (IH, t), 6.36 (IH, m), 6.58 (IH, s), 6.82 (IH, t), 7.33 (IH, m), 7.41 (3H, m), 7.96 (2H, m), 8.76 (IH, s)
Example 64o: 1R NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.22 (6H, s), 1.87 (IH, m), 2.08 (IH, m), 2.78 (2H, m), 3.04-3.20 (3H, m), 3.38 (2H, d), 3.48 (IH, td), 3.63 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.08 (IH, d), 4.44 (IH, br s), 4.95 (IH, t), 5.97 (IH, s), 6.46 (IH, s), 7.32 (2H, m), 7.47 (4H, m), 7.60 (IH, m), 7.78 (2H, d), 8.67 (IH, s)
Example 64p: 1H NMR (400.132 MHz, DMSOd6) δ 1.08 (3H, d), 1.20 (3H, d), 1.87 (IH, m), 2.08 (IH, m), 2.79 (2H, m), 3.04-3.20 (3H, m), 3.36 (2H, m), 3.48 (IH, td), 3.63 (IH, dd), 3.71 (2H, m), 3.96 (IH, dd), 4.07 (IH, d), 4.45 (IH, br s), 4.78 (IH, t), 6.07 (IH, m), 6.46 (IH, s), 7.35 (2H, m), 7.47 (4H, m), 7.60 (IH, m), 7.79 (2H, d), 8.65 (IH, s) Example 64q: 1H NMR (400.132 MHz, DMSOd6) δ 1.08 (3H, d), 1.20 (3H, d), 1.87 (IH, m), 2.08 (IH, m), 2.79 (2H, m), 3.04 -3.20 (3H, m), 3.36 (2H, m), 3.48 (IH, td), 3.63 (IH, dd), 3.71 (IH, m), 3.73 (IH, m), 3.96 (IH, dd), 4.07 (IH, d), 4.45 (IH, br s), 4.78 (IH, t), 6.07 (IH, d), 6.46 (IH, s), 7.35 (2H, d), 7.47 (4H, m), 7.59 (IH, td), 7.79 (2H, m), 8.65 (IH, s) Example 64r: 1R NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.59 (2H, m), 1.87 (IH, m), 2.08 (IH, m), 2.79 (2H, m), 3.04 (2H, m), 3.12 (IH, m), 3.25 (2H, d), 3.46 (3H, m), 3.63 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.07 (IH, m), 4.47 (2H, m), 6.18 (IH, t), 6.46 (IH, s), 7.36 (2H, m), 7.48 (4H, m), 7.59 (IH, m), 7.79 (2H, d), 8.65 (IH, s)
Example 64s: 1U NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.87 (IH, m), 2.12 (IH, m), 2.75 (2H, m), 3.00-3.20 (3H, m), 3.40 (IH, t), 3.45 (2H, m), 3.61 (IH, dd), 3.74 (IH, d), 3.92 (IH, dd), 4.15 (IH, d), 4.41 (2H, m), 4.53 (IH, t), 6.41 (IH, t), 6.47 (IH, s), 7.37 (2H, m), 7.48 (4H, m), 7.60 (IH, t), 7.80 (2H, m), 8.75 (IH, s)
Example 64t: 1H NMR (400.132 MHz, DMSOd6) δ 0.94 (2H, m), 1.03 (2H, m), 1.24 (3H, d), 1.58 (2H, m), 1.65 (2H, m), 3.00 (IH, m), 3.15 (IH, td), 3.36 (IH, m), 3.46 (2H, m), 3.61 (IH, dd), 3.77 (IH, d), 3.94 (IH, dd), 4.20 (IH, d), 4.42 (IH, t), 4.53 (2H, t), 6.43 (IH, t), 6.85 (IH, s), 7.50 (2H, m), 8.22 (2H, m), 8.80 (IH, s)
Example 64u: 1H NMR (400.132 MHz, DMSOd6) δ 0.94 (2H, m), 1.03 (2H, m), 1.24 (3H, d), 1.59 (2H, m), 1.65 (2H, m), 3.00 (IH, m), 3.21 (IH, td), 3.54 (3H, m), 3.64 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.20 (IH, d), 4.54 (IH, br s), 5.90-6.20 (IH, tt), 6.53 (IH, t), 6.85 (IH, s), 7.51 (2H, m), 8.23 (2H, m), 8.91 (IH, s)
Example 64v: 1U NMR (400.132 MHz, DMSOd6) δ 0.94 (2H, m), 1.03 (2H, m), 1.24 (3H, d), 1.59 (2H, m), 1.65 (2H, m), 3.00 (IH, m), 3.19 (IH, td), 3.49 (IH, td), 3.64 (IH, dd), 3.77 (IH, d), 3.96 (IH, dd), 4.20 (IH, d), 4.32 (2H, d), 4.54 (IH, br s), 6.62 (IH, t), 6.85 (IH, s), 6.95 (IH, br s), 7.51 (2H, m), 8.22 (2H, m), 8.92 (IH, s)
Example 64w: 1H NMR (400.132 MHz, DMSOd6) δ 0.76 (2H, m), 0.85 (2H, m), 1.24 (9H, m), 1.90 (IH, m), 2.10 (IH, m), 2.45 (IH, m), 2.80 - 3.30 (4H, m), 3.20 (IH, td), 3.39 (2H, d), 3.50 (IH, td), 3.65 (IH, dd), 3.75 (IH, d), 3.95 (IH, dd), 4.20 (IH, d), 4.50 (IH, br s), 4.95 (IH, t), 6.00 (IH, s), 6.70 (IH, s), 7.45 (2H, m), 8.22 (2H, m), 8.72 (IH, s)
Example 64x: 1U NMR (400.132 MHz, DMSOd6) δ 0.70 (2H, m), 0.85 (2H, m), 1.10 (3H, d), 1.25 (3H, d), 1.90 (IH, m), 2.10 (IH, m), 2.45 (IH, m), 2.80 -3.00 (4H, m), 3.15 (IH, td),
3.35 (2H, m), 3.50 (IH, td), 3.60-3.80 (3H, m), 3.95 (IH, dd), 4.20 (IH, d), 4.55 (IH, br s), 4.75 (IH, t), 6.10 (IH, d), 6.70 (IH, s), 7.45 (2H, m), 8.20 (2H, m), 8.70 (IH, s) Example 64y: 1U NMR (400.132 MHz, DMSOd6) δ 0.70 (2H, m), 0.84 (2H, m), 1.08 (3H, d), 1.23 (3H, d), 1.89 (IH, m), 2.10 (IH, m), 2.46 (IH, m), 2.84-3.00 (4H, m), 3.15 (IH, td),
3.36 (2H, m), 3.51 (IH, td), 3.67 (IH, td), 3.77 (2H, m), 3.95 (IH, dd), 4.20 (IH, d), 4.55 (IH, br s), 4.78 (IH, t), 6.09 (IH, d), 6.70 (IH, s), 7.47 (2H, m), 8.23 (2H, m), 8.70 (IH, s) Example 64z: 1H NMR (400.132 MHz, DMSOd6) δ 0.70 (2H, m), 0.84 (2H, m), 1.20 (3H, d), 1.57 (2H, m), 1.89 (IH, m), 2.10 (IH, m), 2.46 (IH, m), 2.80-3.00 (4H, m), 3.15 (4H, m), 3.45 (2H, m), 3.55 (IH, td), 3.65 (IH, dd), 3.77 (IH, d), 3.95 (IH, dd), 4.20 (IH, d), 4.45 (IH, t), 4.55 (IH, br s), 6.20 (IH, t), 6.70 (IH, s), 7.47 (2H, m), 8.25 (2H, m), 8.70 (IH, s) Example 64aa: 1U NMR (400.132 MHz, DMSOd6) δ 1.23 (3H, m), 1.58 (2H, m), 1.67 (2H, m), 2.47 (3H, s), 3.20 (IH, td), 3.39 (IH, q), 3.46 (2H, m), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.21 (IH, d), 4.42 (IH, t), 4.54 (IH, br s), 4.55 (IH, t), 6.43 (IH, t), 6.77 (IH, s), 7.51 (2H, m), 8.21 (2H, m), 8.82 (IH, s)
Example 64ab: 1H NMR (400.132 MHz, DMSOd6) δ 1.23 (3H, d), 1.56 (2H, m), 1.67 (2H, m), 2.46 (3H, s), 3.15 (IH, td), 3.47 -3.63 (4H, m), 3.76 (IH, d), 3.97 (IH, dd), 4.21 (IH, d), 4.57 (IH, br s), 5.90 - 6.20 (IH, m), 6.53 (IH, t), 6.78 (IH, s), 7.52 (2H, m), 8.22 (2H, m), 8.93 (IH, s
Example 64ac: 1R NMR (400.132 MHz, DMSOd6) δ 1.08 (3H, d), 1.21 (3H, d), 1.77 (2H, m), 1.94 (2H, m), 2.48 (3H, d), 3.18 (IH, td), 3.36 (2H, m), 3.40 (IH, td), 3.63 (IH, dd), 3.71 (IH, m), 3.76 (IH, d), 3.96 (IH, dd), 4.15 (IH, d), 4.45 (IH, br s), 4.78 (IH, t), 6.07 (IH, m), 6.77 (IH, s), 7.39 (2H, m), 7.84-7.90 (3H, m), 8.69 (IH, s)
Example 64ad: 1H NMR (400.132 MHz, DMSOd6) δ 1.08 (3H, d), 1.21 (3H, d), 1.77 (2H, m), 1.94 (2H, m), 2.48 (3H, d), 3.18 (IH, td), 3.36 (2H, m), 3.40 (IH, td), 3.63 (IH, dd), 3.71 (IH, m), 3.76 (IH, d), 3.96 (IH, dd), 4.15 (IH, d), 4.45 (IH, br s), 4.78 (IH, t), 6.07 (IH, m), 6.77 (IH, s), 7.39 (2H, m), 7.84-7.90 (3H, m), 8.70 (IH, s)
Example 64ae: 1R NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.77 (2H, m), 1.96 (2H, m), 2.48 (3H, d), 3.18 (IH, td), 3.38 (IH, m), 3.45 (2H, m), 3.62 (IH, dd), 3.76 (IH, d), 3.96 (IH, dd), 4.15 (IH, d), 4.41 (IH, t), 4.45 (IH, br s), 4.53 (IH, t), 6.41 (IH, t), 6.78 (IH, s), 7.42 (2H, m), 7.84 (IH, s), 7.90 (2H, m), 8.79 (IH, s)
Example 64af: 1H NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 1.74 (2H, m), 1.97 (2H, m), 3.15 (IH, td), 3.4O(1H, td), 3.50 -3.60 (3H, m), 3.74 (IH, d), 3.95 (IH, dd), 4.13 (IH, d), 4.40 (IH, br s), 5.90-6.20 (IH, m), 6.50 (IH, t), 6.70 (IH, s), 7.35 (2H, m), 7.76 (3H, m), 7.95 (IH, m), 8.09 (IH, td), 8.75 (IH, d), 8.83 (IH, s) Example 64ag: 1U NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 1.74 (2H, m), 2.00 (2H, m), 3.15 (IH, td), 3.52 (IH, td), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.13 (IH, d), 4.40 (IH, br s), 6.70 (IH, s), 6.87 (IH, s), 7.43 (2H, m), 7.76-7.81 (3H, m), 7.99 (IH, m), 8.09 (IH, td), 8.75 (IH, s), 8.83 (IH, m), 9.02 (IH, s), 9.60 (IH, s) Example 64ah: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.61 (2H, dd), 1.90 (2H, dd), 3.17 (IH, m), 3.40 - 3.64 (4H, m), 3.75 (IH, d), 3.96 (IH, dd), 4.15 (IH, d), 4.45 (IH, br s), 5.90 - 6.2O(1H, t), 6.49 (IH, t), 6.64 (IH, s), 7.41 (2H, d), 7.66 (2H, m), 7.78 (4H, m), 8.90 (IH, s)
Example 64ai: 1U NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, m), 1.62 (2H, m), 1.91 (2H, m), 3.15 (IH, td), 3,45 (IH, td), 3.61 (IH, dd), 3.75 (IH, d), 3.95 (IH, dd), 4.15 (IH, d), 4.45 (IH, br s), 6.66 (IH, s), 6.87 (IH, s), 7.47 (2H, d), 7.67 (2H, d), 7.79 (2H, d), 7.84 (2H, m), 8.75 (IH, s), 9.10 (IH, s), 9.60 (IH, s)
Example 64aj: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.56 (2H, m), 1.64 (2H, m), 1.94 (2H, m), 3.15-3.25 (2H, m), 3.39 (IH, m), 3.40 - 3.52 (5H, m), 3.65 (IH, dd), 3.75 (IH, d), 3.95 (IH, dd), 4.20 (IH, br s, 4.42 (IH, t), 4.54 (2H, m), 4.69 (IH, t), 6.43 (IH, t), 6.77 (IH, s), 7.50 (2H, m), 8.22 (2H, m), 8.81 (IH, s)
Example 64ak: 1H NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.57 (2H, m), 1.64 (2H, m), 1.94 (2H, m), 3.25 (IH, m), 3.51 (IH, m), 3.53 (4H, m), 3.76 (IH, dd), 3.86 (IH, d), 4.10 (IH, dd), 4.30 (IH, d), 4.65 (IH, br s), 4.70 (IH, t), 6.80 (IH, s), 6.87 (IH, s), 7.57 (2H, m), 8.29 (2H, m), 8.76 (IH, s), 9.07 (IH, s), 9.62 (IH, s)
Example 64al: 1U NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.60 (2H, m), 1.85 (2H, m), 2.78 (IH, s), 2.95 (IH, s), 3.15 (2H, m), 3.42 (2H, m), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.15 (IH, d), 4.45 (IH, s), 4.72 (IH, t), 6.23 (IH, t), 6.70 (IH, s), 7.40 (2H, m), 7.70 -8.00 (3H, m), 8.20 (IH, s), 8.80 (IH, s), 8.91 (IH, s)
The preparation of phenyl Λ/-[4-[4-[l-[4-(difluoromethoxy)phenyl]sulfonylcyclopropyl]-6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl Λ/-[4-[4-[ 1 -[4-(difluoromethoxy)phenyllsulfonylcvclopropyll-6-[(36f)-3- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000778_0001
Phenyl chloro formate (0.170 mL, 1.36 mmol) was added dropwise to 4-[4-[l-[4- (difluoromethoxy)phenyl] sulfonylcyclopropyl] -6- [(35)-3 -methylmorpholin-4-yl]pyrimidin-2- yljaniline (0.700 g, 1.36 mmol) and sodium hydrogen carbonate (0.114 g, 1.36 mmol) in dioxane and the resulting suspension stirred at RT for 6 hours. The reaction mixture was concentrated and diluted with DCM (50 mL), and washed sequentially with water (10 mL), water (10 mL), and saturated brine(10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude solid was triturated with a mixture of diethyl ether: isohexane (20:80) to give the desired material as a white solid (0.710 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, m), 1.62 (2H, dd), 1.90 (2H, dd), 3.16 (IH, td), 3.46 (IH, td), 3.60 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.14 (IH, d), 4.42 (IH, s), 6.67 (IH, s), 7.24 -7.27 (3H, m), 7.37 (3H, m), 7.45 (2H, m), 7.53 (2H, m), 7.84 (2H, m), 7.93 (2H, m), 10.40 (IH, s).
LCMS Spectrum: m/z (ES+)(M+H)+=637; HPLC tR=3.04 min. 4- [4- r 1 -r4-(Difluoromethoxy)phenyllsulfonylcvclopropyll -6- r(3ιSV3 -methylmorpholin-4- yllpyrimidin-2-vH aniline
Figure imgf000779_0001
Trans-Dichlorobis(triphenylphosphine)palladium (II) (0.225 g, 0.32 mmol) was added to 2- chloro-4- [ 1 - [4-(difluoromethoxy)phenyl]sulfonylcyclopropyl] -6- [(35)-3 -methylmorpholin-4- yljpyrimidine (2.95 g, 6.41 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.476 g, 6.74 mmol) and 2M aqueous solution of sodium carbonate (16.04 mL, 32.07 mmol) in the DMF solution (15OmL) (DMF solution was 18% DMF, 82% of a 7:3:2 mixture of DME:H2O:Ethanol) at RT under nitrogen. The resulting solution was stirred at 800C for 5 hours. The reaction was cooled and the reaction mixture diluted with ethyl acetate and water. The reaction mixture was extracted with ethyl acetate and the combined organics dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% ethyl acetate in DCM, to give the desired material as a beige solid (1.35 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.59 (2H, dd), 1.87 (2H, dd), 3.26 (IH, td), 3.50 (IH, td), 3.61 (IH, dd), 3.73 (IH, d), 3.95 (IH, dd), 4.10 (IH, d), 4.40 (IH, br s), 5.51 (2H, br s), 6.50 (2H, m), 6.53 (IH, s), 7.21 - 7.60 (IH, m), 7.35 (2H, m), 7.68 (2H, m), 7.83 (2H, m). LCMS Spectrum: m/z (ES+)(M+H)+=517; HPLC tR=2.53 min.
2-Chloro-4- r 1 - r4-(difluoromethoxy)phenyll sulfonylcyclopropyll -6- [(36^-3 -methylmorpholin- 4-vHpyrimidine
Figure imgf000779_0002
A solution of 50% w/v sodium hydroxide (14.2 mL, 354.96 mmol) was added portionwise to a stirred solution of 2-chloro-4-[[4-(difluoromethoxy)phenyl]sulfonylmethyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidine (2.8 g, 6.45 mmol), tetrabutylammonium bromide (0.208 g, 0.65 mmol) and 1 ,2-dibromoethane (1.668 mL, 19.36 mmol) in toluene (150 mL) and the resulting suspension stirred at 600C for 6 hours. The reaction mixture was diluted with water (50 mL), and the washed sequentially with water (2 x 50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% ethyl acetate in DCM, to give the desired material as a colourless oil which solidified on standing (2.95 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, dd), 1.55 (2H, dd), 1.83 (2H, dd), 3.13 (IH, td), 3.40 (IH, td), 3.54 (IH, dd), 3.69 (IH, d), 3.90 (2H, dd), 4.23 (IH, br s), 6.68 (IH, s), 7.23-7.60 (IH, t), 7.37 (2H, d), 7.82 (2H, d). LCMS Spectrum: m/z (ES+)(M+H)+=459; HPLC tR=2.49 min.
2-Chloro-4-rr4-(difluoromethoxy)phenyllsulfonylmethyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000780_0001
Sodium 4-(difluoromethoxy)benzenesulfinate (2.54 g, 11.03 mmol) was added portionwise to 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (3.25 g, 9.19 mmol) in acetonitrile (125 mL) and the resulting suspension stirred at 800C for 6 hours. Additional sodium 4-(difluoromethoxy)benzenesulfmate (680mg, 3.39 mmol) was added in one portion and the suspension was stirred at 800C for a further 2 hours. The reaction mixture was concentrated and diluted with DCM (200 mL) and washed sequentially with 10% aqueous sodium thiosulfate solution (50 mL), water (50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude gum was triturated with diethyl ether to give the desired material as a beige solid (2.94 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.16 (3H, d), 3.15 (IH, td), 3.42 (IH, m), 3.57 (IH, dd), 3.71 (IH, d), 3.91 (IH, br s), 3.92 (IH, dd), 4.17 (IH, br s), 4.64 (2H, s), 6.68 (IH, s), 7.25-7.60 (IH, t), 7.41 (2H, m), 7.84 (2H, m). LCMS Spectrum: m/z (ES+)(M+H)+=434; HPLC tR=2.29 min.
Sodium 4-(difluoromethoxy)benzenesulfinate
Figure imgf000781_0001
A solution of sodium sulfite (1.470 g, 11.66 mmol) in water (15 mL) was stirred at RT for 10 minutes. Sodium bicarbonate (1.960 g, 23.33 mmol) was added to the stirred solution. The resulting solution was stirred at 500C for 1 hour. 4-(Difluoromethoxy)benzene-l-sulfonyl chloride (2.83 g, 11.66 mmol) was added dropwise with caution to the solution and was stirred at 500C for 18 hours. The reaction mixture was evaporated to dryness and redissolved in methanol (15 mL). The suspension was allowed to stir at RT for 20 minutes. The suspension was filtered and the filtrate was evaporated to give a crude product that was triturated with isohexane to give the desired material as a cream solid (2.85 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 7.10 (2H, dd), 7.50 (2H, dd).
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
The preparation of phenyl N-[4-[4-[l-(3,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl Λ/-r4-r4-ri-(3,4-difluorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- yl1pyrimidin-2-yl1phenvHcarbamate
Figure imgf000781_0002
Phenyl chloroformate (0.206 mL, 1.64 mmol) was added dropwise to 4-[4-[l-(3,4- difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (800 mg, 1.64 mmol) and sodium hydrogen carbonate (138 mg, 1.64 mmol) in dioxane and the resulting suspension was stirred at RT for 6 hours. The reaction mixture was concentrated and diluted with DCM (50 mL), and washed sequentially with water (2 x 10 mL), and saturated brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude solid was triturated with acetonitrile to give the desired material as a white solid (1.0 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.63 (2H, dd), 1.94 (2H, dd), 3.17 (IH, td), 3.47 (IH, td), 3.61 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.18 (IH, d), 4.50 (IH, br s), 6.71 (IH, s), 7.25 (2H, dt), 7.29 (IH, m), 7.45 (2H, dd), 7.54 (2H, d), 7.67 (2H, m), 7.91 (3H, dd), 10.40 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=607; HPLC tR=3.05 min.
4- [4- r 1 -(3 ,4-DifTuorophenvDsulfonylcvclopropyπ -6- [(36^-3 -methylmorpholin-4-vHpyrimidin- 2-vHaniline
Figure imgf000782_0001
Trans-Dichlorobis(triphenylphosphine)palladium (II) (0.252 g, 0.36 mmol) was added to 2- chloro-4- [ 1 -(3 ,4-difiuorophenyl)sulfonylcyclopropyl] -6- [(35)-3 -methylmorpholin-4- yljpyrimidine (3.09 g, 7.19 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.575 g, 7.19 mmol)and a 2M aqueous solution of sodium carbonate (17.97 mL, 35.94 mmol) in the DMF solution (DMF solution was 18% DMF, 82% of a 7:3:2 mixture of DME:H2θ:Ethanol) (15OmL) at RT under nitrogen. The resulting solution was stirred at 800C for 5 hours. The reaction was cooled and the mixture diluted with ethyl acetate and water. The reaction mixture was extracted with ethyl acetate and the combined organics dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient Oto 5% ethyl acetate in DCM, to give a material which was further purified by ion exchange chromatography using an SCXcolumn, eluting with 7M ammonia in methanol, to give the desired material as a tan solid (1.94 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18 (3H, d), 1.59 (2H, dd), 1.91 (2H, dd), 3.10 (IH, td), 3.45 (IH, td), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.13 (IH, m), 4.43 (IH, br s), 5.53 (2H, d), 6.50 (2H, m), 6.57 (IH, s), 7.64 (IH, m), 7.65 (3H, m), 7.89 (IH, m). LCMS Spectrum: m/z (ES+)(M+H)+=487; HPLC tR=2.55 min.
2-Chloro-4-ri-(3,4-difluorophenyl)sulfonylcvclopropyll-6-r(36^-3-methylmorpholin-4- yllpyrimidine
Figure imgf000783_0001
A solution of 50% w/v sodium hydroxide (17.32 mL, 433.10 mmol) was added portionwise to a stirred solution of 2-chloro-4-[(3,4-difluorophenyl)sulfonylmethyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidine (3.18 g, 7.87 mmol), tetrabutylammonium bromide (0.254 g, 0.79 mmol) and 1 ,2-dibromoethane (2.036 mL, 23.62 mmol) in toluene (200 mL) and the resulting suspension stirred at 600C for 6 hours. The reaction mixture was diluted with water (50 mL), and washed sequentially with water (2 x 50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in DCM, to give the desired material as a white solid (3.09 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 1.56 (2H, dd), 1.88 (2H, dd), 3.15 (IH, td), 3.40 (IH, td), 3.54 (IH, dd), 3.69 (IH, d), 3.91 (IH, dd), 3.97 (IH, d), 4.29 (IH, br s), 6.73 (IH, s), 7.65 (IH, m), 7.66 (IH, m), 7.92 (IH, ddd). LCMS Spectrum: m/z (ES+)(M+H)+=430; HPLC tR=2.41 min.
2-Chloro-4-r(3,4-difluorophenyl)sulfonylmethyll-6-r(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000783_0002
Sodium 3,4-difluorobenzenesulfinate (3.40 g, 16.97 mmol) was added portionwise to 2- chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (6 g, 16.97 mmol) in acetonitrile (200 mL) and the resulting suspension stirred at 800C for 6 hours. Additional sodium 3,4-difluorobenzenesulfinate (680mg, 3.39mmol) was added in one portion and the suspension was stirred at 800C for a further 2 hours. The reaction mixture was concentrated and diluted with DCM (200 mL), and washed sequentially with water (2 x 50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% ethyl acetate in DCM, to give the desired material as a yellow solid (4.58 g)-
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, m), 3.10-3.20 (IH, td), 3.40-3.45 (IH, td), 3.55-3.60 (IH, dd), 3.70 (IH, d), 3.90-4.00 (2H, dd), 4.20 (IH, br s), 4.70 (2H, s), 6.77 (IH, s), 7.66 (IH, m), 7.74 (IH, dt), 7.95 (IH, ddd). LCMS Spectrum: m/z (ES+)(M+H)+=404; HPLC tR=2.24 min.
Sodium 3.4-difluorobenzenesulfinate o
FlTYs ° Na+
A solution of sodium sulfite (2.96 g, 23.52 mmol) in water (25 mL) was stirred at RT for 10 minutes. Sodium bicarbonate (3.95 g, 47.04 mmol) was added to the stirred solution. The resulting solutionwas stirred at 500C for 1 hour. 3,4-Difluorobenzene-l-sulfonyl chloride (5 g, 23.52 mmol) was added portionwise to the solution and was stirred at 500C for 18 hours. The reaction mixture was evaporated to dryness and redissolved in methanol (15 mL). The suspension was allowed to stir at RT for 20 minutes. The suspension was filtered and the filtrate was evaporated to afford the desired material as a white solid (5.30 g), which was dried overnight under vacuum and used without further purification.
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 7.28 (IH, ddd), 7.37 (2H, m).
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier The preparation of phenyl Λ/-[4-[4-[l-[l-(difluoromethyl)pyrazol-4-yl]sulfonylcyclopropyl]- 6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N-\4-\4-\\ -\ 1 -(difluoromethvnpyrazol^-yllsulfonylcvclopropyll-ό-rO^-S- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000785_0001
Phenyl chloroformate (0.018 mL, 0.14 mmol) was added dropwise to 4-[4-[l-[l- (difluoromethyl)pyrazol-4-yl]sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl] aniline (70 mg, 0.14 mmol) and sodium hydrogen carbonate (11.99 mg, 0.14 mmol) in dioxane and the resulting suspension stirred at RT for 6 hours. The reaction mixture was concentrated and diluted with DCM (50 mL), and washed sequentially with water (2 x 10 mL), and saturated brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude solid was triturated with diethyl ether: isohexane (20:80) to give the desired material as a white solid (80 mg). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.59 (2H, m), 1.89 (2H, m), 3.15 (IH, td), 3.45 (IH, td), 3.63 (IH, dd), 3.75 (IH, d), 3.95 (IH, dd), 4.15 (IH, d), 4.50 (IH, br s), 6.75 (IH, m), 7.26 (3H, m), 7.45 (2H, m), 7.56 (2H, m), 7.70-8.00 (IH, t),8.00 (2H, m), 8.17 (IH, s), 8.93 (IH, s), 10.40 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=611; HPLC tR=2.83 min.
4-[4-[ 1 -[ 1 -(Difluoromethyl)pyrazol-4-yllsulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidin-2-vH aniline
Figure imgf000785_0002
Trans-Dichlorobis(triphenylphosphine)palladium (II) (0.197 g, 0.28 mmol) was added to 2- chloro-4- [ 1 - [ 1 -(difluoromethyl)pyrazol-4-yl] sulfonylcyclopropyl] -6-[(3S)-3 - methylmorpholin-4-yl]pyrimidine (2.44 g, 5.62 mmol), 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (1.232 g, 5.62 mmol) and a 2M aqueous solution of sodium carbonate (14.06 mL, 28.12 mmol) in the DMF solution (DMF solution was 18% DMF, 82% of a 7:3:2 mixture of DME:H2θ:Ethanol) (15OmL) and the resulting solution stirred at 800C for 5 hours. The reaction mixture was partitioned between ethyl acetate and water, the layers separated and the aqueous layer extracted with ethyl acetate. The combined organics were dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% ethyl acetate in DCM, to give the desired material as a tan solid (0.070 g). LCMS Spectrum: m/z (ES+)(M+H)+=491; HPLC tR=2.23 min.
2-Chloro-4- r 1 - [ 1 -(difluoromethyl)pyrazol-4-yll sulfonylcyclopropyll -6- [(36^-3 - methylmorpholin-4-vHpyrimidine
Figure imgf000786_0001
A solution of 50% w/v sodium hydroxide (16.18 mL, 404.59 mmol) was added portionwise to a stirred solution of 2-chloro-4-[[l-(difluoromethyl)pyrazol-4-yl]sulfonylmethyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidine (3 g, 7.36 mmol), tetrabutylammonium bromide (0.237 g, 0.74 mmol) and 1 ,2-dibromoethane (1.902 mL, 22.07 mmol) in toluene (200 mL) and the resulting suspension stirred at RT for 6 hours. The reaction mixture was diluted with water (50 mL), and washed sequentially with water (2 x 50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% ethyl acetate in DCM, to give the desired material as a yellow oil (2.44 g) which solidified on standing.
NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18 (3H, d), 1.57 (2H, dd), 1.82 (2H, dd), 3.16 (IH, td), 3.40 (IH, td), 3.56 (IH, dd), 3.70 (IH, d), 3.92 (IH, dd), 4.04 (IH, d), 4.30 (IH, br s), 6.78 (IH, s), 7.70-8.00 (IH, t), 8.19 (IH, s), 8.93 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=434; HPLC tR=2.15 min.
2-Chloro-4-[[l-(difluoromethvπpyrazol-4-yllsulfonylmethyll-6-[(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000787_0001
Sodium l-(difluoromethyl)-lH-pyrazole-4-sulfinate (3.28 g, 16.09 mmol) was added portionwise to 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (4.74 g, 13.41 mmol) in acetonitrile (150 mL) and the resulting suspension stirred at 800C for 6 hours. Additional sodium l-(difluoromethyl)-lH-pyrazole-4-sulfinate (680 mg, 3.39mmol) was added in one portion and the suspension was stirred at 800C for a further 2 hours. The reaction mixture was concentrated and diluted with DCM (200 mL), and washed sequentially with 10% aqueous sodium thiosulfate solution (50 mL), water (50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude residue was triturated with diethyl ether to give the desired material as a beige solid (4.50 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 3.18 (IH, td), 3.43 (IH, td), 3.58 (IH, dd), 3.72 (IH, d), 3.93 (2H, dd), 4.21 (IH, br s), 4.67 (2H, s), 6.77 (IH, s), 7.70- 8.05 (IH, t), 8.13 (IH, s), 8.87 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=408; HPLC tR=1.91 min.
Sodium 1 -(difluoromethvD- 1 H-pyrazole-4-sulfinate
S-O- Na+
F 1N^
A solution of sodium sulfite (2.87 g, 22.81 mmol) in water (25 mL) was stirred at RT for 10 minutes. Sodium bicarbonate (3.83 g, 45.62 mmol) was added to the stirred solution. The resulting solution was stirred at 500C for lhour. l-(Difluoromethyl)-lH-pyrazole-4-sulfonyl chloride (4.94 g, 22.81 mmol) was added dropwise with caution to the solution and was stirred at 500C for 18 hours. The reaction mixture was evaporated to dryness and redissolved in methanol (15 mL). The suspension was allowed to stir at RT for 20 minutes. The suspension was filtered and the filtrate evaporated to give a solid which was triturated with isohexane to give the desired material as a white solid (5.85 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 7.60 (IH, m), 7.74 (IH, s), 7.90 (IH, m).
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier
Example 65: l-[4-[4-[l-(4-Fluorophenyl)sulfonylcvclobutyll-6-[(3S)-3-methylmorpholin- 4-yllpyrimidin-2-yllphenyll-3-QH-imidazol-2-ylmethyl)urea
Figure imgf000788_0001
C-(lH-Imidazol-2-yl)-methylamine (17.73 mg, 0.18 mmol) was added in one portion to phenyl 7V-[4-[4-[l-(4-fluorophenyl)sulfonylcyclobutyl]-6-[(3)S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] carbamate (100 mg, 0.17 mmol) and triethylamine (0.069 mL, 0.50 mmol) in NMP (2 mL) at RT and stirred for a period of 16 hours under air. The crude product was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a cream solid (42 mg).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.21 (d, 3H), 1.83 - 1.93 (m, IH), 2.04 - 2.15 (m, IH), 2.75 - 2.82 (m, 2H), 3.02 - 3.11 (m, 2H), 3.16 (td, IH), 3.49 (td, IH), 3.64 (dd, IH), 3.76 (d, IH), 3.97 (dd, IH), 4.15 (d, IH), 4.32 (d, 2H), 4.44 - 4.54 (m, IH), 6.55 (s, IH), 6.60 (t, IH), 6.80 - 6.90 (m, IH), 7.00 - 7.08 (m, IH), 7.29 (dd, 2H), 7.40 (dt, 2H), 7.55 (ddd, 2H), 7.80 (d, 2H), 8.90 (s, IH), 11.85 (s, IH)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 606.55; HPLC tR = 2.09 min. The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[l-(4- fluorophenyl)sulfonylcyclobutyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000789_0001
Figure imgf000790_0001
Example 65a : 1H NMR (399.902 MHz, DMSO-d6) δ 1.21 (d, 3H), 1.57 - 1.63 (m, 2H), 1.83 - 1.94 (m, IH), 2.05 - 2.15 (m, IH), 2.75 - 2.82 (m, 2H), 3.01 - 3.09 (m, 2H), 3.17 (dd, 3H), 3.48 (dd, 3H), 3.64 (dd, IH), 3.76 (d, IH), 3.97 (dd, IH), 4.10 - 4.19 (m, IH), 4.48 (t, 2H), 6.18 (t, IH), 6.54 (s, IH), 7.29 (t, 2H), 7.38 (d, 2H), 7.55 (ddd, 2H), 7.78 (d, 2H), 8.68 (s, IH) Example 65b: 1U NMR (399.902 MHz, DMSOd6) δ 1.21 (d, 3H), 1.83 - 1.94 (m, IH), 2.04 - 2.15 (m, IH), 2.75 - 2.82 (m, 2H), 3.01 - 3.09 (m, 2H), 3.16 - 3.20 (m, 3H), 3.44 - 3.50 (m, 3H), 3.64 (dd, IH), 3.76 (d, IH), 3.97 (dd, IH), 4.09 - 4.19 (m, IH), 4.43 - 4.53 (m, IH), 4.73 (t, IH), 6.23 (t, IH), 6.54 (s, IH), 7.29 (t, 2H), 7.37 (d, 2H), 7.55 (ddd, 2H), 7.78 (d, 2H), 8.77 (s, IH)
Example 65c: 1R NMR (399.902 MHz, DMSOd6) δ 1.21 (d, 3H), 1.25 (s, 6H), 1.83 - 1.94 (m, IH), 2.05 - 2.15 (m, IH), 2.73 - 2.83 (m, 2H), 3.01 - 3.09 (m, 2H), 3.12 - 3.20 (m, IH), 3.39 (d, 2H), 3.49 (td, IH), 3.64 (dd, IH), 3.76 (d, IH), 3.97 (dd, IH), 4.10 - 4.18 (m, IH), 4.43 - 4.53 (m, IH), 4.96 (t, IH), 5.98 (s, IH), 6.54 (s, IH), 7.27 - 7.35 (m, 4H), 7.53 - 7.57 (m, 2H), 7.77 (d, 2H), 8.70 (s, IH)
Example 65d: 1U NMR (399.902 MHz, DMSOd6) δ 1.09 (d, 3H), 1.21 (d, 3H), 1.82 - 1.93 (m, IH), 2.02 - 2.15 (m, IH), 2.75 - 2.82 (m, 2H), 3.01 - 3.11 (m, 2H), 3.16 (td, IH), 3.33 - 3.43 (m, 2H), 3.49 (td, IH), 3.64 (dd, IH), 3.69 - 3.73 (m, IH), 3.76 (d, IH), 3.97 (dd, IH), 4.11 - 4.19 (m, IH), 4.44 - 4.53 (m, IH), 4.79 (t, IH), 6.08 (d, IH), 6.54 (s, IH), 7.29 (ddd, 2H), 7.36 (d, 2H), 7.55 (ddd, 2H), 7.78 (d, 2H), 8.68 (s, IH)
Example 65e: 1R NMR (399.902 MHz, DMSOd6) δ 1.09 (d, 3H), 1.21 (d, 3H), 1.83 - 1.94 (m, IH), 2.05 - 2.15 (m, IH), 2.75 - 2.82 (m, 2H), 3.01 - 3.09 (m, 2H), 3.16 (td, IH), 3.33 - 3.43 (m, 2H), 3.49 (td, IH), 3.64 (dd, IH), 3.69 - 3.73 (m, IH), 3.76 (d, IH), 3.97 (dd, IH), 4.10 - 4.18 (m, IH), 4.44 - 4.53 (m, IH), 4.79 (t, IH), 6.08 (d, IH), 6.54 (s, IH), 7.29 (ddd, 2H), 7.36 (d, 2H), 7.55 (ddd, 2H), 7.78 (d, 2H), 8.68 (s, IH) The preparation of phenyl Λ/-[4-[4-[l-(4-fluorophenyl)sulfonylcyclobutyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below:
Phenyl N-[4-[4-[ 1 -(4-fluorophenyl)sulfonylcvclobutyll-6-[(36f)-3-methylmorpholin-4- vHpyrimidin-2-vHphenvHcarbamate
Figure imgf000791_0001
Phenyl chloroformate (0.285 mL, 2.27 mmol) was added dropwise to 4-[4-[l-(4- fluorophenyl)sulfonylcyclobutyl] -6- [(35)-3 -methylmorpholin-4-yl]pyrimidin-2-yl] aniline (1.095 g, 2.27 mmol) and sodium hydrogencarbonate (0.191 g, 2.27 mmol) in dioxane (20 mL) and the resulting suspension was stirred at RT for 3 hours. The reaction mixture was evaporated and DCM (50 mL) added and washed sequentially with water (2 x 20 mL), and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford desired material as a dry film (1.4 g). NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.22 (d, 3H), 1.84 - 1.95 (m, IH), 2.05 - 2.16 (m, IH), 2.74 - 2.86 (m, 2H), 3.02 - 3.12 (m, 2H), 3.17 (td, IH), 3.45 - 3.55 (m, IH), 3.61 - 3.69 (m, IH), 3.71 - 3.85 (m, IH), 3.93 - 4.03 (m, IH), 4.11 - 4.24 (m, IH), 4.45 - 4.58 (m, IH), 7.22 - 7.35 (m, 5H), 7.42 - 7.49 (m, 2H), 7.50 - 7.60 (m, 4H), 7.88 (d, 2H), 10.40 (s, IH) LCMS Spectrum: m/z (ESI+) (M+H)+ = 603.17; HPLC tR = 3.15 min.
4-r4-ri-(4-Fluorophenyl)sulfonylcvclobutyll-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-2- yll aniline
Figure imgf000791_0002
Bis(triphenylphosphine)palladium(II) chloride (0.086 g, 0.12 mmol) was added in one portion to 2-chloro-4-[ 1 -(4-fluorophenyl)sulfonylcyclobutyl]-6-[(35)-3-methylmorpholin-4- yljpyrimidine (1.046 g, 2.46 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.538 g, 2.46 mmol) and sodium carbonate (6.14 mL, 12.28 mmol) in a DMF:DME : water :ethanol solution and the reaction mixture thoroughly degassed and stirred at 800C for 3 hours under a nitrogen atmosphere. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 100% ethyl acetate in isohexane, to afford desired material as a colourless dry film (1. I g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSO-d6) δ 1.20 (d, 3H), 1.82 - 1.95 (m, IH), 2.03 - 2.14 (m, IH), 2.71 - 2.82 (m, 2H), 2.98 - 3.08 (m, 2H), 3.13 (td, IH), 3.48 (td, IH), 3.63 (dd, IH), 3.75 (d, IH), 3.93 - 3.99 (m, IH), 4.07 - 4.15 (m, IH), 4.41 - 4.49 (m, IH), 5.49 (d, IH), 6.44 (s, IH), 6.49 (d, 2H), 7.28 (ddd, 2H), 7.54 (ddd, 2H), 7.62 (d, 2H) LCMS Spectrum: m/z (ESI+) (M+H)+ = 483.27; HPLC tR = 2.39 min.
2-Chloro-4-ri-(4-fluorophenyl)sulfonylcvclobutyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000792_0001
Sodium hydroxide (50%w/w solution) (16.91 g, 422.79 mmol) was added to 2-chloro-4-[(4- fluorophenyl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (2.966 g, 7.69 mmol), 1,3-dibromopropane (2.341 mL, 23.06 mmol) and tetrabutylammonium bromide (0.248 g, 0.77 mmol) in toluene (150 mL) and the resulting suspension stirred at 45°C for 1 hour. The organics were washed with water twice, dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 10 to 30% ethyl acetate in DCM, to afford desired material as a colourless dry film (1.055 g). NMR Spectrum: 1H NMR (399.902 MHz, DMSO-d6) δ 1.18 (d, 3H), 1.81 - 1.92 (m, IH), 2.01 - 2.12 (m, IH), 2.65 - 2.72 (m, 2H), 2.91 - 3.01 (m, 2H), 3.14 (td, IH), 3.42 (td, IH), 3.57 (dd, IH), 3.71 (d, IH), 3.88 - 4.00 (m, 2H), 4.23 - 4.40 (m, IH), 6.56 (s, IH), 7.38 - 7.44 (m, 2H), 7.54 - 7.60 (m, 2H) LCMS Spectrum: m/z (ESI+) (M+H)+ = 426.06; HPLC tR = 2.52 min.
The preparation of 2-chloro-4-[(4-fiuorophenyl)sulfonylmethyl]-6-[(35)-3-methylmorpholin- 4-yl]pyrimidine was described earlier.
Example 66: 3-α-Hvdroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yll-6-[l-q,3-thiazol- 2-ylsulfonyl)cvclopropyll pyrimidin-2-yll phenyll urea
Figure imgf000793_0001
Ethanolamine (0.052 mL, 0.87 mmol) was added in one portion to phenyl Λ/-[4-[4-[(35)-3- methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2-ylsulfonyl)cyclopropyl]pyrimidin-2- yljphenyl] carbamate (100 mg, 0.17 mmol) and triethylamine (0.072 mL, 0.52 mmol) in NMP (2 mL) and warmed to 550C over a period of 16 hours under air. The crude reaction mixture was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to afford the desired material as a colourless dry film. (84 mg) NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.21 (d, 3H), 1.77 - 1.82 (m, 2H), 1.98 - 2.02 (m, 2H), 3.14 - 3.21 (m, 3H), 3.44 - 3.50 (m, 3H), 3.62 (dd, IH), 3.76 (d, IH), 3.97 (dd, IH), 4.10 - 4.21 (m, IH), 4.40 - 4.51 (m, IH), 4.74 (t, IH), 6.25 (t, IH), 6.74 (s, IH), 7.40 (d, 2H), 7.85 (d, 2H), 8.24 (d, IH), 8.29 (d, IH), 8.78 (s, IH) LCMS Spectrum: m/z (ESI+) (M+H)+ = 545.75; HPLC tR = 1.79 min.
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[(35)-3- methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2-ylsulfonyl)cyclopropyl]pyrimidin-2- yl]phenyl] carbamate and the appropriate amine.
Figure imgf000794_0002
Example 66a : 1H NMR (399.902 MHz, DMSOd6) δ 1.21, 1.60, 1.77 - 1.82, 1.97 - 2.03, 3.14 - 3.21, 3.44 - 3.50, 3.62, 3.76, 3.97, 4.12 - 4.20, 4.40 - 4.52, 4.49, 6.19, 6.74, 7.40, 7.85, 8.23, 8.28, 8.68 Example 66b : 1R NMR (399.902 MHz, DMSOd6) δ 1.21 (d, 3H), 1.77 - 1.82 (m, 2H), 1.97 - 2.03 (m, 2H), 3.14 - 3.21 (m, IH), 3.47 (td, IH), 3.62 (dd, IH), 3.76 (d, IH), 3.97 (dd, IH), 4.11 - 4.21 (m, IH), 4.32 (d, 2H), 4.39 - 4.54 (m, IH), 6.62 (t, IH), 6.74 (s, IH), 6.88 - 7.01 (m, 2H), 7.43 (d, 2H), 7.87 (d, 2H), 8.23 (d, IH), 8.28 (d, IH), 8.90 (s, IH), 11.85 (s, IH)
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]carbamate is described below:
Phenyl N-r4-r4-r(3^-3-methylmorpholin-4-yll-6-ri-(1.3-thiazol-2- ylsulfonyl)cvclopropyllpyrimidin-2-yllphenvHcarbamate
Figure imgf000794_0001
Phenyl chloroformate (0.123 mL, 0.98 mmol) was added dropwise to 4-[4-[(35)-3- methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2-ylsulfonyl)cyclopropyl]pyrimidin-2-yl]aniline (450 mg, 0.98 mmol) and sodium hydrogencarbonate (83 mg, 0.98 mmol) in dioxane and the resulting suspension stirred at RT for 3 hours. The reaction mixture was evaporated and DCM (50 mL) added and washed sequentially with water (2 x 20 mL), and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford desired product as a dry film (522 mg).
NMR Spectrum: 1H NMR (399.902 MHz, DMSO-d6) δ 1.22 (d, 3H), 1.78 - 1.84 (m, 2H), 1.98 - 2.04 (m, 2H), 3.19 (td, IH), 3.48 (td, IH), 3.63 (dd, IH), 3.76 (d, IH), 3.97 (dd, IH), 4.12 - 4.24 (m, IH), 4.40 - 4.52 (m, IH), 6.79 (s, IH), 7.23 - 7.32 (m, 3H), 7.46 (t, 2H), 7.55 (d, 2H), 7.95 (d, 2H), 8.24 (d, IH), 8.29 (d, IH), 10.41 (s, IH) LCMS Spectrum: m/z (ESI+) (M+H)+ = 578.04; HPLC tR = 2.83 min.
4-r4-r(3ιSV3-Methylmorphorin-4-vH-6-r 1 -(1 ,3-thiazol-2-ylsulfonyl)cvclopropyHpyrimidin-2- yll aniline
Figure imgf000795_0001
Bis(triphenylphosphine)palladium(II) chloride (0.139 g, 0.20 mmol) was added in one portion to 2-chloro-4-[(35>3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclopropyl]pyrimidine (1.59 g, 3.97 mmol), 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (0.869 g, 3.97 mmol) and sodium carbonate (9.92 mL, 19.83 mmol) in a DMF, DME, water and ethanol solution at RT under nitrogen. The reaction mixture was thoroughly degassed and was stirred at 800C for 3 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 100 % ethyl acetate in isohexane, to afford desired material as a beige dry film (1.430 g). NMR Spectrum: 1H NMR (399.902 MHz, DMSO-d6) δ 1.16 - 1.21 (m, 3H), 1.75 - 1.79 (m, 2H), 1.96 - 2.01 (m, 2H), 3.14 (td, IH), 3.46 (td, IH), 3.61 (dd, IH), 3.75 (d, IH), 3.96 (dd, IH), 4.07 - 4.17 (m, IH), 4.35 - 4.48 (m, IH), 5.50 - 5.55 (m, IH), 6.52 (d, 2H), 6.63 (s, IH), 7.69 (d, 2H), 8.22 (d, IH), 8.27 (d, IH) LCMS Spectrum: m/z (ESI+) (M+H)+ = 458.16; HPLC tR = 1.68 min.
The preparation of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclopropyl]pyrimidine was described earlier.
Example 67: 3-α-Hvdroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yll-6-[l-q,3-thiazol- 2-ylsulfonyl)cvclopropyll pyrimidin-2-yll phenyll thiourea
Figure imgf000796_0001
A solution of 1 , l'-thiocarbonyldiimidazole (50.6 mg, 0.28 mmol) in DCM (2 mL) was added to a stirred solution 4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]aniline (100 mg, 0.22 mmol) in THF (1 mL) and DCM (2 mL) at RT, over a period of 2 minutes under nitrogen. The resulting solution was stirred at RT for 2 hours. Triethylamine (0.030 mL, 0.22 mmol) and ethanolamine (0.066 mL, 1.09 mmol) were added to the reaction mixture. The resulting solution was stirred at RT for 60 hours. The reaction mixture was evaporated to dryness and redissolved in acetonitrile (2 mL), filtered and purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to afford desired material as a beige solid (88 mg). NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.22 (d, 3H), 1.78 - 1.84 (m, 2H), 1.98 - 2.03 (m, 2H), 3.19 (td, IH), 3.48 (td, IH), 3.54 - 3.60 (m, 3H), 3.63 (dd, IH), 3.76 (d, IH), 3.97 (dd, IH), 4.16 (d, IH), 4.41 - 4.53 (m, IH), 4.78 - 4.88 (m, IH), 6.79 (s, IH), 7.54 (d, 2H), 7.82 - 7.89 (m, IH), 7.92 (dt, 2H), 8.24 (d, IH), 8.28 (d, IH), 9.78 (s, IH) LCMS Spectrum: m/z (ESI+) (M+H)+ = 561.82; HPLC tR = 2.12 min. The preparation of 4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]aniline was described earlier.
Example 68 : 3-C vclopropyl- 1- [4- [4- [(3S)-3-methylmorpholin-4-yll -6- [ l-(4- methylphenyDsulfonylcyclobutyllpyrimidin-l-yllphenyllurea
Figure imgf000797_0001
Triethylamine (0.057 mL, 0.41 mmol) was added to phenyl N-[4-[4-[(35)-3-methylmorpholin-
4-yl]-6-[ 1 -(4-methylphenyl)sulfonylcyclobutyl]pyrimidin-2-yl]phenyl]carbamate (82 mg,
0.14 mmol) and cyclopropylamine (0.047 mL, 0.68 mmol) in NMP (2 mL) and the resulting solution stirred at 500C overnight. The crude product was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid (43 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.40-0.44(2H, m), 0.63-0.67(2H, m),
1.19-1.20(3H, d), 1.81-1.92(1H, m), 2.02-2.13(1H, m), 2.27(3H, s), 2.54-2.59(1H, m), 2.73- 2.79(2H, m), 2.99-3.07(2H, m), 3.09-3.17(1H, td), 3.45-3.51(1H, td), 3.62-3.65(1H, dd), 3.74-
3.77(1H, d), 3.95-3.98(1H, dd), 4.07-4.10(1H, d), 4.44(1H, bs), 6.4O-6.41(1H, d), 6.45(1H, s),
7.24-7.26(2H, d), 7.35-7.40(4H, m), 7.76-7.78(2H, d), 8.49(1H, s).
LCMS Spectrum: m/z (ESI+)(M+H)+562 = HPLC tR =2.60 min.
The following compound was made in an analogous fashion using the appropriate amine.
Figure imgf000797_0002
Example 68a: 1U NMR (400.132 MHz, DMSO-Cl6) δ 1.19-1.21(3H, d), 1.83-1.9O(1H, m), 2.04-2.12(1H, m), 2.28(3H, s), 2.73-2.80(2H, m), 3.00-3.07(2H, m), 3.1O-3.15(1H, td), 3.45- 3.52(1H, td), 3.62-3.66(1H, dd), 3.75-3.78(1H, d), 3.79(3H, s), 3.95-3.99(1H, dd), 4.08- 4.11(1H, d), 4.45(1H, bs), 6.46(1H, s), 7.24-7.26(2H, d), 7.35-7.38(3H, m), 7.42-7.44(2H, d), 7.77(1H, s), 7.79-7.81(2H, d), 8.35(1H, s), 8.79(1H, s).
Phenyl N-r4-r4-r(3^-3-methylmorpholin-4-yll-6-π -(4- methylphenyl)sulfonylcvclobutyllpyrimidin-2-yllphenyllcarbamate
Figure imgf000798_0001
Phenyl chloroformate (0.034 mL, 0.27 mmol) was added to 4-[4-[(35)-3-methylmorpholin-4- yl] -6- [l-(4-methylphenyl)sulfonylcyclobutyl]pyrimidin-2-yl] aniline (129 mg, 0.27 mmol)and sodium hydrogen carbonate (34.0 mg, 0.40 mmol) in dioxane (10 mL). The resulting suspension was stirred at RT for 5 hours. The reaction mixture was evaporated to dryness and redissolved in ethyl acetate(125 mL), and washed sequentially with water (125 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford the desired material (182 mg).
NMR Spectrum: 1H NMR (400.132 MHz, CDC13) δ 1.34 (3H, d), 1.87 - 1.98 (IH, m), 2.19 - 2.30 (4H, m), 2.72 - 2.81 (2H, m), 3.15 - 3.25 (2H, m), 3.30 (IH, td), 3.63 (IH, td), 3.70 (IH, s), 3.72 - 3.82 (3H, m), 4.03 - 4.16 (3H, m), 4.46 (IH, q), 6.56 (IH, s), 7.01 (21H, s), 7.07 (2H, d), 7.19 - 7.27 (3H, m, obscured by CDCL3 peak), 7.35 - 7.42 (6H, m), 7.91 (2H, d). LCMS Spectrum: m/z (ES+)(M+H)+=599; HPLC tR=3.25 min. 4-r4-r(36^-3-Methylmorpholin-4-yll-6-ri-(4-methylphenyl)sulfonylcvclobutyllpyrimidin-2- yll aniline
Figure imgf000799_0001
Bis(triphenylphosphine)palladium(II) chloride (0.131 g, 0.19 mmol) was added in one portion to a mixture of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-[l-(4- methylphenyl)sulfonylcyclobutyl]pyrimidine and 4- [ 1 -(benzenesulfonyl)cyclobutyl] -2- cUoro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (1.522 g), 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (0.817 g, 3.73 mmol) and a solution of sodium carbonate (9.33 mL, 18.66 mmol) in DMF (18 mL), DME (47.8 mL), water (20.5 mL)and ethanol (13.5 mL) and the resulting solution stirred at 800C for 2 hours. The reaction mixture was concentrated in vacuo to remove the ethanol then the reaction mixture was acidified with 2M hydrochloric acid. The resulting suspension was purified by ion exchange chromatography using an SCX column, eluting with 7M ammonia in methanol, followed by preparative HPLC, to give the desired material as an off white solid (0.136 g).
Figure imgf000799_0002
NMR (400.132 MHz, CDCl3) δ 1.32 (3H, d), 1.85 - 1.97 (IH, m), 2.17 - 2.29 (4H, m), 2.71 - 2.81 (2H, m), 3.11 - 3.33 (3H, m), 3.61 (IH, t), 3.74 - 3.90 (4H, m), 4.03 (IH, d), 4.09 - 4.15 (IH, m), 4.44 (IH, q), 6.48 (IH, s), 6.57 (2H, d), 7.07 (2H, d), 7.36 (2H, d), 7.75 (2H, d). LCMS Spectrum: m/z (ES+)(M+H)+=479; HPLC tR=2.23 min.
Mixture of 2-chloro-4-r(3y)-3-methylmorpholin-4-yl1-6-π -(4- methylphenyPsulfonylcyclobutyllpyrimidine and 4- [ 1 -(benzenesulfonyl)cvclobutyll -2- chloro-6- r(3iSV3 -methylmorpholin-4-vHpyrimidine
Figure imgf000799_0003
Sodium hydroxide (50%w/w solution) (52.4 g, 654.89 mmol) was added to a mixture of 2- chloro-4-[(35)-3-methylmorpholin-4-yl]-6-[(4-methylphenyl)sulfonylmethyl]pyrimidine and 4-(benzenesulfonylmethyl)-2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (4.38 g), 1,3-dibromopropane (3.63 mL, 35.72 mmol) and tetrabutylammonium bromide (0.384 g, 1.19
5 mmol) in toluene (270 mL). The resulting suspension was stirred at 45°C for 1 hour. The reaction mixture was diluted with water (300 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give a white solid (1.522 g) which appeared to be a mixture of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-[l-(4- i o methylphenyl)sulfonylcyclobutyl]pyrimidine (12%) and 4- [ 1 -(benzenesulfonyl)cyclobutyl] -2- chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (83%). The mixture was taken through into the next step with no further purification. LCMS Spectrum: m/z (ES+)(M+H)+=422; HPLC tR=2.59 min. LCMS Spectrum: m/z (ES+)(M+H)+=408; HPLC tR=2.45 min.
15
Mixture of 2-chloro-4-r(3y)-3-methylmorpholin-4-yl1-6-r('4- methylphenvDsulfonylmethyllpyrimidine and 4-(benzenesulfonylmethv0-2-chloro-6- [(3 S)- 3 - methylmorpholin-4-vHpyrimidine
Figure imgf000800_0001
20 Benzenesulfinic acid, sodium salt (3.66 g, 22.32 mmol) was added to a mixture of 2-chloro-4- [(35)-3-methylmorpholin-4-yl]-6-[(4-methylphenyl)sulfonylmethyl]pyrimidine and 2-chloro- 4-(chloromethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (5.85 g) in acetonitrile (200 mL) under argon. The resulting suspension was stirred at reflux for 18 hours. Additional benzenesulfinic acid, sodium salt (1.2 g, 7.31 mmol) and sodium iodide (0.335 g, 2.23 mmol)
25 were added and the suspension was stirred at reflux for a further 24 hours. The reaction mixture was evaporated to dryness, redissolved in DCM (500 mL) and washed with water (250 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude material was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in DCM, to give a white solid (4.38 g) which appeared to be a mixture of 2-chloro-4-[(35)-3- methylmorpholin-4-yl]-6-[(4-methylphenyl)sulfonylmethyl]pyrimidine (7%) and 4- (benzenesulfonylmethyl)-2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (93%). The mixture was taken through into the next step with no further purification. LCMS Spectrum: m/z (ES+)(M+H)+=382; HPLC tR=2.23 min. LCMS Spectrum: m/z (ES+)(M+H)+=368; HPLC tR=2.06 min.
Mixture of 2-chloro-4-r(3y)-3-methylmorpholin-4-yl1-6-r(4- methylphenvDsulfonylmethvHpyrimidine and 2-chloro-4-(chloromethyl)-6-IY3S)-3- methylmorpholin-4-vHpyrimidine
Figure imgf000801_0001
A solution of p-toluenesulfonyl chloride (23.47 g, 123.11 mmol) in DCM (50 mL) was added dropwise to a stirred solution of [2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4- yl]methanol (20 g, 82.07 mmol) and DIPEA (21.44 mL, 123.11 mmol) in DCM (200 mL) cooled to 50C, over a period of 1 hour under nitrogen. The resulting solution was stirred at 50C for 72 hours and then at reflux for 24 hours. The reaction mixture was washed with water and the organic layer was dried over MgSO4, filtered and evaporated to afford a brown gum which appeared to be a mixture of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-[(4- methylphenyl)sulfonylmethyl]pyrimidine (11%) and 2-chloro-4-(chloromethyl)-6-[(3S)-3- methylmorpholin-4-yl]pyrimidine (87%). The mixture was taken through into the next step with no further purification.
LCMS Spectrum: m/z (ES+)(M+H)+=398; HPLC tR=2.52 min. LCMS Spectrum: m/z (ES+)(M+H)+=262; HPLC tR=1.97 min.
The preparation of [2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methanol was described earlier. Example 69 : 1- [4- [4- [ l-fBenzenesulfonyDcyclopropyll -6- [(3/?)-3-methylmorpholin-4- yll pyrimidin-2-yll phenyll -3-ethylurea
Figure imgf000802_0001
Triethylamine (0.064 mL, 0.46 mmol) was added to [2-(4-aminophenyl)-6-[l- (benzenesulfonyl)cyclopropyl]pyrimidin-4-yl] trifluoromethanesulfonate (0.104 g, 0.21 mmol), (i?)-3-methylmorpholine (0.042 g, 0.42 mmol) in dioxane (5 mL) and the resulting solution stirred at RT overnight. Ethyl isocyanate (0.494 mL, 6.25 mmol) was added and the solution was allowed to stir at RT overnight. Methanol was added carefully and then all of the solvent was removed. The crude product was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a tan solid (0.052 g).
NMR Spectrum: 1H NMR (400MHz, DMSOd6) 1.05-1.08 (3H, t), 1.16-1.18 (3H, d), 1.60- 1.67 (2H, m), 1.88-1.92 (2H, m), 3.09-3.19 (3H, m), 3.42-3.49 (IH, td), 3.59-3.62 (IH, dd), 3.73-3.76 (IH, d), 3.94-3.97 (IH, dd), 4.08-4.12 (IH, d), 4.37(1H, bs), 6.13-6.16 (IH, t), 6.62 (IH, s), 7.37-7.39 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.78-7.85 (4H, m), 8.63 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=522; HPLC tR=2.32min.
r2-(4-Aminophenyl)-6-ri-(benzenesulfonyl)cvclopropyllpyrimidin-4-vH trifluoromethanesulfonate
Figure imgf000802_0002
2-(4-Aminophenyl)-6-[l-(benzenesulfonyl)cyclopropyl]pyrimidin-4-ol (4.0 g, 10.89 mmol), l,l,l-trifluoro-Λ/-phenyl-Λ/-(trifluoromethylsulfonyl)methanesulfonamide (4.28 g, 11.98 mmol)were dissolved in DCM (75 mL), to this was added DBU (1.791 mL, 11.98 mmol) and the reaction was stirred at RT overnight. The solvent was evaporated to dryness and the gum was quenched with 1.0N citric acid (100 mL) and extracted with diethyl ether (3 x 100 mL). The combined organics were dried over MgSO4, filtered and evaporated to afford an orange solid. The solid was passed through a silica plug, eluting with diethyl ether, to give a yellow solid. This solid was dissolved in a minimum amount hot diethyl ether, to which iso-hexane was added and the system was stirred to afford the desired material as a yellow solid (1.5 g). NMR Spectrum: 1H NMR (400MHz, DMSOd6) 1.79 (2H, q), 2.02 (2H, q), 5.43 (2H, s), 6.62 (2H, d), 7.43 (IH, s), 7.59 (2H, t), 7.68 (2H, d), 7.72 (IH, t), 7.80 (2H, d). LCMS Spectrum: m/z (ES+)(M+H)+=500; HPLC tR=2.96min
2-(4-Aminophenviy6-ri-(benzenesulfonvDcvclopropyHpyrimidin-4-ol
Figure imgf000803_0001
Ethyl 3-[l-(benzenesulfonyl)cyclopropyl]-3-oxopropanoate (5.4 g, 15.12 mmol), 4- aminobenzamidine dihydrochloride (3.78 g, 18.15 mmol) and potassium carbonate (3.83 mL, 63.52 mmol) were added to methanol (150 mL) and heated at reflux overnight. The solvent was evaporated to dryness and the remaining solid was acidified with 1.0N citric acid. The solid was filtered and then triturated with hot acetonitrile to give the desired material as a yellow solid (4.0 g).
NMR Spectrum: 1H NMR (400MHz, DMSOd6) 1.58 (2H, q), 1.86 (2H, q), 5.86 (2H, s), 6.21 (IH, s), 6.50 (2H, d), 7.51 (2H, d), 7.60 (2H, t), 7.72 (IH, t), 7.82 (2H, d), 12.11 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=368; HPLC tR=1.23min
Ethyl 3-[l-(benzenesulfonvDcvclopropyl"|-3-oxopropanoate
Figure imgf000803_0002
Triethylamine (20.70 mL, 148.51 mmol) and magnesium chloride (9.28 g, 97.46 mmol) were added to a stirred solution of potassium 3-ethoxy-3-oxopropanoate (15.80 g, 92.82 mmol) in acetonitrile (150 mL). The reaction was stirred for 2 hours. l-(Benzenesulfonyl)cyclopropane- 1-carboxylic acid (10.5 g, 46.41 mmol) and l,l'-carbonyldiimidazole (9.03 g, 55.69 mmol) were dissolved in acetonitrile (30 mL) and stirred for 2 hours. This was then added to the initial reaction and the system was stirred over the weekend at RT. 2M hydrochloric acid (150 mL) was added and the mixture extracted with diethyl ether (3 x 50 mL), the organics separated and evaporated to afford an orange oil. This oil was washed with a saturated solution of sodium hydrogen carbonate (100 mL) and extracted with diethyl ether (3 x 100 mL). The organics were dried over MgSO4, filtered and evaporated to afford a yellow gum. This was passed through a plug of silica, eluting with DCM, to afford a colourless gum. The crude product was further purified by flash silica chromatography, eluting with DCM, to give the desired material as a colourless gum (5.6 g). NMR Spectrum: 1H NMR (400MHz, CDCl3) δ 1.23 (3H, t), 1.74 (2H, q), 1.99 (2H, q), 3.77 (2H, s), 4.12 (2H, q), 7.57 (2H, t), 7.67 (IH, t), 7.92 (2H, d).
1 -(Benzenesulfonyl)cvclopropane- 1 -carboxylic acid
Figure imgf000804_0001
Methyl l-(benzenesulfonyl)cyclopropane-l-carboxylate (11 g, 45.78 mmol) was added to ethanol (50 mL) and water (50 mL), to this was added sodium hydroxide (1.904 mL, 48.07 mmol) and the reaction was stirred for 1 hour. The ethanol was carefully evaporated and the reaction mixture was extracted with diethyl ether (1 x 100 mL). The aqueous layer was quenched with 2M hydrochloric acid (50 mL), extracted with diethyl ether (3 x 100 mL) and the combined organics dried over MgSO4, filtered and evaporated to afford a white solid. The crude solid was triturated with ethyl acetate to give the desired material as a white solid (10.5 g)-
NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 1.63 (2H, q), 1.85 (2H, q), 7.63 (2H, t),
7.73 (IH, t), 7.97 (2H, d).
Methyl 1 -(benzenesulfonyl)cvclopropane- 1 -carboxylate
Figure imgf000804_0002
Methyl 2-(phenylsulfonyl)acetate (15 g, 70.02 mmol), benzyltriethylammonium chloride (4.77 g, 21.00 mmol), Potassium carbonate (29.0 g, 210.05 mmol) and 1 ,2-dibromoethane (12.07 mL, 140.03 mmol) were added to toluene (200 mL) and heated at 1000C over the weekend. The reaction was filtered and solvent evaporated to afford a viscous gum. This reaction mixture was quenched with water (100 mL) and extracted with diethyl ether (3 x 100 mL). The organics were dried over MgSO4, filtered and evaporated to afford an orange liquid. This liquid was passed through a plug of silica, eluting with diethyl ether, to afford an orange gum. The crude gum was triturated with ethanol to give the desired material as a white solid
(H-O g).
NMR Spectrum: 1H NMR (400MHz, CDCl3) δ 11.70 (2H, q), 2.00 (2H, q), 3.63 (3H, s), 7.55
(2H, t), 7.64 (IH, t), 8.00 (2H, d).
LCMS Spectrum: m/z (ES+)(M+H)+=241; HPLC tR=1.84min
Example 70 : 1- [4- [4- [ l-fBenzenesulfonyDcyclopropyll -6- [(3S)-3-ethylmorpholin-4- yll pyrimidin-2-yll phenyll -3-ethylurea
Figure imgf000805_0001
Triethylamine (0.062 mL, 0.45 mmol) was added to [2-(4-aminophenyl)-6-[l- (benzenesulfonyl)cyclopropyl]pyrimidin-4-yl] trifluoromethanesulfonate (0.102 g, 0.20 mmol), (5)-3-ethylmorpholine (0.047 g, 0.41 mmol) in dioxane (5 mL) and the resulting solution stirred at 500C overnight. Ethyl isocyanate (0.564 mL, 7.12 mmol) was added and the solution allowed to stir at RT overnight. Methanol was added and then the solvent was removed. The crude product was purified by preparative HPLC, to give the desired material as a white solid (0.042 g).
NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 0.83-0.86(3H, t), 1.05-1.08(3H, t), 1.56- 1.67(4H, m), 1.71-1.8O(1H, m), 1.88-1.91(2H, m), 3.09-3.16(3H, m), 3.40-3.47(1H, td), 3.50- 3.54(1H, dd), 3.84-3.87(1H, d), 3.9O-3.94(1H, dd), 4.18(1H, bs), 6.12-6.15(1H, t), 6.61(1H, s), 7.37-7.40(2H, d), 7.57-7.61(2H, t), 7.69-7.74(1H, tt), 7.77-7.80(2H, dd), 7.84-7.86(2H, d), 8.61(1H, s).
LCMS Spectrum: m/z (ES+)(M+H)+=536; HPLC tR=2.43min. The preparation of [2-(4-aminophenyl)-6-[l-(benzenesulfonyl)cyclopropyl]pyrimidin-4-yl] trifluoromethanesulfonate was described earlier.
Example 71: l-[4-[4-[l-fBenzenesulfonyl)cvclopropyll-6-[3-fhvdroxymethyl)morpholin- 4-yll pyrimidin-2-yll phenyll -3-ethylurea
Figure imgf000806_0001
Triethylamine (0.112 mL, 0.80 mmol) was added to [2-(4-aminophenyl)-6-[l- (benzenesulfonyl)cyclopropyl]pyrimidin-4-yl] trifluoromethanesulfonate (0.100 g, 0.20 mmol), morpholin-3-ylmethanol hydrochloride (0.062 g, 0.40 mmol) in dioxane (5 mL) and the resulting solution stirred at 500C overnight. Ethyl isocyanate (0.555 mL, 7.01 mmol) was added and the solution allowed to stir at RT overnight. The solvent was removed and the sludge was taken up in methanol. 30% Sodium methoxide in methanol solution was added and the reaction was allowed to stir overnight. Additional 30% sodium methoxide in methanol solution was added and the reaction refluxed overnight. Approximately 80% of the methanol was removed and the solution was quenched with saturated ammonium chloride solution. The mixture was extracted with DCM, the organics dried over MgSO4, filtered and evaporated. The crude product was purified by preparative HPLC, to give the desired material as a cream solid (0.019 g). NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 1.05-1.08 (3H, t), 1.58-1.66 (2H, m), 1.86- 1.92 (2H, m), 3.07-3.16 (3H, m), 3.42-3.53 (3H, m), 3.69-3.73 (IH, m), 3.92-3.95 IH, dd), 4.05-4.08 (IH, d), 4.18 (IH, bs), 4.93 (IH, bs), 6.14-6.17 (IH, t), 6.68 (IH, s), 7.36 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.79-7.84 (4H, m), 8.64 (IH, s) (1 peak under water or solvent peak). LCMS Spectrum: m/z (ES+)(M+H)+=538; HPLC tR=1.95min.
Morpholin-3 -ylmethanol
CX ,OcH (4-Benzylmorpholin-3-yl)methanol (0.473 g, 2.28 mmol) and palladium (5% on carbon, 50%wet) (0.094 g, 0.02 mmol) in ethanol (50 mL) were stirred under an atmosphere of hydrogen at 5 bar and 25°C for 18 hours. The mixture was filtered and then hydrochloric acid (0.628 mL, 2.51 mmol) added. The reaction was stirred overnight at RT and then the solvent removed to give the desired material (as a hydrochloride salt) as an orangey brown gum (257 mg).
NMR Spectrum: 1H NMR (400MHz, CDCl3) δ 1.43-1.46(1H, t), 3.14-3.67(3H, m), 3.81- 4.18(4H, m), 4.62(1H, bs), 9.32(bs), 9.60(bs), 10.43(bs).
The preparation of [2-(4-aminophenyl)-6-[ 1 -(benzenesulfonyl)cyclopropyl]pyrimidin-4-yl] trifiuoromethanesulfonate was described earlier.
Example 72: l-[4-[4-[l-(Benzenesulfonylkvclopropyll-6-[(3S.5SV3.5- dimethylmorpholin-4-yll pyrimidin-2-yll phenyll -3-ethylurea
Figure imgf000807_0001
DIPEA (0.141 mL, 0.81 mmol) was added to [2-(4-aminophenyl)-6-[l- (benzenesulfonyl)cyclopropyl]pyrimidin-4-yl] trifiuoromethanesulfonate (0.101 g, 0.20 mmol) and (35*,55)-3,5-dimethylmorpholine (hydrochloride salt) (0.061 g, 0.40 mmol) in dioxane (5 mL) under nitrogen. The resulting solution was stirred at 700C overnight then at 9O0C for several hours. Additional (35*,55)-3,5-dimethylmorpholine (hydrochloride salt) was added and the reaction was allowed to stir at 9O0C overnight. Ethyl isocyanate (0.320 mL, 4.05 mmol) was added and the reaction allowed to stir at RT over the weekend. Methanol was added and then the solvent was removed. The crude product was purified by preparative HPLC, to give the desired material as a cream solid (0.029 g). NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 1.05-1.08 (3H, t), 1.27-1.29(6H, d), 1.61- 1.71 (2H, m), 1.88-1.95 (2H, m), 3.09-3.16 (2H, m), 3.67-3.70 (2H, m), 4.10-4.16 (4H, m), 6.14-6.16 (IH, t), 6.60 (IH, s), 7.39-7.41 (2H, d), 7.57-7.61 (2H, t), 7.69-7.73 (IH, tt), 7.78- 7.81 (2H, dd), 7.86-7.89 (2H, d), 8.62 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=536; HPLC tR=2.41min.
The preparation of [2-(4-aminophenyl)-6-[l-(benzenesulfonyl)cyclopropyl]pyrimidin-4-yl] trifluoromethanesulfonate was described earlier.
(3S.5,Sy3.5-Dimethylmorpholine
XX H
Hydrogen chloride (4M solution in dioxane, 30.1 mL, 120.25 mmol) was added to tert-butyl (35*,55)-3,5-dimethylmorpholine-4-carboxylate (5.23 g, 24.29 mmol) in dioxane (50 mL) and the resulting solution stirred at RT overnight. The solvent was removed and the solid was triturated with diethyl ether to give the desired material (as the hydrochloride salt) as a white solid (3.22 g).
NMR Spectrum: 1H NMR (400MHz, CDCl3) δ 1.50-1.51(6H, d), 3.56-3.67 (4H, m), 3.97- 4.00 (2H, dd), 9.96 (2H, bs).
tert-Butyl (3£.5,Sy3.5-dimethylmorpholine-4-carboxylate and tert-butyl (3S,5R)-3,5- dimethylmorpholine-4-carboxylate
Figure imgf000808_0001
(35)-3,5-Dimethylmorpholine (13.73 g, 90.55 mmol) was dissolved in a solution of sodium hydroxide (3.91 mL, 208.26 mmol) in water (100 mL) and di-tert-butyl dicarbonate (22.88 mL, 99.60 mmol) added portionwise. The resulting solution was stirred at RT overnight then extracted with diethyl ether and the organics dried over MgSO4, filtered and evaporated to give a clear liquid. The crude material was purified and the diastereomers separated using silica chromatography, eluting with 0-10% ethyl acetate in isohexane, to give tert-butyl (35*,55)-3,5-dimethylmorpholine-4-carboxylate (first product to elut) as a colourless liquid (5.93 g) and tert-butyl (35*,5i?)-3,5-dimethylmorpholine-4-carboxylate (second product to elut) as a colourless liquid (5.03 g). tert-butyl (35*,55)-3,5-dimethylmorpholine-4-carboxylate:
NMR Spectrum: 1H NMR (400MHz, CDCl3) δ 1.28-1.29(6H, d), 1.47(9H, s), 3.43-3.48 (2H, m), 3.77-3.84 (4H, m). tert-butyl (35*,5i?)-3,5-dimethylmorpholine-4-carboxylate NMR Spectrum: 1H NMR (400MHz, CDCl3) δ 1.30-1.31(6H, d), 1.47(9H, s), 3.52-3.56(2H, dd), 3.68-3.71(2H, d), 3.90-3.96(2H, m).
(36^-3, 5-Dimethylmorpholine xx H 2-[[(2S)-l-Hydroxypropan-2-yl]ammo]propan-l-ol (14.79 g, 111.01 mmol) was cooled to O0C with stirring and concentrated sulfuric acid (19.85 g, 202.39 mmol) added. The mixture was heated to 18O0C for 5 hours. Potassium hydroxide (23.95 g, 426.87 mmol) in water (120 mL) was added slowly then the mixture filtered to leave a dark black aqueous solution. This solution was distilled (distillate came off at 980C) and the distillate acidified with 2M hydrochloric acid. The water was removed to give the desired material (as the hydrochloride salt) as a white solid (13.73g). The material was used in the following step without further purification.
NMR Spectrum: 1H NMR (400MHz, CDCl3) δ 1.44-1.46 (3H, d), 1.48-1.50 (3H, d), 3.31- 3.34 (IH, m), 3.56-3.59 (IH, m), 3.62-3.72 (2H, m), 3.84-3.88 (IH, m), 3.96-3.99 (IH, dd), 9.69-10.12 (2H, bt).
2-1"1"(2SyI -Hydroxypropan-2-yllaminolpropan- 1 -ol
HO ,OH
H
(5)-2-Aminopropan-l-ol (9 g, 119.82 mmol), platinum(IV) oxide (0.052 g, 0.23 mmol) and 1- hydroxypropan-2-one (11.54 g, 155.77 mmol) in methanol (100 mL) were stirred for 1 hour and then placed under an atmosphere of hydrogen at 1 bar and 25°C for 3 hours. The solution was filtered and evaporated to give a crude product that was purified by distillation at (0.55 mBar, 920C) to give the desired material as a yellow oil (10.71 g). NMR Spectrum: 1H NMR (400MHz, CDCl3) δ 1.01-1.03 (3H, d), 1.07-1.09 (3H, d), 2.56 (IH, bs), 2.83-2.94 (2H, m), 3.27-3.32 (2H, m), 3.55-3.61 (2H, m).
Example 73: l-[4-[4-[l-(Benzenesulfonylkyclopropyll-6-[(3R,5S)-3,5- dimethylmorpholin-4-yll pyrimidin-2-yll phenyll -3-ethylurea
Figure imgf000810_0001
DIPEA (0.140 mL, 0.81 mmol) was added to [2-(4-aminophenyl)-6-[l- (benzenesulfonyl)cyclopropyl]pyrimidin-4-yl] trifluoromethanesulfonate (0.101 g, 0.20 mmol), (35*,5i?)-3,5-dimethylmorpholine (as the hydrochloride salt) (0.052 g, 0.34 mmol) in dioxane (5 mL) under nitrogen. The reaction was heated to 900C overnight. The reaction cooled and the solvent was removed. The residue was taken up in dioxane and ethyl isocyanate (0.319 mL, 4.03 mmol) added. The reaction was allowed to stir over the weekend. Methanol was added and the solvent was removed. The crude product was purified by preparative HPLC, to give the desired material as a white solid (9.00 mg). NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 1.05-1.09 (3H, t), 1.17-1.20(6H, m), 1.62- 1.68 (2H, m), 1.89-1.92 (2H, m), 3.09-3.14 (2H, m), 3.43-3.48 (2H, m), 3.86-3.90 (IH, dd), 3.94-4.16 (IH, dd), 4.12-4.16 (IH, m), 4.29-4.31 (IH, m), 6.12-6.15 (IH, t), 6.60 (IH, s), 7.37-7.40 (2H, d), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.79-7.86 (4H, m), 8.61 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=536; HPLC tR=2.38min.
The preparation of [2-(4-aminophenyl)-6-[l-(benzenesulfonyl)cyclopropyl]pyrimidin-4-yl] trifluoromethanesulfonate was described earlier.
f3£.5i?y3.5-Dimethylmorpholine
Figure imgf000810_0002
Hydrogen chloride (4M solution in dioxane, 9.98 mL, 39.92 mmol) was added to tert-butyl (35*,5i?)-3,5-dimethylmorpholine-4-carboxylate (1.910 g, 8.87 mmol) in dioxane (15 mL) and the resulting solution stirred at RT overnight. The solvent was removed and the solid was triturated with diethyl ether to give the desired material (as the hydrochloride salt) as a white solid (0.960 g).
NMR Spectrum: 1H NMR (400MHz, CDCl3) δ 1.47-1.48(6H, d), 3.31-3.40 (2H, m), 3.68-3.74 (2H, t), 3.86-3.90 (2H, dd), 9.77 (IH, bs), 10.22 (IH, bs).
The preparation of tert-butyl (35*,5i?)-3,5-dimethylmorpholine-4-carboxylate was described earlier.
Example 74 : 1- [4- [4- [ l-fBenzenesulfonyDcyclopropyll -6- [(3S)-3-ethylmorpholin-4- yll pyrimidin-2-yll phenyll -3-methylurea
Figure imgf000811_0001
Phenyl 7V-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(35)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate (0.1 g, 0.17 mmol), triethylamine (0.072 mL, 0.51 mmol) and methylamine (0.51 mmol) were dissolved in dioxane (10 mL) and heated at 500C overnight.
The reaction was evaporated to dryness and was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid.
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.84 (3H, t), 1.65 - 1.56 (3H, m), 1.80 - 1.71 (IH, m), 1.91 - 1.87 (2H, m), 2.66 (3H, d), 3.12 (IH, ddd), 3.43 (IH, ddd), 3.51 (IH, dd), 3.85 (IH, d), 3.91 (IH, dd), 4.24 - 4.12 (2H, m), 6.04 (IH, q), 6.61 (IH, s), 7.39 (2H, d),
7.58 (2H, t), 7.71 (IH, t), 7.78 (2H, d), 7.84 (2H, d), 8.69 (IH, s).
LCMS Spectrum: m/z (ES+) (M+H)+ = 522; HPLC tR= 2.31 min;
The following compounds were prepared in an analogous fashion from phenyl 7V-[4-[4-[l- (benzenesulfonyl)cyclopropyl]-6-[(35)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000812_0001
Figure imgf000813_0001
Example 74a: 1U NMR (400.132 MHz, DMSOd6) δ 0.43 - 0.39 (2H, m), 0.67 - 0.62 (2H, m), 0.84 (3H, t), 1.64 - 1.58 (3H, m), 1.80 - 1.73 (IH, m), 1.92 - 1.85 (2H, m), 2.57 - 2.52 (IH, m), 3.12 (IH, ddd), 3.43 (IH, ddd), 3.51 (IH, dd), 3.85 (IH, d), 3.91 (IH, dd), 4.28 - 4.09 (2H, m), 6.40 (IH, s), 6.61 (IH, s), 7.39 (2H, d), 7.58 (2H, t), 7.71 (IH, t), 7.78 (2H, d), 7.85 (2H, d), 8.49 (IH, s);
Example 74b: 1R NMR (400.132 MHz, DMSOd6) δ 0.84 (3H, t), 1.64 - 1.58 (3H, m), 1.80 - 1.73 (IH, m), 1.91 - 1.86 (2H, m), 3.19 - 3.09 (3H, m), 3.48 - 3.40 (3H, m), 3.51 (IH, dd), 3.85 (IH, d), 3.91 (IH, dd), 4.26 - 4.08 (2H, m), 4.72 (IH, t), 6.23 (IH, t), 6.61 (IH, s), 7.38 (2H, d), 7.58 (2H, t), 7.71 (IH, t), 7.78 (2H, d), 7.85 (2H, d), 8.75 (IH, s);
Example 74c: 1U NMR (400.132 MHz, DMSOd6) δ 0.84 (3H, t), 1.64 - 1.58 (3H, m), 1.80 - 1.71 (IH, m), 1.91 - 1.87 (2H, m), 3.12 (IH, ddd), 3.47 - 3.36 (3H, m), 3.51 (IH, dd), 3.85 (IH, d), 3.91 (IH, dd), 4.28 - 4.09 (2H, m), 4.47 (2H, dt), 6.42 (IH, t), 6.62 (IH, s), 7.39 (2H, d), 7.58 (2H, t), 7.71 (IH, t), 7.78 (2H, d), 7.86 (2H, d), 8.77 (IH, s);
Example 74d: 1R NMR (400.132 MHz, DMSOd6) δ 0.84 (3H, t), 1.65 - 1.58 (3H, m), 1.80 - 1.73 (IH, m), 1.91 - 1.87 (2H, m), 3.12 (IH, ddd), 3.43 (IH, ddd), 3.59 - 3.50 (3H, m), 3.85 (IH, d), 3.92 (IH, dd), 4.27 - 4.12 (2H, m), 6.07 (IH, tt), 6.51 (IH, t), 6.62 (IH, s), 7.40 (2H, d), 7.58 (2H, t), 7.71 (IH, t), 7.78 (2H, d), 7.87 (2H, d), 8.87 (IH, s);
Example 74e: 1U NMR (400.132 MHz, DMSOd6) δ 0.85 (3H, t), 1.68 - 1.59 (3H, m), 1.80 - 1.73 (IH, m), 1.92 - 1.87 (2H, m), 3.12 (IH, ddd), 3.43 (IH, ddd), 3.52 (IH, dd), 3.79 (3H, s),
3.86 (IH, d), 3.92 (IH, dd), 4.30 - 4.18 (2H, m), 6.62 (IH, s), 7.38 (IH, s), 7.43 (2H, d), 7.59 (2H, t), 7.72 (IH, t), 7.76 (IH, s), 7.78 (2H, d), 7.88 (2H, d), 8.36 (IH, s), 8.78 (IH, s); Example 74f: 1U NMR (400.132 MHz, DMSOd6) δ 0.84 (3H, t), 1.08 (3H, d), 1.65 - 1.58 (3H, m), 1.82 - 1.73 (IH, m), 1.90 - 1.88 (2H, m), 3.12 (IH, ddd), 3.39 - 3.33 (2H, m), 3.43 (IH, ddd), 3.51 (IH, dd), 3.73 - 3.67 (IH, m), 3.85 (IH, d), 3.91 (IH, dd), 4.25 - 4.13 (2H, m), 4.78 (IH, t), 6.07 (IH, d), 6.61 (IH, s), 7.36 (2H, d), 7.58 (2H, t), 7.71 (IH, t), 7.78 (2H, d), 7.85 (2H, d), 8.66 (IH, s); Example 74g: 1R NMR (400.132 MHz, DMSOd6) δ 0.84 (3H, t), 1.08 (3H, d), 1.67 - 1.58 (3H, m), 1.80 - 1.73 (IH, m), 1.90 - 1.88 (2H, m), 3.12 (IH, ddd), 3.40 - 3.32 (2H, m), 3.44 (IH, ddd), 3.51 (IH, dd), 3.73 - 3.67 (IH, m), 3.85 (IH, d), 3.91 (IH, dd), 4.27 - 4.08 (2H, m), 4.78 (IH, t), 6.07 (IH, d), 6.61 (IH, s), 7.36 (2H, d), 7.58 (2H, t), 7.71 (IH, t), 7.78 (2H, d), 7.85 (2H, d), 8.66 (IH, s); Example 74h: 1U NMR (400.132 MHz, DMSOd6) δ 0.84 (3H, t), 1.64 - 1.56 (5H, m), 1.82 - 1.69 (IH, m), 1.91 - 1.87 (2H, m), 3.19 - 3.08 (3H, m), 3.53 - 3.40 (4H, m), 3.85 (IH, d), 3.91 (IH, dd), 4.26 - 4.08 (2H, m), 4.47 (IH, t), 6.18 (IH, t), 6.61 (IH, s), 7.38 (2H, d), 7.58 (2H, t), 7.71 (IH, t), 7.78 (2H, d), 7.85 (2H, d), 8.66 (IH, s); Example 74i: 1R NMR (400.132 MHz, DMSOd6) δ 0.53 - 0.48 (2H, m), 0.59 - 0.56 (2H, m), 0.84 (3H, t), 1.64 - 1.58 (3H, m), 1.80 - 1.73 (IH, m), 1.92 - 1.88 (2H, m), 3.12 (IH, ddd), 3.21 (2H, d), 3.46 - 3.38 (IH, m), 3.51 (IH, dd), 3.85 (IH, d), 3.91 (IH, dd), 4.27 - 4.05 (2H, m), 6.30 (IH, t), 6.61 (IH, s), 7.38 (2H, d), 7.58 (2H, t), 7.71 (IH, t), 7.78 (2H, d), 7.85 (2H, d), 8.76 (IH, s), hydroxy missing
The preparation of phenyl 7V-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3<S)-3- ethylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl Λ/-[4-[4-[ 1 -(benzenesulfonvπcyclopropyll-ό-rfS^-S-ethylmorpholin^-yllpyrimidin^- yllphenyll carbamate
Figure imgf000815_0001
4- [4- [ 1 -(Benzenesulfonyl)cyclopropyl] -6- [(3 S)-3 -ethylmorpholin-4-yl]pyrimidin-2-yl]aniline (as the hydrochloride salt) (1.418 g, 2.83 mmol) and sodium bicarbonate (2.377 g, 28.30 mmol) were added to DCM (60 mL) and stirred for 10 minutes. Phenyl chloro formate (0.462 mL, 3.68 mmol) was added slowly and the reaction stirred for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford an orange solid. The crude product was purified by flash silica chromatography, elution gradient 30 to 60% ethyl acetate in isohexane, to give the desired material as a yellow solid (1.22 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.84 (3H, t), 1.68 - 1.59 (3H, m), 1.80 - 1.73 (IH, m), 1.92 - 1.89 (2H, m), 3.13 (IH, ddd), 3.43 (IH, ddd), 3.52 (IH, dd), 3.85 (IH, d), 3.92 (IH, dd), 4.18 (2H, s), 6.66 (IH, s), 7.29 - 7.24 (3H, m), 7.45 (2H, t), 7.54 (2H, d), 7.58 (2H, t), 7.71 (IH, t), 7.79 (2H, d), 7.95 (2H, d), 10.39 (IH, s); LCMS Spectrum: m/z (ES+) (M+H)+ = 585; HPLC tR= 3.12 min; 4-r4-ri-(Benzenesulfonyl)cvclopropyll-6-r(36f)-3-ethylmorpholin-4-yllpyrimidin-2-yllaniline
Figure imgf000816_0001
tert-Butyl 7V-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate (1.6 g, 2.83 mmol) was added to 6.0 N hydrogen chloride in propan-2-ol (20 mL) and stirred for 2 hours at RT. The crude solution was triturated with diethyl ether to give the desired material (as the hydrochloride salt) as a yellow solid (1.40 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.81 - 0.71 (3H, m), 1.78 - 1.60 (5H, m), 1.96 - 1.87 (2H, m), 3.20 (IH, ddd), 3.41 (IH, ddd), 3.50 (IH, dd), 3.84 (IH, d), 3.93 (IH, dd), 6.56 (IH, s), 7.01 (2H, s), 7.61 (2H, t), 7.79 - 7.75 (4H, m), 7.95 (2H, d); LCMS Spectrum: m/z (ES+) (M+H)+ = 465; HPLC tR= 2.54 min;
tert-Butyl N-\4-\4-\ 1 -(benzenesulfonyl)cvclopropyl1-6-r(3>Sy3-ethylmorpholm-4- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000816_0002
Sodium hydride (0.724 g, 15.07 mmol) was added rapidly to tert-hvXyl 7V-[4-[4-
(benzenesulfonylmethyl)-6-[(35)-3-ethylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (2.03 g, 3.77 mmol) in DMF (30 mL) and the mixture stirred at RT for 10 minutes before the slow addition 1 ,2-dibromoethane (1.299 mL, 15.07 mmol) in DMF (30 mL). The resulting suspension was stirred at RT for 1 hour. Additional sodium hydride (0.36 g, 7.53 mmol) and 1,2 dibromoethane (0.65 mL, 7.53 mmol) were rapidly added and the reaction was stirred for a further 30 minutes. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford brown gum. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% ethyl acetate in isohexane, to afford yellow foam. This was dissolved in 40% ethyl acetate in isohexane and stirred resulting in the desired material precipitating out as a white solid (1.65 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.84 (3H, t), 1.49 (9H, s), 1.65 - 1.58 (3H, m), 1.80 - 1.73 (IH, m), 1.90 - 1.87 (2H, m), 3.12 (IH, ddd), 3.43 (IH, ddd), 3.51 (IH, dd), 3.85 (IH, d), 3.91 (IH, dd), 4.18 (2H, s), 6.63 (IH, s), 7.45 (2H, d), 7.58 (2H, t), 7.71 (IH, t), 7.78 (2H, d), 7.87 (2H, d), 9.49 (IH, s); LCMS Spectrum: m/z (ES+) (M+H)+ = 565; HPLC tR= 3.23 min;
tert-Butyl Λ/-r4-r4-(benzenesulfonylmethyl)-6-r(36f)-3-ethylmorpholin-4-yllpyrimidin-2- yllphenyl] carbamate
Figure imgf000817_0001
Sodium benzenesulfinate (0.626 g, 3.81 mmol) and tert-butyl Λ/-[4-[4-[(35)-3-ethylmorpholin- 4-yl]-6-(iodomethyl)pyrimidin-2-yl]phenyl]carbamate (2.0 g, 3.81 mmol) were dissolved in DMF (25 mL) and stirred for 1 hour at RT. The solvent was evaporated to afford a yellow solid which was partitioned between aqueous sodium thiosulphate solution (50 mL) and DCM (75 mL). The organics were purified by flash silica chromatography, elution gradient 30 to 60% ethyl acetate in isohexane., to give the desired material as a white foam (1.99 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.86 (3H, t), 1.49 (9H, s), 1.66 - 1.57 (IH, m), 1.82 - 1.74 (IH, m), 3.14 (IH, ddd), 3.45 (IH, ddd), 3.53 (IH, dd), 3.87 (IH, d), 3.93 (IH, dd), 4.16 (2H, s), 4.69 (2H, s), 6.61 (IH, s), 7.45 (2H, d), 7.61 (2H, t), 7.74 (IH, t), 7.85 - 7.80 (4H, m), 9.49 (IH, s); LCMS Spectrum: m/z (ES+) (M+H)+ = 539; HPLC tR= 3.00 min; tert-Butyl Λ/-r4-r4-r(35)-3-ethylmorpholin-4-yll-6-(iodomethyl)pyrimidin-2- yllphenyll carbamate
Figure imgf000818_0001
[6-[(35)-3-Ethylmorpholin-4-yl]-2-[4-[(2-methylpropan-2- yl)oxycarbonylamino]phenyl]pyrimidin-4-yl]methyl methanesulfonate (10.34 g, 20.99 mmol) and lithium iodide (1.208 mL, 31.49 mmol) were added to dioxane (250 mL) and heated at 600C for 1 hour and then at RT overnight. The solvent was evaporated and the reaction mixture quenched with saturated ammonium chloride solution (100 mL) then extracted with DCM (3 x 75 mL). The organic extracts were flushed through a 2 inch silica plug, eluting with ethyl acetate, to give a brown foam. This was dissolved in diethyl ether and isohexane carefully added until a cloudy solution was observed. Upon cooling to 00C, the desired material precipitated out as a white solid and was isolated by filtration (9.80 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.88 (3H, t), 1.50 (9H, s), 1.72 - 1.63 (IH, m), 1.83 - 1.76 (IH, m), 3.17 (IH, ddd), 3.47 (IH, ddd), 3.55 (IH, dd), 3.87 (IH, d), 3.93 (IH, dd), 4.29 (2H, s), 4.38 (2H, s), 6.81 (IH, s), 7.56 (2H, d), 8.22 (2H, d), 9.53 (IH, s); LCMS Spectrum: m/z (ES+) (M+H)+ = 525; HPLC tR= 3.17 min;
r6-r(3y)-3-Ethylmorpholin-4-yl1-2-r4-r('2-methylpropan-2- vDoxycarbonylamino1phenyl1pyrimidin-4-yl"|methyl methanesulfonate
Figure imgf000818_0002
tert-Butyl N-[4-[4-[(35)-3-ethylmoipholin-4-yl]-6-(hydroxymethyl)pyrimidin-2- yl]phenyl]carbamate (8.7 g, 20.99 mmol) and DIPEA (4.40 mL, 25.19 mmol) were added to DCM (80 mL), to this was slowly added methane sulphonyl chloride(1.636 mL, 20.99 mmol) and the reaction was stirred for 30 minutes. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL), extracted with DCM (2 x 100 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford the desired material as a brown gum (10.2 g). This was used without any further purification. LCMS Spectrum: m/z (ES+) (M+H)+ = 493; HPLC tR= 2.90 min;
tert-Butyl Λ/-r4-r4-r(35)-3-ethylmorpholin-4-yll-6-(hvdroxymethyl)pyrimidin-2- yllphenyll carbamate
Figure imgf000819_0001
[2-Chloro-6-[(35)-3-ethylmorpholin-4-yl]pyrimidin-4-yl]methanol (12 g, 46.56 mmol), tert- butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenylcarbamate (14.86 g, 46.56 mmol), sodium carbonate (24.68 g, 232.81 mmol) and 1 , l'-bis(diphenyl phosphino)ferrocenedichloropalladium(II) (3.37 g, 4.66 mmol) were added to DME (150 mL) and water (37.5 mL) and heated to 900C overnight under nitrogen. The solvent was evaporated and the residue was quenched with water (100 mL), extracted with ethyl acetate (3 x 100 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford black gum. The residue was filtered through a plug of silica, eluting with ethyl acetate, to give a very dark gum. This was purified by flash silica chromatography, elution gradient 40 to 100% ethyl acetate in isohexane, to give an orange gum. The gum was dissolved in diethyl ether and isohexane carefully added until a cloudy solution was observed, further stirring gave the desired material as a white solid precipitate which was isolated by filtration (8.7 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 0.89 (3H, t), 1.49 (9H, s), 1.73 - 1.64 (IH, m), 1.84 - 1.77 (IH, m), 3.19 (IH, ddd), 3.47 (IH, ddd), 3.55 (IH, dd), 3.88 (IH, d), 3.94 (IH, dd), 4.33 - 4.23 (2H, m), 4.45 (2H, d), 5.38 (IH, t), 6.67 (IH, s), 7.53 (2H, d), 8.21 (2H, d), 9.50 (IH, s); LCMS Spectrum: m/z (ES+) (M+H)+ = 415; HPLC tR= 2.49 min; r2-Chloro-6-r(36f)-3-ethylmorpholin-4-yllpyrimidin-4-yllmethanol
Figure imgf000820_0001
Lithium borohydride, 2M in THF (17.63 mL, 35.26 mmol) was added dropwise to methyl 2- chloro-6-[(35)-3-ethylmorpholin-4-yl]pyrimidine-4-carboxylate te (15.5 g, 54.25 mmol) in THF (100 mL) at O0C over a period of 30 minutes under nitrogen. The resulting solution was stirred at 00C for 30 minutes then allowed to warm to RT. Water (250 mL) was added and the THF evaporated. The aqueous residues were extracted with ethyl acetate (2 x 500 mL) and the combined organics were washed with water (2 x 300 mL). The organic layer was dried over MgSO4 then evaporated to dryness to afford a viscous oil, this was triturated with hot diethyl ether to give the desired material as a white solid (13.4 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.84 (3H, t), 1.80 - 1.66 (2H, m), 3.19 - 3.14 (IH, m), 3.42 (IH, ddd), 3.51 (IH, dd), 3.82 (IH, d), 3.89 (IH, dd), 4.15 - 4.06 (2H, m), 4.34 (2H, d), 5.50 (IH, t), 6.74 (IH, s); LCMS Spectrum: m/z (ES+) (M+H)+ = 258; HPLC tR= 1.45 min;
Methyl 2-chloro-6- [(36^-3 -ethylmorpholin-4-yllpyrimidine-4-carboxylate
Figure imgf000820_0002
A solution of (S)-3-ethylmorpholine (10 g, 86.83 mmol) in DCM (75 mL) was added dropwise to a stirred solution of methyl 2,6-dichloropyrimidine-4-carboxylate (19.77 g, 95.51 mmol) and triethylamine (24.20 ml, 173.65 mmol) in DCM (200 mL) at RT, over a period of 2 hours under air. The resulting solution was stirred at RT overnight. The reaction mixture was quenched with water (250 mL), extracted with DCM (300 mL) and the solvent was removed to 30% the initial volume. The dark solution was passed through a 2 inch plug of silica, eluting with ethyl acetate, to give an orange gum which was dissolved in ethyl acetate (40 mL). To this was added diethyl ether (120 mL) and then isohexane until a cloudy solution was observed. The reaction was seeded with 15 mg of methyl 2-chloro-6-[(35)-3- methylmorpholin-4-yl]pyrimidine-4-carboxylate and stirred for 15 minutes to afford the desired material as a white solid (15.8 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.83 (3H, t), 1.75 (2H, septet), 3.22 (IH, s), 3.44 (IH, ddd), 3.53 (IH, dd), 3.82 (IH, d), 3.91 - 3.87 (4H, m), 4.22 (2H, m), 7.32 (IH, s);
LCMS Spectrum: m/z (ES+) (M+H)+ = 286; HPLC tR= 1.81 min;
Example 75 : 3-C yclopropyl- 1- [4- [4- [ 1- [ 1 -fdifluoromethyl)-3.,5-dimethylpyrazol-4- yll sulfonylcyclopropyll -6- [(3S)-3-methylmorpholin-4-yH pyrimidin-2-yll phenyll urea
Figure imgf000821_0001
Cyclopropylamine (0.038 mL, 0.54 mmol) was added to a solution of phenyl Λ/-[4-[4-[l-[l- (difluoromethyl)-3,5-dimethylpyrazol-4-yl]sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin- 4-yl]pyrimidin-2-yl]phenyl] carbamate (0.115g, O.lδmmol) in NMP (2 mL) followed by triethylamine (0.076 mL, 0.54 mmol) and the reaction was heated at 500C overnight. The crude product was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as an off white solid (88 mg).
NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 0.40 - 0.44 (2H, m), 0.63 - 0.68 (2H, m), 1.19 - 1.21 (3H, d), 1.46 - 1.54 (2H, m), 1.75 - 1.78 (2H, m), 2.07 (3H, s), 2.34 (3H, s), 2.53 - 2.58 (IH, m), 3.12 - 3.20 (IH, m), 3.44 - 3.50 (IH, m), 3.60 - 3.64 (IH, m), 3.76 (IH, d), 3.95
- 3.99 (IH, m), 4.13 (IH, d), 4.51 (IH, s), 6.42 (IH, d), 6.69 (IH, s), 7.42 - 7.45 (2H, m), 7.64
- 7.93 (IH, t), 7.91 - 7.94 (2H, m), 8.53 (IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 602; HPLC tR = 2.20 min.
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[l-[l- (difluoromethyl)-3,5-dimethylpyrazol-4-yl]sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin- 4-yl]pyrimidin-2-yl]phenyl] carbamate and the appropriate amine.
Figure imgf000822_0001
Figure imgf000823_0001
* In addition to the reaction conditions described above this reaction was subsequently subjected to the addition of DIPEA (3 equivalents) and heating at 950C for 90 minutes.
Example 75a: 1U NMR (399.9 MHz, DMSOd6) δ 1.20 (3H, d), 1.46 - 1.54 (2H, m), 1.75 - 1.78 (2H, m), 2.07 (3H, s), 2.34 (3H, s), 2.68 (3H, d), 3.12 - 3.17 (IH, m), 3.44 - 3.50 (IH, m), 3.60 - 3.64 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.13 (IH, d), 4.51 (IH, s), 6.05 (IH, q), 6.69 (IH, s), 7.42 - 7.44 (2H, m), 7.64 - 7.92 (IH, t), 7.90 - 7.93 (2H, m), 8.73 (IH, s). Example 75b: 1H NMR (399.9 MHz, DMSOd6) δ 1.07 (3H, t), 1.20 (3H, d), 1.49 - 1.51 (2H, m), 1.75 - 1.78 (2H, m), 2.07 (3H, s), 2.34 (3H, s), 3.10 - 3.20 (3H, m), 3.44 - 3.50 (IH, m), 3.60 - 3.64 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.11 - 4.15 (IH, m), 4.51 (IH, s), 6.14 (IH, t), 6.69 (IH, s), 7.41 - 7.44 (2H, m), 7.64 - 7.92 (IH, t), 7.91 - 7.93 (2H, d), 8.65 (IH, s). Example 75c: 1R NMR (399.9 MHz, DMSOd6) δ 1.20 (3H, s), 1.46 - 1.54 (2H, m), 1.75 - 1.78 (2H, m), 2.07 (3H, s), 2.34 (3H, s), 3.12 - 3.20 (3H, m), 3.45 - 3.50 (3H, m), 3.60 - 3.64 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.13 (IH, d), 4.51 (IH, s), 4.74 (IH, t), 6.24 (IH, t), 6.69 (IH, s), 7.42 (2H, d), 7.64 - 7.92 (IH, t), 7.92 (2H, d), 8.79 (IH, s). Example 75d: 1U NMR (399.9 MHz, DMSOd6) δ 1.20 (3H, d), 1.46 - 1.54 (2H, m), 1.75 - 1.78 (2H, m), 2.07 (3H, s), 2.34 (3H, s), 3.16 - 3.19 (IH, m), 3.44 - 3.64 (4H, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.12 - 4.15 (IH, m), 4.51 (IH, s), 5.93 - 6.23 (IH, m), 6.52 (IH, t), 6.70 (IH, s), 7.44 (2H, d), 7.64 - 7.92 (IH, t), 7.95 (2H, d), 8.92 (IH, s).
Example 75e: 1U NMR (399.9 MHz, DMSOd6) δ 1.20 (3H, d), 1.46 - 1.54 (2H, m), 1.73 - 1.78 (2H, m), 2.07 (3H, s), 2.34 (3H, s), 3.14 - 3.20 (IH, m), 3.36 - 3.50 (3H, m), 3.60 - 3.64 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.13 (IH, d), 4.42 (IH, t), 4.54 (2H, t), 6.42 (IH, t), 6.70 (IH, s), 7.43 (2H, d), 7.64 - 7.93 (IH, t), 7.93 (2H, d), 8.80 (IH, s). Example 75f: 1H NMR (399.9 MHz, DMSO-d6) δ 1.20 - 1.21 (3H, m), 1.47 - 1.54 (2H, m), 1.74 - 1.79 (2H, m), 2.07 (3H, s), 2.35 (3H, s), 3.13 - 3.21 (IH, m), 3.44 - 3.51 (IH, m), 3.61 - 3.64 (IH, m), 3.75 - 3.78 (IH, m), 3.80 (3H, s), 3.95 - 3.99 (IH, m), 4.14 (IH, d), 4.52 (IH, s), 6.70 (IH, s), 7.39 - 7.39 (IH, m), 7.46 - 7.49 (2H, m), 7.78 (IH, s), 7.65 - 7.94 (IH, t), 7.96 (2H, d), 8.37 (IH, s), 8.84 (IH, s)
The preparation of phenyl Λ/-[4-[4-[l-[l-(difluoromethyl)-3,5-dimethylpyrazol-4- yl]sulfonylcyclopropyl] -6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl Λ/-[4-[4-[ 1 -[ 1 -(difluoromethvπ-3.5-dimethylpyrazol-4-yllsulfonylcvclopropyll-6- r(36f)-3-methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000824_0001
Phenyl chloro formate (0.176 mL, 1.40 mmol) was added dropwise to a mixture of 4-[4-[l-[l- (difluoromethyl)-3,5-dimethylpyrazol-4-yl]sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin- 4-yl]pyrimidin-2-yl]aniline (0.726 g, 1.4 mmol) and sodium hydrogen carbonate (0.176 g, 2.10 mmol) in dioxane (20 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The precipitate was collected by filtration, washed with a mixture of isohexane (4 mL) and diethyl ether (2 mL), then suspended in water (20 mL) and stirred for 20 minutes. The precipitate was collected by filtration, washed with water (5 mL) then with a mixture of isohexane (10 mL ) and diethyl ether (5 mL) and dried under vacuum to afford the desired material as a white solid (0.826 g).
NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 1.21 (3H, d), 1.48 - 1.55 (2H, m), 1.74 - 1.79 (2H, m), 2.07 (3H, s), 2.35 (3H, s), 3.14 - 3.17 (IH, m), 3.39 - 3.50 (IH, m), 3.61 - 3.64 (IH, m), 3.77 (IH, m), 3.95 - 3.99 (IH, m), 4.16 (IH, d), 4.53 (IH, s), 6.75 (IH, s), 7.24 - 7.31 (3H, m), 7.44 - 7.48 (2H, m), 7.57 (2H, d), 7.64 - 7.93 (IH, t), 8.00 - 8.03 (2H, m), 10.42 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 639; HPLC tR = 2.92 min. 4-[4-[ 1 -[ 1 -(Difluoromethyl)-3,5-dimethylpyrazol-4-yl]sulfonylcyclopropyl]-6-[(3>S}-3- methylmorpholin-4-yl]pyrimidin-2-yl]aniline
Figure imgf000825_0001
Dichlorobis(triphenylphosphine)palladium(II) (0.412 g, 0.59 mmol) was added in one portion to a mixture of sodium carbonate (1.867 g, 17.61 mmol), 2-chloro-4-[l-[l-(difluoromethyl)- 3,5-dimethylpyrazol-4-yl]sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (2.712 g, 5.87 mmol) and (4-aminophenyl)boronic acid pinacol ester (1.351 g, 6.16 mmol) in DME (50 mL)and water (12.5 mL) under nitrogen. The mixture was stirred at 800C for 2 hours, cooled to RT then diluted with DCM (100 mL) and water (50 mL). The organic layer was washed with saturated brine (50 mL) then dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 60% ethyl acetate in isohexane, to give a residue which was further purified by trituration with isohexane (25 mL) and diethyl ether (25 mL), to give the desired material as a yellow solid (2.84 g).
NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 1.18 (3H, m), 1.43 - 1.51 (2H, m), 1.73 - 1.76 (2H, m), 2.07 (3H, s), 2.34 (3H, s), 3.09 - 3.17 (IH, m), 3.42 - 3.49 (IH, m), 3.59 - 3.63 (IH, m), 3.75 (IH, d), 3.94 - 3.97 (IH, m), 4.48 (IH, s), 5.52 (2H, m), 6.52 - 6.55 (2H, m), 6.58 (IH, s), 7.75 - 7.78 (2H, m), 7.64 - 7.93 (IH, t). LCMS Spectrum: m/z (ESI+)(M+H)+ = 519; HPLC tR = 1.91 min. 2-Chloro-4- r 1 - [ 1 -(difluoromethvD-3 ,5 -dimethylpyrazol-4-yll sulfonylcyclopropyll -6- [(36^-3 - methylmorpholin-4-vHpyrimidine
Figure imgf000826_0001
Sodium hydroxide (33.0 mL, 412.50 mmol) was added to 2-chloro-4-[[l-(difluoromethyl)- 3,5-dimethylpyrazol-4-yl]sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (3.27 g, 7.5 mmol), 1 ,2-dibromoethane (1.939 mL, 22.50 mmol) and tetrabutylammonium bromide (0.242 g, 0.75 mmol) in toluene (132 mL). The resulting solution was stirred at 600C for 1 hour. The reaction mixture was diluted with DCM (200 mL), and washed twice with water (200 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in DCM, to give the desired material as a white solid (2.77 g). NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 1.18 (3H, d), 1.45 - 1.52 (2H, m), 1.69 - 1.76 (2H, m), 2.13 (3H, s), 2.37 (3H, s), 3.12 - 3.19 (IH, m), 3.37 - 3.44 (IH, m), 3.53 - 3.57 (IH, m), 3.71 (IH, d), 3.90 - 3.94 (2H, m), 4.35 (IH, s), 6.80 (IH, s), 7.71 - 8.00 (IH, t). LCMS Spectrum: m/z (ESI+)(M+H)+ = 462; HPLC tR = 2.26 min.
2-Chloro-4-rri-(difluoromethvπ-3.5-dimethylpyrazol-4-yl1sulfonylmethyl1-6-r(3y)-3- methylmorpholin-4-vHpyrimidine
Figure imgf000826_0002
Sodium l-(difluoromethyl)-3,5-dimethylpyrazole-4-sulfinate (3.44 g, 14.83 mmol) was added to a solution of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (4.37 g, 12.36 mmol) in DMF (20 mL). The resulting mixture was stirred at RT for 1 hour. The reaction mixture was evaporated to dryness, redissolved in DCM (150 mL), and washed sequentially with water (100 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 60% ethyl acetate in isohexane, to give the desired material as a white solid (5.22 g). NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 1.19 (3H, d), 2.21 (3H, s), 2.42 (3H, s), 3.15 - 3.22 (IH, m), 3.40 - 3.47 (IH, m), 3.57 - 3.60 (IH, m), 3.73 (IH, d), 3.92 - 3.96 (2H, m), 4.25 (IH, s), 4.57 (2H, s), 6.82 (IH, s), 7.73 - 8.02 (IH, t). LCMS Spectrum: m/z (ESI+)(M+H)+ = 436; HPLC tR = 2.13 min.
Sodium l-(difluoromethyl)-3.5-dimethylpyrazole-4-sulfinate
Figure imgf000827_0001
Sodium hydrogen carbonate (3.43 g, 40.88 mmol) was added to a solution of sodium sulfite (2.58 g, 20.44 mmol) in water (25 mL) and the resulting solution was stirred at 500C for 1 hour. l-(Difluoromethyl)-3,5-dimethyl-lH-pyrazole-4-sulfonyl chloride (5 g, 20.44 mmol) was added portionwise and the solution was stirred at 500C for 18 hours. The reaction mixture was evaporated to dryness and methanol (75 mL) was added. The suspension was allowed to stir at RT for 20 minutes, filtered and the filtrate was evaporated. The residue was dissolved in ethanol (50 mL) at 5O0C, filtered and evaporated to afford the desired material as a white solid (4.59 g). NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 2.24 (3H, s), 2.46 (3H, s), 7.44 - 7.74 (IH, t).
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier. Example 76: l-[4-[4-H-(2-Chlorophenvnsulfonylcvclopropyll-6-K3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-cyclopropylurea
Figure imgf000828_0001
Cyclopropylamine (0.037 mL, 0.51 mmol) was added to a solution of phenyl 7V-[4-[4-[l-(2- chlorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate (0.103g, 0.17mmol) in NMP (2 mL) followed by triethylamine (0.072 mL, 0.51 mmol) and the reaction was heated at 500C overnight. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as an off- white solid (82mg, 80%). NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 0.40 - 0.44 (2H, m), 0.63 - 0.68 (2H, m), 1.16 (3H, d), 1.71 - 1.75 (2H, m), 1.97 - 2.01 (2H, m), 2.53 - 2.57 (IH, m), 3.12 - 3.16 (IH, m), 3.41 - 3.48 (IH, m), 3.58 - 3.61 (IH, m), 3.74 (IH, d), 3.93 - 3.97 (IH, m), 4.10 (IH, d), 4.41 (IH, s), 6.42 (IH, d), 6.63 (IH, s), 7.37 - 7.40 (2H, m), 7.43 - 7.46 (IH, m), 7.60 - 7.64 (IH, m), 7.67 - 7.69 (IH, m), 7.78 - 7.82 (2H, m), 7.90 - 7.92 (IH, m), 8.50 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 568; HPLC tR = 2.30 min.
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[l-(2- chlorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000828_0002
Figure imgf000829_0001
* subjected to the addition of DIPEA (3 equivalents) and heating at 950C for 90 minutes. Example 76a: 1H NMR (399.9 MHz, DMSO-d6) δ 1.15 - 1.16 (3H, m), 1.73 2H, m), 1.97 - 2.01 (2H, m), 2.66 (3H, d), 3.12 (IH, d), 3.40 - 3.48 (IH, m), 3.58 - 3.61 (IH, m), 3.74 (IH, d), 3.93 - 3.97 (IH, m), 4.08 (IH, m), 4.41 (IH, s), 6.06 (IH, d), 6.62 (IH, s), 7.38 (2H, d), 7.46 (IH, m), 7.60 - 7.62 (IH, m), 7.67 - 7.69 (IH, m), 7.79 (2H, d), 7.90 - 7.92 (IH, d), 8.70 (IH, s).
Example 76b: 1H NMR (399.9 MHz, DMSOd6) δ 1.07 (3H, t), 1.16 (3H, d), 1.72 - 1.75 (2H, m), 1.97 - 2.01 (2H, m), 3.10 - 3.16 (3H, m), 3.42 - 3.45 (IH, m), 3.58 - 3.61 (IH, m), 3.73 - 3.75 (IH, m), 3.93 - 3.98 (IH, m), 4.10 (IH, d), 4.41 (IH, s), 6.15 (IH, t), 6.63 (IH, s), 7.35 - 7.39 (2H, m), 7.43 - 7.47 (IH, m), 7.60 - 7.64 (IH, m), 7.67 - 7.70 (IH, m), 7.78 - 7.81 (2H, d), 7.90 - 7.92 (IH, m), 8.62 (IH, s).
Example 76c: 1R NMR (399.9 MHz, DMSOd6) δ 1.15 - 1.16 (3H, m), 1.73 (2H, m), 1.97 - 2.01 (2H, m), 3.16 (IH, m), 3.17 - 3.19 (2H, m), 3.46 (3H, m), 3.58 - 3.61 (IH, m), 3.74 (IH, d), 3.93 - 3.97 (IH, m), 4.10 (IH, m), 4.42 (IH, s), 4.74 (IH, t), 6.24 (IH, t), 6.63 (IH, s), 7.36 (2H, d), 7.42 - 7.47 (IH, m), 7.60 - 7.62 (IH, m), 7.67 - 7.70 (IH, m), 7.80 (2H, d), 7.90 - 7.92 (IH, m), 8.76 (IH, s).
Example 76d: 1H NMR (399.9 MHz, DMSOd6) δ 1.16 (3H, d), 1.70 - 1.77 (2H, m), 1.96 - 2.03 (2H, m), 3.09 - 3.16 (IH, m), 3.41 - 3.48 (IH, m), 3.49 - 3.62 (3H, m), 3.74 (IH, d), 3.93
- 3.97 (IH, m), 4.08 - 4.12 (IH, d), 4.41 (IH, s), 5.92 - 6.22 (IH, m), 6.52 (IH, t), 6.64 (IH, s), 7.37 - 7.41 (2H, d), 7.44 - 7.47 (IH, m), 7.60 - 7.62 (IH, m), 7.67 - 7.70 (IH, m), 7.82 (2H, d), 7.90 - 7.92 (IH, m), 8.88 (IH, s).
Example 76e: 1H NMR (399.9 MHz, DMSOd6) δ 1.16 (3H, d), 1.69 - 1.77 (2H, m), 1.95 - 2.03 (2H, m), 3.09 - 3.16 (IH, m), 3.36 - 3.48 (3H, m), 3.58 - 3.62 (IH, m), 3.74 (IH, d), 3.93
- 3.97 (IH, m), 4.10 (IH, d), 4.42 (2H, m), 4.54 (IH, t), 6.42 (IH, t), 6.63 (IH, s), 7.36 - 7.40 (2H, m), 7.43 - 7.47 (IH, m), 7.60 - 7.66 (IH, m), 7.67 - 7.70 (IH, m), 7.80 - 7.82 (2H, m), 7.90 - 7.92 (IH, m), 8.77 (IH, s).
Example 76f: 1U NMR (399.9 MHz, DMSOd6) δ 1.10 - 1.17 (3H, d), 1.72 - 1.75 (2H, m), 1.98 - 2.01 (2H, m), 3.13 - 3.16 (IH, m), 3.42 - 3.48 (IH, m), 3.58 - 3.62 (IH, m), 3.75 (IH, d), 3.80 (3H, s), 3.94 - 3.97 (IH, m), 4.12 (IH, m), 4.42 (IH, s), 6.64 (IH, s), 7.40 - 7.47 (4H, m), 7.61 - 7.63 (IH, m), 7.68 - 7.71 (IH, m), 7.77 (IH, s), 7.83 (2H, d), 7.90 - 7.93 (IH, m), 8.38 (IH, s), 8.80 (IH, s). The preparation of phenyl Λ/-[4-[4-[l-(2-chlorophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N-[4-[4-[ 1 -(2-chlorophenvπsulfonylcvclopropyll-6-[(36f)-3-methylmorpholin-4- vllpyrimidin-2-yllphenyllcarbamate
Figure imgf000831_0001
Phenyl chloro formate (0.189 mL, 1.50 mmol) was added dropwise to a mixture of 4-[4-[l-(2- chlorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (0.727 g, 1.5 mmol) and sodium hydrogen carbonate (0.189 g, 2.25 mmol) in dioxane (20 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The precipitate was collected by filtration, washed with diethyl ether (10 mL), suspended in water (20 mL), stirred for 20 minutes, collected by filtration, washed with water (10 mL) then ether (2 mL) and dried under vacuum to afford the desired material as a white solid (0.735 g). NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 1.17 (3H, d), 1.72 - 1.77 (2H, m), 1.98 - 2.01 (2H, m), 3.10 - 3.18 (IH, m), 3.44 - 3.62 (2H, m), 3.74 (IH, d), 3.93 - 3.97 (IH, m), 4.12 (IH, d), 4.43 (IH, s), 6.67 (IH, s), 7.24 - 7.31 (3H, m), 7.43 - 7.48 (3H, m), 7.51 - 7.53 (2H, m), 7.60 - 7.63 (IH, m), 7.67 - 7.70 (IH, m), 7.88 - 7.92 (3H, m), 10.40 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 605; HPLC tR = 3.02 min.
4-r4-ri-(2-Chlorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-2- yll aniline
Figure imgf000831_0002
Dichlorobis(triphenylphosphine)palladium(II) (0.519 g, 0.74 mmol) was added in one portion to a mixture of sodium carbonate (2.352 g, 22.20 mmol), 2-chloro-4-[l-(2- chlorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (3.169 g, 7.40 mmol) and (4-aminophenyl)boronic acid pinacol ester (1.702 g, 7.77 mmol) in DME (56 mL)and water (14 mL) under nitrogen. The mixture was stirred at 800C for 2 hours, cooled to RT then diluted with DCM (100 mL) and water (50 mL). The organic layer was washed with saturated brine (50 mL) then dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 60% ethyl acetate in isohexane, to give a residue which was further purified by trituration with isohexane (25 mL) and diethyl ether (25 mL), to give the desired material as a yellow solid (3.2I g). NMR Spectrum: 1H NMR (399.9 MHz, DMSO-d6) δ 1.08 - 1.19 (3H, m), 1.67 - 1.75 (2H, m), 1.97 - 2.00 (2H, m), 3.05 - 3.13 (IH, m), 3.39 - 3.43 (IH, m), 3.56 - 3.60 (IH, m), 3.73 (IH, d), 3.91 - 3.96 (IH, m), 4.04 (IH, q), 4.37 (IH, s), 5.49 (2H, m), 6.47 - 6.49 (2H, m), 6.52 (IH, s), 7.43 - 7.47 (IH, m), 7.59 - 7.68 (4H, m), 7.90 - 7.93 (IH, m). LCMS Spectrum: m/z (ESI+)(M+H)+ = 485; HPLC tR = 1.94 min.
2-Chloro-4-[l -^-chlorophenvOsulfonylcvclopropyll-ό- [(36^-3 -methylmorpholin-4- ylipyrimidine
Figure imgf000832_0001
Sodium hydroxide (50%w/w solution) (35.2 mL, 440.00 mmol) was added to 2-chloro-4-[(2- chlorophenyl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (3.22 g, 8mmol), 1 ,2-dibromoethane (2.068 mL, 24.00 mmol) and tetrabutylammonium bromide (0.258 g, 0.80 mmol) in toluene (141 mL). The resulting solution was stirred at 600C for 18 hours. The reaction mixture was diluted with DCM (150 mL), and washed twice with water (150 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% ethyl acetate in DCM, to give the desired material as a colourless dry film (3.23 g). NMR Spectrum: 1H NMR (399.9 MHz, DMSO-d6) δ 1.13 (3H, d), 1.64 - 1.67 (2H, m), 1.92 - 1.95 (2H, m), 3.07 - 3.15 (IH, m), 3.35 - 3.41 (IH, m), 3.51 - 3.55 (IH, m), 3.69 (IH, d), 3.88 - 3.92 (2H, m), 4.24 (IH, s), 6.72 (IH, s), 7.52 - 7.56 (IH, m), 7.66 - 7.73 (2H, m), 7.88 - 7.91
(IH, m).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 428; HPLC tR = 2.42 min.
2-Chloro-4-[(2-chlorophenvπsulfonylmethyll-6-[(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000833_0001
Sodium 2-chlorobenzenesulfinate (3.19 g, 16.07 mmol) was added to a solution of 2-chloro-4- (iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (4.37 g, 12.36 mmol) in DMF (20 mL). The resulting mixture was stirred at RT for 1 hour. The reaction mixture was evaporated to dryness and redissolved in DCM (150 mL) and washed sequentially with water (100 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 60% ethyl acetate in isohexane, to give the desired material as a white solid (4.34 g). NMR Spectrum: 1H NMR (399.9 MHz, DMSOd6) δ 1.16 - 1.18 (3H, d), 3.13 - 3.20 (IH, m), 3.39 - 3.46 (IH, m), 3.56 - 3.59 (IH, m), 3.72 (IH, d), 3.91 - 3.95 (2H, m), 4.22 (IH, s), 4.78 (2H, s), 6.79 (IH, s), 7.56 - 7.59 (IH, m), 7.74 - 7.79 (2H, m), 7.82 - 7.84 (IH, m). LCMS Spectrum: m/z (ESI+)(M+H)+ = 402; HPLC tR = 2.26 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier. Example 77: l-[4-[4-[l-(4-Cvanophenyl)sulfonylcvclopropyll-6-[(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-cyclopropylurea
Figure imgf000834_0001
Cyclopropylamine (32 mg, 0.564 mmol) was added to phenyl 7V-[4-[4-[l-(4- cyanophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl] carbamate (112 mg, 0.188 mmol) and triethylamine (0.080 mL, 0.564 mmol) in NMP (2 mL). The resulting solution was stirred at 500C for 16 hours then cooled to RT and purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a solid (81 mg). NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 0.42 (2H, m), 0.65 (2H, m), 1.19 (3H, d), 1.65 (2H, m), 1.96 (2H, m), 2.56 (IH, m), 3.17 (IH, m), 3.47 (IH, m), 3.61 (IH, m), 3.75 (IH, m), 3.96 (IH, m), 4.16 (IH, m), 4.46 (IH, m), 6.41 (IH, d), 6.67 (IH, s), 7.39 (2H, d), 7.68 (2H, d), 7.98 (2H, d), 8.08 (2H, d), 8.53 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 559; HPLC tR = 2.36 min.
The compounds below were prepared in an analogous fashion from phenyl N- [4- [4- [1 -(4- cyanophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000834_0002
Figure imgf000835_0001
* In addition to the reaction conditions described above this sample was further subjected to the addition of more triethylamine (3 equivalents) and stirred for an additional 7 hours at 8O0C. Example 77a: 1U NMR (399.902 MHz, DMSO-Cl6) δ 1.19 (3H, d), 1.65 (2H, m), 1.95 (2H, m), 2.66 (3H, d), 3.16 (IH, m), 3.47 (IH, m), 3.61 (IH, m), 3.75 (IH, m), 3.96 (IH, m), 4.16 (IH, m), 4.46 (IH, m), 6.06 (IH, q), 6.66 (IH, s), 7.39 (2H, d), 7.68 (2H, d), 7.98 (2H, d), 8.08 (2H, d), 8.73 (IH, s). Example 77b: 1H NMR (399.902 MHz, DMSOd6) δ 1.07 (3H, t), 1.19 (3H, d), 1.65 (2H, m), 1.95 (2H, m), 3.09 - 3.20 (3H, m), 3.47 (IH, m), 3.62 (IH, m), 3.75 (IH, m), 3.96 (IH, m), 4.16 (IH, m), 4.46 (IH, m), 6.15 (IH, t), 6.66 (IH, s), 7.38 (2H, d), 7.67 (2H, d), 7.98 (2H, d), 8.08 (2H, d), 8.65 (IH, s). Example 77c: 1R NMR (399.902 MHz, DMSO-(I6) δ 1.20 (3H, d), 1.65 (2H, m), 1.96 (2H, m), 3.18 (3H, m), 3.47 (3H, m), 3.61 (IH, m), 3.75 (IH, m), 3.96 (IH, m), 4.16 (IH, m), 4.46 (IH, m), 4.74 (IH, t), 6.25 (IH, t), 6.66 (IH, s), 7.37 (2H, d), 7.67 (2H, d), 7.98 (2H, d), 8.09 (2H, d), 8.79 (IH, s).
Example 77d: 1H NMR (399.902 MHz, DMSO-d6) δ 1.20 (3H, d), 1.65 (2H, m), 1.96 (2H, m), 3.17 (IH, m), 3.43 - 3.63 (4H, m), 3.75 (IH, m), 3.96 (IH, m), 4.16 (IH, m), 4.46 (IH, m), 5.92 - 6.22 (IH, m), 6.52 (IH, t), 6.67 (IH, s), 7.39 (2H, d), 7.70 (2H, d), 7.98 (2H, d), 8.08 (2H, d), 8.91 (IH, s).
Example 77e: 1R NMR (399.902 MHz, DMSO-dg) δ 1.20 (3H, d), 1.65 (2H, m), 1.96 (2H, m), 3.16 (IH, m), 3.39 (IH, m), 3.47 (2H, m), 3.61 (IH, m), 3.75 (IH, m), 3.96 (IH, m), 4.16 (IH, m), 4.41 - 4.55 (3H, m), 6.43 (IH, t), 6.67 (IH, s), 7.39 (2H, d), 7.69 (2H, d), 7.98 (2H, d), 8.09 (2H, d), 8.80 (IH, s).
Example 77f: 1H NMR (399.902 MHz, DMSO-d6) δ 1.20 (4H, d), 1.65 (2H, m), 1.96 (3H, m), 3.17 (2H, m), 3.47 (IH, m), 3.62 (IH, m), 3.74 - 3.80 (4H, m), 3.97 (IH, m), 4.17 (IH, m), 4.47 (IH, m), 6.68 (IH, s), 7.38 (2H, s), 7.43 (3H, d), 7.71 (3H, d), 7.77 (2H, s), 7.98 (2H, d), 8.09 (2H, d), 8.38 (IH, s), 8.83 (IH, s).
The preparation of phenyl Λ/-[4-[4-[l-(4-cyanophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below. Phenyl Λ/-[4-[4-[ 1 -(4-cvanophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000837_0001
Phenyl chloro formate (0.185 mL, 1.47 mmol) was added dropwise to 4-[l-[2-(4- aminophenyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4- yl]cyclopropyl]sulfonylbenzonitrile (700 mg, 1.47 mmol) and sodium bicarbonate (185 mg, 2.21 mmol) in dioxane (20 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The precipitate was collected by filtration, washed with diethyl ether (2 mL) and suspended in water (20 mL) and stirred for 20 minutes. The precipitate was collected by filtration, washed with water (5 mL) then diethyl ether (5 mL) and dried under vacuum to afford the desired material as a white solid (786 mg).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.20 (3H, d), 1.67 (2H, m), 1.97 (2H, m), 3.18 (IH, m), 3.45 (IH, m), 3.62 (IH, m), 3.76 (IH, m), 3.97 (IH, m), 4.18 (IH, m), 4.47 (IH, m), 6.71 (IH, s), 7.27 (3H, m), 7.46 (2H, m), 7.53 (2H, d), 7.78 (2H, d), 7.98 (2H, d), 8.09 (2H, d), 10.44 (IH, s).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 596; HPLC tR = 3.01 min.
4-[l-[2-(4-Aminophenvπ-6-[(36f)-3-methylmorpholin-4-yllpyrimidin-4- yllcvclopropyllsulfonylbenzonitrile
Figure imgf000837_0002
Sodium carbonate (1.693 g, 15.97 mmol) was added to 4-[l-[2-chloro-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonylbenzonitrile (2.23 g, 5.32 mmol) and (4-aminophenyl)boronic acid pinacol ester (1.225 g, 5.59 mmol) in a mixture of DME (40 mL) and water (10.00 mL). The mixture was bubbled with nitrogen for 10 minutes then dichlorobis(triphenylphosphine)palladium(II) (0.374 g, 0.53 mmol) was added and the mixture stirred at 800C for 2 hours. The reaction mixture was cooled to RT then diluted with DCM (100 mL) and water (50 mL). The organic layer was washed with saturated brine (50 mL) then dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 40% ethyl acetate in isohexane followed by 40% ethyl acetate in isohexane, to give the desired material as an orange solid (2.31 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.18 (3H, d), 1.62 (2H, m), 1.93 (2H, m), 3.14 (IH, m), 3.45 (IH, m), 3.60 (IH, m), 3.74 (IH, m), 3.95 (IH, m), 4.12 (IH, m), 4.42 (IH, m), 5.55 (2H, s), 6.48 (2H, d), 6.56 (IH, s), 7.50 (2H, d), 7.97 (2H, d), 8.08 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 476; HPLC tR = 2.37 min.
4-ri-r2-Chloro-6-r(3y)-3-methylmorpholin-4-yl1pyrimidin-4- yllcvclopropyllsulfonylbenzonitrile
Figure imgf000838_0001
Sodium hydride, 60% dispersion in mineral oil (0.316 g, 7.91 mmol) was added in one portion to 4- [ [2-chloro-6- [(35)-3 -methylmorpholin-4-yl]pyrimidin-4- yl]methylsulfonyl]benzonitrile (2.96 g, 7.53 mmol) in DMF (20 mL) at O0C under nitrogen. The resulting suspension was stirred for 10 minutes then 1 ,2-dibromoethane (0.682 mL, 7.91 mmol) was added. The mixture was warmed to 100C for 10 minutes then cooled back to 00C and a further portion of sodium hydride, 60% dispersion in mineral oil (0.316 g, 7.91 mmol) added. The mixture was warmed to 500C and stirred at 500C for 2 hours. A further portion of sodium hydride, 60% dispersion in mineral oil (0.158 g, 3.95 mmol) and 1 ,2-dibromoethane (0.341 ml, 3.95 mmol) was added and stirred for a further 2 hours. The reaction mixture was cooled to RT, quenched with saturated aqueous ammonium chloride (2 mL) and the solvents evaporated. The residues were stirred in water (50 mL) for 15 minutes then the resulting solid collected by filtration. The solid was dissolved in DCM (50 mL), washed with water (20 mL), then saturated brine (20 mL), dried over MgSO4, filtered and evaporated to give the crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 40% ethyl acetate in isohexane, to give the desired material as a white solid (2.33 g). NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.16 (3H, d), 1.60 (2H, m), 1.90 (2H, m), 3.15 (IH, m), 3.40 (IH, m), 3.55 (IH, m), 3.70 (IH, m), 3.90 - 3.99 (2H, m), 4.27 (IH, m), 6.72 (IH, s), 7.96 (2H, d), 8.11 (2H, d).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 419; HPLC tR = 2.19 min.
4-rr2-Chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-yllmethylsulfonyllbenzonitrile
Figure imgf000839_0001
2N Sulfuric acid (0.4 mL) was added to a stirred solution of 4-[[2-chloro-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfanyl]benzonitrile (5.18 g, 14.35 mmol) in dioxane (125 mL) and the solution heated to 550C. Sodium tungstate dihydrate (0.095 g, 0.29 mmol) in water (3.5 mL) was added and the solution was allowed to stir for 5 minutes. Hydrogen peroxide, 30% by wt solution in water (8.80 mL, 86.13 mmol) was added dropwise and the solution stirred at 55°C for 3 hours. The reaction was cooled to RT then water added until precipitation ceased. The precipitate was collected by filtration, washed with water and dried under vacuum to afford the desired material as a white solid (5.0 g). NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.18 (3H, d), 3.18 (IH, m), 3.43 (IH, m), 3.58 (IH, m), 3.73 (IH, m), 3.91 (2H, m), 4.18 (IH, m), 4.77 (2H, s), 6.76 (IH, s), 7.99 (2H, d), 8.15 (2H, d).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 393; HPLC tR = 1.99 min.
4-rr2-Chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-yllmethylsulfanyllbenzonitrile
Figure imgf000839_0002
4-Mercaptobenzonitrile (3.48 g, 25.74 mmol) was added to 2-chloro-4-(iodomethyl)-6-[(35)- 3-methylmorpholin-4-yl]pyrimidine (7 g, 19.80 mmol) and DIPEA (5.32 mL, 29.70 mmol) in THF (50 mL). The resulting slurry was stirred at RT for 16 hours then the temperature was increased to 7O0C for a further 16 hours. The reaction mixture was cooled to RT then diluted with DCM (200 mL), and washed sequentially with water (200 mL) then saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 30% ethyl acetate in isohexane, to give the desired material as a yellow solid (5.18 g). NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.15 (3H, d), 3.16 (IH, m), 3.42 (IH, m), 3.57 (IH, m), 3.71 (IH, m), 3.90 - 3.99 (2H, m), 4.26 (3H, m), 6.88 (IH, s), 7.55 (2H, d), 7.75 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 361; HPLC tR = 2.33 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Example 78: S-Cyclopropyl-l-N-N-H-fq^-dimethyl-U-thiazol-S- vDsulfonyll cyclopropyll -6- [(3S)-3-methylmorpholin-4-yH pyrimidin-2-yll phenyll urea
Figure imgf000840_0001
Cyclopropylamine (26 mg, 0.450 mmol) was added to phenyl Λ/-[4-[4-[l-[(2,4-dimethyl-l,3- thiazol-5-yl)sulfonyl]cyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl] carbamate (91 mg, 0.150 mmol) and triethylamine (0.063 mL, 0.450 mmol) in NMP (2 mL). The resulting solution was stirred at 500C for 16 hours then cooled to RT and purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid (64 mg).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 0.42 (2H, m), 0.66 (2H, m), 1.21 (3H, d), 1.62 (2H, m), 1.79 (2H, m), 2.22 (3H, s), 2.56 (IH, m), 2.62 (3H, s), 3.18 (IH, m), 3.48 (IH, m), 3.63 (IH, m), 3.76 (IH, m), 3.97 (IH, m), 4.16 (IH, m), 4.49 (IH, m), 6.43 (IH, d),
6.73 (IH, s), 7.45 (2H, d), 7.93 (2H, d), 8.53 (IH, s).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 569; HPLC tR = 2.27 min.
The compounds below were prepared in an analogous fashion from phenyl 7V-[4-[4-[l-[(2,4- dimethyl- 1 ,3 -thiazol-5 -yl)sulfonyl] cyclopropyl] -6-[(3S)-3 -methylmorpholin-4-yl]pyrimidin- 2-yl]phenyl] carbamate and the appropriate amine.
Figure imgf000841_0001
Figure imgf000842_0001
* Stirred for an additional 4 hours at 8O0C
Example 78a: 1H NMR (399.902 MHz, DMSOd6) δ 1.21 (3H, d), 1.61 (2H, m), 1.79 (2H, m), 2.22 (3H, s), 2.62 (3H, s), 2.67 (3H, d), 3.18 (IH, m), 3.48 (IH, m), 3.63 (IH, m), 3.76 (IH, m), 3.97 (IH, m), 4.16 (IH, m), 4.49 (IH, m), 6.06 (IH, q), 6.72 (IH, s), 7.44 (2H, d), 7.92 (2H, d), 8.74 (IH, s).
Example 78b: 1H NMR (399.902 MHz, DMSOd6) δ 1.07 (3H, t), 1.21 (3H, d), 1.62 (2H, m), 1.79 (2H, m), 2.22 (3H, s), 2.62 (3H, s), 3.10 - 3.22 (3H, m), 3.48 (IH, m), 3.63 (IH, m), 3.76 (IH, m), 3.98 (IH, m), 4.16 (IH, m), 4.49 (IH, m), 6.15 (IH, t), 6.72 (IH, s), 7.43 (2H, d), 7.92 (2H, d), 8.66 (IH, s).
Example 78c: 1R NMR (399.902 MHz, DMSOd6) δ 1.21 (3H, d), 1.62 (2H, m), 1.79 (2H, m), 2.22 (3H, s), 2.62 (3H, s), 3.14 - 3.22 (3H, m), 3.44 - 3.51 (3H, m), 3.63 (IH, m), 3.76 (IH, m), 3.97 (IH, m), 4.16 (IH, m), 4.49 (IH, m), 4.74 (IH, t), 6.24 (IH, t), 6.73 (IH, s), 7.43 (2H, d), 7.93 (2H, d), 8.80 (IH, s). Example 78d: 1H NMR (399.902 MHz, DMSOd6) δ 1.21 (3H, d), 1.62 (2H, m), 1.79 (2H, m), 2.22 (3H, s), 2.62 (3H, s), 3.18 (IH, m), 3.45 - 3.65 (4H, m), 3.76 (IH, m), 3.97 (IH, m), 4.16 (IH, m), 4.49 (IH, m), 5.93 - 6.23 (IH, m), 6.53 (IH, t), 6.74 (IH, s), 7.45 (2H, d), 7.95 (2H, d), 8.92 (IH, s). Example 78e: 1R NMR (399.902 MHz, DMSOd6) δ 1.21 (3H, d), 1.62 (2H, m), 1.79 (2H, m), 2.22 (3H, s), 2.62 (3H, s), 3.18 (IH, m), 3.37 - 3.51 (3H, m), 3.63 (IH, m), 3.77 (IH, m), 3.98 (IH, m), 4.16 (IH, m), 4.41 - 4.55 (3H, m), 6.43 (IH, t), 6.73 (IH, s), 7.44 (2H, d), 7.93 (2H, d), 8.81 (IH, s).
Example 78f: 1H NMR (399.902 MHz, DMSOd6) δ 1.21 (3H, d), 1.62 (2H, m), 1.80 (2H, m), 2.23 (3H, s), 2.63 (3H, s), 3.19 (IH, m), 3.48 (IH, m), 3.64 (IH, m), 3.77 (IH, m), 3.80 (3H, s), 3.98 (IH, m), 4.17 (IH, m), 4.49 (IH, m), 6.74 (IH, s), 7.39 (IH, s), 7.49 (2H, d), 7.78 (IH, s), 7.96 (2H, d), 8.38 (IH, s), 8.83 (IH, s).
The preparation of phenyl Λ/-[4-[4-[l-[(2,4-dimethyl-l,3-thiazol-5-yl)sulfonyl]cyclopropyl]-6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N-[4-r4-ri -r(2.4-dimethyl-l .S-thiazol-S-vnsulfonyllcvclopropyll-o-rfS^-S- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000843_0001
Phenyl chloro formate (0.181 mL, 1.44 mmol) was added dropwise to 4-[4-[l-[(2,4-dimethyl- l,3-thiazol-5-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl] aniline (700 mg, 1.44 mmol) and sodium bicarbonate (182 mg, 2.16 mmol) in dioxane (20 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The precipitate was collected by filtration, washed with diethyl ether (2 mL) and suspended in water (20 mL) and stirred for 20 minutes. The precipitate was collected by filtration, washed with water (5 mL) then diethyl ether (5 mL) and dried under vacuum to afford the desired material as a beige solid (637 mg).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.22 (3H, d), 1.63 (2H, m), 1.81 (2H, m), 2.24 (3H, s), 2.61 (3H, s), 3.20 (IH, m), 3.49 (IH, m), 3.63 (IH, m), 3.77 (IH, m), 3.98 (IH, m), 4.17 (IH, m), 4.51 (IH, m), 6.78 (IH, s), 7.28 (3H, m), 7.46 (2H, m), 7.58 (2H, d), 8.02 (2H, d), 10.43 (IH, s).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 606; HPLC tR = 2.91 min. 4-r4-ri-r(2.4-Dimethyl-1.3-thiazol-5-yl)sulfonyl1cvclopropyl1-6-r(3y)-3-methylmorpholin-4- vHpyrimidin-2-yll aniline
Figure imgf000844_0001
Sodium carbonate (2.105 g, 19.86 mmol) was added to 2-chloro-4-[l-[(2,4-dimethyl-l,3- thiazol-5-yl)sulfonyl]cyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (2.84 g, 6.62 mmol) and (4-aminophenyl)boronic acid pinacol ester (1.523 g, 6.95 mmol) in a mixture of DME (40 mL) and water (10 mL). The mixture was bubbled with nitrogen for 10 minutes then dichlorobis(triphenylphosphine)palladium(II) (0.465 g, 0.66 mmol) was added and the mixture stirred at 800C for 2 hours. Further dichlorobis(triphenylphosphine)palladium(II) (0.232 g, 0.33 mmol) was added and the mixture was stirred at 800C for a further 4 hours. The reaction mixture was cooled to RT then diluted with DCM (250 mL) and water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 40 to 50% ethyl acetate in isohexane followed by 50% ethyl acetate in isohexane, to give a material which was further purified by ion exchange chromatography using an SCX column, eluting with 2M ammonia in methanol, to give the desired material as an orange solid (2.59 g). NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.19 (3H, d), 1.59 (2H, m), 1.77 (2H, m), 2.22 (3H, s), 2.62 (3H, s), 3.15 (IH, m), 3.47 (IH, m), 3.61 (IH, m), 3.75 (IH, m), 3.96 (IH, m), 4.12 (IH, m), 4.45 (IH, m), 5.54 (2H, s), 6.54 (2H, d), 6.62 (IH, s), 7.76 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 486; HPLC tR = 2.17 min.
2-Chloro-4- r 1 - IY2.4-dimethyl- 1.3 -thiazol-5 -vOsulfonyll cvclopropyll-6- [(36^-3 - methylmorpholin-4-vHpyrimidine
Figure imgf000844_0002
Sodium hydroxide (15.94 g, 398.59 mmol) in water (16 mL) was added to a stirred solution of 2-chloro-4-[(2,4-dimethyl-l,3-thiazol-5-yl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4- yljpyrimidine (2.92 g, 7.25 mmol), 1 ,2-dibromoethane (1.874 mL, 21.74 mmol) and tetrabutylammonium bromide (0.234 g, 0.72 mmol) in toluene (100 mL). The resulting solution was stirred at RT for 90 minutes then at 600C for 1 hour. The reaction mixture was diluted with water (300 mL), the organic layer separated and washed with saturated brine (100 mL) then dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% ethyl acetate in isohexane, to give the desired material as a white solid (2.84 g). NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.18 (3H, d), 1.59 (2H, m), 1.76 (2H, m), 2.29 (3H, s), 2.68 (3H, s), 3.17 (IH, m), 3.42 (IH, m), 3.56 (IH, m), 3.72 (IH, m), 3.91 - 4.00 (2H, m), 4.33 (IH, m), 6.82 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 429; HPLC tR = 2.09 min.
2-Chloro-4-r(2.4-dimethyl-1.3-thiazol-5-vπsulfonylmethyl1-6-r(3y)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000845_0001
Sodium 2,4-dimethylthiazole-5-sulfinate (5.2 g, 26.10 mmol) was added to 2-chloro-4- (iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (4.01 g, 11.35 mmol) in DMF (50 mL). The resulting mixture was stirred at RT for 1 hour. The reaction mixture was evaporated to dryness and redissolved in DCM (250 mL), and washed sequentially with water (150 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% ethyl acetate in isohexane followed by 50% ethyl acetate in isohexane, to give the desired material as a yellow solid (4.77 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSO-d6) δ 1.19 (3H, d), 2.40 (3H, s), 2.67 (3H, s), 3.19 (IH, m), 3.44 (IH, m), 3.59 (IH, m), 3.73 (IH, m), 3.93 (2H, m), 4.23 (IH, m), 4.69 (2H, s), 6.83 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 403; HPLC tR = 1.82 min.
Sodium 2,4-dimethylthiazole-5-sulfinate
Figure imgf000846_0001
A solution of sodium sulfite (2.98 g, 23.62 mmol) in water (25 mL) was stirred at RT for 10 minutes. Sodium bicarbonate (3.97 g, 47.24 mmol) was added and the resulting solution was stirred at 500C for 1 hour. 2,4-Dimethylthiazole-5-sulfonyl chloride (5 g, 23.62 mmol) was added portion wise to the solution and stirring was continued at 500C for 18 hours. The reaction mixture was evaporated to dryness and redissolved in methanol (75 mL). The suspension was allowed to stir at RT for 20 minutes. The suspension was filtered and the filtrate evaporated to afford the desired material as a yellow solid (5.21 g), which was dried under vacuum and used without further purification. NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 2.28 (3H, s).
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Example 79 : 3-C yclopr opyl- 1- [4- [4- [ l-f3-hvdroxy-3-methylbutyl)sulfonylcvclopropyll -6- [(3S)-3-methylmorpholin-4-yll pyrimidin-2-yll phenyll urea
Figure imgf000846_0002
Cyclopropylamine (33 mg, 0.573 mmol) was added to phenyl Λ/-[4-[4-[l-(3-hydroxy-3- methylbutyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl] carbamate (111 mg, 0.191 mmol) and triethylamine (0.080 mL, 0.573 mmol) in NMP (2 mL). The resulting solution was stirred at 500C for 16 hours then cooled to RT and purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid (83 mg). NMR Spectrum: 1H NMR (399.902 MHz, DMSO-d6) δ 0.43 (2H, m), 0.65 (2H, m), 1.12 (6H, s), 1.24 (3H, d), 1.56 (2H, m), 1.65 (2H, m), 1.85 (2H, m), 2.56 (IH, m), 3.21 (IH, m), 3.49 (IH, m), 3.56 (2H, m), 3.63 (IH, m), 3.77 (IH, m), 3.98 (IH, m), 4.22 (IH, m), 4.49 (IH, s), 4.56 (IH, m), 6.44 (IH, d), 6.76 (IH, s), 7.50 (2H, d), 8.24 (2H, d), 8.57 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 544; HPLC tR = 2.10 min.
The compounds below were prepared in an analogous fashion from phenyl N- [4- [4- [1 -(3- hydroxy-3 -methylbuty^sulfonylcyclopropyl] -6- [(35)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000847_0001
Figure imgf000848_0001
6 Equivalents of triethylamine were used.
Example 79a: 1H NMR (399.902 MHz, DMSOd6) δ 1.13 (6H, s), 1.23 (3H, d), 1.55 (2H, m), 1.65 (2H, m), 1.85 (2H, m), 2.67 (3H, d), 3.21 (IH, m), 3.45 - 3.58 (3H, m), 3.63 (IH, m), 3.77 (IH, m), 3.98 (IH, m), 4.22 (IH, m), 4.49 (IH, s), 4.57 (IH, m), 6.07 (IH, m), 6.75 (IH, s), 7.49 (2H, d), 8.23 (2H, d), 8.77 (IH, s).
Example 79b: 1H NMR (399.902 MHz, DMSOd6) δ 1.13 (6H, s), 1.24 (3H, d), 1.55 (2H, m), 1.65 (2H, m), 1.85 (2H, m), 3.16 - 3.24 (3H, m), 3.45 - 3.49 (3H, m), 3.56 (2H, m), 3.63 (IH, m), 3.77 (IH, m), 3.98 (IH, m), 4.22 (IH, m), 4.49 (IH, s), 4.56 (IH, m), 4.74 (IH, t), 6.25 (IH, t), 6.76 (IH, s), 7.48 (2H, d), 8.23 (2H, d), 8.82 (IH, s).
Example 79c: 1R NMR (399.902 MHz, DMSO-(I6) δ 1.13 (6H, s), 1.24 (3H, d), 1.56 (2H, m), 1.65 (2H, m), 1.85 (2H, m), 3.21 (IH, m), 3.45 - 3.65 (6H, m), 3.77 (IH, m), 3.98 (IH, m), 4.23 (IH, m), 4.49 (IH, s), 4.57 (IH, m), 5.93 - 6.23 (IH, m), 6.53 (IH, t), 6.77 (IH, s), 7.50 (2H, d), 8.26 (2H, d), 8.95 (IH, s). Example 79d: 1H NMR (399.902 MHz, DMSOd6) δ 1.12 (6H, s), 1.24 (3H, d), 1.55 (2H, m), 1.65 (2H, m), 1.85 (2H, m), 3.21 (IH, m), 3.36 - 3.58 (5H, m), 3.64 (IH, m), 3.77 (IH, m), 3.98 (IH, m), 4.22 (IH, m), 4.41 - 4.58 (4H, m), 6.43 (IH, t), 6.76 (IH, s), 7.49 (2H, d), 8.25 (2H, d), 8.83 (IH, s). Example 79e: 1R NMR (399.902 MHz, DMSOd6) δ 1.13 (6H, s), 1.24 (3H, d), 1.56 (2H, m), 1.66 (2H, m), 1.86 (2H, m), 3.22 (IH, m), 3.49 (IH, m), 3.57 (2H, m), 3.64 (IH, m), 3.78 (4H, m), 3.98 (IH, m), 4.23 (IH, m), 4.50 (IH, s), 4.57 (IH, m), 6.77 (IH, s), 7.39 (IH, s), 7.54 (2H, d), 7.78 (IH, s), 8.27 (2H, d), 8.38 (IH, s), 8.86 (IH, s)
Example 79f: 1H NMR (399.902 MHz, DMSOd6) δ 1.07 (3H, t), 1.12 (6H, s), 1.23 (3H, d), 1.59 (4H, m), 1.84 (2H, m), 3.17 (3H, m), 3.54 (4H, m), 3.76 (IH, m), 3.98 (IH, m), 4.23 (IH, m), 4.56 (2H, m), 6.17 (IH, m), 6.75 (IH, s), 7.48 (2H, d), 8.23 (2H, d), 8.72 (IH, s)
The preparation of phenyl Λ/-[4-[4-[l-(3-hydroxy-3-methylbutyl)sulfonylcyclopropyl]-6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl JV-[4-[4-[ 1 -π-hvdroxy-S-methylbutvOsulfonylcvclopropyli-ό-l'π.SyS- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000849_0001
Phenyl chloro formate (0.191 mL, 1.52 mmol) was added dropwise to 4-[l-[2-(4- aminophenyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonyl-2- methylbutan-2-ol (700 mg, 1.52 mmol) and sodium bicarbonate (192 mg, 2.28 mmol) in dioxane (20 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The precipitate was collected by filtration then washed with diethyl ether (2 mL). The precipitate was suspended in water (20 mL) then extracted into DCM (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford the desired material as a yellow solid (774 mg).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.12 (6H, s), 1.24 (3H, d), 1.57 (2H, m), 1.66 (2H, m), 1.85 (2H, m), 3.22 (IH, m), 3.46 - 3.57 (3H, m), 3.64 (IH, m), 3.77 (IH, m), 3.98 (IH, m), 4.24 (IH, m), 4.58 (IH, m), 6.80 (IH, s), 7.28 (3H, m), 7.46 (2H, m), 7.62 (2H, d), 8.33 (2H, d), 10.43 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 581; HPLC tR = 2.63 min. 4-ri-r2-(4-Aminophenyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4- yll cyclopropyll sulfonyl-2-methylbutan-2-ol
Figure imgf000850_0001
TFA (5 mL) was added to tert-butyl 7V-[4-[4-[l-(3-hydroxy-3- methylbutyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl] carbamate (2.08 g, 3.71 mmol) in DCM (5 mL). The resulting solution was stirred at RT for 1 hour then added to an SCX column. The crude product was eluted from the column using 2M ammonia in methanol the further purified by flash silica chromatography, elution gradient 40 to 50% ethyl acetate in isohexane, to give the desired material as a white solid (1.15 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.13 (6H, s), 1.22 (3H, d), 1.52 (2H, m), 1.63 (2H, m), 1.85 (2H, m), 3.18 (IH, m), 3.48 (IH, m), 3.55 (2H, m), 3.62 (IH, m), 3.76 (IH, m), 3.97 (IH, m), 4.19 (IH, m), 4.48 (IH, s), 4.53 (IH, m), 5.57 (2H, s), 6.59 (2H, d), 6.65 (IH, s), 8.07 (2H, d). LCMS Spectrum: m/z (ESI+)(M+H)+ = 461; HPLC tR = 1.96 min.
tert-Butyl N- \4- \4- \ 1 -(3 -hvdroxy-3 -methylbutvDsulfonylcvclopropyll -6- \(3S)-3 - methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000850_0002
Sodium carbonate (1.299 g, 12.25 mmol) was added to 4-[l-[2-chloro-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonyl-2-methylbutan-2-ol (1.65 g, 4.08 mmol) and (4-boc-aminophenyl)boronic acid pinacol ester (1.369 g, 4.29 mmol) in a mixture of DME (40 mL) and water (10 mL). The mixture was bubbled with nitrogen for 10 minutes then l,r-bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.296 g, 0.41 mmol) was added and the mixture stirred at 800C for 8 hours. The reaction mixture was cooled to RT then diluted with DCM (150 mL), and washed with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% ethyl acetate in isohexane, to give the desired material as a yellow gum (2.08 g).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 561; HPLC tR = 2.69 min.
4-ri-r2-Chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-yllcvclopropyllsulfonyl-2- methylbutan-2-ol
Figure imgf000851_0001
Sodium hydroxide (11.93 g, 298.37 mmol) in water (12 mL) was added to a stirred solution of 4-[[2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]-2-methylbutan- 2-ol (2.05 g, 5.42 mmol), 1 ,2-dibromoethane (1.402 mL, 16.27 mmol) and tetrabutylammonium bromide (0.175 g, 0.54 mmol) in toluene (75 mL). The resulting solution was stirred at RT for 5 hours then at 45°C for 3 hours. The reaction mixture was diluted with water (100 mL), the organic layer separated and dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% ethyl acetate in isohexane, to give the desired material as a yellow dry film (1.75 g). NMR Spectrum: 1H NMR (399.902 MHz, DMSO-d6) δ 1.13 (6H, s), 1.22 (3H, d), 1.52 (2H, m), 1.61 (2H, m), 1.80 (2H, m), 3.21 (IH, m), 3.36 - 3.47 (3H, m), 3.58 (IH, m), 3.72 (IH, m), 3.93 (IH, m), 4.05 (IH, m), 4.40 (IH, m), 4.46 (IH, s), 6.94 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 404; HPLC tR = 1.83 min. 4-rr2-Chloro-6-r(36^-3-methylmorpholin-4-yllpyrimidin-4-yllmethylsulfonyll-2-methylbutan-
2-ol
Figure imgf000852_0001
2N Sulfuric Acid (0.307 mL) was added to a stirred solution of 4-[[2-chloro-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfanyl]-2-methylbutan-2-ol (3.78 g, 10.93 mmol) in dioxane (100 mL) and the solution heated to 550C. Sodium tungstate dihydrate (0.072 g, 0.22 mmol) in water (3 mL) was added and the solution was allowed to stir for 5 minutes. Hydrogen peroxide, 30% by wt solution in water (6.7 mL, 65.57 mmol) was added dropwise and the solution stirred at 55°C for 2.5 hours. The reaction mixture was cooled to RT and diluted with water (100 mL), and extracted with DCM (2 x 200 mL). The organic layer was washed with brine (50 mL) then dried over MgSO4, filtered and evaporated to afford the desired material as a cream solid (4.39 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.15 (6H, s), 1.23 (3H, d), 1.82 (2H, m), 3.19 - 3.30 (3H, m), 3.46 (IH, m), 3.61 (IH, m), 3.74 (IH, m), 3.93 - 4.02 (2H, m), 4.31 (IH, m), 4.46 (2H, s), 4.48 (IH, s), 6.95 (IH, s).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 378; HPLC tR = 1.64 min.
4-rr2-Chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4-yllmethylsulfanyll-2-methylbutan- 2-ol
Figure imgf000852_0002
Methylmagnesium bromide, 3M in diethyl ether (13.17 mL, 39.50 mmol) was added dropwise to methyl 3-[[2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4- yl]methylsulfanyl]propanoate (4.14 g, 11.97 mmol) in THF (50 mL) at O0C over a period of 10 minutes under nitrogen. The resulting solution was stirred at 00C for 30 minutes then at RT for 90 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (1 mL), diluted with water (100 mL) then extracted with DCM (3 x 100 mL), the organic layer was washed with brine (100 mL) then dried over MgSO4, filtered and evaporated to afford the desired material as a yellow gum (3.96 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.08 (6H, s), 1.21 (3H, d), 1.61 (2H, m), 2.54 (2H, m), 3.18 (IH, m), 3.44 (IH, m), 3.57 (2H, s), 3.61 (IH, m), 3.72 (IH, m), 3.91 - 4.01 (2H, m), 4.23 (IH, s), 4.32 (IH, m), 6.78 (IH, s).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 346; HPLC tR = 1.79 min.
Methyl 3 -[ [2-chloro-6- [(36^-3 -methylmorpholin^-ylipyrimidin^- yllmethylsulfanyllpropanoate
Figure imgf000853_0001
Methyl 3-mercaptopropionate (2.55 g, 21.21 mmol) was added to 2-chloro-4-(iodomethyl)-6- [(35)-3-methylmorpholin-4-yl]pyrimidine (5 g, 14.14 mmol) and DIPEA (3.80 mL, 21.21 mmol) in THF (50 mL). The resulting slurry was stirred at RT for 16 hours. The reaction mixture was diluted with DCM (150 mL), and washed sequentially with water (100 mL) then saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 30% ethyl acetate in isohexane, to give the desired material as a colourless liquid (4.6 g). NMR Spectrum: 1H NMR (399.902 MHz, DMSO-d6) δ 1.21 (3H, d), 2.65 (2H, t), 2.76 (2H, t), 3.19 (IH, m), 3.45 (IH, m), 3.56 - 3.64 (6H, m), 3.72 (IH, m), 3.91 - 4.00 (2H, m), 4.33 (IH, m), 6.81 (IH, s). LCMS Spectrum: m/z (ESI+)(M+H)+ = 346; HPLC tR = 2.05 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier. Example 80 : 3-(2.2-DifluoroethylV 1- [4- [4- [ 1- K4.5-dimethyl- 1.3-thiazol-2- vDsulfonyll cyclopropyll -6- [(3S)-3-methylmorpholin-4-yH pyrimidin-2-yll phenyll urea
Figure imgf000854_0001
Phenyl JV-[4-[4-[l -[(4,5-dimethyl-l, 3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (150 mg, 0.25 mmol), triethylamine (0.104 mL, 0.74 mmol) and 2,2-difluoroethanamine (60.2 mg, 0.74 mmol) were added to dioxane (10 mL) and heated at 500C for 72 hours. The reaction mixture was evaporated under reduced pressure to a gum which was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid (83 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.77 - 1.72 (2H, m), 1.95 - 1.88 (2H, m), 2.37 (3H, s), 2.40 (3H, s), 3.23 - 3.13 (IH, m), 3.66 - 3.41 (4H, m), 3.80 - 3.73 (IH, m), 3.97 (IH, d), 4.17 (IH, d), 4.51 - 4.41 (IH, m), 6.23 - 5.91 (IH, m), 6.51 (IH, t), 6.79 (IH, s), 7.44 (2H, d), 7.90 (2H, d), 8.91 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 493; HPLC tR = 2.42 min.
The compounds below were prepared in an analogous fashion from phenyl 7V-[4-[4-[l-[(4,5- dimethyl- 1 ,3 -thiazol-2-yl)sulfonyl] cyclopropyl] -6-[(3S)-3 -methylmorpholin-4-yl]pyrimidin- 2-yl]phenyl] carbamate and the appropriate amine.
Figure imgf000854_0002
Figure imgf000855_0001
* Stirred at RT for 16 hours
Example 80a: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.78 - 1.71 (2H, m), 1.94 - 1.89 (2H, m), 2.37 (3H, s), 2.40 (3H, s), 3.24 - 3.13 (IH, m), 3.51 - 3.35 (4H, m), 3.65 - 3.59 (IH, m), 3.79 - 3.74 (IH, m), 4.01 - 3.94 (IH, m), 4.17 (IH, d), 4.56 - 4.38 (3H, m), 6.41 (IH, t), 7.43 (2H, d), 7.89 (2H, d), 8.80 (IH, s)
Example 80b: 1U NMR (400.132 MHz, DMSOd6) δ 0.45 - 0.38 (2H, m), 0.69 - 0.61 (2H, m), 1.21 (3H, d), 1.76 - 1.72 (2H, m), 1.94 - 1.89 (2H, m), 2.37 (3H, s), 2.41 (3H, s), 2.59 - 2.53 (IH, m), 3.24 - 3.13 (IH, m), 3.47 (IH, t), 3.64 - 3.59 (IH, m), 3.80 - 3.72 (IH, m), 3.98 (IH, d), 4.17 (IH, d), 4.50 - 4.41 (IH, m), 6.41 (IH, d), 6.78 (IH, s), 7.43 (2H, d), 7.88 (2H, d), 8.53 (IH, s)
Example 80c: 1U NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.77 - 1.72 (2H, m), 1.94 - 1.89 (2H, m), 2.37 (3H, s), 2.40 (4H, s), 3.51 - 3.42 (3H, m), 3.65 - 3.59 (IH, m), 3.79 - 3.74 (IH, m), 3.97 (IH, d), 4.06 (2H, q), 4.17 (IH, d), 4.50 - 4.41 (IH, m), 4.72 (IH, t), 6.23 (IH, t), 6.78 (IH, s), 7.41 (2H, d), 7.88 (2H, d), 8.79 (IH, s)
Example 8Od: 1R NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.78 - 1.72 (2H, m), 1.94 - 1.89 (2H, m), 2.37 (3H, s), 2.40 (3H, s), 2.66 (3H, d), 3.23 - 3.13 (IH, m), 3.52 - 3.42 (IH, m), 3.65 - 3.59 (IH, m), 3.79 - 3.74 (IH, m), 3.97 (IH, d), 4.20 - 4.13 (IH, m), 4.49 - 4.41 (IH, m), 6.07 - 6.03 (IH, m), 6.78 (IH, s), 7.43 (2H, d), 7.87 (2H, d), 8.73 (IH, s)
Example 8Oe: 1U NMR (400.132 MHz, DMSOd6) δ 1.07 (3H, t), 1.21 (3H, d), 1.77 - 1.71 (2H, m), 1.95 - 1.88 (2H, m), 2.37 (3H, s), 2.41 (3H, s), 3.23 - 3.07 (3H, m), 3.47 (IH, t), 3.65 - 3.59 (IH, m), 3.79 - 3.73 (IH, m), 3.98 (IH, d), 4.16 (IH, d), 4.51 - 4.40 (IH, m), 6.14 (IH, t), 6.78 (IH, s), 7.42 (2H, d), 7.88 (2H, d), 8.65 (IH, s)
The preparation of phenyl Λ/-[4-[4-[l-[(4,5-dimethyl-l,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N-r4-r4-ri-r(4.5-dimethyl-1.3-thiazol-2-vnsulfonyllcvclopropyll-6-r(3^-3- methylmorpholin-4-yllpyrimidin-2-yllphenvHcarbamate
Figure imgf000856_0001
Phenyl chloroformate (0.866 mL, 6.91 mmol) was added dropwise to 4-[4-[l-[(4,5-dimethyl- l,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (2.58 g, 5.31 mmol) and sodium hydrogencarbonate (8.93 g, 106.26 mmol) in DCM (52.3 mL) at RT under nitrogen. The resulting suspension was stirred at RT for 90 minutes, saturated ammonium chloride solution added followed by DCM (40 mL). The organics were separated, washed with water (50 mL) and saturated brine (50 mL), dried over MgSO4 and evaporated to give the desired material (2.91 g). NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.34 (3H, d), 1.87 - 1.77 (2H, m), 2.14 - 2.10 (2H, m), 2.34 (3H, s), 2.36 (3H, s), 3.32 (IH, t), 3.60 (IH, t), 3.77 - 3.72 (IH, m), 3.85 - 3.81 (IH, m), 4.04 (IH, d), 4.20 (IH, d), 4.53 - 4.44 (IH, m), 7.04 (IH, s), 7.10 (IH, s), 7.28 ■ 7.17 (3H, m), 7.40 (2H, t), 7.46 (2H, d), 8.16 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 606; HPLC tR = 2.90 min.
4-r4-ri-r(4.5-Dimethyl-1.3-thiazol-2-yl)sulfonyl1cvclopropyl1-6-r(3y)-3-methylmorpholin-4- yllpyrimidin-2-vH aniline
Figure imgf000857_0001
Dichlorobis(triphenylphosphine)palladium(II) (0.219 g, 0.31 mmol) was added in one portion to 2-chloro-4-[ 1 - [(4,5 -dimethyl- 1 ,3 -thiazol-2-yl)sulfonyl] cyclopropyl] -6- [(3S>3 - methylmorpholin-4-yl]pyrimidine (2.68 g, 6.25 mmol), 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (1.369 g, 6.25 mmol) and sodium bicarbonate (15.62 mL, 31.24 mmol) in a mix of solvents (18% DMF, 82% of a 7:3:2 mixture of DME: water :ethanol) (75 mL) and the resulting mixture stirred at 800C for 16 hours under an inert atmosphere. The reaction mixture was diluted with ethyl acetate (200 mL), and washed sequentially with water (2 x 150 mL) and saturated brine (3 x 100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a yellow foam (2.85 g).
NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.32 (3H, d), 1.88 - 1.75 (2H, m), 2.16 - 2.06 (2H, m), 2.34 (3H, s), 2.36 (3H, s), 3.33 - 3.24 (IH, m), 3.63 - 3.55 (IH, m), 3.88 - 3.71 (4H, m), 4.03 (IH, d), 4.18 (IH, d), 4.51 - 4.43 (IH, m), 6.64 (2H, d), 7.04 (IH, s), 8.01 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 486; HPLC tR = 1.65 min. 2-Chloro-4- r 1 - [(4.5 -dimethyl- 1.3 -thiazol-2-vnsulfonyll cyclopropyll-ό- IY35V3 - methylmorpholin-4-vHpyrimidine
Figure imgf000858_0001
Sodium hydroxide (50% w/w) (45.9 g, 573.32 mmol) was added in one portion to 2-chloro-4- [(4,5-dimethyl- 1 ,3-thiazol-2-yl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (4.2 g, 10.42 mmol), tetrabutylammonium bromide (0.336 g, 1.04 mmol) and 1,2- dibromoethane (2.69 mL, 31.27 mmol) in toluene (52.1 mL) and the resulting mixture stirred at 600C for 5 hours. The reaction mixture was diluted with toluene (50 mL) and water (100 mL) and washed sequentially with water (2 x 100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in DCM, to give the desired material as a white foam (3.42 g). NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.34 (3H, d), 1.83 - 1.72 (2H, m), 2.11 - 2.02 (2H, m), 2.37 (3H, s), 2.44 (3H, s), 3.29 (IH, t), 3.54 (IH, t), 3.72 - 3.66 (IH, m), 3.82 - 3.76 (IH, m), 4.13 - 3.97 (2H, m), 4.35 (IH, s), 7.29 (IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 429; HPLC tR = 2.35 min.
2-Chloro-4-r(4.5-dimethyl-1.3-thiazol-2-vπsulfonylmethyl1-6-r('3y)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000858_0002
3-Chloroperoxybenzoic acid (11.18 g, 49.88 mmol) was added portionwise to (2-chloro-4- [(4,5-dimethyl-l,3-thiazol-2-yl)sulfanylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (7.4 g, 19.95 mmol) in DCM (100 mL) at 50C over a period of 15 minutes under nitrogen. The resulting suspension was stirred at 50C for 1 hour then allowed to warm to RT and stirred for 3 hours. A saturated solution of sodium hydrogen carbonate (100 mL) was added and the organics separated and washed with water (100 mL) and brine (100 mL), dried over MgSO4 and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 30 to 60% ethyl acetate in DCM, to give the desired material as a white solid (4.2 g).
NMR Spectrum: 1H NMR (400.132 MHz, CDCl3) δ 1.32 (3H, d), 2.42 (3H, s), 2.46 (3H, s), 3.28 (IH, t), 3.54 (IH, t), 3.71 - 3.66 (IH, m), 3.81 - 3.76 (IH, m), 4.09 - 3.96 (2H, m), 4.35 - 4.23 (IH, m), 4.51 (2H, s), 6.59 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 403; HPLC tR = 2.02 min.
2-Chloro-4-r(4.5-dimethyl-1.3-thiazol-2-vπsulfanylmethyl1-6-r('3y)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000859_0001
2-Chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (7 g, 19.80 mmol) was added to 4,5-dimethylthiazole-2-thiol (3.16 g, 21.78 mmol) and DIPEA (5.17 mL, 29.70 mmol) in THF (10 mL) and the slurry stirred at RT for 7 hours. The solvent was removed under reduced pressure and the residue diluted with DCM and washed sequentially with water and saturated brine. The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in DCM, to give the desired material as a yellow gum (7.95 g). NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.16 - 1.19 (3H, m), 2.23 (3H, d), 2.29 (3H, d), 3.16 - 3.20 (IH, td), 3.39 - 3.46 (IH, td), 3.55 - 3.59 (IH, dd), 3.71 (IH, d), 3.91 - 3.94 (2H, dd), 4.21 - 4.29 (3H, m), 6.80 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 371; HPLC tR = 2.31 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier. Example 81: l-[4-[4-H-K4.5-Dimethyl-1.3-thiazol-2-vnsulfonyllcvclopropyll-6-K3S)-3- methylmorpholin-4-yllpyrimidin-2-yllphenyll-3-Q-methylpyrazol-4-yl)urea
Figure imgf000860_0001
Phenyl iV-[4-[4-[l -[(4,5-dimethyl-l, 3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (150 mg, 0.25 mmol), 1-methyl-lH- pyrazol-4-amine dihydrochloride (126 mg, 0.74 mmol) and DIPEA (0.428 mL, 2.48 mmol) were dissolved in dioxane (10 mL) and sealed into a microwave tube. The reaction was heated to 1000C for 150 minutes in the microwave reactor and cooled to RT. The solvent was evaporated under reduced pressure, and the crude product was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid (70 mg).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.77 - 1.72 (2H, m), 1.95 - 1.89 (2H, m), 2.37 (3H, s), 2.41 (3H, s), 3.24 - 3.14 (IH, m), 3.52 - 3.43 (IH, m), 3.65 - 3.59 (IH, m), 3.81 - 3.75 (4H, m), 4.00 - 3.95 (IH, m), 4.22 - 4.11 (IH, m), 4.51 - 4.41 (IH, m), 6.79 (IH, s), 7.38 (IH, s), 7.47 (2H, d), 7.77 (IH, s), 7.92 (2H, d), 8.36 (IH, s), 8.83 (IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 609; HPLC tR = 2.09 min.
The preparation of phenyl Λ/-[4-[4-[l-[(4,5-dimethyl-l,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate was described earlier.
Example 82 : 1- [4- [4- [ l-(4-Fluor o^-methylphenynsulfonylcyclopropyll -6- \(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-methylurea
Figure imgf000860_0002
Phenyl 7V-[4-[4-[ 1 -(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (0.150 g, 0.25 mmol), triethylamine (0.104 mL, 0.75 mmol) and methylamine (0.75 mmol) were dissolved in dioxane (10 mL) and heated at 500C overnight. The reaction was evaporated to dryness and was purified by preparative HPLC, eluting with using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid. NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 1.63 - 1.60 (2H, m), 1.85 - 1.83 (2H, m), 2.44 (3H, s), 2.66 (3H, d), 3.13 (IH, ddd), 3.45 (IH, ddd), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.10 (IH, d), 4.42 (IH, s), 6.04 (IH, q), 6.62 (IH, s), 7.17 (IH, ddd), 7.24 (IH, dd), 7.40 (2H, d), 7.84 - 7.81 (3H, m), 8.71 (IH, s); LCMS Spectrum: m/z (ES+) (M+H)+ = 540; HPLC tR= 2.34 min
The following compounds were prepared in an analogous fashion from phenyl N-[4-[4-[l-(4- fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000861_0001
Figure imgf000862_0001
Example 82a: 1U NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 1.63 - 1.60 (2H, m), 1.85 - 1.83 (2H, m), 2.44 (3H, s), 2.66 (3H, d), 3.13 (IH, ddd), 3.45 (IH, ddd), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.10 (IH, d), 4.42 (IH, s), 6.04 (IH, q), 6.62 (IH, s), 7.17 (IH, ddd), 7.24 (IH, dd), 7.40 (2H, d), 7.84 - 7.81 (3H, m), 8.71 (IH, s);
Example 82b: 1U NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 1.63 - 1.60 (2H, m), 1.85 - 1.83 (2H, m), 2.44 (3H, s), 3.20 - 3.09 (3H, m), 3.48 - 3.42 (3H, m), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.10 (IH, d), 4.42 (IH, s), 4.73 (IH, t), 6.23 (IH, t), 6.62 (IH, s), 7.17 (IH, ddd), 7.24 (IH, dd), 7.39 (2H, d), 7.85 - 7.80 (3H, m), 8.77 (IH, s); Example 82c: 1U NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 1.63 - 1.60 (2H, m), 1.85 - 1.83 (2H, m), 2.44 (3H, s), 3.13 (IH, ddd), 3.47 - 3.36 (3H, m), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.10 (IH, d), 4.55 - 4.40 (3H, m), 6.41 (IH, t), 6.63 (IH, s), 7.17 (IH, ddd), 7.24 (IH, dd), 7.40 (2H, d), 7.86 - 7.81 (3H, m), 8.78 (IH, s); Example 82d: 1R NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 1.63 - 1.60 (2H, m), 1.86 - 1.83 (2H, m), 2.44 (3H, s), 3.13 (IH, ddd), 3.62 - 3.42 (4H, m), 3.74 (IH, d), 3.95 (IH, dd), 4.10 (IH, d), 4.42 (IH, s), 6.07 (IH, ddt), 6.50 (IH, t), 6.63 (IH, s), 7.17 (IH, ddd), 7.24 (IH, dd), 7.41 (2H, d), 7.86 - 7.80 (3H, m), 8.90 (IH, s);
Example 82e: 1U NMR (400.132 MHz, DMSOd6) δ 1.07 (3H, t), 1.16 (3H, d), 1.63 - 1.60 (2H, m), 1.85 - 1.83 (2H, m), 2.44 (3H, s), 3.18 - 3.09 (3H, m), 3.44 (IH, ddd), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, ddd), 4.42 (IH, s), 6.13 (IH, t), 6.62 (IH, s), 7.17 (IH, ddd), 7.24 (IH, dd), 7.39 (2H, d), 7.84 - 7.81 (3H, m), 8.63 (IH, s);
Example 82f: 1R NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 1.64 - 1.61 (2H, m), 1.86 - 1.83 (2H, m), 2.45 (3H, s), 3.14 (IH, ddd), 3.45 (IH, ddd), 3.60 (IH, dd), 3.74 (IH, d), 3.79 (3H, s), 3.96 (IH, dd), 4.11 (IH, d), 4.43 (IH, s), 6.64 (IH, s), 7.18 (IH, ddd), 7.25 (IH, dd), 7.38 (IH, s), 7.45 (2H, d), 7.77 (IH, s), 7.88 - 7.81 (3H, m), 8.36 (IH, s), 8.81 (IH, s);
The preparation of phenyl Λ/-[4-[4-[l-(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(35)- 3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl A/-[4-[4-[ 1 -(4-fluoro-2-methylphenyl)sulfonylcvclopropyll-6-r(35)-3- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000863_0001
4-[4-[l-(4-Fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]aniline (as the hydrochloride salt) (1.8O g, 3.47 mmol) and sodium bicarbonate (2.91 g, 34.68 mmol) were added to DCM (60 mL) and stirred for 10 minutes. Phenyl chloro formate (0.566 mL, 4.51 mmol) was added slowly and the reaction stirred for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford an orange solid. The crude product was purified by flash silica chromatography, elution gradient 30 to 60% ethyl acetate in isohexane, to give the desired material as a yellow solid (1.73 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 1.65 - 1.62 (2H, m), 1.87 - 1.84 (2H, m), 2.45 (3H, s), 3.14 (IH, ddd), 3.49 - 3.42 (IH, m), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.12 (IH, d), 4.45 (IH, s), 6.67 (IH, s), 7.17 (IH, ddd), 7.30 - 7.23 (4H, m), 7.45 (2H, t), 7.54 (2H, d), 7.83 (IH, dd), 7.93 (2H, d), 10.40 (IH, s); LCMS Spectrum: m/z (ES+) (M+H)+ = 603; HPLC tR= 3.15 min
4-[4-[l-(4-Fluoro-2-methylphenvπsulfonylcvclopropyll-6-[(36f)-3-methylmorpholin-4- yllpyrimidin-2-vH aniline
Figure imgf000864_0001
tert-Butyl N-[4-[4-[ 1 -(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (2.03 g, 3.48 mmol) was added to 6.0 N hydrogen chloride in propan-2-ol (30 mL) and stirred for 2 hours at RT. The crude solution was triturated with diethyl ether to give the desired material (as the hydrochloride salt) as a white solid (1.80 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.04 (3H, d), 1.70 - 1.65 (2H, m),
1.89 - 1.86 (2H, m), 2.45 (3H, s), 3.22 (IH, ddd), 3.44 (IH, ddd), 3.59 (IH, dd), 3.75 (IH, d), 3.97 (IH, dd), 4.21 (IH, s), 4.50 (IH, s), 6.14 (2H, s), 6.70 (IH, s), 7.14 - 7.03 (2H, m), 7.21
(IH, t), 7.31 (IH, d), 7.82 (IH, dd), 7.93 (2H, d);
LCMS Spectrum: m/z (ES+) (M+H)+ = 483; HPLC tR= 2.67 min
tert-Butγ\ N-\4-\4-\ 1 -(4-fluoro-2-methylphenyl)sulfonylcvclopropyll-6-r(3^-3- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000864_0002
To tert-butyl N-[4-[4-[(4-fluoro-2-methylphenyl)sulfonylmethyl]-6-[(3)S)-3-methylmorpholin- 4-yl]pyrimidin-2-yl]phenyl]carbamate (3.36 g, 6.04 mmol) in DMF (30 mL) was added rapidly sodium hydride (1.159 g, 24.14 mmol), this was stirred at RT for 10 minutes before the slow addition 1 ,2-dibromoethane (2.081 mL, 24.14 mmol) in DMF (30 mL). The resulting suspension was stirred at RT for 1 hour. A further portion of sodium hydride (0.58 g, 12.07 mmol) and 1,2 dibromoethane (1.04 mL, 12.07 mmol) were rapidly added and the reaction was stirred for a further 30 minutes. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford brown gum. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% ethyl acetate in isohexane, to give the desired material as a white foam (2.05 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 1.49 (9H, s), 1.63 - 1.60 (2H, m), 1.86 - 1.83 (2H, m), 2.44 (3H, s), 3.13 (IH, ddd), 3.45 (IH, ddd), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.11 (IH, d), 4.43 (IH, s), 6.65 (IH, s), 7.17 (IH, ddd), 7.24 (IH, dd), 7.47 (2H, d), 7.82 (IH, dd), 7.86 (2H, d), 9.50 (IH, s); LCMS Spectrum: m/z (ES+) (M+H)+ = 583; HPLC tR= 3.17 min
tert-Butyl Λ/-r4-r4-r(4-fluoro-2-methylphenyl)sulfonylmethyll-6-r(36^-3-methylmorpholin-4- vllpyrimidin-2-yllphenyllcarbamate
Figure imgf000865_0001
Sodium 4-fluoro-2-methylbenzenesulfinate (1.663 g, 7.84 mmol) and tert-butyl Λ/-[4-[4- (iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate (4.0 g, 7.84 mmol) were dissolved in DMF (25 mL) and stirred for 1 hour at RT. The solvent was evaporated to afford a yellow solid. This was partitioned between aqueous sodium thiosulphate solution (50 mL) and DCM (75 mL). The organics were purified by flash silica chromatography, elution gradient 30 to 60% ethyl acetate in isohexane, to give the desired material as a white foam (4.20 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.49 (9H, s), 2.65 (3H, s), 3.16 (IH, ddd), 3.48 (IH, ddd), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.11 (IH, d), 4.39 (IH, s), 4.67 (2H, s), 6.67 (IH, s), 7.15 (IH, ddd), 7.39 (IH, dd), 7.45 (2H, d), 7.68 (IH, dd), 7.80 (2H, d), 9.50 (IH, s); LCMS Spectrum: m/z (ES+) (M+H)+ = 557; HPLC tR= 3.06 min
Sodium 4-fluoro-2-methylbenzenesulfinate
Figure imgf000866_0001
A solution of sodium sulfate (15.1O g, 119.82 mmol) in water (100 mL) was stirred at RT for 10 minutes. Sodium bicarbonate (20.13 g, 239.65 mmol) was added to the stirred solution. The resulting solution was stirred at 500C for 10 minutes. 4-Fluoro-2-methylbenzene-l- sulfonyl chloride (25 g, 119.82 mmol) was added portionwise to the solution and was stirred at 500C for 2 hours. The reaction mixture was evaporated to dryness and re-dissolved in ethanol (200 mL). The suspension was allowed to stir at RT for 20 minutes. The suspension was filtered and the filtrate evaporated to afford a white solid, this was stirred with acetonitrile (50 mL) and then filtered to afford the desired material as a white solid (17.5 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 2.46 (3H, s), 6.86 (IH, dd), 6.95 (IH, ddd), 7.66 (IH, dd);
The preparation of tert-butyl Λ/-[4-[4-(iodomethyl)-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] carbamate was described earlier.
Example 83 : 3-(2-HydroxyethyD-l- [4-[4- [(3S)-3-methylmorpholin-4-yH -6-(l-pyridin-4- ylsulfonylcyclobutyl)pyrimidin-2-yll phenyll urea
Figure imgf000866_0002
A solution of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclobuty^pyrimidin^-yljphenyljcarbamate (100 mg, 0.17 mmol) in NMP (2 mL) was treated with ethanolamine (11 mg, 0.18 mmol) and triethylamine (51 mg, 0.5 mmol) and stirred at RT overnight. The crude reaction mixture was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material (66mg).
NMR Spectrum: 1H NMR (400 MHz, DMSOd6) δ 1.20 - 1.22 (3H, m), 1.93 (IH, t), 2.11 - 2.16 (IH, m), 2.78 - 2.85 (2H, m), 3.09 - 3.19 (5H, m), 3.45 - 3.52 (3H, m), 3.63 - 3.66 (IH, 5 m), 3.75 - 3.78 (IH, m), 3.97 (IH, d), 4.15 - 4.19 (IH, m), 4.51 (IH, s), 4.78 (IH, s), 6.26 (IH, t), 6.63 (IH, s), 7.35 (2H, d), 7.46 (2H, d), 7.68 (2H, d), 8.72 (2H, d), 8.80 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 553.48; HPLC tR = 1.93 min.
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[(3S)-3- i o methylmorpholin-4-yl] -6-( 1 -pyridin-4-ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl] carbamate and the appropriate amine.
Figure imgf000867_0001
Figure imgf000868_0001
Example 83a: 1H NMR (400 MHz, DMSOd6) δ 1.07 - 1.09 (3H, m), 1.20 (3H, d), 1.91 - 1.93 (IH, m), 2.13 (IH, t), 2.78 - 2.85 (2H, m), 3.08 - 3.19 (3H, m), 3.38 - 3.41 (2H, m), 3.45
- 3.54 (IH, td), 3.60 - 3.82 (3H, m), 3.96 (IH, dd), 4.16 (IH, d), 4.50 (IH, s), 4.83 (IH, t), 6.09 - 6.11 (IH, m), 6.63 (IH, s), 7.34 (2H, d), 7.46 - 7.47 (2H, m), 7.68 (2H, d), 8.70 - 8.72 (3H, m)
Example 83b: 1H NMR (400 MHz, DMSOd6) δ 1.07 - 1.09 (3H, m), 1.20 (3H, d), 1.91 - 1.93 (IH, m), 2.13 (IH, t), 2.78 - 2.85 (2H, m), 3.08 - 3.19 (3H, m), 3.38 - 3.41 (2H, m), 3.45
- 3.54 (IH, td), 3.60 - 3.82 (3H, m), 3.96 (IH, dd), 4.16 (IH, d), 4.50 (IH, s), 4.83 (IH, t), 6.09 - 6.11 (IH, m), 6.63 (IH, s), 7.34 (2H, d), 7.46 - 7.47 (2H, m), 7.68 (2H, d), 8.70 - 8.72 (3H, m)
Example 83c: 1H NMR (400 MHz, DMSOd6) δ 1.21 (3H, d), 1.24 (6H, s), 1.91 - 1.93 (IH, m), 2.11 - 2.16 (IH, m), 2.77 - 2.84 (2H, m), 3.08 - 3.20 (3H, m), 3.39 (2H, d), 3.46 - 3.52 (IH, m), 3.62 - 3.66 (IH, m), 3.76 (IH, d), 3.95 - 3.99 (IH, m), 4.17 (IH, d), 4.51 (IH, s), 5.00 (IH, t), 6.00 (IH, s), 6.63 (IH, s), 7.29 - 7.32 (2H, m), 7.46 - 7.47 (2H, m), 7.65 - 7.67 (2H, m), 8.71 - 8.72 (3H, m)
Example 83d: 1H NMR (400 MHz, DMSOd6) δ 1.21 (3H, d), 1.92 (IH, q), 2.11 - 2.16 (1H, m), 2.81 (2H, s), 3.09 - 3.18 (3H, m), 3.49 (IH, t), 3.64 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.17 (IH, d), 4.32 (2H, d), 4.51 (IH, s), 6.64 (2H, s), 6.84 (IH, s), 7.04 (IH, s), 7.38 (2H, d), 7.46 (2H, d), 7.69 (2H, d), 8.72 (2H, d), 8.92 (IH, s), 11.87 (IH, s)
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl] carbamate is described below: Phenyl N-r4-r4-r(3y)-3-methylmorpholin-4-yl1-6-(l-pyridin-4- ylsulfonylcvclobutyl)pyrimidin-2-yllphenyllcarbamate
Figure imgf000869_0001
Phenyl chloro formate (0.241 mL, 1.92 mmol) was added dropwise to 4-[4-[(35)-3- methylmorpholin-4-yl]-6-(l-pyridin-4-ylsulfonylcyclobutyl)pyrimidin-2-yl] aniline (894 mg, 1.92 mmol) and sodium bicarbonate (161 mg, 1.92 mmol) in dioxane (10 mL) at RT under air. The resulting solution was stirred at RT for 2hours. The reaction was evaporated to dryness and the residue was taken up in water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with water, brine and then dried (MgSO4). The solution was evaporated to dryness and the crude material was chromatographed on a silica, eluting with 50% ethyl acetate in isohexane, to give the desired material as a cream coloured solid (690 mg).
NMR Spectrum: 1H NMR (400 MHz, DMSOd6) δ 1.17 - 1.23 (3H, m), 1.90 - 1.92 (IH, m), 2.00 (IH, s), 2.12 (IH, t), 2.77 - 2.83 (2H, m), 3.06 - 3.17 (3H, m), 3.47 - 3.50 (IH, m), 3.61 - 3.65 (IH, m), 3.75 (IH, d), 3.94 - 3.98 (IH, m), 4.15 (IH, d), 4.50 (IH, s), 5.54 (IH, d), 6.46 (IH, d), 6.53 (IH, s), 6.75 - 6.79 (2H, m), 7.15 - 7.19 (IH, m), 7.43 - 7.49 (2H, m), 7.49 (IH, d), 7.53 (IH, s), 8.70 - 8.72 (2H, m), 9.34 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 586.18; HPLC tR = 2.87 min.
The preparation of 4-[4-[(35)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclobutyl)pyrimidin-2-yl]aniline was described earlier. Example 84: l-[4-[4-K3S)-3-Ethylmorpholin-4-yll-6-(l- methylsulfonylcvclopropyl)pyrimidin-2-yll phenyll -3-methylurea
Figure imgf000870_0001
Phenyl N- [4- [4- [(35)-3 -ethylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yljphenyl] carbamate (54.0 mg, 0.10 mmol), triethylamine (0.043 mL, 0.31 mmol) and methyl amine (-, 0.31 mmol) were dissolved in dioxane (10 mL) and heated at 50 °C over the weekend. The reaction was evaporated to dryness and was purified by preparative HPLC (Waters XTerra Cl 8 column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-l-(4-(4-(3-ethylmorpholino)-6-(l- (methylsulfonyl)cyclopropyl)pyrimidin-2-yl)phenyl)-3-methylurea as a white solid. NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.89 (3H, t), 1.56 - 1.54 (2H, m), 1.69 - 1.64 (2H, m), 1.83 - 1.69 (2H, m), 2.66 (3H, d), 3.22 - 3.14 (IH, m), 3.27 (3H, s), 3.47 (IH, ddd), 3.55 (IH, dd), 3.87 (IH, d), 3.93 (IH, dd), 4.41 - 4.27 (2H, m), 6.07 (IH, q), 6.78 (IH, s), 7.50 (2H, d), 8.19 (2H, d), 8.74 (IH, s);
LCMS Spectrum: m/z (ESI+) (M+H)+ = 460; HPLC tR = 1.98 min.
The following compounds were prepared in an analogous fashion from phenyl N- [4- [4- [(3S)- 3 -ethylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2 -yljphenyl] carbamate and the appropriate amine.
Figure imgf000870_0002
Figure imgf000871_0001
Example 84a: 1H NMR (400.132 MHz, DMSOd6) δ 0.44 - 0.40 (2H, m), 0.65 - 0.64 (2H, m), 0.89 (3H, t), 1.57 - 1.53 (2H, m), 1.66 (2H, m), 1.68 - 1.64 (2H, m), 3.23 - 3.14 (IH, m), 3.50 - 3.44 (IH, m), 3.55 (IH, dd), 3.87 (IH, d), 3.94 - 3.92 (IH, m), 4.47 - 4.22 (2H, m), 6.44 (IH, s), 6.78 (IH, s), 7.51 (2H, d), 8.19 (2H, d), 8.54 (IH, s); 4 protons missing due to very weak sample! !
Example 84b: 1R NMR (400.132 MHz, DMSOd6) δ 0.89 (3H, t), 1.57 - 1.53 (2H, m), 1.69 - 1.64 (2H, m), 1.83 - 1.71 (2H, m), 3.22 - 3.16 (3H, m), 3.27 (3H, s), 3.49 - 3.44 (3H, m), 3.55 (IH, dd), 3.87 (IH, d), 3.94 - 3.92 (IH, m), 4.39 - 4.24 (2H, m), 4.73 (IH, t), 6.25 (IH, t), 6.78 (IH, s), 7.49 (2H, d), 8.19 (2H, d), 8.80 (IH, s);
Example 84c: 1U NMR (400.132 MHz, DMSOd6) δ 0.89 (3H, t), 1.58 - 1.54 (2H, m), 1.69 - 1.64 (2H, m), 1.83 - 1.69 (2H, m), 3.22 - 3.17 (IH, m), 3.29 (s, 3H), 3.49 - 3.37 (3H, m), 3.55 (IH, dd), 3.87 (IH, d), 3.94 - 3.92 (IH, m), 4.40 - 4.16 (2H, m), 4.48 (2H, dt), 6.44 (IH, t), 6.78 (IH, s), 7.50 (2H, d), 8.20 (2H, d), 8.81 (IH, s); Example 84d: 1R NMR (400.132 MHz, DMSOd6) δ 0.89 (3H, t), 1.57 - 1.54 (2H, m), 1.67 -
1.64 (2H, m), 1.83 - 1.69 (2H, m), 3.22 - 3.16 (IH, m), 3.29 (3H, s), 3.60 - 3.44 (4H, m), 3.87 (IH, d), 3.93 (IH, dd), 4.48 - 4.21 (2H, m), 6.07 (IH, tt), 6.53 (IH, t), 6.79 (IH, s), 7.51 (2H, d), 8.21 (2H, d), 8.92 (IH, s);
Example 84e: 1U NMR (400.132 MHz, DMSOd6) δ 0.89 (3H, t), 1.07 (3H, t), 1.56 - 1.54 (2H, m), 1.68 - 1.65 (2H, m), 1.83 - 1.69 (2H, m), 3.22 - 3.09 (3H, m), 3.29 (3H, s), 3.47 (IH, ddd), 3.55 (IH, dd), 3.87 (IH, d), 3.93 (IH, dd), 4.40 - 4.24 (2H, m), 6.16 (IH, t), 6.78 (IH, s), 7.50 (2H, d), 8.19 (2H, d), 8.66 (IH, s); Example 84f: 1U NMR (400.132 MHz, DMSOd6) δ 0.89 (3H, t), 1.57 - 1.54 (2H, m), 1.69 -
1.65 (2H, m), 1.84 - 1.70 (2H, m), 3.23 - 3.17 (IH, m), 3.47 (IH, ddd), 3.56 (IH, dd), 3.79 (3H, s), 3.88 (IH, d), 3.94 (IH, dd), 4.41 - 4.23 (2H, m), 6.80 (IH, s), 7.38 (IH, s), 7.55 (2H, d), 7.76 (IH, s), 8.23 (2H, d), 8.39 (IH, s), 8.84 (IH, s); Methyl sulfone hidden under water peak (3H missing).
The preparation of phenyl Λ/-[4-[4-[(35)-3-ethylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N- [4- [4- [(36^-3 -ethylmorpholin-4-yll-6-(l-methylsulfonylcvclopropyl)pyrimidin-2- yllphenyll carbamate
Figure imgf000872_0001
4-[4-[(35)-3-Ethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2-yl]aniline (as the hydrochloride salt) (0.43 g, 0.98 mmol) and sodium bicarbonate (0.823 g, 9.80 mmol) were added to DCM (60 mL) and stirred for 10 minutes. Phenyl chloro formate (0.160 mL, 1.27 mmol) was added slowly and the reaction stirred for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford an orange solid. The crude product was purified by flash silica chromatography, elution gradient 30 to 60% ethyl acetate in isohexane, to give the desired material as a yellow solid (0.46 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.89 (3H, t), 1.58 - 1.55 (2H, m), 1.69 - 1.65 (2H, m), 1.84 - 1.70 (2H, m), 3.20 (IH, ddd), 3.27 (3H, s), 3.47 (IH, ddd), 3.56 (IH, dd), 3.87 (IH, d), 3.93 (IH, dd), 4.41 - 4.24 (2H, m), 6.82 (IH, s), 7.30 - 7.24 (3H, m), 7.45 (2H, t), 7.64 (2H, d), 8.29 (2H, d), 10.44 (IH, s); LCMS Spectrum: m/z (ESI+) (M+H)+ = 523; HPLC tR = 2.85 min.
4-r4-r(35)-3-Ethylmorpholin-4-yll-6-(l-methylsulfonylcvclopropyl)pyrimidin-2-yllaniline
Figure imgf000873_0001
tert-Butyl N- [4- [4- [(35)-3 -ethylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl] carbamate (0.5 g, 0.99 mmol) was added to 6.0 N hydrogen chloride in propan-2-ol (30 mL) and stirred for 2 hours at RT. The crude solution was triturated with diethyl ether to give the desired material (as the hydrochloride salt) as a yellow solid (0.43 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.89 (3H, t), 1.65 - 1.60 (2H, m), 1.75 - 1.67 (2H, m), 1.83 - 1.80 (2H, m), 3.24 (3H, s), 3.38 - 3.28 (IH, m), 3.52 - 3.46 (IH, m), 3.58 (IH, dd), 3.89 (IH, d), 3.96 (IH, dd), 4.48 - 4.33 (2H, m), 7.09 - 6.98 (3H, m), 8.21 - 8.08 (2H, m); NH2 missing; LCMS Spectrum: m/z (ESI+) (M+H)+ = 403; HPLC tR = 2.23 min. te^Butyl Λ/-r4-r4-r(36^-3-ethylmorpholin-4-yll-6-(l-methylsulfonylcvclopropyl)pyrimidin-2- yllphenyll carbamate
Figure imgf000874_0001
Sodium hydride (0.705 g, 14.69 mmol) was added rapidly to tert-butyl N-[4-[4-[(3S)-3- ethylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]carbamate (1.75 g, 3.67 mmol) in DMF (30 mL) and the mixture stirred at RT for 10 minutes before the slow addition 1 ,2-dibromoethane (1.266 mL, 14.69 mmol) in DMF (30 mL). The resulting suspension was stirred at RT for 1 hour. The reaction was heated to 400C and a further portion of sodium hydride (2.0 eq) and 1,2 dibromoethane (2.0 eq) were rapidly added and the reaction was stirred for a further 30 minutes. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford brown gum. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% ethyl acetate in isohexane, to give the desired material as a yellow foam (0.30 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.89 (3H, t), 1.50 (9H, s), 1.57 - 1.54 (2H, m), 1.68 - 1.66 (2H, m), 1.83 - 1.70 (2H, m), 3.22 - 3.16 (IH, m), 3.50 - 3.44 (IH, m), 3.57 - 3.53 (IH, m), 3.87 (IH, d), 3.94 - 3.92 (IH, m), 4.38 - 4.24 (2H, m), 6.80 (IH, s), 7.57 (2H, d), 8.21 (2H, d), 9.55 (IH, s); methyl peak under water (3H missing).
tert-Butyl N- [4- [4- [(35)-3 -ethylmorpholin-4-yll -6-(methylsulfonylmethyl)pyrimidin-2- yllphenyll carbamate
Figure imgf000874_0002
tert-Butyl Λ/-[4-[4-[(35)-3-ethylmorpholin-4-yl]-6-(iodomethyl)pyrimidin-2- yl]phenyl]carbamate (2.0 g, 3.81 mmol) and sodium methanesulfinate (0.389 g, 3.81 mmol) were dissolved in DMF (25 mL) and stirred for 1 hour at RT. The solvent was evaporated to afford a yellow solid which was partitioned between aqueous sodium thiosulphate solution (50 mL) and DCM (75 mL). The layers were separated, the aquoes layer further extracted with DCM (75 mL), the combined organics purified by flash silica chromatography, elution gradient 30 to 60% ethyl acetate in isohexane, to give the desired material as a white foam
(1-V g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 0.90 (3H, t), 1.50 (9H, s), 1.73 - 1.64 (IH, m), 1.85 - 1.78 (IH, m), 3.24 - 3.18 (4H, m), 3.48 (IH, ddd), 3.57 (IH, dd), 3.89 (IH, d), 3.95 (IH, dd), 4.30 (2H, s), 4.48 (2H, s), 6.80 (IH, s), 7.57 (2H, d), 8.23 (2H, d), 9.55 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 477; HPLC tR = 2.67 min.
The preparation of tert-butyl Λ/-[4-[4-[(35)-3-ethylmorpholin-4-yl]-6-(iodomethyl)pyrimidin- 2-yl]phenyl] carbamate was described earlier.
Example 85 : 3-Chloro-4- [ 1- [2- [4-(methylcarbamoylamino)phenyll -6- [(3S)-3- methylmorpholin-4-yll pyrimidin-4-yll cyclopropyll sulfonylbenzamide
Figure imgf000875_0001
Methylamine (0.347 mL, 0.69 mmol) was added to phenyl Λ/-[4-[4-[l-(4-carbamoyl-2- chlorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yljphenyl] carbamate (150 mg, 0.23 mmol) and triethylamine (0.096 mL, 0.69 mmol) in DMF
(0.714 mL) and resulting solution was stirred at 500C for 2 hours. The crude mixture was purified by prep HPLC to give the desired material.
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.15 (3H, d), 1.72 - 1.76 (2H, m),
1.99 - 2.02 (2H, m), 2.65 (3H, d), 3.09 - 3.17 (IH, m), 3.44 (IH, dt), 3.59 (IH, dd), 3.73 (IH, d), 3.94 (IH, d), 4.09 (IH, d), 4.41 (IH, s), 6.03 - 6.07 (IH, m), 6.61 (IH, s), 7.35 (2H, d),
7.67 (IH, s), 7.74 (2H, d), 7.88 (IH, dd), 7.99 (IH, d), 8.12 (IH, d), 8.20 (IH, s), 8.68 (IH, s)
LCMS Spectrum: m/z (ES+) (M+H)+ = 586; HPLC tR= 1.86 min. The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[l-(4- carbamoyl-2-chlorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin- 2-yl]phenyl] carbamate or phenyl N-[4-[4-[l-(2-chloro-4-cyanophenyl)sulfonylcyclopropyl]-6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate and the appropriate amine.
Figure imgf000876_0001
Figure imgf000877_0001
Example 85a: 1R NMR (400.132 MHz, DMSOd6) δ 1.06 (3H, t), 1.15 (3H, d), 1.72 - 1.76 (2H, m), 1.99 - 2.02 (2H, m), 3.09 - 3.18 (3H, m), 3.44 (IH, dt), 3.59 (IH, dd), 3.73 (IH, d), 3.94 (IH, d), 4.09 (IH, d), 4.41 (IH, s), 6.13 (IH, t), 6.61 (IH, s), 7.34 (2H, d), 7.67 (IH, s), 7.74 (2H, d), 7.88 (IH, dd), 7.99 (IH, d), 8.12 (IH, d), 8.21 (IH, s), 8.60 (IH, s) Example 85b: 1H NMR (400.132 MHz, DMSO-d6) δ 0.39 - 0.43 (2H, m), 0.62 - 0.67 (2H, m), 1.15 (3H, d), 1.72 - 1.76 (2H, m), 1.99 - 2.02 (2H, m), 2.54 - 2.55 (IH, m), 3.13 (IH, dt), 3.44 (IH, dt), 3.59 (IH, dd), 3.73 (IH, d), 3.94 (IH, dd), 4.09 (IH, d), 4.41 (IH, s), 6.40 (IH, d), 6.62 (IH, s), 7.35 (2H, d), 7.67 (IH, s), 7.74 (2H, d), 7.88 (IH, dd), 7.99 (IH, d), 8.12 (IH, d), 8.21 (IH, s), 8.48 (IH, s)
Example 85c: 1R NMR (400.132 MHz, CDCl3) δ 1.29 (3H, d), 1.54 - 1.56 (2H, m), 2.15 - 2.19 (2H, m), 3.27 (IH, dt), 3.51 - 3.62 (2H, m), 3.72 (IH, dd), 3.81 (IH, d), 4.02 (IH, dd), 4.08 (IH, d), 4.40 (IH, s), 4.46 (IH, t), 4.58 (IH, t), 5.63 (IH, t), 6.58 (IH, s), 7.17 (IH, s), 7.17 (IH, s), 7.24 (2H, d), 7.45 - 7.56 (2H, m), 7.64 - 7.69 (IH, m), 7.84 - 7.88 (2H, m), 7.90 (2H, d)
Example 85d: 1H NMR (400.132 MHz, DMSOd6) δ 1.15 (3H, d), 1.72 - 1.76 (2H, m), 1.99 -
2.02 (2H, m), 3.09 - 3.12 (IH, m), 3.15 - 3.19 (2H, m), 3.43 - 3.48 (3H, m), 3.59 (IH, dd), 3.73 (IH, d), 3.93 (IH, dd), 4.09 (IH, d), 4.41 (IH, s), 4.72 (IH, t), 6.24 (IH, t), 6.61 (IH, s), 7.33 (2H, d), 7.66 (IH, s), 7.74 (2H, d), 7.88 (IH, dd), 7.99 (IH, d), 8.12 (IH, d), 8.21 (IH, s), 8.74 (IH, s)
Example 85e: 1R NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.72 - 1.78 (2H, m), 2.00 -
2.03 (2H, m), 2.66 (3H, d), 3.10 - 3.15 (IH, m), 3.45 (IH, dt), 3.60 (IH, dd), 3.74 (IH, d), 4.06 (IH, q), 4.14 (IH, d), 4.47 (IH, s), 6.04 - 6.09 (IH, m), 6.66 (IH, s), 7.38 (2H, d), 7.66 (2H, d), 7.90 (IH, d), 8.02 (IH, d), 8.34 (IH, d), 8.71 (IH, s) Example 85f: 1H NMR (400.132 MHz, DMSOd6) δ 1.07 (3H, t), 1.18 (3H, d), 1.73 - 1.77 (2H, m), 1.99 - 2.03 (2H, m), 3.09 - 3.16 (2H, m), 3.16 - 3.19 (IH, m), 3.45 (IH, dt), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.14 (IH, d), 4.47 (IH, s), 6.16 (IH, t), 6.66 (IH, s), 7.37 (2H, d), 7.66 (2H, d), 7.90 (IH, dd), 8.02 (IH, d), 8.35 (IH, d), 8.62 (IH, s) Example 85g: 1U NMR (400.132 MHz, DMSOd6) δ 0.40 - 0.44 (2H, m), 0.62 - 0.67 (2H, m), 1.18 (3H, d), 1.73 - 1.77 (2H, m), 2.00 - 2.03 (2H, m), 2.53 - 2.59 (IH, m), 3.11 - 3.18 (IH, m), 3.45 (IH, dt), 3.58 - 3.62 (IH, m), 3.74 (IH, d), 3.95 (IH, dd), 4.14 (IH, d), 4.47 (IH, s), 6.42 (IH, d), 6.66 (IH, s), 7.38 (2H, d), 7.66 (2H, d), 7.90 (IH, dd), 8.02 (IH, d), 8.35 (IH, d), 8.50 (IH, s) Example 85h: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.73 - 1.77 (2H, m), 2.00 - 2.03 (2H, m), 3.15 (IH, dt), 3.42 - 3.51 (IH, m), 3.54 - 3.62 (3H, m), 3.74 (IH, d), 3.95 (IH, dd), 4.15 (IH, d), 4.47 (IH, s), 6.07 (IH, app t), 6.53 (IH, t), 6.67 (IH, s), 7.39 (2H, d), 7.68 (2H, d), 7.90 (IH, dd), 8.02 (IH, d), 8.35 (IH, d), 8.89 (IH, s) Example 85i: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18 (3H, d), 1.73 - 1.77 (2H, m), 2.00 - 2.03 (2H, m), 3.15 (IH, dt), 3.39 (IH, q), 3.42 - 3.48 (2H, m), 3.60 (IH, dd), 3.74 (IH, d), 3.96 (IH, dd), 4.14 (IH, d), 4.42 (IH, t), 4.48 (IH, s), 4.53 (IH, t), 6.44 (IH, t), 6.66 (IH, s), 7.38 (2H, d), 7.67 (2H, d), 7.90 (IH, dd), 8.02 (IH, d), 8.35 (IH, d), 8.77 (IH, s) Example 85j: 1R NMR (400.132 MHz, DMSO-de) δ 1.18 (3H, d), 1.73 - 1.77 (2H, m), 2.00 ■ 2.03 (2H, m), 3.14 - 3.20 (3H, m), 3.43 - 3.48 (3H, m), 3.60 (IH, dd), 3.74 (IH, d), 3.95 (IH, dd), 4.14 (IH, d), 4.48 (IH, s), 4.73 (IH, t), 6.26 (IH, t), 6.66 (IH, s), 7.37 (2H, d), 7.66 (2H, d), 7.90 (IH, dd), 8.02 (IH, d), 8.35 (IH, d), 8.77 (IH, s)
The preparation of phenyl Λ/-[4-[4-[l-(4-carbamoyl-2-chlorophenyl)sulfonylcyclopropyl]-6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl Λ/-[4-[4-[ 1 -(4-carbamoyl-2-chlorophenv0sulfonylcvclopropyl"|-6-r(3ιSy3- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000879_0001
Sodium bicarbonate (0.263 g, 3.12 mmol) was added to 4-[l-[2-(4-aminophenyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonyl-3-chlorobenzamide (1.1 g, 2.08 mmol), in 1,4-dioxane (10.15 mL) and to the resulting suspension was added phenyl chloroformate (0.262 mL, 2.08 mmol) dropwise over 2 minutes. The reaction was stirred at RT for 2 hours then evaporated to dryness and the residue redissolved in DCM (20 mL), and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford a solid which was triturated with diethyl ether to give the desired material as a beige solid (0.9 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.16 (3H, d), 1.73 - 1.77 (2H, m), 1.99 - 2.03 (2H, m), 3.12 - 3.17 (IH, m), 3.40 - 3.47 (IH, m), 3.57 - 3.61 (IH, m), 3.73 (IH, d), 3.91 - 3.96 (IH, m), 4.06 - 4.10 (IH, m), 4.44 (IH, s), 6.67 (IH, s), 7.24 - 7.30 (2H, m), 7.45 (2H, t), 7.50 (2H, d), 7.85 (2H, d), 7.88 - 7.90 (IH, m), 8.00 (IH, d), 8.13 (IH, d), 8.22 (IH, s), 10.40 (IH, s) LCMS Spectrum: m/z (ES+) (M+H)+ = 648; HPLC tR= 2.62 min.
4-ri-r2-(4-Aminophenyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4- yl] cvclopropyl] sulfonyl-3 -chlorobenzamide
Figure imgf000880_0001
Bis(triphenylphosphine)palladium(II) chloride (0.271 g, 0.39 mmol) was added to 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (2.199 g, 10.04 mmol) and 3-chloro-4-[l-[2- chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonylbenzonitrile (3.5 g, 7.72 mmol) and 2M aqueous solution of sodium carbonate (11.58 mL, 23.16 mmol) in a solvent mixture of DME (20 mL), ethanol (10 mL) and water (10 mL) and the resulting mixture stirred at 95°C for 16 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2 x 20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanol in DCM, to give the desired material as a brown solid (1.1 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.13 (3H, d), 1.71 - 1.73 (2H, m), 1.97 - 2.01 (2H, m), 3.06 - 3.13 (IH, m), 3.37 - 3.45 (IH, m), 3.58 (IH, dd), 3.72 (IH, d), 3.92 - 3.94 (IH, m), 4.04 - 4.08 (IH, m), 4.37 (IH, s), 5.48 (2H, s), 6.50 (IH, s), 7.58 (2H, d), 7.89 (IH, dd), 8.00 (2H, d), 8.11 (IH, d), 8.21 (IH, s) LCMS Spectrum: m/z (ES+) (M+H)+ = 528; HPLC tR= 1.99 min.
3 -Chloro-4- r 1 - [2-ChIOrO-O- r(3ιSV3 -methylmorpholin^-yllpyrimidin^- yllcvclopropyllsulfonylbenzonitrile
Figure imgf000880_0002
1,2-Dibromoethane (1.654 ml, 19.19 mmol) was added to 3-chloro-4-[[2-chloro-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]benzonitrile (4.1 g, 9.60 mmol), sodium hydroxide (50% w/w) (9.60 mL, 95.95 mmol) and tetrabutylammonium bromide (0.619 g, 1.92 mmol) in DCM and the resulting solution stirred at 400C for 5 hours. The reaction mixture was washed sequentially with water (200 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 50% ethyl acetate in DCM, to give the desired material as a cream solid (3.50 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.15 (3H, d), 1.68 - 1.72 (2H, m), 1.95 - 1.98 (2H, m), 3.11 - 3.17 (IH, m), 3.29 - 3.30 (IH, m), 3.39 (IH, dt), 3.54 (IH, dd), 3.69 (IH, d), 3.91 (IH, dd), 4.30 (IH, s), 6.76 (IH, s), 8.03 (2H, s), 8.33 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 453; HPLC tR = 2.41 min.
3-Chloro-4-rr2-chloro-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-4- yllmethylsulfonyllbenzonitrile
Figure imgf000881_0001
Sodium 2-chloro-4-cyanobenzenesulfmate (4.43 g, 19.80 mmol) was added in one portion to 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (7 g, 19.80 mmol) in acetonitrile (99 mL) and the resulting suspension stirred at 800C for 6 hours. The reaction mixture was evaporated to dryness, redissolved in DCM (200 mL) and washed with water (200 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a cream solid (6.20 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18 (3H, d), 3.15 - 3.21 (IH, m), 3.43 (IH, dt), 3.58 (IH, dd), 3.72 (IH, d), 3.93 (2H, m), 4.24 (IH, s), 4.86 (2H, s), 6.87 (IH, s), 7.96 (IH, d), 8.06 (IH, dd), 8.43 (IH, d) LCMS Spectrum: m/z (ESI+) (M+H)+ = 427; HPLC tR = 2.28 min. Sodium 2-chloro-4-cyanobenzenesulfinate
Figure imgf000882_0001
A solution of sodium sulfite (6.02 g, 47.74 mmol) in water (100 mL) was stirred at RT for 10 minutes. Sodium bicarbonate (8.02 g, 95.48 mmol) was added to the stirred solution. The resulting solution was stirred at 500C for 10 minutes. 2-Chloro-4-cyanobenzene-l-sulfonyl chloride (11.27 g, 47.74 mmol) was added dropwise to the solution and was stirred at 500C for 2 hours. The reaction mixture was evaporated to dryness and redissolved in ethanol (200 mL). The suspension was allowed to stir at RT for 20 minutes. The suspension was filtered and the filtrate evaporated to afford a white solid, this was stirred with acetonitrile (50 mL) and then filtered to afford the desired material as a white solid (10.0 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 7.80 - 7.77 (2H, m), 7.84 (IH, d)
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
The preparation of phenyl Λ/-[4-[4-[l-(2-chloro-4-cyanophenyl)sulfonylcyclopropyl]-6-[(35)- 3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N-\4-\4-\ 1 -(2-chloro-4-cvanophenyl)sulfonylcvclopropyll-6-r(36^-3- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000882_0002
Sodium bicarbonate (1.400 g, 16.67 mmol) was added to 4-[l-[2-(4-aminophenyl)-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonyl-3-chlorobenzonitrile (1.7 g, 3.33 mmol), in 1,4-dioxane (16.25 mL) and to the resulting suspension was added phenyl chloro formate (0.42 mL, 3.33 mmol) dropwise over 2 minutes. The reaction was stirred at RT for 2 hours then evaporated to dryness, the residue redissolved in DCM (20 mL), and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford a solid which was triturated with diethyl ether to give the desired material as a cream solid (1.4 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.76 - 1.80 (2H, m), 2.01 - 2.04 (2H, m), 3.14 - 3.19 (IH, m), 3.43 - 3.48 (IH, m), 3.59 - 3.62 (IH, m), 3.74 (IH, d), 3.94 - 3.97 (IH, m), 4.16 (IH, d), 4.49 (IH, s), 6.71 (IH, s), 7.24 - 7.30 (3H, m), 7.45 (2H, t), 7.53 (2H, d), 7.77 (2H, d), 7.90 - 7.92 (IH, m), 8.02 (IH, d), 8.35 (IH, d), 10.44 (IH, s) LCMS Spectrum: m/z (ES+) (M+H)+ = 630; HPLC tR= 3.02 min.
4-[l-[2-(4-Aminophenvπ-6-[(36f)-3-methylmorpholin-4-yllpyrimidin-4- yl] cvclopropyl] sulfonyl-3 -chlorobenzonitrile
Figure imgf000883_0001
tert-Butyl N-[4-[4-[ 1 -(2-chloro-4-cyanophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (3.4 g, 5.57 mmol) was dissolved in methanol (17.86 mL) and to this was added 6 N hydrogen chloride in propan-2-ol (10 mL) and the reaction stirred for 2 hours at RT. The crude solution was triturated with diethyl ether to give the desired material as a white solid (3.50 g). The material was used without further purification. MR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.76 - 1.79 (2H, m), 2.01 - 2.04 (2H, m), 3.18 - 3.24 (IH, m), 3.42 - 3.48 (IH, m), 3.60 (IH, dd), 3.74 - 3.77 (IH, m),
3.94 - 3.98 (IH, m), 4.20 (IH, s), 4.51 (IH, s), 6.76 (IH, s), 7.11 - 7.14 (2H, m), 7.86 (2H, d),
7.95 - 7.97 (2H, m), 8.07 (IH, d), 8.37 (IH, d)
LCMS Spectrum: m/z (ES+) (M+H)+ = 510; HPLC tR= 2.49 min. tert-Butγ\ N-\4-\4-\ 1 -(2-chloro-4-cvanophenv0sulfonylcvclopropyl"|-6-r(3ιSy3- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000884_0001
Sodium hydride (1.282 g, 26.71 mmol) was added rapidly to tert-butyl 7V-[4-[4-[(2-chloro-4- cyanophenyl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate (3.9 g, 6.68 mmol) in DMF (70 mL) and the mixture stirred at RT for 10 minutes before the slow addition 1 ,2-dibromoethane (2.302 mL, 26.71 mmol) in DMF (70 mL) at RT. The resulting suspension was stirred at RT for 90 minutes. A further portion of sodium hydride (1.0 eq) and 1,2 dibromoethane (1.0 eq) were rapidly added and the reaction was stirred for a further 30 minutes. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford brown gum. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% ethyl acetate in isohexane, to give the desired material as a yellow solid (3.40 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.50 (9H, s), 1.73 - 1.78 (2H, m), 1.99 - 2.05 (2H, m), 3.12 - 3.18 (IH, m), 3.45 (IH, t), 3.60 (IH, d), 3.74 (IH, d), 3.95 (IH, d), 4.15 (IH, d), 4.48 (IH, s), 6.68 (IH, s), 7.45 (2H, d), 7.69 (2H, d), 7.90 (IH, d), 8.01 (IH, d), 8.35 (IH, s), 9.52 (IH, s) LCMS Spectrum: m/z (ES+) (M+H)+ = 610; HPLC tR= 3.10 min.
tert-Butyl Λ/-r4-r4-r(2-chloro-4-cvanophenyl)sulfonylmethyll-6-r(36f)-3-methylmorpholin-4- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000884_0002
Sodium 2-chloro-4-cyanobenzenesulfinate (1.753 g, 7.84 mmol) and tert-butyl 7V-[4-[4- (iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (4 g, 7.84 mmol) were dissolved in DMF (50 mL) and stirred for 1 hour at RT. The solvent was evaporated to afford a yellow solid which was partitioned between water (50 mL) and DCM (75 mL). The layers were separated, the aqueous layer extracted with DCM (75 mL) and the combined organics concentrated in vacuo to give a yellow solid. This was rapidly stirred with ether (100 mL), to afford the desired material as an off white solid (3.90 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.49 (9H, s), 3.19 (IH, dt), 3.48 (IH, dt), 3.63 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.13 (IH, d), 4.41 (IH, s), 4.97 (2H, s), 6.79 (IH, s), 7.43 (2H, d), 7.61 (2H, d), 7.86 (IH, d), 7.91 (IH, dd), 8.53 (IH, d), 9.54 (IH, s) LCMS Spectrum: m/z (ES+) (M+H)+ = 583.94; HPLC tR= 3.07 min.
The preparation of tert-butyl Λ/-[4-[4-(iodomethyl)-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] carbamate was described earlier.
Example 86 : 1- [4- [4- [ l-α^-DifluorophenvDsulfonylcvclopropyll -6- \(3S)-3- methylmorpholin-4-yll pyrimidin-2-yll phenyll -3-methylurea
Figure imgf000885_0001
Phenyl 7V-[4-[4-[ 1 -(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate (0.15 g, 0.25 mmol), triethylamine (0.103 mL, 0.74 mmol) and methylamine (0.74 mmol) were dissolved in dioxane (10 mL) and stirred at RT overnight. The reaction was evaporated to dryness and was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid.
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.69 - 1.67 (2H, m), 1.94 - 1.91 (2H, m), 2.66 (3H, d), 3.17 (IH, ddd), 3.47 (IH, ddd), 3.62 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.16 (IH, d), 4.49 (IH, s), 6.04 (IH, q), 6.74 (IH, s), 7.25 (2H, t), 7.35 (2H, d),
7.80 - 7.73 (3H, m), 8.69 (IH, s);
LCMS Spectrum: m/z (ESI+) (M+H)+ = 544; HPLC tR = 1.82 min
The following compounds were prepared in an analogous fashion from phenyl N-[4-[4-[l- (2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000886_0001
Figure imgf000887_0001
Example 86a: 1R NMR (400.132 MHz, DMSOd6) δ 1.06 (3H, t), 1.20 (3H, d), 1.71 - 1.65 (2H, m), 1.93 - 1.89 (2H, m), 3.20 - 3.09 (3H, m), 3.47 (IH, ddd), 3.62 (IH, dd), 3.75 (IH, d), 3.96 (2H, ddd), 4.48 (IH, s), 6.14 (IH, t), 6.74 (IH, s), 7.25 (2H, t), 7.35 (2H, d), 7.80 - 7.73 (3H, m), 8.61 (IH, s);
Example 86b: 1R NMR (400.132 MHz, DMSOd6) δ 0.43 - 0.39 (2H, m), 0.67 - 0.62 (2H, m), 1.20 (3H, d), 1.71 - 1.65 (2H, m), 1.92 - 1.91 (2H, m), 2.57 - 2.54 (IH, m), 3.17 (IH, ddd), 3.47 (IH, ddd), 3.62 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.16 (IH, d), 4.48 (IH, s), 6.40 (IH, s), 6.75 (IH, s), 7.25 (2H, t), 7.36 (2H, d), 7.80 - 7.73 (3H, m), 8.49 (IH, s);
Example 86c: 1R NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.71 - 1.65 (2H, m), 1.94 -
1.88 (2H, m), 3.21 - 3.14 (3H, m), 3.50 - 3.44 (3H, m), 3.62 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.16 (IH, d), 4.48 (IH, s), 4.72 (IH, t), 6.23 (IH, t), 6.74 (IH, s), 7.25 (2H, t), 7.34 (2H, d), 7.80 - 7.73 (3H, m), 8.75 (IH, s); Example 86d: 1R NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.69 - 1.67 (2H, m), 1.93 -
1.89 (2H, m), 3.17 (IH, ddd), 3.50 - 3.36 (3H, m), 3.62 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.16 (IH, d), 4.47 (2H, tt), 4.49 (IH, s), 6.41 (IH, t), 6.75 (IH, s), 7.25 (2H, t), 7.36 (2H, d), 7.80 - 7.74 (3H, m), 8.76 (IH, s);
Example 86e: 1R NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.69 - 1.67 (2H, m), 1.93 - 1.89 (2H, m), 3.17 (IH, ddd), 3.59 - 3.44 (3H, m), 3.62 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.16 (IH, d), 4.48 (IH, s), 6.07 (IH, tt), 6.51 (IH, t), 6.75 (IH, s), 7.25 (2H, t), 7.37 (2H, d), 7.80 - 7.72 (3H, m), 8.87 (IH, s);
Example 86f: 1U NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.70 - 1.68 (2H, m), 1.94 - 1.89 (2H, m), 3.18 (IH, ddd), 3.47 (IH, ddd), 3.63 (IH, dd), 3.76 (IH, d), 3.79 (3H, s), 3.97 (IH, dd), 4.16 (IH, d), 4.49 (IH, s), 6.76 (IH, s), 7.26 (2H, t), 7.41 - 7.38 (3H, m), 7.80 - 7.73 (4H, m), 8.36 (IH, s), 8.79 (IH, s).
The preparation of phenyl Λ/-[4-[4-[l-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl Λ/-[4-[4-[ 1 -(2.6-difluorophenvπsulfonylcvclopropyll-6-[(36f)-3-methylmorpholin-4- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000888_0001
4-[4-[l-(2,6-Difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin- 2-yl]aniline (as the hydrochloride salt) (1.67 g, 3.19 mmol) and sodium bicarbonate (2.68 g, 31.93 mmol) were added to DCM (60 mL) and stirred for 10 minutes. Phenyl chloro formate (0.521 mL, 4.15 mmol) was added slowly and the reaction stirred for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford an orange solid. The crude product was purified by flash silica chromatography, elution gradient 30 to 60% ethyl acetate in isohexane, to give the desired material as a yellow solid (1.4 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.72 - 1.66 (2H, m), 1.93 - 1.92 (2H, m), 3.18 (IH, ddd), 3.47 (IH, ddd), 3.62 (IH, dd), 3.76 (IH, d), 3.96 (IH, dd), 4.18 (IH, d), 4.50 (IH, s), 6.79 (IH, s), 7.30 - 7.23 (5H, m), 7.45 (2H, t), 7.49 (2H, d), 7.79 - 7.72 (IH, m), 7.84 (2H, d), 10.38 (IH, s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 607; HPLC tR = 3.02 min. 4-r4-ri-(2,6-Difluorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4-yllpyrimidin- 2-vHaniline
Figure imgf000889_0001
tert-Butyl 7V-[4-[4-[ 1 -(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate (2.15 g, 3.66 mmol) was added to 6.0 N hydrogen chloride in propan-2-ol (30 mL) and stirred for 2 hours at RT. The crude solution was triturated with diethyl ether to give the desired material (as the hydrochloride salt) as a white solid (1.67 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.04 (3H, d), 1.76 - 1.72 (2H, m), 1.98 - 1.90 (2H, m), 3.24 (IH, ddd), 3.46 (IH, ddd), 3.60 (IH, dd), 3.76 (IH, d), 3.97 (IH, dd), 4.25 (IH, s), 4.53 (IH, s), 6.85 (IH, s), 7.15 - 7.02 (2H, m), 7.29 (2H, t), 7.84 - 7.77 (IH, m), 7.91 (2H, d); NH2 not visible)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 487; HPLC tR = 2.45 min.
tert-Butyl N-\4-\4-\ 1 -(2,6-difluorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000889_0002
Sodium hydride (1.027 g, 21.41 mmol) was added rapidly to tert-butyl 7V-[4-[4-[(2,6- difluorophenyl)sulfonylmethyl] -6- [(35)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate (3.0 g, 5.35 mmol) in DMF (70 mL) and stirred at RT for 10 minutes before the slow addition 1 ,2-dibromoethane (1.845 mL, 21.41 mmol) in DMF (70 mL). The resulting suspension was stirred at RT for 1.5 hours. A further portion of sodium hydride (2.0 eq) and 1,2 dibromoethane (2.0 eq) were rapidly added and the reaction was stirred for a further 30 minutes. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford brown gum. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% ethyl acetate in isohexane, to afford a yellow foam. This was dissolved in 40% ethyl acetate in isohexane and upon stirring the desired material precipitated as a white solid (2.15 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.49 (9H, s), 1.71 - 1.65 (2H, m), 1.93 - 1.90 (2H, m), 3.17 (IH, ddd), 3.47 (IH, ddd), 3.62 (IH, dd), 3.75 (IH, d), 3.96 (IH, dd), 4.16 (IH, d), 4.48 (IH, s), 6.76 (IH, s), 7.25 (2H, t), 7.42 (2H, d), 7.80 - 7.72 (3H, m), 9.49 (IH, s); LCMS Spectrum: m/z (ESI+) (M+H)+ = 587; HPLC tR = 3.12 min.
tert-Butyl Λ/-r4-r4-r(2,6-difluorophenyl)sulfonylmethyll-6-r(3^-3-methylmorpholin-4- vHpyrimidin-2-vHphenvH carbamate
Figure imgf000890_0001
Sodium 2,6-difluorobenzenesulfonate (1.270 g, 5.88 mmol) and tert-butyl N-[4-[4-
(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (3 g, 5.88 mmol) were dissolved in DMF (50 mL) and stirred for 1 hour at RT. The solvent was evaporated to afford a yellow solid which was partitioned between water (50 mL) and DCM (75 mL). The layers were separated, the aqueous layer extracted with DCM (75 mL) and the combined organics concentrated in vacuo to give a yellow solid. The solid was rapidly stirred with ether (100 mL), to afford a solid which was collected by filtration and dried under vacuum to give the desired material as an off white solid (3.0 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.49 (9H, s), 3.20 (IH, ddd), 3.49 (IH, ddd), 3.64 (IH, dd), 3.77 (IH, d), 3.98 (IH, dd), 4.14 (IH, d), 4.42 (IH, s), 4.78 (2H, s), 6.81 (IH, s), 7.32 (2H, t), 7.42 (2H, d), 7.73 (2H, d), 7.85 - 7.78 (IH, m), 9.50 (IH, s); LCMS Spectrum: m/z (ESI+) (M+H)+ = 561; HPLC tR = 2.84 min. The preparation of tert-butyl Λ/-[4-[4-(iodomethyl)-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl] carbamate was described earlier.
Example 87: l-[4-[4-Q-Ethylsulfonylcyclobutyl)-6-[(35V3-methylmorpholin-4- yll pyrimidin-2-yll phenyll -3-(2-hydroxyethyl)urea
Figure imgf000891_0001
Ethanolamine (0.023 mL, 0.37 mmol) was added in one portion to phenyl N-[4-[4-(l- ethylsulfonylcyclobutyl)-6- [(35)-3 -methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate
(101 mg, 0.19 mmol) and triethylamine (0.078 mL, 0.56 mmol) in NMP (2 mL) at RT and stirred for a period of 16 hours. The crude product was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to afford desired material as a cream solid (71 mg).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.15 (t, 3H), 1.23 (d, 3H), 1.86 - 1.97
(m, IH), 2.01 - 2.11 (m, IH), 2.77 - 2.87 (m, 2H), 2.90 - 2.99 (m, 4H), 3.16 - 3.25 (m, 2H), 3.46 (q, IH), 3.52 (dd, 3H), 3.65 (dd, IH), 3.77 (d, IH), 3.98 (dd, IH), 4.20 - 4.28 (m, IH),
4.52 - 4.61 (m, IH), 4.77 (t, IH), 6.28 (t, IH), 6.72 (s, IH), 7.50 (d, 2H), 8.22 (d, 2H), 8.84 (s,
IH)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 504; HPLC tR = 1.79 min.
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-(l- ethylsulfonylcyclobutyl)-6- [(35)-3 -methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate and the appropriate amine.
Figure imgf000891_0002
Figure imgf000892_0001
Example 87a: 1H NMR (399.902 MHz, DMSO-de) δ 1.15 (t, 3H), 1.23 (d, 3H), 1.87 - 1.97 (m, IH), 2.02 - 2.10 (m, IH), 2.77 - 2.87 (m, 2H), 2.90 - 3.01 (m, 4H), 3.17 - 3.25 (m, IH), 3.50 (td, IH), 3.65 (dd, IH), 3.77 (d, IH), 3.98 (dd, IH), 4.21 - 4.29 (m, IH), 4.33 (d, 2H), 4.52 - 4.61 (m, IH), 6.65 (t, IH), 6.73 (s, IH), 6.82 - 6.86 (m, IH), 7.02 - 7.07 (m, IH), 7.52 (d, 2H), 8.24 (d, 2H), 8.97 (s, IH), 11.87 (s, IH)
Example 87b: 1U NMR (399.902 MHz, DMSOd6) δ 1.15 (t, 3H), 1.23 (d, 3H), 1.60 (quintet, 2H), 1.86 - 1.97 (m, IH), 2.01 - 2.11 (m, IH), 2.77 - 2.87 (m, 2H), 2.90 - 2.99 (m, 4H), 3.14 - 3.25 (m, 3H), 3.47 (q, 2H), 3.49 - 3.54 (m, IH), 3.65 (dd, IH), 3.77 (d, IH), 3.98 (dd, IH), 4.20 - 4.30 (m, IH), 4.51 - 4.61 (m, IH), 4.52 (t, IH), 6.23 (t, IH), 6.72 (s, IH), 7.50 (d, 2H), 8.22 (d, 2H), 8.75 (s, IH)
Example 87c: 1U NMR (399.902 MHz, DMSOd6) δ 1.15 (t, 3H), 1.23 (d, 3H), 1.85 - 1.97 (m, IH), 2.00 - 2.10 (m, IH), 2.66 (d, 3H), 2.77 - 2.87 (m, 2H), 2.90 - 3.00 (m, 4H), 3.21 (td, IH), 3.50 (td, IH), 3.65 (dd, IH), 3.77 (d, IH), 3.98 (dd, IH), 4.20 - 4.29 (m, IH), 4.52 - 4.60 (m, IH), 6.09 (q, IH), 6.72 (s, IH), 7.51 (d, 2H), 8.22 (d, 2H), 8.79 (s, IH) Example 87d: 1R NMR (399.902 MHz, DMSOd6) δ 1.15 (t, 3H), 1.23 (d, 3H), 1.24 (s, 6H), 1.86 - 1.97 (m, IH), 2.01 - 2.11 (m, IH), 2.76 - 2.87 (m, 2H), 2.90 - 3.01 (m, 4H), 3.22 (dd, IH), 3.39 (d, 2H), 3.50 (td, IH), 3.65 (dd, IH), 3.77 (d, IH), 3.98 (dd, IH), 4.19 - 4.30 (m, IH), 4.51 - 4.61 (m, IH), 5.00 (t, IH), 6.02 (s, IH), 6.72 (s, IH), 7.46 (d, 2H), 8.21 (d, 2H), 8.77 (s, IH)
Example 87e: 1U NMR (399.902 MHz, DMSOd6) δ 1.09 (d, 3H), 1.15 (t, 3H), 1.23 (d, 3H), 1.86 - 1.97 (m, IH), 2.01 - 2.11 (m, IH), 2.77 - 2.87 (m, 2H), 2.90 - 3.00 (m, 4H), 3.21 (td, IH), 3.32 - 3.42 (m, 2H), 3.50 (td, IH), 3.65 (dd, IH), 3.68 - 3.74 (m, IH), 3.77 (d, IH), 3.98 (dd, IH), 4.20 - 4.29 (m, IH), 4.52 - 4.61 (m, IH), 4.83 (t, IH), 6.12 (d, IH), 6.72 (s, IH), 7.49 (d, 2H), 8.22 (d, 2H), 8.75 (s, IH)
Example 87f: 1R NMR (399.902 MHz, DMSOd6) δ 1.08 (d, 3H), 1.15 (t, 3H), 1.23 (d, 3H), 1.86 - 1.97 (m, IH), 2.01 - 2.11 (m, IH), 2.77 - 2.87 (m, 2H), 2.90 - 3.00 (m, 4H), 3.21 (td, IH), 3.32 - 3.42 (m, 2H), 3.50 (td, IH), 3.65 (dd, IH), 3.68 - 3.74 (m, IH), 3.76 - 3.79 (m, IH), 3.98 (dd, IH), 4.20 - 4.29 (m, IH), 4.52 - 4.61 (m, IH), 4.83 (t, IH), 6.12 (d, IH), 6.72 (s, IH), 7.48 (d, 2H), 8.22 (d, 2H), 8.75 (s, IH)
The preparation of phenyl Λ/-[4-[4-(l-ethylsulfonylcyclobutyl)-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]carbamate is described below:
Phenyl N- [4- r4-(l-ethylsulfonylcvclobutyl)-6- [(36^-3 -methylmorpholin^-yllpyrimidin^- yllphenyll carbamate
Figure imgf000893_0001
Phenyl chloroformate (0.211 mL, 1.68 mmol) was added dropwise to 4-[4-(l- ethylsulfonylcyclobutyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl] aniline (700 mg, 1.68 mmol) and sodium hydrogen carbonate (141 mg, 1.68 mmol) in dioxane (20 mL) and the resulting suspension stirred at RT for 3 hours. The reaction mixture was evaporated and DCM (50 mL) added and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford desired material as a yellow oil which solidified on standing. (930 mg)
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.16 (t, 3H), 1.25 (d, 3H), 1.87 - 1.98 (m, IH), 2.02 - 2.12 (m, IH), 2.78 - 2.88 (m, 2H), 2.92 - 3.00 (m, 4H), 3.23 (td, IH), 3.48 - 3.55 (m, IH), 3.66 (dd, IH), 3.78 (d, IH), 3.99 (dd, IH), 4.21 - 4.32 (m, IH), 4.53 - 4.64 (m, IH), 6.76 (s, IH), 7.24 - 7.32 (m, 3H), 7.46 (dt, 2H), 7.64 (d, 2H), 8.32 (d, 2H), 10.44 (s, IH) LCMS Spectrum: m/z (ESI+) (M+H)+ = 537.15; HPLC tR = 2.95 min.
4-r4-(l-Ethylsulfonylcvclobutyl)-6-r(36f)-3-methylmorpholin-4-yllpyrimidin-2-vHaniline
Figure imgf000894_0001
Bis(triphenylphosphine)palladium(II) chloride (0.137 g, 0.19 mmol) was added in one portion to 2-chloro-4-(l-ethylsulfonylcyclobutyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (1.4 g, 3.89 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.852 g, 3.89 mmol) and sodium carbonate (9.73 ml, 19.45 mmol) in a DMF / DME / water / ethanol solution at RT under nitrogen. The reaction mixture was thoroughly degassed and was stirred at 800C for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 100% ethyl acetate in DCM, to afford desired material as a yellow dry film (1.536 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSO-d6) δ 1.15 (t, 3H), 1.22 (d, 3H), 1.85 - 1.96 (m, IH), 2.02 - 2.11 (m, IH), 2.75 - 2.86 (m, 2H), 2.89 - 2.99 (m, 4H), 3.19 (td, IH), 3.50 (td, IH), 3.64 (dd, IH), 3.76 (d, IH), 3.97 (dd, 2H), 4.16 - 4.25 (m, IH), 5.56 (s, 2H), 6.59 - 6.63
(m, 3H), 8.06 (d, 2H)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 417.25; HPLC tR = 2.03 min.
2-Chloro-4-(l-ethylsulfonylcvclobutvπ-6-[(36f)-3-methylmorpholin-4-yllpyrimidine
Figure imgf000895_0001
Sodium hydroxide (50% w/w solution) (27.4 g, 683.96 mmol) was added to 2-chloro-4- (ethylsulfonylmethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (3.977 g, 12.44 mmol), 1,3-dibromopropane (3.79 mL, 37.31 mmol) and tetrabutylammonium bromide (0.401 g, 1.24 mmol) in toluene (200 mL) and the resulting suspension stirred at 45°C for 3 hours. The organics were washed with water twice, dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% ethyl acetate in DCM, to afford desired material as a colourless dry film (1.47 g). NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.13 - 1.19 (m, 3H), 1.22 (d, 3H), 1.84 - 1.95 (m, IH), 1.98 - 2.10 (m, IH), 2.65 - 2.77 (m, 2H), 2.82 - 2.92 (m, 2H), 2.96 (q, 2H), 3.18 - 3.25 (m, IH), 3.45 (td, IH), 3.60 (dd, IH), 3.73 (d, IH), 3.94 (dd, IH), 3.99 - 4.12 (m, IH), 4.36 - 4.50 (m, IH), 6.83 (s, IH) LCMS Spectrum: m/z (ESI+) (M+H)+ = 360.22; HPLC tR = 2.13 min.
The preparation of 2-chloro-4-(ethylsulfonylmethyl)-6-[(35)-3-methylmorpholin-4- yljpyrimidine was described earlier.
Example 88: l-[4-[4-Q-Ethylsulfonylcyclobutyl)-6-[(35V3-methylmorpholin-4- yll pyrimidin-2-yll phenyll -3-(3-hydr oxypropyDthiourea
Figure imgf000895_0002
A solution of 1 , l'-thiocarbonyldiimidazole (55.6 mg, 0.31 mmol) in DCM (2 mL) was added to a stirred solution of 4-[4-(l-ethylsulfonylcyclobutyl)-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl] aniline (100 mg, 0.24 mmol) in THF (1 mL) and DCM (2 mL) at RT, over a period of 2 minutes under nitrogen. The resulting solution was stirred at RT for 2 hours. Triethylamine (0.033 mL, 0.24 mmol) and 3-amino-l-propanol (0.092 mL, 1.20 mmol) were added to the reaction mixture. The resulting solution was stirred at RT for 60 hours. The reaction mixture was evaporated to dryness and redissolved in acetonitrile (2 mL), filtered and purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to dryness to afford desired material as a beige solid. (100 mg) NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.15 (t, 3H), 1.24 (d, 3H), 1.72 (quintet, 2H), 1.86 - 1.97 (m, IH), 2.03 - 2.12 (m, IH), 2.77 - 2.88 (m, 2H), 2.91 - 3.00 (m, 4H), 3.18 - 3.26 (m, IH), 3.45 - 3.59 (m, 5H), 3.65 (dd, IH), 3.77 (d, IH), 3.98 (dd, IH), 4.19 - 4.29 (m, IH), 4.49 - 4.63 (m, 2H), 6.75 (s, IH), 7.57 (d, 2H), 7.86 - 7.94 (m, IH), 8.28 (d, 2H), 9.65 - 9.74 (m, IH) LCMS Spectrum: m/z (ES+) (M+H)+= 534.8; HPLC tR= 2.16 min.
The compounds below were prepared in an analogous fashion from either 4-[4-(l- ethylsulfonylcyclobutyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline or 4-[4-(l- ethylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline and the appropriate amine.
Figure imgf000896_0001
Figure imgf000897_0001
Example 88a: 1H NMR (399.902 MHz, DMSOd6) δ 1.15 (t, 3H), 1.24 (d, 3H), 1.86 - 1.97 (m, IH), 2.03 - 2.11 (m, IH), 2.77 - 2.88 (m, 2H), 2.91 - 3.00 (m, 4H), 3.18 - 3.27 (m, IH), 3.51 (td, IH), 3.55 - 3.60 (m, 4H), 3.65 (dd, IH), 3.77 (d, IH), 3.98 (dd, IH), 4.18 - 4.30 (m, IH), 4.54 - 4.63 (m, IH), 4.77 - 4.86 (m, IH), 6.75 (s, IH), 7.62 (d, 2H), 7.84 - 7.90 (m, IH), 8.28 (d, 2H), 9.81 (s, IH)
Example 88b: 1U NMR (399.902 MHz, DMSOd6) δ 1.15 (t, 3H), 1.24 (d, 3H), 1.86 - 1.97 (m, IH), 2.02 - 2.12 (m, IH), 2.78 - 2.88 (m, 2H), 2.91 - 3.00 (m, 4H), 3.18 - 3.26 (m, IH), 3.51 (td, IH), 3.66 (dd, IH), 3.77 (d, IH), 3.98 (dd, IH), 4.19 - 4.30 (m, IH), 4.53 - 4.63 (m, IH), 4.71 (d, 2H), 6.75 (s, IH), 6.99 (s, 2H), 7.69 (d, 2H), 8.18 - 8.25 (m, IH), 8.30 (d, 2H), 9.98 - 10.09 (m, IH), 11.84 - 12.09 (m, IH)
Example 88c: 1R NMR (399.902 MHz, DMSOd6) δ 1.24 (d, 3H), 1.33 (t, 3H), 1.54 - 1.59 (m, 2H), 1.61 - 1.66 (m, 2H), 1.72 (quintet, 2H), 3.22 (td, IH), 3.40 - 3.59 (m, 7H), 3.64 (dd, IH), 3.77 (d, IH), 3.98 (dd, IH), 4.16 - 4.28 (m, IH), 4.52 - 4.64 (m, 2H), 6.83 (s, IH), 7.58 (d, 2H), 7.90 - 7.97 (m, IH), 8.25 (d, 2H), 9.74 (s, IH) Example 88d: 1U NMR (399.902 MHz, DMSO-Cl6) δ 1.24 (d, 3H), 1.33 (t, 3H), 1.55 - 1.59 (m, 2H), 1.61 - 1.66 (m, 2H), 3.22 (td, IH), 3.44 (q, 2H), 3.45 - 3.52 (m, IH), 3.55 - 3.60 (m, 4H), 3.64 (dd, IH), 3.77 (d, IH), 3.98 (dd, IH), 4.15 - 4.28 (m, IH), 4.52 - 4.63 (m, IH), 4.82 - 4.90 (m, IH), 6.82 (s, IH), 7.63 (d, 2H), 7.88 - 7.93 (m, IH), 8.25 (d, 2H), 9.85 (s, IH) Example 88e: 1R NMR (399.902 MHz, DMSOd6) δ 1.24 (d, 3H), 1.33 (t, 3H), 1.54 - 1.59 (m, 2H), 1.61 - 1.66 (m, 2H), 3.22 (td, IH), 3.45 (q, 2H), 3.45 - 3.52 (m, IH), 3.64 (dd, IH), 3.77 (d, IH), 3.98 (dd, IH), 4.15 - 4.28 (m, IH), 4.53 - 4.63 (m, IH), 4.69 - 4.74 (m, 2H), 6.83 (s, IH), 6.86 - 7.15 (m, 2H), 7.70 (d, 2H), 8.22 - 8.29 (m, IH), 8.27 (d, 2H), 10.05 (s, IH), 11.95 (s, IH)
The preparation of both 4-[4-(l-ethylsulfonylcyclobutyl)-6-[(35)-3-methylmorpholin-4- yl]pyrimidin-2-yl]aniline and 4-[4-(l-ethylsulfonylcyclopropyl)-6-[(35)-3-methylmorpholin- 4-yl]pyrimidin-2-yl]aniline were described earlier.
Example 89: 4-[6-[l-(Benzenesulfonyl)cvclopropyll-2-[4- fethylcarbamoylamino)phenyllpyrimidin-4-yllmorpholine-3-carboxamide
Figure imgf000898_0001
DIPEA (0.411 mL, 2.36 mmol) was added to [2-(4-aminophenyl)-6-[l- (benzenesulfonyl)cyclopropyl]pyrimidin-4-yl] trifluoromethanesulfonate (0.102 g, 0.20 mmol) and morpholine-3-carboxamide (as a mixture of the trifiuoroacetic acid salts and the hydrochloride salt) (0.212 g, 1.63 mmol) in dioxane (5 mL) under nitrogen. The reaction was stirred at 700C for several hours. The solvent was removed and then the gum was taken up in dioxane again. Ethyl isocyanate (0.032 mL, 0.41 mmol) was added and the reaction stirred at RT over the weekend. Further ethyl isocyanate (an excess) was added and the reaction stirred for several days. Methanol was added and the solvent was removed. The crude product was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a yellow solid (0.027 g). NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.05-1.08 (3H, t), 1.59-1.62 (IH, m), 1.65-1.68 (IH, m), 1.87-1.95 (2H, m), 3.09-3.17 (2H, m), 3.17-3.19 (IH, d), 3.41-3.54 (3H, m), 3.70-3.73 (IH, dd), 3.94-3.97 (IH, d), 4.30-4.33 (IH, d), 6.13-6.16 (IH, t), 6.72 (IH, s), 7.15 (IH, bs), 7.36-7.38 (2H, d), 7.52 (IH, bs), 7.57-7.61 (2H, t), 7.70-7.74 (IH, tt), 7.79-7.82 (4H, m), 8.62 (IH, s).
LCMS Spectrum: m/z (ES+)(M+H)+=551; HPLC tR=1.84min.
The preparation of [2-(4-aminophenyl)-6-[l-(benzenesulfonyl)cyclopropyl]pyrimidin-4-yl] trifluoromethanesulfonate was described earlier
Morpholine-3-carboxamide
Figure imgf000899_0001
Hydrogen chloride (2.420 mL, 9.68 mmol) (4M solution in dioxane) was added to tert-butyl 3-cyanomorpholine-4-carboxylate (0.419 g, 1.98 mmol) in dioxane (15 mL) and the resulting solution stirred at RT over the weekend. The solvent was removed. The solid was taken up in dioxane and trifiuoroacetic acid (1.2 eq) added. The reaction was allowed to stir at RT overnight. The solvent was removed, the crude material taken up in DCM and trifiuoroacetic acid (0.734 mL, 9.88 mmol) added. The reaction was stirred overnight and then the solvent was removed to give the desired material (isolated as potentially a mixture of the trifiuoroacetic acid salts and the hydrochloride salt). The material was used without further purification.
NMR Spectrum: 1H NMR (400 MHz, DMSOd6) δ 3.07-3.16 (IH, m), 3.58-3.70 (IH, m), 3.79-3.82 (IH, m), 3.87-3.93 (IH, m), 4.00-4.07 (IH, m), 4.11-4.22 (IH, m), 4.71-4.89 (IH, m), 7.76-8.16 (t) (TFA salt), 9.15-9.78 (bt) (HCl salt).
tert-Butyl 3 -cyanomorpholine-4-carboxylate
Figure imgf000899_0002
tert-Butyl 3-carbamoylmorpholine-4-carboxylate (0.929 g, 4.03 mmol) was dissolved in dry DCM (10 mL) and triethylamine (1.181 mL, 8.47 mmol) was added. The solution was put under nitrogen and cooled to 00C. Trifluoroacetic anhydride (0.627 mL, 4.44 mmol) was then added and the reaction was allowed to slowly warm up to RT, followed by stirring at RT for at least 3 hours. The solvent was removed and then ethyl acetate added. The organic layer was washed with brined, dried over MgSO4, filtered and evaporated, he crude product was purified by flash silica chromatography, elution gradient 0 to 30% ethyl acetate in DCM, to give the desired material as a light yellow crystalline solid (0.419 g). NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.50 (9H, s), 3.24 (IH, bt), 3.45-3.52 (IH, td), 3.60-3.64 (IH, dd), 3.80-3.83 (IH, d), 3.94-3.97 (IH, d), 4.04-4.07 (IH, d), 4.89 (IH, bs).
ferf -butyl 3-carbamoylmorpholine-4-carboxylate
Figure imgf000900_0001
HATU (5.92 g, 15.57 mmol) was added to a solution of 4-(tert-butoxycarbonyl)morpholine-3- carboxylic acid (3 g, 12.97 mmol), DIPEA (3.40 mL, 19.46 mmol) and ammonium chloride (3.47 g, 64.87 mmol) in DMF (70 mL) and the resulting suspension stirred at RT for 12 hours under nitrogen. The reaction mixture was concentrated and diluted with ethyl acetate (150 mL), and washed sequentially with water (2 x 50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford the desired material as an oil (4.0 g), which was used without further purification.
NMR Spectrum: 1R NMR (400MHz, DMSO-de) δ 1.39 (9H, s), 3.15 (2H, m), 3.54 (2H, m), 3.63 (2H, m), 3.75 (IH, m), 4.17 (2H, m).
Example 90: 4-[6-[l-(Benzenesulfonyl)cvclopropyll-2-[4- fethylcarbamoylamino)phenyllpyrimidin-4-yll-A/,A/-dimethylmorpholine-3-carboxamide
Figure imgf000900_0002
DIPEA (0.141 mL, 0.81 mmol) was added to [2-(4-aminophenyl)-6-[l- (benzenesulfonyl)cyclopropyl]pyrimidin-4-yl] trifluoromethanesulfonate (0.101 g, 0.20 mmol) and Λ/,Λ/-dimethylmorpholine-3-carboxamide (as the hydrochloride salt) (0.079 g, 0.41 mmol) in dioxane (5 mL) under nitrogen. The reaction was stirred at 70°C for several hours then allowed to cool and ethyl isocyanate (0.321 mL, 4.05 mmol) added. The reaction was stirred at RT overnight, additional ethyl isocyanate added and the reaction stirred at RT overnight. Methanol was added and the solvent was removed. The crude product was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a cream solid (0.047 g). NMR Spectrum: 1H NMR (400 MHz, DMSOd6) δ 1.05-1.08 (3H, t), 1.58-1.62 (IH, m), 1.68-1.73 (IH, m), 1.86-1.97 (2H, m), 2.82 (3H, bs), 3.09-3.16 (2H, m), 3.19 (3H, bs), 3.53- 3.60 (IH, m), 3.67-3.71 (IH, m), 3.79-3.84 (IH, dd), 4.00-4.02 (IH, d), 4.14-4.17 (IH, d), 5.44 (IH, bs), 6.15-6.18 (IH, t), 6.77 (IH, s), 7.37-7.39 (2H, d), 7.56-7.60 (2H, t), 7.70-7.74 (IH, t), 7.76-7.80 (4H, m), 8.61 (IH, s). (1 peak under water or solvent peak). LCMS Spectrum: m/z (ES+)(M+H)+=579; HPLC tR=2.01min.
The preparation of [2-(4-aminophenyl)-6-[l-(benzenesulfonyl)cyclopropyl]pyrimidin-4-yl] trifluoromethanesulfonate was described earlier
A/,A/-Dimethylmorpholine-3-carboxamide
Figure imgf000901_0001
Hydrogen chloride (3.57 mL, 14.28 mmol) (4M solution in dioxane) was added to tert-butyl 3-(dimethylcarbamoyl)morpholine-4-carboxylate (0.820 g, 3.17 mmol) in dioxane (25 mL) and the resulting solution stirred at RT overnight. The solvent was removed and the gum was triturated with diethyl ether to give the desired material (as the hydrochloride salt) as a solid which turned to a gum on standing (0.70 g).
NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 2.89 (3H, s), 3.07 (3H, s), 3.13-3.16 (IH, dd), 3.20-3.23 (IH, dt), 3.42-3.48 (IH, m), 3.69-3.75 (IH, td), 3.92-3.96 (IH, dt), 4.15-4.19 (IH, dd), 4.57-4.61 (IH, dd), 9.47 (IH, bs). tert-Butyl 3 -(dimethylcarbamoyl)morpholine-4-carboxylate
Figure imgf000902_0001
HATU (1.97 g, 5.19 mmol) was added to a solution of 4-(tert-butoxycarbonyl)morpholine-3- carboxylic acid (1 g, 4.32 mmol), DIPEA (1.133 ml, 6.49 mmol) and dimethylamine 2.0M in THF (10.81 mL, 21.62 mmol) in DMF and the resulting solution stirred at RT for 15 hours under nitrogen. The reaction mixture was concentrated and diluted with ethyl acetate (100 mL), and washed sequentially with water(25 mL), 5% aqueous citric acid solution (25 mL), and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product and dried under vacuum to the desired material as an oil (0.91 g), which was used without further purification.
NMR Spectrum: 1U NMR (400 MHz, DMSOd6) δ 1.36 (9H, br s), 2.83 (3H, s), 2.98 (3H, s), 3.35 (IH, m), 3.48 (IH, m), 3.63 (IH, dd), 3.80 (IH, m), 3.90 - 4.04 (2H, m), 4.70 (IH, m).
Example 91: 3-Cvclopropyl-l-[4-[4-K3S.5S)-3.5-dimethylmorpholin-4-yll-6-(l- methylsulfonylcvclopropyDpyrimidin-l-yll phenyll urea
Figure imgf000902_0002
Cyclopropylamine (0.10 mmol) was added to phenyl N-[4-[4-[(3S,5S)-3,5- dimethylmorpholin-4-yl] -6-( 1 -methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl] carbamate (50 mg, 0.10 mmol) and triethylamine (0.027 mL, 0.19 mmol) in DMF (1 mL) at RT. The resulting solution was stirred at 500C for 2 hours and the material purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid (40mg).
NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 0.40 - 0.44 (2H, m), 0.63 - 0.67 (2H, m), 1.36 (6H, d), 1.53 - 1.61 (2H, m), 1.64 - 1.72 (2H, m), 2.54 - 2.59 (IH, m), 3.26 (3H, s), 3.72 (2H, dd), 4.16 (2H, dd), 4.25 - 4.31 (2H, m), 6.44 (IH, d), 6.72 (IH, s), 7.52 (2H, d), 8.21 (2H, d), 8.54 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=486; HPLC tR=2.13min.
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-[(3S,5S)- 3,5-dimethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000903_0001
Example 91a: 1R NMR (400.132 MHz, DMSOd6) δ 1.36 (6H, d), 1.55 - 1.61 (2H, m), 1.64 1.70 (2H, m), 2.66 (3H, d), 3.26 (3H, s), 3.72 (2H, dd), 4.16 (2H, dd), 4.27 - 4.28 (2H, m), 6.07 - 6.08 (IH, m), 6.72 (IH, s), 7.51 (2H, d), 8.20 (2H, d), 8.74 (IH, s). Example 91b: 1H NMR (400.132 MHz, DMSOd6) δ 1.07 (3H, t), 1.36 (6H, d), 1.55 - 1.61 (2H, m), 1.64 - 1.73 (2H, m), 3.09 - 3.16 (2H, m), 3.26 (3H, s), 3.72 (2H, dd), 4.16 (2H, dd), 4.27 - 4.28 (2H, m), 6.17 (IH, t), 6.72 (IH, s), 7.50 (2H, d), 8.20 (2H, d), 8.66 (IH, s). Example 91c: 1H NMR (400.132 MHz, DMSO-Cl6) δ 1.36 (6H, d), 1.55 - 1.59 (2H, m), 1.64 ■ 1.70 (2H, m), 3.26 (3H, s), 3.42 (2H, dq), 3.72 (2H, dd), 4.16 (2H, dd), 4.26 - 4.29 (2H, m), 4.42 (IH, t), 4.54 (IH, t), 6.44 (IH, t), 6.72 (IH, s), 7.51 (2H, d), 8.21 (2H, d), 8.81 (IH, s). Example 91d: 1H NMR (400.132 MHz, DMSOd6) δ 1.36 (6H, d), 1.55 - 1.60 (2H, m), 1.65 1.72 (2H, m), 3.16 - 3.20 (2H, m), 3.26 (3H, s), 3.44 - 3.48 (2H, m), 3.72 (2H, dd), 4.16 (2H, dd), 4.24 - 4.31 (2H, m), 4.73 (IH, t), 6.26 (IH, t), 6.72 (IH, s), 7.50 (2H, d), 8.20 (2H, d), 8.81 (IH, s).
The preparation of phenyl N-[4-[4-[(35',55)-3,5-dimethylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N-r4-r4-r(3^5^-3.5-dimethylmorpholin-4-yll-6-(l- methylsulfonylcvclopropyl)pyrimidin-2-yllphenyllcarbamate
Figure imgf000904_0001
Sodium bicarbonate (104 mg, 1.24 mmol) was added to 4-[4-[(35*,55)-3,5-dimethylmorpholin- 4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2-yl]aniline (250 mg, 0.62 mmol) in 1,4- dioxane (3 mL) and phenyl chloroformate (0.078 mL, 0.62 mmol) was added dropwise to the resulting suspension. The reaction stirred at RT for 2 hours then evaporated to dryness, redissolved in DCM (20 mL), and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford a solid which was triturated with diethyl ether to give the desired material as a cream solid (250 mg).
NMR Spectrum: 1H NMR (400MHz, DMSO-d6) δ 1.37 (6H, d), 1.56 - 1.62 (2H, m), 1.65 - 1.71 (2H, m), 3.27 (3H, s), 3.73 (2H, dd), 4.17 (2H, dd), 4.29 - 4.31 (2H, m), 6.77 (IH, s), 7.24 - 7.30 (3H, m), 7.45 (2H, t), 7.65 (2H, d), 8.30 (2H, d), 10.45 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=523; HPLC tR=2.74min. 4-r4-r(36*,56^-3,5-Dimethylmorpholin-4-yll-6-(l-methylsulfonylcvclopropyl)pyrimidin-2- yll aniline
Figure imgf000905_0001
Bis(triphenylphosphine)palladium(II) chloride (35.5 mg, 0.05 mmol) was added to 2-chloro- 4-[(35*,55)-3,5-dimethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidine (350 mg, 1.01 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (222 mg, 1.01 mmol) and 2M aqueous sodium carbonate solution (1.52 mL, 3.04 mmol), in ethanol (0.89 mL), DME (1.77 mL) and water (0.89 mL) and the reaction stirred at 900C for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (20 mL), and saturated brine(20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 10% methanol in DCM, to give the desired material as a beige solid (250 mg). NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 1.34 (6H, d), 1.50 - 1.58 (2H, m), 1.62 - 1.70 (2H, m), 3.25 (3H, s), 3.70 (2H, dd), 4.14 (2H, dd), 4.22 - 4.25 (2H, m), 5.56 (IH, s), 6.61 (2H, d), 8.04 (2H, d). LCMS Spectrum: m/z (ES+)(M+H)+=403; HPLC tR=2.05min.
2-Chloro-4-r(3^5^-3.5-dimethylmorpholin-4-yll-6-(l- methylsulfonylcvclopropyDpyrimidine
Figure imgf000905_0002
A solution of 50% w/v sodium hydroxide (6.12 mL, 154.44 mmol) was added portionwise to a stirred solution of 2-chloro-4-[(35*,55)-3,5-dimethylmorpholin-4-yl]-6- (methylsulfonylmethyl)pyrimidine (898 mg, 2.81 mmol), tetrabutylammonium bromide (91 mg, 0.28 mmol) and 1 ,2-dibromoethane (0.726 mL, 8.42 mmol) in toluene (50 mL) and the resulting suspension stirred at 600C for 6 hours. The reaction mixture was diluted with water (50 mL), and washed sequentially with water (2 x 50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in DCM, to give the desired material as a solid (350 mg).
NMR Spectrum: 1H NMR (400MHz, CDCl3) δ 1.43 (3H, d), 1.44 (3H, d), 1.50 (2H, m), 1.82 (2H, m), 3.02 (3H, s), 3.78 (2H, dd), 4.16 (2H, m), 4.24 (2H, dd), 6.77 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=346; HPLC tR=1.83min.
2-Chloro-4-[(36'.56f)-3.5-dimethylmorpholin-4-yll-6-(methylsulfonylmethvπpyrimidine
Figure imgf000906_0001
Sodium methanesulfinate (0.542 g, 5.31 mmol) was added portionwise to 2-chloro-4-[(35*,55)- 3,5-dimethylmorpholin-4-yl]-6-(iodomethyl)pyrimidine (1.86 g, 5.06 mmol) in acetonitrile (50 mL) and the resulting suspension stirred at 800C for 6 hours. Further sodium methanesulfinate (0.5 equivalents) was added and the reaction was heated a further 8 hours. The solvent was removed and the solid was taken up in DMF. Further sodium methanesulfinate (1 equivalent) was added and the mixture allowed to stir until the reaction was complete. The solvent was removed and ethyl acetate added. The mixture was washed with 10% sodium thiosulfate, brine and water and the organics dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% ethyl acetate in DCM, to give the desired material as a yellow gum (0.898 g). NMR Spectrum: 1H NMR (400MHz, CDCl3) δ 1.44-1.45 (6H, d), 3.02 (3H, s), 3.77-3.80 (2H, dd), 4.14-4.16 (2H, m), 4.17-4.18 (2H, d), 4.23-4.27 (2H, dd), 6.46 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=320; HPLC tR=1.59 min. 2-Chloro-4-r(36',56f)-3,5-dimethylmorpholin-4-yll-6-(iodomethyl)pyrimidine
Figure imgf000907_0001
[2-Chloro-6-[(35*,55)-3,5-dimethylmorpholin-4-yl]pyrimidin-4-yl]methyl methanesulfonate (5.21 g, 15.51 mmol) and lithium iodide (1.190 mL, 31.03 mmol) were added to dioxane (250 mL) and heated at 600C for 1 hour and then at RT overnight. The mixture was evaporated to dryness and partitioned between saturated ammonium chloride solution (100 mL) and DCM (75 mL). The layers were separated and the aqueous layer further extracted with DCM (2 x 75 mL) then the combined organics washed sequentially with 10% sodium thiosulfate solution (100 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product as a brown oil (5.59 g). The material was used without further purification.
NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 1.32 (6H, d), 3.69 (2H, dd), 4.08 (2H, m), 4.14 (2H, dd), 4.34 (2H, s), 6.84 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=368; HPLC tR=2.26min.
[2-Chloro-6-[(36'.56f)-3.5-dimethylmorpholin-4-yllpyrimidin-4-yllmethyl methanesulfonate
Figure imgf000907_0002
Methanesulfonyl chloride (1.802 mL, 23.28 mmol) was added dropwise to [2-chloro-6- [(35*,55)-3,5-dimethylmorpholin-4-yl]pyrimidin-4-yl]methanol (4.00 g, 15.52 mmol) and DIPEA (4.03 mL, 23.28 mmol) in DCM (100 mL) at O0C over a period of 2 minutes and the resulting solution allowed to gradually warm up to RT over a period of 2 hours. The reaction mixture was diluted with DCM (50 mL), and washed with water. The organic layer was dried over MgSO4, filtered and evaporated to afford the desired material as a yellow gum (5.56 g). This was used without further purification. NMR Spectrum: 1H NMR (400MHz, CDCl3) δ 1.42-1.44 (6H, d), 3.14 (3H, s), 3.76-3.80 (2H, dd), 4.13-4.18 (2H, m), 4.22-4.26 (2H, dd), 5.11 (2H, d), 6.48 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=336; HPLC tR=1.88min.
r2-Chloro-6-[(36',56f)-3,5-dimetliylmorpholin-4-yllpyrimidin-4-yllmetlianol
Figure imgf000908_0001
Lithium borohydride, 2M in THF (6.54 mL, 13.09 mmol) was added dropwise to methyl 2- chloro-6-[(35*,55)-3,5-dimethylmorpholin-4-yl]pyrimidine-4-carboxylate (4.40 g, 15.40 mmol) in THF (75 mL) at O0C over a period of 30 minutes under nitrogen. The resulting solution was stirred at 00C for 30 minutes then allowed to warm to RT. Water (250 mL) was added and the organics removed in vacuo. The aqueous residues were extracted with ethyl acetate then the combined organics were washed with brine. The organic layer was dried over MgSO4 then evaporated to dryness to afford the desired material as a white solid (4.0 g). NMR Spectrum: 1H NMR (400MHz, CDCl3) δ 1.41-1.42 (6H, d), 2.69-2.71 (IH, t), 3.75-3.78 (2H, dd), 4.12-4.18 (2H, m), 4.21-4.25 (2H, dd), 4.59-4.60 (2H, d), 6.39 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=258; HPLC tR=1.38min.
Methyl 2-chloro-6-[(36'.56f)-3.5-dimethylmorpholin-4-yllpyrimidine-4-carboxylate
Figure imgf000908_0002
Methyl 2,4-dichloropyrimidine-6-carboxylate (4.45 g, 21.50 mmol) was dissolved in dry DCM (10OmL) and DIPEA (9.67 mL, 55.89 mmol) was added. (3S,5S)-3,5- Dimethylmorpholine (as the hydrochloride salt) (3.42 g, 22.57 mmol)in DCM (20 mL) was added to this solution dropwise over several minutes and the reaction allowed to stir at RT for 5 days then at 5O0C for several days. The crude reaction mixture was washed with water, dried over MgSO4 and filtered. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% ethyl acetate in DCM, to give the desired material as a cream solid (4.4 g). NMR Spectrum: 1H NMR
Figure imgf000909_0001
CDCl3) δ 1.44-1.46 (6H, d), 3.78-3.81 (2H, dd), 3.98 (3H, s), 4.16-4.22 (2H, m), 4.24-4.28 (2H, dd), 7.10 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=286; HPLC tR=1.72min.
The preparation of (35*,55)-3,5-dimethylmorpholine was described earlier.
Example 92: 3-Cvclopropyl-l-[4-[4-(l-cvclopropylsulfonylcvclopropyl)-6-[(3S.,5S)-3.,5- dimethylmorpholin-4-yll pyrimidin-2-yll phenyll urea
Figure imgf000909_0002
Cyclopropanamine (12.49 mg, 0.22 mmol) was added to phenyl Λ/-[4-[4-(l- cyclopropylsulfonylcyclopropyl)-6-[(35',55)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yl]phenyl] carbamate (120 mg, 0.22 mmol) and triethylamine (0.091 mL, 0.66 mmol) in DMF (1 mL) at RT. The resulting solution was stirred at 500C for 2 hours. The crude product was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid (82 mg).
NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 0.40 - 0.44 (2H, m), 0.63 - 0.67 (2H, m), 0.87 - 1.04 (4H, m), 1.36 (6H, d), 1.57 - 1.70 (4H, m), 2.54 - 2.58 (IH, m), 2.91 - 2.97 (IH, m), 3.71 (2H, dd), 4.16 (2H, dd), 4.25 - 4.27 (2H, m), 6.43 (IH, s), 6.81 (IH, s), 7.51 (2H, d), 8.22 (2H, d), 8.52 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=512; HPLC tR=2.25min.
The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-(l- cyclopropylsulfonylcyclopropyl)-6-[(35',55)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000909_0003
Figure imgf000910_0001
Figure imgf000911_0001
Example 92a: 1H NMR (400.132 MHz, DMSOd6) δ 0.87 - 1.06 (4H, m), 1.36 (6H, d), 1.55 -
1.70 (4H, m), 2.91 - 2.97 (IH, m), 3.50 - 3.60 (2H, m), 3.72 (2H, dd), 4.16 (2H, dd), 4.25 - 4.28 (2H, m), 6.07 (IH, t), 6.54 (IH, t), 6.82 (IH, s), 7.52 (2H, d), 8.24 (2H, d), 8.91 (IH, s). Example 92b: 1H NMR (400.132 MHz, DMSOd6) δ 0.88 - 1.07 (4H, m), 1.36 (6H, d), 1.56 -
1.71 (4H, m), 2.91 - 2.98 (IH, m), 3.72 (2H, dd), 3.79 (3H, s), 4.16 (2H, dd), 4.26 - 4.29 (2H, m), 6.82 (IH, s), 7.39 (IH, s), 7.55 (2H, d), 7.76 (IH, s), 8.25 (2H, d), 8.39 (IH, s), 8.83 (IH, s).
Example 92c: 1R NMR (400.132 MHz, DMSOd6) δ 0.89 - 1.04 (4H, m), 1.36 (6H, d), 1.57 - 1.68 (4H, m), 2.66 (3H, d), 2.91 - 2.97 (IH, m), 3.71 (2H, ddd), 4.16 (2H, dd), 4.25 - 4.27 (2H, m), 6.06 - 6.07 (IH, m), 7.50 (2H, d), 7.55 - 7.58 (IH, m), 8.21 (2H, d), 8.73 (IH, s). Example 92d: 1H NMR (400.132 MHz, DMSOd6) δ 0.87 - 1.04 (4H, m), 1.07 (3H, t), 1.36 (6H, d), 1.55 - 1.70 (4H, m), 2.91 - 2.97 (IH, m), 3.09 - 3.16 (2H, m), 3.71 (2H, dd), 4.16 (2H, dd), 4.24 - 4.27 (2H, m), 6.16 (IH, t), 6.81 (IH, s), 7.49 (2H, d), 8.21 (2H, d), 8.65 (IH, S).
Example 92e: 1U NMR (400.132 MHz, DMSOd6) δ 0.87 - 1.06 (4H, m), 1.36 (6H, d), 1.55 - 1.70 (4H, m), 2.91 - 2.97 (IH, m), 3.39 (IH, q), 3.46 (IH, q), 3.72 (2H, dd), 4.16 (2H, dd), 4.22 - 4.29 (2H, m), 4.42 (IH, t), 4.54 (IH, t), 6.44 (IH, t), 6.81 (IH, s), 7.51 (2H, d), 8.23 (2H, d), 8.80 (IH, s). Example 92f: 1H NMR (400.132 MHz, DMSOd6) δ 0.87 - 1.04 (4H, m), 1.36 (6H, d), 1.55 - 1.69 (4H, m), 2.90 - 2.97 (IH, m), 3.16 - 3.20 (2H, m), 3.44 - 3.48 (2H, m), 3.71 (2H, dd), 4.16 (2H, dd), 4.24 - 4.29 (2H, m), 4.73 (IH, t), 6.26 (IH, t), 6.81 (IH, s), 7.49 (2H, d), 8.22 (2H, d), 8.79 (IH, s). The preparation of phenyl Λ/-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(35',55)-3,5- dimethylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl Λ/-[4-[4-(l-cvclopropylsulfonylcvclopropyπ-6-[(36'.5y)-3.5-dimethylmorpholin-4- vllpyrimidin-2-yllphenyllcarbamate
Figure imgf000912_0001
Sodium bicarbonate (286 mg, 3.41 mmol) was added to 4-[4-(l- cyclopropylsulfonylcyclopropyl)-6-[(35',55)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yljaniline (730 mg, 1.70 mmol), in 1,4-dioxane (8.3 mL) and phenyl chloroformate (0.214 mL, 1.70 mmol) added dropwise to the resulting suspension. The mixture was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (20 mL), and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford a solid which was triturated with diethyl ether to give the desired material as a cream solid (800 mg). NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 0.88 - 1.05 (4H, m), 1.37 (6H, d), 1.59 - 1.70 (4H, m), 2.92 - 2.99 (IH, m), 3.73 (2H, dd), 4.17 (2H, dd), 4.28 - 4.30 (2H, m), 6.86 (IH, s), 7.24 - 7.30 (3H, m), 7.45 (2H, t), 7.64 (2H, d), 8.30 (2H, d), 10.45 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=549; HPLC tR=2.66min.
4-r4-(l-Cvclopropylsulfonylcvclopropyl)-6-r(36',56^-3,5-dimethylmorpholin-4-yllpyrimidin- 2-vHaniline
Figure imgf000912_0002
Bis(triphenylphosphine)palladium(II) chloride (60.4 mg, 0.09 mmol) was added to 2-chloro- 4-(l-cyclopropylsulfonylcyclopropyl)-6-[(35',55)-3,5-dimethylmorpholin-4-yl]pyrimidine (640 mg, 1.72 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (490 mg, 2.24 mmol) and 2M sodium carbonate solution (2.6 mL, 5.16 mmol) in water (1.5 mL), ethanol (1.5 mL), and DME (3 mL) and the resulting solution was stirred at 95°C for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine(10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanol in DCM, to give the desired material as a beige solid (740 mg). NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 0.89 - 1.03 (4H, m), 1.34 (6H, d), 1.54 - 1.67 (4H, m), 2.89 - 2.96 (IH, m), 3.70 (2H, dd), 4.14 (2H, dd), 4.20 - 4.24 (2H, m), 6.61 (2H, d), 6.73 (IH, s), 8.05 (2H, d) LCMS Spectrum: m/z (ES+)(M+H)+=429; HPLC tR=2.18min.
2-Chloro-4-(l-cvclopropylsulfonylcvclopropyl)-6-r(36',56f)-3,5-dimethylmorpholin-4- yllpyrimidine
Figure imgf000913_0001
A solution of 50% w/v sodium hydroxide (7.06 mL, 176.52 mmol) was added portionwise to a stirred solution of 2-chloro-4-(cyclopropylsulfonylmethyl)-6-[(35',55)-3,5- dimethylmorpholin-4-yl]pyrimidine (1.11 g, 3.21 mmol), tetrabutylammonium bromide (0.103 g, 0.32 mmol) and 1 ,2-dibromoethane (0.830 mL, 9.63 mmol) in toluene (50 mL) and the resulting suspension stirred at 600C for 6 hours. The reaction mixture was diluted with water (50 mL), and washed sequentially with water (2 x 50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in DCM, to give the desired material as a solid (0.64 g).
NMR Spectrum: 1H NMR (400MHz, DMSO-d6) δ 0.86 - 0.99 (2H, m), 1.01 (2H, m), 1.31 (3H, d), 1.33 (3H, d), 1.51 (2H, m), 1.63 (2H, m), 2.86 (IH, m), 3.70 (2H, dd), 4.13 (2H, m), 4.16 (2H, m), 6.90 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=372; HPLC tR=1.97min. 2-Chloro-4-(cvclopropylsulfonylmethyl)-6-r(36',56f)-3,5-dimethylmorpholin-4-yllpyrimidine
Figure imgf000914_0001
Sodium cyclopropanesulfinate (0.648 g, 5.06 mmol) was added portionwise to 2-chloro-4- [(35*,55)-3,5-dimethylmorpholin-4-yl]-6-(iodomethyl)pyrimidine (1.86 g, 5.06 mmol) in acetonitrile (50 mL) and the resulting suspension stirred at 800C for 6 hours. Further sodium cyclopropanesulfinate (259mg, 2.02mmol) was added in one portion and the suspension was stirred at 800C for a further 2 hours. The reaction mixture was concentrated and diluted with DCM (200 mL), and washed sequentially with water (50 mL), 10% sodium thiosulfate solution (50 mL), and saturated brine(50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient Oto 20% ethyl acetate in DCM, to give the desired material as a yellow solid (1.11 g). NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 0.97 (2H, m), 1.03 (2H, m), 1.32 (3H, d), 1.34 (3H, d), 2.79 (IH, m), 3.70 (2H, dd), 4.09 (2H, m), 4.15 (2H, dd), 4.49 (2H, d), 6.82 (IH, s). LCMS Spectrum: m/z (ES+)(M+H)+=346; HPLC tR=1.77 min.
The preparation of 2-chloro-4-[(35*,55)-3,5-dimethylmorpholin-4-yl]-6- (iodomethyl)pyrimidine was described earlier.
Example 93: l-[4-[4-[l-(Benzenesulfonylkyclopropyll-6-[(3S,5S)-3,5- dimethylmorpholin-4-yll pyrimidin-2-yll phenyll -3-cvclopropylurea
Figure imgf000914_0002
Cyclopropylamine (19.0 mg, 0.34 mmol) was added to phenyl N-[4-[4-[l- (benzenesulfonyl)cyclopropyl]-6-[(35',55)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yl]phenyl] carbamate (100 mg, 0.17 mmol) and triethylamine (52 mg, 0.51 mmol) in dioxane (1OmL) at RT. The resulting solution was stirred at 500C overnight. The crude product was purified by preparative HPLC, eluting with decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile, to give the desired material as a white solid (64 mg). NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 0.43 - 0.39 (2H, m), 0.67 - 0.62 (2H, m), 1.28 (6H, d), 1.69 - 1.62 (2H, m), 1.93 - 1.89 (2H, m), 2.59 - 2.50 (m, IH), 3.70 - 3.67 (2H, m), 4.18 - 4.10 (4H, m), 6.41 (IH, s), 6.60 (IH, s), 7.41 (2H, d), 7.59 (2H, t), 7.70 (IH, t), 7.79 (2H, d), 7.88 (2H, d), 8.49 (IH, s).
LCMS Spectrum: m/z (ES+)(M+H)+=548; HPLC tR=2.49min.
The compounds below were prepared in an analogous fashion from phenyl 7V-[4-[4-[l- (benzenesulfonyl)cyclopropyl]-6-[(35',55)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate and the appropriate amine.
Figure imgf000915_0001
Figure imgf000916_0001
1 - [4- [4- [ 1 -(Benzenesulfonyl)cyclopropyl] -6- [(3<S,5<S)-3 ,5 -dimethylmorpholin-4-yl]pyrimidin- 2-yl]phenyl]-3-ethylurea (Example 72) can also be prepared in this fashion.
Example 93a: 1R NMR (400.132 MHz, DMSOd6) δ 1.28 (6H, d), 1.69 - 1.62 (2H, m), 1.93 - 1.89 (2H, m), 2.68 - 2.65 (3H, m), 3.70 - 3.67 (2H, m), 4.16 - 4.10 (4H, m), 6.05 (IH, q), 6.59 (IH, s), 7.40 (2H, d), 7.59 (2H, t), 7.70 (IH, t), 7.79 (2H, d), 7.87 (2H, d), 8.69 (IH, s). Example 93b: 1H NMR (400.132 MHz, DMSOd6) δ 1.28 (6H, d), 1.69 - 1.63 (2H, m), 1.93 - 1.89 (2H, m), 3.18 - 3.15 (2H, m), 3.46 (2H, q), 3.70 - 3.67 (2H, m), 4.18 - 4.10 (4H, m), 4.72 (IH, t), 6.24 (IH, t), 6.60 (IH, s), 7.39 (2H, d), 7.59 (2H, t), 7.70 (IH, t), 7.79 (2H, d), 7.88 (2H, d), 8.76 (IH, s).
Example 93c: 1U NMR (400.132 MHz, DMSOd6) δ 1.28 (6H, d), 1.69 - 1.64 (2H, m), 1.93 - 1.89 (2H, m), 3.41 (2H, dq), 3.70 - 3.68 (2H, m), 4.18 - 4.10 (4H, m), 4.47 (2H, dt), 6.42 (IH, t), 6.60 (IH, s), 7.40 (2H, d), 7.59 (2H, t), 7.70 (IH, t), 7.79 (2H, d), 7.88 (2H, d), 8.76 (IH, s).
Example 93d: 1H NMR (400.132 MHz, DMSOd6) δ 1.28 (6H, d), 1.69 - 1.61 (2H, m), 1.93 -
1.90 (2H, m), 3.59 - 3.49 (2H, m), 3.70 - 3.68 (2H, m), 4.18 - 4.10 (4H, m), 6.07 (IH, tt), 6.52 (IH, t), 6.60 (IH, s), 7.41 (2H, d), 7.59 (2H, t), 7.70 (IH, t), 7.79 (2H, d), 7.89 (2H, d), 8.87 (IH, s).
Example 93e: 1R NMR (400.132 MHz, DMSOd6) δ 1.28 (6H, d), 1.72 - 1.62 (2H, m), 1.94 - 1.90 (2H, m), 3.70 - 3.68 (2H, m), 3.79 (3H, s), 4.18 - 4.10 (4H, m), 6.61 (IH, s), 7.38 (IH, s), 7.45 (2H, d), 7.59 (2H, t), 7.71 (IH, t), 7.76 (IH, s), 7.80 (2H, d), 7.91 (2H, d), 8.37 (IH, s), 8.79 (IH, s).
The preparation of phenyl Λ/-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(35',55)-3,5- dimethylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl Λ/-r4-r4-ri-(benzenesulfonyl)cvclopropyll-6-r(36',56f)-3,5-dimethylmorpholin-4- vllpyrimidin-2-yllphenyllcarbamate
Figure imgf000917_0001
4-[4-[l-(Benzenesulfonyl)cyclopropyl]-6-[(35',55)-3,5-dimethylmorpholin-4-yl]pyrimidin-2- yljaniline (0.6 g, 1.29 mmol) and sodium bicarbonate (1.085 g, 12.91 mmol) were added to DCM (60 mL) and stirred for 10 minutes. Phenyl chloro formate (0.211 mL, 1.68 mmol) was added slowly and the reaction was stirred for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford an orange solid. The crude product was purified by flash silica chromatography, elution gradient 30 to 60% ethyl acetate in isohexane, to give the desired material as a yellow solid (0.73 g).
NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 1.29 (6H, d), 1.71 - 1.64 (2H, m), 1.94 - 1.89 (2H, m), 3.71 - 3.68 (2H, m), 4.18 - 4.11 (4H, m), 6.63 (IH, s), 7.30 - 7.23 (3H, m), 7.45 (2H, t), 7.54 (2H, d), 7.59 (2H, t), 7.70 (IH, t), 7.81 - 7.79 (2H, m), 7.97 (2H, d), 10.39 (IH, s).
LCMS Spectrum: m/z (ES+)(M+H)+=585; HPLC tR=3.02min.
4-[4-[l-(Benzenesulfonvπcvclopropyll-6-[(36'.5y)-3.5-dimethylmorpholin-4-yllpyrimidin-2- yll aniline
Figure imgf000918_0001
Bis(triphenylphosphine)palladium(II) chloride (0.053 g, 0.07 mmol) was added to 4-[l- (benzenesulfonyl)cyclopropyl]-2-chloro-6-[(35',55)-3,5-dimethylmorpholin-4-yl]pyrimidine (0.611 g, 1.50 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.427 g, 1.95 mmol) and 2M sodium carbonate solution (2.247 mL, 4.49 mmol) in water (3 mL), ethanol (3 mL), and DME (6 mL) and the resulting solution stirred at 95°C overnight. The reaction mixture was diluted with ethyl acetate (75 mL), and washed sequentially with water (10 mL) and saturated brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford the crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% ethyl acetate in DCM, to give the desired material as a white foam (0.6 g).
NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 1.25 (6H, d), 1.69 - 1.60 (2H, m), 1.93 - 1.85 (2H, m), 3.68 - 3.64 (2H, m), 4.13 - 4.06 (4H, m), 5.50 (IH, s), 6.52 - 6.50 (4H, m), 7.58 (2H, t), 7.74 - 7.67 (3H, m), 7.80 - 7.78 (2H, m).
LCMS Spectrum: m/z (ES+)(M+H)+=465; HPLC tR=2.50min.
4-[l-(Benzenesulfonvπcvclopropyll-2-chloro-6-[(36'.5y)-3.5-dimethylmorpholin-4- yllpyrimidine
Figure imgf000918_0002
A solution of 50% w/v sodium hydroxide (4.99 mL, 124.73 mmol) was added portionwise to a stirred solution of 4-(benzenesulfonylmethyl)-2-chloro-6-[(35',55)-3,5-dimethylmorpholin- 4-yl]pyrimidine (866 mg, 2.27 mmol), tetrabutylammonium bromide (73.1 mg, 0.23 mmol) and 1 ,2-dibromoethane (0.586 mL, 6.80 mmol) in toluene (50 mL) and the resulting suspension stirred at 600C for 6 hours. The reaction mixture was diluted with water (50 mL), and washed sequentially with water (2 x 50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in DCM, to give the desired material as a solid (611 mg). NMR Spectrum: 1H NMR (400MHz, DMSOd6) δ 1.20 (6H, m), 1.59 (2H, m), 1.86 (2H, m), 3.66 (2H, dd), 4.02 (2H, m), 4.10 (2H, dd), 6.62 (IH, s), 7.61 (2H, m), 7.74 (IH, m), 7.75 (2H, m). LCMS Spectrum: m/z (ES+)(M+H)+=408; HPLC tR=2.26min.
4-(Benzenesulfonylmethyl)-2-chloro-6-r(36',56f)-3,5-dimethylmorpholin-4-yllpyrimidine
Figure imgf000919_0001
Sodium benzenesulfmate (0.872 g, 5.31 mmol) was added portionwise to 2-chloro-4-[(35*,55)- 3,5-dimethylmorpholin-4-yl]-6-(iodomethyl)pyrimidine (1.86 g, 5.06 mmol) in acetonitrile (50 mL) and the resulting suspension stirred at 800C for 6 hours. Further sodium benzenesulfmate (0.5 equivalents) was added and the reaction was heated for a further 8 hours. The solvent was removed and the solid was taken up in DMF. Further sodium benzenesulfmate (1 equivalent) was added and the reaction allowed to stir until complete (some sodium iodide was added to speed up the reaction). 10% Aqueous sodium thiosulfate solution was added and the acetonitrile removed, ethyl acetate was added and the layers separated. The organic layer was washed with brine and water, dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% ethyl acetate in DCM, to give the desired material as a white solid (0.866 g). NMR Spectrum: 1H NMR (400MHz, CDCl3) δ 1.42-1.44(6H, d), 3.76-3.79(2H, dd), 4.10- 4.16(2H, m), 4.22-4.26(2H, dd), 4.32(2H, s), 6.56(1H, s), 7.52-7.56(2H, t), 7.64-7.68(1H, t), 7.77-7.79(2H, d). LCMS Spectrum: m/z (ES+)(M+H)+=382; HPLC tR=2.11min.
The preparation of 2-chloro-4-[(35*,55)-3,5-dimethylmorpholin-4-yl]-6- (iodomethyl)pyrimidine was described earlier.
Example 94
The following samples were prepared by heating a mixture of the carbamate (1 equivalent), triethylamine (4 equivalents) and the amine (4 equivalents) in NMP (2 mL) at 7O0C for 2 hours. The compounds were purified by preparative HPLC.
The following compounds were prepared in an analogous fashion from either phenyl N- [4- [4- [(35)-3-methylmorpholin-4-yl]-6-[l-(oxan-4-ylsulfonyl)cyclopropyl]pyrimidin-2- yl]phenyl]carbamate or phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-(oxolan-3- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]carbamate and the appropriate amine.
Figure imgf000920_0001
Figure imgf000921_0001
Figure imgf000922_0001
Example 94a: 1R NMR (400.132 MHz, DMSOd6) δ 1.24 (3H,d), 1.52- 1.56 (2H,m), 1.58 1.61 (2H, m), 1.65 - 1.77 (2H, m), 2.10 - 2.19 (2H, m), 3.17 - 3.33 (3H, m), 3.48 (IH, td), 3.63 (IH, d), 3.75 - 3.87 (2H, m), 3.95 - 4.05 (3H, m), 4.17 - 4.27 (IH, m), 4.55 (IH, s), 6.00 - 6.15 (IH, m), 6.78 (IH, s), 7.52 (2H, d), 8.18 (2H, d), 8.75 (IH, s)
Example 94b: 1H NMR (400.132 MHz, DMSOd6) δ 1.07 (3H, t), 1.24 (3H, d), 1.52 - 1.56 (2H, m), 1.57 - 1.62 (2H, m), 1.65 - 1.78 (2H, m), 2.09 - 2.19 (2H, m), 3.09 - 3.24 (3H, m), 3.26 - 3.35 (2H, m), 3.48 (IH, td), 3.63 (IH, d), 3.74 - 3.88 (2H, m), 3.94 - 4.04 (3H, m), 4.22 (IH, d), 4.55 (IH, s), 6.17 (IH, t), 6.78 (IH, s), 7.51 (2H, d), 8.18 (2H, d), 8.67 (IH, s) Example 94c: 1R NMR (400.132 MHz, DMSOd6) δ 0.38 - 0.46 (2H, m), 0.62 - 0.69 (2H, m), 1.24 (3H, d), 1.50 - 1.56 (2H, m), 1.56 - 1.62 (2H, m), 1.66 - 1.78 (2H, m), 2.09 - 2.19 (2H, m), 2.54 - 2.60 (IH, m), 3.21 (IH, td), 3.28 - 3.34 (2H, m), 3.48 (IH, td), 3.63 (IH, d), 3.76 (IH, d), 3.79 - 3.88 (IH, m), 3.94 - 4.04 (3H, m), 4.22 (IH, d), 4.55 (IH, s), 6.45 (IH, s), 6.78 (IH, s), 7.52 (2H, d), 8.19 (2H, d), 8.55 (IH, s)
Example 94d: 1H NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.50 - 1.56 (2H, m), 1.56 - 1.62 (2H, m), 1.64 - 1.77 (2H, m), 2.09 - 2.20 (2H, m), 3.15 - 3.23 (2H, m), 3.25 - 3.35 (2H, m), 3.43 - 3.50 (2H, m), 3.61 - 3.66 (IH, m), 3.74 - 3.87 (2H, m), 3.94 - 4.04 (3H, m), 4.22 (IH, d), 4.55 (IH, s), 4.73 (IH, t), 6.27 (IH, t), 6.78 (IH, s), 7.50 (2H, d), 8.18 (2H, d), 8.82 (IH, s)
Example 94e: 1R NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.51 - 1.57 (2H, m), 1.58 - 1.62 (2H, m), 1.67 - 1.78 (2H, m), 2.10 - 2.21 (2H, m), 3.18 - 3.34 (3H, m), 3.49 (IH, td),
3.64 (IH, d), 3.73 - 3.88 (5H, m), 3.95 - 4.05 (3H, m), 4.23 (IH, d), 4.55 (IH, s), 6.79 (IH, s), 7.39 (IH, s), 7.56 (2H, d), 7.77 (IH, s), 8.22 (2H, d), 8.40 (IH, s), 8.85 (IH, s)
Example 94f: 1H NMR (400.132 MHz, DMSOd6) δ 1.23 (3H, d), 1.49 - 1.77 (8H, m), 1.81 - 1.91 (2H, m), 2.09 - 2.25 (4H, m), 3.21 (IH, td), 3.26 - 3.35 (2H, m), 3.48 (IH, td), 3.63 (IH, d), 3.71 - 3.89 (2H, m), 3.94 - 4.04 (3H, m), 4.08 - 4.25 (2H, m), 4.55 (IH, s), 6.47 (IH, d), 6.78 (IH, s), 7.49 (2H, d), 8.18 (2H, d), 8.57 (IH, s) Example 94g: 1U NMR (400.132 MHz, DMSOd6) δ 1.23 (3H, d), 1.52 - 1.58 (2H, m), 1.62 - 1.70 (2H, m), 2.17 - 2.30 (2H, m), 2.66 (3H, d), 3.14 - 3.28 (IH, m), 3.49 (IH, td), 3.61 - 3.72 (2H, m), 3.73 - 3.82 (2H, m), 3.93 - 4.04 (2H, m), 4.21 (IH, d), 4.27 - 4.39 (IH, m), 4.55 (IH, s), 6.07 (IH, t), 6.79 (IH, s), 7.51 (2H, d), 8.20 (2H, d), 8.74 (IH, s) Example 94h: 1H NMR (400.132 MHz, DMSOd6) δ 1.07 (3H, t), 1.23 (3H, d), 1.52 - 1.59 (2H, m), 1.63 - 1.69 (2H, m), 2.18 - 2.30 (2H, m), 3.09 - 3.17 (2H, m), 3.17 - 3.24 (IH, m), 3.49 (IH, td), 3.61 - 3.71 (2H, m), 3.73 - 3.83 (2H, m), 3.94 - 4.02 (3H, m), 4.21 (IH, d), 4.30 - 4.38 (IH, m), 4.54 (IH, s), 6.17 (IH, t), 6.79 (IH, s), 7.50 (2H, d), 8.20 (2H, d), 8.66 (IH, s) Example 94i: 1H NMR (400.132 MHz, DMSO-d6) δ 0.40 - 0.44 (2H, m), 0.62 - 0.68 (3H, m), 1.23 (4H, d), 1.52 - 1.60 (4H, m), 1.63 - 1.70 (3H, m), 2.16 - 2.30 (3H, m), 2.52 - 2.61 (18H, m), 3.21 (3H, td), 3.49 (IH, td), 3.59 - 3.72 (3H, m), 3.72 - 3.84 (3H, m), 3.93 - 4.03 (3H, m), 4.21 (IH, d), 4.28 - 4.40 (IH, m), 4.54 (IH, s), 6.44 (IH, s), 6.80 (IH, s), 7.52 (2H, d), 8.20 (2H, d), 8.54 (IH, s)
Example 94j: 1H NMR (400.132 MHz, DMSOd6) δ 1.23 (3H, d), 1.51 - 1.60 (2H, m), 1.62 - 1.69 (2H, m), 2.18 - 2.30 (2H, m), 3.14 - 3.24 (4H, m), 3.43 - 3.50 (2H, m), 3.61 - 3.71 (IH, m), 3.74 - 3.81 (2H, m), 3.94 - 4.02 (3H, m), 4.21 (IH, d), 4.30 - 4.38 (IH, m), 4.54 (IH, s), 4.69 - 4.77 (IH, m), 6.26 (IH, t), 6.79 (IH, s), 7.50 (2H, d), 8.20 (2H, d), 8.81 (IH, s) Example 94k: 1H NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.50 - 1.60 (2H, m), 1.63 - 1.68 (2H, m), 2.20 - 2.30 (2H, m), 3.16 - 3.28 (IH, m), 3.44 - 3.57 (IH, m), 3.61 - 3.70 (IH, m), 3.74 - 3.84 (4H, m), 3.94 - 4.05 (3H, m), 4.22 (IH, d), 4.31 - 4.38 (IH, m), 4.55 (IH, s), 6.81 (IH, s), 7.39 (IH, s), 7.56 (2H, d), 7.76 (IH, s), 8.24 (2H, d), 8.39 (IH, s), 8.84 (IH, s)
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-(oxan-4- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N-r4-r4-r(3y)-3-methylmorpholin-4-yl1-6-ri-(oxan-4- ylsulfonvπcvclopropyllpyrimidin-2-yllphenyllcarbamate
Figure imgf000924_0001
Phenyl chloro formate (0.436 mL, 3.47 mmol) was added to 4-[4-[(35)-3-methylmorpholin-4- yl] -6- [l-(oxan-4-ylsulfonyl)cyclopropyl]pyrimidin-2-yl] aniline (1.06 g, 2.31 mmol), sodium hydrogen carbonate (0.291 g, 3.47 mmol) in dioxane (40 mL) at 50C under a nitrogen atmosphere. The resulting mixture was stirred at RT for 1.5 hours. The reaction mixture was diluted with ethyl acetate (150 mL), and washed sequentially with water (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a beige solid (1.14 g).
NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.24 (3H, d), 1.52 - 1.58 (2H, m), 1.58 - 1.64 (2H, m), 1.65 - 1.77 (2H, m), 2.10 - 2.20 (2H, m), 3.17 - 3.54 (2H, m), 3.63 (2H, d), 3.74 - 3.87 (3H, m), 3.96 - 4.04 (3H, m), 4.24 (IH, d), 4.56 (IH, s), 6.83 (IH, s), 7.20 - 7.32 (3H, m), 7.42 - 7.50 (2H, m), 7.63 (2H, d), 8.28 (2H, d), 10.45 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 579; HPLC tR = 2.8 min.
4-[4-[(35)-3-Methylmorpholin-4-yll-6-[l-(oxan-4-ylsulfonvπcvclopropyllpyrimidin-2- yl] aniline
Figure imgf000925_0001
Bis(triphenylphosphine)palladium(II) chloride (0.187 g, 0.27 mmol) was added to 2-chloro-4- [(3S)-3-methylmorpholin-4-yl]-6-[l-(oxan-4-ylsulfonyl)cyclopropyl]pyrimidine (1.6 g, 3.98 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.308 g, 5.97 mmol) and 2M aqueous sodium carbonate solution (1 mL, 2.00 mmol) in a solvent mixture of DMF (5 mL), DME (12 mL), water (1 mL) and ethanol (1 mL) at RT . The resulting mixture was stirred at 9O0C for 7 hours under an inert atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL), and washed sequentially with water (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 50% ethyl acetate in isohexane, and the crude product then further purified by ion exchange chromatography using an SCX column, eluting with 7M ammonia in methanol, to give a solid. The solid was further purified by trituration with a mixture of diethyl ether and isohexane to give the desired material as a beige solid (1.0 g).
NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.22 (3H, d), 1.48 - 1.53 (2H, m), 1.55 - 1.59 (2H, m), 1.66 - 1.76 (2H, m), 2.11 - 2.18 (2H, m), 3.18 (IH, dd), 3.30 - 3.34 (2H, m), 3.47 (IH, td), 3.62 (IH, d), 3.75 (IH, d), 3.81 - 3.90 (IH, m), 3.93 - 4.05 (3H, m), 4.18 (IH, d), 4.51 (IH, s), 5.58 (2H, s), 6.62 (2H, d), 6.67 (IH, s), 8.02 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 459; HPLC tR = 2.11 min.
2-Chloro-4-[(36f)-3-methylmorpholin-4-yll-6-[l-(oxan-4-ylsulfonvπcvclopropyllpyrimidine
Figure imgf000926_0001
Aqueous sodium hydroxide solution (10 mL, 186.39 mmol) was added to 2-chloro-4-[(35)-3- methylmorpholin-4-yl]-6-(oxan-4-ylsulfonylmethyl)pyrimidine (1.5 g, 3.99 mmol), tetraethylammonium bromide (0.168 g, 0.80 mmol) andl,2-dibromoethane (2.75 mL, 31.93 mmol) in toluene (10 mL) at RT under a nitrogen atmosphere. After stirring at RT for 2 hours the reaction mixture was diluted with ethyl acetate (200 mL), and washed with water (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 60% ethyl acetate in isohexane, to give the desired material as an oil which solidified on standing (1.64 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.20 - 1.25 (3H, m), 1.50 - 1.54 (2H, m), 1.55 - 1.59 (2H, m), 1.61 - 1.72 (2H, m), 1.97 - 2.07 (2H, m), 3.18 - 3.27 (IH, m), 3.26 - 3.36 (2H, m), 3.44 (IH, td), 3.58 (IH, d), 3.65 - 3.78 (2H, m), 3.90 - 4.01 (3H, m), 4.01 - 4.10 (IH, m), 4.39 (IH, s), 6.96 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 402; HPLC tR = 1.99 min.
2-Chloro-4-r(36f)-3-methylmorpholin-4-yll-6-(oxan-4-ylsulfonylmethyl)pyrimidine
Figure imgf000926_0002
3-Chloroperoxybenzoic acid (381 mg, 2.21 mmol) was added to 2-chloro-4-[(35)-3- methylmorpholin-4-yl]-6-(oxan-4-ylsulfanylmethyl)pyrimidine (345 mg, 1.00 mmol)in DCM (10 mL) at RT under a nitrogen atmosphere. The resulting solution was stirred at RT for 2 hours then diluted with DCM (100 mL), and washed sequentially with 10% aqueous sodium metabisulphite solution (200 mL), saturated aqueous sodium hydrogencarbonate (200 mL), dried over Na2SO4, filtered and evaporated to afford crude product. The crude solid was triturated with a mixture of diethyl ether and isohexane to give the desired material as a cream solid (200 mg).
NMR Spectrum: 1H NMR (399.902 MHz. DMSOdn) δ 1.19 - 1.26 (3H, m), 1.60 - 1.76 (2H, m), 1.95 - 2.06 (2H, m), 3.19 - 3.29 (IH, m), 3.31 - 3.39 (2H, m), 3.40 - 3.65 (3H, m), 3.74 (IH, d), 3.90 - 4.04 (3H, m), 4.30 (IH, s), 4.48 (2H, s), 6.93 (IH, s)
2-Chloro-4-[(36f)-3-methylmorpholin-4-yll-6-(oxan-4-ylsulfanylmethvπpyrimidine
Figure imgf000927_0001
DIPEA (1.762 mL, 10.18 mmol) was added to oxane-4-thiol (1.203 g, 10.18 mmol), in acetonitrile (20 mL) at RT under a nitrogen atmosphere. The resulting solution was stirred at RT for 5mins then 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (2.4 g, 6.79 mmol) added. The resulting mixture was stirred at RT for 1 hour then diluted with ethyl acetate (75 mL), and washed sequentially with water (2 x 75 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 70% ethyl acetate in isohexane, to give the desired material as a brown gum (2.5 g).
NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.19 (3H, d), 1.39 - 1.51 (2H, m), 1.82 - 1.92 (2H, m), 2.92 - 3.02 (IH, m), 3.13 - 3.23 (IH, m), 3.26 - 3.37 (2H, m), 3.44 (IH, td), 3.54 - 3.66 (IH, m), 3.72 (IH, d), 3.78 - 3.88 (2H, m), 3.90 - 4.02 (2H, m), 4.31 (IH, s), 6.81 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 344; HPLC tR = 1.99 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier. Oxane-4-thiol
Figure imgf000928_0001
7M Ammonia in methanol (20 mL, 140.00 mmol) was added to 5*-(oxan-4-yl) ethanethioate (2.27 g, 14.17 mmol) at RT. The resulting solution was stirred at RT for 1 hour then the mixture concentrated in vacuo and used without further purifiaction. NMR Spectrum: none LCMS Spectrum: no mass ion; HPLC tR = 0.61 min.
ιS*-(Oxan-4-yl) ethanethioate
O r^γV O
Potassium thioacetate (4.68 g, 40.98 mmol) was added to oxan-4-yl methanesulfonate (4.2 g, 23.30 mmol), in DMA (80 mL) at RT. The resulting mixture was stirred at 650C for 18 hours. The reaction mixture was diluted with ethyl acetate (400 mL), and washed sequentially with water (2 x 150 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 30% ethyl acetate in isohexane, to give the desired material as a orange oil (2.27 g).
NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.47 - 1.65 (2H, m), 1.76 - 1.90 (2H, m), 2.35 (3H, s), 3.36 - 3.51 (2H, m), 3.53 - 3.69 (IH, m), 3.67 - 3.82 (2H, m). LCMS Spectrum: no mass ion; HPLC tR = 1.45 min.
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-(oxolan-3- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]carbamate is described below. Phenyl N- \4-\4-\(3S)-3 -methylmorpholin-4-yll -6- \ 1 -(oxolan-3 - ylsulfonyl)cvclopropyllpyrimidin-2-yllphenyllcarbamate
Figure imgf000929_0001
Phenyl chloroformate (0.297 mL, 2.36 mmol) was added to 4-[4-[(35)-3-methylmorpholin-4- yl]-6-[l-(oxolan-3-ylsulfonyl)cyclopropyl]pyrimidin-2-yl]aniline (700 mg, 1.57 mmol), sodium hydrogen carbonate (198 mg, 2.36 mmol) in dioxane (30 mL) at 50C under a nitrogen atmosphere. The resulting mixture was stirred at RT for 1.5 hours then diluted with ethyl acetate (150 mL), and washed sequentially with water (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude gum was triturated with a mixture of diethyl ether and isohexane to give the desired material as a beige solid (600 mg).
NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.25 (3H, d), 1.52 - 1.59 (2H, m), 1.64 - 1.71 (2H, m), 2.15 - 2.30 (2H, m), 3.22 (IH, td), 3.44 - 3.54 (IH, m), 3.61 - 3.70 (2H, m), 3.73 - 3.83 (2H, m), 3.94 - 4.03 (3H, m), 4.23 (IH, d), 4.30 - 4.38 (IH, m), 4.56 (IH, s), 6.84 (IH, s), 7.21 - 7.32 (3H, m), 7.41 - 7.50 (2H, m), 7.64 (2H, d), 8.30 (2H, d), 10.44 (IH, s)
4-[4-[(35)-3-Methylmorpholin-4-yll-6-[l-(oxolan-3-ylsulfonyl)cvclopropyllpyrimidin-2- yl] aniline
Figure imgf000929_0002
Bis(triphenylphosphine)palladium(II) chloride (0.233 g, 0.33 mmol) was added to 2-chloro-4- [(35)-3-methylmorpholin-4-yl]-6-[l-(oxolan-3-ylsulfonyl)cyclopropyl]pyrimidine (1.92 g, 4.95 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.627 g, 7.42 mmol) and sodium carbonate (1 mL, 2.00 mmol) in a solvent mixture of DMF (5 mL), DME (12 mL), water (1 mL) and ethanol (1 mL) at RT. The resulting mixture was stirred at 9O0C for 7 hours under an inert atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL), and washed sequentially with water (2 x 100 mL).The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 50% ethyl acetate in isohexane, to give a product that was further purified by ion exchange chromatography using an SCX column, eluting with 7M ammonia in methanol, to give a solid. The crude solid was triturated with a mixture of diethyl ether and isohexane to give the desired material as a beige solid (0.821 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.22 (3H, d), 1.49 - 1.54 (2H, m), 1.61 - 1.66 (2H, m), 2.16 - 2.26 (2H, m), 3.18 (IH, dd), 3.39 - 3.53 (IH, m), 3.59 - 3.71 (3H, m), 3.70 - 3.83 (2H, m), 3.90 - 4.01 (3H, m), 4.17 (IH, d), 4.33 (IH, q), 4.51 (IH, s), 5.57 (2H, s), 6.61 (2H, d), 6.69 (IH, s), 8.03 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 447; HPLC tR = 1.91 min.
2-Chloro-4-r(36f)-3-methylmorpholin-4-yll-6-ri-(oxolan-3-ylsulfonyl)cvclopropyllpyrimidine
Figure imgf000930_0001
Aqueous sodium hydroxide solution (10 mL, 186.39 mmol) was added to 2-chloro-4-[(35)-3- methylmorpholin-4-yl]-6-(oxolan-3-ylsulfonylmethyl)pyrimidine (1.9 g, 5.25 mmol), tetraethylammonium bromide (0.221 g, 1.05 mmol), andl,2-dibromoethane (3.62 mL, 42.01 mmol) in toluene (30 mL) at RT under a nitrogen atmosphere. After being stirred at RT for 1.5 hours the reaction mixture was diluted with ethyl acetate (200 mL), and washed with water (125 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 60% ethyl acetate in isohexane, to give the desired material as a colourless gum (1.92 g).
NMR Spectrum: none
LCMS Spectrum: m/z (ESI+)(M+H)+ = 388; HPLC tR = 1.91 min. 2-Chloro-4- [(36^-3 -methylmorpholin-4-yll-6-(oxolan-3-ylsulfonylmethyl)pyrimidine
Figure imgf000931_0001
3-Chloroperoxybenzoic acid (4.26 g, 24.68 mmol) was added to 2-chloro-4-[(35)-3- methylmorpholin-4-yl]-6-(oxolan-3-ylsulfanylmethyl)pyrimidine (3.7 g, 11.22 mmol)in DCM (200 mL) at RT under a nitrogen atmosphere. The resulting solution was stirred at RT for 2 hours then diluted with DCM (100 mL), and washed sequentially with 10% aqueous sodium metabisulphite solution (200 mL) and a saturated aqueous solution of sodium hydrogencarbonate (200 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude solid was triturated with a mixture of diethyl ether and isohexane to give the desired material as a cream solid (3.03 g).
NMR Spectrum: 1H NMR (399.902 MHz, DMSOd6) δ 1.20 - 1.26 (3H, m), 2.18 - 2.31 (2H, m), 3.20 - 3.31 (IH, m), 3.37 - 3.52 (IH, m), 3.60 (IH, d), 3.65 - 3.77 (2H, m), 3.80 - 3.89 (IH, m), 3.90 - 3.99 (3H, m), 4.03 - 4.16 (2H, m), 4.31 (IH, s), 4.49 (2H, s), 6.94 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 362; HPLC tR = 1.59 min.
2-Chloro-4-r(36f)-3-methylmorpholin-4-yll-6-(oxolan-3-ylsulfanylmethyl)pyrimidine
Figure imgf000931_0002
DIPEA (3.67 mL, 21.21 mmol) was added to oxolane-3 -thiol (2.210 g, 21.21 mmol), in acetonitrile (100 mL) at RT under a nitrogen atmosphere. The resulting solution was stirred for 5 minutes then 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (5 g, 14.14 mmol) added. The resulting mixture was stirred at RT for 1 hour then diluted with ethyl acetate (75 mL), and washed sequentially with water (2 x 75 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 70% ethyl acetate in isohexane, to give the desired material as a brown gum (3.75 g).
NMR Spectrum: 1H NMR (399.902MHz. DMSO-dfi) δ 1.17 - 1.24 (3H, m), 1.63 - 1.75 (2H, m), 2.17 - 2.30 (2H, m), 3.19 (IH, td), 3.40 - 3.50 (2H, m), 3.59 (IH, d), 3.63 - 3.80 (3H, m), 3.91 - 4.04 (4H, m), 4.33 (IH, s), 6.82 (IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 330; HPLC tR = 1.89 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Oxolane-3 -thiol or
7M ammonia in methanol (20 mL, 140.00 mmol) was added to 5*-(Oxolan-3-yl) ethanethioate (20.47 g, 140.00 mmol) at RT. The resulting solution was stirred at RT for 1 hour then concentrated in vacuo to give the desired material which was used without further purification or characterisation.
ιS*-(Oxolan-3-yl) ethanethioate
oJ o Potassium thioacetate (16.60 g, 145.31 mmol) was added to oxolan-3-yl methanesulfonate (13.8 g, 83.03 mmol), in DMA (150 mL) at RT. The resulting mixture was stirred at 650C for 7 hours. The reaction mixture was diluted with ethyl acetate (400 mL), and washed sequentially with water (2 x 150 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% ethyl acetate in isohexane, to give the desired material as a brown oil (9.50 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.70 - 1.80 (IH, m), 2.25 - 2.40 (4H, m), 3.44 - 3.52 (IH, m), 3.67 - 3.81 (2H, m), 3.84 - 3.94 (IH, m), 3.97 - 4.08 (IH, m) LCMS Spectrum: no mass ion; HPLC tR = 1.18 min. Oxolan-3-yl methanesulfonate
S
\J Oo' b
Methanesulfonyl chloride (11.86 mL, 153.23 mmol) was added dropwise to tetrahydrofuran- 3-ol (9 g, 102.15 mmol) and triethylamine (21.36 mL, 153.23 mmol) in DCM (300 mL) at RT over a period of 30 minutes under a nitrogen atmosphere. The resulting mixture was stirred at RT for 1 hour then diluted with ethyl acetate (400 mL) and washed with water (250 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford the desired material, which was used without further purification. NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 2.03 - 2.14 (IH, m), 2.17 - 2.29 (IH, m), 3.21 (3H, s), 3.69 - 3.92 (4H, m), 5.28 - 5.33 (IH, m)
Example 95
The following samples were prepared by heating a mixture of the carbamate (1 equivalent), triethylamine (4 equivalents) and the amine (1.2 equivalents) in NMP (2 mL) at 5O0C for 2 hours. The compounds were purified by preparative HPLC.
The following compounds were prepared in an analogous fashion from either phenyl N- [4- [4- [ 1 -(3 -chloro-4-fluorophenyl)sulfonylcyclopropyl] -6- [(35)-3 -methylmorpholin-4-yl]pyrimidin- 2-yl]phenyl] carbamate or phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-[ 1 -(4- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]carbamate and the appropriate amine.
Figure imgf000933_0001
Figure imgf000934_0001
Figure imgf000935_0001
Figure imgf000936_0001
Figure imgf000937_0001
4 equivalents of amine used.
Example 95a: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.59 - 1.64 (2H, m), 1.90 - 1.98 (2H, m), 2.68 (3H, s), 3.12 - 3.23 (IH, m), 3.46 (IH, dd), 3.61 (IH, d), 3.75 (IH, d), 3.96 (IH, d), 4.15 (IH, d), 4.48 (IH, s), 6.04 (IH, s), 6.67 (IH, s), 7.39 (2H, d), 7.58 - 7.68 (IH, m), 7.73 - 7.83 (3H, m), 7.99 (IH, d), 8.74 (IH, s)
Example 95b: 1H NMR (400.132 MHz, DMSOd6) δ 0.37 - 0.44 (2H, m), 0.60 - 0.69 (2H, m), 1.20 (3H, d), 1.60 - 1.64 (2H, m), 1.89 - 1.98 (2H, m), 2.56 - 2.60 (IH, m), 3.11 - 3.23 (IH, m), 3.42 - 3.52 (IH, m), 3.61 (IH, d), 3.75 (IH, d), 3.95 (IH, d), 4.15 (IH, d), 4.49 (IH, s), 6.39 (IH, s), 6.67 (IH, s), 7.40 (2H, d), 7.57 - 7.68 (IH, m), 7.73 - 7.85 (3H, m), 7.92 - 8.03 (IH, m), 8.54 (IH, s) Example 95c: 1R NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.59 - 1.64 (2H, m), 1.91 -
1.96 (2H, m), 3.14 - 3.22 (2H, m), 3.40 - 3.50 (3H, m), 3.61 (IH, d), 3.75 (IH, d), 3.96 (IH, d), 4.16 (IH, d), 4.48 (IH, s), 4.72 (IH, t), 6.23 (IH, s), 6.67 (IH, s), 7.38 (2H, d), 7.63 (IH, t), 7.75 - 7.84 (3H, m), 7.98 (IH, d), 8.80 (IH, s)
Example 95d: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.59 - 1.65 (2H, m), 1.88 -
1.97 (2H, m), 3.36 - 3.51 (4H, m), 3.62 (IH, d), 3.75 (IH, d), 3.95 (IH, d), 4.12 - 4.23 (IH, m), 4.41 (IH, t), 4.45 - 4.51 (IH, m), 4.53 (IH, t), 6.40 (IH, s), 6.68 (IH, s), 7.39 (2H, d), 7.60 - 7.69 (IH, m), 7.72 - 7.86 (3H, m), 7.99 (IH, d), 8.81 (IH, s) Example 95e: 1R NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.59 - 1.65 (2H, m), 1.89 - 1.97 (2H, m), 3.12 - 3.22 (IH, m), 3.41 - 3.64 (3H, m), 3.75 (IH, d), 3.96 (IH, d), 4.15 (IH, d), 4.49 (IH, s), 5.87 - 6.22 (IH, m), 6.49 (IH, t), 6.68 (IH, s), 7.40 (2H, d), 7.63 (IH, t), 7.77 - 7.86 (3H, m), 7.97 - 8.00 (IH, m), 8.92 (IH, s) Example 95f: 1H NMR (400.132 MHz, DMSO-d6) δ 1.07 (3H, t), 1.20 (3H, d), 1.59 - 1.65 (2H, m), 1.90 - 1.98 (2H, m), 3.09 - 3.21 (3H, m), 3.42 - 3.52 (IH, m), 3.61 (IH, d), 3.75 (IH, d), 3.96 (IH, d), 4.09 - 4.21 (IH, m), 4.44 - 4.53 (IH, m), 6.12 (IH, t), 6.67 (IH, s), 7.39 (2H, d), 7.63 (IH, t), 7.75 - 7.85 (3H, m), 7.99 (IH, d), 8.66 (IH, s) Example 95g: 1R NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.59 - 1.66 (2H, m), 1.91 - 1.99 (2H, m), 3.11 - 3.21 (IH, m), 3.47 (IH, td), 3.62 (IH, d), 3.70 - 3.83 (4H, m), 3.96 (IH, d), 4.17 (IH, d), 4.49 (IH, s), 6.69 (IH, s), 7.38 (IH, s), 7.44 (2H, d), 7.64 (IH, t), 7.75 - 7.85 (3H, m), 7.99 (IH, d), 8.34 (IH, s), 8.84 (IH, s) Example 95h: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.53 - 1.59 (2H, m), 1.77 - 1.83 (2H, m), 2.63 - 2.67 (3H, m), 2.82 (3H, d), 3.10 - 3.19 (IH, m), 3.46 (IH, dd), 3.61 (IH, d), 3.75 (IH, d), 3.95 (IH, d), 4.09 (IH, d), 4.39 (IH, s), 6.00 - 6.08 (IH, m), 6.47 (IH, t), 6.59 (IH, s), 6.70 (IH, d), 7.41 (2H, d), 7.48 - 7.57 (2H, m), 7.94 (2H, d), 8.70 (IH, s) Example 95i: 1U NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.53 - 1.60 (2H, m), 1.77 - 1.83 (2H, m), 3.14 - 3.19 (2H, m), 3.25 - 3.32 (2H, m), 3.39 - 3.50 (3H, m), 3.55 - 3.65 (3H, m), 3.75 (IH, d), 3.96 (IH, d), 4.10 (IH, d), 4.38 (IH, s), 4.73 (IH, t), 4.82 (IH, t), 6.15 (IH, t), 6.24 (IH, t), 6.59 (IH, s), 6.84 (IH, d), 7.40 (2H, d), 7.48 (2H, d), 7.54 (IH, d), 7.95 (2H, d), 8.76 (IH, s)
Example 95j: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.52 - 1.60 (2H, m), 1.78 - 1.83 (2H, m), 3.09 - 3.19 (IH, m), 3.35 - 3.49 (4H, m), 3.52 - 3.58 (IH, m), 3.57 - 3.65 (2H, m), 3.74 (IH, d), 3.95 (IH, d), 4.07 (IH, d), 4.37 - 4.44 (2H, m), 4.49 - 4.55 (IH, m), 4.63 (IH, t), 6.38 - 6.50 (2H, m), 6.58 (IH, s), 6.89 (IH, d), 7.40 (2H, d), 7.48 (2H, d), 7.53 (IH, s), 7.96 (2H, d), 8.76 (IH, s) Example 95k: 1H NMR (400.132 MHz, DMSOd6) δ 1.06 (3H, t), 1.13 - 1.21 (6H, m), 1.49 -
1.58 (2H, m), 1.78 - 1.82 (2H, m), 3.08 - 3.18 (2H, m), 3.22 - 3.33 (7H, m), 3.46 (IH, dd), 3.61 (IH, d), 3.74 (IH, d), 3.95 (IH, d), 4.09 (IH, d), 4.39 (IH, s), 6.13 (IH, t), 6.28 (IH, t),
6.59 (IH, s), 6.77 (IH, d), 7.39 (2H, d), 7.46 (2H, d), 7.52 (IH, s), 7.96 (2H, d), 8.61 (IH, s) Example 951: 1U NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 1.56 - 1.64 (2H, m), 1.82 - 1.89 (2H, m), 2.40 (3H, s), 2.68 (3H, s), 3.08 - 3.17 (IH, m), 3.45 (IH, td), 3.60 (IH, d), 3.74 (IH, d), 3.95 (IH, d), 4.10 (IH, d), 4.38 (IH, s), 6.04 (IH, t), 6.61 (IH, s), 7.33 - 7.44 (4H, m), 7.66 (2H, d), 7.82 (2H, d), 8.70 (IH, s)
Example 95m: 1H NMR (400.132 MHz, DMSOd6) δ 0.42 - 0.50 (2H, m), 0.66 - 0.75 (2H, m), 1.23 (3H, d), 1.60 - 1.69 (2H, m), 1.87 - 1.98 (2H, m), 2.46 (3H, s), 2.62 - 2.70 (IH, m), 3.19 (IH, td), 3.46 - 3.57 (IH, m), 3.66 (IH, d), 3.80 (IH, d), 4.01 (IH, d), 4.16 (IH, d), 4.43 (IH, s), 6.46 (IH, s), 6.67 (IH, s), 7.39 - 7.49 (4H, m), 7.71 (2H, d), 7.88 (2H, d), 8.56 (IH, s) Example 95n: 1H NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 1.57 - 1.65 (2H, m), 1.83 - 1.90 (2H, m), 2.42 (3H, s), 3.13 - 3.20 (3H, m), 3.40 - 3.50 (3H, m), 3.60 (IH, d), 3.74 (IH, d), 3.95 (IH, d), 4.09 (IH, d), 4.37 (IH, s), 4.72 (IH, t), 6.22 (IH, t), 6.61 (IH, s), 7.35 - 7.43 (4H, m), 7.66 (2H, d), 7.82 (2H, d), 8.77 (IH, s) Example 95o: 1R NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 1.56 - 1.65 (2H, m), 1.81 -
1.90 (2H, m), 2.40 (3H, s), 3.07 - 3.22 (IH, m), 3.36 - 3.50 (3H, m), 3.60 (IH, d), 3.74 (IH, d), 3.96 (IH, d), 4.12 (IH, d), 4.33 - 4.45 (2H, m), 4.53 (IH, t), 6.41 (IH, t), 6.61 (IH, s), 7.34 - 7.43 (4H, m), 7.66 (2H, d), 7.83 (2H, d), 8.77 (IH, s)
Example 95p: 1H NMR (400.132 MHz, DMSOd6) δ 1.17 (3H, d), 1.56 - 1.65 (2H, m), 1.82 -
1.91 (2H, m), 2.40 (3H, s), 3.10 - 3.18 (IH, m), 3.41 - 3.65 (4H, m), 3.74 (IH, d), 3.96 (IH, d), 4.09 (IH, d), 4.37 (IH, s), 5.91 - 6.23 (IH, m), 6.50 (IH, t), 6.62 (IH, s), 7.35 - 7.44 (4H, m), 7.66 (2H, d), 7.84 (2H, d), 8.89 (IH, s) Example 95q: 1H NMR (400.132 MHz, DMSOd6) δ 1.06 (3H, t), 1.17 (3H, d), 1.52 - 1.66 (2H, m), 1.85 - 1.90 (2H, m), 2.40 (3H, s), 3.07 - 3.20 (3H, m), 3.45 (IH, td), 3.60 (IH, d), 3.74 (IH, d), 3.95 (IH, d), 4.12 (IH, d), 4.37 (IH, s), 6.13 (IH, t), 6.61 (IH, s), 7.35 - 7.44 (4H, m), 7.66 (2H, d), 7.82 (2H, d), 8.62 (IH, s) Example 95r: 1R NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.57 - 1.66 (2H, m), 1.84 - 1.90 (2H, m), 2.41 (3H, s), 3.08 - 3.18 (IH, m), 3.46 (IH, td), 3.61 (IH, d), 3.72 - 3.83 (4H, m), 3.96 (IH, d), 4.10 (IH, d), 4.37 (IH, s), 6.62 (IH, s), 7.35 - 7.49 (5H, m), 7.66 (2H, d), 7.76 (IH, s), 7.86 (2H, d), 8.35 (IH, s), 8.80 (IH, s)
The preparation of phenyl Λ/-[4-[4-[l-(3-chloro-4-fluorophenyl)sulfonylcyclopropyl]-6-[(35)- 3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below. Phenyl N- \4- \4-\ 1 -(3 -chloro-4-fluorophenyl)sulfonylcvclopropyll -6- [(36^-3 - methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000940_0001
Sodium hydrogen carbonate (0.501 g, 5.96 mmol) was added to 4-[4-[l-(3-chloro-4- fluorophenyl)sulfonylcyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (2 g, 3.98 mmol) in dioxane (30 mL) at 50C under nitrogen. Phenyl chloro formate (0.749 mL, 5.96 mmol) was then added and the resulting mixture stirred at RT for 2 hours. The reaction mixture was diluted with DCM (50 mL) and washed with water (75 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was triturated with a mixture of diethyl ether and isohexane to give the desired material as a cream solid (1.45 g).
NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.21 (3H, d), 1.59 - 1.66 (2H, m), 1.91 - 1.96 (2H, m), 3.12 - 3.24 (IH, m), 3.40 - 3.52 (IH, m), 3.62 (IH, d), 3.75 (IH, d), 3.96 (IH, d), 4.18 (IH, d), 4.50 (IH, s), 6.74 (IH, s), 7.23 - 7.32 (3H, m), 7.41 - 7.49 (2H, m), 7.54 (2H, d), 7.58 - 7.68 (IH, m), 7.79 - 7.83 (IH, m), 7.88 (2H, d), 7.96 - 8.02 (IH, m), 10.40 (IH, s) LCMS Spectrum: m/z (ESI+)(M+H)+ = 622; HPLC tR = 3.21 min.
4- [4- [ 1 -(3 -Chloro-4-fluorophenvπsulfonylcvclopropyll -6-\(3S)-3 -methylmorpholin-4- yllpyrimidin-2-vHaniline
Figure imgf000940_0002
Bis(triphenylphosphine)palladium(II) chloride (0.242 g, 0.35 mmol) was added to 2-chloro-4- [l-(3-chloro-4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yljpyrimidine (2.3 g, 5.15 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.411 g, 6.44 mmol) and 2M aqueous sodium carbonate solution (3 mL, 6.00 mmol) in a solvent mixture of DMF (5 mL), DME (8 mL), water (2 mL) and ethanol (1.5 mL) at RT. The resulting mixture was stirred at 9O0C, under an inert atmosphere for 5 hours then left at RT for 16 hours. The reaction mixture was diluted with ethyl acetate (200 mL), and washed sequentially with water (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 80% ethyl acetate in isohexane, to give the desired material as a yellow gum (2.0 g). NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.18 (3H, d), 1.57 - 1.61 (2H, m), 1.87 - 1.96 (2H, m), 3.14 (IH, td), 3.41 - 3.50 (IH, m), 3.60 (IH, d), 3.74 (IH, d), 3.95 (IH, d), 4.13 (IH, d), 4.44 (IH, s), 5.52 (IH, d), 6.49 (2H, d), 6.57 (IH, s), 7.57 - 7.68 (3H, m), 7.75 - 7.85 (IH, m), 7.99 (IH, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 503; HPLC tR = 2.66 min.
2-Chloro-4-ri-(3-chloro-4-fluorophenyl)sulfonylcvclopropyll-6-r(36f)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000941_0001
Aqueous sodium hydroxide solution (20 mL, 142.76 mmol) was added to 2-chloro-4-[(3- chloro-4-fluorophenyl)sulfonylmethyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (2.5 g, 5.95 mmol), 1 ,2-dibromoethane (2.56 mL, 29.74 mmol) and tetrabutylammonium bromide (0.192 g, 0.59 mmol) in toluene (100 mL) at RT under a nitrogen atmosphere and the mixture stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 100% ethyl acetate in isohexane, to give the desired material as a colourless gum (2.3 g). NMR Spectrum: 1H NMR (400.132 MHz. DMSO-(U δ 7.98 (IH. d). 1.18 (3H, d), 1.54 - 1.61 (2H, m), 1.84 - 1.91 (2H, m), 3.15 (IH, td), 3.36 - 3.45 (IH, m), 3.55 (IH, d), 3.70 (IH, d), 3.90 (IH, d), 4.08 (IH, s), 4.31 (IH, s), 6.74 (IH, s), 7.62 - 7.71 (IH, m), 7.76 - 7.83 (IH, m) LCMS Spectrum: m/z (ESI+)(M+H)+ = 446; HPLC tR = 2.56 min.
2-Chloro-4-r(3-chloro-4-fluorophenyl)sulfonylmethyll-6-r(3S)-3-methylmorpholin-4- yllpyrimidine
Figure imgf000942_0001
Sodium 3-chloro-4-fluorobenzenesulfinate (3.52 g, 16.26 mmol) was added to 2-chloro-4- (iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (5 g, 14.14 mmol) in acetonitrile (150 mL) at RT under a nitrogen atmosphere. The resulting mixture was stirred at 8O0C for 3 hours. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with water (100 mL), The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 70% ethyl acetate in isohexane, to give a colourless oil which solidified on standing. The crude solid was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (4.0 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18 (3H, d), 3.18 (IH, dd), 3.28 (IH, d), 3.43 (IH, td), 3.58 (IH, d), 3.72 (IH, d), 3.94 (IH, d), 4.21 (IH, s), 4.73 (2H, s), 6.78 (IH, s), 7.66 - 7.74 (IH, m), 7.78 - 7.87 (IH, m), 8.02 (IH, d)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 420; HPLC tR = 2.38 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Sodium 3-chloro-4-fluorobenzenesulfinate
[Na]+
Figure imgf000942_0002
A solution of sodium sulfite (8.25 g, 65.49 mmol) in water (75 mL) was stirred at RT for 10 minutes. Sodium bicarbonate (11.0 g, 130.97 mmol) was added to the stirred solution and the resulting solution stirred at 500C for 1 hour. 3-Chloro-4-fiuorobenzene-l-sulfonyl chloride (15 g, 65.49 mmol) was added portionwise to the solution and was stirred at 500C for 18 hours. The reaction mixture was evaporated to dryness and redissolved in methanol (300 mL). The suspension was allowed to stir at RT for 20 minutes then filtered and the filtrate evaporated to afford the desired material as a white solid, which was air dried overnight under vacuum and used without further purification (16.5 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 7.34 (IH, t), 7.40 - 7.46 (IH, m), 7.58 (IH, d)
The preparation of phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-(4- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl N-r4-r4-r(3^-3-methylmorpholin-4-yll-6-π -(4- methylphenvπsulfonylcvclopropyllpyrimidin-2-yllphenyllcarbamate
Figure imgf000943_0001
Sodium hydrogen carbonate (0.570 g, 6.78 mmol) was added to 4-[4-[(35)-3- methylmorpholin-4-yl]-6-[ 1 -(4-methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]aniline (2.1 g, 4.52 mmol) in dioxane (6 mL) at 50C under a nitrogen atmosphere. Phenyl chloroformate (0.852 mL, 6.78 mmol) was then added and the resulting mixture stirred at RT for 2 hours. The reaction mixture was diluted with DCM (50 mL) and washed with water (75 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude gum was triturated with a mixture of diethyl ether and isohexane to give the desired material as a cream solid (1.52 g).
NMR Spectrum: 1H NMR (400.132 MHz. DMSOdn) δ 1.17 (3H, d), 1.58 - 1.64 (2H, m), 1.85 - 1.91 (2H, m), 2.40 (3H, s), 3.09 - 3.23 (IH, m), 3.41 - 3.51 (IH, m), 3.60 (IH, d), 3.75 (IH, d), 3.96 (IH, d), 4.12 (IH, d), 4.39 (IH, s), 6.65 (IH, s), 7.21 - 7.31 (3H, m), 7.36 - 7.41 (2H, m), 7.42 - 7.48 (2H, m), 7.50 - 7.56 (2H, m), 7.63 - 7.71 (2H, m), 7.89 (2H, d), 10.38
(IH, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 535; HPLC tR = 3.1 min.
4-[4-[(35)-3-Methylmorpholin-4-yll-6-[l-(4-methylphenvπsulfonylcvclopropyllpyrimidin-2- yll aniline
Figure imgf000944_0001
Bis(triphenylphosphine)palladium(II) chloride (0.225 g, 0.32 mmol) was added to 2-chloro-4- [(35)-3-methylmorpholin-4-yl]-6-[l-(4-methylphenyl)sulfonylcyclopropyl]pyrimidine (1.95 g, 4.78 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.362 g, 6.21 mmol) and 2M aqueous sodium carbonate solution (3 mL, 6.00 mmol) in a solvent mixture of DMF (5 mL), DME (8 mL), water (2 mL) and ethanol (1.5 mL) at RT. The resulting mixture was stirred at 9O0C for 5 hours under an inert atmosphere, then left at RT for 16 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 80% ethyl acetate in isohexane, to give crude material which was further purified by ion exchange chromatography using an SCX column, eluting with 7M ammonia in methanol, to give the desired material as a white solid (2.1 g). NMR Spectrum: 1H NMR (400.132 MHz. DMSOdn) δ 1.15 (3H, d), 1.54 - 1.63 (2H, m), 1.81 - 1.89 (2H, m), 1.99 (3H, s), 3.11 (IH, td), 3.37 - 3.49 (IH, m), 3.59 (IH, d), 3.73 (IH, d), 3.94 (IH, d), 4.06 (IH, s), 4.32 (IH, s), 5.50 (IH, s), 6.50 (3H, d), 7.38 (2H, d), 7.62 - 7.72 (4H, m) LCMS Spectrum: m/z (ESI+)(M+H)+ = 465; HPLC tR = 2.48 min. 2-Chloro-4-r(3^-3-methylmorpholin-4-yll-6-ri-(4- methylphenvDsulfonylcvclopropyHpyrimidine
Figure imgf000945_0001
Aqueous sodium hydroxide solution (20 mL, 125.69 mmol) was added to 2-chloro-4-[(35)-3- methylmorpholin-4-yl]-6-[(4-methylphenyl)sulfonylmethyl]pyrimidine (2 g, 5.24 mmol), 1,2- dibromoethane (2.257 mL, 26.19 mmol) and tetrabutylammonium bromide (0.169 g, 0.52 mmol) in DCM (100 mL) at RT under a nitrogen atmosphere then stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 60% ethyl acetate in isohexane, to give the desired material as a colourless gum (1.9 g). NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.13 (3H, d), 1.52 - 1.56 (2H, m), 1.79 - 1.84 (2H, m), 1.99 (3H, s), 3.12 (IH, td), 3.35 - 3.47 (IH, m), 3.54 (IH, d), 3.71 (IH, d), 3.84 - 3.95 (2H, m), 4.17 (IH, s), 6.63 (IH, s), 7.41 (2H, d), 7.63 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 408; HPLC tR = 2.35 min.
2-Chloro-4-r(36f)-3-methylmorpholin-4-yll-6-r(4-methylphenyl)sulfonylmethyllpyrimidine
Figure imgf000945_0002
Sodium 4-methylbenzenesulfinate (2.9 g, 16.28 mmol) was added to 2-chloro-4-(iodomethyl)- 6-[(35)-3-methylmorpholin-4-yl]pyrimidine (5 g, 14.14 mmol), in acetonitrile (150 mL) at RT under a nitrogen atmosphere. The resulting mixture was stirred at 8O0C for 3 hours. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in isohexane, to give the desired material as a beige solid (3.10 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.15 (3H, d), 2.41 (3H, s), 3.14 (IH, td), 3.38 - 3.46 (IH, m), 3.56 (IH, d), 3.71 (IH, d), 3.80 - 3.96 (2H, m), 4.13 (IH, s), 4.60 (2H, s), 6.60 (IH, s), 7.43 (2H, d), 7.66 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 382; HPLC tR = 2.16 min.
The preparation of 2-chloro-4-(iodomethyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidine was described earlier.
Sodium 4-methylbenzenesulfinate o rf^V^cr [Na]+
A solution of sodium sulfite (9.92 g, 78.68 mmol) in water (75 mL) was stirred at RT for 10 minutes. Sodium bicarbonate (13.22 g, 157.36 mmol) was added to the stirred solution. The resulting solution was stirred at 500C for 1 hour. 4-Methylbenzene-l-sulfonyl chloride (15 g, 78.68 mmol) was added portionwise to the solution and was stirred at 500C for 18 hours. The reaction mixture was evaporated to dryness and redissolved in methanol (400 mL). The suspension was allowed to stir at RT for 20 minutes then filtered and the filtrate evaporated to afford the desired material as a white solid, which was air dried overnight under vacuum and used without further purification (17.3 g).
Example 96
The following samples were prepared by heating a mixture of the carbamate (1 equivalent), triethylamine (4 equivalents) and the amine (4 equivalents) in NMP (2 mL) at RT for between 2 -16 hours. The compounds were purified by preparative HPLC.
The following compounds were prepared in an analogous fashion from phenyl N-[4-[4-[l-[3- (difluoromethoxy)propylsulfonyl]cyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]carbamate (contaminated with phenyl 7V-[4-[4-[l-[3-
(difiuoromethoxy)propylsulfonyl]propyl] -6- [(35)-3 -methylmorpholin-4-yl]pyrimidin-2- yljphenyl] carbamate) and the appropriate amine.
Figure imgf000947_0001
Figure imgf000948_0001
Example 96a: 1H NMR (400.132 MHz, DMSO-Cl6) δ 1.23 (3H, d), 1.54 - 1.59 (2H, m), 1.62 - 1.69 (2H, m), 2.09 - 2.18 (2H, m), 3.17 - 3.25 (IH, m), 3.35 - 3.42 (IH, m), 3.43 - 3.52 (2H, m), 3.56 - 3.66 (3H, m), 3.78 (IH, d), 3.94 - 4.02 (3H, m), 4.21 (IH, d), 4.42 (IH, t), 4.52 - 4.60 (2H, m), 6.43 (IH, t), 6.47 - 6.89 (IH, m), 6.77 (IH, s), 7.49 (2H, d), 8.20 (2H, d), 8.81 (IH, s)
Example 96b: 1H NMR (400.132 MHz, DMSOd6) δ 1.23 (3H, d), 1.53 - 1.60 (2H, m), 1.62 - 1.69 (2H, m), 2.08 - 2.17 (2H, m), 3.16 - 3.25 (IH, m), 3.43 - 3.66 (6H, m), 3.76 (IH, d), 3.94 - 4.00 (3H, m), 4.22 (IH, d), 4.56 (IH, s), 5.91 - 6.23 (IH, m), 6.43 - 6.88 (IH, m), 6.52 (IH, t), 6.77 (IH, s), 7.50 (2H, d), 8.21 (2H, d), 8.93 (IH, s)
Example 96c: 1R NMR (400.132 MHz, DMSO-(I6) δ 1.08 (3H, t), 1.23 (3H, d), 1.54 - 1.60 (2H, m), 1.63 - 1.69 (2H, m), 2.09 - 2.18 (2H, m), 3.07 - 3.25 (3H, m), 3.48 (IH, td), 3.55 - 3.66 (3H, m), 3.76 (IH, d), 3.93 - 4.01 (3H, m), 4.21 (IH, d), 4.56 (IH, s), 6.15 (IH, t), 6.42 - 6.88 (IH, m), 6.76 (IH, s), 7.49 (2H, d), 8.18 (2H, d), 8.66 (IH, s) Example 96d: 1H NMR (400.132 MHz, DMSO-d6) δ 1.24 (3H, d), 1.55 - 1.60 (2H, m), 1.63 - 1.69 (2H, m), 2.09 - 2.18 (2H, m), 3.18 - 3.26 (IH, m), 3.44 - 3.53 (IH, m), 3.55 - 3.67 (3H, m), 3.72 - 3.80 (4H, m), 3.93 - 4.03 (3H, m), 4.22 (IH, d), 4.57 (IH, s), 6.43 - 6.86 (IH, m), 6.78 (IH, s), 7.38 (IH, s), 7.54 (2H, d), 7.77 (IH, s), 8.22 (2H, d), 8.37 (IH, s), 8.85 (IH, s) Example 96e: 1R NMR (400.132 MHz, DMSO-de) δ 0.38-0.40 (2H,m), 0.61-0.64 (2H,m), 1.20-1.22 (3H,d), 1.51-1.53 (2H,m), 1.61-1.64 (2H,m), 2.18-2.24 (2H,m), 2.52-2.58 (lH,m), 3.18-3.20 (lH,dd), 3.55-3.68 (3H,m), 3.72-3.78 (lH,m), 3.90-3.95 (3H,m), 4.20 (lH,s), 4.55 (lH,s), 6.40 (lH,s), 6.60 (lH,s), 7.45 (2H,d), 8.18 (2H,d), 8.54 (lH,s) The preparation of phenyl Λ/-[4-[4-[l-[3-(difluoromethoxy)propylsulfonyl]cyclopropyl]-6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl JV-[4-[4-[ 1 -[3-(difluoromethoxy)propylsulfonyllcvclopropyll-6-[(3y)-3- methylmorpholin-4-yllpyrimidin-2-yllphenyllcarbamate
Figure imgf000949_0001
Sodium hydrogen carbonate (65.3 mg, 0.78 mmol) was added to 4-[4-[l-[3- (difluoromethoxy)propylsulfonyl]cyclopropyl]-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-2- yljaniline (contaminated with 4-[4-[l-[3-(difluoromethoxy)propylsulfonyl]propyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2 -yljaniline) (250 mg, 0.52 mmol) in dioxane (6 mL) at 50C under a nitrogen atmosphere. Phenyl chloroformate (0.098 mL, 0.78 mmol) was added and the resulting mixture stirred at RT for 2 hours. The reaction mixture was diluted with DCM (50 mL), the organics dried over Na2SO4, filtered and evaporated to afford crude product. The crude material was triturated with a mixture of diethyl ether and isohexane to give the desired material (contaminated with phenyl Λ/-[4-[4-[l-[3-(difluoromethoxy)propylsulfonyl]propyl]- 6- [(35)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] carbamate) as a cream solid (200 mg). The material was used without further purification. NMR Spectrum: none LCMS Spectrum: m/z (ESI+)(M+H)+ = 604; HPLC tR = 2.97 min.
4- [4- r 1 -[3 -(Difluoromethoxy)propylsulfonyllcvclopropyH -6- [(36^-3 -methylmorpholin-4- yllpyrimidin-2-vH aniline
Figure imgf000949_0002
5% Palladium on charcoal (400 mg, 3.6 mmol) was added to 4-[l-[3- (difluoromethoxy)propylsulfonyl]cyclopropyl] -6- [(35)-3 -methylmorpholin-4-yl] -2-(4- nitrophenyl)pyrimidine (2 g, 3.90 mmol) in ethyl acetate (200 mL) and methanol (30 mL) at RT. The flask was evacuated and the atmosphere replaced with first nitrogen and then hydrogen and the mixture left to stir under hydrogen at RT for 36 hours. The crude product was purified by flash silica chromatography, elution gradient 30 to 90% ethyl acetate in isohexane, to give a white solid (1.7 g) which appears to be the desired material (-30%) contaminated with 4-[4-[ 1 -[3-(difluoromethoxy)propylsulfonyl]propyl]-6-[(35)-3- methylmorpholin-4-yl]pyrimidin-2-yl]aniline (-60%). The material was used without further purification.
NMR Spectrum: none
LCMS Spectrum: m/z (ESI+)(M+H)+ = 483; HPLC tR = 1.76 min.
LCMS Spectrum: (4-[4- [ 1 - [3 -(difluoromethoxy)propylsulfonyl]propyl] -6- [(3 S)-3 - methylmorpholin-4-yl]pyrimidin-2-yl]aniline) m/z (ESI+)(M+H)+ = 485; HPLC tR = 2.0 min.
4- [ 1 - [3 -(Difluoromethoxy)propylsulfonyllcvclopropyll -6-\(3S)-3 -methylmorpholin-4-yll -2- (4-nitrophenvDpyrimidine
Figure imgf000950_0001
A solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (4.56 mL, 44.11 mmol) in acetonitrile (25 mL) was added dropwise over 1.5 hours to a stirred solution of 3-[l-[6-[(35)-3- methylmorpholin-4-yl]-2-(4-nitrophenyl)pyrimidin-4-yl]cyclopropyl]sulfonylpropan-l-ol (3.4g, 7.35 mmol) and copper(I) iodide (280 mg, 1.47 mmol) in acetonitrile (100 mL) at 550C under a nitrogen atmosphere. The mixture was stirred at 550C for a further 1 hour then diluted with ethyl acetate (300 mL) and washed with water (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 50% ethyl acetate in isohexane, to give the desired material as a yellow solid (2.0 g). NMR Spectrum: 1H NMR (400.132 MHz. DMSO-(U δ 1.26 (3H, d), 1.59 - 1.64 (2H, m), 1.67 - 1.72 (2H, m), 2.11 - 2.17 (2H, m), 3.22 - 3.28 (IH, m), 3.46 - 3.59 (3H, m), 3.65 (IH, d), 3.78 (IH, d), 3.93 - 4.01 (3H, m), 4.25 (IH, s), 4.61 (IH, s), 6.96 (IH, s), 8.33 (2H, d), 8.55 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 513; HPLC tR = 2.87 min.
3-ri-r6-r(3y)-3-Methylmorpholin-4-yl1-2-(4-nitrophenvπpyrimidin-4- yllcvclopropyllsulfonylpropan-l-ol
Figure imgf000951_0001
Bis(triphenylphosphine)palladium(II) chloride (0.636 g, 0.91 mmol) was added to 3-[l-[2- chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]sulfonylpropoxy- tri(propan-2-yl)silane (7.2 g, 13.53 mmol), 2M aqueous sodium carbonate solution (15 mL, 30.00 mmol) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)nitrobenzene (6.74 g, 27.06 mmol) in DME (100 mL) and water (5 mL) at RT. The mixture was stirred at 9O0C for 16 hours under a nitrogen atmosphere then allowed to cool. The reaction mixture was diluted with ethyl acetate (400 mL), and washed sequentially with water (100 mL) then additional water (200 mL).The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was dissolved in DCM then tetrabutylammonium fluoride (67.6 mL, 67.64 mmol) added and left to stir for 1 hour. A saturated aqueous solution of ammonium chloride was added, the organics separated and dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 10 to 100% ethyl acetate in isohexane, to give crude material which was further purified by ion exchange chromatography using an SCX column, eluting with 7M ammonia in methanol, to give the desired material as a brown solid (3.60 g). NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.26 (3H, d), 1.56 - 1.63 (2H, m), 1.66 - 1.70 (2H, m), 1.91 - 1.98 (2H, m), 3.22 - 3.29 (3H, m), 3.47 - 3.57 (3H, m), 3.65 (IH, d), 3.78 (IH, d), 3.99 (IH, dd), 4.25 (IH, d), 4.60 (IH, s), 4.72 (IH, t), 6.96 (IH, s), 8.33 (2H, d), 8.58 (2H, d) LCMS Spectrum: m/z (ESI+)(M+H)+ = 463; HPLC tR = 2.37 min.
The preparation of 3-[l-[2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4- yl]cyclopropyl]sulfonylpropoxy-tri(propan-2-yl)silane was described earlier.
5
Example 97: 3-Methyl-l-[4-[4-[l-f2-methylaminoethylsulfonyl)cvclopropyll-6- morpholin-4-ylpyrimidin-2-yll phenyll urea
Figure imgf000952_0001
Methylamine (2 M in THF, 4 equivalents) was added to phenyl 7V-[4-[4-[l-[2- i o (difluoromethoxy)ethylsulfonyl] cyclopropyl] -6-morpholin-4-ylpyrimidin-2- yl]phenyl] carbamate in NMP and resulting solution stirred at RT for 30 minutes then purified by preparative HPLC to give the desired material (0.012 g)
NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.52 - 1.57 (2H, m), 1.62 - 1.66 (2H, m), 2.67 (3H, d), 2.92 - 3.01 (2H, m), 3.31 (3H, s), 3.55 - 3.64 (2H, m), 3.72 (8H, s), 6.06 is (IH, t), 6.81 (IH, s), 7.50 (2H, d), 8.21 (2H, d), 8.75 (IH, s)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 475; HPLC tR = 1.65 min.
The preparation of phenyl Λ/-[4-[4-[l-[2-(difluoromethoxy)ethylsulfonyl]cyclopropyl]-6- morpholin-4-ylpyrimidin-2-yl]phenyl]carbamate is described below.
20
Phenyl Λ/-[4-[4-[ 142-(difluoromethoxy)ethylsulfonyl1cvclopropyl1-6-morpholin-4- ylpyrimidin-2-vπphenvπ carbamate
Figure imgf000952_0002
Sodium hydrogen carbonate (1.5 equivalents) was added to 4-[4-[l-[2- (difluoromethoxy)ethylsulfonyl]cyclopropyl]-6-morpholin-4-ylpyrimidin-2-yl]aniline (1 equivalent) in dioxane at 50C under nitrogen. Phenyl chloroformate (1.5 equivalents) was then added. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with DCM, the organics dried over Na2SO4, filtered and evaporated to afford crude product. The crude gum was triturated with a mixture of ethyl acetate and isohexane to give the desired material as a cream solid. NMR Spectrum: none LCMS Spectrum: m/z (ESI+) (M+H)+ = 575; HPLC tR = 2.8 min.
4-[4-[l-[2-(Difluoromethoxy)ethylsulfonyllcvclopropyll-6-morpholin-4-ylpyrimidin-2- yll aniline
Figure imgf000953_0001
Palladium, 5% On Charcoal (6.59 mg, 0.06 mmol) was added to 4-[l-[2- (difluoromethoxy)ethylsulfonyl]cyclopropyl]-6-morpholin-4-yl-2-(4-nitrophenyl)pyrimidine (150 mg, 0.31 mmol), in ethyl acetate (20 mL) and methanol (3 mL) at RT and left to stir under an atmosphere of hydrogen for 24 hours. The mixture was filtered through celite® and the filtrate purified by flash silica chromatography, elution gradient 10 to 70% ethyl acetate in isohexane, to give the desired material as a yellow gum (90 mg). NMR Spectrum: none
LCMS Spectrum: m/z (ESI+) (M+H)+ = 455; HPLC tR = 2.2 min. 4-ri-r2-(Difluoromethoxy)ethylsulfonyllcvclopropyll-6-morpholin-4-yl-2-(4- nitrophenvDpyrimidine
Figure imgf000954_0001
A solution of 2,2-difluoro-2-(fluorosulfbnyl)acetic acid (0.856 mL, 8.29 mmol) in acetonitrile (4 mL) was added dropwise over 1 hour to a stirred solution of 2-[l-[6-morpholin-4-yl-2-(4- nitrophenyl)pyrimidin-4-yl]cyclopropyl]sulfonylethanol (480 mg, 1.10 mmol) and copper(I) iodide (742 mgl, 0.22 mmol) in acetonitrile (15 mL) at 550C under a nitrogen atmosphere.
The mixture was stirred at 550C for 90 minutes, allowed to cool and diluted with ethyl acetate
(300 mL) and washed with water (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 50% ethyl acetate in isohexane, to give the desired material as a yellow solid (195 mg).
NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.59 - 1.68 (2H, m), 1.70 - 1.78 (2H, m), 3.70 - 3.81 (8H, m), 3.88 - 3.96 (2H, m), 4.28 - 4.35 (2H, m), 7.01 (IH, s), 8.33 (2H, d), 8.56 (2H, d)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 485; HPLC tR = 2.73 min.
2-ri-r6-Mrpholin-4-yl-2-(4-nitrophenyl)pyrimidin-4-yllcvclopropyllsulfonylethanol
Figure imgf000954_0002
Bis(triphenylphosphine)palladium(II) chloride (84 mg, 0.12 mmol) was added to 2-[l-(2- chloro-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]sulfonylethoxy-tri(propan-2-yl)silane (900 mg, 1.79 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)nitrobenzene (889 mg, 3.57 mmol) and 2M aqueous solution of sodium carbonate (3 mL, 6.00 mmol) in a solvent mixture of DME (25 mL) and water (1 mL). The mixture was stirred at 9O0C for 18 hours under an inert atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was dissolved in DCM then IM solution of tetrabutylammonium fluoride (8.93 mL, 8.93 mmol) added and left to stir 1 hour. A saturated aqueous solution of ammonium chloride was added, the layers separated and the organics dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 10 to 70% ethyl acetate in isohexane, to give a material which was further purified by ion exchange chromatography using an SCX column, eluting with 7M ammonia in methanol, and finally triturated with a mixture of diethyl ether and isohexane to give the desired material as a beige solid (670 mg).
NMR Spectrum: 1H NMR (400.132 MHz. DMSO-dfi) δ 1.53 - 1.62 (2H, m), 1.65 - 1.73 (2H, m), 3.56 - 3.67 (2H, m), 3.66 - 3.82 (8H, m), 3.80 - 3.97 (2H, m), 5.01 (IH, t), 7.01 (IH, s), 8.34 (2H, d), 8.57 (2H, d) LCMS Spectrum: m/z (ESI+) (M+H)+ = 435; HPLC tR = 2.18 min.
The preparation of 2-[l-(2-chloro-6-morpholin-4-ylpyrimidin-4- yl)cyclopropyl]sulfonylethoxy-tri(propan-2-yl)silane was described earlier.
Example 98
The following samples were prepared by heating a mixture of the carbamate (1 equivalent), triethylamine (4 equivalents) and the amine (4 equivalents) in NMP (2 mL) at 5O0C for 2 hours. The compounds were purified by preparative HPLC.
The following compounds were prepared in an analogous fashion from phenyl N- [4- [4- [(3S)- 3-methylmorpholin-4-yl]-6-[ 1 -[(4-methyl- 1 ,3-thiazol-2-yl)sulfonyl]cyclobutyl]pyrimidin-2- yl]phenyl]carbamate or phenyl Λ/-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]carbamate and the appropriate amine.
Figure imgf000956_0001
Figure imgf000957_0001
Figure imgf000958_0001
Example 98a: 1R NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.24 (6H, s), 1.83 - 2.01 (IH, m), 2.12 - 2.20 (IH, m), 2.37 (3H, s), 2.83 - 2.92 (2H, m), 3.10 - 3.22 (4H, m), 3.36 -
3.41 (IH, m), 3.49 (IH, td), 3.64 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.13 (IH, d), 4.48 (IH, s), 4.95 (IH, t), 5.99 (IH, s), 6.54 (IH, s), 7.36 (2H, d), 7.68 (IH, s), 7.86 (2H, d), 8.71 (IH, s) Example 98b: 1H NMR (400.132 MHz, DMSOd6) δ 1.08 (3H, d), 1.21 (3H, d), 1.88 - 1.99 (IH, m), 2.12 - 2.21 (IH, m), 2.82 - 2.92 (2H, m), 3.10 - 3.23 (2H, m), 3.31 (3H, s), 3.32 -
3.42 (3H, m), 3.44 - 3.54 (IH, m), 3.61 - 3.78 (3H, m), 3.97 (IH, d), 4.09 - 4.17 (IH, m), 4.49 (IH, s), 4.78 (IH, t), 6.08 (IH, d), 6.54 (IH, s), 7.39 (2H, d), 7.68 (IH, s), 7.87 (2H, d), 8.68 (IH, s)
Example 98c: 1U NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.89 - 1.99 (IH, m), 2.11 - 2.20 (IH, m), 2.37 (3H, s), 2.85 - 2.95 (2H, m), 3.10 - 3.22 (3H, m), 3.43 - 3.54 (IH, m), 3.64 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.14 (IH, d), 4.33 (2H, s), 4.50 (IH, s), 6.53 - 6.63 (2H, m), 6.93 - 7.05 (IH, m), 7.43 (2H, d), 7.68 (IH, s), 7.85 - 7.93 (2H, m), 8.90 (IH, s) Example 98d: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.56 - 1.63 (2H, m), 1.86 - 1.97 (2H, m), 2.12 - 2.22 (2H, m), 2.77 - 2.92 (2H, m), 3.13 - 3.22 (3H, m), 3.25 - 3.34 (2H, m), 3.43 - 3.52 (3H, m), 3.64 (IH, d), 3.72 - 3.80 (IH, m), 3.97 (IH, d), 4.13 (IH, d), 4.44 - 4.53 (2H, m), 6.18 (IH, t), 6.54 (IH, s), 7.41 (2H, d), 7.68 (IH, s), 7.87 (2H, d), 8.68 (IH, s) Example 98e: 1H NMR (400.132 MHz, DMSO-Cl6) δ 1.21 (3H, d), 1.87 - 1.97 (IH, m), 2.15 -
2.21 (IH, m), 2.37 (3H, s), 2.79 - 2.94 (2H, m), 3.12 - 3.21 (3H, m), 3.27 - 3.34 (2H, m), 3.42 - 3.52 (3H, m), 3.64 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.13 (IH, d), 4.49 (IH, s), 4.72 (IH, t), 6.24 (IH, t), 6.54 (IH, s), 7.40 (2H, d), 7.68 (IH, s), 7.87 (2H, d), 8.78 (IH, s) Example 98f: 1H NMR (400.132 MHz, DMSOd6) δ 1.08 (3H, d), 1.21 (3H, d), 1.87 - 1.99 (IH, m), 2.12 - 2.23 (IH, m), 2.37 (3H, s), 2.83 - 2.92 (2H, m), 3.12 - 3.23 (4H, m), 3.34 - 3.41 (IH, m), 3.45 - 3.52 (IH, m), 3.64 (IH, d), 3.75 (IH, d), 3.97 (IH, d), 4.13 (IH, d), 4.50 (IH, s), 4.78 (IH, t), 6.05 - 6.10 (IH, m), 6.54 (IH, s), 7.40 (2H, d), 7.68 (IH, s), 7.87 (2H, d), 8.68 (IH, s) Example 98g: 1U NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.25 (6H, s), 1.90 - 1.99 (IH, m), 2.14 - 2.21 (IH, m), 2.84 - 2.93 (2H, m), 3.17 - 3.25 (2H, m), 3.29 - 3.33 (IH, m), 3.45 - 3.52 (IH, m), 3.64 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.13 (IH, d), 4.48 (IH, s), 4.95 (IH, t), 5.99 (IH, s), 6.53 (IH, s), 7.35 (2H, d), 7.83 (2H, d), 8.15 (IH, s), 8.70 (IH, s) Example 98h: 1H NMR (400.132 MHz, DMSOd6) δ 1.08 (3H, d), 1.20 (3H, d), 1.91 - 2.00 (IH, m), 2.13 - 2.22 (IH, m), 2.85 - 2.95 (2H, m), 3.14 - 3.21 (2H, m), 3.30 - 3.42 (4H, m), 3.44 - 3.52 (IH, m), 3.64 - 3.78 (2H, m), 3.96 (IH, d), 4.13 (IH, d), 4.49 (IH, s), 4.78 (IH, t), 6.06 - 6.13 (IH, m), 6.53 (IH, s), 7.38 (2H, d), 7.85 (2H, d), 8.14 (IH, s), 8.67 (IH, s) Example 98i: 1R NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.93 - 2.00 (IH, m), 2.13 - 2.20 (IH, m), 2.83 - 2.93 (2H, m), 3.14 - 3.24 (3H, m), 3.43 - 3.53 (IH, m), 3.64 (IH, d), 3.76 (IH, d), 3.96 (IH, d), 4.15 (IH, d), 4.32 (2H, s), 4.48 (IH, s), 6.54 (IH, s), 6.63 (IH, t), 6.93 (IH, s), 7.42 (2H, d), 7.87 (2H, d), 8.14 (IH, s), 8.90 (IH, s)
Example 98j: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.56 - 1.63 (2H, m), 1.88 - 2.01 (IH, m), 2.09 - 2.22 (IH, m), 2.84 - 2.94 (2H, m), 3.12 - 3.24 (5H, m), 3.43 - 3.54 (3H, m), 3.65 (IH, d), 3.76 (IH, d), 3.95 (IH, d), 4.06 - 4.20 (IH, m), 4.46 - 4.51 (IH, m), 6.19 (IH, t), 6.53 (IH, s), 7.39 (2H, d), 7.85 (2H, d), 8.15 (IH, s), 8.67 (IH, s)
Example 98k: 1H NMR (400.132 MHz, DMSOd6) δ 1.20 (3H, d), 1.90 - 2.00 (IH, m), 2.12 -
2.22 (IH, m), 2.84 - 2.94 (2H, m), 3.14 - 3.22 (3H, m), 3.25 - 3.34 (2H, m), 3.39 - 3.52 (3H, m), 3.63 (IH, d), 3.76 (IH, d), 3.96 (IH, d), 4.13 (IH, d), 4.48 (IH, s), 4.72 (IH, t), 6.24 (IH, t), 6.53 (IH, s), 7.39 (2H, d), 7.85 (2H, d), 8.15 (IH, s), 8.76 (IH, s) Example 981: 1R NMR (400.132 MHz, DMSOd6) δ 1.08 (3H, d), 1.20 (3H, d), 1.89 - 1.98 (IH, m), 2.12 - 2.23 (IH, m), 2.80 - 2.93 (2H, m), 3.14 - 3.24 (3H, m), 3.30 - 3.40 (2H, m), 3.45 - 3.53 (IH, m), 3.60 - 3.77 (3H, m), 3.96 (IH, d), 4.13 (IH, d), 4.49 (IH, s), 4.78 (IH, t), 6.08 (IH, d), 6.53 (IH, s), 7.38 (2H, d), 7.85 (2H, d), 8.15 (IH, s), 8.67 (IH, s)
The preparation of phenyl 7V-[4-[4-[(3<S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3- thiazol-2-yl)sulfonyl]cyclobutyl]pyrimidin-2-yl]phenyl] carbamate is described below.
Phenyl N-r4-r4-r(3y)-3-methylmorpholin-4-yl1-6-ri-r(4-methyl-1.3-thiazol-2- vDsulfonyli cvclobutvHpyrimidin-2-vHphenvH carbamate
Figure imgf000960_0001
Sodium hydrogen carbonate (0.311 g, 3.71 mmol) was added to 4-[4-[(35)-3- methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2-yl)sulfonyl]cyclobutyl]pyrimidin-2- yljaniline (1.2 g, 2.47 mmol) in dioxane (30 mL) at 50C under nitrogen. Phenyl chloroformate (0.466 mL, 3.71 mmol) was then added and the resulting mixture stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (75 mL) and the organic layer dried over Na2SO4, filtered and evaporated to afford crude product. The crude gum was triturated with a mixture of diethyl ether and isohexane to give the desired material as a cream solid (1.2 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.88 - 2.00 (IH, m), 2.10 - 2.21 (IH, m), 2.36 (3H, s), 2.83 - 2.95 (2H, m), 3.10 - 3.24 (3H, m), 3.44 - 3.53 (IH, m), 3.64 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.15 (IH, d), 4.52 (IH, s), 6.59 (IH, s), 7.21 - 7.32 (3H, m), 7.39 - 7.47 (2H, m), 7.55 (2H, d), 7.68 (IH, s), 7.97 (2H, d), 10.39 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 606; HPLC tR = 3.12 min. 4-r4-r(35)-3-Methylmorpholin-4-yll-6-ri-r(4-methyl-1.3-thiazol-2- yl)sulfonyllcvclobutyllpyrimidin-2-yllaniline
Figure imgf000961_0001
Bis(triphenylphosphine)palladium(II) chloride (0.115 g, 0.16 mmol) was added to 2-chloro-4- [(35)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclobutyl]pyrimidine (1.4 g, 3.26 mmol), 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (1.073 g, 4.90 mmol) and 2M aqueous odium carbonate solution (5 mL, 10.00 mmol) in a solvent mixture of DMF (6 mL), DME (12 mL), ethanol (3 mL) and water (3.5 mL) and the resulting mixture stirred at 95°Cfor 5 hours under an inert atmosphere. The reaction mixture was diluted with ethyl acetate (250 mL), and washed with water (2 x 150 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 60% ethyl acetate in isohexane, to give the desired material as a beige solid (1.17 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.19 (3H, d), 1.92 (IH, m), 1.99 (IH, s), 2.10 - 2.18 (IH, m), 2.39 (3H, s), 2.80 - 2.91 (2H, m), 3.09 - 3.24 (2H, m), 3.47 (IH, td), 3.62 (IH, d), 3.75 (IH, d), 3.95 (IH, d), 4.09 (IH, d), 4.45 (IH, s), 5.50 (2H, s), 6.43 (IH, s), 6.54 (2H, d), 7.61 - 7.80 (3H, m) LCMS Spectrum: m/z (ESI+) (M+H)+ = 486; HPLC tR = 2.51 min.
2-Chloro-4-r(3y)-3-methylmorpholin-4-yl1-6-ri-r('4-methyl-1.3-thiazol-2- yPsulfonyllcvclobutyllpyrimidine
Figure imgf000961_0002
Tetrabutylammonium bromide (0.912 g, 2.83 mmol) was added to 2-chloro-4-[(35)-3- methylmorpholin-4-yl]-6-[(4-methyl-l,3-thiazol-2-yl)sulfonylmethyl]pyrimidine (11 g, 28.29 mmol), 1,3-dibromopropane (17.23 mL, 169.71 mmol) and sodium hydroxide solution (50% w/w) (30 mL) in toluene (200 mL) and the resulting mixture stirred at 350C for 2.5 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 50% ethyl acetate in isohexane, to give the desired material as a yellow gum (1.7 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 7.88 (IH, s), 1.18 (3H, d), 1.85 - 1.97 (IH, m), 2.04 - 2.18 (IH, m), 2.70 - 2.85 (2H, m), 3.00 - 3.21 (3H, m), 3.29 (3H, s), 3.37 - 3.49 (IH, m), 3.57 (IH, d), 3.71 (IH, d), 3.86 - 4.01 (2H, m), 4.34 (IH, s), 6.59 (IH, s) 7.91(lH,s). LCMS Spectrum: m/z (ESI+) (M+H)+ = 429; HPLC tR = 2.36 min.
The preparation of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-[(4-methyl- 1 ,3-thiazol-2- yl)sulfonylmethyl]pyrimidine was described earlier.
The preparation of phenyl N-[4-[4-[(35)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]carbamate is described below.
Phenyl N- \4-\4-\(3S)-3 -methylmorpholin-4-yli -6-[1-(1.3 -thiazol-2- ylsulfonyl)cvclobutyllpyrimidin-2-yllphenyllcarbamate
Figure imgf000962_0001
Sodium hydrogen carbonate (0.267 g, 3.18 mmol) was added to 4-[4-[(35)-3- methylmorpholin-4-yl]-6-[ 1 -(1 ,3-thiazol-2-ylsulfonyl)cyclobutyl]pyrimidin-2-yl]aniline (I g, 2.12 mmol) in dioxane (30 mL) at 50C under nitrogen .Phenyl chloroformate (0.4 mL, 3.18 mmol) was then added. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (75 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude gum was triturated with a mixture of diethyl ether and isohexane to give the desired material as a cream solid (0.80 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.21 (3H, d), 1.89 - 2.01 (IH, m), 2.12 - 2.22 (IH, m), 2.84 - 2.97 (2H, m), 3.11 - 3.26 (3H, m), 3.44 - 3.54 (IH, m), 3.64 (IH, d), 3.76 (IH, d), 3.97 (IH, d), 4.15 (IH, d), 4.50 (IH, s), 6.57 (IH, s), 7.15 - 7.35 (3H, m), 7.38 - 7.48 (2H, m), 7.49 - 7.60 (2H, m), 8.15 (2H, s), 10.39 (IH, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 592; HPLC tR = 3.06 min.
4-r4-r(35)-3-Methylmorpholin-4-yl1-6-r 1 -(I J-thiazol^-ylsulfonvOcyclobutyllpyrimidin^- yl] aniline
Figure imgf000963_0001
Bis(triphenylphosphine)palladium(II) chloride (0.093 g, 0.13 mmol) was added to 2-chloro-4- [(35)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2-ylsulfonyl)cyclobutyl]pyrimidine (l.l g, 2.65 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.871 g, 3.98 mmol) and 2M aqueous sodium carbonate solution (5 mL, 10.00 mmol) in a solvent mixture of DMF (6 mL), DME (12 mL), ethanol (3 mL) and water (3.5 mL) and the resulting mixture stirred at 95°Cfor 5 hours under an inert atmosphere. The reaction mixture was diluted with ethyl acetate (250 mL), and washed with water (2 x 150 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 70% ethyl acetate in isohexane, to give the desired material as a yellow solid (0.99 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.18 (3H, d), 1.88 - 1.96 (IH, m), 2.11 - 2.21 (IH, m), 2.82 - 2.91 (2H, m), 3.05 - 3.23 (3H, m), 3.47 (IH, td), 3.62 (IH, d), 3.74 (IH, d), 3.95 (IH, d), 4.10 (IH, s), 4.44 (IH, s), 5.50 (2H, s), 6.42 (IH, s), 6.51 (2H, d), 7.70 (2H, d), 8.15 (2H, s) 2-Chloro-4- IY35V3 -methylmorpholin-4-yll -641 -( 1.3 -thiazol-2- ylsulfonvDcvclobutvHpyrimidine
Figure imgf000964_0001
Tetrabutylammonium bromide (0.559 g, 1.73 mmol) was added to 2-chloro-4-[(35)-3- methylmorpholin-4-yl]-6-(l,3-thiazol-2-ylsulfonylmethyl)pyrimidine (6.5 g, 17.34 mmol), 1,3-dibromopropane (10.56 mL, 104.04 mmol) and sodium hydroxide (50% w/w) (10 mL) in toluene (20 mL) and the resulting mixture stirred at 7O0C for 30 minutes. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 60% ethyl acetate in isohexane, to give the desired material as a yellow gum (1.0 g).
NMR Spectrum: 1H NMR (400.132 MHz, DMSOd6) δ 1.86 - 1.97 (IH, m), 2.07 - 2.18 (IH, m), 2.72 - 2.84 (2H, m), 3.04 - 3.19 (3H, m), 3.42 (IH, td), 3.57 (IH, d), 3.70 (IH, d), 3.89 - 3.99 (2H, m), 4.33 (IH, s), 6.60 (IH, s), 8.19 (IH, d), 8.30 (IH, d)
The preparation of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-(l,3-thiazol-2- ylsulfonylmethyl)pyrimidine was described earlier.
Example 99
The following samples were prepared by heating a mixture of the aniline (1 equivalent) and 1,1 thiocarbonyldiimidazole (1.2 equivalents) in a mixture of DCM:THF (2:1) at RT for 30 minutes then adding the amine (5 equivalents) and stirring at 5O0C for 2 hours. The compounds were purified by preparative HPLC.
The following compounds were prepared in an analogous fashion from either 3-[l-[2-(4- aminophenyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclobutyl]sulfonylpropan-l- ol or 3-[ 1 -[2-(4-aminophenyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4- yl]cyclopropyl]sulfonylpropan-l-ol and the appropriate amine.
Figure imgf000965_0001
Figure imgf000966_0001
Figure imgf000967_0001
Example 99a: 1H NMR (400.132 MHz, DMSO-Cl6) δ 1.24 (3H, d), 1.73 - 1.81 (2H, m), 1.88 - 1.97 (IH, m), 2.03 - 2.10 (IH, m), 2.76 - 2.87 (2H, m), 2.89 - 3.05 (7H, m), 3.19 - 3.26 (IH, m), 3.36 - 3.41 (2H, m), 3.46 - 3.55 (IH, m), 3.66 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.23 (IH, d), 4.52 - 4.61 (2H, m), 6.76 (IH, s), 7.55 (2H, d), 7.85 (IH, s), 8.28 (2H, d), 9.73 (IH, s) Example 99b: 1R NMR (400.132 MHz, DMSOd6) δ 0.56 - 0.64 (2H, m), 0.73 - 0.80 (2H, m), 1.25 (3H, d), 1.72 - 1.81 (2H, m), 1.88 - 1.96 (IH, m), 2.03 - 2.10 (IH, m), 2.80 - 3.04 (6H, m), 3.17 - 3.26 (IH, m), 3.34 - 3.41 (2H, m), 3.45 - 3.57 (IH, m), 3.66 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.23 (IH, d), 4.49 - 4.64 (2H, m), 6.76 (IH, s), 7.59 - 7.66 (2H, m), 7.96 (IH, s), 8.28 (2H, d), 9.51 (IH, s)
Example 99c: 1R NMR (400.132 MHz, DMSOd6) δ 1.25 (3H, d), 1.73 - 1.82 (2H, m), 1.89 -
1.97 (IH, m), 2.04 - 2.11 (IH, m), 2.78 - 2.88 (2H, m), 2.92 - 2.99 (2H, m), 2.98 - 3.05 (2H, m), 3.20 - 3.26 (IH, m), 3.34 - 3.42 (2H, m), 3.46 - 3.57 (IH, m), 3.66 (IH, d), 3.77 (IH, d),
3.98 (IH, d), 4.04 - 4.10 (IH, m), 4.25 (IH, d), 4.54 - 4.63 (2H, m), 4.71 (2H, s), 6.76 (IH, s), 6.99 (2H, s), 7.69 (2H, d), 8.21 (IH, s), 8.29 (2H, d), 10.03 (IH, s)
Example 99d: 1U NMR (400.132 MHz, DMSOd6) δ 1.25 (3H, d), 1.45 (6H, s), 1.73 - 1.80 (2H, m), 1.87 - 1.95 (IH, m), 2.03 - 2.10 (IH, m), 2.79 - 2.87 (2H, m), 2.92 - 2.98 (2H, m),
2.97 - 3.05 (2H, m), 3.20 - 3.24 (IH, m), 3.35 - 3.42 (2H, m), 3.48 - 3.57 (3H, m), 3.66 (IH, d), 3.77 (IH, d), 3.95 - 4.01 (IH, m), 4.03 - 4.09 (IH, m), 4.25 (IH, d), 4.52 - 4.62 (2H, m), 6.75 (IH, s), 7.61 (2H, d), 8.27 (2H, d), 9.92 (IH, s)
Example 99e: 1R NMR (400.132 MHz, DMSOd6) δ 1.14 (3H, t), 1.24 (3H, d), 1.72 - 1.82 (2H, m), 1.88 - 1.98 (IH, m), 2.01 - 2.11 (IH, m), 2.76 - 2.87 (2H, m), 2.89 - 2.98 (2H, m),
2.98 - 3.06 (2H, m), 3.21 - 3.27 (IH, m), 3.35 - 3.42 (2H, m), 3.46 - 3.56 (3H, m), 3.66 (IH, d), 3.77 (IH, d), 3.98 (IH, d), 4.24 (IH, d), 4.52 - 4.62 (2H, m), 6.75 (IH, s), 7.57 (2H, d),
7.89 (IH, s), 8.28 (2H, d), 9.63 (IH, s)
Example 99f: 1U NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.73 - 1.81 (2H, m), 1.86 -
1.97 (IH, m), 2.02 - 2.12 (IH, m), 2.79 - 2.87 (2H, m), 2.92 - 2.99 (2H, m), 2.97 - 3.05 (2H, m), 3.20 - 3.28 (IH, m), 3.35 - 3.43 (2H, m), 3.47 - 3.60 (3H, m), 3.66 (IH, d), 3.77 (IH, d),
3.98 (IH, d), 4.25 (IH, d), 4.50 - 4.63 (2H, m), 4.81 (IH, s), 6.75 (IH, s), 7.63 (2H, d), 7.88 (IH, s), 8.28 (2H, d), 9.81 (IH, s)
Example 99g: 1R NMR (400.132 MHz, DMSOd6) δ 10.01 (IH, s), 8.31 (2H, d), 8.12 (IH, s), 7.59 (2H, d), 6.77 (IH, s), 6.39 - 6.03 (IH, m), 4.64 - 4.54 (2H, m), 4.25 (IH, d), 4.05 - 3.94 (3H, m), 3.77 (IH, d), 3.66 (IH, d), 3.56 - 3.46 (IH, m), 3.42 - 3.36 (2H, m), 3.27 - 3.19
(IH, m), 3.05 - 2.98 (2H, m), 2.98 - 2.91 (2H, m), 2.89 - 2.79 (2H, m), 2.12 - 1.98 (IH, m),
1.97 - 1.87 (IH, m), 1.81 - 1.73 (2H, m), 1.25 (3H, d)
Example 99h: 1U NMR (400.132 MHz, DMSOd6) δ 10.01 (IH, s), 8.31 (2H, d), 8.12 (IH, s), 7.59 (2H, d), 6.77 (IH, s), 6.39 - 6.03 (IH, m), 4.64 - 4.54 (2H, m), 4.25 (IH, d), 4.05 - 3.94 (3H, m), 3.77 (IH, d), 3.66 (IH, d), 3.56 - 3.46 (IH, m), 3.42 - 3.36 (2H, m), 3.27 - 3.19
(IH, m), 3.05 - 2.98 (2H, m), 2.98 - 2.91 (2H, m), 2.89 - 2.79 (2H, m), 2.12 - 1.98 (IH, m),
1.97 - 1.87 (IH, m), 1.81 - 1.73 (2H, m), 1.25 (3H, d)
Example 99i: 1R NMR (400.132 MHz, DMSOd6) δ 1.24 (3H, d), 1.69 - 1.80 (4H, m), 1.88 -
1.98 (IH, m), 2.03 - 2.09 (IH, m), 2.78 - 2.89 (2H, m), 2.90 - 2.97 (2H, m), 2.98 - 3.05 (2H, m), 3.17 - 3.25 (IH, m), 3.35 - 3.42 (2H, m), 3.46 - 3.59 (5H, m), 3.66 (IH, d), 3.77 (IH, d),
3.98 (IH, d), 4.25 (IH, d), 4.52 - 4.61 (2H, m), 6.75 (IH, s), 7.58 (2H, d), 7.90 (IH, s), 8.28
(2H, d), 9.69 (IH, s)
Example 99j : Spectrum not recorded.
The preparations of 3-[l-[2-(4-aminophenyl)-6-[(35)-3-methylmorpholin-4-yl]pyrimidin-4- yl]cyclobutyl]sulfonylpropan-l-ol and 3-[l-[2-(4-aminophenyl)-6-[(35)-3-methylmorpholin- 4-yl]pyrimidin-4-yl]cyclopropyl]sulfonylpropan-l-ol were described earlier.

Claims

1. A compound of formula (I)
Figure imgf000969_0001
formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is
CR8; X is a linker group selected from -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C≡CCR6R7-,
-CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-,
-NR4S(O)2CR6R7-, and -S(O)2NR4CR6R7-;
R1 is a group selected from hydrogen, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -SR9,
-SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10,
-NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10;
R2 is a group selected from C1-6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -
R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12,
-NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -SR13,
-SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO2R14 and -NR13SO2R14;
R4 and R5 are independently hydrogen or Chalky!; or R1 and R4 together with the atom or atoms to which they are attached form a 4- to 10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloC i -βalkyl, haloC i -6alkoxy , hydroxyC i -βalkyl, hydroxyC i -6alkoxy , C i -6alkoxyC i -βalkyl, C i . 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000970_0001
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci .6alkylcarbamoyl and bis(C i .6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3- to 10- membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000970_0002
Figure imgf000970_0003
Ci-όalkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000970_0004
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000970_0005
carbamoyl, C i .6alkylcarbamoyl and bis(C i .6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and Ci-6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1- 6alkyl,
Figure imgf000970_0006
Ci- 6alkoxyCi_6alkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi.6alkyl,
Figure imgf000970_0007
bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000970_0008
C1- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci- 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000970_0009
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R , R , R and R are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi. 6alkoxy,
Figure imgf000971_0001
amino,
Figure imgf000971_0002
bis(Ci. 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci-6alkanoylamino,
Figure imgf000971_0003
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl;
R13, R14, R15 and R16 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000971_0004
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi. βalkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000971_0005
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-OaIk-UiOyI(C1- 6alkyl)amino, carbamoyl,
Figure imgf000971_0006
and bis(Ci.6alkyl)carbamoyl;
R19 is hydrogen, cyano or a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi-όalkyl, heterocyclyl and heterocyclylCi-όalkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi. 6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, C1- 6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl, (C1- 6alkyl)aminoCi-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, C1- 6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1-6alkylsulfamoyl, bis(C1-6alkyl)sulfamoyl, Ci-6alkanoylamino, C1-6alkanoyl(C1-6alkyl)amino, carbamoyl, C1- 6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloCi-6alkoxy, hydroxyC1-6alkyl, hydroxyCi-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, C1- 6alkylamino, bis(Ci-6alkyl)amino, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(Ci_ 6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, Ci-6alkylsulfonylamino, C1- 6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1-6alkylsulfamoyl, bis(C1-6alkyl)sulfamoyl, Ci- 6alkanoylamino,
Figure imgf000972_0001
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci_ 6alkyl)carbamoyl.
2. A compound, or a pharmaceutically acceptable salt thereof, according to claim 1, 5 wherein m is 0, 1 or 2;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and the other is CR8; X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,o -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- and -S(O)2NR4CR6R7;
R1 is a group selected from Ci_6alkyl, carbocyclyl, carbocyclylCi_6alkyl, heterocyclyl and heterocyclylC i_6alkyl, which group is optionally substituted by one or more substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10;s Or X-R1 Is -CR6R7OH;
R2 is a group selected from carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent group independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, - NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19; o each R3, when present, is selected from cyano, R13, and -CONR13R14; R4 and R5 are independently hydrogen or Ci-6alkyl; or, when X is -NR4CR6R7-, -NR4C(O)CR6R7- or -NR4C(O)NR5CR6R7-, R1 and R4 together with the atom or atoms to which they are attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N or O and which ring is optionally5 substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci-6alkyl, Ci_6alkoxy,
Figure imgf000972_0002
haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci.6alkoxyCi.6alkyl,
Figure imgf000972_0003
amino,
Figure imgf000972_0004
bis(Ci.6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl,
Figure imgf000972_0005
Ci- 6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-0 6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000972_0006
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; R6 and R7 together with the carbon atom to which they are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi-6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd. βalkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000973_0001
6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, Ci- 6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino, Ci-6alkanoyl(Ci-6alkyl)amino, carbamoyl, Ci .6alkylcarbamoyl and bis(C i .6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1-6alkyl;
R9 and R10 are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000973_0002
haloCi_6alkoxy,
Figure imgf000973_0003
amino, C1- 6alkylamino and bis(Ci-6alkyl)amino;
R , R , R and R are independently hydrogen or a group selected from Ci_6alkyl, carbocyclyl and heterocyclyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl,
Figure imgf000973_0004
haloCi-6alkyl, haloCi. βalkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci-όalkoxyCi-όalkyl, Ci-ealkoxyCi-όalkoxy, amino, Ci.6alkylamino and bis(Ci.6alkyl)amino;
R13 and R14 are independently hydrogen or a
Figure imgf000973_0005
which is optionally substituted by one or more substituent groups selected from halo, cyano, hydroxy and
Figure imgf000973_0006
and R19 is hydrogen, cyano or a group selected from Ci_6alkyl, C3_6Cycloakyl, aryl, heteroaryl, arylCi-6alkyl and heteroarylCi-6alkyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, Ci_6alkoxy,
Figure imgf000973_0007
6alkoxyCi_6alkoxy, amino, Ci-6alkylamino, bis(Ci-6alkyl)amino, aminoCi-6alkyl,
Figure imgf000973_0008
bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi_6alkyl, Ci-6alkylsulfonyl, C1- 6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealky^amino, sulfamoyl, Ci-6alkylsulfamoyl, bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000973_0009
carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl; or R18 and R19 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or O and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-ealkyFjaminoCi-ealkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000974_0001
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000974_0002
6alkyl)amino, carbamoyl,
Figure imgf000974_0003
and bis(Ci.6alkyl)carbamoyl.
3. A compound, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2 wherein 1Y is CH and Y2 is N.
4 A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3 wherein X is a -S(O)2CR6R7- linker group
5. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4 wherein R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert- butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3.
6. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5 wherein R2 is
Figure imgf000974_0004
wherein A1 and A2 are selected from CH or N provided that at least one of A1 or A2 is CH
7. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6 wherein R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyrazolylmethyl, pyridinyl and pyrimidinyl which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, haloCi-6alkyl, haloCi-6alkoxy, hydroxyCi-6alkyl, hydroxyCi_6alkoxy, Ci-ealkoxyd-όalkyl, Ci-ealkoxyd-όalkoxy, amino, Ci-6alkylamino, bis(Ci_ 6alkyl)amino, aminoCi-6alkyl, (Ci-6alkyl)aminoCi-6alkyl, bis(Ci-6alkyl)aminoCi-6alkyl, cyanoCi-6alkyl, Ci-6alkylsulfonyl, Ci-6alkylsulfonylamino, Ci-ealkylsulfony^Ci-ealkyFjamino, sulfamoyl,
Figure imgf000975_0001
bis(Ci-6alkyl)sulfamoyl, Ci-6alkanoylamino,
Figure imgf000975_0002
6alkyl)amino, carbamoyl, Ci-6alkylcarbamoyl and bis(Ci-6alkyl)carbamoyl.
8. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7 wherein R6 and R7 together with the carbon atom to which they are attached form a 3- to 5-membered carbocyclic ring
9. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IA), (IB) or (IC)
Figure imgf000975_0003
where
X is a -S(O)2CR6R7- linker group; 1Y is CH and Y2 is N; R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2C(OH)(CH3)2, -CH2CH2CH2OCHF2, -CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2C(O)NH2, -CH2C(O)NHMe, -CH2CH2NHMe, phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2-fluoro-4-methylaminophenyl, 4-fluoro-2-methylphenyl, 5-fluoro-2-methylphenyl, 3-fluoro-4-(2-hydroxyethylamino)phenyl, 4-(difluoromethoxy)phenyl, 4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methylaminophenyl, 3-chloro-4-ethylaminophenyl, 3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-hydroxyethylamino)phenyl, 2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-(trifluoromethyl)phenyl, 2-methylphenyl, 4-methylphenyl, 4-(2-hydroxyethylamino)phenyl, lH-imidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, l-(difluoromethyl)pyrazol-4-yl, l-(difluoromethyl)-3,5- dimethylpyrazol-4-yl, l,3-dimethylpyrazol-4-yl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2- yl, 5-fluoropyridin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 2,4-dimethylthiazol-5-yl, 5-methyl-l,3,4-thiadiazol-2-yl, terahydrofuran-3-yl and terahydropyran-4-yl; R2 is
Figure imgf000976_0001
wherein A1 and A2 are CH;
R17 is hydrogen;
R18 is hydrogen; and
R19 is is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl,
-CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH,
-C(CH3)2CH2OH, -CH2C(CH3)2OH, -CH2C(CH3)2CH2OH,
-CH2CH2OH, -CH2CH2CH2OH, -CH2CF3, -CH2CHF2, -CH2CH2F,
-CH2CH2Cl, -CH2CH2SO2Me, -CH2CH(OH)CF3, -CH2CH2CN,
-CH2CN, -CH2CONMe2, -CH2CO2H, l-(methyl)cyclopropyl,
-CH2( 1 -hydroxycyclopropyl), 1 -(hydroxymethyl)cyclopropyl,
( 1 R)-2-hydroxy- 1 -methylethyl, ( 1 S)-2-hydroxy- 1 -methylethyl, phenyl,
4-methylphenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 4- fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, -CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2-yl), l-methylimidazol-4-yl, oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, l,l-dioxothiolan-3-yl, 5-methylisoxazol-3-yl, -CH2(I -methylpyrazol-4-yl), 1-methylpyrazol- 4-yl, -CH2(I -methylpyrazol-4-yl), 5-methylpyrazin-2-yl,
-CH2(2H-l,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl, 5- fluoropyridin-2-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl and 1 -methylpyrazol-3 -yl;
R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R3A is hydrogen, R3B is hydrogen, methyl, ethyl, hydroxymethyl, dimethylcarbamoyl or carbamoyl; or when R3 is methyl, R3 is methyl.
10. A compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IA), (IB) or (IC)
Figure imgf000977_0001
(IA) (IB) (IC) where X is a -S(O)2CR6R7- linker group; 1Y is CH and Y2 is N;
R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, -CH2CH2OH, CH2CH2CH2OH, -CH2CH2C(OH)(CH3)2, -CH2CH2CH2OCHF2, -CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2CH2NHMe, phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-fluoro-4-methylaminophenyl, 4-fluoro-2-methylphenyl, 5-fiuoro-2- methylphenyl, 3 -fluoro-4-(2-hydroxyethylamino)phenyl, 4-(difluoromethoxy)phenyl, 4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chloro-4-fiuorophenyl, 3-chloro-4-methylaminophenyl, 3-chloro-4-ethylaminophenyl, 3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-hydroxyethylamino)phenyl, 2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-methylphenyl, 4-methylphenyl, lH-imidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, 1 -(difluoromethyl)pyrazol-4-yl, 1 ,3-dimethylpyrazol-4- yl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl, 4-methylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 2,4-dimethylthiazol-5-yl and 5-methyl-l,3,4-thiadiazol-2-yl; R2 is
Figure imgf000978_0001
wherein A1 and A2 are CH; R17 is hydrogen;
R ,18 is hydrogen; and
R |19 is hydrogen or a group selected from methyl, ethyl, propyl, i- propyl, cyclopropyl, cyclobutyl, -CH^cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CH2CN, -CH2( 1 -hydroxycyclopropyl), 1 -(hydroxymethyl)cyclopropyl, ( 1 R)-2-hydroxy- 1 -methylethyl, ( 1 S)-2-hydroxy- 1 -methylethyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, -CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2-yl), l-methylimidazol-4-yl, oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, 5-methylisoxazol-3-yl, 1 -methylpyrazol-4-yl, 5-methylpyrazin-2-yl, 6-methoxypryridin-3-yl, thiazol-2-yl, l,2,4-thiadiazol-5-yl and l-methylpyrazol-3-yl; R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R3A is hydrogen, R3B is hydrogen, methyl or ethyl; or when R3A is methyl, R3B is methyl.
11. A compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IA), (IB) or (IC)
Figure imgf000979_0001
(IA) (IB) (IC)
5 where
X is a -S(O)2CR6R7- linker group;
1Y is CH and Y2 is N;
R1 is a group selected from methyl, ethyl, cyclopropyl, -CH2CH2CH2OH, phenyl,
2-fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-chlorophenyl, 2-methylphenyl, o 5-fiuoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl;
R2 is
Figure imgf000979_0002
wherein A1 and A2 are CH;
R17 is hydrogen > s R18 is hydrogen; and
R19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl, -CH(CH3)CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CHF2, -CH2CH2F, -CH2CH2CN, (lR)-2-hydroxy-l-methylethyl, (lS)-2- hydroxy-1-methylethyl, -CH2(imidazol-2-yl), oxazolyl-2-yl, isoxazolyl-o 3-yl, l-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, thiazol-2-yl and l,2,4-thiadiazol-5-yl;
R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R3A is hydrogen, R3B is hydrogen, methyl or ethyl; or when R3A is methyl, R3B is methyl.
12. A compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia), (Ib) or (Ic)
Figure imgf000980_0001
5 (IA) (IB) (IC) or a pharmaceutically acceptable salt thereof;
X is a -S(O)2CR6R7- linker group;
1Y is CH and Y2 is N;
R1 is a group selected from methyl, ethyl, cyclopropyl, -CH2CH2CH2OH, phenyl, o 2-fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2-chlorophenyl, 2-methylphenyl,
5-fiuoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl;
R2 is
Figure imgf000980_0002
wherein A1 and A2 are CH; s R17 is hydrogen;
R18 is hydrogen; and
R19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl, -CH(CH3)CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CHF2, -CH2CH2F, -CH2CH2CN, (lR)-2-hydroxy-l-methylethyl, (lS)-2-o hydroxy- 1-methylethyl, -CH2(imidazol-2-yl), oxazolyl-2-yl, isoxazolyl-
3-yl, l-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, thiazol-2-yl and l,2,4-thiadiazol-5-yl;
R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and when R3A is hydrogen, R3B is methyl or ethyl; or when R3A is methyl, R3B is methyl.
13. A compound according to any one of claims 1 to 12 where R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring
14. A compound of formula (I) according to claim 1 selected from any one of the Examples, or a pharmaceutically acceptable salt thereof.
15. A compound of formula (I) according to claim 1 selected from any one of l-[4-[4-(l-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl] -3 -methyl-urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, 3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
3 -cyclopropyl- 1 - [4- [4-( 1 -methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2- yl]phenyl]urea,
1 - [4- [4-[ 1 -(4-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin- 2-yl]phenyl] -3 -(2-hydroxyethyl)urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-2- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, l-[4-[4-(l-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)thiourea, 3 -cyclopropyl- 1 - [4- [4-[ 1 -(4-fluorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]thiourea,
3 -cyclopropyl- 1 -[4-[4-[ 1 -(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]thiourea, l-ethyl-3-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]thiourea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclobutyl)-6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylthiourea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(lH-imidazol-2-ylmethyl)thiourea, 3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(l-pyridin-4- ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-fluoroethyl)urea, l-[4-[4-[l-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] -3 -(2-hydroxyethyl)urea,
3-(2-hydroxyethyl)- 1 -[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[ 1 -(2- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea, 3-(2-fluoroethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(2- methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea,
1 - [4- [4-[ 1 -(2-chlorophenyl)sulfonylcyclopropyl] -6- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin- 2-yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2S)-l-hydroxypropan-2-yl]urea, 1 - [4- [4-( 1 -cyclopropylsulfonylcyclobuty^-ό- [(3 S)-3 -methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2S)-l-hydroxypropan-2-yl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2R)-l-hydroxypropan-2-yl]urea, 3-(2-fluoroethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-[(4-methyl-l,3-thiazol-2- yl)sulfonyl]cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-methylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-cyclopropylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2-fluoroethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(2,2-difluoroethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2S)-l-hydroxypropan-2-yl]urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2R)-l-hydroxypropan-2-yl]urea, 3 -cyclopropyl- 1 - [4- [4-[(3 S)-3 -ethylmorpholin-4-yl]-6-( 1 - methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S)-3-ethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4- yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1 - [4- [4-( 1 -cyclopropylsulfonylcyclopropy^-ό- [(3 S ,5 S)-3 ,5 -dimethylmorpholin-4- yl]pyrimidin-2-yl]phenyl] -3 -(2-hydroxyethyl)urea, 3-cyclopropyl-l-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(l- methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea, l-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(2-fluoroethyl)urea, 5 l-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] -3 -methylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin- i o 2-yl]phenyl] -3 -cyclopropylurea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-
2-yl]phenyl] -3 -(2-hydroxyethyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(2S)-l-hydroxypropan-2-yl]urea, is l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-(3-hydroxypropyl)urea, l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-yl]pyrimidin-2- yl]phenyl]-3-[(l-hydroxycyclopropyl)methyl]urea, l-[4-[4-(l-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]- 20 3-(2-hydroxyethyl)thiourea, l-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(l-methylsulfonylcyclopropyl)pyrimidin-2- yl]phenyl]-3-ethylurea,
3-[(2S)-l-hydroxypropan-2-yl]-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[l-(l,3-thiazol-2- ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea, and 25 l-[4-[4-[l-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-(2-fluoroethyl)urea, or a pharmaceutically acceptable salt thereof.
16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to 30 any one of claims 1 to 15 for use as a medicament.
17. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 15 in the manufacture of a medicament for use in the treatment of proliferative disease.
18. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 15 for the production of an anti-pro liferative effect in a warm-blooded animal such as man.
19. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 15 in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.
20. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 15 in the manufacture of a medicament for use in the providing a mTOR kinase inhibitory effect in a warm-blooded animal such as man.
21. A method for producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 15.
22. A method for producing a mTOR kinase inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 15.
23. A method for treating cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 15.
24. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.
PCT/GB2008/050546 2007-07-09 2008-07-08 Trisubstituted pyrimidine derivatives for the treatment of proliferative diseases WO2009007748A2 (en)

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AU2008273889A AU2008273889B2 (en) 2007-07-09 2008-07-08 Trisubstituted pyrimidine derivatives for the treatment of proliferative diseases
CN200880106248A CN101801962A (en) 2007-07-09 2008-07-08 Trisubstituted pyrimidine derivatives for the treatment of proliferative diseases
BRPI0814818A BRPI0814818A2 (en) 2007-07-09 2008-07-08 compound, use of a compound, methods for producing an antiproliferative effect and a inhibitor effect of mtor kinase in a warm-blooded animal, method for treating disease, and, pharmaceutical composition
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